HK1161873B - Spiro-oxindole compounds and their uses as therapeutic agents - Google Patents

Abstract

This invention is directed to spiro-oxindole compounds of formula (I): wherein k, j, Q, R1, R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3d are as defined herein, as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, which are useful for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain. Pharmaceutical compositions comprising the compounds and methods of preparing and using the compounds are also disclosed.

Description

Spiro-indolone compounds and their use as therapeutic agents

Technical Field

The present invention relates to spiro-indolone compounds. In particular, the invention relates to spiro-indolone compounds that are sodium channel blockers and, thus, are useful in the treatment of diseases or conditions mediated by sodium channels, such as pain, as well as other diseases and conditions associated with the mediation of sodium channels.

Background

Voltage-gated sodium channels, transmembrane proteins that produce action potentials in nerves, muscles and other electrically excitable cells, are essential components of normal sensation, emotion, thought and action (cotterall, w.a., Nature (2001), vol.409, pp.988-990). These channels are composed of highly processed α -subunit binding-assisted β -subunits. Pore-forming α -subunits are sufficient for channel function, but the kinetic and voltage-dependent part of channel gating is modified by β -subunits (Goldin et al, Neuron (2000), vol.28, pp.365-368). Each α -subunit contains four homologous domains I to IV, each with six predicted transmembrane segments. The sodium channel has an alpha-subunit with a relative molecular weight of 260,000, which forms the ion conduction pore and contains a voltage sensor that modulates sodium ion conduction. Electrophysiological recording, biochemical purification, and molecular cloning have identified ten different sodium channel α -subunits and four β -subunits (Yu, f.h., et al, sci.stke (2004), 253; and Yu, f.h., et al, Neurosci (2003), 20: 7577-85).

Characteristics of sodium channels include rapid activation and deactivation upon voltage depolarization across the plasma membrane of excitable cells (voltage-dependent gating), and efficient and selective conduction of sodium ions through conductance pores within the protein structure (Sato, c., et al., Nature (2001), 409: 1047-1051). At negative or hyperpolarized membrane potentials, sodium channels are closed. Following membrane depolarization, sodium channels open rapidly and then fail. The channel conducts current only in the on state and, once it fails, must return to a quiescent state that is favored by membrane hyperpolarization before it can reopen. Different sodium channel subtypes differ in their voltage ranges of activation and deactivation and their kinetics of activation and deactivation.

Proteins of the sodium channel family have been extensively studied and shown to be involved in many important bodily functions. Studies in this area have identified variants of the a-subunit that result in major alterations in channel function and activity that can ultimately lead to major pathophysiological disease states. Functionally, this family of proteins is considered to be a major point of therapeutic intervention. Na (Na)_V1.1 with Na_V1.2 are highly expressed in the brain (Raymond, C.K., et al, J.biol.chem. (2004), 279 (44): 46234-41) and are important for normal brain function. Na in humans _V1.1 with Na_V1.2 mutations lead to severe epileptic states and in some cases to mental retardationJian (Rhodes, T.H., 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). These two channels have therefore been identified as proven targets for the treatment of epilepsy (see published PCT patent publication No. WO 01/38564).

Na_V1.3 is expressed systemically (Raymond, C.K., et al., op.cit.). It has been shown to be up-regulated in dorsal horn sensory neurons after damage to the rat nervous system (Hains, b.d., et., j.neurosci. (2003), 23 (26): 8881-92). Many experts in this field have exchanged Na_V1.3 are considered suitable targets for pain therapy (Lai, J., et al, curr. Opin. Neurobiol. (2003), (3): 291-72003; Wood, J.N., et al, J.Neurobiol. (2004), 61 (1): 55-71; Chung, J.M., et al, Novartis foot Symp. (2004), 261: 19-27; discussions 27-31, 47-54).

Na_V1.4 is essentially restricted to muscle (Raymond, c.k., et al., op.cit.). Mutations in this gene have been shown to have profound effects on muscle function, including paralysis (Tamaoka, a., lntern.med. (2003), (9): 769-70). Thus, this channel can be considered as a target for the treatment of abnormal muscle contractility, spasticity or paralysis.

Cardiac sodium channel Na_V1.5 is expressed primarily in the ventricles and atria (Raymond, c.k., et al., op.cit.), and can be found in the sinoatrial node, the ventricular node, and possibly Purkinje cells. The rapid rise in cardiac action potential and the rapid conduction of pulses through cardiac tissue are due to Na_V1.5. Thus, Na_V1.5 plays an important role in the occurrence of arrhythmia. Human Na_V1.5 mutations lead to multiple arrhythmia syndromes, including, for example, Long QT3(LQT3), Brugada Syndrome (BS), hereditary cardiac conduction defects, sudden nocturnal sudden death syndrome (SUNDS) of unknown cause and Sudden Infant Death Syndrome (SIDS) (Liu, H., et al., am. J. Pharmacogenomics (2003), 3 (3): 173-9). Sodium channel blocker therapy has been widely usedCan be used for treating arrhythmia. The first antiarrhythmic drug, quinidine, found in 1914 was classified as a sodium channel blocker.

Na_V1.6 encodes a large number of widely distributed voltage-gated sodium channels found throughout the central and peripheral nervous systems and concentrated in the Ranvier node of nerve axons (Caldwell, J.H., et al, Proc. Natl. Acad. Sci. USA (2000), 97 (10): 5616-20). Although no mutation has been detected in humans, it is believed that Na _V1.6 play a role in the manifestations of the syndrome associated with multiple sclerosis and are considered targets for the treatment of this disease (Craner, m.j., et al., proc.natl.acad.sci.usa (2004), 101 (21): 8168-73).

Na_V1.7 was originally cloned from the pheochromocytoma PC12 cell line (Toledo-Aral, J.J., et al, Proc. Natl. Acad. Sci.USA (1997), 94: 1527-. It is present at high levels in growth cone cells of small diameter neurons, suggesting that it may play a role in the transmission of nociceptive information. This has been challenged by experts in the field, since Na_V1.7 is also expressed in neuroendocrine cells associated with the autonomous system (Klugbauer, n., et al., EMBO J. (1995), 14 (6): 1084-90) and is therefore implicated in autonomous processes. Through Na_V1.7 Generation of null mutations demonstrates an implicit role in autonomous function; deletion of Na in all sensory and sympathetic neurons_V1.7 causes a lethal perinatal phenotype (Nassar, et al, Proc. Natl. Acad. Sci. USA (2004), 101 (34): 12706-11). In contrast, by deleting Na from a subset of major nociceptive sensory neurons_V1.7 expression demonstrates its role in pain mechanisms (Nassar, et al, op. cit.). Na (Na) _V1.7 more support of the activity of blockers in the neuronal subgroup comes from the following findings: it has been shown that the two human inherited pain disease states primary erythromelalgia and familial rectal pain are mapped to Na_V1.7(Yang，Y.，et al，J.Med.Genet.(2004)，41(3)：171-4)。

Na_V1.8 is essentially restricted to DRG (Raymond, C.K., et al, op.cit.). For Na_V1.8 No confirmed human mutations. However, Na_V1.8-null mutant mice were viable, reproducible and normal in appearance. The absence of significant pain to noxious mechanical stimuli, the small impairment of noxious temperature sensations, and the delayed development of inflammatory hyperalgesia suggest Na to researchers_V1.8 plays a major role in pain signaling (Akopian, A.N., et al., nat. neurosci (1999), 2 (6): 541-8). Blockade of this channel is widely accepted as a potential treatment for pain (Lai, J, et al, op.cit.; Wood, j.n., et al, op.cit.; Chung, j.m. et al, op.cit.). Published PCT patent application No. WO03/037274A2 describes pyrazolylamides and sulfonamides that treat central or peripheral nervous system disease states, particularly pain and chronic pain, by blocking sodium channels associated with the onset or recurrence of the indicated symptoms. Published PCT patent application No. WO03/037890A2 describes piperidines for the treatment of central or peripheral nervous system conditions, particularly pain and chronic pain, by blocking sodium channels associated with the onset or recurrence of the indicated symptoms. The compounds, compositions and methods of these inventions are directed to inhibiting flux through membranes comprising PN3 (Na) _V1.8) ion flow in channels containing subunits is particularly useful for treating neuropathic pain or inflammatory pain.

Dib-Hajj, S.D. et al disclose tetrodotoxin-insensitive peripheral sodium channels Na_V1.9 (see Dib-Hajj, S.D., et al, Proc. Natl. Acad. Sci. USA (1998), 95 (15): 8963-8) was shown to be present only in the dorsal root ganglia. Has proven to be Na_V1.9 is the basis for the depolarization and excitation caused by neurotrophic factor (BDNF), and it is shown to be the only ligand-mediated member of the voltage-gated sodium channel superfamily (Blum, R., Kafitz, K.W., Konnerth, A., Nature (2002), 419 (6908): 687-93). The restricted expression pattern of this channel makes it a candidate target for pain therapy (Lai, J, et al, op.cit.; Wood, j.n., et al, op.cit.; Chung, j.m., et al, op.cit.).

NaX is a putative sodium channel, which is not shown to be voltage gated. In addition to expression in Schwann cells of the lung, heart, dorsal root ganglion, and peripheral nervous system, NaX is found in neurons and ependymal cells in limited areas of the CNS, particularly in the periventricular organs involved in humoral homeostasis (Watanabe, e., et al, j. neurosci. (2000), 20 (20): 7743-51). NaX-null mice showed abnormal uptake of hypertonic saline under water-deficient and salt-deficient conditions. These findings suggest that NaX plays an important role in the central perception of body fluid sodium levels and the regulation of salt uptake behavior. Its expression pattern and function suggest it as a target for the treatment of cystic fibrosis and other related salt-regulated diseases.

Studies using tetrodotoxin (TTX), a sodium channel blocker used to reduce neuronal activity in certain regions of the brain, have shown its potential use in treating addiction. Concomitant drug stimulation causes drug craving and relapse in addicts and drug finding behavior in rats. The functional integrity of the basolateral amygdala (BLA) is essential for the recovery of the cocaine pursuit behaviour caused by the stimulation of cocaine conditions, but not for the recovery caused by cocaine itself. BLAs play a similar role in the restoration of heroin pursuit behavior. In the rat model, TTX-induced inactivation of BLA abolishes the recovery of behavior pursued by conditions or heroin-induced disappeared heroins (Fuchs, R.A. and See, R.E., Psychopharmacology (2002)160 (4): 425-33).

This closely related family of proteins has long been recognized as a target for therapeutic intervention. Sodium channels are the target of a variety of pharmacological agents. These include neurotoxins, antiarrhythmic agents, anticonvulsants, and local anesthetics (Clare, J.J., et al, Drug discovery Today (2000) 5: 506-. All existing pharmacological agents that act on sodium channels have receptor sites on the α -subunit. At least six different receptor sites for neurotoxins have been identified as well as one for local anesthetics and related drugs (cestele, s., et al, Biochimie (2000), vol.82, pp.883-892).

Small molecule sodium channel blockers or local anesthetics and related antiepileptics and antiarrhythmics interact with overlapping receptor sites located in the lumen of the sodium channel pore (Catterall, w.a., Neuron (2000), 26: 13-25). Amino acid residues in the S6 fragment from at least three of the four domains contribute to this complex drug receptor site, while the IVS6 fragment dominates. These regions are highly conserved and therefore most of the sodium channel blockers known to date interact with similar potency with all channel subtypes. Nevertheless, it has been possible to produce sodium channel blockers that are therapeutically selective and have an adequate therapeutic window for the treatment of epilepsy (e.g., lamotrigine, phenytoin, and carbamazepine) and certain arrhythmias (e.g., lidocaine, tocainide, and mexiletine). However, the potency and therapeutic index of these blockers are not optimal and limit the use of these compounds in a variety of therapeutic areas where sodium channel blockers are ideally suited.

Treatment of acute and chronic pain

Pharmacotherapy is the mainstay of treatment for acute and chronic pain in all age groups including neonates, infants and children. Pain medications are divided into three main categories by the american society for pain: 1) non-opioid analgesics Acetaminophen and non-sterol anti-inflammatory drugs (NSAIDs) including salicylates (e.g., aspirin), 2) opioid analgesics and 3) co-analgesics.

Non-opioid analgesics such as acetaminophen and NSAIDs are used for acute and chronic pain due to a variety of causes including surgery, trauma, arthritis and cancer. Because acetaminophen lacks anti-inflammatory activity, NSAIDs are indicated for pain related inflammation. Opioids also lack anti-inflammatory activity. All NSAIDS inhibit Cyclooxygenase (COX), thus inhibiting prostaglandin synthesis and reducing the inflammatory pain response. There are at least two COX isozymes, COX-1 and COX-2. Common non-selective COX inhibitors include ibuprofen and naproxen. Inhibition of COX-1 found in platelets, gastrointestinal tract, kidney and most other human tissues is thought to be associated with side effects such as gastrointestinal bleeding. The development of selective COX-2 NSAIDs, such as celecoxib, valdecoxib and rofecoxib, has the advantages of non-selective NSAIDs and a reduced side effect profile in the intestine and kidney. However, evidence suggests that chronic use of certain selective COX-2 inhibitors may lead to an increased risk of stroke.

The american academy of pain began recommending the use of opioid analgesics based on the history of pain-related medical and physical examinations, including repeated pain assessments. Due to the wide side effect spectrum associated with opioid use, treatment should include diagnosis, comprehensive interdisciplinary treatment planning, and appropriate continuous monitoring of the patient. Opioids have also been suggested in addition to non-opioids to treat acute pain that does not respond to non-opioids alone and pain associated with cancer. Opioid analgesics act as agonists of specific receptors of the μ and κ type in the central and peripheral nervous systems. Depending on the opioid and its formulation or mode of administration, the duration may be short or long. All opioid analgesics run the risk of causing respiratory depression, liver failure, addiction and dependence and are therefore not ideal for long-term or chronic pain treatment.

Many other types of drugs may enhance the effects of opioids or NSAIDs, in some cases have independent analgesic activity, or counteract the side effects of analgesics. Regardless of the effect these drugs have, they are collectively referred to as "co-analgesics". Tricyclic antidepressants, antiepileptics, local anesthetics, glucocorticoids, skeletal muscle relaxants, antispasmodics, antihistamines, benzodiazepines, caffeine, topical agents (e.g., capsaicin), dexamphetamines, and phenothiazines are all used clinically as adjunctive therapeutic agents or alone for pain treatment. In particular, antiepileptic drugs have met with some success in treating painful conditions. For example, gabapentin, the target of which has not yet been identified, is indicated for neuropathic pain. Other clinical trials are attempting to establish that central neuropathic pain may be responsive to ion channel blockers such as calcium, sodium and/or NMDA (N-methyl-D-aspartate) channel blockers. Currently under development are low affinity NMDA channel blockers for the treatment of neuropathic pain. The literature provides a large body of preclinical electrophysiological evidence that supports the use of NMDA antagonists in the treatment of neuropathic pain. These agents may also be used to control pain after tolerance to opioid analgesics, especially in cancer patients.

A distinction is made between systemic analgesics, such as NSAIDS and opioids, and therapeutic agents which are only local analgesics/anesthetics. Known local analgesics, such as lidocaine and xylocaine, are non-selective ion channel blockers that can be lethal when administered systemically. A good description of non-selective sodium channel blockers is found in Madge, d., et al, j.med.chem. (2001), 44 (2): 115-37.

Several sodium channel modulators such as carbamazepine, amitriptyline, lamotrigine and riluzole are known as antispasmodics or antidepressants, all targeting brain tetrodotoxin-sensitive (TTX-S) sodium channels. These TTX-S agents have dose-limiting side effects, including dizziness, movement disorders, and lethargy, primarily due to TTX-S channels acting on the brain.

Role of sodium channels in pain

Sodium channels have a variety of roles in maintaining normal and pathological states, including the long-recognized role of voltage-gated sodium channels in producing abnormal neuronal activity and neuropathic or pathological pain (Chung, j.m., et al.). Peripheral nerve injury following trauma or disease can lead to altered sodium channel activity and the development of abnormal afferent activity, including ectopic discharges from axon-severed afferents and the spontaneous activity of sensitized intact nociceptors. These changes can produce long-term abnormal hypersensitivity to normal non-noxious stimuli or allodynia. Examples of neuropathic pain include, but are not limited to, post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic low back pain, phantom limb pain, and pain due to cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome, and related neuralgia.

Treatment of neuropathic pain conditions by using drugs such as gabapentin and, more recently, pregabalin, as short-term first-line therapy has met with some degree of success. However, neuropathic pain medications generally have limited success rates and have minimal response to commonly used pain-reducing drugs such as NSAIDs and opioids. There is therefore still a need to develop new therapeutic approaches.

There are only a limited number of potentially effective sodium channel blockers with minimal side effects in the clinic. There is an unmet medical need for effective treatment of neuropathic pain and other sodium channel-associated pathological conditions without adverse side effects. The present invention provides compounds that meet these important needs, methods of use, and compositions comprising these compounds.

Summary of The Invention

The present invention relates to spiro-indolone compounds useful in the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain. The compounds of the present invention may also be useful in the treatment of other sodium channel mediated diseases or conditions, including but not limited to central nervous conditions such as epilepsy, anxiety, depression, and bipolar disorders; cardiovascular disease states such as arrhythmia, atrial fibrillation, and ventricular fibrillation; neuromuscular disease states such as restless leg syndrome, essential tremor and muscle paralysis or tetanus; neuroprotective effects against stroke, glaucoma, nerve trauma and multiple sclerosis; and channelopathies, such as erythematous myalgia and familial proctalgia syndrome.

Accordingly, one aspect of the present invention is to provide a compound of general formula (I), a stereoisomer, an enantiomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein:

j and k are each independently 0, 1, 2 or 3;

q is-C (R)^1a)H-、-C(O)-、-O-、-S(O)_m- (wherein m is 0, 1 or 2), -CF₂-、-C(O)O-、-C(O)N(R⁵) -or-N (R)⁵)C(O)-；

R^1aIs hydrogen OR-OR⁵；

R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R⁸-OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

Or R¹Is represented by-C (O) N (R)⁶)R⁷A substituted aralkyl group, wherein:

R⁶is hydrogen, alkyl, aryl or aralkyl; and is

R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN、-R⁹-OR⁵、-R⁹-N(R⁴)R⁵Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;

or R⁶And R⁷Together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group;

and wherein R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, -R⁸-CN、-R⁸-OR⁵Heterocyclyl and heteroaryl;

Or R¹Is optionally substituted by one or more groups selected from-R⁸-OR⁵、-C(O)OR⁵Aralkyl substituted with a substituent of halogen, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclic group and heteroaryl;

or R¹is-R⁹-N(R¹⁰)R¹¹、-R⁹-N(R¹²)C(O)R¹¹or-R⁹-N(R¹⁰)C(O)N(R¹⁰)R¹¹Wherein:

each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁹-OC(O)R⁵、-R⁹-C(O)OR⁵、-R⁹-C(O)N(R⁴)R⁵、-R⁹-C(O)R⁵、-R⁹-N(R⁴)R⁵、-R⁹-OR⁵or-R⁹-CN；

R¹²Is hydrogen, alkyl, aryl, aralkyl or-C (O) R⁵；

And wherein R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) is optionally substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, nitro, -R⁸-CN、-R⁸-OR⁵、-R⁸-C(O)R⁵Heterocyclyl and heteroaryl;

or R¹Is heterocyclylalkyl or heteroaralkyl, wherein the heterocyclylalkyl or heteroaralkyl is optionally substituted with one or more substituents selected from the group consisting of keto, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-OR⁵、-R⁸-C(O)OR⁵、-R⁸-N(R⁴)R⁵、-R⁸-C(O)N(R⁴)R⁵、-R⁸-N(R⁵)C(O)R⁴、-R⁸-S(O)_mR⁴(wherein m is 0, 1 or 2), -R ⁸-CN or-R⁸-NO₂Substituted with the substituent(s);

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl group of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxyHalogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴、-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2cAnd R^2dAs defined above;

or R^2b、R^2cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R ^2aAnd R^2dAs defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAs defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴；-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dAs defined above;

or R^3b、R^3cMay form, together with the carbon ring atom to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and R^3aAnd R^3dAs defined above;

or R^3c、R^3dMay form, together with the carbon ring atom to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and R^3aAnd R^3bAs defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

Or when R is⁴And R⁵Are all connected toOn the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 present invention provides a method of treating pain in a mammal, preferably a human, wherein said method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention as described above.

In another aspect, the invention provides methods of treating or lessening the severity of a disease, disease state, or disorder, wherein the disease state involves Na_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 one or more of overactive or overactive.

In another aspect, the invention provides a method of treating a sodium channel mediated disease or condition, such as HIV-associated pain, HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, eudynia, thermal sensitivity, sarcoidosis, irritable bowel syndrome, crohn's disease, pain associated with Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudo-aldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, a sodium channel toxin-associated disease, familial erythromelalgia, primary erythromelalgia, familial rectal pain, Cancer, epilepsy, partial and generalized seizures, restless legs syndrome, cardiac arrhythmias, fibromyalgia, neuroprotection in ischemic conditions due to stroke, glaucoma or neurotrauma, tachyarrhythmia, atrial fibrillation and ventricular fibrillation.

In another aspect, the present invention provides a method of treating a sodium channel mediated disease or condition by inhibiting ion flux through a voltage-gated sodium channel in a mammal, preferably a human, wherein said method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention as described above.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention as described above, together with a pharmaceutically acceptable excipient. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the present invention in a pharmaceutically acceptable carrier and in an amount effective to treat a disease or condition associated with pain when administered to an animal, preferably a mammal, most preferably a human.

In another aspect, the invention provides a pharmaceutical therapy in combination with one or more other compounds of the invention or one or more other accepted therapies of the invention, or any combination thereof, to increase the efficacy of existing or future pharmaceutical therapies, or to reduce the side effects associated with accepted therapies. In one embodiment, the invention relates to pharmaceutical compositions combining the compounds of the invention with established or future therapies for the indications listed in the present invention.

Detailed Description

Definition of

The shorthand notation preceded by certain chemical groups named herein indicates the total number of carbon atoms present at the indicated chemical group. E.g. C₇-C₁₂Alkyl describes an alkyl group having a total of 7 to 12 carbon atoms, as defined below, and C₄-C₁₂Cycloalkylalkyl describes cycloalkylalkyl groups having a total of 4 to 12 carbon atoms as defined below. In shorthand notationThe total number of carbons in (a) does not contain carbons that may be present in the substituents of the group. For example, the following terms have the indicated meanings:

“C₁-C₁₀alkyl "refers to an alkyl group as defined below containing one to ten carbon atoms. C₁-C₁₀Alkyl groups may be optionally substituted with substituents such as alkyl groups as defined below.

“C₂-C₁₂Alkynyl "refers to alkynyl groups containing from two to twelve carbon atoms as defined below. C₂-C₁₂The alkynyl group may be optionally substituted with substituents as defined below for the alkenyl group.

“C₁-C₁₂Alkoxy "refers to alkoxy groups containing one to twelve carbon atoms as defined below. C₁-C₁₂The alkyl portion of the alkoxy group may be optionally substituted with substituents such as alkyl groups as defined below.

“C₂-C₁₂Alkoxyalkyl "refers to an alkoxyalkyl group containing two to twelve carbon atoms, as defined below. C ₂-C₁₂Each alkyl moiety of an alkoxyalkyl group may be optionally substituted with a substituent of an alkyl group as defined below.

“C₇-C₁₂Aralkyl "refers to aralkyl groups containing seven to twelve carbon atoms as defined below. C₇-C₁₂The aryl portion of an aralkyl group may be optionally substituted with substituents such as aryl groups as defined below. C₇-C₁₂The alkyl portion of an aralkyl group may be optionally substituted with substituents such as alkyl groups as defined below.

“C₇-C₁₂Aralkenyl "refers to aralkenyl groups containing seven to twelve carbon atoms as defined below. C₇-C₁₂The aryl portion of the aralkenyl can be optionally substituted with substituents as defined below for the aryl group. C₇-C₁₂The alkenyl moiety of the aralkenyl canOptionally substituted with substituents such as alkenyl groups as defined below.

“C₃-C₁₂Cycloalkyl "refers to cycloalkyl groups containing three to twelve carbon atoms as defined below. C₃-C₁₂The cycloalkyl group may be optionally substituted with substituents of the cycloalkyl group as defined below.

“C₄-C₁₂Cycloalkylalkyl "refers to cycloalkylalkyl groups containing four to twelve carbon atoms as defined below. C₄-C₁₂The cycloalkyl group may be optionally substituted with a substituent of a cycloalkylalkyl group as defined below.

In addition to the foregoing, when used in the specification and appended claims of this patent, the following terms have the meanings indicated, unless otherwise specified:

"amino" means-NH₂A group.

"cyano" refers to the group-CN.

"hydroxy" means an-OH group.

"imino" means an ═ NH substituent.

"nitro" means-NO₂A group.

"keto" refers to an ═ O substituent.

"thioketo" refers to an ═ S substituent.

"trifluoromethyl" means-CF₃A group.

"alkyl" means a straight or branched hydrocarbon chain radical consisting exclusively of carbon and hydrogen atoms, free of unsaturation, having from one to twelve carbon atoms, preferably from one to eight carbon atoms or from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, for example methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl)Mesityl), 3-methylhexyl, 2-methylhexyl, and the like. Unless expressly stated otherwise in the specification, alkyl groups may be optionally substituted with one of the following groups: alkyl, alkenyl, halogen, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, keto, trimethylsilyl, -OR ¹⁴、-OC(O)-R¹⁴、-N(R¹⁴)₂、-C(O)R¹⁴、-C(O)OR¹⁴、-C(O)N(R¹⁴)₂、-N(R¹⁴)C(O)OR¹⁶、-N(R¹⁴)C(O)R¹⁶、-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -S (O)_tOR¹⁶(wherein t is 1 to 2), -S (O)_tR¹⁶(wherein t is 0 to 2) and-S (O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and each R¹⁶Is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted, unless otherwise specified.

"alkenyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably from one to eight carbon atoms, and which is attached to the remainder of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1, 4-dienyl, and the like. Unless expressly stated otherwise in the specification, an alkenyl group may be optionally substituted with one of the following groups: alkyl, alkenyl, halogen, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, keto, trimethylsilyl, -OR ¹⁴、-OC(O)-R¹⁴、-N(R¹⁴)₂、-C(O)R¹⁴、-C(O)OR¹⁴、-C(O)N(R¹⁴)₂、-N(R¹⁴)C(O)OR¹⁶、-N(R¹⁴)C(O)R¹⁶、-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -S (O)_tOR¹⁶(wherein t is 1 to 2), -S (O)_tR¹⁶(wherein t is 0 to 2) and-S (O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and each R¹⁶Is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted, unless otherwise specified.

"alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, linking the remainder of the molecule and groups, consisting only of carbon and hydrogen, free of unsaturation, and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. The alkylene chain may be bonded to the rest of the molecule and to the group via one or any two carbons in the chain. Unless explicitly stated otherwise in the specification, the alkylene chain may optionally be substituted by one of the following groups: alkyl, alkenyl, halogen, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, keto, trimethylsilyl, -OR ¹⁴、-OC(O)-R¹⁴、-N(R¹⁴)₂、-C(O)R¹⁴、-C(O)OR¹⁴、-C(O)N(R¹⁴)₂、-N(R¹⁴)C(O)OR¹⁶、-N(R¹⁴)C(O)R¹⁶、-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -S (O)_tOR¹⁶(wherein t is 1 to 2), -S (O)_tR¹⁶(wherein t is 0 to 2) and-S (O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclylHeterocyclylalkyl, heteroaryl, or heteroaralkyl; and each R¹⁶Is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted, unless otherwise specified.

"alkenylene" and "alkenylene chain" refer to a straight or branched divalent hydrocarbon chain linking the remainder of the molecule and groups consisting only of carbon and hydrogen, containing at least one double bond, and having from two to twelve carbon atoms, such as ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is connected to the rest of the molecule by a single bond and to the group by a double or single bond. The point of attachment of the alkenylene chain to the rest of the molecule and to the group may be through one or any two carbons in the chain. Unless explicitly stated otherwise in the specification, the alkenylene chain may be optionally substituted with one of the following groups: alkyl, alkenyl, halogen, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, keto, trimethylsilyl, -OR ¹⁴、-OC(O)-R¹⁴、-N(R¹⁴)₂、-C(O)R¹⁴、-C(O)OR¹⁴、-C(O)N(R¹⁴)₂、-N(R¹⁴)C(O)OR¹⁶、-N(R¹⁴)C(O)R¹⁶、-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -S (O)_tOR¹⁶(wherein t is 1 to 2), -S (O)_tR¹⁶(wherein t is 0 to 2) and-S (O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and each R¹⁶Is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted, unless otherwise specified.

"Alkynylene" or "alkynylene chain" meansA linear or branched divalent hydrocarbon chain, linking the remainder of the molecule and the group, consisting solely of carbon and hydrogen, containing at least one triple bond, and having from two to twelve carbon atoms, such as propynyl, n-butynyl, and the like. An alkynylene chain is connected to the rest of the molecule by a single bond, and to the group by a double or single bond. The point of attachment of the alkynylene chain to the rest of the molecule and to the group may be through one or any two carbons in the chain. Unless explicitly stated otherwise in the specification, the alkynylene chain may be optionally substituted with one of the following groups: alkyl, alkenyl, halogen, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, keto, trimethylsilyl, -OR ¹⁴、-OC(O)-R¹⁴、-N(R¹⁴)₂、-C(O)R¹⁴、-C(O)OR¹⁴、-C(O)N(R¹⁴)₂、-N(R¹⁴)C(O)OR¹⁶、-N(R¹⁴)C(O)R¹⁶、-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -S (O)_tOR¹⁶(wherein t is 1 to 2), -S (O)_tR¹⁶(wherein t is 0 to 2) and-S (O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and each R¹⁶Is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted, unless otherwise specified.

"alkynyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms, preferably from one to eight carbon atoms, and which is attached to the remainder of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless explicitly stated otherwise in the specification, alkynyl groups may be optionally substituted by one of the following groups: alkyl, alkenyl, halogen, haloalkyl, halogenAlkenylene, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -OR ¹⁴、-OC(O)-R¹⁴、-N(R¹⁴)₂、-C(O)R¹⁴、-C(O)OR¹⁴、-C(O)N(R¹⁴)₂、-N(R¹⁴)C(O)OR¹⁶、-N(R¹⁴)C(O)R¹⁶、-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -S (O)_tOR¹⁶(wherein t is 1 to 2), -S (O)_tR¹⁶(wherein t is 0 to 2) and-S (O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and each R¹⁶Is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

"alkoxy" means a group of the formula-OR_aGroup, wherein R_aIs an alkyl group as defined above, containing from one to twelve carbon atoms. The alkyl portion of the alkoxy group may be optionally substituted with substituents such as alkyl as defined above.

"alkoxyalkyl" means a group of the formula-R_a-O-R_aGroup, wherein each R_aIndependently an alkyl group as defined above. The oxygen atom may be bonded to any carbon in any of the alkyl groups. Each alkyl moiety of an alkoxyalkyl group may be optionally substituted with substituents such as alkyl as defined above.

"aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system consisting only of hydrogen and carbon and containing from 6 to 18 carbon atoms, wherein the ring system may be partially saturated. Aryl groups include, but are not limited to, groups such as fluorenyl, phenyl, and naphthyl. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "aryl-" (as in "aralkyl") is intended to include aryl groups, which may optionally be substituted with one or more substituents Substituted, the substituents being independently selected from alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, heteroaryl, heteroarylalkyl, -R¹⁵-OR¹⁴、-R¹⁵-OC(O)-R¹⁴、-R¹⁵-N(R¹⁴)₂、-R¹⁵-C(O)R¹⁴、-R¹⁵-C(O)OR¹⁴、-R¹⁵-C(O)N(R¹⁴)₂、-R¹⁵-N(R¹⁴)C(O)OR¹⁶、-R¹⁵-N(R¹⁴)C(O)R¹⁶、-R¹⁵-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tOR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tR¹⁶(wherein t is 0 to 2) and-R¹⁵-S(O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; each R¹⁵Independently a chemical bond or a linear or branched alkylene or alkenylene chain; and each R¹⁶Is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

"aralkyl" means a group of the formula-R_aR_bGroup, wherein R_aIs alkyl as defined above, and R_bIs one or more aryl groups as defined above, such as benzyl, benzhydryl, and the like. Aryl groups may be optionally substituted as described above.

"aryloxy" means a group of the formula-OR_bGroup, wherein R_bIs aryl as defined above. The aryl portion of the aryloxy group can be optionally substituted as defined above.

"aralkenyl" means a group of formula-R _cR_bGroup, wherein R_cIs alkenyl as defined above, and R_bIs one or more aryl groups as defined above, which may be optionally substituted as defined above. Aromatic alkeneThe aryl portion of the group may be optionally substituted with aryl substituents as described above. The alkenyl portion of an aralkenyl can be optionally substituted with substituents such as the alkenyl described above.

"aralkoxy" means a compound of the formula-OR_bGroup, wherein R_bIs aralkyl as defined above. The aralkyl portion of the aralkoxy group may be optionally substituted as defined above.

"cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may contain a fused or bridged ring system, having three to fifteen carbon atoms, preferably three to ten carbon atoms, and which is saturated or unsaturated and is linked to the rest of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decahydronaphthyl, 7-dimethyl-bicyclo [2.2.1]Heptalkyl, and the like. Unless specifically stated otherwise in the specification, the term "cycloalkyl" is intended to include cycloalkyl, which may be optionally substituted with one or more substituents independently selected from alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, keto, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ¹⁵-OR¹⁴、-R¹⁵-OC(O)-R¹⁴、-R¹⁵-N(R¹⁴)₂、-R¹⁵-C(O)R¹⁴、-R¹⁵-C(O)OR¹⁴、-R¹⁵-C(O)N(R¹⁴)₂、-R¹⁵-N(R¹⁴)C(O)OR¹⁶、-R¹⁵-N(R¹⁴)C(O)R¹⁶、-R¹⁵-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)^tOR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tR¹⁶(wherein t is 0 to 2) and-R¹⁵-S(O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,Aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; each R¹⁵Independently a chemical bond or a linear or branched alkylene or alkenylene chain; and each R¹⁶Is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

"Cyclohydrocarbylalkyl" means a compound of the formula-R_aR_dGroup, wherein R_aIs alkyl as defined above, and R_dIs a cyclic hydrocarbon group as defined above. The alkyl and cycloalkyl groups may be optionally substituted as defined above.

"halogen" means bromine, chlorine, fluorine or iodine.

"haloalkyl" means an alkyl group as defined above substituted with one or more halogens as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl portion of the haloalkyl group may be optionally substituted with substituents as defined above for the alkyl group.

"heterocyclyl" refers to a stable 3-to 18-membered non-aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless expressly stated otherwise in the specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thiophene [1, 3 ]]Dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-ketopiperazinyl, 2-ketopiperidinyl, 2-ketopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofurfurylPyranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-keto-thiomorpholinyl, and 1, 1-diketo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above, which may be optionally substituted by one or more substituents selected from alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, keto, thioketo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ¹⁵-OR¹⁴、-R¹⁵-OC(O)-R¹⁴、-R¹⁵-N(R¹⁴)₂、-R¹⁵-C(O)R¹⁴、-R¹⁵-C(O)OR¹⁴、-R¹⁵-C(O)N(R¹⁴)₂、-R¹⁵-N(R¹⁴)C(O)OR¹⁶、-R¹⁵-N(R¹⁴)C(O)R¹⁶、-R¹⁵-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tOR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tR¹⁶(wherein t is 0 to 2) and-R¹⁵-S(O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; each R¹⁵Independently a chemical bond or a linear or branched alkylene or alkenylene chain; and each R¹⁶Is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

"Heterocyclylalkyl" means a compound of the formula-R_aR_eGroup, wherein R_aIs alkyl as defined above, and R_eIs a heterocyclic group as defined above, and if the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group may be attached to an alkyl group at that nitrogen atom. The alkyl portion of the heterocyclylalkyl group may optionally be substituted as described aboveSubstituents of the defined alkyl groups. The heterocyclyl portion of the heterocyclylalkyl group may be optionally substituted with substituents of the heterocyclyl group as defined above.

"heteroaryl" refers to a 5-to 18-membered aromatic ring group containing one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen, and sulfur. For the purposes of the present invention, heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may comprise fused or bridged ring systems; and the nitrogen, carbon or sulfur atom in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. Examples include, but are not limited to, azanyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ][1，4]Dioxacycloheptyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxanyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzotriazolyl, benzo [4, 6 ] benzo]Imidazo [1, 2-a ]]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyl, naphthyridinyl, oxadiazolyl, 2-ketoazanyl, oxazolyl, oxiranyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, 2, 3-naphthyridinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalyl, quinolyl (quinolinyl), quinuclidinyl, isoquinolyl (isoquinoquinolinyl), tetrahydroquinolyl (tetrahydroquinolinyl), thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, imidazolyl, indazolyl, oxazolyl, oxidazolyl, oxidolyl, quinoxalinyl, quinonyl, triazinyl and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl as defined above, which may optionally have one or more substituents A substituent selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, haloalkyl, haloalkenyl, cyano, keto, thioketo, nitro, keto, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R¹⁵-OR¹⁴、-R¹⁵-OC(O)-R¹⁴、-R¹⁵-N(R¹⁴)₂、-R¹⁵-C(O)R¹⁴、-R¹⁵-C(O)OR¹⁴、-R¹⁵-C(O)N(R¹⁴)₂、-R¹⁵-N(R¹⁴)C(O)OR¹⁶、-R¹⁵-N(R¹⁴)C(O)R¹⁶、-R¹⁵-N(R¹⁴)S(O)_tR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tOR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tR¹⁶(wherein t is 0 to 2) and-R¹⁵-S(O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R¹⁴Independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; each R¹⁵Independently a chemical bond or a linear or branched alkylene or alkenylene chain; and each R¹⁶Is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

"Heteroaralkyl" means a group of the formula-R_aR_fGroup, wherein R_aIs alkyl as defined above, and R_fIs heteroaryl as defined above. The heteroaryl portion of a heteroarylalkyl group may be optionally substituted with a substituent as defined above for the heteroaryl group. The alkyl portion of the heteroaralkyl can be optionally substituted with substituents such as alkyl as defined above.

"Heteroaralkenyl" means a compound of the formula-R_bR_fGroup, wherein R_bIs alkenyl as defined above, and R_fIs heteroaryl as defined above. The heteroaryl portion of the heteroarylalkenyl group canOptionally substituted with a heteroaryl substituent as defined above. The alkenyl moiety of the heteroarylalkenyl group may be optionally substituted with a substituent of the alkenyl group as defined above.

"Trihaloalkyl" means an alkyl group as defined above substituted with three halogens as defined above, e.g., trifluoromethyl. The alkyl portion of the trihaloalkyl group may be optionally substituted with substituents such as alkyl as defined above.

"Trihaloalkoxy" means a compound of the formula-OR_gGroup, wherein R_gIs a trihaloalkyl group as defined above. The trihaloalkyl portion of the trihaloalkoxy group may be optionally substituted with a trihaloalkyl substituent as defined above.

"analgesia" refers to the absence of pain in response to a stimulus that normally causes pain.

"allodynia" refers to a condition of a normally innocuous sensation, such as pressure or light touch, perceived as extreme pain.

"prodrug" is intended to mean a compound that can be converted under physiological conditions or by solvolysis to the biologically active compounds of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may be inactive when administered to a patient in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to the parent compound of the invention, for example by hydrolysis in blood. Prodrug compounds often provide the advantages of solubility, histocompatibility, or delayed release in mammalian organisms (see Bundgard, h., Design of produgs (prodrug Design) (1985), pp.7-9, 21-24, (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T.T., et al, "Pro-drugs as Novel Delivery Systems", A.C.S.Sympossium Series, Vol.14 and Bioreproducible Carriers in Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

The term "prodrug" is also intended to include any covalently bonded carriers that release the active compounds of the invention in vivo when the prodrugs are administered to a mammalian subject. Prodrugs of the compounds of the present invention may be prepared by modifying functional groups present on the compounds of the present invention in such a way that, in routine manipulation or in vivo, the modified species are cleaved to the parent compound of the present invention. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or mercapto group is bonded to any group that, when the prodrug of the compound of the present invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups, or amide derivatives of amine functional groups in the compounds of the invention, and the like.

Objects of the invention disclosed herein also include all isotopically-labeled pharmaceutically acceptable compounds of formula (I) wherein one or more atoms are replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ²H、³H、¹¹C、¹³C、¹⁴C、 ¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. these radiolabeled compounds can be used to help determine or measure the potency of a compound by characterizing, for example, the site or pattern of action on a sodium channel, or by characterizing the binding affinity to a pharmacologically important site of action on a sodium channel. Certain isotopically-labeled compounds of formula (I), for example those into which a radioisotope is incorporated, are useful in drug and/or substrate tissue distribution studies. Radioisotope tritium, i.e.³H and carbon-14, i.e.¹⁴C due to its easy incorporationAnd ready-to-use detection methods, and are particularly useful for this purpose.

With heavier isotopes such as deuterium, i.e.²H substitution, due to its higher metabolic stability, may provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, and is therefore preferred in certain circumstances.

With positron-emitting isotopes such as¹¹C、¹⁸F、¹⁵O and¹³n substitution, useful in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques familiar to those skilled in the art or by processes analogous to those described in the examples and preparations below, using an appropriate isotopically-labelled reagent in place of the unlabelled reagent previously used.

The invention disclosed herein is also directed to in vivo metabolites comprising the disclosed compounds. These products are obtained by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compounds mainly due to the enzymatic process. Accordingly, the present invention includes compounds produced by a method comprising contacting a compound of the present invention with a mammal for a time sufficient to produce a metabolite thereof. These products are generally identified by administering a radiolabeled compound of the invention to an animal, such as a rat, mouse, guinea pig, monkey, or human in a detectable dose, allowing sufficient time for metabolism to occur, and isolating its conversion products from urine, blood or other biological samples.

"stable compounds" and "stable structures" are intended to mean compounds that are sufficiently robust to be isolated from a reaction mixture in a useful purity and formulated into an effective therapeutic agent.

"mammal" includes humans and domestic animals such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals such as wild animals and the like.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes substituted aryl groups as well as aryl groups having no substituents.

A "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is approved by the U.S. food and drug administration for acceptable use in humans or livestock.

"pharmaceutically acceptable salts" include acid and base addition salts.

"pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, as well as organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, acetic acid, and the like, Gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-keto-glutaric acid, glycerylphosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, phenylglycolic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

"pharmaceutically acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. 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, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist in hydrate forms, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as in corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases the compounds of the present invention may retain only incidental water or be a mixture of water plus a portion of incidental solvent.

"pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human. The medium includes all pharmaceutically acceptable carriers, diluents or excipients for its use.

By "therapeutically effective amount" is meant an amount of a compound of the present invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment of a sodium channel mediated disease or condition in the mammal, preferably a human, as defined below. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art in view of his own knowledge and this disclosure.

As used herein, "treating" or "treatment" encompasses treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:

(i) preventing a disease or disease state from occurring in mammals, particularly when such mammals are predisposed to, but have not yet been diagnosed with, the disease state;

(ii) inhibiting a disease or disease state, i.e., arresting its development;

(iii) alleviating a disease or condition, i.e., causing regression of the disease or condition; or

(iv) Relief of symptoms resulting from such disease or condition, i.e., relief of pain rather than treatment of the underlying disease or condition. As used herein, the terms "disease" and "disease state" are used interchangeably, or may be different in that the particular disease or disease state may not have a known pathogen (and therefore etiology has not been studied), and it has therefore not been considered a disease, but merely an undesirable disease state or syndrome, where a more or less specific combination of symptoms has been confirmed by a clinician.

The compounds of the present invention or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers and other stereoisomers, which are defined in absolute stereochemistry as (R) -or (S) -or (D) -or (L) -for amino acids. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing/separating the individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, it is also intended to include all tautomeric forms.

"stereoisomers" refers to compounds consisting of the same atoms joined by the same chemical bond, but having different three-dimensional structures that are not interchangeable. The present invention is intended to encompass each stereoisomer and mixtures thereof, and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

"tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The invention includes tautomers of any of the compounds.

Intermediate compounds of formula (I) as well as all polymorphs and crystal habit of the aforementioned species are also within the scope of the present invention.

The chemical nomenclature protocol and the structural diagrams used herein are modified forms of the i.u.p.a.c. nomenclature system using the ACD/nomenclature version 9.07 software program, wherein the compounds of the invention are referred to herein as derivatives of the central core structure (i.e., the indolinone structure). For complex chemical names used herein, substituents are named before the group to which they are attached. For example, cyclopropylethyl contains an ethyl backbone with a cyclopropyl substituent. All chemical bonds are identified in the chemical structure diagram except for certain carbon atoms that are presumed to have bound sufficient hydrogen atoms to complete the valence state.

Thus, for example, compounds of formula (I) wherein j is 0, k is 1, Q is-O-, R¹Is pentyl radical, R^2aIs 3, 5-dichlorophenyl, R^2b、R^2cAnd R^2dEach is hydrogen, R^3aAnd R^3dEach is hydrogen, and R^3bAnd R^3cTogether with the carbon ring atoms to which they are attached, form a fused dioxolyl ring; i.e. a compound of the formula:

designated herein as 4 ' - (3, 5-dichlorophenyl) -1 ' -pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one.

Detailed description of the invention

In each of the aspects of the invention set forth in the summary above, certain specific embodiments are preferred.

One embodiment of the present invention is a compound of general formula (I) set forth in the summary above, wherein:

at least one of j and k is 1 and the other is 0 or 1;

q is-O-;

R¹is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R⁸-OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b、R^2cAnd R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenylAlkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴、-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2cAnd R^2dAre all as defined above;

or R^2b、R^2cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2dAre all as defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAre all as defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dAre all as defined above;

or R^3b、R^3cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

or R^3c、R^3dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3bAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R⁸-OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b、R^2cAnd R^2dEach independently selected from hydrogen, halogen or alkyl;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3b、R^3cTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3cAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R ⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

each R⁹Is straight chain or branched chainAn alkylene chain, a linear or branched alkenylene chain or a linear or branched alkynylene chain.

Another embodiment of the invention is a compound of general formula (I) as set forth in the summary above, wherein:

R¹is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, -R⁸-OR⁵、-R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b，、R^2cAnd R^2dEach independently selected from hydrogen, halogen or alkyl;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atom to which they are directly attached form a fused dioxolyl ring;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group;

each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

R¹is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, -R⁸-OR⁵、-R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b、R^2cAnd R^2dEach independently selected from hydrogen, halogen or alkyl;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、 -N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴And R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group;

each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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) as set forth in the summary above, wherein:

R¹is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, -R⁸-OR⁵、-R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b、R^2cAnd R^2dEach independently selected from hydrogen, halogen or alkyl;

R^3aand R^3dAre all hydrogen;

R^3b、R^3cis directly connected with itTogether form a fused and optionally substituted heterocyclyl ring, or form a fused and optionally substituted cycloalkyl ring;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group;

each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

R¹is aryl, heteroaryl or heterocyclyl;

R^2a、R^2b、R^2cand R^2dAre all hydrogen; and is

R^3b、R^3cTogether with the carbon ring atom to which they are directly attached form a fused dioxolyl ring.

Another embodiment of the invention is a compound of general formula (I) as set forth in the summary above, wherein:

at least one of j and k is 1 and the other is 0 or 1;

q is-O-;

R¹is hydrogen, alkyl, -R⁸-C(O)OR⁵or-R⁸-C(O)N(R⁴)R⁵；

R^2aSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴；-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2aEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) is optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴、-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

R^2b、R^2cand R^2dAre all hydrogen;

R^3a、R^3b、R^3cand R^3dEach independently selected from hydrogen or halogen;

or R^3b、R^3cTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1, or j is 1 and k is 0;

q is-O-;

R¹is hydrogen or alkyl;

R^2aselected from the group consisting of alkyl, haloalkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heteroaryl, -R ⁸-C(O)N(R⁴)R⁵and-R⁸-N(R⁴)R⁵；

Wherein R is^2aEach aryl, aralkyl, aralkenyl, heterocyclyl and heteroaryl of (a) is optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴、-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

R^2b、R^2cand R^2dAre all hydrogen;

R^3a、R^3b、R^3cand R^3dEach independently selected from hydrogen or halogen;

or R^3b、R^3cTogether with the carbon ring atom to which it is directly attached form a fused dioxolyl ring, or form a fused and optionally substituted tetrahydrofuranyl ring, and R^3aAnd R^3dAre all as defined above;

R⁴and R⁵Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylAlkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl groups;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain.

Another embodiment of the invention is a compound of general formula (I) as set forth in the summary above, wherein:

at least one of j and k is 1 and the other is 0 or 1;

q is-O-;

R¹is represented by-C (O) N (R)⁶)R⁷A substituted aralkyl group, wherein:

R⁶is hydrogen, alkyl, aryl or aralkyl; and is

R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN、-R⁹-OR⁵、-R⁹-N(R⁴)R⁵Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;

or R⁶、R⁷Together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group;

and wherein R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, -R⁸-CN、-R⁸-OR⁵Heterocyclyl and heteroaryl;

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、 -R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

And wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴；-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2cAnd R^2dAre all as defined above;

or R^2b、R^2cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2dAre all as defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAre all as defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dAre all as defined above;

or R^3b、R^3cTogether with the carbon ring atoms to which they are directly attached may form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

or R^3c、R^3dTogether with the carbon ring atoms to which they are directly attached may form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3bAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is represented by-C (O) N (R)⁶)R⁷A substituted aralkyl group, wherein:

R⁶is hydrogen, alkyl, aryl or aralkyl; and is

R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN、-R⁹-OR⁵、-R⁹-N(R⁴)R⁵Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;

or R⁶、R⁷Together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group;

and wherein R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, -R⁸-CN、-R⁸-OR⁵Heterocyclyl and heteroaryl;

R^2a、R^2b、R^2cand R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atoms to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

Or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is represented by-C (O) N (R)⁶)R⁷A substituted aralkyl group, wherein:

R⁶is hydrogen, alkyl, aryl or aralkyl; and is

R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN、-R⁹-OR⁵or-R⁹-N(R⁴)R⁵；

Or R⁶、R⁷Together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group;

wherein R is⁶And R⁷Each aryl, aralkyl, heterocyclyl and heteroaryl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, -R⁸-CN、-R⁸-OR⁵Heterocyclic and heteroaryl radicalsSubstituent groups;

R^2a、R^2b、R^2cand R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atom to which they are directly attached form a fused dioxolyl ring;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

Or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is represented by-C (O) N (R)⁶)R⁷A substituted aralkyl group, wherein:

R⁶is hydrogen, alkyl, aryl or aralkyl; and is

R⁷Is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;

and wherein R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, -R⁸-CN、-R⁸-OR⁵Heterocyclyl and heteroaryl;

R^2a、R^2b、R^2cand R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atom to which they are directly attached form a fused dioxolyl ring;

R⁴And R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

at least one of j and k is 1 and the other is 0 or 1;

q is-O-;

R¹is optionally substituted by one or more groups selected from-R⁸-OR⁵、-C(O)OR⁵Aralkyl substituted with a substituent of halogen, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclic group and heteroaryl;

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, haloAlkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴；-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2cAnd R^2dAre all as defined above;

or R^2b、R^2cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2dAre all as defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAre all as defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、 、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dAre all as defined above;

or R^3b、R^3cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

or R^3c、R^3dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3bAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is optionally substituted by one or more groups selected from-R⁸-OR⁵、-C(O)OR⁵Aralkyl substituted with a substituent of halogen, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclic group and heteroaryl;

R^2a、R^2b、R^2cand R^2dEach independently selected from hydrogen, alkyl or halogen;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dAre all as defined above;

or R^3b、R^3cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

or R^3c、R^3dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R ^3aAnd R^3bAre all as defined above;

each R⁵Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl; and is

Each R⁸Is a bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain.

Another embodiment of the present invention are compounds of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is optionally substituted by one or more groups selected from-R⁸-OR⁵、-C(O)OR⁵Aralkyl substituted with a substituent of halogen, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclic group and heteroaryl;

R^2a、R^2b、R^2cand R^2dEach independently selected from hydrogen, alkyl or halogen;

R^3a、R^3b、R^3cand R^3dEach independently selected from hydrogen, halogen and-R⁸-OR⁵；

Or R³b、R^3cTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, dioxolyl, tetrahydrofuryl and heteroaryl, and R^3aAnd R^3dAre all hydrogen;

each R⁵Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl; and is

Each R⁸Is a bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain.

Another embodiment of the invention is a compound of general formula (I) as set forth in the summary above, wherein:

at least one of j and k is 1 and the other is 0 or 1;

q is-O-;

R¹is-R⁹-N(R¹0)R¹¹、-R⁹-N(R¹²)C(O)R¹¹or-R⁹-N(R¹⁰)C(O)N(R¹⁰)R¹¹Wherein:

each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁹-OC(O)R⁵、-R⁹-C(O)OR⁵、-R⁹-C(O)N(R⁴)R⁵、-R⁹-C(O)R⁵、-R⁹-N(R⁴)R⁵、-R⁹-OR⁵or-R⁹-CN；

R¹²Is hydrogen, alkyl, aryl, aralkyl or-C (O) R⁵；

And wherein R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, nitro, -R⁸-CN、-R⁸-OR⁵、-R⁸-C(O)R⁵Heterocyclyl and heteroaryl;

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴；-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2cAnd R^2dAre all as defined above;

or R^2b、R^2cTo the carbon ring atom I directly attached theretoMay form a condensed ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2dAre all as defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAre all as defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、 -R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)ⁿN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a ring selected from cycloalkyl, heterocyclylA condensed ring of aryl or heteroaryl, and R^3cAnd R^3dAre all as defined above;

or R^3b、R^3cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

or R^3c、R^3dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3bAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is-R⁹-N(R¹0)R¹¹、-R⁹-N(R¹²)C(O)R¹¹or-R⁹-N(R¹⁰)C(O)N(R¹⁰)R¹¹Wherein:

each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁹-OC(O)R⁵、 -R⁹-C(O)OR⁵、-R⁹-C(O)N(R⁴)R⁵、-R⁹-C(O)R⁵、-R⁹-N(R⁴)R⁵、-R⁹-OR⁵or-R⁹-CN；

R¹²Is hydrogen, alkyl, aryl, aralkyl or-C (O) R⁵；

And wherein R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, nitro, -R⁸-CN、-R⁸-OR⁵、-R⁸-C(O)R⁵Heterocyclyl and heteroaryl;

R^2a、R^2b、R^2cand R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atoms to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

Or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵To which it is connectedThe attached nitrogen atoms together may form a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is-R⁹-N(R¹⁰)R¹¹Wherein:

each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁹-OC(O)R⁵、-R⁹-C(O)OR⁵、-R⁹-C(O)N(R⁴)R⁵、-R⁹-C(O)R⁵、-R⁹-N(R⁴)R⁵、-R⁹-OR⁵or-R⁹-CN；

And wherein R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, nitro, -R⁸-CN、-R⁸-OR⁵、-R⁸-C(O)R⁵Heterocyclyl and heteroaryl;

R^2a、R^2b、R^2cand R ^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atom to which they are directly attached form a fused dioxolyl ring;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is-R⁹-N(R¹²)C(O)R¹¹Wherein:

each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁹-OC(O)R⁵、-R⁹-C(O)OR⁵、-R⁹-C(O)N(R⁴)R⁵、-R⁹-C(O)R⁵、-R⁹-N(R⁴)R⁵、-R⁹-OR⁵or-R⁹-CN；

R¹²Is hydrogen, alkyl, aryl, aralkyl or-C (O) R⁵；

And wherein for R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, nitro, -R⁸-CN、-R⁸-OR⁵、-R⁸-C(O)R⁵Heterocyclyl and heteroaryl; r^2a、R^2b、R^2cAnd R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atom to which they are directly attached form a fused dioxolyl ring;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is-R⁹-N(R¹⁰)C(O)N(R¹⁰)R¹¹Wherein:

each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁹-OC(O)R⁵、-R⁹-C(O)OR⁵、-R⁹-C(O)N(R⁴)R⁵、-R⁹-C(O)R⁵、-R⁹-N(R⁴)R⁵、-R⁹-OR⁵or-R⁹-CN；

And wherein R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, nitro, -R⁸-CN、-R⁸-OR⁵、-R⁸-C(O)R⁵Heterocyclyl and heteroaryl;

R^2a、R^2b、R^2cand R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atom to which they are directly attached form a fused dioxolyl ring;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heterocycleArylalkyl, heteroaryl and heteroarylalkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R ⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

at least one of j and k is 1 and the other is 0 or 1;

q is-O-;

R¹is heterocyclylalkyl or heteroaralkyl, wherein the heterocyclylalkyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of keto, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-OR⁵、-R⁸-C(O)OR⁵、-R⁸-N(R⁴)R⁵、-R⁸-C(O)N(R⁴)R⁵、-R⁸-N(R⁵)C(O)R⁴、-R⁸-S(O)_mR⁴(wherein m is 0, 1 or 2), -R⁸-CN or-R⁸-NO₂Substituted with the substituent(s);

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroalkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴、-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein m is each independentlyIndependently 0, 1 or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2cAnd R^2dAre all as defined above;

or R^2b、R^2cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2dAre all as defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAre all as defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dAre all as defined above;

or R^3b、R^3cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

or R^3c、R^3dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3bAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵Together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is heterocyclylalkyl or heteroaralkyl, wherein the heterocyclylalkyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of keto, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-OR⁵、-R⁸-C(O)OR⁵、-R⁸-N(R⁴)R⁵、-R⁸-C(O)N(R⁴)R⁵、-R⁸-N(R⁵)C(O)R⁴、-R⁸-S(O)_mR⁴(wherein m is 0, 1 or 2), -R⁸-CN or-R⁸-NO₂Substituted with the substituent(s);

R^2a、R^2b、R^2cand R^2dEach independently selected from hydrogen, halogen, alkyl or-R⁸-OR⁵；

R^3a、R^3b、R^3cAnd R^3dEach independently selected from hydrogen, halogen, alkyl or-R⁸-OR⁵；

Or R^3b、R^3cTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all hydrogen;

each R⁵Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl; and is

Each R⁸Is a bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain.

Another embodiment of the present invention are compounds of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1;

q is-O-;

R¹is heterocyclylalkyl or heteroaralkyl, wherein the heterocyclylalkyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of keto, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-OR⁵、-R⁸-C(O)OR⁵、-R⁸-N(R⁴)R⁵、-R⁸-C(O)N(R⁴)R⁵、-R⁸-N(R⁵)C(O)R⁴、-R⁸-S(O)_mR⁴(wherein m is 0, 1 or 2), -R⁸-CN or-R⁸-NO₂Substituted with the substituent(s);

R^2a、R^2b、R^2cand R^2dEach independently selected from hydrogen, halogen, alkyl or-R⁸-OR⁵；

R^3a、R^3b、R^3cAnd R^3dEach independently selected from hydrogen, halogen, alkyl or-R⁸-OR⁵；

Or R^3b、R^3cTogether with the carbon ring atom to which they are directly attached form a fused ring selected from dioxolyl or tetrahydrofuranyl, and R^3aAnd R^3dAre all hydrogen;

each R⁵Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl; and is

Each R⁸Is a bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain.

Another embodiment of the invention is a compound of general formula (I) as set forth in the summary above, wherein:

at least one of j and k is 1 and the other is 0 or 1;

Q is-O-;

R¹is heterocyclylalkyl or heteroaralkyl, wherein the heterocyclylalkyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of keto, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-OR⁵、-R⁸-C(O)OR⁵、-R⁸-N(R⁴)R⁵、-R⁸-C(O)N(R⁴)R⁵、-R⁸-N(R⁵)C(O)R⁴、-R⁸-S(O)_mR⁴(wherein m is 0, 1 or 2), -R⁸-CN or-R⁸-NO₂Substituted with the substituent(s);

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、 -R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴；-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

R^3aand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3b、R^3cMay form, together with the carbon ring atom to which they are directly attached, a fused ring selected from dioxolyl or tetrahydrofuranyl, and R^3aAnd R^3dAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵Together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

at least one of j and k is 1 and the other is 0 or 1;

q is-O-;

R¹is heterocyclylalkyl or heteroaralkyl, wherein the heterocyclylalkyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of keto, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-OR⁵、-R⁸-C(O)OR⁵、-R⁸-N(R⁴)R⁵、-R⁸-C(O)N(R⁴)R⁵、-R⁸-N(R⁵)C(O)R⁴、-R⁸-S(O)_mR⁴(wherein m is 0, 1 or 2), -R⁸-CN or-R⁸-NO₂Substituted with the substituent(s);

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、 -R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴；-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1 or 2;

q is-O-;

R¹is hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, aryl, cycloalkyl or cycloHydrocarbyl alkyl, heteroaryl, heterocyclyl, -R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、 -S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R⁸OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b、R^2cAnd R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atoms to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵May form, together with the nitrogen atom to which they are attached, a heterocyclic or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

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)-；

R^1aIs hydrogen OR-OR⁵；

R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R⁸-OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

Or R¹Is represented by-C (O) N (R)⁶)R⁷A substituted aralkyl group, wherein:

R⁶is hydrogen, alkyl, aryl or aralkyl; and is

R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN、-R⁹-OR⁵、-R⁹-N(R⁴)R⁵Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;

or R⁶、R⁷Together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group;

and wherein R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, -R⁸-CN、-R⁸-OR⁵Heterocyclyl and heteroaryl;

or R¹Is optionally substituted by one or more groups selected from-R⁸-OR⁵、-C(O)OR⁵Halogen, haloalkyl, alkyl, nitro, cyano, arylAralkyl substituted with substituents for aralkyl, heterocyclic and heteroaryl;

or R¹is-R⁹-N(R¹⁰)R¹¹、-R⁹-N(R¹²)C(O)R¹¹or-R⁹-N(R¹⁰)C(O)N(R¹⁰)R¹¹Wherein:

each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁹-OC(O)R⁵、-R⁹-C(O)OR⁵、-R⁹-C(O)N(R⁴)R⁵、-R⁹-C(O)R⁵、-R⁹-N(R⁴)R⁵、-R⁹-OR⁵or-R⁹-CN；

R¹²Is hydrogen, alkyl, aryl, aralkyl or-C (O) R⁵；

And wherein R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, nitro, -R⁸-CN、-R⁸-OR⁵、-R⁸-C(O)R⁵Heterocyclyl and heteroaryl;

or R¹Is heterocyclylalkyl or heteroaralkyl, wherein the heterocyclylalkyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of keto, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-OR⁵、-R⁸-C(O)OR⁵、-R⁸-N(R⁴)R⁵、-R⁸-C(O)N(R⁴)R⁵、-R⁸-N(R⁵)C(O)R⁴、-R⁸-S(O)_mR⁴(wherein m is 0, 1 or 2), -R⁸-CN or-R⁸-NO₂Substituted with the substituent(s);

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、 -R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl Aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴；-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2cAnd R^2dAre all as defined above;

or R^2b、R^2cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2dAre all as defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAre all as defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R ^3cAnd R^3dAre all as defined above;

or R^3b、R^3cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

or R^3c、R^3dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3bAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵To the nitrogen atom to which it is attachedTogether form a heterocyclyl or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1 or 2;

q is-C (R)^1a)H-；

R^1aIs hydrogen OR-OR ⁵；

R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R⁸-OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b、R^2cAnd R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、 -R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴；-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R ^2cAnd R^2dAre all as defined above;

or R^2b、R^2cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2dAre all as defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAre all as defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independentlyIs 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dAre all as defined above;

or R^3b、R^3cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre all as defined above;

or R^3c、R^3dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R ^3aAnd R^3bAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵Together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1 or 2;

q is-C (R)^1a)H-；

R^1aIs hydrogen OR-OR⁵；

R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R⁸-OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b、R^2cAnd R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atoms to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

each R ⁵Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl;

each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1 or 2;

q is-C (R)^1a)H-；

R^1aIs hydrogen OR-OR⁵；

R¹Is a pentyl group;

R^2a、R^2b、R^2cand R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atom to which they are directly attached form a fused dioxolyl ring; and is

Each R⁵Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl.

Another embodiment of the invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1 or 2;

q is-C (O) -, -CF₂-, -C (O) O-or-N (R)⁵)C(O)-；

R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R ⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R⁸-OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

Or R¹Is represented by-C (O) N (R)⁶)R⁷A substituted aralkyl group, wherein:

R⁶is hydrogen, alkyl, aryl or aralkyl; and is

R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN、-R⁹-OR⁵、-R⁹-N(R⁴)R⁵Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;

or R⁶、R⁷Together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group;

and wherein R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl of (a) may optionally be substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, -R⁸-CN、-R⁸-OR⁵Heterocyclyl and heteroaryl;

or R¹Is optionally substituted by one or more groups selected from-R⁸-OR⁵、-C(O)OR⁵Aralkyl substituted with a substituent of halogen, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclic group and heteroaryl;

or R¹is-R⁹-N(R¹⁰)R¹¹、-R⁹-N(R¹²)C(O)R¹¹or-R⁹-N(R¹⁰)C(O)N(R¹⁰)R¹¹Wherein:

each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁹-OC(O)R⁵、-R⁹-C(O)OR⁵、-R⁹-C(O)N(R⁴)R⁵、-R⁹-C(O)R⁵、-R⁹-N(R⁴)R⁵、-R⁹-OR⁵or-R⁹-CN；

R¹²Is hydrogen, alkyl, aryl, aralkyl or-C (O) R⁵；

And whereinR¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl of (a) is optionally substituted with one or more groups selected from alkyl, cycloalkyl, aryl, aralkyl, halogen, haloalkyl, nitro, -R⁸-CN、-R⁸-OR⁵、-R⁸-C(O)R⁵Heterocyclyl and heteroaryl;

or R¹Is heterocyclylalkyl or heteroaralkyl, wherein the heterocyclylalkyl or heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of keto, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-OR⁵、-R⁸-C(O)OR⁵、-R⁸-N(R⁴)R⁵、-R⁸-C(O)N(R⁴)R⁵、-R⁸-N(R⁵)C(O)R⁴、-R⁸-S(O)_mR⁴(wherein m is 0, 1 or 2), -R⁸-CN or-R⁸-NO₂Substituted with the substituent(s);

R^2a、R^2b、R^2cand R^2dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、 -R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(＝N-CN)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

and wherein R^2a、R^2b、R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl of (a) may optionally be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-S(O)_mR⁴、-R⁸-S(O)_nN(R⁴)R⁵、-R⁸-C(O)R⁴；-R⁸-C(O)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-N(R⁵)C(O)R⁴and-N (R)⁵)S(O)_nR⁴Wherein each m is independently 0, 1, or 2, and each n is independently 1 or 2;

or R^2a、R^2bMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2cAnd R^2dAre all as defined above;

or R^2b、R^2cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2dAre all as defined above;

or R^2c、R^2dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^2aAnd R^2bAre all as defined above;

R^3a、R^3b、R^3cand R^3dEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R⁸-CN、-R⁸-NO₂、-R⁸-OR⁵、-R⁸-N(R⁴)R⁵、-N＝C(R⁴)R⁵、-S(O)_mR⁴、-OS(O)₂CF₃、-R⁸-C(O)R⁴、-C(S)R⁴、-C(R⁴)₂C(O)R⁵、-R⁸-C(O)OR⁴、-C(S)OR⁴、-R⁸-C(O)N(R⁴)R⁵、-C(S)N(R⁴)R⁵、-N(R⁵)C(O)R⁴、-N(R⁵)C(S)R⁴、-N(R⁵)C(O)OR⁴、-N(R⁵)C(S)OR⁴、-N(R⁵)C(O)N(R⁴)R⁵、-N(R⁵)C(S)N(R⁴)R⁵、-N(R⁵)S(O)_nR⁴、-N(R⁵)S(O)_nN(R⁴)R⁵、-R⁸-S(O)_nN(R⁴)R⁵、-N(R⁵)C(＝NR⁵)N(R⁴)R⁵and-N (R)⁵)C(N＝C(R⁴)R⁵)N(R⁴)R⁵Wherein each m is independently 0, 1 or 2, and each n is independently 1 or 2;

or R^3a、R^3bTogether with the carbon ring atom to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dAre all as defined above;

or R^3b、R^3cMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R ^3aAnd R^3dAre all as defined above;

or R^3c、R^3dMay form, together with the carbon ring atoms to which they are directly attached, a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3bAre all as defined above;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl;

or when R is⁴And R⁵All attached to the same nitrogen atom, R⁴、R⁵Together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group; and is

Each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1 or 2;

q is-C (O) -, -CF₂-, -C (O) O-or-N (R)⁵)C(O)-；

R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C(O)R⁵、-R⁸-C(O)OR⁵、-R⁸-C(O)N(R⁴)R⁵、-S(O)₂-R⁵、-R⁹-S(O)_m-R⁵(wherein m is 0, 1 or 2), -R ⁸-OR⁵、-R⁸-CN、-R⁹-P(O)(OR⁵)₂or-R⁹-O-R⁹-OR⁵；

R^2a、R^2b、R^2cAnd R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3ctogether with the carbon ring atoms to which they are directly attached form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

each R⁵Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl;

each R⁸Is a chemical bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

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 invention is a compound of general formula (I) as set forth in the summary above, wherein:

j is 0 and k is 1 or 2;

q is-C (O) -, -CF₂-, -C (O) O-or-N (R)⁵)C(O)-；

R¹Is a pentyl group;

R^2a、R^2b、R^2cand R^2dAre all hydrogen;

R^3aand R^3dAre all hydrogen;

R^3b、R^3cto carbon ring atoms directly bound theretoTogether form a fused dioxolyl ring; and is

Each R⁵Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl.

Particular embodiments of the compounds of formula (I) are described in more detail below in the preparation of the compounds of the invention.

Application and testing of the Compounds of the invention

The present invention relates to compounds, pharmaceutical compositions, and methods of using these compounds and pharmaceutical compositions for the treatment of sodium channel mediated disorders, preferably pain related disorders, central nervous system disorders such as epilepsy, anxiety, depression, and bipolar disorder; cardiovascular disease states such as arrhythmia, atrial fibrillation, and ventricular fibrillation; neuromuscular conditions such as restless legs syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neurotrauma and multiple sclerosis; and ion channel pathologies such as erythromelalgia and familial rectal pain syndrome by administering to a patient in need of such treatment an effective amount of a sodium channel blocker modulator, especially an inhibitor.

In general, the present invention provides methods of treating or protecting a patient from developing a sodium channel mediated disease (especially pain) comprising administering to an animal, such as a mammal, especially a human patient, in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, wherein the compound modulates the activity of one or more voltage dependent sodium channels.

General values for the compounds of the invention that mediate, and in particular inhibit, sodium channel ion flux can be determined using the assay methods described below in the biological assays section. Alternatively, the general value of a compound for treating a disease state and disease can be established in an industry standard animal model used to demonstrate the efficacy of a compound for treating pain. Animal models of human neuropathic pain states have been developed which lead, over a sustained period of time, to reproducible sensory deficits (allodynia, hyperalgesia and spontaneous pain) that can be assessed by sensory examination. By establishing the extent of mechanical, chemical and temperature-induced allodynia and hyperalgesia present, several pathophysiological conditions observed in humans can be mimicked to allow the evaluation of drug therapy.

In a rat model of peripheral nerve injury, ectopic activity in the injured nerve corresponded to behavioral signs of pain. In these models, intravenous administration of a sodium channel blocker and the local anesthetic lidocaine, inhibited ectopic activity and reversed tactile allodynia at concentrations that did not affect general behavioral and motor functions (Mao, J.and Chen, L.L, Pain (2000), 87: 7-17). The measurement of effective doses in these rat models translates to doses that are similarly shown to be effective in humans (Tanelian, D.L.and Brose, W.G., Anesthesiology (1991), 74 (5): 949-. In addition, applied in the form of skin patches Lidocaine, currently an FDA-approved therapeutic drug for post-herpetic neuralgia (Devers, a.andglaler, b.s., clin.j.pain (2000), 16 (3): 205-8).

Sodium channel blockers have clinical uses other than pain. Epilepsy and arrhythmias are often the target of sodium channel blockers. Recent evidence from animal models indicates that sodium channel blockers can also be used for neuroprotection in ischemic states due to stroke or neurotrauma and in patients with Multiple Sclerosis (MS) (Clare, j.j.et al, op.cit. and Anger, t.et al, op.cit.).

The compounds of the present invention modulate, preferably inhibit, ion flux through voltage-gated sodium channels in mammals, especially humans. Any of these modulations, whether they partially or completely inhibit or prevent ion flux, are sometimes referred to herein as "blockades", and the corresponding compounds are referred to as "blockers". In general, the compounds of the invention down-regulate sodium channel activity, inhibit voltage-dependent activity of sodium channels by preventing sodium channel activity such as ion flux and/or reduce or prevent sodium ion flux across cell membranes.

The compounds of the present invention are sodium channel blockers and, therefore, are useful in the treatment of diseases and conditions in humans and other organisms, including all those human diseases and conditions which are a result of aberrant voltage-dependent sodium channel biological activity or which can be ameliorated by modulation of voltage-dependent sodium channel biological activity.

As defined herein, a sodium channel-mediated disease or condition refers to a disease or condition that is ameliorated by modulation of sodium channels and includes, but is not limited to, pain, central nervous disease states such as epilepsy, anxiety, depression, and bipolar disorder; cardiovascular disease states such as arrhythmia, atrial fibrillation, and ventricular fibrillation; neuromuscular conditions such as restless legs syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neurotrauma and multiple sclerosis; and ion channel pathologies such as erythromelalgia and familial rectal pain syndrome.

Sodium channel mediated diseases or conditions also include pain associated with HIV, neuropathy resulting from HIV treatment, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathy secondary to metastatic infiltration, painful obesity, thalamic injury, hypertension, autoimmune diseases, asthma, drug addiction (e.g., opiates, benzodiazepines, amphetamines, cocaine, alcohol, butane inhalation), Alzheimer's disease, dementia, age-related memory impairment, Korsakoff's syndrome, restenosis, urinary dysfunction, incontinence, Parkinson's disease, cerebrovascular ischemia, neurosis, gastrointestinal disease, sickle cell anemia, transplant rejection, heart failure, myocardial infarction, reperfusion injury, intermittent claudication, angina, convulsions, respiratory disorders, cerebral or myocardial ischemia, long-term-QT syndrome, catecholamine-responsive ventricular tachycardia, peripheral vascular disease, peripheral, Ophthalmological diseases, spasticity, spastic paraplegia, myopathy, myasthenia gravis, congenital myotonia, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, baldness, anxiety, psychosis, mania, delusional mania, seasonal affective disorder, panic disorder, Obsessive Compulsive Disorder (OCD), phobias, autism, Aspergers syndrome, Rattes syndrome, breakdown disorders, attention deficit disorder, aggression, impulse control disorders, thrombosis, preeclampsia, congestive heart failure, cardiac arrest, Freidrich's ataxia, spinocerebellar ataxia, myelopathy, radiculopathy, systemic lupus erythematosus, granulomatosis, olive-pontocerebral atrophy, spinocerebellar ataxia, paroxysmal ataxia, muscle twitching, progressive globus atrophy, progressive supranuclear and spastic paralysis, Traumatic brain injury, cerebral edema, hydrocephalus injury, spinal cord injury, anorexia nervosa, bulimia nervosa, Prader-Willi syndrome, obesity, optic neuritis, cataract, retinal hemorrhage, ischemic retinopathy, retinitis pigmentosa, acute and chronic glaucoma, macular degeneration, retinal artery occlusion, chorea, huntington's chorea, cerebral edema, proctitis, postherpetic neuralgia, eudynia, thermal sensitivity, sarcoidosis, irritable bowel syndrome, tics-coprolalia syndrome, lesch-nier syndrome, Brugado syndrome, likle syndrome, crohns disease, multiple sclerosis and pain associated with Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), disseminated sclerosis, diabetic neuropathy, peripheral neuropathy, peroneal atrophy syndrome, arthritis, rheumatoid arthritis, Osteoarthritis, chondroclerotic disorders, atherosclerosis, seizure dyskinesia, myasthenia syndrome, myotonia, myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, psychological disorders, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related disorders, familial erythromelalgia, primary erythromelalgia, rectal pain, cancer, epilepsy, partial and generalized seizures, febrile seizures, absence seizures (petit mal seizures), myoclonic seizures, dystonia seizures, clonic seizures, lin-go syndrome, West syndrome (infantile spasm), multidrug resistant seizures, seizure prevention (anti-seizure), familial mediterranean fever syndrome, gout, restless leg syndrome, arrhythmia, cardiac arrhythmia, Fibromyalgia, neuroprotection in ischemic conditions due to stroke or neurotrauma, tachyarrhythmia, atrial and ventricular fibrillation and as a general or local anaesthetic.

The term "pain" as used herein refers to all kinds of pain and is considered to include, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, glial pain, orofacial pain, causalgia, burning mouth syndrome, somatic pain, visceral pain, musculofacial pain, dental pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, post-surgical pain, labor pain, sympathetic reflex dystrophy, brachial plexus laceration, neurogenic bladder disorder, acute pain (e.g., musculoskeletal and post-surgical pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, familial hemiplegic migraine, conditions associated with headache, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, post-stroke pain, Thalamic injury, radiculopathy, HIV pain, post-herpes zoster pain, non-cardiac chest pain, irritable bowel syndrome and pain associated with bowel disease and dyspepsia, and combinations thereof.

The compounds identified in this patent specification inhibit ion flux through voltage-dependent sodium channels. These compounds are preferably state or frequency dependent modulators of sodium channels, with low affinity for the rest/off state and high affinity for the failure state. Like the other state-dependent sodium channel blockers described (cestele, s.et al., op.cit.), these compounds may interact with overlapping sites located in the lumen of the sodium-conducting pore of the channel. These compounds may also interact with sites outside the lumen and have an allosteric effect on sodium ion conduction through the pore of the channel.

Any of these results may ultimately be responsible for the overall therapeutic benefit provided by these compounds.

The present invention readily provides a number of different ways to identify sodium channel modulators useful as therapeutic agents. Validation of sodium channel modulators can be assessed using a variety of in vitro and in vivo assays, such as measuring current, measuring membrane potential, measuring ion flux (e.g., sodium or guanidinium salts), measuring sodium concentration, measuring second messengers and transcript levels, and using, for example, voltage sensitive dyes, radiotracers, and patch clamp electrophysiology.

One such experimental design involves screening for chemical agents that have the ability to modulate the activity of sodium channels, thereby identifying them as modulators.

Bean et al, j. general physics (1983), 83: 613-: 47-54, using the patch clamp technique to study the behavior of the channel. Such techniques are known to those skilled in the art and can be developed into low or medium throughput assays using current techniques to assess the ability of a compound to modulate sodium channel behavior.

Competitive binding assays using known sodium channel toxins, such as tetrodotoxin, alpha-scorpion toxin, aconitine, BTX, and the like, may be useful for identifying potential therapeutic agents with high selectivity for a particular sodium channel. The use of BTX in these binding assays is well known and is described in McNeal, e.t.et al, j.med.chem. (1985), 28 (3): 381-8 and creating, C.R.et al, Methods in Neuroscience, Vol.8: neurotoxins (Conn PM Ed) (1992), pp.25-37, Academic Press, New York.

These assays can be performed in cells or cell or tissue extracts to express the channel of interest in a native endogenous environment or in a recombinant environment. Assays that can be used include plate assays by measuring surrogate markers such as¹⁴Measuring Na + influx by C-guanidine influx, or using fluorescenceDyes such as FRET-based dyes, and other fluorometric methods to measure cell depolarization, and radiolabel-binding assays using radiolabeled aconitine, BTX, TTX or STX. More direct measurements may be performed by a manual or automated electrophysiology system. Guanidine influx assay is explained in more detail in the biological assay section below.

Throughput of test compounds is an important consideration in selecting screening assays. In some strategies hundreds of thousands of compounds need to be detected, and the use of a low throughput approach is not desirable. But in other cases, a low throughput can satisfactorily identify important differences between a limited number of compounds. Often different assay types must be combined to identify a particular sodium channel modulating compound.

Electrophysiological assays using patch clamp techniques are accepted as the gold standard for the detailed characterization of sodium channel compound interactions and are described in Bean et al, op.cit. and Leuwer, m.etal., op.cit. A manual Low Throughput Screening (LTS) method can compare 2-10 compounds per day; one recently developed automated Medium Throughput Screening (MTS) system has 20-50 patches (i.e., compounds) per day; and a technology from molecular devices, Inc. (Sunnyvale, Calif.) that allows automated High Throughput Screening (HTS) of 1000-3000 membranes (i.e., compounds) per day.

An automated patch clamp system utilizes planar electrode technology to accelerate the rate of drug discovery. The planar electrode enables high resistance, cell adhesion sealing, and stable low noise whole cell recording thereafter, comparable to conventional recording, compared to recording. A suitable instrument is PatchXpress 7000A (Axon Instruments Inc, Union City, Calif.). Various cell lines and culture techniques, including adherent cells as well as cells that grow spontaneously in suspension, are graded in terms of providing sealing success and stability. Immortalized cells (e.g., HEK and CHO) that stably express high levels of the relevant sodium ion channel can be adapted to high density suspension cultures.

Other assays may be selected that allow the researcher to identify compounds that block specific channel states, such as open, closed, or quiescent states, or that block transitions from open to closed, closed to quiescent, or quiescent to open. One skilled in the art will be generally familiar with these assays.

Binding assays can also be used, but these have limited functional value and information content. The design includes binding detection based on conventional radioactive filters, or confocal-based fluorescence systems, available from the company Evotec OAI group (Hamburg, Germany), both of which are HTS.

Radioactive flux assays may also be used. In this assay, the channel is stimulated to open by wortriedin (veratridine) or aconitine and is held in a stable open state by the toxin and recognizes the channel blocker by its ability to prevent ion influx. The assay may use radioactivity²²[Na]And¹⁴[C]guanidine salt ions as a tracer. FlashPlate in Living cells&Cytostar-T plates avoid the separation step and are suitable for HTS. The scintillator plate technology has also advanced this approach to HTS. The information content is reasonably good due to the functionality of the assay.

Yet another format measures membrane potential redistribution using the FLIPR system membrane potential kit (HTS), which is commercially available from Molecular Dynamics (amersham biosciences, a department of amersham biosciences, Piscataway, NJ). This approach is limited to slow down membrane potential changes. The fluorescent background of the compound can create certain problems. The test compound may also directly affect the fluidity of the cell membrane and result in an increase in the intracellular dye concentration. Nevertheless, the amount of information is reasonably good due to the functionality of the assay.

Sodium dyes can be used to measure the rate or amount of sodium ion influx through a channel. Such assays provide a very high amount of information about potential channel blockers. The assay was functional and the Na + influx was measured directly. CoroNa red, SBFI, and/OR sodium green (Molecular Probes, inc. eugene OR) can be used to measure Na influx; all are Na responsive dyes. It can be used in conjunction with a FLIPR instrument. The use of these dyes in screening has not previously 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 a test compound to block Na influx directly. Commercially available HTS systems include VIPR^TMThe II FRET system (a division of the Aurora Biosciences Corporation, San Diego, Calif., Vertex pharmaceuticals) can be used in conjunction with the use of a FRET dye, which is also available from Aurora Biosciences. The assay measures the sub-second response to a change in voltage. No channel function regulator is required. This assay measures depolarization and excessive polarization and provides a ratiometric output for quantification. A somewhat less expensive version of the MTS version of the assay employs FLEXstation^TM(molecular devices Co.) was combined with FRET dyes available from Aurora Biotechnology. Other methods of testing the compounds disclosed herein are also known and available to those skilled in the art.

These results provide the basis for the analysis of the structure-activity relationship (SAR) between the test compound and the sodium channel. Certain substituents on the core structure of the test compound tend to provide more effective inhibitory compounds. SAR analysis is one of the tools currently employed by those skilled in the art to identify preferred embodiments of the compounds of the present invention for use as therapeutic agents.

The modulators so identified are then tested in a variety of in vivo models to determine whether they will alleviate pain, particularly chronic pain or other disease states such as cardiac arrhythmias and epilepsy, with minimal adverse events. The assays described below in the biological assays section can be used to assess the biological activity of the compounds of the invention.

Generally, successful therapeutic agents of the present invention will meet some or all of the following criteria. The oral availability should be at or above 20%. The animal model efficacy is less than about 0.1 microgram to about 100 mg/kg body weight, and the target human dose is 0.1 microgram to about 100 mg/kg body weight, although doses outside this range are acceptable ("mg/kg")"refers to the number of milligrams of compound per kilogram of body mass of the subject being administered). The therapeutic index (or ratio of toxic dose to therapeutic dose) should be greater than 100. Efficacy (with IC)₅₀Values are expressed) should be below 10. mu.M, preferably below 1. mu.M, most preferably below 50 nM. IC (integrated circuit)₅₀("50% inhibitory concentration") is a measure of the amount of compound required to achieve 50% inhibition of ion flux through the sodium channel over a specified period of time in an assay of the invention. In guanidine influx assay, the compounds of the invention have demonstrated IC-50 ranging from less than 1nM to less than 10. mu.M.

In another application of the invention, the compounds of the invention may be used in vitro or in vivo studies, as exemplified reagents for comparison purposes, to find other compounds that may also be useful in the treatment or protection of diseases not otherwise disclosed herein.

Another aspect of the invention relates to Na inhibition in a biological sample or 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 activity comprising administering to a patient, or contacting a biological sample with, a compound of formula I or a composition comprising the compound. The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material from a mammal or extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Na in biological sample_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 inhibition of activity, can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, sodium ion channel studies in biological and pathological phenomena; and comparative evaluation of novel sodium channel inhibitors.

Pharmaceutical compositions and administration of the invention

The invention also relates to pharmaceutical compositions containing the compounds of the invention disclosed herein. In one embodiment, the invention relates to a composition comprising a compound of the invention in a pharmaceutically acceptable carrier in an amount effective to modulate, preferably inhibit, ion flux through voltage-gated sodium channels when administered to an animal, preferably a mammal, most preferably a human patient, to treat a sodium channel mediated disorder, such as pain.

Pharmaceutical compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which comprises any agent that does not itself cause the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol, and ethanol, among others. A thorough discussion of pharmaceutically acceptable carriers, diluents and other excipients is found in REMINGTON's pharmaceutical SCIENCES (Mack pub.co., n.j., current edition).

Those skilled in the art know how to determine the appropriate dosage of a compound for treating the diseases and conditions contemplated herein. Therapeutic doses are generally confirmed by dose ranging studies in humans based on preliminary evidence from animal studies. The dosage must be sufficient to achieve the desired therapeutic benefit without causing unwanted side effects to the patient.

Typical regimens for the treatment of sodium channel mediated diseases include administration of an effective amount over a period of between one or more days up to and including one week to about six months, or may be chronic. It will be appreciated that the dosage of the diagnostic/pharmaceutical compounds or compositions of the invention administered in vivo or in vitro will depend upon the age, sex, health and weight of the recipient, the severity of the symptoms, the type of concurrent therapy (if any), the frequency of therapy, the individual response, and the nature of the diagnostic/pharmaceutical effect desired. The effective dosage ranges provided herein are not intended to be limiting, but rather represent preferred agents Amount ranges. However, as will be understood and appreciated by those skilled in the relevant art, the most preferred dosage will be tailored to the individual patient. (see, e.g., Berkow et al, eds., Merck Manual, 16)^thedition, Merck and co., Rahway, n.j., 1992; goodmanetna, eds., Goodman and Cilman's The Pharmacological Basis of Therapeutics, 10^thedition, Pergamon Press, inc., Elmsford, n.y., (2001); avery's Drug Treatment: principles and Practice of clinical Pharmacology and Therapeutics, 3rd edition, ADIS Press, Williams and Wilkins, Baltimore, MD. (1987), Ebadi, Pharmacology, Little, Brown and Co., Boston (1985); osolci et al, eds., Remington's Pharmaceutical Sciences, 18^thedition, Mack Publishing Co., Easton, Pa (1990); katzung, Basic and Clinical Pharmacology (Basic and Clinical Pharmacology), Appleton and Lange, Norwalk, CT (1992)).

The total dose required for each treatment can be administered in multiple doses or in a single dose over the course of a day, if desired. Typically, treatment is initiated with smaller doses than the optimum dose of the compound. The dose is then increased in small increments until the optimum effect is achieved under the circumstances. Diagnostic pharmaceutical compounds or compositions may be administered alone or in combination with other diagnostic agents and/or medicaments directed against the pathology or against other symptoms of the pathology. An effective amount of a diagnostic pharmaceutical compound or composition of the invention is from about 0.1 microgram to about 100 mg/kg body weight, administered at 4-72 hour intervals over a period of 2 hours to 1 year, and/or any range or value therein, such as 0.0001-0.001, 0.001-0.01, 0.01-0.1, 0.1-1.0, 1.0-10, 5-10, 10-20, 20-50, and 50-100 mg/kg, administered at 1-4, 4-10, 10-16, 16-24, 24-36, 36-48, 48-72 hour intervals over a period of 1-14, 14-28, or 30-44 days or 1-24 weeks, or any range or value therein. The recipient to whom the compounds and/or compositions of the invention are administered may be any vertebrate, such as a mammal. Among mammals, preferred recipients are primates (including humans, apes and monkeys), artiodactyls (including horses, goats, cattle, sheep, pigs), rodents (including mice, rats, homes and hamsters), and carnivores (including cats and dogs). In birds, the preferred recipients are turkeys, chickens, and other members of the same order. Most preferably the recipient is a human.

For topical application, it is preferred to administer an effective amount of the pharmaceutical composition according to the invention to a target area, such as a skin surface, a mucous membrane, etc., adjacent to the peripheral neurons to be treated. This amount will generally range from about 0.0001 mg to about 1 g of a compound of the invention per application, depending on the area to be treated, whether the application is diagnostic, prophylactic or therapeutic, the severity of the symptoms and the nature of the topical carrier employed. Preferred topical formulations are ointments in which from about 0.001 to about 50 mg of active ingredient is applied per cc of ointment base. The pharmaceutical compositions may be formulated as transdermal compositions or transdermal delivery devices ("patches"). These compositions include, for example, backings, active compound reservoirs, control films, liners, and contact adhesives. These transdermal patches may be used to provide continuous pulsatility, or to deliver the compounds of the invention as desired.

The composition may be intended for rectal administration, for example in the form of a suppository which will melt in the rectum and release the drug. Typical suppository formulations will generally comprise the active ingredient together with a binding and/or lubricating agent such as gelatin or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Typical formulations for intramuscular or intrathecal administration include suspensions or solutions of the active substance in oils, or solutions of the active ingredient in oils, for example arachis oil or sesame oil. Typical formulations for intravenous or intrathecal administration include sterile isotonic aqueous solutions containing, for example, the active ingredient in admixture with dextrose or sodium chloride or dextrose and sodium chloride.

The compositions of the present invention may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems include osmotic pump systems and dissolution systems, which contain polymer coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are shown in U.S. patent nos. 3,845,770 and 4,326,525 and p.j.kuzma et al, Regional animal 2 (6): 543 551(1997), the entire contents of which are incorporated herein by reference.

The compositions of the present invention may also be delivered via intranasal delivery systems for topical, systemic, and nasal-to-brain drug therapy. Controlled Particle Dispersion (CPD) is known to those skilled in the art^TMTechniques, conventional nasal spray bottles, inhalers, or nebulizers provide effective local and systemic delivery of drugs by targeting the olfactory region and paranasal sinuses.

The invention also relates to a device suitable for administration to the vaginal endoconch or core of a female human or animal. The device may contain an active pharmaceutical ingredient in a polymer matrix and surrounded by a sheath and which is capable of releasing the compound on a day-by-day basis in a substantially zero order pattern, similar to the design for testosterone administration as described in PCT patent No. WO 98/50016.

Current methods for ocular delivery include topical administration (eyedrops), subconjunctival injection, periocular injection, intravitreal injection, surgical implants, and iontophoresis (which uses small electrical currents to transport ionized drugs into and through body tissues). One skilled in the art can combine the most suitable excipients with the compound to provide safe and effective intraocular administration.

The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining methods of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, appropriate pharmaceutical excipients, and other considerations related to delivering the compounds to a subject in need thereof.

Combination therapy

The compounds of the present invention may be useful in combination with one or more other compounds of the present invention or one or more other therapeutic agents, or as any combination thereof, in the treatment of sodium channel mediated diseases and conditions. For example, the compounds of formula (I) may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including but not limited to:

opiate analgesics such as morphine, heroin, cocaine, oxymorphone, levorphanol, naltrexone, hydrocodone, hydromorphone, meliodide (meripidine), methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;

Non-opiate analgesics such as acetomenifene (acementioniphen), salicylates (e.g., aspirin);

non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenil, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, oxaprozin, phenylbutazone, piroxicam, salicylzine sulfate, sulindac, tolmetin, and chlorobenzoyl dimethylpyrrole acetic acid;

anticonvulsants such as carbamazepine, oxcarbazepine, lamotrigine, pivalate, topiramate, gabapentin and pregabalin;

antidepressants, such as tricyclic antidepressants, such as amitriptyline, chlorpheniramine, desipramine, imipramine and nortriptyline;

COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib;

α -adrenergic agents, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetylamidine, modafinil and 4-amino-6, 7-dimethoxy-2- (5-methanesulfonamido-1, 2, 3, 4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline;

Barbiturate sedatives, such as amobarbital, alprenbital, sec-butyl barbital, butabarbital, cresital, methamphetal, methohexital, pentobarbital, phenobarbital, secobarbital, talbarbital, schilemiral (theomylal), and thiopental;

tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (α R, 9R) -7- [3, 5-bis (trifluoromethyl) benzyl ] -8, 9, 10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1, 4] diazacyclo-cycloocta-tetraeno [2, 1-g ] [1, 7] naphthyridine-6, 13-dione (TAK-637), 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, and 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] methylamino ] -2-phenyl-piperidine (2S, 3S);

coal tar analgesics, especially paracetamol;

5-hydroxytryptamine reuptake inhibitors such as paroxetine, sertraline, norfluoxetine (fluoxetine demethylated metabolite), the metabolite desmethylsertraline, ` 3-fluvoxamine, paroxetine, citalopram, the citalopram metabolite desmethylcitalopram, escitalopram, d, l-phenformin, femoxetine, fluoxetine, cyano-dosulpine, ritoxetine, dapoxetine, nefazodone, cilazalone, trazodone, and fluoxetine;

Norepinephrine (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamide, tomoxetine, mirnserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazineEspecially selective norepinephrine reuptake inhibitors such as reboxetine, especially (S, S) -reboxetine, and venlafaxine, duloxetine neuroleptic sedatives/anxiolytics;

dual 5-hydroxytryptamine-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran, and imipramine;

acetylcholinesterase inhibitors, such as donepezil;

5-HT3 antagonists, such as ondansetron;

metabotropic glutamate receptor (mGluR) antagonists;

local anesthetics such as mexiletine and lidocaine;

corticosteroid hormones, such as dexamethasone;

antiarrhythmic drugs such as mexiletine and phenytoin;

muscarinic antagonists such as tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, tilmicorine and ipratropium;

A cannabinoid;

capsaicin receptor agonists (such as rexinafatin) or antagonists (such as capsicum azone);

sedatives such as glutethimide, meprobamate, methaqualone and dichlofenoxate;

anxiolytics, such as benzodiazepines,

antidepressants, such as mirtazapine,

topical agents (such as lidocaine, caboxacin, and resiniferatoxin);

muscle relaxants, such as benzodiazepine, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, and orfenadine (orphreadine);

an antihistamine or H1 antagonist;

an NMDA receptor antagonist;

5-HT receptor agonists/antagonists;

PDEV inhibitors;

a cholinergic (nicotinic) analgesic;

α -2-ligands;

prostaglandin E2 subtype antagonists;

leukotriene B4 antagonist;

5-lipoxygenase inhibitors; and

5-HT3 antagonists.

Sodium channel mediated diseases and conditions that can be treated and/or prevented using these combinations include, but are not limited to, pain, central and peripheral modulated acute, chronic, neuropathogenic, and other diseases with associated pain, and other central nervous disorders such as epilepsy, anxiety, depression, and bipolar disease; or cardiovascular diseases such as arrhythmia, atrial fibrillation, and ventricular fibrillation; neuromuscular diseases such as restless legs syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neurotrauma and multiple sclerosis; and channel diseases such as erythromelalgia and familial rectal pain syndrome.

As used herein, "combination" refers to any mixture or substitution of one or more compounds of the present invention with one or more other compounds of the present invention or one or more other therapeutic agents. Unless the context clearly dictates otherwise, "combination" may include the simultaneous or sequential delivery of a compound of the invention with one or more therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include a dosage form of a compound of the invention with another therapeutic agent. Unless the context clearly dictates otherwise, "combination" may include the route of administration of a compound of the invention with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include formulation of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

Accessory kit

The invention also provides kits comprising pharmaceutical compositions comprising one or more compounds of the above general formula. The kit also includes instructions for using the pharmaceutical composition to modulate ion channel activity, treat pain, and other uses as disclosed herein. Commercial packages preferably contain one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be an amount sufficient to prepare an intravenous injection. It will be apparent to those of ordinary skill in the art that compounds that are sensitive to light and/or air may require special packaging and/or formulation. For example, packages that are opaque to light and/or sealed from contact with ambient air and/or formulated with suitable coatings or excipients may be used.

Preparation of the Compounds of the invention

The following reaction scheme illustrates a process for preparing a compound of the present invention, i.e., a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the form of its stereoisomers, enantiomers, tautomers or mixtures thereof:

wherein k, j, Q, R¹、R^2a、R^2b、R^2c、R^2d、R^3a、R^3b、R^3cAnd R^3dAre as defined herein.

It will be appreciated that combinations of substituents and/or variables of the formulae depicted in the description below are permissible only if such combinations result in stable compounds.

It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxyl groups include trialkylsilyl or diaralkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for a thiol group include-C (O) -R '(where R' is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed according to standard techniques known to those skilled in the art and as described herein.

The use of protecting Groups is described in detail in Green, T.W.and P.G.M.Wuts, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. The protecting group may also be a polymer resin, such as Wang resin or chlorinated 2-chlorotrityl methane resin.

One skilled in the art will also appreciate that while these protected derivatives of the compounds of the present invention may not be pharmacologically active in themselves, they may be administered to a mammal and then metabolized in the body to form pharmacologically active compounds of the present invention. These derivatives may thus be described as "prodrugs". All prodrugs of the compounds of the present invention are included within the scope of the present invention.

The following reaction scheme illustrates the process for preparing the compounds of the present invention. It will be appreciated that those skilled in the art can prepare these compounds by analogous methods or by methods known to those skilled in the art. It will also be appreciated that the skilled person will be able to manufacture other compounds of general formula (I) not explicitly illustrated below in a similar manner to that described below, using appropriate starting materials and modifying the synthesis parameters as required. In general, the starting materials may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybrid, Matrix Scientific, TCI, and FluoroChem USA, or synthesized according to sources known to those skilled in the art (references such as Smith, M.B. and J.March, Advanced Organic Chemistry: Reactions, Mechanisms, and structures), 5th edition (Wiley, December 2000) or prepared as described herein.

In the following reaction scheme, R¹、R^2a、R^2b、R^2c、R^2d、R^3a、R^3b、R^3cAnd R^3dAre as defined in the specification, unless explicitly defined otherwise. And X is Cl or Br. R¹¹Is an alkyl group.

In general, compounds of general formula (I) of the present invention, wherein Q is-O-, j is 0, and k is 1, can be synthesized according to the general procedure as described in scheme 1 below. The isatin compound of formula (101) is alkylated with a chloro or bromo compound of formula (102) as described below to give the product of formula (103). The phenol compound of formula (104) is treated with a Grignard reagent of formula (105) at low temperature (0 ℃) to form a phenoxymagnesium halide intermediate which is reacted with the ketocarbonyl group of the isatin compound of formula (103) in a solvent such as, but not limited to, dichloromethane or toluene to afford the oxindole of formula (106). Treatment of the compound of formula (106) with a silane, such as triethylsilane, removes the hydroxy group at the C-3 position of the oxindole to provide a compound of formula (107). The compound of formula (107) may also be prepared by reacting a compound of formula (107) with SOCl₂/NEt₃Treating the compound of formula (106) and then reducing the compound with Zn powder. Converting formula (107) intoThe compound is treated with a silyl compound such as, but not limited to, trimethylsilyl chloride to provide a silyl ether intermediate, which is treated with ytterbium (III) trifluoromethanesulfonate and formaldehyde to provide the compound of formula (108). Alternatively, it can be prepared by using bases such as, but not limited to, LiOH, iPr ₂NH, LDA treatment of the compound of formula (107) followed by reaction with formaldehyde gives the compound of formula (108). The intramolecular cyclization reaction is carried out by a Mitsunobu reaction to obtain the compound with the general formula (I) of the invention, wherein Q is-O-, j is 0, and k is 1.

Reaction scheme 1

The following scheme 1.1 illustrates a synthetic scheme of an amide and a heterocyclic compound as a compound of the general formula (I). When R is¹When an ester group is included, a compound such as a compound of formula (109) (wherein A is an alkyl or aralkyl group) can be converted to its corresponding carboxylic acid compound of formula (110) by treating the compound of formula (109) with a base such as, but not limited to, lithium hydroxide, sodium hydroxide or potassium hydroxide in a mixed solvent such as, but not limited to, tetrahydrofuran or methanol and water. The acid compound of formula (110) can be converted to the corresponding acid chloride by treatment with isobutyl chloroformate in the presence of a base such as, but not limited to, N-methylmorpholine, or by treatment with oxalyl chloride in the presence of catalytic amounts of N, N-dimethylformamide in a solvent such as, but not limited to, toluene, dichloromethane or chloroform. The mixed anhydride can be reacted directly with, or the acid chloride can be reacted with, a primary or secondary amine in the presence of a base such as, but not limited to, triethylamine or diisopropylethylamine to form the amide compound of formula (111) as the compound of general formula (I). The carboxylic acid compound of formula (110) may be reacted with an aromatic diamine compound in a solvent such as, but not limited to, toluene to form a benzimidazole compound of formula (111.1) as the compound of general formula (I).

Reaction scheme 1.1

The following reaction scheme 1.2 illustrates a synthetic scheme of an amine compound as a compound of general formula (I). After removal of a Protecting Group (PG) such as, but not limited to, phthalimido or tert-butoxycarbonyl group in compound (112), a primary or secondary amino compound of formula (113) may be formed from compound (112). The reaction of the amino compound of formula (113) with an acid chloride in the presence of a base such as, but not limited to, triethylamine or diisopropylethylamine in a solvent such as, but not limited to, toluene, dichloromethane or chloroform provides an amide compound of formula (114) as a compound of general formula (I). The amino compound of formula (113) is treated with an isocyanate in the presence of a base such as, but not limited to, triethylamine or diisopropylethylamine in a solvent such as, but not limited to, dichloromethane or chloroform to give a urea compound of formula (115) as the compound of general formula (I). Treatment of a primary or secondary amino compound of formula (113) with an aldehyde or ketone in the presence of a reducing agent such as, but not limited to, sodium cyanoborohydride or sodium triacetoxyborohydride in a solvent such as, but not limited to, dichloromethane produces a higher order functionalized amine (116) as the compound of formula (I).

Reaction scheme 1.2

The following reaction scheme 1.3 illustrates a synthetic scheme of an amine compound as a compound of the general formula (I). The protecting group in the compound of formula (117) is removed and the alcohol compound of formula (118) is then oxidized to the aldehyde compound of formula (119) with an oxidizing agent such as, but not limited to, pyritinol dichromate, or Dess-Martin reagent. Similar to the process for converting the compound of formula (113) into the compound of formula (116) as shown in reaction formula 1.2, the amine compound of formula (120) can be obtained as the compound of general formula (I) by reductive amination of the aldehyde compound of formula (119) with a primary or secondary amine.

Reaction scheme 1.3

The following scheme 1.4 illustrates another synthetic method for compounds of general formula (I) wherein multiple R's are introduced¹A group. Compounds of formula (121) can be synthesized by the sequence as shown in scheme 1 above, wherein PG is a protecting group such as, but not limited to, benzhydryl. The protecting group can be removed under high pressure hydrogen, such as 60psi, to form the oxindole compound of formula (122). With a halide reagent XR in the presence of a base such as, but not limited to, sodium hydride, sodium bis (trimethylsilyl) amine, and lithium hydroxide in a solvent such as, but not limited to, N-dimethylformamide, tetrahydrofuran, acetone, or acetonitrile¹(wherein X is chlorine, bromine or iodine) to form the compound of formula (I). Alternatively, a compound of formula (122) is reacted with an alcohol under Mitsunobu reaction conditions in the presence of a phosphine reagent such as, but not limited to, triphenylphosphine, tributylphosphine, or trimethylphosphine, and a diethyl, diisopropyl, or di-tert-butyl nitrogen dicarboxylate in a solvent such as, but not limited to, tetrahydrofuran, ethyl acetate, or dichloromethane to provide a compound of formula (I). Alternatively, treatment of a compound of formula (122) with a base such as, but not limited to, sodium hydride or lithium hydroxide, followed by reaction with an acid chloride or anhydride, or with a sulfonyl chloride reagent, affords the corresponding acyl or sulfonyl group (R) of formula (I), respectively ¹) A compound is provided.

Reaction scheme 1.4

When R of the compound of formula (I)^2a、R^2b、R^2c、R^2d、R^3a、R^3b、R^3cOr R^3dIs bromine or trifluoromethanesulfonic acidWhen the acyloxy group is present, other derivatives can be synthesized as shown in reaction scheme 1.5 and reaction scheme 1.6 below. The bromine compound is treated with diborane in the presence of a palladium catalyst and then successively oxidized with hydrogen peroxide/sodium hydroxide and reacted with trifluoromethanesulfonic anhydride to give the trifluoromethanesulfonate compound. Compounds of formula (123) or (129) (having, for example, R)^2a、R^2b、R^2c、R^2d、R^3a、R^3b、R^3cOr R^3dBromine or trifluoromethylsulfonyloxy) can be reacted with zinc cyanide or tributyltin cyanide and potassium cyanide in the presence of a palladium catalyst such as, but not limited to, palladium acetate or tris (dibenzylideneacetone) dipalladium (0) with a ligand such as, but not limited to, tris (o-tolyl) phosphine, 1' -bis (diphenylphosphino) ferrocene or 2- (di-t-butylphosphino) biphenyl in a solvent such as, but not limited to, N-dimethylformamide or acetonitrile to provide a cyano compound of formula (124) or formula (130) as a compound of general formula (I) (see Marcantonio, k.m., et al, org.lett. (2004), 6: 3723-5 and Yang, c., et al., org.lett. (2004), 6: 2837-40). A compound of formula (123) or formula (129) (having, for example, R)^2a、R^2b、R^2c、R^2d、R^3a、R^3b、R^3cOr R ^3dBromide or trifluoromethylsulfonyloxy) in the presence of a palladium catalyst such as, but not limited to, palladium acetate, tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0), under carbon monoxide pressure in a solvent such as, but not limited to, N-dimethylformamide or acetonitrile, to give an amide compound of formula (125) or formula (131) as a compound of general 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 Ullmann coupling reaction conditions, a compound of formula (123) or formula (129) (having, for example, R)^2a、R^2b、R^2c、R^2d、R^3a、R^3b、R^3cOr R^3dBromo or trifluoromethylsulfonyloxy) can be performed in a copper reagent such as, but not limited to, copper iodide or bromide, a base such as, but not limited to, cesium carbonate or potassium carbonate, an amino acid such as, but not limited to, a salt of cesium carbonate or potassium carbonate, a salt of a carboxylic acid, a salt of aWithout limitation, N, N-dimethylglycine is reacted with a phenolic compound in the presence of a solvent such as, but not limited to, dimethylsulfoxide, dioxane or acetonitrile to form a diaryl ether compound of formula (126) or formula (132) as a compound of general formula (I) (see Sawyer, J.S. tetrahedron (2000), 56: 5045-65 and Ma, D.et., org.Lett. (2003), 5 (21): 3799-802). A compound of formula (123) or formula (129) (having, for example, R) ^2a、R^2b、R^2c、R^2d、R^3a、R^3b、R^3cOr R^3dBromine or trifluoromethylsulfonyloxy) can be reacted with an arylboronic acid in the presence of a palladium catalyst such as, but not limited to, palladium acetate, tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0) with or without a ligand such as, but not limited to, triphenylphosphine, tris (o-tolyl) phosphine, 1' -bis (diphenylphosphino) ferrocene or 2- (di-t-butylphosphino) biphenyl, and a base such as, but not limited to, sodium carbonate, cesium carbonate or sodium bicarbonate, in a solvent such as, but not limited to, ethylene glycol dimethyl ether, dioxane or tetrahydrofuran, to provide a coupling product of formula (127) or formula (133) as a compound of general formula (I) (see Kotha, s, et al, Tetrahedron (2002), 58: 9633 and Miyaura, n., et al., chem.rev. (1995), 95: 2457). A compound of formula (123) or formula (129) (having, for example, R)^2a、R^2b、R^2c、R^2d、R^3a、R^3b、R^3cOr R^3dBromine or trifluoromethylsulfonyloxy) can be reacted with a primary or secondary amine in the presence of a palladium catalyst such as, but not limited to, tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0) with or without a ligand such as, but not limited to, triphenylphosphine, tris (o-tolyl) phosphine, 1' -bis (diphenylphosphino) ferrocene or 2- (di-t-butylphosphino) biphenyl, and a base such as, but not limited to, sodium carbonate, cesium carbonate or sodium t-butoxide, in a solvent such as, but not limited to, dioxane or tetrahydrofuran, to provide an amino compound of formula (128) or formula (134) as a compound of general formula (I) (see Muci, a.r.et al, Topics in Current Chemistry) (2002), 219: 131).

Reaction scheme 1.5

Reaction scheme 1.6

Alternatively, the compounds of general formula (I) of the present invention, wherein Q is — O and k is 1, can be synthesized according to the general procedure as described in scheme 2 below. As described below, the compound of formula (201) is treated with a lithium reagent of formula (202), such as, but not limited to, n-BuLi, at low temperature, and then reacted with the ketocarbonyl group of the isatin compound of formula (103) in a solvent, such as, but not limited to, THF, to give the oxindole of formula (203). The compound of formula (203) is treated with a silane, such as triethylsilane, to remove the hydroxyl group at the C-3 position of the oxindole to provide a compound of formula (204). Can also be prepared by using SOCl₂/NEt₃The compound of formula (203) is treated and then reduced with Zn powder to give the compound of formula (204). Treatment of the compound of formula (204) with a silyl compound such as, but not limited to, trimethylchlorosilane to produce a silyl ether intermediate, with ytterbium (III) trifluoromethanesulfonate and formaldehyde gives the compound of formula (205). Alternatively, it can be prepared by using bases such as, but not limited to, LiOH, iPr₂Treating the compound of formula (204) with NH or LDA, and then reacting with formaldehyde to obtain the compound of formula (205). The compounds of general formula (I) according to the invention are obtained by intramolecular cyclization by the Mitsunobu reaction, wherein Q is-O-and k is 1.

Reaction formula 2

Alternatively, the compound of general formula (I) of the present invention, wherein Q is-O-or-S-and k is 0, can be synthesized according to the general procedure described in the following reaction scheme 3, wherein the compound of general formula (203) is subjected to intramolecular cyclization reaction by Mitsunobu reaction to obtain the compound of general formula (I) of the present invention, wherein Q is-O-or-S-and k is 0.

Reaction formula 3

Alternatively, the compounds of general formula (I) of the present invention, wherein Q is-C (O) -, - (CH) may be synthesized according to the general procedure as described in the following reaction scheme 4₂) -or- (CF)₂) -, and j is 0. The Grignard reagent of formula (401) is reacted with the ketocarbonyl group of the isatin compound of formula (103) in a solvent such as, but not limited to, dichloromethane or toluene as described below to afford the oxindole of formula (402). Treatment of the compound of formula (402) with a silane, such as triethylsilane, removes the hydroxy group at the C-3 position of the oxindole to provide a compound of formula (403). The compound of formula (403) may also be prepared by reacting a compound of formula (403) with SOCl₂/NEt₃Treating the compound of formula (402) and then reducing the compound with Zn powder. Alkylation of the oxindole ring of the compound of formula (403) with the compound of formula (404) affords the compound of formula (405), which is subjected to saponification to yield the carboxylic acid of formula (406). The carboxylic acid is then converted to the acid chloride of formula (407) following procedures known to those skilled in the art. Intramolecular cyclization reactions in the presence of a Lewis acid such as, but not limited to, stannic chloride (IV) produce compounds of general formula (I) of the present invention wherein Q is-C (O) -, and j is 0. Removal of the carbonyl group of the compound of formula (I) using a silane such as triethylsilane or other reagents known to those skilled in the art yields the compounds of formula (I) of the present invention wherein Q is-CH ₂-, and j is 0. The carbonyl group of compound (408) of formula (I) is reacted with a fluorinating agent such as, but not limited to, bis (2-methoxyethyl) aminosulfur trifluoride to form the difluoro compounds of formula (I) of the present invention wherein Q is-CF₂-, and j is 0. Reduction of the carbonyl group of compound (408) of formula (I) with a reducing agent such as, but not limited to, sodium borohydride provides the hydroxy group of formula (I) of the present inventionA compound wherein Q is-CH (OH) -, and j is 0. The alkylated compound of general formula (I) according to the invention is obtained by further alkylating the hydroxy compound of general formula (I) wherein Q is-CH (OR) by methods known to the person skilled in the art⁵) -, and j is 0.

Reaction formula 4

Reaction scheme 4 sequence

Alternatively, the compounds of general formula (I) of the present invention, wherein Q is-O-, j is 0, and k is 1, can be synthesized according to the general procedure as described in the following reaction scheme 5. As described below, the phenol compound of formula (104) is treated with a Grignard reagent of formula (105) at low temperature (0 ℃) to form a phenoxymagnesium halide intermediate, which is reacted with the ketocarbonyl group of the isatin compound of formula (101) in a solvent such as, but not limited to, tetrahydrofuran, dichloromethane or toluene to give the heterocyclic compound of formula (501). The compound of formula (502) can be obtained by treating the compound of formula (501) with a silane such as triethylsilane to remove the hydroxyl group of the heterocyclic compound. The compound of formula (502) may also be prepared by reacting a compound of formula (502) with SOCl ₂/NEt₂Treating the compound of formula (501) and then reducing the compound with Zn powder. Treatment of the compound of formula (502) with a silyl compound such as, but not limited to, trimethylsilyl chloride produces a silyl ether intermediate, which is treated with ytterbium (III) trifluoromethanesulfonate and formaldehyde to provide the compound of formula (503). Alternatively, the compound of formula (503) may be prepared by reaction of a base such as, but not limited to, LiOH, iPr₂NH or LDA treatment of the compound of formula (502), followed by reaction with formaldehyde. The compound of formula (504) is obtained by intramolecular cyclization of the Mitsunobu reaction, which can be alkylated with a chloro or bromo compound of formula (102) to give the compound of general formula (I) of the present invention, wherein Q is-O-, and j is0, and k is 1.

Reaction formula 5

Alternatively, the compounds of general formula (I) of the present invention, wherein Q is-NHC (O) -, and j is 0, can be synthesized according to the general procedure as described in the following reaction scheme 6. Treatment of ketone compound (408) with an azide, such as, but not limited to, sodium azide, in an acid, such as, but not limited to, trifluoroacetic acid, as described below, provides a Schmidt reaction product of general formula (I) of the present invention, wherein Q is-NHC (O) -, and J is 0.

Reaction formula 6

Alternatively, compounds of general formula (I) of the present invention, wherein Q is-C (O) O-, and j is 0, can be synthesized according to the general procedure described in scheme 7 below. As described hereinafter, the compound of formula (701) wherein Q is-C (O) O-, j is 0 is treated with a base such as, but not limited to, lithium hydroxide, sodium hydroxide or potassium hydroxide in a mixed solvent such as, but not limited to, tetrahydrofuran or methanol with water to form the lactone product of general formula (I) of the present invention, which compound of formula (701) is obtainable according to a procedure analogous to the synthesis of the compound of formula (405) as described in scheme 4.

Reaction formula 7

In the following examples relating to the preparation of intermediates for the preparation of compounds of general formula (I), and relating to compounds of general formula (I) below, the compound numbers appearing do not correspond to the compound numbers in the above reaction schemes.

Preparation 1

Synthesis of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

A.Synthesis of 4-bromo-1-pentyl-1H-indole

To a mixture of sodium hydride (2.54g, 66.3mmol, 60% dispersion in mineral oil) in anhydrous N, N-dimethylformamide (50.0mL) was added 4-bromoindole (10.0g, 51.0mmol) at 0 ℃. The reaction mixture was stirred for 0.5h, then 1-bromopentane (9.25g, 61.2mmol) was added at 0 ℃. The reaction mixture was stirred at ambient temperature for 6h and quenched with brine (20.0 mL). The reaction mixture was diluted with water (100mL) and extracted with ether (3X 200 mL). The combined organic layers were washed with brine (100mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. Column chromatography of the residue was performed, eluting with hexane (100%) to give the title compound as a yellow oil (13.3g, 98%):¹H NMR(300MHz，CDCl₃)7.30-7.27(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)136.3，129.2，128.4，122.2，122.1，114.9，108.7，101.3，46.8，29.9，29.1，22.3，13.9。

B.Synthesis of 4-bromo-1-pentyl-1H-indole-2, 3-dione

To a solution of 4-bromo-1-pentyl-1H-indole (25.0g, 93.9mmol) in anhydrous dimethyl sulfoxide (350mL) was added N-bromosuccinimide (50.2g, 282mmol) portionwise over 30 min. The reaction mixture was heated at 60 ℃ for 3h, during which time the internal temperature increased to 120 ℃. After cooling to ambient temperature, the reaction mixture was poured onto ethyl acetate/water (1/1, 600 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3X 500 mL). The combined organic layers were washed with water (3X 500mL),dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo to give the title compound as a yellow solid (25.7g, 92%):¹H NMR(300MHz，CDCl₃)7.38(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)180.9，157.2，152.6，138.4，128.3，121.7，116.3，108.9，40.4，28.9，26.9，22.3，13.9。

synthesis of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

To a solution of 1, 3-benzodioxol-5-ol (12.8g, 92.9mmol) in tetrahydrofuran (200mL) was added a solution of isopropyl magnesium chloride (50.7mL, 101mmol, 2.0M in ether) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5h, during which time a colorless precipitate formed. After removal of the solvent under reduced pressure, the residue was dissolved in dichloromethane (100mL) and added to a solution of 4-bromo-1-pentyl-1H-indole-2, 3-dione (25.0g, 84.5mmol) in dichloromethane (100mL) at 0 ℃ via cannula over 10 min. The reaction mixture was stirred at ambient temperature for 16h, quenched with saturated ammonium chloride solution (100mL), and the organic layer was separated. 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 in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate-hexane to give the title compound as a brown sticky substance (34.9g, 97%): ¹H NMR(300MHz，DMSO-d₆)8.95(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)177.6，152.6，149.1，144.8，141.2，131.7，127.7，127.6，121.0，113.8，108.3，106.7，101.7，101.4，80.540.5，28.8，26.7，22.2，13.9。

D.4-Synthesis of bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

To a solution of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one (34.9g, 80.4mmol) in dichloromethane (100mL) was added trifluoroacetic acid (18.7g, 161mmol) and triethylsilane (18.3g, 161 mmol). The brown solution was stirred at ambient temperature for 3h and concentrated to dryness in vacuo. The residue was diluted with dichloromethane (200mL), washed with saturated ammonium chloride solution (50.0mL), brine (3X 50.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was crystallized from ether to give the title compound as a brown solid (16.5g, 49%):¹H NMR(300MHz，CDCl₃)7.29-7.21(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)177.9，150.9，147.6，145.4，141.6，130.3，127.1，126.8，120.8，113.3，108.0，106.7，101.5，101.2，59.9，48.6，40.7，28.9，26.9，22.3，13.9；MS(ES+)m/z418.3(M+1)，420.3(M+1)。

e.4 Synthesis of bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

To a solution of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one (7.50g, 17.9mmol) in anhydrous dichloromethane (150mL) was added triethylamine (10.9g, 108mmol) and trimethylsilyl chloride (7.80g, 71.8mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2h and diluted with dichloromethane (100 mL). The mixture was washed with water (3 × 50.0mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in THF (150mL) and then formaldehyde solution (4.90mL, 179mmol, 37 wt% in water) and ytterbium (III) trifluoromethanesulfonate (1.11g, 1.79mmol) were added. Will form The mixture was stirred at ambient temperature for 36 h. After removing the solvent under reduced pressure, the residue was diluted with dichloromethane (200mL), washed with saturated sodium bicarbonate (50.0mL), saturated ammonium chloride (50.0mL), 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 as a fluffy solid (6.32g, 79%):¹H NMR(300MHz，CDCl₃)8.28(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)178.1，150.3，147.2，147.2，140.5，129.6，129.2，125.6，118.4，114.8，109.2，106.9，101.0，98.2，62.6，57.6，39.9，28.9，26.7，22.2，13.5。

preparation 2

Synthesis of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

A.1- (2-Cyclopropylethyl) -1H-indole-2, 3-dione Synthesis

To a suspension of sodium hydride (1.61g, 41.9mmol, 60% dispersion in mineral oil) in anhydrous N, N-dimethylformamide (25.0mL) was added isatin (6.17g, 41.9mmol) at 0 ℃. The reaction mixture was stirred for 0.5h, then (2-bromoethyl) cyclopropane (Maercker, A.et al, Justus Liebigs Ann. chem. (1972), 759: 132-157) (9.25g, 61.2mmol) was added. The resulting mixture was stirred at ambient temperature for 16h, and the reaction was quenched with water (50.0 mL). The mixture was extracted with ethyl acetate (3X 100 mL). The combined organic layers were washed with water (3 × 50.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo to give the title compound as a viscous gum (6.50g, 90%): ¹H NMR(300 MHz，CDCl₃)7.57-7.51(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)183.7，158.2，151.2，138.4，125.4，123.6，117.5，110.3，40.3，32.2，8.6，4.3。

Synthesis of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

To a solution of 1, 3-benzodioxol-5-ol (1.25g, 9.06mmol) in THF (20.0mL) was added dropwise a solution of isopropyl magnesium chloride (4.53mL, 9.06mmol, 2.0M in THF) at 0 deg.C over 5 min. The reaction mixture was stirred for 0.5h, during which time a colorless precipitate formed. After removing the solvent under reduced pressure, the residue was dissolved in dichloromethane (20.0mL) and cooled to 0 ℃. A solution of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione (1.77g, 8.23mmol) in dichloromethane (20.0mL) was added to the above solution at 0 ℃. The resulting mixture was stirred at ambient temperature for 16h and the reaction quenched with saturated ammonium chloride solution (30.0 mL). The organic layer was separated and washed with water (3 × 25.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was crystallized from ethyl acetate and ether to give the title compound as a colorless solid (2.22g, 76%):¹H NMR(300MHz，CDCl₃)9.52(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)179.1，152.4，148.8，142.7，141.3，130.3，129.1，126.3，123.7，117.3，109.5，106.9，101.9，101.4，79.3，40.6，32.2，8.6，4.3，4.2；MS(ES+)m/z 337.6(M-17)。

C.Synthesis of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

In the presence of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxanTo a solution of cyclopenten-5-yl) -1, 3-dihydro-2H-indol-2-one (2.22g, 6.27mmol) in dichloromethane (30.0mL) was added trifluoroacetic acid (2.12g, 18.8mmol) and triethylsilane (2.14g, 18.8 mmol). The brown solution was stirred at ambient temperature for 0.5h and concentrated to dryness in vacuo. The residue was diluted with dichloromethane (100mL), washed with water (3 × 50.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (20/80), to give the title compound as a brown solid (1.69g, 80%):¹H NMR(300MHz，CDCl₃)9.21-9.10(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)178.8，151.3，147.6，144.1，141.5，128.7，126.2，123.1，115.2，109.5，109.4，106.5，101.5，101.2，47.4，40.5，32.2，8.6，4.3，4.2；MS(ES+)m/z 338.3(M+1)。

synthesis of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, making the change to replace 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one with 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained (53%): r_f0.28 (EtOAc/hexanes, 1/1).

Preparation 3

Synthesis of ethyl [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl ] acetate

Synthesis of ethyl (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate

Following the procedure as described in preparation 2A, with non-critical changes, substituting ethyl bromoacetate for (2-bromoethyl) cyclopropane, the title compound was obtained as a light yellow powder (79%):¹HNMR(300MHz，CDCl₃)7.64-7.54(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)。

[ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 2B, and making non-critical changes, (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetic acid ethyl ester was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to obtain the title compound (95%):¹H NMR(300MHz，DMSO-d₆)9.08(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/z370.2(M-1)。

[3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 1D, with non-critical changes, [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one gave the title compound as a white powder (84%): ¹H NMR(300MHz，DMSO-d₆)9.37(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/z378.2(M+23)。

[3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, with non-critical changes, [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Ethyl acetate instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one gave the title compound as a white powder:¹H NMR(300MHz，DMSO-d₆)9.03(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/z408.1(M+23)。

preparation 4

Synthesis of methyl 3- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] methyl } benzoate

3- [ (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) methyl]Synthesis of methyl benzoate

Following the procedure as described in preparation 2A, with non-critical changes, methyl 3- (bromomethyl) benzoate was substituted for (2-bromoethyl) cyclopropane to afford the title compound as an orange solid (84%):¹H NMR(300MHz，CDCl₃)7.99-7.95(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)。

3- { [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

Following the procedure as described in preparation 2B, with non-critical changes, 3- [ (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) methyl ]Methyl benzoate instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, the title compound was obtained (96%):¹H NMR(300MHz，CDCl₃)8.65(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)178.7，167.0，151.0，148.5，142.1，141.1，135.7，131.6，130.5，130.1，129.1，129.0，128.4，125.5，123.9，116.7，109.7，106.5，101.3，100.5，78.6，60.6，52.4，43.6；MS(ES+)m/z456.1(M+23)。

3- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

Following the procedure as described in preparation 2C, and making non-critical changes, the title compound was obtained (98%) by replacing 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one with methyl 3- { [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] methyl } benzoate: MS (ES +) M/z 418.2(M + 1).

3- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

Following the procedure as described in preparation 1E, and making non-critical changes, 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was replaced with methyl 3- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] methyl } benzoate to give the title compound as a white powder (81%): MS (ES +) M/z 470.3(M +23), 448.3(M + 1).

Preparation 5

Synthesis of methyl 4- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] methyl } benzoate

A.4- [ (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) methyl]Synthesis of methyl benzoate

Following the procedure as described in preparation 2A, with non-critical changes, methyl 4- (bromomethyl) benzoate was substituted for (2-bromoethyl) cyclopropane to afford the title compound as an orange solid (84%):¹H NMR(300MHz，CDCl₃)8.00(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)。

4- { [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

Following the procedure as described in preparation 2B, and making non-critical changes, methyl 4- [ (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) methyl ] benzoate was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to give the title compound (79%): MS (ES +) M/z 416.1 (M-17).

C.4- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

Following the procedure as described in preparation 2C, and making variations, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-1-yl ] methyl } benzoic acid methyl ester was replaced with 4- { [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] methyl } benzoic acid methyl ester to give the title compound as a solid (98%): MS (ES +) M/z 418.1(M + 1).

4- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

Following the procedure as described in preparation 1E, and making non-critical changes, 4- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] methyl } benzoic acid methyl ester was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (81%): MS (ES +) M/z 448.1(M + 1).

Preparation 6

Synthesis of 2- {3- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] propyl } -1H-isoindole-1, 3(2H) -dione

A.1- [3- (1, 3-diketo-1, 3-dihydro-isoindol-2-yl) -propyl]Synthesis of (E) -1H-indole-2, 3-dione

Following the procedure as described in preparation 2A, with non-critical changes, replacing (2-bromoethyl) cyclopropane with 2- (3-bromopropyl) -1H-isoindole-1, 3(2H) -dione, the title compound was obtained (92%):¹H NMR(300MHz，CDCl₃)7.80-7.79(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-keto-2, 3-dihydro-1H-indol-1-yl ]Synthesis of propyl } -1H-isoindole-1, 3(2H) -dione

Following the procedure as described in preparation 2B, with non-critical changes, 1- [3- (1, 3-diketo-1, 3-dihydro-isoindol-2-yl) -propyl]-1H-indole-2, 3-dione instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, the title compound was obtained (96%):¹H NMR(300MHz，CDCl₃)7.86-7.78(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/z473.4(M-17)。

2- {3- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of propyl } -1H-isoindole-1, 3(2H) -dione

Following the procedure as described in preparation 1D, with non-critical changes, 2- {3- [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Propyl } -1H-isoindole-1, 3(2H) -dione instead of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained (94%):¹H NMR(300MHz，CDCl₃)7.81-7.78(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/z457.0(M+1)。

2- {3- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Synthesis of propyl } -1H-isoindole-1, 3(2H) -dione

Following the procedure as described in preparation 1E, with non-critical changes, 2- {3- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]Propyl } -1H-isoindole-1, 3(2H) -dione instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained as a foamy solid (94%):¹H NMR(300MHz，CDCl₃)9.20(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)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/z487.3(M+1)。

preparation 7

Synthesis of 2- {2- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] ethyl } -1H-isoindole-1, 3(2H) -dione

A.1- [2- (1, 3-diketo-1, 3-dihydro-isoindol-2-yl) -ethyl]Synthesis of (E) -H-indole-2, 3-dione

Following the procedure as described in preparation 2A, and making non-critical changes, substituting 2- (2-bromoethyl) -1H-isoindole-1, 3(2H) -dione for (2-bromoethyl) cyclopropane, the title compound was obtained (75%):¹H NMR(300MHz，CDCl₃)7.85-7.78(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/z321(M+1)，343(M+23)。

b.2- {2- [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl } -1H-isoindole-1, 3(2H) -dione

Following the procedure as described in preparation 2B, with non-critical changes, 1- [2- (1, 3-diketo-1, 3-dihydro-isoindol-2-yl) -ethyl ] -ethyl]-1H-indole-2, 3-dione instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, the title compound was obtained (99%):¹H NMR(300MHz，CD₃OD)7.85-7.68(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/z441(M-17)，458(M+23)。

2- {2- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]Synthesis of ethyl } -1H-isoindole-1, 3(2H) -dione

Following the procedure as described in preparation 1D, with non-critical changes, 2- {2- [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl } -1H-isoindole-1, 3(2H) -dione instead of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained as a white solid (90%):¹H NMR(300MHz，CD³OD)10.15-10.05(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/z443(M +1)。

2- {2- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl } -1H-isoindole-1, 3(2H) -dione

Following the procedure as described in preparation 1E, a modification was made using 2- {2- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl } -1H-isoindole-1, 3(2H) -dione instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained (56%):¹H NMR(300MHz，CD₃OD)9.97(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)。

preparation 8

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

A.1- (Diphenylmethyl) -1H-indole-2, 3-dione Synthesis

Following the procedure as described in preparation 2A, with non-critical changes, replacing (2-bromoethyl) cyclopropane with 1, 1' - (bromomethylene) diphenyl, the title compound was obtained as an orange solid (68%): MS (ES +) M/z 336.4(M + 23).

Synthesis of 1- (benzhydryl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 1- (benzhydryl) -1H-indole-2, 3-dione was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to give the title compound as an off-white powder (99%): MS (ES +) M/z 474.5(M + 23).

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making the change, 1- (benzhydryl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound as an off-white solid (84%): MS (ES +) M/z458.4(M + 23).

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, using 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained (56%): MS (ES +) M/z488.3(M + 23).

Preparation 9

Synthesis of 1- [3- (benzyloxy) propyl ] -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

A.1- [3- (benzyloxy) propyl]Synthesis of (E) -1H-indole-2, 3-dione

Following the procedure as described in preparation 1A, with non-critical changes, substituting isatin for 4-bromoindole and benzyl 3-bromopropyl ether for 1-bromopentane, the title compound was obtained as a light yellow syrup (95%):¹H NMR(300MHz，CDCl₃)7.57-6.92(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]Synthesis of (E) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1C, with non-critical changes, 1- [3- (benzyloxy) propyl]-1H-indole-2, 3-dione instead of 4-bromo-1-pentyl-1H-indole-2, 3-dione, the title compound was obtained (70%): ¹H NMR(300MHz，CDCl₃)9.42(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/z416.3(M-17)，456.3(M+23)。

C.1- [3- (benzyloxy) propyl]Synthesis of (E) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1D, with non-critical changes, 1- [3- (benzyloxy) propyl]-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one instead of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound (92%) was obtained:¹H NMR(300MHz，CDCl₃)7.42-6.95(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]Synthesis of (E) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, replacing 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one with 1- [3- (benzyloxy) propyl ] -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one gives the title compound (93%): MS (ES +) M/z 448.2(M + 1).

Preparation 10

Synthesis of methyl 2- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] methyl } benzoate

2- [ (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) methyl]Synthesis of methyl benzoate

Following the procedure as described in preparation 2A, with non-critical changes, methyl 2- (bromomethyl) benzoate was substituted for (2-bromoethyl) cyclopropane to afford the title compound as a yellow solid (68%):¹H NMR(300MHz，CDCl₃)8.05(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)。

2- { [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

Following the procedure as described in preparation 2B, with non-critical changes, 2- [ (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) methyl]Methyl benzoate instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, the title compound was obtained as a colorless solid (97%):¹H NMR(300MHz，DMSO-d₆)9.29(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)。

2- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

Following the procedure as described in preparation 2C, and carrying outA key modification is the use of 2- { [ 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Methyl } benzoate instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained as a white solid (100%): ¹H NMR(300MHz，DMSO-d₆)9.32(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/z418.2(M+1)。

2- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl } benzoate

2- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]A solution of methyl } benzoate (17.1g, 40.0mmo1) and paraformaldehyde (10.3g, 330mmol) in THF (500mL) was degassed. To this solution was slowly added lithium diisopropylamide solution (45.1mL, 2M solution, 90.0mmol) at-78 ℃. The mixture was stirred at ambient temperature overnight and the reaction quenched with saturated ammonium chloride solution. The mixture was concentrated in vacuo to remove THF, then ethyl acetate (500mL) was added. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was recrystallized from ethyl acetate/hexane to give the title compound (13.7g, 75%):¹H NMR(300MHz，DMSO-d₆)9.20(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)。

preparation 11

Synthesis of [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl ] acetic acid

A.1 Synthesis of 1-pentyl-1H-indole-2, 3-dione

Following the procedure as described in preparation 2A, with non-critical changes, replacing (2-bromoethyl) cyclopropane with 1-bromopentane, the title compound was obtained as an orange solid (85%): ¹H NMR(300MHz，CDCl₃)7.60-7.52(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)。

BSynthesis of 3- (1, 3-benzodioxol-5-yl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one

To a solution of 1-pentyl-1H-indole-2, 3-dione (2.80g, 12.8mmol) in THF (50.0mL) was added slowly 3, 4- (methylenedioxy) phenylmagnesium bromide (14.0mL, 1M in THF, 14.0mmol) at-78 ℃. The mixture was stirred at 0 ℃ for 1h and the reaction quenched with ammonium chloride solution. The mixture was poured into water (150mL) 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 in vacuo. Flash column chromatography of the residue afforded the title compound (3.10g, 71%) as an orange oil:¹H NMR(300MHz，CDCl₃)7.34-7.23(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 3- (1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, replacing 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one with 3- (1, 3-benzodioxol-5-yl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained as an oil (90%):¹H NMR(300MHz，CDCl₃)7.30(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)176.8，148.1，147.2，143.5，130.0，129.4，128.4，125.1，122.9，122.0，108.7，108.6，101.1，51.9，40.4，29.0，27.1，22.3，14.0。

[3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl ] ]Synthesis of methyl acetate

A solution of 3- (1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one (1.00g, 3.10mmol) and methyl bromoacetate (0.44mL, 4.60mmol) in THF (20.0mL) was degassed by bubbling argon for 1H. Sodium hydride (0.19g, 4.60mmol) was added at 0 ℃. The mixture was stirred at 0 ℃ for 1h and the reaction quenched with ammonium chloride solution. The mixture was poured into water (150mL) 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 in vacuo. Flash column chromatography of the residue afforded the title compound (0.94g, 76%) as a colorless oil:¹H NMR(300MHz，CDCl₃)7.30(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)177.8，170.0，147.9，147.0，143.9，133.1，131.3，128.6，124.6，122.3，119.9，108.7，108.1，107.4，101.2，52.8，51.6，41.8，40.4，29.0，26.8，22.3，14.0；MS(ES+)m/z418.1(M+23)，396.1(M+1)。

[3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl ]]Synthesis of acetic acid

In [3- (1, 3-benzodioxan)Cyclopenten-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl]To a solution of methyl acetate (5.90g, 15.0mmol) in THF/water (2/1v/v, 120mL) was added lithium hydroxide monohydrate (1.26g, 28.0 mmol). The mixture was stirred at ambient temperature overnight. Most of the THF was removed under vacuum and water (150mL) was added. The solution was extracted with ethyl acetate/hexane (1/3v/v, 50.0 mL). The aqueous layer was acidified with 1N HCl solution to pH 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 in vacuo to afford the title compound as a white solid (5.00g, 88%): ¹H NMR(300MHz，CDCl₃)7.29(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)178.2，174.0，148.0，147.1，143.4，132.6，131.4，128.7，124.4，122.7，119.8，108.9，108.2，107.2，101.2，52.6，41.5，40.4，29.0，26.6，22.3，14.0；MS(ES+)m/z404.0(M+23)，382.0(M+1)。

Preparation 12

Synthesis of 3- [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl ] propionic acid

3- [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl]Synthesis of methyl propionate

Following the procedure as described in preparation 11D, and making non-critical changes, methyl bromoacetate was replaced with methyl 3-bromopropionate to afford the title compound as a colorless oil (76%):¹H NMR(300MHz，CDCl₃)7.28(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)；¹³CNMR(75MHz，CDCl₃)177.8，173.1，147.9，146.9，143.2，133.5，131.6，128.5，124.9，122.6，120.1，108.7，108.1，107.6，101.1，55.2，51.6，40.2，32.4，29.5，29.1，27.1，22.3，14.0；MS(ES+)m/z410.1(M+1)，432.0(M+23)。

3- [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl]Synthesis of propionic acid

Following the procedure as described in preparation 11E, and making non-critical changes, methyl 3- [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl ] propanoate was used instead of methyl [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl ] acetate to give the title compound as a colourless solid (92%): MS (ES-) M/z394.2 (M-1).

Preparation 13

Synthesis of 3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Synthesis of 3- (4, 5-difluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, substituting 1-pentyl-1H-indole-2, 3-dione for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione and 3, 4-difluorophenol for 1, 3-benzodioxol-5-ol, the title compound was obtained (31%):¹H NMR(300MHz，CDCl₃)9.69-9.65(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/z330(M-17)，370(M+23)。

synthesis of 3- (4, 5-difluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

According to the followingPreparation of the procedure described in 2C, with non-critical changes, replacing 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one with 3- (4, 5-difluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one, gave the title compound (98%):¹H NMR(300MHz，CDCl₃)7.46-7.19(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 3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (4, 5-difluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (96%): MS (ES +) M/z 344(M-17), 384(M + 23).

Preparation 14

Synthesis of 3- (5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Synthesis of 3- (5-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1C, and making non-critical changes, substituting 1-pentyl-1H-indole-2, 3-dione for 4-bromo-1-pentyl-1H-indole-2, 3-dione and 4-fluorophenol for 1, 3-benzodioxol-5-ol, the title compound was obtained (53%):¹H NMR(300MHz，CDCl₃)9.42-9.14(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)。

3- (5-fluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indoleSynthesis of (E) -2-ketones

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

Synthesis of 3- (5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

To a solution of 3- (5-fluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one (2.10g, 6.70mmol) in THF (20.0mL) was added paraformaldehyde (1.76g, 58.8mmol) and lithium diisopropylamide (7.35mL, 2.0M in THF, 14.7mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2h, then ammonium chloride solution (10.0mL) and ethyl acetate (100mL) were added. The organic layer was washed with water and brine, and Na was added ₂SO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo to afford the title compound:¹H NMR(300MHz，CDCl₃)9.55-9.10(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+23)。

preparation 15

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1C, and making non-critical changes, substituting 1-pentyl-1H-indole-2, 3-dione for 4-bromo-1-pentyl-1H-indole-2, 3-dione and 4-bromophenol for 1, 3-benzodioxol-5-ol, the title was obtainedCompound (41%):¹H NMR(300MHz，CDCl₃)9.46-9.25(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 3- (5-bromo-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

To a solution of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one (2.22g, 5.64mmol) in dichloromethane (10.0mL) was added trifluoroacetic acid (1.00mL) and triethylsilane (1.00mL) at ambient temperature. The reaction mixture was stirred at 50 ℃ for 15h and concentrated to dryness in vacuo to afford the title compound: MS (ES +) M/z 374(M +1), 376(M + 1).

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 14C, and making non-critical changes, replacing 3- (5-fluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one with 3- (5-bromo-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES +) M/z 386(M-17), 388(M-17), 426(M +23), 428(M + 23).

Preparation 16

Synthesis of 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Synthesis of 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1C, with non-critical changes, replacing 4-bromo-1H-pentyl-1H-indole-2, 3-dione with 1-pentyl-1H-indole-2, 3-dione and 1, 3-benzodioxol-5-ol with 4-chloro-3-fluorophenol, the title compound was obtained (33%):¹H NMR(300 MHz，CDCl₃)9.80(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 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 15B, and making non-critical changes, 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (99%):¹HNMR(300MHz，CDCl₃)10.0-9.70(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 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (46%): MS (ES +) M/z 360(M-17), 400(M + 23).

Preparation 17

Synthesis of 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Synthesis of 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1C, with non-critical changes, replacing 4-bromo-1H-pentyl-1H-indole-2, 3-dione with 1-pentyl-1H-indole-2, 3-dione and 1, 3-benzodioxol-5-ol with 3-chloro-4-fluorophenol, the title compound was obtained (14%): MS (ES +) M/z346(M-17), 386(M + 23).

Synthesis of 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 15B, and making non-critical changes, 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z 348(M + 1).

Synthesis of 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (50%, two-step total yield): MS (ES +) M/z360(M-17), 400(M + 23).

Preparation 18

Synthesis of 3- (4, 5-dichloro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

A.Synthesis of 3- (4, 5-dichloro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1C, and making non-critical changes, substituting 1-pentyl-1H-indole-2, 3-dione for 4-bromo-1H-indole-2, 3-dione and 3, 4-dichlorophenol for 1, 3-benzodioxol-5-ol, the title compound was obtained (26%):¹H NMR(300MHz，CDCl₃)9.60(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/z363(M-17)，403(M+23)。

synthesis of 3- (4, 5-dichloro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 15B, and making non-critical changes, 3- (4, 5-dichloro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (86%):¹H NMR(300MHz，CDCl₃)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/z348(M+1)。

synthesis of 3- (4, 5-dichloro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (4, 5-dichloro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z 376(M-17), 416(M + 23).

Preparation 19

Synthesis of 3- (hydroxymethyl) -3- [ 2-hydroxy-5- (trifluoromethyl) phenyl ] -1-pentyl-1, 3-dihydro-2H-indol-2-one

A.3-hydroxy-3- [ 2-hydroxy-5- (trifluoromethyl) phenyl]Synthesis of (E) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1C, with non-critical changes, replacing 4-bromo-1-pentyl-1H-indole-2, 3-dione with 1-pentyl-1H-indole-2, 3-dione and 1, 3-benzodioxol-5-ol with α, α, α -trifluorocresol, the title compound was obtained (46%):¹H NMR(300MHz，CDCl₃)9.75(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)。

b.3- [ 2-hydroxy-5- (trifluoromethyl) phenyl]Synthesis of (E) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 15B, and making non-critical changes, 3-hydroxy-3- [ 2-hydroxy-5- (trifluoromethyl) phenyl]-1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained (78%):¹H NMR(300MHz，CDCl₃)8.20-8.00(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)。

3- (hydroxymethyl) -3- [ 2-hydroxy-5- (trifluoromethyl) phenyl]Synthesis of (E) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- [ 2-hydroxy-5- (trifluoromethyl) phenyl ] -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z376(M-17), 416(M + 23).

Preparation 20

Synthesis of 3- (2-hydroxy-4-methoxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

A.3- (5-bromo-2-hydroxy-4-methoxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one synthesis

Following the procedure as described in preparation 1C, and making non-critical changes, 1-pentyl-1H-indole-2, 3-dione was used instead of 4-bromo-1-pentyl-1H-indole-2, 3-dione, and 4-bromo-3-methoxyphenol instead of 1, 3-benzodioxol-5-ol to obtain the title compound (48%):¹H NMR(300MHz，CDCl³)9.85(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/z402(M-17)，404(M-17)，442(M+23)，444(M+23)。

synthesis of 3- (2-hydroxy-4-methylhydrophenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 15B, and making non-critical changes, 3- (5-bromo-2-hydroxy-4-methoxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (83%):¹H NMR(300MHz，CDCl₃)9.78-9.20(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/z326(M+1)。

synthesis of 3- (2-hydroxy-4-methoxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (2-hydroxy-4-methoxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (41%): ¹H NMR(300MHz，CDCl₃)10.79(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/z338(M-17)，378(M+23)。

Preparation 21

Synthesis of ethyl [3- (6-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate

[ 3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 1C, and making non-critical changes, replacing 4-bromo-1-pentyl-1H-indole-2, 3-dione with ethyl (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate and 1, 3-benzodioxol-5-ol with 5-indanol, the title compound was obtained (84%):¹H NMR(300MHz，CDCl₃)8.76(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/z350(M-17)，390(M+23)。

[3- (6-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 15B, and making non-critical changes, with [ 3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one gave the title compound:¹H NMR(300MHz，CDCl₃)8.50-7.90(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/z352(M+1)。

[3- (6-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, [3- (6-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES +) M/z364(M-17), 404(M + 23).

Preparation 22

Synthesis of ethyl [3- (hydroxymethyl) -3- (3-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate

[ 3-hydroxy-3- (3-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 1C, and making non-critical changes, the title compound was obtained (81%) using ethyl (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate instead of 4-bromo-1-pentyl-1H-indole-2, 3-dione and 5, 6, 7, 8-tetrahydronaphthalen-2-ol instead of 1, 3-benzodioxol-5-ol:¹H NMR(300MHz，CDCl₃)8.61(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/z364(M-17)，404(M+23)。

[3- (3-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 15B, and making non-critical changes, with [ 3-hydroxy-3- (3-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one gave the title compound:¹H NMR(300MHz，CDCl₃)7.42-7.32(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/z366(M+1)。

[3- (hydroxymethyl) -3- (3-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, [3- (3-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z378(M-17), 418(M + 23).

Preparation 23

Synthesis of ethyl [ 4-bromo-3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate

Synthesis of ethyl (4-bromo-2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate

Following the procedure as described in preparation 2A, and making non-critical changes, replacing isatin with 4-bromoisatin and (2-bromoethyl) cyclopropane with bromoethyl acetate, the title compound was obtained as a yellow solid (68%):¹H NMR(300MHz，CDCl₃)7.39(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/z312(M+1)，314(M+1)，334(M+23)，336(M+23)。

[ 4-bromo-3- (4, 5-difluoro-2-hydroxyphenyl) -3-hydroxy-2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 2B, and making non-critical changes, substituting ethyl (4-bromo-2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione and 3, 4-difluorophenol for 1, 3-benzodioxol-5-ol, the title compound was obtained as a white solid (42%); MS (ES +) M/z424(M-17), 426(M-17), 464(M +23), 466(M + 23).

[ 4-bromo-3- (4, 5-difluoro-2-hydroxyphenyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Reacting [ 4-bromo-3- (4, 5-difluoro-2-hydroxyphenyl) -3-hydroxy-2-oxo-2, 3-dihydro-1H-indol-1-yl]A mixture of ethyl acetate (0.90g, 2.00mmol), triethylsilane (2.00mL, 12.2mmol) and trifluoroacetic acid (0.94mL, 12.2mmol) was heated at 90 ℃ for two days. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (200mL), washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/3) to give the title compound (0.37g, 43%):¹H NMR(300MHz，CDCl₃)7.35-7.22(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/z426.4(M+1)，428.4(M+1)。

[ 4-bromo-3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, [ 4-bromo-3- (4, 5-difluoro-2-hydroxyphenyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (83%): MS (ES +) M/z456.3(M +1), 458.3(M + 1).

Preparation 24

Synthesis of ethyl [ 4-bromo-3- (6-hydroxy-2, 2-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate

A.6- (benzyloxy) -2, 2-dimethylbenzofuran-3 (2H) -one synthesis

To a solution of 6- (benzyloxy) benzofuran-3 (2H) -one (Adams, J.L., et al., J.Med.Chem. (1996), 39 (26): 5035-46) (1.60g, 6.67mmol) in DMF (50.0mL) was added sodium hydride (0.59g, 14.7mmol) and iodomethane (1.46mL, 23.3mmol) at 0 ℃. The reaction mixture was stirred at ambient temperature for 16h and quenched with saturated ammonium chloride (50.0 mL). The aqueous mixture was extracted with ethyl acetate (3X 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/10) to give the title compound (0.85g, 47%):¹H NMR(300MHz，CDCl₃)7.55(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/z269.5(M+1)。

B.Synthesis of 2, 2-dimethyl-2, 3-dihydrobenzofuran-6-ol

To a solution of 6- (benzyloxy) -2, 2-dimethylbenzofuran-3 (2H) -one (0.85g, 3.20mmol) in methanol (100mL) was added palladium hydroxide (0.22g, 20 wt% loading, 0.32 mmol). The resulting mixture was hydrogenated under 60psi of hydrogen for 16 h. The reaction mixture was filtered through celite, washing with methanol. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.46g, 88%): ¹HNMR(300MHz，CDCl₃)6.92(d，1H)，6.30-6.21(m，2H)，4.77(s，1H)，2.90(s，2H)，1.44(s，6H)。

[ 4-bromo-3-hydroxy-3- (6-hydroxy-2, 2-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 2B, and making non-critical changes, the title compound was obtained by substituting ethyl (4-bromo-2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione and 2, 2-dimethyl-2, 3-dihydrobenzofuran-6-ol for 1, 3-benzodioxol-5-ol: MS (ES +) M/z498.5(M +23), 500.5(M + 23).

[ 4-bromo-3- (6-hydroxy-2, 2-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] -1]Synthesis of ethyl acetate

Reacting [ 4-bromo-3-hydroxy-3- (6-hydroxy-2, 2-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]A mixture of ethyl acetate (1.32g, 2.80mmol), triethylsilane (2.00mL, 12.2mmol) and trifluoroacetic acid (0.94mL, 12.2mmol) in dichloromethane (50.0mL) was stirred at 35 ℃ for 3 h. The mixture was diluted with dichloromethane (100mL), washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/3) to give the title compound (1.04g, 81%): ¹H NMR(300MHz，CDCl³)7.32-7.15(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/z460.5(M+1)，462.5(M+1)。

[ 4-bromo-3- (6-hydroxy-2, 2-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, the title compound was obtained by substituting ethyl [ 4-bromo-3- (6-hydroxy-2, 2-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate for 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one (25%): MS (ES +) M/z490.5(M +1), 492.5(M + 1).

Preparation 25

Synthesis of 3, 3-dimethyl-2, 3-dihydro-1-benzofuran-6-ol

A.4- (benzyloxy) -1-bromo-2- (2-methylpropenyl)Synthesis of oxy) benzene

To a solution of 5- (benzyloxy) -2-bromophenol (Simas, A.B.C., et al, Synthesis (1999): 1017-21) (8.15g, 29.3mmol) in DMF (150mL) was slowly added potassium carbonate (4.46g, 32.2mmol) at 0 ℃. The mixture was stirred at ambient temperature for half an hour, then 3-bromo-2-methylpropene (3.35mL, 32.2mmol) was added at 0 ℃ over a half hour. The mixture was stirred at ambient temperature overnight and the reaction quenched with saturated ammonium chloride (50 mL). The aqueous mixture was extracted with ethyl acetate (3X 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 (10.0g, 94%): ¹H NMR(300MHz，CDCl₃)7.43-7.29(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)159.1，155.6，140.1，136.5，133.1，128.6，128.1，127.5，112.9，107.2，103.3，102.0，72.4，70.3，19.3。

B.Synthesis of 6- (benzyloxy) -3, 3-dimethyl-2, 3-dihydrobenzofuran

To a solution of 4- (benzyloxy) -1-bromo-2- (2-methylallyloxy) benzene (5.00g, 15.1mmol) in benzene (400mL) was added tributyltin hydride (7.42mL, 27.2mmol) and benzoyl peroxide (0.70g, 2.90mmol) at 0 ℃. The resulting mixture was refluxed at 100 ℃ 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 in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/20) to give the title compound (3.48g, 91%): MS (ES +) M/z 255.6(M + 1).

Synthesis of 3, 3-dimethyl-2, 3-dihydro-1-benzofuran-6-ol

To a solution of 6- (benzyloxy) -3, 3-dimethyl-2, 3-dihydrobenzofuran (3.48g, 13.7mmol) in methanol (200mL) was added Pd/C (1.45g), and the mixture was hydrogenated under 40psi of hydrogen overnight. The reaction mixture was filtered through celite, washing with methanol. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/7) to give the title compound (1.66g, 74%): MS (ES +) M/z 165.4(M + 1).

Preparation 26

Synthesis of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Synthesis of 1- (benzhydryl) -3-hydroxy-3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, with non-critical changes, substituting 2, 3-dihydrobenzofuran-5-ol (Alabaster, r.j., et al.; Synthesis (1988), 12: 950-2) for 1, 3-benzodioxol-5-ol and 1- (benzhydryl) -1H-indole-2, 3-dione for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, the title compound was obtained: MS (ES +) M/z472.2(M + 23).

Synthesis of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 1- (benzhydryl) -3-hydroxy-3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z 434.4(M + 1).

Synthesis of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

To a solution of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one (1.01g, 2.30mmol) in THF (50.0mL) was added paraformaldehyde (1.00g, 30.0 mmol). Argon was bubbled through the reaction mixture for 1h, then diisopropylamine (1.00g, 10.0mmol) was added at 0 ℃. The reaction mixture was stirred at ambient temperature for 20h and diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (2 × 50.0mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo to give 0.67g (65%) of the title compound: MS (ES +) M/z 486.4(M + 23).

Preparation 27

Synthesis of 3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -4-methoxy-1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1, 3-dihydro-2H-indol-2-one

A.Synthesis of ethyl 2- (2- (tert-butoxycarbonylamino) -6-methoxyphenyl) -2-ketoacetate

To a solution of tert-butyl 3-methoxyphenylcarbamate (25.6g, 0.11mol) in THF (300mL) was added n-BuLi (0.25mol, 1.6M solution in pentane) at-78 ℃. The resulting solution was stirred at 0 ℃ for 3h and cooled to-78 ℃ again, then diethyl oxalate (20.1g, 0.14mol) was added. The mixture was stirred at-78 ℃ for 45min and at ambient temperature for 1h 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 in vacuo. The residue is subjected to column chromatography to give 3.70g (27% based on the starting material recovered) of the title compound: MS (ES +) M/z 324.3(M + 1).

B.Synthesis of 4-methoxy-1H-indole-2, 3-dione

2- (2- (tert-Butoxycarbonylamino) -6-methoxyphenyl) -2-ketoacetic acid ethyl ester (3.70g, 110mmol) was reacted with 10% H₂SO₄(100mL) the mixture was heated at 100 ℃ for 10 h. After cooling to ambient temperature, the reaction mixture was extracted with ether (3 × 100 mL). The combined ether solutions were washed with water (2 × 50.0mL), dried over sodium sulfate, and filtered. Filtering the filtrateConcentrate to dryness in vacuo. The residue was subjected to column chromatography to give 0.37g (19%) of the title compound: MS (ES +) M/z200.1(M + 23).

C.4-methoxy-1- { [5- (trifluoromethyl) -2-furyl]Synthesis of methyl } -1H-indole-2, 3-dione

Following the procedure as described in preparation 1A, and making non-critical changes, substituting 4-methoxy-1H-indole-2, 3-dione for 4-bromoindole and 2- (bromomethyl) -5- (trifluoromethyl) furan for 1-bromopentane, the title compound was obtained (26%): MS (ES +) M/z 348.2(M + 23).

3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -4-methoxy-1- { [5- (trifluoromethyl) -2-bisfuroyl]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, the title compound was obtained by substituting 4-methoxy-1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1H-indole-2, 3-dione for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione (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]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, the title compound was obtained (86%) using 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -4-methoxy-1- { [5- (trifluoromethyl) -2-bisfuroyl ] methyl } -1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one: MS (ES +) M/z 448.4(M + 1).

3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -4-methoxy-1- { [5- (trifluoromethyl) -2-furyl]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 26C, and making non-critical changes, 3- (6-hydroxy-1, 3-benzodioxol-5-yl) -4-methoxy-1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1, 3-dihydro-2H-indol-2-one was used instead of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (64%): MS (ES +) M/z 500.4(M + 23).

Preparation 28

Synthesis of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

A.Synthesis of 4, 7-dichloro-1-pentyl-1H-indole-2, 3-dione

To a mixture of sodium hydride (0.17g, 6.94mmol, 60% dispersion in mineral oil) in dry N, N-dimethylformamide (5.00mL) was added a solution of 4, 7-dichloro-1H-indole-2, 3-dione (1.00g, 4.60mmol) in N, N-dimethylformamide (5.00mL) at 0 ℃. The brown reaction mixture was stirred for 0.5h, then a solution of 1-bromopentane (0.84g, 5.55mmol) in dry N, N-dimethylformamide (5.00mL) was added. The reaction mixture was stirred at ambient temperature for 16h and poured into moist diethyl ether (30.0 mL). After separating the organic layer, it was washed with water (2 × 20.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The gummy residue was dried under vacuum and the solid was triturated with ether to give the title compound (0.98g, 98%): MS (ES +) M/z 286.2(M + 1).

Synthesis of 4, 7-dichloro-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, substituting 4, 7-dichloro-1-pentyl-1H-indole-2, 3-dione for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, the title compound was obtained (68%) as a white solid:¹H NMR(300MHz，CDCl₃)8.61(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)。

synthesis of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dichloro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 4, 7-dichloro-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (72%) as a white solid:¹H NMR(300MHz，CDCl₃)7.27-7.23(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/z409.2(M+1)。

synthesis of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (94%) as a sticky solid: MS (ES +) M/z 439.3(M + 1).

Preparation 29

Synthesis of ethyl 2- (4-chloro-3- (6-hydroxy-2, 3-dihydrobenzofuran-5-yl) -3- (hydroxymethyl) -2-ketoindolin-1-yl) acetate

A. (4-chloro-2, 3-diketo-2, 3-di-oxo)Synthesis of hydrogen-1H-indol-1-yl) ethyl acetate

Following the procedure as described in preparation 2A, and making non-critical changes, replacing isatin with 4-chloro-1H-indole-2, 3-dione and (2-bromoethyl) cyclopropane with ethyl bromoacetate, the title compound was obtained (95%) as a colorless solid:¹H NMR(300MHz，CDCl₃)7.48(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/z268.6(M+1)。

[ 4-chloro-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 2B, and making non-critical changes, (4-chloro-2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetic acid ethyl ester was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to obtain the title compound (75%) as a white solid:¹H NMR(300MHz，CDCl₃)8.70(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/z387.8(M-17)。

[ 4-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 2C, with non-critical changes, [ 4-chloro-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] -2 ]Ethyl acetate instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one gave the title compound (75%) as a white solid:¹H NMR(300MHz，CDCl₃)7.33-7.27(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/z388.8(M+1)。

[ 4-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, [ 4-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (99%) as a sticky solid: MS (ES +) M/z418.7(M + 1).

Preparation 30

Synthesis of 3-hydroxy-3- [6- (hydroxymethyl) -1, 3-benzodioxol-5-yl ] -1-pentyl-1, 3-dihydro-2H-indol-2-one

To a solution of (6-bromo-1, 3-benzodioxol-5-yl) methanol (Mann, J., et al., J.chem.Soc.Perkin Trans.1 (1984): 2081-8) (1.27g, 5.50mmol) in THF (45.0mL) was added n-BuLi (5.00mL, 2.0M, 10.0mmol) dropwise at-75 ℃. The reaction mixture was stirred at-75 ℃ for 45min, then a solution of 1-pentyl-1H-indole-2, 3-dione (1.00g, 4.60mmol) in THF (20.0mL) was added at-75 ℃. The resulting mixture was stirred at ambient temperature for 12h and the reaction quenched with ammonium chloride solution (5.00 mL). More ethyl acetate and water were added and separated. The organic layer was concentrated to dryness in vacuo. The residue was subjected to column chromatography with 50% EtOAc: hexane elution yielded the title compound (0.29g, 25%) as a solid: ¹H NMR(300MHz，CDCl₃)7.38-7.24(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)177.8，147.4，147.2，142.8，133.5，132.2，131.1，130.1，125.3，123.8，111.4，109.2，108.1，101.5，79.5，64.7，40.4，29.0，26.8，22.3，13.9；MS(ES+)m/z352.1(M-17)。

Preparation 31

Synthesis of ethyl [ 1-hexyl-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-3-yl ] acetate

A.1-hexyl-1H-indole-2, 3-diones Synthesis

Following the procedure as described in preparation 2A, with non-critical changes, substituting N-bromohexane for (2-bromoethyl) cyclopropane, the title compound (90%) was obtained as a viscous gum:¹H NMR(300MHz，CDCl₃)7.58-7.51(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)。

synthesis of 1-hexyl-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, with non-critical changes, 1-hexyl-1H-indole-2, 3-dione instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, the title compound was obtained (53%) as a colorless solid:¹H NMR(300MHz，CDCl₃)9.44(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)179.0，152.3，148.8，142.5，141.3，130.3，129.2，126.1，123.7，117.2，109.5，106.8，101.9，101.4，79.2，40.4，31.3，27.1，26.4，22.4，13.9；MS(ES+)m/z352.5(M-17)。

synthesis of 1-hexyl-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, with non-critical changes, 1-hexyl-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxoleEn-5-yl) -1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one, the title compound (98%) was obtained as a white solid: ¹HNMR(300MHz，CDCl₃)7.38-7.13(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/z354.2(M+1)。

[ 1-hexyl-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -2-keto-2, 3-dihydro-1H-indol-3-yl ]]Synthesis of ethyl acetate

To a solution of diisopropylamine (1.14g, 11.0mmol) in THF (10.0mL) was added n-butyllithium (7.00mL, 11.0mmol, 1.6M solution in hexanes) at-75 deg.C. The resulting mixture was stirred at-75 ℃ for half an hour and slowly added to a solution of 1-hexyl-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one in THF (20.0mL) at-75 ℃. After stirring at-75 ℃ for a further half an hour, ethyl bromoacetate was added. The mixture was stirred at ambient temperature for 18h and the reaction quenched with saturated ammonium 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 ammonium chloride (25.0mL), brine (50.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with 40% EtOAc/hexanes to give the title compound (0.19g, 8%) as an oil: MS (ES +) M/z440.5(M + 1).

Preparation 32

Synthesis of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Synthesis of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

According to the preparation2B, and making non-critical changes, replacing 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione with 4-bromoisatin to give the title compound (95%) as a beige solid:¹H NMR(300MHz，DMSO-d₆)10.40(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)178.0，148.7，147.0，145.8，139.5，131.3，130.8，125.4，118.8，118.4，109.4，108.9，101.0，97.4，76.6；MS(ES+)m/z366.4(M+1)，364.5(M+1)。

synthesis of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1D, and making non-critical changes, 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (95%) as a cream yellow solid: MS (ES +) M/z348.5(M +1), 346.3(M + 1).

Synthesis of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 31D, and making non-critical changes, 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1-hexyl-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one, and paraformaldehyde was used instead of ethyl bromoacetate, the title compound (70%) was obtained as a colorless solid: ¹HNMR(300MHz，DMSO-d₆)9.00(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)177.8，150.4，147.1，146.8，139.8，130.2，129.3，125.8， 117.7，115.8，109.3，107.9，101.2，97.6，63.5，57.4。

Preparation 33

Synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Synthesis of 4-bromo-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, substituting 4-bromoisatin for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione and 2, 3-dihydrobenzofuran-6-ol for 1, 3-benzodioxol-5-ol, the title compound (78%) was obtained as a colorless solid:¹H NMR(300MHz，DMSO-d₆)10.36(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)178.4，160.2，154.0，145.7，131.6，130.7，125.5，125.4，118.9，117.7，116.1，108.8，96.8，76.9，71.8，29.1；MS(ES-)m/z 344.4(M-17)，360.4(M-1)。

synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1D, and making non-critical changes, 4-bromo-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (62%) as a solid: MS (ES +) M/z 346.5(M +1), 348.5(M + 1).

Synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 31D, and making non-critical changes, 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1-hexyl-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one, and paraformaldehyde was used instead of ethyl bromoacetate, the title compound was obtained and used directly for further reactions.

Preparation 34

Synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1, 3-dihydro-2H-indol-2-one

A.Synthesis of 4-bromo-1- (pyridin-2-ylmethyl) -1H-indole-2, 3-dione

To a solution of 4-bromoisatin (8.94g, 39.5mmol) in anhydrous N, N-dimethylformamide (100mL) was added sodium hydride (3.34g, 86.9mmol, 60% dispersion in mineral oil) portionwise at 0 ℃. The brown reaction mixture was stirred for 30min, then a solution of 2- (bromomethyl) pyridine hydrobromide (10.0g, 39.5mmol) in N, N-dimethylformamide neutralized with sodium hydride (1.52g, 39.5mmol, 60% dispersion in mineral oil) was added at 0 ℃. The reaction mixture was stirred for 16h and quenched with water (100 mL). The reaction mixture was extracted with diethyl ether (3X 100mL), and the aqueous layer was extracted with ethyl acetate (3X 100 mL). The combined organic layers were washed with water (5 × 200mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was triturated with ether to give the title compound (10.6g, 85%) as a brown solid: ¹H NMR(300MHz，DMSO-d₆)8.53(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)180.5，157.3，154.2，152.3，149.5，138.4，137.5，128.6，123.3，122.3，121.5，116.4，110.3，45.8。

Synthesis of 4-bromo-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1- (pyridin-2-ylmethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, substituting 4-bromo-1- (pyridin-2-ylmethyl) -1H-indole-2, 3-dione for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione and 2, 3-dihydrobenzofuran-6-ol for 1, 3-benzodioxol-5-ol, the title compound (91%) was obtained as a colorless solid: melting point > 225 ℃;¹H NMR(300MHz，DMSO-d₆)9.29(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)176.9，160.4，156.3，153.8，149.6，146.1，137.5，130.9，130.8，126.5，125.8，123.1，121.5，118.8，117.3，116.4，108.3，96.7，76.6，71.9，45.7，29.1；MS(ES+)m/z455.4(M+1)，437.4(M-17)。

synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1- (pyridin-2-ylmethyl) -1, 3-dihydro-2H-indol-2-one

To a solution of 4-bromo-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1- (pyridin-2-ylmethyl) -1, 3-dihydro-2H-indol-2-one (1.12g, 2.48mmol) in anhydrous dichloromethane (25.0mL) was added triethylamine (1.40mL, 9.91mmol) and SOCl at 0 deg.C₂(0.40mL, 4.96 mmol). The reaction mixture was stirred at 0 ℃ for 2h and quenched with water (30.0 mL). The organic layer was separated, washed with water (3 × 30.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo to give a sticky mass. The residue was dissolved in acetic acid/tetrahydrofuran (3.00mL/22.0mL), and then zinc powder (0.81g, 12.4mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 16 h. After removal of the solid by filtration, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100mL), washed with water (3X 30.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo to afford the title compound (1.50g, 77%) as a sticky material: MS (ES +) M/z 437.3(M + 1).

Synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1- (pyridin-2-ylmethyl) -1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (34%): MS (ES +) M/z 468.4(M + 1).

Preparation 35

Synthesis of 5-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1, 3-dihydro-2H-indol-2-one

A.5-fluoro-1- { [5- (trifluoromethyl) -2-furyl]Synthesis of methyl } -1H-indole-2, 3-dione

Following the procedure as described in preparation 2A, and making non-critical changes, isatin was replaced with 5-fluoroisatin and (2-bromoethyl) cyclopropane with 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound (59%) as a red solid:¹H NMR(300MHz，DMSO-d₆)7.54-7.50(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)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]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, with non-critical changes, 5-fluoro-1- { [5- (trifluoromethyl) -2-furyl]Methyl } -1H-indole-2, 3-dione instead of 1-, (2)2-cyclopropylethyl) -1H-indole-2, 3-dione to give the title compound (66%) as a light yellow solid:¹HNMR(300MHz，DMSO-d₆)9.15(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)176.7，160.57，157.4，154.0，148.6，147.4，140.1(m)，139.6(m)，134.7(d，²J_CF＝29.4Hz)，121.3，119.5，117.7，115.1(d，1JCF＝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/z450.3(M+1)。

c.5-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1- { [5- (trifluoromethyl) -2-furyl]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1D, with non-critical changes, 5-fluoro-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1- { [5- (trifluoromethyl) -2-furyl]Methyl } -1, 3-dihydro-2H-indol-2-one instead of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound (72%) was obtained as a light yellow solid:¹H NMR(300MHz，DMSO-d₆)9.31(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)176.1，160.5，157.4，153.9，150.5，147.5，140.2，139.6，139.1，132.3(d，2JCF＝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/z436.2(M+1)。

d.5-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1- { [5- (trifluoromethyl) -2-furyl]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Reacting 5-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1- { [5- (trifluoromethyl) -2-furyl]A mixture of methyl } -1, 3-dihydro-2H-indol-2-one (3.64g, 8.41mmol), paraformaldehyde (2.52g, 84.1mmol) and lithium hydroxide monohydrate (1.06g, 25.2mmol) in tetrahydrofuran (84.0mL) and water (10.0mL) was stirred at 0 ℃ for 4H. After removal of the solvent in vacuo, the residue was dissolved in ethyl acetate (100mL), washed with 10% aqueous HCl (3 × 25.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (50%) to give the title compound (0.65g, 59%) as a colorless solid: ¹H NMR(300MHz，DMSO-d₆)9.11(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)；¹³CNMR(75MHz，DMSO-d₆)176.1，160.5；MS(ES+)m/z466.2(M+1)，448.2(M-17)。

Preparation 36

Synthesis of tert-butyl- (2-chloromethyl-5-trifluoromethylthiophen-3-yloxy) dimethylsilane

Synthesis of methyl 3-tert-butyldimethylsilyloxy-5-trifluoromethyl-2-thiophenecarboxylate

To a solution of methyl 3-hydroxy-5-trifluoromethyl-2-thiophenecarboxylate (Karp, G.M., et al, Synthesis (2000), 8: 1078-1080) (19.4g, 85.8mmol) in N, N-dimethylformamide (50.0mL) was added imidazole (8.77g, 129mmol) at 0 ℃ followed by tert-butyldimethylsilyl chloride (19.4g, 129 mmol). The reaction mixture was stirred at ambient temperature overnight. More imidazole (7.50g) and tert-butyldimethylsilyl chloride (10.5g) were added. The reaction mixture was stirred for an additional 4h and quenched with water (100 mL). The reaction mixture was extracted with ether (3X 500 mL). The combined organic layers were washed with water (3 × 500mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. Subjecting the residue to column chromatography with ethyl acetateHexanes (1/9) to give the title compound (26.5g, 90%) as a yellow oil:¹H NMR(300MHz，CDCl₃)6.91(s，1H)，3.82(s，3H)，0.21(s，6H)，0.06(s，9H)；¹³C NMR(75MHz，CDCl₃)161.5，155.5，133.7，133.2，123.6(q，¹J_CF＝14.4Hz)，119.8，51.9，25.4，18.2，-4.6。

[3- (tert-butyldimethylsilyloxy) -5-trifluoromethylthiophen-2-yl ]]Methanol synthesis

To a mixture of lithium aluminum hydride (1.67g, 43.9mmol) in anhydrous ether (75.0mL) was added a solution of methyl 3-tert-butyldimethylsilyloxy-5-trifluoromethyl-2-thiophenecarboxylate (10.0g, 29.3mmol) in anhydrous ether (25.0mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30min and quenched by the slow addition of water (50.0 mL). After separating the aqueous layer, the organic layer was washed with saturated ammonium chloride (3X 20.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (1/9), to give the title compound (6.95g, 76%) as a yellow oil: ¹H NMR(300MHz，CDCl₃)6.89(s，1H)，4.68(s，2H)，2.11(br，1H)，0.96(s，9H)，0.88(s， 6H)；¹³C NMR(75MHz，CDCl₃)148.0，127.0，124.0，122.4(q， ¹J_CF＝14.7Hz)，120.5，56.1，25.5，18.1，-4.6。

C. Synthesis of tert-butyl- (2-chloromethyl-5-trifluoromethylthiophen-3-yloxy) dimethylsilane

To a solution of [3- (tert-butyldimethylsilyloxy) -5-trifluoromethylthiophen-2-yl ] methanol in dry dichloromethane (100mL) was added triethylamine (4.05g, 40.0mmol) at 0 ℃ followed by thionyl chloride (2.38g, 20.0 mmol). The reaction mixture was stirred for 30min and quenched with water (50.0 mL). After separation, the organic layer was washed with water (3 × 50.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with hexane, to give the title compound (2.31g, 70%) as a yellow oil, which was used directly.

Preparation 37

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -5-methyl-1, 3-dihydro-2H-indol-2-one

A.1- (Diphenylmethyl) -5-methyl-1H-indole-2, 3-dione Synthesis

Following the procedure as described in preparation 2A, and making non-critical changes, isatin was replaced with 5-methylindolyl and (2-bromoethyl) cyclopropane with 1, 1' - (bromomethylene) diphenyl to give the title compound (74%) as a bright orange solid: ¹H NMR(300MHz，CDCl₃)7.42-7.26(m，11H)，7.09(d，1H)，6.95(s，1H)，6.37(d，1H)，2.24(s，3H)。

Synthesis of 1- (benzhydryl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -5-methyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 1- (benzhydryl) -5-methyl-1H-indole-2, 3-dione was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to give the title compound (92%) as a colorless solid:¹H NMR(300MHz，CDCl₃)9.23(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(br s，1H)，2.28(s，3H)；MS(ES+)m/z 448.4(M-17)。

synthesis of 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -5-methyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 1- (benzhydryl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -5-methyl-1, 3-dihydro-2H-indole-2-The ketone was substituted for 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to give the title compound (84%) as a colorless solid:¹H NMR(300MHz，CDCl₃)7.37-7.25(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/z450.3(M+1)。

synthesis of 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -5-methyl-1, 3-dihydro-2H-indol-2-one

To a solution of 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -5-methyl-1, 3-dihydro-2H-indol-2-one (1.61g, 3.60mmol) and paraformaldehyde (0.43g, 14.6mmol) in dichloromethane (60.0mL) was added diisopropylamine (7.20 mmol). After stirring at ambient temperature for 3h, the reaction was quenched with saturated aqueous ammonium chloride (60.0 mL). The organic layer was separated and washed with water (3 × 100mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (20-60%) to give the title compound (1.07g, 63%) as a colorless solid: ¹H NMR(300MHz，CDCl₃)10.09(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/z480.4(M+1)。

Preparation 38

Synthesis of 3- (hydroxymethyl) -3- (5-hydroxy-2-methyl-1, 3-benzothiazol-6-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Synthesis of 3-hydroxy-3- (5-hydroxy-2-methyl-1, 3-benzothiazol-6-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 1-pentyl-1H-indole-2, 3-dione was used instead1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, and 2-methyl-1, 3-benzothiazol-5-ol instead of 1, 3-benzodioxol-5-ol, the title compound (81%) was obtained as a colorless solid:¹H NMR(300MHz，DMSO-d₆)9.90(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/z383.4(M+1)。

synthesis of 3- (5-hydroxy-2-methyl-1, 3-benzothiazol-6-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

A suspension of 3-hydroxy-3- (5-hydroxy-2-methyl-1, 3-benzothiazol-6-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one (0.50g, 1.31mmol) in hydroiodic acid (10.0mL) was refluxed for 1.5 days. The reaction mixture was concentrated to dryness in vacuo. The residue was used directly in the next step.

Synthesis of 3- (hydroxymethyl) -3- (5-hydroxy-2-methyl-1, 3-benzothiazol-6-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (5-hydroxy-2-methyl-1, 3-benzothiazol-6-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z 367.5(M + 1).

Preparation 39

Synthesis of (5-chloro-1, 3, 4-thiadiazol-2-yl) methanol

To a solution of ethyl 5-chloro-1, 3, 4-thiadiazole-2-carboxylate (0.51g, 2.60mmol) in anhydrous methanol (5.00mL) was added sodium borohydride (0.30g, 7.99mmol) at 0 ℃. The reaction mixture was stirred at ambient temperature for 16h, diluted with acetic acid (3.00mL), and extracted with ethyl acetate (2X 150 mL). The combined organic material was washed with saturated aqueous sodium bicarbonate (3X 25.0mL) and saturatedAqueous sodium chloride (2X 25.0mL) was washed. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo to afford the title compound (0.30g, 75%) as a pale yellow semi-solid:¹H NMR(300MHz，CDCl₃)5.04(s，2H)，2.80(br，1H)；MS(ES+)151.1(M+1)，153.1(M+1)。

preparation 40

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-3, 3-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

A.Synthesis of 1- (benzhydryl) -3-hydroxy-3- (6-hydroxy-3, 3-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 1- (benzhydryl) -1H-indole-2, 3-dione was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, and 3, 3-dimethyl-2, 3-dihydro-1-benzofuran-6-ol was used instead of 1, 3-benzodioxol-5-ol, the title compound was obtained: MS (ES +) M/z478.5(M + 1).

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-3, 3-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 1- (benzhydryl) -3-hydroxy-3- (6-hydroxy-3, 3-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (73%, two-step total yield):¹H NMR(300MHz，CDCl₃)7.38-7.20(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/z426.6(M+1)。

C.synthesis of 1- (benzhydryl) -3- (6-hydroxy-3, 3-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 26C, and making non-critical changes, 1- (benzhydryl) -3- (6-hydroxy-3, 3-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z492.5(M + 1).

Preparation 41

Synthesis of 7-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

A.Synthesis of 7-fluoro-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, substituting 7-fluoro-1H-indole-2, 3-dione for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, the title compound was obtained (80%):¹H NMR(300MHz，DMSO-d₆)10.66(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/z304.5(M+1)。

b.7 Synthesis of fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 7-fluoro-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (100%):¹H NMR(300MHz，DMSO-d₆)10.84(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/z288.5(M+1)。

preparation 42

Synthesis of ethyl [ 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl ] acetate

[ 4-bromo-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 2B, and making non-critical changes, 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione was replaced with ethyl (4-bromo-2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate and 1, 3-benzodioxol-5-ol was replaced with 2, 3-dihydrobenzofuran-6-ol to give the title compound (68%) as a white solid: ¹H NMR(300MHz，CDCl₃)8.66(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/z432.2(M-17)。

[ 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 2C, with non-critical changes, [ 4-bromo-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Ethyl acetate instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one gave the title compound (81%) as a white solid:¹H NMR(CDCl₃，300MHz)7.31-7.19(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/z433.3(M+1)。

[ 4-bromo-3- (6-hydroxy-4-bromo-)2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, [ 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (99%): MS (ES +) M/z463.2(M + 1).

Preparation 43

Synthesis of ethyl [ 5-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl ] acetate

Synthesis of ethyl (5-chloro-2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate

Following the procedure as described in preparation 2A, with non-critical changes, 5-chloro-1H-indole-2, 3-dione instead of isatin and 2-bromoethyl acetate instead of (2-bromoethyl) cyclopropane, the title compound (98%) was obtained as a solid:¹H NMR(300MHz，CDCl³)7.60(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/z268.6(M+1)。

[ 5-chloro-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 1C, and making non-critical changes, the title compound was obtained (85%) as a white solid, substituting ethyl (5-chloro-2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate for 4-bromo-1-pentyl-1H-indole-2, 3-dione and 2, 3-dihydrobenzofuran-6-ol for 1, 3-benzodioxol-5-ol:¹H NMR(300MHz，CDCl₃)8.70(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/z387.8(M-17)。

[ 5-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 1D, with non-critical changes, [ 5-chloro-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound (94%) was obtained as a white solid: ¹H NMR(300MHz，CDCl₃)7.30-7.24(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/z388.8(M+1)。

[ 5-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, [ 5-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (99%): MS (ES +) M/z418.7(M + 1).

Preparation 44

Synthesis of methyl [3- (4-chloro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate

Synthesis of methyl (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetate

Following the procedure as described in preparation 2A, and making non-critical changes, methyl bromoacetate was used instead of (2)-bromoethyl) cyclopropane to give the title compound (72%):¹H NMR(300MHz，CDCl₃)7.64-7.53(m，2H)，7.14(t，1H)，6.77(d，1H)，4.48(s，2H)，3.76(s，3H)；MS(ES+)m/z220.4(M+1)。

[3- (4-chloro-2-hydroxyphenyl) -3-hydroxy-2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of methyl acetate

Following the procedure as described in preparation 1C, and making non-critical changes, (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetic acid methyl ester was used instead of 4-bromo-1-pentyl-1H-indole-2, 3-dione, and 3-chlorophenol was used instead of 1, 3-benzodioxol-5-ol to give the title compound (29%) as a yellow solid: ¹H NMR(300MHz，CDCl₃)9.10(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/z370.5(M+23)，372.4(M+23)。

[3- (4-chloro-2-hydroxyphenyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl acetate

Following the procedure as described in preparation 2C, with non-critical changes, [3- (4-chloro-2-hydroxyphenyl) -3-hydroxy-2-oxo-2, 3-dihydro-1H-indol-1-yl]Methyl acetate instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to give the title compound (83%) as a semi-solid;¹H NMR(300MHz，CDCl₃)7.36(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)。

[3- (4-chloro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of methyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, the title compound was obtained by substituting methyl [3- (4-chloro-2-hydroxyphenyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate for 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one: MS (ES +) M/z 362.5(M +1), 364.5(M + 1).

Preparation 45

Synthesis of ethyl [3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate

[3- (4, 5-difluoro-2-hydroxyphenyl) -3-hydroxy-2-keto-2, 3-dihydro-1H-indol-1-yl ]]Synthesis of ethyl acetate

Following the procedure as described in preparation 2B, and making non-critical changes, (2, 3-diketo-2, 3-dihydro-1H-indol-1-yl) acetic acid ethyl ester was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to obtain the title compound as a brown oil: MS (ES +) M/z 364.3(M +1), 348.5 (M-17).

[3- (4, 5-difluoro-2-hydroxyphenyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl acetate

Following the procedure as described in preparation 2C, with non-critical changes, [3- (4, 5-difluoro-2-hydroxyphenyl) -3-hydroxy-2-oxo-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one gave the title compound (83%) as a pale yellow oil:¹H NMR(300MHz，CDCl₃)7.39(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)。

[3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Synthesis of ethyl acetate

Following the procedure as described in preparation 1E, and making non-critical changes, the title compound was obtained by substituting methyl [3- (4-chloro-2-hydroxyphenyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetate for 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one: MS (ES +) M/z 378.3(M +1), 361.3 (M-17).

Preparation 46

Synthesis of 3- (4-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Synthesis of 3- (4-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1C, and making non-critical changes, replacing 4-bromo-1-pentyl-1H-indole-2, 3-dione with 1-pentyl-1H-indole-2, 3-dione and 1, 3-benzodioxol-5-ol with 3-bromophenol, the title compound (48%) was obtained as a white solid:¹H NMR(300MHz，CDCl₃)9.66(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 3- (4-bromo-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1D, and making non-critical changes, replacing 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one with 3- (4-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound (91%) was obtained as a white powder:¹H NMR(300MHz，CDCl₃)7.40(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)。

3- (4-bromo-2-hydroxyphenyl) -3- (hydroxymethyl)Synthesis of 1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (4-bromo-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound: r _f0.5 (EtOAc/hexanes, 1/4).

Preparation 47

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, substituting isatin for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione and 4-bromophenol for 1, 3-benzodioxol-5-ol, the title compound (71%) was obtained as a yellow solid: MS (ES +) M/z 319.4(M +1), 321.4(M + 1).

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1D, and making non-critical changes, replacing 4-bromo-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one with 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1, 3-dihydro-2H-indol-2-one, the title compound (98%) was obtained as a white powder: MS (ES +) M/z 306.2(M +1), 304.2(M + 1).

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 35D, and making non-critical changes, 3- (5-bromo-2-hydroxyphenyl) -1, 3-dihydro-2H-indol-2-one was used instead of 5-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z 334.2(M +1), 336.2(M + 1).

Preparation 48

Synthesis of 1- (benzhydryl) -3- (hydroxymethyl) -3- [ 2-hydroxy-4- (trifluoromethoxy) phenyl ] -1, 3-dihydro-2H-indol-2-one

1- (Diphenylmethyl) -3-hydroxy-3- [ 2-hydroxy-4- (trifluoromethoxy) phenyl]Synthesis of (E) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, substituting 1- (benzhydryl) -1H-indole-2, 3-dione for 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione and 3- (trifluoromethoxy) phenol for 1, 3-benzodioxol-5-ol, the title compound was obtained (75%): MS (ES +) M/z 514.5(M + 23).

1- (benzhydryl) -3- [ 2-hydroxy-4- (trifluoromethoxy) phenyl]Synthesis of (E) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 1- (benzhydryl) -3-hydroxy-3- [ 2-hydroxy-4- (trifluoromethoxy) phenyl ] -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (82%): MS (ES +) M/z 498.4(M + 23).

C.1- (Diphenylmethyl) -3- (hydroxymethyl) -3- [ 2-hydroxy-4- (trifluoromethoxy) phenyl ]Synthesis of (E) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 1- (benzhydryl) -3- [ 2-hydroxy-4- (trifluoromethoxy) phenyl ] -1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z 488(M-17), 528(M + 23).

Preparation 49

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Synthesis of 1- (benzhydryl) -3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 1, 3-benzodioxol-5-ol was replaced with 2, 3-dihydrobenzofuran-6-ol (Foster et al, j. chem. soc.1948: 2254-2258) and 1- (benzhydryl) -1H-indole-2, 3-dione was replaced with 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to give the title compound (68%) as a white solid: MS (ES +) M/z 450.4(M + 1).

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 1- (benzhydryl) -3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (67%) as a white solid: MS (ES +) M/z 434.3(M + 1).

Synthesis of 1- (benzhydryl) -3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) - (3-hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 26C, and making non-critical changes, 1- (benzhydryl) -3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (45%) as a white solid: MS (ES +) M/z 464.5(M + 1).

Preparation 50

Synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Synthesis of 4-bromo-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 1, 3-benzodioxol-5-ol was replaced with 2, 3-dihydrobenzofuran-6-ol and 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione was replaced with 4-bromo-1H-indole-2, 3-dione to obtain the title compound (78%) as a white solid:¹H NMR(300MHz，DMSO-d₆)10.36(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)178.4，160.2，154.0，145.7，131.6，130.7，125.5，125.4，118.9，117.7，116.1，108.8，96.8，76.9，71.8，29.1；MS(ES-)m/z 344.4(M-17)，360.4(M-1)。

synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 4-bromo-3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (62%) as a white solid: MS (ES +) M/z346.5(M +1), 348.5(M + 1).

Synthesis of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 14C, and making non-critical changes, with 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzopyran-5-yl) -1, 3-dihydro-2H-indol-2-one instead of 3- (5-fluoro-2-hydroxyphenyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained (16%): r _f0.21 (EtOAc/hexanes, 7/3).

Preparation 51

Synthesis of 7-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1, 3-dihydro-2H-indol-2-one

A.7-fluoro-1- { [5- (trifluoromethyl) -2-furyl]Synthesis of methyl } -1H-indole-2, 3-dione

Following the procedure as described in preparation 1A, and making non-critical changes, substituting 7-fluoroisatin for 4-bromoindole and 2- (bromomethyl) -5- (trifluoromethyl) furan for 1-bromopentane, 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]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 7-fluoro-1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1H-indole-2, 3-dione was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to obtain the title compound (75%): MS (ES +) M/z 474.3(M + 23).

C.7-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1- { [5- (trifluoromethyl) -2-furyl]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, the title compound was obtained (65%) using 7-fluoro-3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one: MS (ES +) M/z 436.4(M + 1).

D.7-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1- { [5- (trifluoromethyl) -2-furyl]Synthesis of methyl } -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 26C, and making non-critical changes, 7-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1- { [5- (trifluoromethyl) -2-furyl ] methyl } -1, 3-dihydro-2H-indol-2-one was used instead of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (67%): MS (ES +) M/z 488.4(M + 23).

Preparation 52

Synthesis of 3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Synthesis of 3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, with non-critical changes, replacing 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione with 1-pentyl-1H-indole-2, 3-dione and 1, 3-benzodioxol-5-ol with 2, 3-dihydrobenzofuran-6-ol, the title compound was obtained (90%) as a white powder: MS (ES +) M/z 376.3(M + 23).

Synthesis of 3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 3-hydroxy-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (76%): MS (ES +) M/z338.3(M + 1).

Synthesis of 3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (46%): MS (ES +) M/z 368.3(M +1), 380.4(M + 23).

Preparation 53

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -1- (benzhydryl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -1- (benzhydryl) -3-hydroxy-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 1- (benzhydryl) -1H-indole-2, 3-dione was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione, and 4-bromophenol was used instead of 1, 3-benzodioxol-5-ol, the title compound was obtained (90%) as an orange solid: MS (ES +) M/z 486.2(M +1), 488.2(M + 1).

Synthesis of 3- (5-bromo-2-hydroxyphenyl) -1- (benzhydryl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 15B, and making non-critical changes, 3- (5-bromo-2-hydroxyphenyl) -1- (benzhydryl) -3-hydroxy-1, 3-dihydro-2H-indol-2-one was used instead of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (99%) as a white powder:¹H NMR(300MHz，CDCl₃)7.39-7.20(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 3- (5-bromo-2-hydroxyphenyl) -1- (benzhydryl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 26C, and making non-critical changes, 3- (5-bromo-2-hydroxyphenyl) -1- (benzhydryl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound: MS (ES +) M/z500.4(M +1), 502.4(M + 1).

Preparation 54

Synthesis of 3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

A.1 Synthesis of 1-pentyl-1H-indole-2, 3-dione

Following the procedure as described in preparation 2A, with non-critical changes, replacing (2-bromoethyl) cyclopropane with 1-bromopentane, the title compound was obtained (72%) as a red solid:¹H NMR(300MHz，CDCl₃)7.90(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)183.6，158.1，151.0，138.4，125.3，123.5，117.5，110.2，40.2，28.9，26.9，22.2，13.9。

synthesis of 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2B, and making non-critical changes, 1-pentyl-1H-indole-2, 3-dione was used instead of 1- (2-cyclopropylethyl) -1H-indole-2, 3-dione to give the title compound (47%) as a colorless solid:¹H NMR(300MHz，CDCl₃)9.41(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)178.9，152.2，148.8，142.5，141.3，130.3，129.3，126.1，123.8，117.1，109.5，106.8，101.8，101.4，79.3，40.4，28.9，26.8，22.3，13.9；MS(ES+1)m/z355.5(M+1)。

synthesis of 3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 2C, and making non-critical changes, 3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (81%) as a colorless solid: ¹HNMR(300MHz，CDCl₃)9.67(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)178.8，151.3，147.6，143.9，141.53，128.7，126.4，126.2，123.1，115.3，109.4，106.5，101.5，101.2，47.4，40.5，28.9，26.9，22.3，13.9；MS(ES+)m/z340(M+1)。

Synthesis of 3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one

Following the procedure as described in preparation 1E, and making non-critical changes, 3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (67%):¹H NMR(300MHz，CDCl₃)10.85-10.63(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)180.3，152.6，148.1，143.2，141.3，129.2，129.1，126.2，123.3，112.4，109.6，108.2，101.9，101.3，64.6，59.8，40.6，28.9，26.9，22.2，13.9；MS(ES+)m/z370.1(M+1)。

example 1

Synthesis of 1 '- (2-cyclopropylethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

To a solution of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one (0.92g, 2.51mmol) in dry THF (20.0mL) was added triphenylphosphine (0.82g, 3.13mmol) and diethyl azodicarboxylate (0.55, 3.13mmol) at-78 ℃. The brown reaction solution was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride (50.0 mL). The organic solvent was removed under reduced pressure and the aqueous mixture was extracted with ethyl acetate (3X 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The brown residue was subjected to column chromatography, eluting with ethyl acetate/hexane (5% to 20%, gradient) to give the title compound (0.63g, 72%) which was crystallized from ether to give a colorless solid: melting point is 125-127 ℃; ¹H NMR(300MHz，CDCl₃)7.30-7.25(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)177.4，155.9，148.8，142.6，142.3，132.4，128.8，124.0，123.1，119.5，108.6，103.1，101.5，93.6，80.6，58.2，40.5，32.5，30.8，8.7，4.4；MS(ES+)m/z350.3(M+1)。

Example 1.1

Synthesis of 1 '-pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound (80%) was obtained as a white solid: the melting point is 85-87 ℃;¹H NMR(300MHz，CDCl₃)7.28(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)177.3，155.9，148.8，142.4，142.3，132.5，128.9，123.9，119.6，108.6，103.0，101.5，93.6，80.5，58.2，40.4，29.0，27.1，22.3，14.0；MS(ES+)m/z352(M+1)。

example 1.2

Synthesis of 4 ' -bromo-1 ' -pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained as a colorless solid:¹H NMR(300MHz，CDCl₃)7.16(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)177.1，157.2，149.1，144.6，142.0，130.3，130.1，127.0，120.0，116.5，107.6，102.5，101.5，93.3，77.3，59.6，40.6，29.0，27.0，22.3，14.0；MS(ES+)m/z430(M+1)。

example 1.3

Synthesis of ethyl (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) acetate

Following the procedure as described in example 1, with non-critical changes, [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] -was used]Ethyl acetate instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one gave the title compound as a white powder in 90% yield:¹H NMR(300MHz，DMSO-d₆)7.31-7.26(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)177.3，168.3，155.6，148.8，142.4，142.1，132.0，129.3，124.1，123.7，120.4，109.6，103.3，101.9，93.8，79.8，61.8，57.8，41.8，14.5；MS(ES+)m/z390.2(M+23)。

example 1.4

Synthesis of methyl 2- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoate

Following the procedure as described in example 1, with non-critical changes, 2- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Methyl } benzoate instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 74% yield: the melting point is 166-167 ℃;¹H NMR(300MHz，CDCl₃)8.05(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)177.8，167.5，156.0，148.9，142.4，142.3，137.4，132.8，132.1，131.4，129.0，128.6，127.4，126.5，123.9，123.6，119.4，109.5，103.1，101.5，93.7，80.7，58.4，52.3，42.4；MS(ES+)m/z430.3(M +1)，452.3(M+23)。

example 1.5

Synthesis of methyl 3- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoate

Following the procedure as described in example 1, with non-critical changes, 3- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Methyl } benzoate instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 73% yield;¹H NMR(300MHz，CDCl₃)7.97-7.95(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)177.7，166.6，156.0，149.0，142.4，141.7，136.1，132.2，131.7，130.9，129.2，128.1，124.0，123.7，119.4，109.2，103.1，101.6，93.7，80.5，64.3，58.3，52.3，43.7；MS(ES+)m/z 430(M+1)。

example 1.6

4- [ (2 '-Ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoic acid methyl ester

Following the procedure as described in example 1, with non-critical changes, 4- { [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Methyl } benzoic acid methyl esterInstead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 87% yield:¹H NMR(300MHz，CDCl₃)8.01(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)177.7，166.6，156.0，149.0，142.4，141.8，140.8，132.1，130.3，129.8，129.0127.3，124.1，123.7，119.3，109.2，103.0，102.0，93.7，80.5，58.3，52.2，43.9；MS(ES+)m/z430.1(M+1)。

example 1.7

Synthesis of 1 '- (benzhydryl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound as a white powder in 26% yield: MS (ES +) M/z 462.3(M + 1).

Example 1.8

Synthesis of spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

In 1' - (benzhydryl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a solution of-2 '(1' H) -one (2.10g, 4.70mmol) in EtOAc (100mL) and acetic acid (0.10mL) was added palladium on carbon (1.00 g). The reaction mixture was hydrogenated at 60psi hydrogen at ambient temperature for 5 days and filtered. The filtrate was concentrated to dryness in vacuo. Column chromatography of the residue yielded the title compound (0.87g, 66%) as a white powder: melting point 252 ℃ (decomposition);¹H NMR(300MHz，CDCl₃)10.55(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

Synthesis of 2- [3- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) propyl ] -1H-isoindole-1, 3(2H) -dione

Following the procedure as described in example 1, with non-critical changes, 2- {3- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl is used]Propyl } -1H-isoindole-1, 3(2H) -dione instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 45% yield:¹H NMR(300MHz，CDCl₃)7.83-7.80(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)；¹³CNMR(75MHz，CDCl₃)177.4，168.2，155.9，148.8，142.4，141.9，134.0，132.5，132.0，128.9，124.1，123.4，123.3，119.4，108.4，103.2，101.5，93.6，80.4，58.2，38.0，35.6，26.8；MS(ES+)m/z469.3(M+1)，491.3(M+23)。

example 1.10

Synthesis of 2- [2- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) ethyl ] -1H-isoindole-1, 3(2H) -dione

Following the procedure as described in example 1, with non-critical changes, 2- {2- [3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl was used]Ethyl } -1H-isoindole-1, 3(2H) -dione instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 61% yield:¹H NMR(300MHz，CDCl₃)7.81-7.73(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)；¹³CNMR(75MHz，CDCl₃)178，168.2，156.1，148.7，142.2，141.9，134.1，132.4，131.8，128.7，124.1，123.4，123.3，119.0，107.8，103.7，101.4，93.4，80.9，58.1，39.0，35.6；MS(ES+)m/z455(M+1)，477(M+23)。

example 1.11

Synthesis of 1 '- [3- (benzyloxy) propyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, with non-critical changes, 1- [3- (benzyloxy) propyl ] is used]-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 98% yield as a light yellow slurry:¹H NMR(300MHz，CDCl₃)7.38-6.95(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)177.4，155.9，148.8，142.5，142.2，138.1，132.3，128.9，127.9，127.6，123.9，123.1，119.5，108.7，103.0，101.4，93.6，80.4，73.1，67.4，58.1，37.7，27.9；MS(ES+)m/z430.3(M+1)。

example 1.12

Synthesis of 5, 6-difluoro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 71% yield: melting point of 48-50 deg.C；¹H NMR(300MHz，CDCl₃)7.33(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)176.6，156.8，152.9，149.8，144.2，142.6，131.8，129.4，124.1， 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/z344(M+1)。

Example 1.13

Synthesis of 5-fluoro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 3% yield: ¹H NMR(300MHz，CDCl₃)7.37-7.28(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)176.7，159.4，156.6，132.2，130.1，129.3，124.1，123.4，116.3，110.8，110.5，108.9，80.4，58.4，40.6，29.2，27.3，22.5，14.1；MS(ES+)m/z326(M+1)。

Example 1.14

Synthesis of 5-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (5-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 4% yield:¹H NMR(300MHz，CDCl₃)7.38-7.23(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)176.7，160.1，142.6，132.7，132.1，131.4，129.3，126.5，124.1，123.5，113.1，112.2，108.9，80.3，58.0，40.6，29.2，27.3，22.5，14.2；MS(ES+)m/z386(M+1)，388(M+23)。

example 1.15

Synthesis of 5-chloro-6-fluoro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 80% yield; melting point of 74-76 deg.C;¹H NMR(300MHz，CDCl₃)7.38-7.27(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)176.5，160.6，157.4，142.6，133.9，131.8，129.5，124.6，124.1，123.5，113.1，109.0，100.0，81.2，57.5，40.6，29.2，27.2，22.5，14.1；MS(ES+)m/z360(M+1)。

example 1.16

Synthesis of 6-methoxy-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (2-hydroxy-4-methoxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 99% yield: ¹H NMR(300MHz，CDCl₃)7.30(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)；¹³CNMR(75MHz，CDCl₃)177.4，162.1，161.5，142.5，132.9，128.8，123.9，123.5，123.1，121.0，108.5，107.5，96.6，80.5，57.6，55.6，40.3，29.0，27.1，22.3，14.0；MS(ES+)m/z338(M+1)。

Example 1.17

Synthesis of 6-chloro-5-fluoro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 44% yield:¹H NMR(300MHz，CDCl₃)7.34(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)176.2，156，9，154.8，151.6，142.5，131.5，129.4，128.6，123.7，121.7，121.9，111.2，108.9，80.6，57.9，40.5，29.0，27.1，22.3，14.0；MS(ES+)m/z 360(M+1)。

example 1.18

Synthesis of 1 '-pentyl-5- (trifluoromethyl) spiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, with non-critical changes, 3- (hydroxymethyl) -3- [ 2-hydroxy-5- (trifluoromethyl) phenyl]-1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 27% yield:¹H NMR(300MHz，CDCl₃)7.48(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)176.5，163.3，142.6，131.8，129.8，129.3，127.7，124.1，124.0，123.9，123.6，121.0，110.6，108.9，80.5，57.6，40.5，29.0，27.1，22.3，13.9；MS(ES+)m/z376(M+1)。

example 1.19

Synthesis of 5, 6-dichloro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (4, 5-dichloro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 43% yield. ¹H NMR(300MHz，CDCl₃)7.35(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)176.2，159.9，142.5，133.3，131.5，129.4，124.6，124.5，123.9，123.4，112.4，108.9，80.8，57.5，40.5，29.0，27.1，22.3，14.0；MS(ES+)m/z376(M+1)，378(M+1)。

Example 1.20

1' - (benzhydryl) -5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, 1- (benzhydryl) -3- (6-hydroxy-3, 3-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound: melting point 190-;¹H NMR(300MHz，CDCl₃)7.40-7.26(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)178.1，161.1，161.0，141.8，137.9，137.2，132.8，130.0，128.6，128.5，128.4，128.2，128.0，127.8，123.9，123.1，120.8，116.1，112.1，93.4，85.4，80.4，58.7，57.4，41.3，27.7，27.6；MS(ES+)m/z474.5(M+1)。

example 1.21

5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

In the presence of 1' - (benzhydryl) -5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]To a solution of-2 '(1' H) -one (0.23g, 0.49mmol) in methanol (50.0mL) was added palladium on carbon (0.10 g). The mixture was hydrogenated at 120psi hydrogen and ambient temperature overnight. The reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane) 1/2) to give the title compound (0.10g, 68%): the melting point is 95-100 ℃;¹H NMR(300MHz，CDCl₃)8.74(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)180.4，161.3，161.0，140.3，133.0，130.1，128.8，124.2，123.4，120.0，116.6，110.1，93.4，85.5，80.6，58.3，41.4，27.7，27.6；MS(ES+)m/z308.6(M+1)。

example 1.22

Synthesis of 4 ', 7' -dichloro-1 '-pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

To a solution of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one (0.69g, 1.57mmol) in anhydrous tetrahydrofuran (15.0mL) was added triphenylphosphine (0.54g, 2.04mmol) followed by slow addition of diisopropyl azodicarboxylate (0.41g, 2.04mmol) at 0 ℃. The brown reaction mixture was stirred at ambient temperature for 16 hours and the reaction quenched with ammonium chloride solution (2.00 mL). The organic solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20.0mL), washed with 10% aqueous HCl (10.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. 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 (0.13g, 20%) as a colorless solid: melting point 106-108 ℃;¹H NMR(300MHz，CDCl₃)7.24-7.16(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)；¹³CNMR(75MHz，CDCl₃)177.5，157.0，149.2，142.1，140.0，132.3，131.0，130.2，124.6，116.0，113.8，102.3，101.5，93.3，77.2，58.5，42.1，29.5，28.7，22.3，14.0；MS(ES+)m/z420.4(M+1)。

example 1.23

Synthesis of 4 '-bromospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1.22, and making non-critical changes, using 4-bromo-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one instead of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 71% yield as a colorless solid:¹H NMR(300MHz，DMSO-d₆)10.79(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)178.5，157.0，148.8，144.5，141.9，131.2，130.6，126.1，119.2，117.5，109.8，103.3，101.8，93.3，77.6，59.7；MS(ES-)m/z360.4(M-1)，358.4(M-1)。

example 1.24

4' -bromo-5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

To a solution of 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one (1.80g, 4.80mmol) in anhydrous ethyl acetate (50mL) was added tributylphosphine (1.26g, 1.54mL, 6.24mmol) at 0 ℃ under nitrogen. A solution of di-tert-butyl azodicarboxylate (1.44g, 6.24mmol) in anhydrous ethyl acetate (15.0mL) was added over 10 minutes, the reaction solution was stirred for 2 hours, and then the reaction was quenched with saturated ammonium chloride solution (30.0 mL). After separating the aqueous layer, the organic layer was washed with 10% aqueous HCl (2X 25.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate-hexane (70%) to obtain a solid, which was triturated with ether to give the title compound (0.64g, 37%) as a colorless solid: ¹H NMR(300MHz，DMSO-d₆)10.77(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)178.7，162.2，161.7，144.5，131.1，131.0，126.1，119.8，119.2，119.1，118.3，109.7，92.4，77.6，72.5，59.2，28.8；MS(ES-)m/z358.4(M-1)，356.3(M-1)。

Example 1.25

4 '-bromo-1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1, 3-dihydro-2H-indol-2-one (1.81g, 3.88mmol), triphenylphosphine (2.04g, 7.7 mmol)7mmol) and diisopropyl azodicarboxylate (1.57g, 7.77mmol) in anhydrous dioxane (60mL) were heated at reflux for 16 h. After cooling to ambient temperature, the solvent was removed in vacuo. The gummy residue was diluted with ethyl acetate (50.0mL), washed with water (3 × 25.0mL), brine (3 × 25.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (80%) to give the title compound (0.64g, 37%) as a colorless solid: melting point is more than 200 ℃;¹HNMR(300MHz，DMSO-d₆)8.47(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)177.4，162.2，161.8，155.3，149.8，145.3，137.6，131.0，130.5，126.8，123.3，122.2，119.9，119.5，119.0，118.1，109.3，92.4，77.5，72.5，58.8，45.3，28.8；MS(ES+)m/z451.3(M+1)。

example 1.26

Synthesis of 5 ' -fluoro-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

From 5-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1- { [5- (trifluoromethyl) -2-furyl ]To a solution of methyl } -1, 3-dihydro-2H-indol-2-one (3.34g, 7.18mmol) in anhydrous tetrahydrofuran (80.0mL) was added tributylphosphine (2.18g, 2.70mL, 10.8mmol) under nitrogen. Over 10 minutes, a solution of di-tert-butyl azodicarboxylate (2.49g, 10.8mmol) in dry tetrahydrofuran (25.0mL) was added. The reaction solution was stirred for 1 hourThe reaction was quenched with saturated ammonium chloride (30.0 mL). After removing the solvent under reduced pressure, the sticky material was extracted with ethyl acetate (3X 75.0 mL). The organic layer was washed with 10% aqueous HCl (2X 25.0mL), saturated aqueous sodium bicarbonate (3X 25.0mL), brine (3X 25.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (30%) to obtain the title compound (1.10g, 34%) as a colorless solid: melting point 139-141 ℃;¹H NMR(300MHz，CDCl₃)7.02-6.96 (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)176.9，161.5，158.3，155.9，151.7，149.2，142.6，137.1，137.1，133.7，118.6，115.6，115.3，112.7，112.4，112.0，109.7，109.6，109.4，102.8，101.7，93.8，80.1，58.6，37.1；MS(ES+)m/z448.2(M+1)。

example 1.27

Synthesis of 1 ' - (benzhydryl) -5 ' -methyl spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

To a solution of 1- (benzhydryl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -5-methyl-1, 3-dihydro-2H-indol-2-one (1.31g, 2.72mmol) in ethyl acetate (50.0mL) was added tributylphosphine (0.82g, 4.07 mmol). A solution of di-tert-butyl azodicarboxylate (0.94g, 4.07mmol) in ethyl acetate (45.0mL) was added to the reaction mixture over 5 minutes. After stirring for 10 minutes in N ₂Next, the reaction was quenched with saturated aqueous ammonium chloride (60.0 mL). The organic layer was separated and washed with 1.0N hydrochloric acid solution (3X 100mL) and sulfuric acidSodium was dried and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (10-50%) to give the title compound (0.98g, 78% yield):¹H NMR(300MHz，CDCl₃)7.40-7.25(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

Synthesis of 5 '-methyl spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Continuously adding 1 '- (benzhydryl) -5' -methyl spiro [ furo [2, 3-f ] into a stainless steel hydrogenation container][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one (0.90g, 1.95mmol), glacial acetic acid (50.0mL) and palladium hydroxide (0.10g, 1.35mmol, 20 wt% on carbon). The vessel was flushed with nitrogen, sealed, then heated to 60 ℃ and placed at 120psi H₂The following steps. After stirring for 4 days, the reaction mixture was diluted with ethyl acetate and passed through a bed of celite. The filtrate was washed with water (6 × 100mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (40-50%) to give the title compound (0.25g, 43%): melting point 269-271 deg.C; ¹H NMR(300MHz，DMSO-d₆)10.45(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/z296.28(M+1)。

Example 1.29

Synthesis of 5 ' -methyl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

To a suspension of sodium hydride (0.03g, 0.63mmol, 60% dispersion in mineral oil) in N, N-dimethylformamide (5.00mL) was slowly added 5' -methylspiro [ furo [2, 3-f ] at 0 deg.C][1，3]Benzodioxole-7, 3' -indoles]-a solution of 2 '(1' H) -one (0.10g, 0.33mmol) in N, N-dimethylformamide (5.00 mL). After stirring at 0 ℃ for 15 minutes, a solution of 2- (bromomethyl) -5- (trifluoromethyl) furan (0.11g, 0.49mmol) in N, N-dimethylformamide (40.0mL) was added. The resulting mixture was stirred at ambient temperature for 4 hours and the reaction quenched with water (20.0 mL). The mixture was extracted with ethyl acetate (3X 25.0 mL). The combined organic layers were washed with water (50.0mL) and brine (2X 25.0mL), 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 (0.11g, 77% yield): the melting point is 96-98 ℃;¹HNMR(300MHz，CDCl₃)7.09(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/z444.2(M+1)。

example 1.30

Synthesis of 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1.22, and making non-critical changes, using 3- (4-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 82% yield as a colorless solid:¹H NMR(300MHz，CDCl₃)7.33(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)176.6，161.6，142.5，132.1，129.1，128.4，124.4，123.9，123.3，122.8，114.1，108.8，80.4，57.6，40.4，29.0，27.1，22.3，14.0；MS(ES+)m/z386.3(M+1)，388.3(M+1)。

example 1.31

Synthesis of 5-bromo-1 '- (benzhydryl) spiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (5-bromo-2-hydroxyphenyl) -1- (benzhydryl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound (72%) was obtained as a white solid:¹HNMR(300MHz，CDCl₃)7.43-7.25(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/z484.4(M+1)，482.4(M+1)。

example 1.32

Synthesis of 2-methyl-1 '-pentylspiro [ furo [2, 3-f ] [1, 3] benzothiazol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1.22, and making non-critical changes, using 3- (hydroxymethyl) -3- (5-hydroxy-2-methyl-1, 3-benzothiazol-6-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound (50%) was obtained as a white solid: melting point 105-; ¹H NMR(300MHz，CDCl₃)7.59(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)；¹³CNMR(75MHz，CDCl₃)176.7，169.2，160.2，149.2，142.7，138.3，132.7，129.0，128.6，123.5，122.7，122.1，120.2，108.6，108.3，80.1，58.1，40.7，29.1，27.0，22.5，20.2，14.1；MS(ES+)m/z 379.5(M+1)。

Example 1.33

Synthesis of 5-bromo-1 '- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1.22, and making non-critical changes, 3- (hydroxymethyl) -3- (5-hydroxy-2-methyl-1, 3-benzothiazol-6-yl) -1-pentyl-1, 3-dihydro-2H-indol-2-one was used instead of 4, 7-dichloro-3- (6-hydroxy-2-ol)1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one to obtain the title compound (30%) as a white solid: melting point 143-145 ℃;¹H NMR(300MHz，CDCl₃)7.35-7.27(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/z464.2(M+1)，466.2(M+1)。

example 1.34

Synthesis of 5-bromospiro [ 1-benzofuran-3, 3 ' -indole ] -2 ' (1 ' H) -one

Following the procedure as described in example 1, and making non-critical changes, using 3- (5-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound (25%) was obtained as a white solid: melting point 225-;¹H NMR(300MHz，CDCl₃)10.65(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 '- (benzhydryl) -6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

In 1- (benzhydryl) ) -3- (hydroxymethyl) -3- [ 2-hydroxy-4- (trifluoromethoxy) phenyl]To a solution of-1, 3-dihydro-2H-indol-2-one (17.3mmol) in anhydrous THF (200mL) was added triphenylphosphine (6.34g, 24.2mmol) followed by diethyl azodicarboxylate (4.39mL, 24.2mmol) at 0 ℃. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonium chloride (40.0 mL). The aqueous mixture was extracted with ethyl acetate (3X 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 (6.00g, 71%):¹H NMR(300MHz，CDCl₃)7.45-6.51(m，18H)，5.08(d，1H)，4.81(d，1H)；MS(ES+)m/z488(M+1)。

example 1.36

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

In 1 '- (diphenylmethyl) -6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indole]To a suspension of-2 '(1' H) -one (6.00g, 12.3mmol) in methanol (100mL) and acetic acid (1.00mL) was added 10% palladium on carbon (0.65g, 0.62mmol) and the mixture was hydrogenated at 130psi hydrogen at ambient temperature for 5 days. The reaction mixture was filtered over celite, and the filtrate was concentrated to dryness in vacuo. The residue was subjected to flash chromatography, eluting with 30% ethyl acetate in hexanes to give the title compound (2.95g, 75%) as a white solid: melting point 180-; ¹H NMR(300MHz，CDCl₃)9.19(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)179.9，161.9，150.6，132.3，129.4，127.4，125.6，124.3，124.2，123.8，120.5，114.1，110.7， 104.3，80.8，58.2；MS(ES+)m/z 322(M+1)。

Example 1.37

Synthesis of ethyl (4 '-bromo-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) acetate

Following the procedure as described in example 1.22, and making non-critical changes, using [ 4-bromo-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester instead of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound (41%) was obtained as a colorless solid: MS (ES +) M/z 445.5(M + 1).

Example 1.38

Synthesis of ethyl (4 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) acetate

Following the procedure as described in example 1.22, and making non-critical changes, using [ 4-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester instead of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 63% yield as a colorless solid: MS (ES +) M/z 400.8(M + 1).

Example 1.39

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

Following the procedure as described in example 1, with non-critical changes, using [ 4-bromo-3- (6-hydroxy-2, 2-dimethyl-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one gave the title compound in 52% yield:¹H NMR(300MHz，CDCl₃)7.22-7.10(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 ' -ketospiro [ 1-benzofuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) acetate

Following the procedure as described in example 1, and making non-critical changes, [ 4-bromo-3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester was used instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound in 81% yield: MS (ES +) M/z438.4(M +1), 440.4(M + 1).

Example 1.41

Synthesis of ethyl (5 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) acetate

Following the procedure as described in example 1.22, and making non-critical changes, using [ 5-chloro-3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl ] acetic acid ethyl ester instead of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the title compound was obtained in 90% yield as a colorless solid: MS (ES +) M/z 400.8(M + 1).

Example 1.42

Synthesis of 7 '-fluorospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

A solution of 7-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -1, 3-dihydro-2H-indol-2-one (2.00g, 7.00mmol) and paraformaldehyde (2.10g, 61.0mmol) in THF (50mL) was degassed by bubbling argon for 1 hour, then lithium diisopropylamide (48.8mL, a 0.50M solution as prepared) was slowly added at-78 deg.C,25 mmol). The mixture was stirred at ambient temperature overnight and the reaction quenched with saturated ammonium chloride (50.0 mL). The mixture was extracted with ethyl acetate (3X 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in anhydrous ethyl acetate (50mL) and tributylphosphine (2.10mL, 8.00mmol) and di-tert-butyl azodicarboxylate (1.90g, 8.00mmol) were added at 0 ℃. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonium chloride (30.0 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in methanol (70.0mL), and then a saturated sodium bicarbonate solution (30.0mL) was added. The resulting mixture was refluxed at 100 ℃ for 1 hour. After cooling to ambient temperature, the mixture was extracted with ethyl acetate (3 × 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.27g, 17%): ¹H NMR(300MHz，DMSO-d₆)11.06(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 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1 '(2' H) -yl) acetate

Following the procedure as described in example 1.22, with non-critical changes, using [3- (4-chloro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Methyl acetate instead of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one, the titled compound was obtainedCompound, 74% yield, as colorless solid:¹H NMR(300MHz，CDCl₃)7.29(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/z344.5(M+1)，346.5(M+1)。

example 1.44

Synthesis of ethyl (5, 6-difluoro-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1 '(2' H) -yl) acetate

Following the procedure as described in example 1.22, with non-critical changes, use is made of [3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of 4, 7-dichloro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-dihydro-2H-indol-2-one gave the title compound in 46% yield as a light yellow oil:¹H NMR(300MHz，CDCl₃)7.31(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/z360.5(M+1)。

example 1.45

Synthesis of ethyl (2 '-keto-6, 7-dihydro-5H-spiro [ indeno [5, 6-b ] furan-3, 3' -indol ] -1 '(2' H) -yl) acetate

In [3- (6-hydroxy)-2, 3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]To a solution of ethyl acetate (4.20mmol) in anhydrous THF (60.0mL) was added triphenylphosphine (1.43g, 5.46mmol) and diethyl azodicarboxylate (0.95g, 5.46mmol) at 0 deg.C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonium chloride (20.0 mL). The mixture was extracted with ethyl acetate (3X 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/4) to give the title compound (0.25g, 16%, three-step total yield):¹H NMR(300MHz，CDCl₃)7.29(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/z364(M+1)。

example 1.46

Synthesis of ethyl (2-keto-5 ', 6 ', 7 ', 8 ' -tetrahydrospiro [ indole-3, 3 ' -naphtho [2, 3-b ] furan ] -1(2H) -yl) acetate

Following the procedure as described in example 1.45, with non-critical changes, using [3- (hydroxymethyl) -3- (3-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of [3- (6-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate to obtain the title compound (24%, three-step total yield): ¹H NMR(300MHz，CDCl₃)7.29(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/z378(M+1)。

Example 1.47

Synthesis of ethyl (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) acetate

Following the procedure as described in example 1.45, with non-critical changes, [ 4-bromo-3- (4, 5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-keto-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate instead of [3- (6-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-oxo-2, 3-dihydro-1H-indol-1-yl]Ethyl acetate to obtain the title compound (41%): melting point 133-134 ℃;¹H NMR(300MHz，CDCl₃)7.26-7.15(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)176.5，166.8，157.1，143.7，130.7，129.0，127.8，120.0，111.8，111.6，107.5，99.8，99.5，62.2，59.1，41.7，14.1；MS(ES+)m/z 438(M+1)，440(M+1)，460(M+23)，462(M+23)。

example 1.48

1' - (benzhydryl) -6, 7-dihydrospiro [ benzo [1, 2-b: synthesis of 4, 5-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 1, and making non-critical changes, 1- (benzhydryl) -3- (5-hydroxy-2, 3-dihydro-1-benzofuran-6-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (43%): MS (ES +) M/z 446.4(M + 1).

Example 1.49

6, 7-dihydrospiro [ benzo [1, 2-b: synthesis of 4, 5-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

1' - (benzhydryl) -6, 7-dihydrospiro [ benzo [1, 2-b: a mixture of 4, 5-b '] difuran-3, 3' -indole ] -2 '(1' H) -one (0.29g, 0.65mmol) and palladium hydroxide (0.10g, 20% on activated carbon) in acetic acid (20.0mL) was hydrogenated under normal pressure hydrogen at 60 ℃ for 20H. The reaction mixture was filtered through celite and washed with acetone (50.0 mL). The filtrate was concentrated to dryness in vacuo to afford the title compound (0.13g, 69%): MS (ES +) M/z 280.2(M + 1).

Example 1.50

1' - (benzhydryl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 1, and making non-critical changes, 1- (benzhydryl) -3- (6-hydroxy-2, 3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one was used instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one to obtain the title compound (51%) as a white solid: MS (ES +) M/z 446.3(M + 1).

Example 1.51

5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1.49, and making non-critical changes, the reaction mixture was purified using 1' - (benzhydryl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 ' (1 ' H) -one instead of 1 ' - (benzhydryl) -6, 7-dihydrospiro [ benzo [1, 2-b: 4, 5-b']Difuran-3, 3' -indoles]-2 '(1' H) -one to obtain the title compound (68%): melting point 208-;¹H NMR(300MHz，DMSO-d₆)10.53(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

Synthesis of ethyl (2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ' ] difuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) acetate

Reacting 5, 6-dihydrospiro [ benzo [1, 2-b: a mixture of 5, 4-b '] difuran-3, 3' -indole ]2 '(1' H) -one (0.28g, 1.00mmol), ethyl 2-bromoacetate (0.17g, 1.00mmol) and cesium carbonate (0.98g, 3.00mmol) in acetone (20.0mL) was stirred at reflux for 5H. After cooling to ambient temperature, the mixture was filtered. The filtrate was evaporated under reduced pressure, and the residue was subjected to column chromatography to give the title compound (0.23g, 63%) as a white solid: MS (ES +) M/z 366.4(M + 1).

Example 1.53

Synthesis of 4 ' -methoxy-1 ' { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure described in example 1, with non-critical changes, 3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -4-methoxy-1- { [5- (trifluoromethyl) -2-furyl]Methyl } -1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound (33%) was obtained as a white solid: melting point 149-153 ℃;¹H NMR(300MHz，DMSO-d₆)7.32-7.24(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

Synthesis of 7 ' -fluoro-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure described in example 1, with non-critical changes, 7-fluoro-3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1- { [5- (trifluoromethyl) -2-furyl]Methyl } -1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound (32%) was obtained as a white solid: melting point 116-;¹H NMR(300MHz，DMSO-d₆)7.36-6.88(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)176.9，155.8，154.1，149.1，148.8，145.6，142.4，140.9，140.3，139.2，139.2，135.2，135.2，128.5，128.4，124.9，128.4，124.9，124.8，124.7，121.2，120.4，120.4，119.8，117.6，117.2，117.0，114.5，114.5，109.5，103.2，102.0，93.8，80.1，58.3，58.2，39.0，38.9；MS(ES+)m/z 448.3(M+1)。

example 2

Synthesis of (2 '-oxaspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) acetic acid

From (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indole]To a suspension of ethyl (1 ') (2' H) -acetate (10.5g, 24.5mmol) in THF (200mL) and water (100mL) was added lithium hydroxide monohydrate (3.98g, 95.0mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for 17 hours. The mixture was neutralized with 4M HCl (15.0 mL). Removing the residue obtained after the solventThe retentate was acidified to pH 3 by addition of 4MHCl (6.2 mL). The solid was filtered, washed with water and hexanes, and dried under reduced pressure to give the title compound (8.48g, 87%) as a white solid:¹H NMR(300MHz，CDCl₃)7.32-7.06(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)177.8，171.8，155.8，149.0，142.4，141.2，132.0，129.0，124.1，124.0，119.2，108.3，103.4，101.5，93.5，80.2，58.2，41.1；MS(ES-)m/z 338.2(M-1)。

example 2.1

Synthesis of (2 '-keto-6, 7-dihydro-5H-spiro [ indeno [5, 6-b ] furan-3, 3' -indol ] -1 '(2' H) -yl) acetic acid

Following the procedure as described in example 2, and making non-critical changes, the title compound was obtained in 74% yield using ethyl (2 '-keto-6, 7-dihydro-5H-spiro [ indeno [5, 6-b ] furan-3, 3' -indol ] -1 '(2' H) -yl) acetate instead of ethyl (2 '-keto-spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) acetate; MS (ES-) M/z354 (M-1).

Example 2.2

Synthesis of (4 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indole ] - '(2' H) -yl) acetic acid

Following the procedure as described in example 2, with non-critical changes, (4 ' -chloro-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ']Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) acetic acid ethyl ester instead of (2 ' -ketospiro [ furo [2, 3-f)][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) ethyl acetate to give the title compound in 92% yield as a colorless solid: melting point 228-;¹H NMR(300MHz，CDCl₃)7.26-7.21(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)177.8，170.9，162.1，162.1，143.1，131.7，130.0，128.6，124.7，119.6，118.7，117.0，106.7，92.8，77.2，72.3，58.1，41.2，28.9；MS(ES-)m/z370.4(M-1)。

example 2.3

Synthesis of (4 '-bromo-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) acetic acid

Following the procedure as described in example 2, and making non-critical changes, (4 '-bromo-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) acetic acid ethyl ester was used instead of (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) acetic acid ethyl ester to obtain the title compound (98%) as a colorless solid: MS (ES-) M/z 415.2 (M-1).

Example 2.4

Synthesis of (5 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) acetic acid

Following the procedure as described in example 2, with non-critical changes, (5 ' -chloro-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ']Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) acetic acid ethyl ester instead of (2 ' -ketospiro [ furo [2, 3-f)][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) ethyl acetate to give the title compound in 98% yield as a colorless solid:¹H NMR(300MHz，CDCl₃)7.27-7.25(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)177.8，170.9，162.1，162.1，143.1，131.7，130.0，128.6，124.7，119.6，118.7，117.0，106.7，92.8，77.2，72.3，58.1，41.2，28.9；MS(ES-)m/z 370.4(M-1)。

example 2.5

Synthesis of (2-keto-5 ', 6 ', 7 ', 8 ' -tetrahydrospiro [ indole-3, 3 ' -naphtho [2, 3-b ] furan ] -1(2H) -yl) acetic acid

Following the procedure as described in example 2, and making non-critical changes, (2-keto-5 ', 6 ', 7 ', 8 ' -tetrahydrospiro [ indole-3, 3 ' -naphtho [2, 3-b ] furan ] -1(2H) -yl) acetic acid ethyl ester was used instead of (2 ' -ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -1 ' (2 ' H) -yl) acetic acid ethyl ester to obtain the title compound (99%): MS (ES-) M/z 348 (M-1).

Example 2.6

Synthesis of (2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ' ] difuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) acetic acid

Prepared from (2 '-keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-1 '(2' H) -yl) ethyl acetate (0.23g, 0.63mmol) with LiOH (0.10g, 4.20mmol) in MeOH/H₂The mixture in O (1/1, 20.0mL) was stirred at ambient temperature for 20 hours. The mixture was acidified with 0.1MHCl to pH 2-3. The solid was filtered off and dried to give the title compound (0.15g, 70%): MS (ES-) M/z336.3 (M-1).

Example 3

Synthesis of N- (4-chlorobenzyl) -2- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) acetamide

A. (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]Preparation of stock solution of (E) -1 '(2' H) -yl) isobutyl acetyl carbonate

To a solution of (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -1 '(2' H) -yl) acetic acid (0.30g, 0.88mmol) in dichloromethane (12.5mL) was added N-methylmorpholine (0.09g, 0.88mmol) and isobutyl chloroformate (0.12g, 0.88mmol) dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 1.5 hours and at ambient temperature for 3 hours. This mixture was used as the mixed anhydride in the next step of amide formation.

N- (4-chlorobenzyl) -2- (2' -ketospiro [ furo [2, 3-f)][1，3]Benzodioxole-7, 3' -indoles]Synthesis of (E) -1 '(2' H) -yl) acetamide

To the above stock solution of mixed anhydride (2.50mL, 0.18mmol) was added a solution of 4-chlorobenzylamine in dichloromethane (0.35mL, 0.50M, 0.18mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 23 hours, washed with saturated aqueous sodium carbonate solution and water. After removal of the solvent, ether was added and the precipitate was collected by filtration to give the title compound (0.04g, 46%):¹H NMR(300MHz，CDCl₃)7.39-6.97(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/z485.2(M+23)。

example 3.1

The compounds listed in the table below were synthesized using similar conditions as described in example 3. The compound numbers listed below do not correspond to the compound numbers provided in the general reaction schemes above.

Example 3.2

Synthesis of N- (2-fluorophenyl) -2- (2 '-keto-6, 7-dihydro-5H-spiro [ indeno [5, 6-b ] furan-3, 3' -indol ] -1 '(2' H) -yl) acetamide

On 2' -keto-6, 7-dihydro-5H-spiro [ indeno [5, 6-b ]]Furan-3, 3' -indoles]To a solution of-1 '(2' H) -yl) acetic acid (0.18g, 0.54mmol) in chloroform (5.00mL) was added oxalyl chloride (0.09mL, 1.07mmol) and a drop of DMF. The mixture was refluxed for 2 hours and evaporated to dryness under reduced vacuum. To the residue was added Et ₃N (0.66mL, 4.72mmol), 2-fluoroaniline (0.10mL, 1.00mmol) and THF (5.00 mL). The reaction mixture was stirred at ambient temperature overnight and evaporated to dryness. Column chromatography of the residue (25% ethyl acetate in hexanes) yielded the title compound (0.04g, 17%):¹H NMR(300MHz，CDCl₃)8.26(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)178.6，165.0，159.8，146.9，141.5，137.5，132.5，129.2，126.3，125.2，124.8，124.4，124.3，121.9，118.9，115.2，114.9，109.0，106.8，79.9，58.2，45.3，33.2，32.0，26.1；MS(ES+)m/z429(M+1)，451(M+23)。

example 3.3

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

Following the procedure as described in example 3.2, with non-critical changes, (2-keto-5 ', 6 ', 7 ', 8 ' -tetrahydrospiro [ indole-3, 3 ' -naphtho [2, 3-b ]) was used]Furan compounds]-1(2H) -yl) acetic acid instead of 2' -ketone6, 7-dihydro-5H-spiro [ indeno [5, 6-b ] yl]Furan-3, 3' -indoles]-1 '(2' H) -yl) acetic acid to give the title compound in 5% yield:¹H NMR(300MHz，CDCl₃)8.27(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/z443(M+1)，465(M+23)。

example 3.4

Synthesis of 2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) -N- (2-fluorophenyl) acetamide

A. (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole)]Synthesis of (E) -1 '(2' H) -yl) acetic acid

Following the procedure as described in example 2, and making non-critical changes, (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) ethyl acetate was used instead of ethyl (2 ' -ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] - ] ' (2 ' H) -yl) acetate to obtain the title compound in 100% yield. The product was used directly in the next step.

B.2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole)]Synthesis of (E) -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

From (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole)]-1 '(2' H) -yl) acetic acid (0.24g, 0.59mmol) and oxalyl chloride (0.15mL, 1.76mmol) in toluene (7.00mL) was added a drop of DMF and the resulting mixture was addedStir at ambient temperature overnight. The mixture was concentrated under vacuum. The bond residue was dissolved in dichloromethane (5.00mL) and 2-fluoroaniline (0.18mL, 1.89mmol) was added at ambient temperature. The mixture was stirred at ambient temperature for 1 hour. More dichloromethane (100mL) 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 (0.23g, 76%):¹H NMR(300MHz，CDCl₃)8.20(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)177.1，163.9，157.8，143.6，131.0，128.8，128.1，124.7，121.8，120.0，115.0，111.6，108.1，99.8，77.5，59.2，44.7；MS(ES+)m/z 503.4(M+1)，505.4(M+1)。

example 3.5

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

A. (4 ' -bromo-6, 6-dimethyl-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ' ]Difuran-3, 3' -indoles]Synthesis of (E) -1 '(2' H) -yl) acetic acid

Following the procedure as described in example 2, and making non-critical changes, (4 '-bromo-6, 6-dimethyl-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) acetic acid ethyl ester was used instead of (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) acetic acid ethyl ester to obtain the title compound. The product was used directly in the next step.

B.2- (4 ' -bromo-6, 6-dimethyl-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ']Difuran-3, 3' -indoles]Synthesis of (E) -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 3.4B, and making non-critical changes, (4 ' -bromo-6, 6-dimethyl-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-B: 5, 4-B ' ] difuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) acetic acid was used instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) acetic acid to obtain the title compound (61%, two-step total yield): MS (ES +) M/z537.4(M +1), 539.4(M + 1).

Example 3.6

Synthesis of 2- (4 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 3.4B, with non-critical changes, (4 ' -chloro-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-B: 5, 4-B ']Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole]-1 '(2' H) -yl) acetic acid to give the title compound (69%) as a colorless solid: melting point 243-245 ℃;¹H NMR(300MHz，CDCl₃)8.19(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)178.2，164.4，162.2，162.1，143.2，131.6，130.2，128.5，125.2，125.1，124.9，124.6，121.9，119.7，118.6，116.8，115.1，114.8，107.3，92.9，77.2，72.4，58.2，44.9，28.9；MS(ES+)m/z465.5(M+1)。

example 3.7

Synthesis of 2- (5 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 3.4B, with non-critical changes, (5 ' -chloro-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-B: 5, 4-B ']Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole]-1 '(2' H) -yl) acetic acid to give the title compound (91%) as a colorless solid: melting point 229-; ¹H NMR(300MHz，CDCl₃)8.21(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)177.8，170.9，162.1，162.1，143.1，131.7，130.0，128.6，124.7，119.6，118.7，117.0，106.7，92.8，77.2，72.3，58.1，41.2，28.9；MS(ES+)m/z465.4(M+1)。

Example 3.8

Synthesis of 2- (6-chloro-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 3.4B, with non-critical changes, (6-chloro-2 '-ketospiro [ 1-benzofuran-3, 3' -indole) was used]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole]-1 '(2' H) -yl) acetic acid to give the title compound (10%) as a white solid: melting point is 70-75 ℃;¹H NMR(300MHz，CDCl₃)8.21(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)177.7，164.6，161.4，141.4，135.5，131.6，129.4，127.3，125.2，125.0，124.7，124.6，124.4，124.3，124.1，121.9，121.8，115.1，114.8，111.3，109.0，80.3，57.6，44.9；MS(ES+)m/z423.4(M+1)。

example 3.9

Synthesis of 2- (5, 6-difluoro-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 3.4B, with non-critical changes, (5, 6-difluoro-2 '-ketospiro [ 1-benzofuran-3, 3' -indole)]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole]-1 '(2' H) -yl) acetic acid to give the title compound (35%) as a white solid: melting point is 97-100 ℃;¹H NMR(300MHz，CDCl₃)8.20-8.10(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)177.4，164.3，141.4，131.2，129.7，125.6，125.5，125.3，125.2，125.1，124.7，124.4，124.1，121.8，115.1，114.9，112.1，111.8，109.1，100.3，100.0，80.7，57.9；MS(ES+)m/z425.5(M+1)。

example 3.10

Synthesis of 2- (5-bromo-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 3.4B, with non-critical changes, (5-bromo-2 '-ketospiro [ 1-benzofuran-3, 3' -indole) was used ]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole]-1 '(2' H) -yl) acetic acid to give the title compound (94%) as a light yellow solid: melting point 100-;¹H NMR(300MHz，CDCl₃)8.26(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/z467.3(M+1)。

example 3.11

Synthesis of 2- (4 '-fluoro-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 3.4B, with non-critical changes, (4 ' -fluoro-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-B: 5, 4-B ']Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole]-1 '(2' H) -yl) acetic acid to give the title compound:¹H NMR(300MHz，CDCl₃)8.20(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/z449.5(M+1)。

example 3.12

Synthesis of 2- (4 '-bromo-2' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 3.4B, and making non-critical changes, (4 ' -bromo-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-B: 5, 4-B ']Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole ]-1 '(2' H) -yl) acetic acid to give the title compound (75%) as a colorless solid: melting point 245-246 ℃;¹H NMR(300MHz，CDCl₃)8.20(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)178.3， 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/z509(M+1)，511(M+1)。

example 3.13

Synthesis of N- (2-fluorophenyl) -2- (2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ' ] difuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) acetamide

Following the procedure as described in example 3.4B, with non-critical changes, (2 '-keto-5, 6-dihydrospiro [ benzo [1, 2-B: 5, 4-B']Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole]-1 '(2' H) -yl) acetic acid to give the title compound (68%) as a white solid: melting point 210 ℃ and 212 ℃;¹H NMR(300MHz，DMSO-d₆)10.18(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/z431.4(M+1)。

example 3.14

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

Following the procedure as described in example 3.4B, and making non-critical changes, (4 '-fluoro-7' -methyl-2 '-keto-5, 6-dihydrospiro [ benzo [1, 2-B: 5, 4-B']Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) acetic acid instead of (4 ' -bromo-5, 6-diFluoro-2 '-ketospiro [ 1-benzofuran-3, 3' -indoles ]-1 '(2' H) -yl) acetic acid to give the title compound (21%) as a white solid: melting point 250-255 ℃;¹H NMR(300MHz，DMSO-d₆)10.23(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/z463.4(M+1)。

example 4

Synthesis of 4 ' - [6- (dimethylamino) pyridin-3-yl ] -1 ' -pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Oven dried flask was charged with [6- (dimethylamino) pyridin-3-yl]Dihydroxyborane (37.0mg, 0.17mmol), Pd (PPh)₃)₄(13.5mg, 0.012mmol) and then flashed with nitrogen. The flask was charged with 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one (50.0mg, 0.12mmol) in anhydrous dioxane (2.00mL) and 2.0M Na was added₂CO₃(0.24 mL). The reaction mixture was heated at reflux for 48 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (2.00mL), washed with saturated ammonium chloride (2.00mL), and concentrated to dryness in vacuo. The residue is subjected to column chromatography to yield the title compound:¹H NMR(300MHz，CDCl₃)7.77(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)177.9，158.3，156.1，148.8，147.3，142.9，142.0，137.8，137.2，129.9，128.9，125.6，122.0，121.0，107.6，104.3，102.5，101.5，93.6，77.8，58.5，40.5，38.2，29.1，27.2，22.4，14.0；MS(ES+，m/z)472.0(M+1)。

example 4.1

The compounds listed in the table below were synthesized using similar conditions as described in example 4. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 4.2

Synthesis of 2- (5, 6-difluoro-2 ' -keto-4 ' -pyrimidin-5-ylspiro [ 1-benzofuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) -N- (2-fluorophenyl) acetamide

From 2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole)]To a solution of (E) -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide (0.15g, 0.30mmol) in anhydrous 1, 4-dioxane (5.00mL) was added Pd (PPh)₃)₄(0.03g, 0.03mmol) and stirred at ambient temperature for 10 min. Pyrimidine-5-dihydroxyborane (0.06g, 0.45mmol) and sodium carbonate (0.90mL of a 2M solution, 1.80mmol) were added. The reaction mixture was refluxed at 120 ℃ 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 column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.13g, 84%):¹H NMR(300MHz，CDCl₃)9.13(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)177.1，163.9，157.7，156.4，155.7，141.9，132.9，130.0，126.0，124.7，121.9，115.0，111.6，109.8，100.2，79.4，57.9，44.7；MS(ES+)m/z503.5(M+1)。

example 4.3

Synthesis of 2- (6, 6-dimethyl-2 '-keto-4' -pyrimidin-5-yl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide

Following the procedure as described in example 4.2, a variation was made using 2- (4 ' -bromo-6, 6-dimethyl-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ' ]Difuran-3, 3' -indoles]-1 ' (2 ' H) -yl) -N- (2-fluorophenyl) acetamide instead of 2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole]-1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide to obtain the title compound (95%): melting point is more than 250 ℃;¹H NMR(300MHz，CDCl₃)9.10(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)178.4，164.5，161.1，157.4，155.8，154.1，150.8，141.7，132.9，132.2，131.3，129.4，125.9，125.5，125.2，124.7，121.9，120.8，119.3，118.8，115.0，109.5，93.5，88.5，78.9，58.0，45.0，42.0，28.0，27.9；MS(ES+)m/z537.5(M+1)。

example 4.4

Synthesis of 4 '- (3-furyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4, a modification was made using 4' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 3-furandihydroxyborane instead of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (66%) as a colorless solid: melting point 270-272 deg.C;¹H NMR(300MHz，CDCl₃)7.32(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)180.4，156.2，149.2，142.9，142.1，141.2，140.4，131.3，129.2，128.5，125.3，122.6，120.6，111.0，109.5，102.9，101.6，94.0，77.2，59.0；MS(ES+)m/z348.4(M+1)。

example 4.5

Synthesis of 4 '-dibenzo [ b, d ] furan-4-yl spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

The procedure was as described in example 4And making non-critical changes using 4' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles ]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and dibenzo [ b, d ]]Furan-4-yl dihydroxy borane instead of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (10%) as a colorless solid: melting point > 230 ℃;¹H NMR(300MHz，DMSO-d₆)10.77(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

Synthesis of 4 ' - (6-methoxypyridin-3-yl) -1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure as described in example 4, with non-critical changes, 4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl ] was used]Methyl } spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and (6-methoxypyridin-3-yl) dihydroxyborane instead of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (51%) as a colorless solid: melting point 174-176 ℃;¹H NMR(300MHz，CDCl₃)7.73(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)177.7，163.5，158.4，156.1，151.8，151.8，149.2，147.8，146.1，142.3，141.6，138.8，136.9，132.6，130.0，129.1，127.8，127.2，126.2，119.9，112.7，112.7，110.9，109.6，109.5，108.5，102.3，101.6，93.6，78.2，58.5，53.6，37.0；MS(ES+)m/z 537.4(M+1)。

example 4.7

Synthesis of 4 ' - [6- (dimethylamino) pyridin-3-yl ] -1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure as described in example 4, and making non-critical changes, using 4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 '-indol ] -2' (1 'H) -one instead of 4' -bromo-1 '-pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one, the title compound (37%) was obtained as a colorless solid: melting point 174-176 ℃; MS (ES +) M/z 550.4(M + 1).

Example 4.8

Synthesis of 4 '-pyrimidin-5-ylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4 and proceedingWith non-critical changes, 4' -bromospiro [ furo [2, 3-f ] is used][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and pyrimidin-5-yl dihydroxy borane in place of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (32%) as a colorless solid: melting point 185-187 deg.C;¹H NMR(300MHz，DMSO-d₆)10.85(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)178.7，157.5，156.0，155.6，148.8，142.3，133.1，132.6，131.8，129.5，124.5，120.3，110.9，103.2，101.9，93.3，79.5，66.8，58.5；MS(ES+)m/z 360.4(M+1)。

example 4.9

4 '- (3-furanyl) -1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4, with non-critical changes, 4 '-bromo-1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 3-furandihydroxyborane instead of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (75%) as a colorless solid: melting point 195-197 ℃;¹H NMR(300MHz，CDCl₃)8.58(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' -pyrimidin-5-yl-5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4, with non-critical changes, 4 '-bromo-1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and pyrimidin-5-yl dihydroxyborane instead of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (16%) as a colorless solid: melting point is more than 200 ℃; ¹H NMR(300MHz，CDCl₃)9.09(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/z449.5(M+1)。

Example 4.11

4 '-pyridin-3-yl-1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4, with non-critical changes, 4 '-bromo-1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and pyridin-3-yldihydroxyborane instead of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (9%) as a colorless solid: melting point is more than 200 ℃;¹H NMR(300MHz，DMSO-d₆)8.52(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/z448.5(M+1)。

example 4.12

4 '- (3-furyl) -1' - { [5- (trifluoromethyl) -2-furyl ] methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4, with non-critical changes, 4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl ] was used]Methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ] ][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 3-furyldihydroxyborane instead of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (27%) as a colorless solid: melting point 167-169 deg.C;¹H NMR(300MHz，CDCl₃)7.34-7.29(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

Synthesis of 4 ' -quinolin-3-yl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure as described in example 4, with non-critical changes, 4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl ] was used]Methyl } spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, quinolin-3-yl dihydroxyborane instead of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (50%) as a colorless solid:¹H NMR(300MHz，CDCl₃)8.52(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)177.4，156.0，151.8，150.0，149.3，147.0，142.4，141.8，136.8，135.8，131.1，130.2，129.9，129.3，129.0，128.8，128.0，127.1，127.0，126.4，126.0，120.4，112.7，109.5，108.8，102.5，101.7，93.7，78.3，58.5，37.1；MS(ES+)m/z557.4(M+1)。

example 4.14

4 '-pyrimidin-5-yl-1' - { [5- (trifluoromethyl) -2-furanyl ] methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl ]Methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]A mixture of-2 '(1' H) -one (0.11g, 0.21mmol), pyrimidine-5-dihydroxyborane (0.04g, 0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.03g, 0.02mmol), 2.00M sodium carbonate (1.00mL), and 1, 2-dimethoxyethane (10.0mL) was heated at reflux under nitrogen for 16H. After evaporation of the organic solvent in vacuo, the black residue was extracted with ethyl acetate (3X 35.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue is subjected to column chromatography with ethyl acetate: hexane (35%) eluted to give the title compound (0.03g, 26%): melting point 263-266 deg.C;¹H NMR(300MHz，CDCl₃)9.10(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)177.3，162.5，161.0，157.4，155.9，151.6，142.2，141.7，132.8，132.3，131.3，129.3，125.7，120.6，120.2，118.3，117.0，112.7，109.7，109.4，93.5，78.9，72.5，57.7，37.1，28.9；MS(ES+)m/z506.5(M+1)。

example 4.15

Synthesis of tert-butyl 4- [ (2 ' -keto-4 ' -pyrimidin-5-yl-spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -1 ' (2 ' H) -yl) methyl ] piperidine-1-carboxylate

Following the procedure as described in example 4.14, with non-critical changes, 4- [ (4 '-bromo-2' -ketospiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Piperidine-1-carboxylic acid tert-butyl ester instead of 4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl ]Methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one to obtain the title compound (91%) as a colorless solid:¹H NMR(300MHz，CDCl₃)9.13(s，1H)，8.23(s，2H)，8.24-7.37(m，5H)，7.01(d，1H)，6.85(d，1H)，6.14(dd，2H)，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

Synthesis of 1 ' -methyl 4 ' -pyrimidin-5-yl spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure as described in example 4.14, with non-critical changes, 4 '-bromo-1' -methyl spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl]Methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one to obtain the title compound (22%) as a colorless solid:¹H NMR(300MHz，CDCl₃)9.10(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

Synthesis of 4 ' - (3-furyl) -1 ' -methylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure as described in example 4.14, with non-critical changes, 4 '-bromo-1' -methyl spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl ]Methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one, and 3-furandihydroxyborane instead of pyrimidin-5-dihydroxyborane, to obtain the title compound (81%) as a colorless solid:¹H NMR(300MHz，CDCl₃)7.40-7.28(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/z362.4(M+1)。

example 4.18

Synthesis of 4 ' - (6-fluoropyridin-3-yl) -1 ' -methylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

According to the following factsThe procedure described in example 4.14, with non-critical changes, was followed using 4 '-bromo-1' -methyl spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl]Methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one, and (6-fluoropyridin-3-yl) dihydroxyborane instead of pyrimidin-5-dihydroxyborane, the title compound (100%) was obtained as a colorless solid:¹HNMR(300MHz，CDCl₃)7.75-7.65(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

Synthesis of 1 ' - (2-cyclopropylethyl) -4 ' -quinolin-3-ylspiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure as described in example 4, and making non-critical changes, using 4 '-bromo-1' - (2-cyclopropylethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 '-indol ] -2' (1 'H) -one instead of 4' -bromo-1 '-pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one, and quinolin-3-yl dihydroxyborane instead of [6- (dimethylamino) pyridin-3-yl ] dihydroxyborane, the title compound was obtained: MS (ES +) M/z 477.5(M + 1).

Example 4.20

Synthesis of N- (2-fluorophenyl) -2- (2 '-keto-4' -pyrimidin-5-yl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -1 '(2' H) -yl) acetamide

Following the procedure as described in example 4, with non-critical changes, 2- (4 ' -bromo-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ']Difuran-3, 3' -indoles]-1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide in place of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f)][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and pyrimidine-5-dihydroxyborane in place of [6- (dimethylamino) pyridin-3-yl]Dihydroxy borane to obtain the title compound (53%) as a colorless solid: melting point 229-;¹H NMR(300MHz，CDCl₃)9.10(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)；¹³CNMR(75MHz，CDCl₃)178.2，164.4，162.5，161.0，157.0，155.8，141.8，132.6，131.1，129.4，125.8，125.5，125.4，125.2，125.1，124.7，121.9，120.6，119.9，118.7，115.1，114.8，109.5，93.4，79.0，72.4，57.8，44.9，28.9；MS(ES+)m/z 509.5(M+1)。

example 5

Synthesis of 4 ' - [ (6-methoxypyridin-3-yl) amino ] -1 ' -pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Oven dried two-necked 25mL round bottom flask equipped with a condenserIn a bottle, 4 '-bromo-1' -pentylspiro- (6, 7-dihydrofuro- [2, 3-f) was added][1，3]Benzodioxole-7, 3 ' -indole) -2 ' - (1 ' H) -one (50.5mg, 0.12mmol), 5-amino-2-methoxypyridine (22.3mg, 0.18mmol), Pd ₂(dba)₃(10 mol%), BINAP (10 mol%) and sodium methoxide (12.9mg, 0.24 mmol). The flask was flushed with nitrogen for 5 minutes, then degassed toluene (5.00mL) was added. The reaction mixture was heated at reflux for 16 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0mL) and washed with saturated ammonium chloride (10.0mL), brine (10.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The brown residue was subjected to column chromatography, eluting with ethyl acetate-hexane (20% to 50%) to give the title compound (30.0mg), 54% yield: MS (ES +) M/z 474.3(M + 1).

Example 5.1

The compounds listed in the following table were synthesized using similar conditions as described in example 5. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 5.2

Synthesis of 4 ' -bromo-1 ' -pentylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one (0.05g, 0.12mmol), 3- (trifluoromethyl) aniline (0.03g, 0.17mmol), Pd ₂(dba)₃A mixture of (0.02g, 0.01mmol), xanthphos (0.007g, 0.01mmol) and sodium tert-butoxide (0.02g, 0.17mmol) in toluene (5.00mL) was heated at 110 ℃ 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 in vacuo. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane to give the title compound (0.06g, 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 similar conditions as described in example 5.2. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 6

Synthesis of 2- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoic acid

In 2- [ (2' -ketospiro)[ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]To a solution of methyl benzoate (7.56g, 17.6mmol) in a THF/water mixture (2/1v/v, 180mL) was added lithium hydroxide monohydrate (1.48g, 35.2 mmol). The resulting mixture was stirred at ambient temperature overnight and concentrated in vacuo, then water (150mL) was added. The mixture was extracted with ethyl acetate/hexane (1/3v/v, 50.0 mL). The aqueous layer was acidified to pH 2 with 1N HCl solution. The precipitate was filtered and dried to give the title compound (7.30g, 100%) as a white solid: melting point is more than 250 ℃; ¹H NMR(300MHz，DMSO-d₆)13.25(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)；¹³CNMR(75MHz，DMSO-d₆)177.6，168.8，156.0，148.8，143.0，142.3，137.6，133.1，132.1，131.5，129.9，129.4，127.7，126.5，124.2，123.6，120.1，109.8，103.8，101.9，93.8，80.5，58.0，42.6。

Example 7

Synthesis of N- [2- (4-chlorophenyl) ethyl ] -2- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzamide

A.2- [ (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Preparation of stock solutions of benzoyl chloride

A solution of 2- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoic acid (0.21g, 0.50mmol), oxalyl chloride (0.09mL, 1.00mmol) and one drop of DMF in toluene (10.0mL) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give a solid, which was dissolved in dichloromethane (5.00mL) to form a stock solution of acid chloride (0.10mmol/mL) for use.

N- [2- (4-chlorophenyl) ethyl]-2- [ (2' -ketospiro [ furo [2, 3-f)][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Synthesis of benzamide

The acid chloride stock solution obtained above (1.00mL, 0.10mmol) was added to a mixture of 2- (4-chlorophenyl) ethylamine (0.02g, 0.13mmol), triethylamine (0.14mL, 1.00mmol) in dichloromethane (1.00 mL). 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 bicarbonate solution, dried over sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo to afford the title compound as a white powder: ¹H NMR(300MHz，CDCl₃)7.70-7.13(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 similar conditions as described in example 7. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 8

Synthesis of 3- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoic acid

Following the procedure described in example 6, with non-critical changes, 3- [ (2' -ketospiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Replacement of 2- [ (2' -Keto spiro [ furo [2, 3-f ] with methyl benzoate][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Methyl benzoate, the title compound (100%) was obtained:¹HNMR(300MHz，CDCl₃)13.03(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)；¹³CNMR(75MHz，CDCl₃)177.4，167.5，155.9，148.9，142.5，142.3，137.3，132.2，131.7，129.6，129.4，128.8，128.1，124.3，123.7，120.1，109.9，103.3，101.9，93.9，80.3，58.0，43.2；MS(ES+)m/z 416.2(M+1)。

example 9

Synthesis of N- [2- (3-chlorophenyl) ethyl ] -3- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzamide

A.3- [ (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Preparation of stock solutions of benzoyl chloride

To a stirred slurry of 3- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoic acid (2.08g, 5.00mmol) in anhydrous chloroform (50.0mL) was added oxalyl chloride (0.95g, 7.5mmol) at ambient temperature followed by 1 drop of DMF. The mixture was stirred at ambient temperature overnight and evaporated to dryness in vacuo. The residue was dissolved in anhydrous dichloromethane (60.0mL) to form an acid chloride stock solution for use.

N- [2- (3-chlorophenyl) ethyl]-3- [ (2' -ketospiro [ furo [2, 3-f)][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Synthesis of benzamide

To a solution of 2- (3-chlorophenyl) ethylamine (0.02mL, 0.24mmol) in anhydrous dichloromethane (2.00mL) and triethylamine (0.05mL, 0.32mmol) at ambient temperature was added the stock solution of acid chloride obtained above (2.0mL, 0.081M, dichloromethane). The mixture was stirred for 2 hours, washed with 15% HCl solution and water. Separating the organic layer with Na₂SO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and the product was precipitated by addition of hexane. The white solid was filtered and collected to give the title compound (0.06g), 65% yield:¹H NMR(300MHz，CDCl₃)7.97-7.95(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 similar procedure as described in example 9. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 10

Synthesis of 1 '- (4-fluorobenzyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

In spiro [ furo [2, 3-f ] ][1，3]Benzodioxole-7, 3' -indoles]To a solution of-2 '(1' H) -one (0.16g, 0.57mmol) in ethylmethylketone (5.00mL) was added Cs₂CO₃(0.40g, 1.20 mmol). The reaction mixture was stirred at ambient temperature for 15 minutes, then benzyl 4-fluorobenzo bromide (0.20g, 1.0mmol) was added. The reaction mixture was refluxed for 4 hours. After completion of the reaction, the mixture was filtered, and the solvent was removed under reduced pressure. The residue was recrystallized from EtOAc/hexanes to give the title compound (0.111g) as a white solid, 50% yield: MS (ES +) M/z 390.3(M + 1).

Example 10.1

The compounds listed in the table below were synthesized using a similar procedure as described in example 10. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 10.2

Synthesis of 1 '- (piperidin-4-ylmethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 10, and making non-critical changes, using tert-butyl 4- (bromomethyl) piperidine-1-carboxylate instead of benzyl 4-fluorobenzyl bromide, the title compound was obtained in 67% yield as a white solid after acidification of the intermediate with 33% HBr: MS (ES +) M/z 379.3(M + 1).

Example 10.3

Synthesis of 1 '- [ (1-methylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

To a solution of 1 '- (piperidin-4-ylmethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one (0.19g, 0.50mmol) in dichloroethane (5.00mL) was added formaldehyde (0.10mL, 33% solution, 0.03g, 1.10mmol) and sodium triacetoxyborohydride (0.30g, 1.40 mmol). After stirring at ambient temperature for 20 h, the reaction mixture was diluted with dichloromethane (20.0mL) and washed with water (2X 20.0 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, and the product was dissolved in dichloromethane (5.00mL) and excess HCl in ether was added. The precipitate was filtered to give the title compound, 20% yield: MS (ES +) M/z 393.3(M + 1).

Example 10.4

Synthesis of 1 '- [ (1-ethylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, acetaldehyde was used instead of formalin to obtain the title compound in 20% yield as a white solid: MS (ES +) M/z407.3(M + 1).

Example 10.5

Synthesis of 1 '- [ (1-cyclohexylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, cyclohexanone was used instead of formalin to obtain the title compound in 24% yield as a white solid: MS (ES +) M/z 461.5(M + 1).

Example 10.6

Synthesis of 1 '- { [ 1-cyclopropylmethyl) piperidin-4-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, cyclopropanecarboxaldehyde was used instead of formalin to obtain the title compound in 14% yield as a white solid: MS (ES +) M/z 433.5(M + 1).

Example 10.7

Synthesis of 1 '- [ (1-cyclopentylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, cyclopentanone was used instead of formalin to obtain the title compound in 37% yield as a white solid: MS (ES +) M/z 447.3(M + 1).

Example 10.8

Synthesis of 1 '- { [1- (pyridin-3-ylmethyl) piperidin-4-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, using nicotinaldehyde instead of formalin, the title compound was obtained in 11% yield as a white solid: MS (ES +) M/z 470.4(M + 1).

Example 10.9

Synthesis of 1 '- { [1- (3-methylbutyl) piperidin-4-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, using 3-methylbutanal instead of formalin, the title compound was obtained in 15% yield as a white solid: MS (ES +) M/z449.5(M + 1).

Example 10.10

Synthesis of 1 '- { [1- (1-ethylpropyl) piperidin-4-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, using pentane-3-one instead of formalin, the title compound was obtained in 17% yield as a white solid: MS (ES +) M/z 449.4(M + 1).

Example 10.11

Synthesis of 1 '- [ (1-cyclobutylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, cyclobutanone instead of formalin, the title compound was obtained in 31% yield as a white solid: MS (ES +) M/z 433.4(M + 1).

Example 10.12

Synthesis of 1 '- [ (1-isopropylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, using acetone instead of formalin, the title compound was obtained in 31% yield as a white solid:¹H NMR(300MHz，DMSO-d₆)10.36(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

Synthesis of 1 '- { [1- (pyridin-2-ylmethyl) piperidin-4-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, picolinic aldehyde was used instead of formalin to obtain the title compound in 15% yield as a white solid: MS (ES +) M/z 470.4(M + 1).

Example 10.14

Synthesis of 1 '- { [1- (2-thienylmethyl) piperidin-4-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, using thiophene-2-carboxaldehyde instead of formalin, the title compound was obtained in 21% yield as a white solid: MS (ES +) M/z 475.3(M + 1).

Example 10.15

Synthesis of 1 '- ({1- [3- (methylthio) propyl ] piperidin-4-yl } methyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, using 3- (methylthio) propanal instead of formalin, the title compound was obtained in 7% yield as a white solid: MS (ES +) M/z 467.5(M + 1).

Example 10.16

Synthesis of 1 '- { [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, tetrahydro-4H-pyran-4-one was used instead of formalin to obtain the title compound in 33% yield as a white solid: MS (ES +) M/z 463.4(M + 1).

Example 10.17

Synthesis of 1 '- { [1- (3, 3-dimethylbutyl) piperidin-4-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.3, and making non-critical changes, using 3, 3-dimethylbutyraldehyde instead of formalin, the title compound was obtained in 19% yield as a white solid: MS (ES +) M/z 463.5(M + 1).

Example 10.18

Synthesis of tert-butyl 4- [ (5, 5-dimethyl-2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ' ] difuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) methyl ] piperidine-1-carboxylate

Following the procedure as described in example 10, with non-critical changes, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and tert-butyl 4- (tosyloxymethyl) piperidine-1-carboxylate instead of benzyl 4-fluorobromide to give the title compound in 70% yield: the melting point is 65-75 ℃;¹H NMR(300MHz，CDCl₃)7.30(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)178.0，161.3，161.0，154.7，142.8，132.6，129.9，128.7，124.2，123.3，120.3，116.2，108.5，93.4，85.4，80.6，79.5，57.7，45.7，41.3，35.0，30.0，28.4，27.8，27.5；MS(ES+)m/z527.5(M+23).

example 10.19

5, 5-dimethyl-1' - (piperidin-4-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one hydrochloride

From 4- [ (5, 5-dimethyl-2 '-keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-1 '(2' H) -yl) methyl]To a stirred solution of tert-butyl piperidine-1-carboxylate (80mg, 0.16mmol) in 10.0mL of dichloromethane was slowly added hydrobromic acid (0.50 mL. gtoreq.33% hydrobromic acid in glacial acetic acid at 0 ℃,1.60 mmol). The mixture was stirred at ambient temperature for 1 hour and concentrated to dryness in vacuo. The residue was treated with 10.0mL of 2N sodium hydroxide solution and extracted with dichloromethane (3X 30.0 mL). The combined organic layers were washed with brine (100mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (2% methanol in ethyl acetate) to give 5, 5-dimethyl-1' - (piperidin-4-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one (0.03g, 46%) which was treated with 2.0M HCl in diethyl ether to give the title compound:¹HNMR(300MHz，CD₃OD)7.41(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)181.4，163.9，163.4，144.7，134.7，132.3，131.0，125.9，125.8，122.6，118.4，111.3，94.9，87.4，82.6，60.2，46.7，45.7，45.6，43.3，34.6，28.8，28.7，28.6；MS(ES+)m/z 405.4(M+1).

example 10.20

Synthesis of 7 ' -fluoro-1 ' - [ (1-isopropylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one hydrochloride

A. Following the procedures as described in examples 10.18 and 10.19, and making non-critical changes, 7 '-fluorospiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one was used instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ' ] difuran-3, 3 ' -indol ] -2 ' (1 ' H) -one to give 7 ' -fluoro-1 ' - (piperidin-4-ylmethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one and is used in the next step.

B. In 7 '-fluoro-1' - (piperidin-4-ylmethyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a stirred solution of-2 '(1' H) -one (120mg, 0.28mmol) and triethylamine (3.9. mu.L, 0.028mmol) in 5.00mL of dichloromethane was added acetone (4.1. mu.L, 0.56mmol) followed by sodium triacetoxyborohydride (124mg, 0.56mmol) at ambient temperature. The mixture was stirred at ambient temperature overnight and the reaction quenched with water (10.0 mL). The mixture was extracted with dichloromethane (3X 30.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue is subjected to column chromatography (2% methanol in ethyl acetate/hexane) to give 7 '-fluoro-1' - [ (1-isopropylpiperidin-4-yl) methyl ]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one (85mg, 69%) as a white solid, which was treated with 2.0M HCl in diethyl ether to obtain the title compound: melting point 157-160 ℃;¹H NMR(300MHz，CD₃OD)7.22-7.05(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)179.7，157.6，150.6，150.4，147.1，143.9，136.6，125.8，121.2，120.3，118.0，103.9，103.0，94.3，81.8，60.1，59.7，47.6，35.33，35.30，28.6，28.5，16.98，16.96；MS(ES+)m/z439.27(M+1)。

example 10.21

5, 5-dimethyl-1' - { [5- (trifluoromethyl) -2-furyl ] methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

In the presence of a compound of formula (I) in 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]To a solution of-2 '(1' H) -one (0.09g, 0.29mmol) in 2-butanone (10.0mL) was added 2-bromomethyl-5- (trifluoromethyl) furan (0.08g, 0.35mmol) at 0 deg.C followed by cesium carbonate (0.19g, 0.58 mmol). 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 (0.06g, 45%): melting point 155-160 ℃;¹H NMR(300MHz， CDCl₃)7.29(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)177.5，161.2，161.0，152.0，141.4，132.5，130.1，128.8，124.2，123.8，120.1，116.4，112.6，109.3，108.7，93.4，85.5，80.6，57.7，41.4，36.9，27.6，27.5；MS(ES+)m/z456.5(M+1)。

example 10.22

5, 5-dimethyl-1' - (pyridin-3-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one hydrochloride

In the presence of a compound of formula (I) in 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b' ]Difuran-3, 3' -indoles]To a solution of-2 '(1' H) -one (0.08g, 0.26mmol) in DMF (10mL) was slowly added sodium hydride (0.03g, 0.78mmol) at 0 ℃. After 30 minutes3- (bromomethyl) -pyridine hydrobromide (0.10g, 0.39mmol) was added. The mixture was stirred at ambient temperature overnight and the reaction quenched with saturated ammonium chloride (10.0 mL). The mixture was extracted with ethyl acetate (3X 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) to give 5, 5-dimethyl-1' - (pyridin-3-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one as a white solid (0.05g, 48%), which was treated with 2.0M HCl in diethyl ether to obtain the title compound: melting point 124-;¹H NMR(300MHz，CD₃OD)8.96(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)178.9，161.6，161.1，145.4，141.3，141.1，132.5，130.1，128.8，124.0，123.9，120.1，116.2，108.8，92.6，85.1，80.2， 57.8，41.0，40.5，26.5，26.4；MS(ES+)m/z 399.5(M+1)。

example 10.23

5, 5-dimethyl-1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.22, and making non-critical changes, using 2- (bromomethyl) -pyridine hydrobromide instead of 3- (bromomethyl) -pyridine hydrobromide, the title compound was obtained (45%): melting point 145-147 deg.C; ¹H NMR(300MHz，CD₃OD)8.86(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)177.4，160.0，159.6，150.3，144.7，141.0，139.7，131.0，128.6，127.2，124.3，123.7，122.6，122.4，118.5，114.8，107.2，91.0，83.6，78.7，56.3，40.1，39.4，24.9，24.8；MS(ES+)m/z399.5(M+1)。

Example 10.24

Synthesis of 1 '- [ (6-methylpyridin-3-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.21, and making non-critical changes, (6-methylpyridin-3-yl) methyl 4-benzenesulphonate was used instead of 2-bromomethyl-5- (trifluoromethyl) furan, and spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 ' (1 ' H) -one to give 1 ' - [ (6-methylpyridin-3-yl) methyl]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one (56%) which was treated with 2.0M HCl in diethyl ether to obtain the title compound:¹H NMR(300MHz，CD₃OD)8.77(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)180.0，157.6，155.1，150.6，146.6，143.8，142.7，141.2，135.7，133.5，130.3，129.5，125.3，125.2，120.5，110.3，103.8，103.0，94.3，81.5，59.7，41.5，19.5；MS(ES+)m/z387.4(M+1)。

example 10.25

Synthesis of 1 '- [ (6-methoxypyridin-3-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 10.21, and making non-critical changes, (6-methoxypyridin-3-yl) methyl 4-benzenesulphonate was used instead of 2-bromomethyl-5- (trifluoromethyl) furan, and spiro [ furo [2, 3-f ] ][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one to obtain the title compound (45%):¹H NMR(300MHz，CDCl₃)8.19(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)177.6，163.7，155.9，149.0，145.3，142.4，141.6，138.9，132.2，129.0，124.4，124.1， 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/z403.2(M+1)。

example 10.26

Synthesis of 1 '- [ (6-chloropyridin-3-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, 2-chloro-5- (chloromethyl) pyridine was used instead of 2-bromomethyl-5- (trifluoromethyl) furan, and spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one to obtain the title compound (69%):¹H NMR(300MHz，CDCl₃)8.42(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

Synthesis of 1 '- { [6- (dimethylamino) pyridin-3-yl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Adding 1' - ((6-chloropyridin-3-yl) methyl) -6H-spiro [ benzofuro [6, 5-d) to a sealed tube][1，3]Dioxole-7, 3' -indolines]-2' -one (0.10g, 0.25mmol) and dimethylamine (2.00mL, 2M in THF, 4.00 mmol). The mixture was stirred at 130 ℃ overnight. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/2) to give 1' - { [6- (dimethylamino) pyridin-3-yl ]Methyl } spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one as a white solid (50mg, 48%), which was treated with 2.0M HCl in diethyl ether to afford the title compound: melting point 146-;¹H NMR(300MHz，CD₃OD)8.03(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)179.9，157.6，154.6，150.5，143.8，143.4，142.9，137.7，133.5，130.2，125.1，121.8，120.6，113.2，110.4，103.7，103.0，94.3，81.4，59.7，41.1，39.5；MS(ES+)m/z416.5(M+1)。

example 10.28

Synthesis of 1 '- [ (6-morpholin-4-ylpyridin-3-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.27, and making non-critical changes, morpholine was used instead of dimethylamine solution, the title compound was obtained (52%): melting point 185-200 ℃;¹H NMR(300MHz，CD₃OD)8.13-8.04(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)180.0，157.6，153.7，150.5，145.1，143.8，142.8，136.3，133.5，130.3，125.2，125.1，123.6，120.6，114.6，110.4，103.7，103.0，94.3， 81.5，66.7，59.7，47.2，40.9；MS(ES+)m/z458.5(M+1)。

example 10.29

Synthesis of 1 '- [ (6-pyrrolidin-1-ylpyridin-3-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.27, and making non-critical changes, pyrrolidine was used instead of dimethylamine solution, the title compound was obtained (45%): melting point 160-;¹H NMR(300MHz，CD₃OD)7.99-7.91(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)177.0，154.6，148.0，147.6，141.1，140.8，139.9，132.5，130.5，127.3，122.2，118.8，117.6，112.0，107.4，100.7，100.0，91.3，78.5，56.7，38.0，23.2；MS(ES+)m/z442.2(M+1)。

example 10.30

Synthesis of 1 '- (2-chloro-4-fluorobenzyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and 1- (bromomethyl) -2-chloro-4-fluorobenzene instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (54%) was obtained as a white solid: melting point 174-175 ℃; MS (ES +) M/z 424.2(M + 1).

Example 10.31

Synthesis of 1 '- [ (2-methylcyclopropyl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and 1- (bromomethyl) -2-methylcyclopropane instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (37%) was obtained as a white solid: MS (ES +) M/z 350.3(M + 1).

Example 10.32

Synthesis of 1 '- (3-cyclopropyl propyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and (3-bromopropyl) cyclopropane instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (51%) was obtained as a white solid: melting point 111-113 ℃; MS (ES +) M/z 364.3(M + 1).

Example 10.33

Synthesis of 1 '-butylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and 1-bromobutane instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (62%) was obtained as a white solid: melting point 119-120 ℃; MS (ES +) M/z 338.3(M + 1).

Example 10.34

Synthesis of 1 '- [ (5-methylisoxazol-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one, and 4- (bromomethyl) -5-methylisoxazole instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (25%) was obtained as a white solid: melting point 159-161 deg.C; ¹H NMR(300MHz，DMSO-d₆) 7.39-6.91(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/z377.3(M+1)。

Example 10.35

Synthesis of 1 '- (tetrahydro-2H-pyran-4-ylmethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one, and 4- (bromomethyl) tetrahydro-2H-pyran instead of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound (25%) as a white solid: melting point 142-144 ℃;¹H NMR(300MHz，DMSO-d₆)7.34-6.85(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/z380.3(M+1)。

example 10.36

Synthesis of 1 '[ 2- (trifluoromethoxy) benzyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and 1- (bromomethyl) -2- (trifluoromethoxy) benzene instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (77%) was obtained as a white solid: melting point 130-; MS (ES +) M/z 456.3(M + 1).

Example 10.37

Synthesis of 1 '[ 3- (trifluoromethoxy) benzyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one and 1- (bromomethyl) -3- (trifluoromethoxy) benzene was used instead of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound (65%) as a white solid: the melting point is 88-91 ℃; MS (ES +) M/z 456.3(M + 1).

Example 10.38

Synthesis of 1 '[ 4- (trifluoromethoxy) benzyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one and 1- (bromomethyl) -4- (trifluoromethoxy) benzene instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (50%) was obtained as a white solid: the melting point is 99-101 ℃; MS (ES +) M/z 456.3(M + 1).

Example 10.39

Synthesis of 1 '-methyl spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and iodomethane instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (72%) was obtained as a white solid: melting point 142-144 ℃; MS (ES +) M/z 296.2(M + 1).

Example 10.40

Synthesis of 1 '-propylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and 1-bromopropane instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (64%) was obtained as a white solid: melting point 158-160 ℃; MS (ES +) M/z 324.4(M + 1).

Example 10.41

Synthesis of 1 '- (2, 1, 3-benzoxadiazol-5-ylmethyl) spiro [ furo-2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and 5- (bromomethyl) benzo [ c ] [1, 2, 5] oxadiazole instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (17%) was obtained as a white solid: melting point 163-; MS (ES +) M/z 414.4(M + 1).

Example 10.42

Synthesis of 1 '[ (1-methyl-1H-benzotriazol-6-yl) methyl ] spiro [ furo-2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, and making non-critical changes, the 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and 6- (bromomethyl) -1-methyl-1H-benzotriazole instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (17%) was obtained as a white solid: melting point 230-; MS (ES +) M/z 427.3(M + 1).

Example 10.43

Synthesis of tert-butyl 4- [ (2 ' -keto-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b ' ] difuran-3, 3 ' -indol ] -1 ' (2 ' H) -yl) methyl ] piperidine-1-carboxylate

Following the procedure described in example 10.21, with non-critical changes, 5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one, and tert-butyl 4- (bromomethyl) piperidine-1-carboxylate instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, to give the title compound (58%) as a white solid: the melting point is 96-98 ℃;¹H NMR(300MHz，DMSO-d₆)7.84-6.85(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/z477.4(M+1)。

example 10.44

1' - (2, 3-difluorobenzyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, with non-critical changes, 5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one, and 1- (bromomethyl) -2, 3-difluorobenzene instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, to give the title compound (67%) as a white solid: melting point 156-; ¹H NMR(300MHz，DMSO-d₆)7.50-6.85(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/z406.2(M+1)。

Example 10.45

1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure described in example 10.21, with non-critical changes, 5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 ' (1 ' H) -one, and 2- (bromomethyl) pyridine hydrobromide in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give 1 ' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5,4-b′]Difuran-3, 3' -indoles]2 '(1' H) -one (27%) as a white solid, which was in CH₂Cl₂Using excess HCl in ether treatment to obtain the title compound: melting point 208-;¹H NMR(300MHz，DMSO-d₆)8.78-8.53(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/z371.4(M+1)。

example 10.46

1' - (4-methoxybenzyl) -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.21, with non-critical changes, 5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one, and 1- (chloromethyl) -4-methoxybenzene instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (56%) was obtained as a white solid: melting point 120-; MS (ES +) M/z 400.2(M + 1).

Example 10.47

Synthesis of 4 ' -bromo-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

In 4' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a solution of-2 '(1' H) -one (0.48g, 1.33mmol) in N, N-dimethylformamide (5.00mL) was added sodium hydride (0.08g, 1.98mmol, 60% dispersion in mineral oil) in one portion at 0 ℃. The reaction mixture was stirred for 0.5 h, then a solution of 2- (bromomethyl) -5-trifluoromethyl) furan in N, N-dimethylformamide (1.00mL) was added. The reaction mixture was stirred at ambient temperature for 16 hours and quenched by the slow addition of water (5.00 mL). The reaction mixture was extracted with ethyl acetate (3 × 20.0mL), washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue is subjected to column chromatography with ethyl acetate: hexane (35%) was eluted to give the title compound (0.46g, 69%) as a colorless solid:¹H NMR(300MHz，CDCl₃)7.22-7.14(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，2H)，4.94(ABq，2H)，4.92(ABq，2H)； ¹³C NMR(75MHz，CDCl₃)177.0，157.2，151.6，151.5，149.3，143.4，142.2，130.5，127.8，129.6，120.1，116.0，112.7，109.5，107.9，102.5，101.6，93.3，77.1，59.6，37.1；MS(ES+)m/z508.2(M+2)。

example 10.48

4 '-bromo-1' - { [5- (trifluoromethyl) -2-furanyl ] methyl } -5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, with non-critical changes, 4' -bromo-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 ' (1 ' H) -one instead of 4 '-bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one to obtain the title compound (76%) as a colorless solid: melting point 182-;¹H NMR(300MHz，CDCl₃)7.21-7.11(m，2H)，6.92(dd，1H)，6.74(d，1H)，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)177.3，162.4，162.2，151.5，143.4，130.2，127.7，120.5，120.0，119.7，118.4，117.0，112.7，112.6，109.5，107.8，92.9，77.1，72.4，59.1，37.0，28.9；MS(ES+)m/z506.3(M+1)。

example 10.49

Synthesis of 4 ' -bromo-1 ' -methyl spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure described in example 10.47, and making non-critical changes, iodomethane was used instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (79%) was obtained as a colorless solid: melting point 155-;¹H NMR(300MHz，CDCl₃)7.19(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)177.3，157.2，149.2，145.1，142.0，130.4，129.9，127.3，119.9，116.3，107.3，102.7，101.5，93.3，77.3，59.7，26.9；MS(ES+)m/z376.4(M+2)。

example 10.50

Synthesis of tert-butyl 4- [ (4 ' -bromo-2 ' -ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -1 ' (2 ' H) -yl) methyl ] piperidine-1-carboxylate

Following the procedure described in example 10.47, with non-critical changes, using 4- ({ [ (4-methylphenyl) sulfonyl]Oxy } methyl) piperidine-1-carboxylic acid tert-butyl ester instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (43%) was obtained as a colorless solid: ¹H NMR(300MHz，CDCl₃)7.17(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)177.6，157.3，154.7，149.2，144.8，142.1，130.3，129.8，127.3，120.2，116.3，107.6，102.4，101.6，93.4，79.6，77.2，59.6，46.1，43.4，34.9，28.4；MS(ES+)m/z581.4(M+23)，579.4(M+23)，503.3(M-57)，501.3(M-57)。

Example 10.51

Synthesis of 1 '- [ (3, 5-dimethylisoxazol-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, substituted with 4- (chloromethyl) -3, 5-dimethylisoxazoleInstead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (35%) was obtained as a colorless solid: melting point 165-167 ℃;¹H NMR(300MHz，CDCl₃)7.24(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)177.5，167.1，159.1，156.1，149.1，142.4，141.7，131.8，129.0，124.3，123.8，118.9，108.8，108.6，102.9，101.6，93.8，80.6，58.2，33.3，11.5，10.7；MS(ES+)m/z391.3(M+1)。

example 10.52

Synthesis of 1 '- (2-furylmethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 2-chloromethylfuran instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (40%) as a colorless solid: melting point 110-; ¹H NMR(300MHz，CDCl₃)7.35-7.33(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)177.1，155.9，149.0，148.9，142.6，142.3，141.8，132.2，128.9，123.8，123.5，119.5，110.6，109.3，108.7，103.1，101.5，93.6，80.4，58.2，37.1；MS(ES+)m/z362.5(M+1)。

Example 10.53

Synthesis of ethyl 5- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) pentanoate

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and substituting ethyl 5-bromopentanoate for 2- (bromomethyl) -5- (trifluoromethyl) furan to obtain the title compound (62%) as a sticky substance:¹H NMR(300MHz，CDCl₃)7.28(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)177.4，173.1，155.9，148.8，142.3，142.2，132.5，128.9，124.04，123.3，119.5，108.6，103.0，101.5，93.6，80.5，60.4，58.2，39.9，33.7，26.8，22.2，14.2；MS(ES+)m/z432.09(M+23)。

example 10.54

Synthesis of ethyl 4- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) butyrate

According toThe procedure described in example 10.47, with non-critical changes, was followed using the spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and substituting ethyl 4-bromobutyrate for 2- (bromomethyl) -5- (trifluoromethyl) furan to obtain the title compound (80%) as a sticky substance:¹H NMR(300MHz，CDCl₃)7.29(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)177.4，172.8，156.0，148.9，142.4，142.2，132.4，129.0，124.0，123.3，119.4，108.7，103.0，101.5，93.6，80.5，60.7，58.2，39.6，31.2，22.6，14.3；MS(ES+)m/z 418.08(M+23)，396.1(M+1)。

example 10.55

Synthesis of 1 '- (1, 2, 4-oxadiazol-3-ylmethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 3- (chloromethyl) -1, 2, 4-oxadiazole instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (36%) was obtained as a colorless solid: melting point 160-162 ℃;¹H NMR(300MHz，CDCl₃)7.39(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)176.7，156.0，149.3，142.5，139.6，131.6，129.4，124.8，124.5，118.4，113.6，108.7，103.0，101.7，93.7，80.3，58.2，29.7，28.0；MS(ES+)m/z365.2(M+1)。

example 10.56

Synthesis of 1 '- { [5- (3-chlorophenyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one from 2- (chloromethyl) -5- [ 3-chlorophenyl]Furan instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (22%) was obtained as a colorless solid: melting point 205-; ¹H NMR(300MHz，CDCl₃)7.55(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)177.2，155.9，152.5，149.2，148.9，142.4，141.7，134.8，132.1，132.0，130.1，128.9，127.5，124.0，123.7，123.6，121.7，119.4，110.8，109.2，106.9，103.0，101.5，93.6，80.4，58.2，37.3；MS(ES+)m/z472.2(M+1)。

Example 10.57

Synthesis of 1 '- (3-chloropropyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and replacing 2- (bromomethyl) -5- (trifluoromethyl) furan with 1-bromo-3-chloropropane to give the title compound (22%) as a colorless solid: melting point 144-146 ℃;¹H NMR(300MHz，CDCl₃)7.31(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)177.2，155.8，148.7，142.9，142.2，132.4，129.3，124.1，123.3，120.3，109.3，103.6，101.7，80.3，57.8，43.4，30.6；MS(ES+)m/z358.2(M+1)。

example 10.58

Synthesis of 1 '- [ (2-isopropyl-1, 3-thiazol-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 4Chloromethyl-2-isopropylthiazole instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (22%) was obtained as a colorless solid: melting point 118-; ¹H NMR(300MHz，DMSO-d₆)7.97(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)176.9，169.1，155.6，148.7，142.4，142.2，136.8，135.2，132.4，129.2，123.9，123.4，120.5，109.9，103.6，101.9，93.7，79.9，57.9，36.2，28.1，20.7，20.6；MS(ES+)m/z405.2(M+1)。

Example 10.59

Synthesis of 1 '- [ (1-methyl-1H-benzimidazol-2-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 2- (bromomethyl) -1-methyl-1H-benzimidazole instead of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound (22%) as a colorless solid: melting point is more than 250 ℃;¹H NMR(300MHz，CDCl₃)7.71(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)177.2，155.9，150.6，149.6，148.9，142.3，141.7，132.1，131.8，129.8，128.9，127.9，126.8，126.7，126.6，123.9，123.6，119.4，111.0，110.9，110.6，109.3，103.1，101.5，93.6，80.4，58.2，37.3；MS(ES+)m/z506.3(M+1)。

example 10.60

Synthesis of 1 '- [ (2-keto-1, 3-benzothiazol-3 (2H) -yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 3- (bromomethyl) -benzo [ d]Thiazol-2 (3H) -one instead of 2- (bromomethyl) -5- (trifluoromethyl) furan gave the title compound (31%) as a colorless solid: ¹H NMR(300MHz，DMSO-d₆)7.67(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)178.1，170.6，155.9，148.9，142.2，141.0，136.1，131.8，129.6，127.3，124.5，124.4，124.3，123.7，121.5，119.8，112.1，110.0，103.4，101.9，93.8，80.3，58.3，47.9；MS(ES+)m/z467.2(M+23)。

Example 10.61

Synthesis of 1 ' - [ (5-chloro-2-thienyl) methyl ] -5 ' -fluorospiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure described in example 10.47, with non-critical changes, 5' -fluorospiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 5-chloro-2- (chloromethyl) thiophene instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (76%) was obtained as a colorless solid: melting point 142-144 ℃;¹H NMR(300MHz，DMSO-d₆)7.22-7.17(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)176.9，161.0，157.8，156.0，149.0，142.2，138.3，138.2(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/z430.1(M+1)。

example 10.62

Synthesis of 1 '- [ (5-chloro-2-furyl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

To an ice-cooled solution of (5-chloro-2-furyl) methanol (2.03g, 15.3mmol) in anhydrous dichloromethane (50.0mL) was added triethylamine (4.64)g, 45.9mmol) followed by thionyl chloride (3.64g, 30.6 mmol). The reaction mixture was stirred at 0 ℃ for 30 minutes and quenched with saturated ammonium chloride (25.0 mL). After separating the aqueous layer, the organic layer was washed with 10% aqueous HCl (20.0mL), brine (20mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo to give 5-chloro-2-chloromethylfuran as a yellow oil. A solution of this oil in anhydrous N, N-dimethylformamide (3.00mL) was added directly to the spiro [ furo [2, 3-f ] without any further purification ][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one (0.84g, 3.00mmol) in a mixture with sodium hydroxide (0.48g, 12.0mmol) in anhydrous N, N-dimethylformamide (9.00 mL). The reaction mixture was heated at 70 ℃ for 16 h, cooled to ambient temperature, and then saturated ammonium chloride (5.0) was added. N, N-dimethylformamide was removed under high vacuum. The residue was diluted with ethyl acetate (100mL), washed with 10% aqueous HCl (25.0mL), brine (25.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The brown residue was subjected to column chromatography, eluting with ethyl acetate/hexane (35%) to give the title compound (0.74g, 62%) as a colorless solid: melting point 148-;¹H NMR(300MHz，DMSO-d₆)7.29(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)176.9，155.8，149.7，148.8，142.2，142.1，134.8，132.1，129.3，124.1，123.7，120.2，112.0，109.9，108.2，103.2，101.9，93.8，80.0，57.9，37.0；MS(ES+)m/z396(M+1)。

example 10.63

Synthesis of 1 '- [ (4-hydroxy-1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.62, with non-critical changes, 5, 6, 7, 7-pentamethyl-1-oxa-6-azaspiro [2.5 ] was used]Octane instead of (5-chloro-2-furyl) methanol, the title compound (70%) was obtained as a colorless solid: melting point 210-; ¹H NMR(300MHz，DMSO-d₆)7.29(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)178.5，156.0，148.7，144.5，142.2，132.3，128.9，123.8，123.2，120.3，110.9，104.1，101.9，93.7，80.9，71.6，65.3，57.8，52.6，30.2，28.7，22.1；MS(ES+)m/z465.4(M+1)。

Example 10.64

Synthesis of 1 '- { [5- (2-chlorophenyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.62, and making non-critical changes, [5- (2-chlorophenyl) -2-furyl ] was used]Methanol instead of (5-chloro-2-furyl) methanol, the title compound (48%) was obtained as a colorless solid: melting point 148-;¹H NMR(300MHz，CDCl₃)7.74(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)177.2，155.9，150.3，149.0，148.6，142.4，141.8，132.1，130.8，130.0，128.9，128.7，128.2，127.7，126.9，123.9，123.6，119.4，111.8，110.7，109.2，103.1，101.5，93.6，80.4，58.2，37.3；MS(ES+)m/z472.2(M+1)。

example 10.65

Synthesis of 1 '- [ (5-methyl-2-furyl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.62, and making non-critical changes, (5-methyl-2-furyl) methanol was used instead of (5-chloro-2-furyl) methanol to give the title compound (70%) as a colorless solid: melting point 117-;¹H NMR(300MHz，DMSO-d₆)7.26(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)176.8，155.7，151.9，148.8，147.7，142.3，142.2，132.1，129.2，124.0，123.5，120.4，110.1，110.0，107.0，103.2，101.9，93.8，79.9，57.9，37.2，13.7；MS(ES+)m/z376(M+1)。

example 10.66

Synthesis of 1 '- [ (5-bromo-2-furyl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.62, and making non-critical changes, (5-bromo-2-furyl) methanol was used instead of (5-chloro-2-furyl) methanol to give the title compound (76%) as a colorless solid: ¹H NMR(300MHz，DMSO-d₆)9.29(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)176.9，160.4，156.3，153.8，149.7，146.1，137.5，130.9，130.8，126.5，125.8，123.1，121.5，118.8，116.4，108.3，96.7，76.6，71.9，45.7，29.1；MS(ES+)m/z440.1(M+1)，442.1(M+1)。

Example 10.67

Synthesis of 1 '- [ (5-chloro-2-thienyl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.62, and making non-critical changes, (5-chloro-2-thienyl) methanol was used instead of (5-chloro-2-furyl) methanol to give the title compound (77%) as a colorless solid: melting point 145-146 deg.C;¹H NMR(300MHz，DMSO-d₆)7.28(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/z411.9(M+1)。

example 10.68

Synthesis of 1 '- { [ 3-hydroxy-5- (trifluoromethyl) -2-thienyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.62, and making non-critical changes, using 2- (hydroxymethyl) -5- (trifluoromethyl) thiophen-3-ol instead of (5-chloro-2-furanyl) methanol, the title compound was obtained (48%) as a colorless solid: melting point 225-;¹H NMR(300MHz，DMSO-d₆)10.4(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)；¹³CNMR(75MHz，DMSO-d₆)176.9，155.8，152.3，148.9，142.2，141.9，132.1，129.4，125.9，125.4，124.5，124.2，123.8，122.6，120.9，120.0，116.5，109.5，103.3，101.9，93.8，80.2，57.9，34.9；MS(ES+)m/z460.38(M-1)。

example 10.69

Synthesis of 1 ' - ((5- (2- (trifluoromethyl) phenyl) furan-2-yl) methyl) -6H-spiro [ benzofuran [6, 5-d ] [1, 3] dioxolane-7, 3 ' -indol ] -2 ' -one

Following the procedure described in example 10.62, and making non-critical changes, {5- [2- (trifluoromethyl) phenyl ]]-2-furyl } methanol instead of (5-chloro-2-furyl) methanol, the title compound (28%) was obtained as a colorless solid: melting point 124-; ¹H NMR(300MHz，CDCl₃)7.71(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)177.2，155.9，150.6，149.6，148.9，142.3，141.7，132.1，131.8，129.8，128.9，127.9，126.8，126.7，126.6，123.9，123.6，119.4，111.0，110.9，110.6，109.3，103.1，101.5，93.6，80.4，58.2，37.3；MS(ES+)m/z 506.27(M+1)。

Example 10.70

Synthesis of 1 '[ (2-chloro-1, 3-thiazol-5-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

In (2-chloro-1, 3-thiazol-5-yl) methanol (0.30g, 2.00mmol) in anhydrous CH₂Cl₂To a solution (20.0mL) was added thionyl chloride (0.50g, 4.20mmol) followed by triethylamine (0.40g, 4.00mmol) at 0 ℃. After stirring at 0 ℃ for 1 hour and at ambient temperature for 1 hour, the reaction mixture is stirred with CH₂Cl₂Diluted (50.0mL) and extracted with water (2X 20 mL). The organic phase is treated with Na₂SO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in methyl-ethyl ketone (10.0mL) and then spiro [ furo [2, 3-f ] was added][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one (0.36g, 2.00mmol) and cesium carbonate (1.95g, 6.00 mmol). The reaction mixture was heated at 70 ℃ overnight, cooled, filtered and the filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography to give the title compound (0.032g, 3.4%) as a colorless solid: melting point 195-198 deg.C;¹H NMR(300MHz，DMSO-d₆)7.81(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-furanyl ] methyl } -6, 7-dihydrospiro [ benzo [1, 2-b: synthesis of 4, 5-b '] difuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 10.21, with non-critical changes, the reaction was carried out using the 6, 7-dihydrospiro [ benzo [1, 2-b: 4, 5-b']Difuran-3, 3' -indoles]-2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one to obtain the title compound (19%) as a white solid: melting point 174-177 ℃;¹H NMR(300MHz，DMSO-d₆)7.33-6.95(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/z428.0(M+1)。

example 10.72

1' { [5- (trifluoromethyl) -2-furyl ] methyl }5, 6-dihydrospiro [ benzo [1, 2-b: synthesis of 5, 4-b '] difuran-3, 3' -indole ]2 '(1' H) -one

Following the procedure described in example 10.21, with non-critical changes, 5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]2 '(1' H) -one instead of 5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1, 2-b: 5, 4-b']Difuran-3, 3' -indoles]-2 '(1' H) -one to obtain the title compound (71%) as a white solid: melting point 173-176 ℃;¹H NMR(300MHz，DMSO-d₆)7.50-6.90(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)；¹³CNMR(75MHz，DMSO-d₆)177.2，161.7，161.0，153.5，142.0，140.3，139.7，139.2，132.6，129.1，124.1，123.8，121.2，121.0，120.3，119.1， 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/z428.2(M+1)。

example 10.73

Synthesis of 1 '- { [5- (trifluoromethyl) -2-thienyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

To 1' - { [ 3-hydroxy-5- (trifluoromethyl) -2-thienyl ]Methyl } spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a solution of-2 '(1' H) -one (0.75g, 1.62mmol) in dry dichloromethane (12.0mL) was added triethylamine (0.49g, 0.70mL, 4.85mmol) and trifluoromethanesulfonic anhydride (0.91g, 0.50mL, 3.24mmol) at 0 deg.C under nitrogen. The reaction mixture was stirred for 30 minutes and quenched with saturated ammonium chloride (15.0 mL). After separating the aqueous layer, the organic layer was washed with 10% HCl (10.0mL), brine (10.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography to provide a brown sticky substance as trifluoromethanesulfonate. A mixture of this trifluoromethanesulfonate (15.3mmol), tetrakis (triphenylphosphine) palladium (0) (0.19g, 0.17mmol), triethylamine (1.66g, 2.30mL, 16.5mmol) and formic acid (0.76mg, 0.60mL, 16.5mmol) in anhydrous dioxane (24mL) was heated at reflux for 16 h. After cooling the reaction mixture to ambient temperature, the solvent was removed under reduced pressure. The black residue was washed with ethyl acetateThe ester (50.0mL) was diluted, washed with 10% HCl (20.0mL), saturated ammonium chloride (20.0mL), brine (20.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue is subjected to column chromatography with ethyl acetate: hexane (35%) eluted to give the title compound (0.65g, 89%) as a colorless solid: melting point 127-; ¹H NMR(300MHz，DMSO-d₆)7.58-7.56(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)177.0，155.9，148.9，144.7，142.2，141.8，132.1，130.6，130.5，129.3，128.7，128.0，124.3，123.9， 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

Synthesis of 1 '- { [ 3-methoxy-5- (trifluoromethyl) -2-thienyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

1' - { [ 3-hydroxy-5- (trifluoromethyl) -2-thienyl]Methyl } spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]A mixture of-2 '(1' H) -one (0.18g, 0.39mmol), NaOH (0.08g, 1.96mmol) and iodomethane (0.17g, 1.18mmol) in dry N, N-dimethylformamide (2.00mL) was stirred at ambient temperature for 16H. The reaction was quenched by the addition of saturated ammonium chloride (10.0mL) and extracted with ethyl acetate (3X 50.0 mL). The combined organic layers were washed with water (3 × 20.0mL), brine (20.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The colorless solid was triturated with ether to give the title compound (0.15g, 81%): melting point 178-;¹H NMR(300MHz，DMSO-d₆)7.71(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)；¹³CNMR(75MHz，DMSO-d₆)177.0，155.8，154.9，148.9，142.2，141.8，132.1，129.4，125.7，124.3，123.8，120.4，120.3，120.0，119.5，109.4，103.2，102.0，93.9，80.1，59.9，57.9，34.9；MS(ES+)m/z476.3(M+1)。

example 10.75

Synthesis of 4 ' -methyl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Reacting 4 '-bromo-1' - ((5- (trifluoromethyl) furan-2-yl) methyl) -6H-spiro [ benzofuro [6, 5-d) ][1，3]Dioxole-7, 3' -indolines]-2' -one (0.51g, 1.00mmol), lithium chloride (0.09mg, 2.00mmol), Pd₂(dba)₃(0.09mg, 10 mol%) of the mixture was flushed with nitrogen. To the above mixture, anhydrous 1-methyl-2-pyrrolidone (5.00mL) and tetramethyltin (0.27mg, 0.20mL, 1.50mmol) were added. The reaction mixture was heated at 60 ℃ for 16 h and quenched with saturated ammonium chloride (10.0 mL). The reaction mixture was extracted with ethyl acetate (3X 10.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue is subjected to column chromatography with ethyl acetate: hexane (20%) eluted to give the title compound (0.07g, 16%) as a colorless solid: melting point 117-;¹H NMR(300MHz，CDCl₃)7.18(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)177.6，156.2，152.0，149.1，142.3，141.3，135.6，129.4，128.9，126.0，120.6，117.2，112.7，112.6，109.2，106.5，102.9，101.6，93.3，78.4，58.3，37.0，17.1；MS(ES+)m/z444.1(M+1)。

example 10.76

Synthesis of 5 ' -methyl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3 ' -indol ] -2 ' (1 ' H) -one

Following the procedure described in example 10.47, with non-critical changes, 5' -methyl spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles ]-2 '(1' H) -ketone to give the title compound (77%): the melting point is 96-98 ℃;¹H NMR(300MHz，CDCl₃)7.09(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/z444.2(M+1)。

example 10.77

Synthesis of 1 '- ({5- [4- (trifluoromethyl) phenyl ] -1, 2, 4-oxadiazol-3-yl } methyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one from 3-chloromethyl-5- [4- (trifluoromethyl) phenyl]-1, 2, 4-oxadiazole instead of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound (44%):¹H NMR(300MHz，CDCl₃)8.22(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/z508.1(M+1)。

example 10.78

Synthesis of 1 '- (2-thienylmethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.62, and making non-critical changes, using 2-thiophenemethanol instead of (5-chloro-2-furanyl) methanol, the title compound was obtained (37%) as a colorless solid:¹H NMR(300MHz，CDCl₃)7.26-7.20(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

Synthesis of 5- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indole ]1 '(2' H) -yl) methyl ] thiophene-2-carbonitrile

1' - [ (5-bromo-2-thienyl) methyl]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]A mixture of-2 ' (1 ' H) -one (0.23g, 0.49mmol), zinc cyanide (0.07g, 0.59mmol), tris (dibenzylideneacetone) dipalladium (0) (0.10g, 0.11mmol), 1 ' -bis (diphenylphosphino) ferrocene (0.06g, 0.11mmol), N-dimethylformamide (6.00mL), and a catalytic amount of water (2 drops) was heated at 120 ℃ for 24 hours. After cooling to ambient temperature, the organic solvent was evaporated in vacuo. The residue was extracted with ethyl acetate (5 × 15.0mL) and the combined organic solutions were passed through a bed of celite. The filtrate was washed successively with saturated aqueous ammonium chloride (25.0mL), water (2X 35.0mL) and brine (40.0 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography, eluting with 20-35% ethyl acetate in hexane to give a solid which was further purified by preparative thin layer chromatography, eluting with 20% ethyl acetate in hexane to afford the title compound (0.09g, 44%):¹H NMR(300MHz，CDCl₃)7.50(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/z403.0(M+1)。

example 10.80

Synthesis of 5- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] -2-furancarbonitrile

Following the procedure described in example 10.79 and carrying outA key modification is the use of 1' - [ (5-bromo-2-furyl) methyl]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 1 ' - [ (5-bromo-2-thienyl) methyl]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one to obtain the title compound (44%) as a colorless solid: melting point 167-169 deg.C;¹H NMR(300MHz，CDCl₃)7.34-7.27(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/z387.2(M+1)。

example 10.81

Synthesis of 1 '- { [5- (methylsulfonyl) -2-furyl ] methyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

1' - [ (5-bromo-2-furyl) methyl]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]A mixture of-2 '(1' H) -one (0.70g, 1.59mmol), sodium methanesulfinate (85%, 0.23g, 1.91mmol), copper (I) iodide (0.04g, 0.22mmol), L-proline (0.04g, 0.35mmol) and dimethyl sulfoxide (4.00mL) was heated at 100 ℃. After 3 days, the reaction mixture was cooled to ambient temperature, quenched with water (50.0mL), and extracted with ethyl acetate (3X 40.0 mL). The combined organic layers were washed with brine (2 × 50.0mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue is subjected to column chromatography with ethyl acetate: hexane (30-50%) eluted to give the title compound (0.50g, 71%): melting point 177-179 ℃; ¹H NMR(300MHz，CDCl₃)7.29(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)177.3，155.9，154.5，149.1，149.1，142.4，141.1，131.9，129.1，124.2，124.1，119.0，118.4，109.9，108.7，102.9，101.6，93.7，80.3，58.2，43.4，37.2；MS(ES+)m/z440.0(M+1)。

Example 10.82

Synthesis of 1 '- [ (6-keto-1, 6-dihydropyridin-3-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

In 1' - [ (6-methoxypyridin-3-yl) methyl]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a mixture of-2 '(1' H) -one (0.23g, 0.57mmol), sodium iodide (0.28g, 1.87mmol), water (2 drops) in anhydrous acetonitrile (5.00mL) was added trimethylsilicon chloride (0.19g, 1.78mmol) at 0 ℃. 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 (100mL) and washed with brine (2 × 25.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was triturated with ether (2 × 10.0mL) to give the title compound (0.16g, 72%) as a light yellow solid: melting point 247-;¹H NMR(300MHz，DMSO-d₆)11.50(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/z389.15(M+1)。

example 10.83

Synthesis of 1 '- [ (1-methyl-6-keto-1, 6-dihydropyridin-3-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in preparation 1A, with non-critical changes, 1' - [ (6-keto-1, 6-dihydropyridin-3-yl) methyl ] was used ]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one instead of 4-bromoindole and iodomethane instead of 1-bromopentane to obtain the title compound (78%): melting point 115-118 ℃;¹H NMR(300MHz，CDCl₃)7.39-7.23(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)177.8，162.5，155.9，149.1，142.4，141.6，139.7，137.6，132.1，129.1，124.4，123.9，121.3，119.1，114.0，108.6，102.8，101.6，93.7，80.3，58.2，40.8，38.0；MS(ES+)m/z403.3(M+1)。

example 10.84

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

Following the procedure described in example 10, with non-critical changes, 5-bromospiro [ 1-benzofuran-3, 3' -indole was used]-2 '(1' H) -one instead of spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and substituting 2-chloro-5- (chloromethyl) thiophene for 4-fluorobromideBenzyl to obtain the title compound (95%) as a white solid: melting point 140-142 ℃;¹H NMR(300MHz，CDCl₃)7.33-7.26(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/z446.7(M+1)，448.7(M+1)。

example 10.85

Synthesis of 1 '- [ (5-chloro-1, 3, 4-thiadiazol-2-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

In spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a solution of-2 '(1' H) -one (0.56g, 1.99mmol) and (5-chloro-1, 3, 4-thiadiazol-2-yl) methanol (0.30g, 1.99mmol) in anhydrous tetrahydrofuran (12.0mL) was added tributylphosphine (0.60g, 2.99mmol) at 0 ℃. The reaction mixture was stirred for 15 minutes, then N, N, N ', N' -tetramethylazodicarboxamide (0.51g, 2.99mmol) was added. The reaction mixture was stirred at ambient temperature overnight, quenched with aqueous ammonium chloride (10.0mL), and diluted with ethyl acetate (350 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (2X 25.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/2) to give the title compound (0.20g, 24%) as a yellowish solid: melting point 194 ℃ and 197 ℃; ¹H NMR(300MHz，DMSO-d₆)7.30(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)177.2，168.3，155.8，155.4，148.9，142.2，141.9，132.2，129.4，124.2，124.0，120.1，109.8，103.7，101.9，93.8，80.1，67.5，57.9，25.6；MS(ES+)m/z414.2(M+1)，416.2(M+1)。

Example 10.86

Synthesis of 1 '- [ (1-pyridin-2-ylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

1' - (piperidin-4-ylmethyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]A mixture of-2 '(1' H) -keto hydrobromide (0.20g, 0.44mmol), 2-bromopyridine (0.16mL, 0.65mmol), tetrabutylammonium iodide (0.05g), and DBU (0.16mL, 1.09mmol) in DMF (5.00mL) was heated at 120 ℃ for 15H. After cooling to ambient temperature, water (30.0mL) was added. The mixture was extracted twice with ethyl acetate (50.0mL) and the combined organic phases were extracted with Na₂SO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to flash chromatography, eluting with 30% ethyl acetate in hexane to give a white solid (0.05g, 27%): the melting point is 95-97 ℃;¹H NMR(300MHz，CDCl₃)8.17(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)177.9，158.8，156.1，149.0，147.4，142.8，142.5，138.0，132.4，129.1，124.2，123.5，119.5，112.9，108.8，107.7，103.1，101.7，93.8，80.7，58.3，46.0，45.5，45.4，35.2，29.8，29.7；MS(ES+)m/z456(M+1)。

example 10.87

Synthesis of 1 '- [ (1-phenyl-2-ylpiperidin-4-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

1' - (piperidin-4-ylmethyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxodioxole-7, 3' -indoles]-2 '(1' H) -keto hydrobromide (0.20g, 0.44mmol), 2-bromobenzene (0.07mL, 0.65mmol), Pd ₂(dba)₃(0.03g, 0.03mmol), BINAP (0.06g, 0.10mmol) and NaOBu^t(0.13g, 1.30mmol) in toluene was heated under nitrogen at 100 ℃ for 15 hours. After cooling to ambient temperature, water (30.0mL) was added. The mixture was extracted twice with ethyl acetate (50.0mL) and the combined organic phases were extracted with Na₂SO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to flash chromatography, eluting with 30% ethyl acetate in hexane to give a white solid (0.10g, 48%): melting point 76-78 deg.C;¹H NMR(300MHz，CDCl₃)7.37-7.16(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)；¹³CNMR(75MHz，CDCl₃)177.9，156.1，149.0，142.9，142.5，132.4，129.2，129.1，124.2，123.4，119.9，119.5，116.9，108.8，103.1，101.6，93.8，80.8，60.5，58.3，49.8，46.1，34.8，30.1，30.0；MS(ES+)m/z455(M+1)。

example 10.88

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

Following the procedure described in example 10.47, with non-critical changes, 6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indole]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and replacing 2- (bromomethyl) -2- (trifluoromethyl) furan with 2- (bromomethyl) pyridine hydrobromide to give 1 '- (pyridin-2-ylmethyl) -6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indole]-2 '(1' H) -one, which was treated with 4.0M HCl in dioxane to afford the title compound (39%): melting point 150-; ¹HNMR(300MHz，CD₃OD)8.89-8.78(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)179.4，163.5，153.1，152.7，148.2，143.8，142.8，133.1，130.6，129.3，127.4，126.8，125.7，125.6，125.4，114.9，110.4，104.9，82.0，58.9，43.0；MS(ES+)m/z413(M+1)。

Example 10.89

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

Following the procedure described in example 10.47, with non-critical changes, 6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indole]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, in combination with3- (bromomethyl) pyridine hydrobromide instead of 2- (bromomethyl) -5- (trifluoromethyl) furan to give 1 '- (pyridin-3-ylmethyl) -6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indole]-2 '(1' H) -one, which was treated with 4.0M HCl in dioxane to give the title compound (70%) as a white solid: melting point 151-;¹H NMR(300MHz，CD₃OD)9.07-8.61(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)；¹³CNMR(75MHz，CD₃OD)179.43，163.5，151.8，147.0，142.9，142.4，142.2，133.0，130.6，129.3，128.9，125.5，125.4，125.3，114.9，110.5，104.9，82.0，58.9，42.0；MS(ES+)m/z413(M+1)。

example 10.90

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

Following the procedure described in example 10.47, with non-critical changes, 6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indole]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles ]-2 '(1' H) -one to obtain the title compound (82%) as a white solid: melting point is 78-80 ℃;¹H NMR(300MHz，CDCl₃)7.33(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)176.7，161.7，151.9，150.6，141.5，131.7，129.5，127.5，124.2，124.2，124.0，114.1，112.8，112.8，109.6，109.2，104.3，80.7，57.6，37.1；MS(ES+)m/z470(M+1)。

example 10.91

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

Following the procedure described in example 10.47, with non-critical changes, 6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indole]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and substituting 4-methoxybenzyl chloride for 2- (bromomethyl) -5- (trifluoromethyl) furan to obtain the title compound (91%) as a white solid: melting point is 82-84 ℃;¹H NMR(300MHz，CDCl₃)7.32-6.80(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)171.1，161.8，159.4，150.5，142.3，132.0，129.2，128.9，127.7，124.1，124.0，123.7，122.2，118.8，114.4，114.1，109.7，104.3，80.9，57.6，55.4，43.9；MS(ES+)m/z442(M+1)。

example 10.92

Synthesis of 1 '- (cyclohexylmethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-73' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and bromomethylcyclohexane instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, the title compound (74%) was obtained as a white solid: melting point 153-; ¹H NMR(300MHz，CDCl₃)7.30(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)177.8，156.1，148.9，143.0，142.4，132.5，128.9，124.0，123.2，119.7，109.0，103.2，101.6，93.7，80.8，58.3，46.8，36.3，31.1，31.0，26.4，25.9，25.8；MS(ES+)m/z378(M+1)，400(M+23)。

Example 10.93

Synthesis of 1 '- (methylsulfonyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.47, and making non-critical changes, spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 4 ' -bromospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and methanesulfonyl chloride instead of 2- (bromomethyl) -5- (trifluoromethyl) furan, to give the title compound (51%) as a white solid: melting point 215-217 ℃;¹H NMR(300MHz，CDCl₃)7.83(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)176.9，155.8，149.5，142.7，138.1，130.5，129.7，125.9，124.3，118.5，113.8，102.9，101.8，93.8，80.6，58.8，41.8；MS(ES+)m/z360(M+1)，382(M+23)。

example 10.94

Synthesis of 1 '- (2-piperidin-1-ylethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

1' - (2-aminoethyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]A mixture of-2 '(1' H) -one (0.20g, 0.62mmol), 1, 5-dibromopentane (0.08mL, 0.62mmol) and triethylamine (0.17mL, 1.23mmol) in THF (10.0mL) was refluxed for 15H and concentrated to dryness in vacuo. The residue was subjected to flash chromatography, eluting with 10% methanol in ethyl acetate to give 1' - (2-piperidin-1-ylethyl) spiro [ furo [2, 3-f ] ][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, which was treated with 4.0M HCl in dioxane to afford the title compound (28%): the melting point is more than 240 ℃;¹H NMR(300MHz，CD₃OD)7.40(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)180.4，157.5，150.5，143.8，142.5，133.9，130.3，125.3，125.1，120.6，110.2，103.9，102.9，94.2，81.4，59.7，55.4，54.9，53.9，36.4，24.2，22.6；MS(ES+)m/z393(M+1)。

example 10.95

Synthesis of 1 '- [2- (pyridin-2-ylamino) ethyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one and 1 '- [2- (bispyridin-2-ylamino) ethyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Following the procedure described in example 10.87, with non-critical changes, 1' - (2-aminoethyl) spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one instead of 1 ' - (piperidin-4-ylmethyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 ' (1 ' H) -one, and substituting 2-bromopyridine for 2-bromobenzene to obtain 1 ' - (2- (pyridin-2-ylamino) ethyl) -spiro [ furo [2, 3-f)][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, the first eluting component from chromatography, as a white solid (5%): melting point is 61-63 ℃;¹H NMR(300MHz，CDCl₃)8.05(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)；¹³CNMR(75MHz，CDCl₃)178.4, 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/z402(M + 1). To obtain 1' - (2- (bipyridin-2-ylamino) ethyl) -spiro [ furo [2, 3-f ] ][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, second eluting component from chromatography (31%): melting point 165-167 ℃;¹H NMR(300MHz，CDCl₃)8.31(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)177.6，157.0，156.0，148.8，148.4，143.1，142.3，137.4，132.3，128.9，123.6，123.1，119.6，117.5，114.5，109.3，103.4，101.6，93.6，80.7，58.2，45.9，39.5；MS(ES+)m/z479(M+1)。

example 10.96

Synthesis of tert-butyl 4- [2- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indole ] -1 '(2' H) -yl) ethyl ] piperidine-1-carboxylate

Following the procedure as described in example 10, and making non-critical changes, 4- (2- { [ (4-methylphenyl) sulfonyl was used]Oxy } ethyl) piperidine-1-carboxylic acid tert-butyl ester instead of benzyl 4-fluorobenzo bromide gave the title compound in 95% yield: melting point 173-175 ℃;¹H NMR(300MHz，CDCl₃)7.31(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)177.5，156.0，155.0，149.0，142.4，142.2，132.6，129.0，124.2，123.4，119.5，108.6，103.0，101.6，93.8，80.5，79.5，58.3，38.0，34.0，33.9，32.1，31.9，28.6；MS(ES+)m/z515(M+23)，393(M-100)。

example 10.97

Synthesis of 1 '- (2-piperidin-4-ylethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

In the presence of 4- [2- (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) ethyl]To a solution of tert-butyl piperidine-1-carboxylate (0.94g, 1.91mmol) in dioxane (5.00mL) was added 4.0M HCl in dioxane (2.00mL, 8.00 mmol). The mixture was stirred at ambient temperature for 30 minutes, then anhydrous ether (40.0mL) was added. The precipitated white solid was filtered, washed with ether, and dried to give the title compound (0.75g, 91%): ¹H NMR(300MHz，CD₃OD)7.37(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)179.8，157.6，150.4，143.7，143.4，133.6，130.3，124.9，124.8，120.8，110.3，103.7，102.9，94.3，81.4，59.8，45.2，38.5，34.4，32.6，29.8，29.7；MS(ES+)m/z393(M+1)。

Example 10.98

Synthesis of 1 '- [2- (1-cyclopentylpiperidin-4-yl) ethyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

To a solution of cyclopentanone (0.04mL, 0.45mmol) and triethylamine (0.12mL, 0.84mmol) in dichloroethane (5.00mL) was added 1' - (2-piperidin-4-ylethyl) spiro [ furo [2, 3-f ] ethanol][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one hydrochloride (0.12g, 0.28mmol) and sodium triacetoxyborohydride (0.10g, 0.45 mmol). The reaction mixture was stirred for 16 hours and concentrated to dryness in vacuo. Subjecting the residue to flash chromatography with ethyl acetate/methanol/ammonium hydroxide(15/1/0.1) to give 1' - [2- (1-cyclopentylpiperidin-4-yl) ethyl]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one as a white solid, which was treated with 4.0M HCl in dioxane to give the title compound (0.05g, 32% yield): melting point 153-155 ℃;¹H NMR(300MHz，CD₃OD)7.37(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)179.8，157.6，150.4，143.8，143.4，133.6，130.3，124.9，124.8，120.8，110.3，103.7，103.0，94.3，81.4，69.1，59.8，53.2，38.6，34.3，32.5，30.6，30.5，29.4，24.7；MS(ES+)m/z461(M+1)。

example 10.99

Synthesis of 1 '- [2- (1-isopropylpiperidin-4-yl) ethyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.98, and making non-critical changes, using acetone instead of cyclopentanone, the title compound (42%) was obtained as a white solid: melting point 155-; ¹H NMR(300MHz，CD₃OD)7.37(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)179.8，157.6，150.5，143.8，143.4，133.6，130.3，125.0，124.8，120.8，110.3，103.7，103.0，94.3，81.4，59.8，59.6，38.6，34.2，32.7，30.6，30.5，24.2，16.9，15.4；MS(ES+)m/z435(M+1)。

Example 10.100

Synthesis of 1 '- [2- (1-cyclobutyl-piperidin-4-yl) ethyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 10.98, and making non-critical changes, cyclobutanone instead of cyclopentanone, the title compound was obtained (81%) as a white solid: melting point 158-160 ℃;¹H NMR(300MHz，CD₃OD)7.37(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)179.8，157.6，150.4，143.7，143.4，133.6，130.3，124.9，124.8，120.8，110.4，103.8，103.0，94.2，81.5，60.5，59.8，50.8，38.6，34.4，32.5，30.1，26.8，14.4；MS(ES+)m/z447(M+1)。

example 10.101

1' - {2- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl ] ethyl } spiro [ furo [2, 3-f ] [1, 3] benzene

Synthesis of benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one hydrochloride

According to the followingThe procedure described in example 10.98, and with non-critical changes, was used tetrahydro-4H-pyran-4-one instead of cyclopentanone to obtain the title compound (45%) as a white solid: melting point 168 and 170 ℃;¹H NMR(300MHz，CD₃OD)7.37(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)179.8，157.6，150.4，143.7，143.4，133.6，130.3，125.0，124.8，120.8，110.3，103.8，102.9，94.3，81.4，67.2，64.1，59.8，50.7，38.6，34.2，32，7，30.6，30.5，28.7；MS(ES+)m/z 477(M+1)。

example 11

Synthesis of 4- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoic acid

Following the procedure described in example 6, with non-critical changes, 4- [ (2' -ketospiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Replacement of 2- [ (2' -Keto spiro [ furo [2, 3-f ] by methyl benzoate ][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Methyl benzoate, the title compound (100%) was obtained:¹HNMR(300MHz，CDCl₃)12.96(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)177.4，167.5，156.0，148.9，142.6，142.3，141.8，132.1，130.5，130.3，129.3，127.7，124.2，123.7，120.1，109.9，103.5，101.9，93.8，80.4，58.0，43.4。

example 12

Synthesis of N- (3-fluorophenyl) -4- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzamide

A.4- [ (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Preparation of stock solutions of benzoyl chloride

To a stirred slurry of 4- [ (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -1 '(2' H) -yl) methyl ] benzoic acid (2.08g, 5.00mmol) in anhydrous chloroform (50.0mL) was added oxalyl chloride (0.95g, 7.50mmol) at ambient temperature followed by 1 drop of DMF. The mixture was stirred at ambient temperature for 2 hours and evaporated to dryness in vacuo. The residue was dissolved in anhydrous dichloromethane (60.0mL) to form a stock solution of acid chloride for use.

N- (3-fluorophenyl) -4- [ (2' -ketospiro [ furo [2, 3-f)][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) methyl]Synthesis of benzamide

To a solution of 3-fluoroaniline (0.02mL, 0.24mmol) in anhydrous dichloromethane (2.00mL) and triethylamine (0.05mL, 0.32mmol) at ambient temperature was added the stock solution of acid chloride obtained above (2.0mL, 0.081M in dichloromethane). The mixture was stirred for 2 hours, washed with 15% HCl solution and water. Separating the organic layer with Na ₂SO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and the product was precipitated by addition of hexane. Mixing white solidFiltration and collection gave the title compound (0.06g), 70% yield:¹H NMR(300MHz，CDCl₃)8.30(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/z509.1(M+1)。

example 12.1

The compounds listed in the table below were prepared using a similar procedure as described in example 12. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 13

Synthesis of 1 '- (3-hydroxypropyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

1' - [3- (benzyloxy) propyl]Spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]A suspension of-2 '(1' H) -one (6.27g, 14.5mmol) in 10% Pd/C (0.5g) in MeOH (150mL) was hydrogenated under atmospheric hydrogen overnight and filtered through a pad of celite. The filtrate was concentrated to dryness in vacuo. Will be provided withThe residue was crystallized from ether to give the title compound (4.82g) as a white solid in 98% yield:¹H NMR(300MHz，CDCl₃)7.38-6.93(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)178.8，156.0，148.9，142.4，142.1，132.3，129.0，128.9，124.1，123.9，119.0，108.6，103.0，101.5，93.6，80.4，58.3，37.8，29.8；MS(ES+)m/z340.2(M+1)。

example 14

Synthesis of 3- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) propanal

In 1' - (3-hydroxypropyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a solution of-2 '(1' H) -one (4.82g, 14.2mmol) in dichloromethane (150mL) was added 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) -one (7.00g, 16.7mmol) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 4 hours, diluted with ethyl acetate and successively with 10% Na₂S₂O₃Solution, saturated NaHCO₃And washed with brine and anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to flash chromatography and the product was recrystallized from ethyl acetate/hexane to give the title compound (3.86g), 80% yield:¹H NMR(300MHz，CDCl₃)9.83(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

Synthesis of 1 '- {3- [ (cyclopropylmethyl) amino ] propyl } spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

In 3- (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a solution of-1 '(2' H) -propionaldehyde (0.07g, 0.20mmol) in THF (5.00mL) was added (aminomethyl) cyclopropane (0.30mmol) and MP-triacetoxyborohydride (0.26g, 0.60 mmol). After shaking overnight, polymer bound 4-phenoxybenzaldehyde (0.25g, 0.18mmol) was added. After shaking overnight, the mixture was diluted with ether (10.0mL) and filtered. The filtrate was concentrated to dryness in vacuo. The residue was recrystallized to give the title compound (0.05g) in 62% yield as a white solid: ¹H NMR(300MHz，CDCl₃)7.32-6.92(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/z393.3(M+1)。

Example 15.1

The compounds listed in the table below were prepared using a similar procedure as described in example 15. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 16

Synthesis of 1 '- (3-aminopropyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

On 2- [3- (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) propyl]To a solution of (E) -1H-isoindole-1, 3(2H) -dione (3.20g, 6.80mmol) in ethanol (70.0mL) was added hydrazine monohydrate (1.87g, 37.0 mmol). The mixture was stirred at ambient temperature for 4 hours. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed with sodium bicarbonate and brine solution, over MgSO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo. The residue was crystallized from hexane to give the title compound (2.50g), 75% yield:¹H NMR(300MHz，CDCl₃)7.31-7.24(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)177.8，155.9，148.9，142.3，142.2，132.4，129.0，124.0，123.4，119.4，108.7，103.0，101.5，93.6，80.5，58.2，38.8，37.5，30.6；MS(ES+)m/z339.3(M+1)。

example 17

Synthesis of 3-chloro-N- [3- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) propyl ] thiophene-2-carboxamide

In 1' - (3-aminopropyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a solution of-2 '(1' H) -one (0.05g, 0.13mmol) in dichloromethane (4.00mL) was added triethylamine (0.03g, 0.26mmol) and 3-chlorothiophene-2-carbonyl chloride (0.02g, 0.12mmol) at 0 ℃. The mixture was stirred for 2 hours, washed with 15% HCl solution and water. The organic layer was washed with MgSO₄Drying and passing throughAnd (5) filtering. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and the product was precipitated by addition of hexane. The white solid was collected by filtration and dried in vacuo to give the title compound (0.04g), 67% yield:¹H NMR(300MHz，CDCl₃)7.60(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)178.3，160.6，156.0，149.0，142.4，141.8，132.5，129.4，129.2，129.1，124.2，123.7，123.6，119.2，108.5，102.9，101.6，93.7，80.5，58.3，37.4，36.5，27.3；MS(ES+)m/z 483(M+1)。

example 17.1

The compounds listed in the table below were synthesized using a similar procedure as described in example 17. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 18

Synthesis of 1 '- (2-aminoethyl) spiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -2 '(1' H) -one

On 2- [2- (2' -ketospiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-1 '(2' H) -yl) ethyl]-1H-isoindole-1, 3 (2) H) To a suspension of the diketone (20.0g, 44.0mmol) in methanol (400mL) was added hydrazine (8.00 mL). The mixture was stirred at ambient temperature for 48 hours and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to flash chromatography, eluting with ethyl acetate/methanol/ammonia (10/1/0.2) to give the crude product, which was recrystallized from ethyl acetate to give the title compound (8.0g) in 56% yield as a white solid:¹H NMR(300MHz，CDCl₃)7.34(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)178.0，155.9，148.8，142.3，132.4，128.9，124.0，123.4，119.5，108.6，103.1，101.5，93.6，80.5，58.2，43.4，39.8；MS(ES+)m/z325(M+1)，308(M-16)。

example 19

Synthesis of 1- (4-fluorophenyl) -3- [2- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) ethyl ] urea

In 1' - (2-aminoethyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]To a mixture of-2 '(1' H) -one (0.15mmol) and triethylamine (0.o1mmol) in dry dichloromethane was added 1-fluoro-4-isocyanatobenzene (0.14mmol) at ambient temperature. The mixture was stirred for 16 h, diluted with dichloromethane (5.00mL), washed with 10% HCl solution and brine, and Na₂SO₄Dried and filtered. The filtrate was concentrated to dryness in vacuo to afford the title compound (0.05g), 82% yield:¹H NMR(300MHz，DMSO-d₆)8.54(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/z462(M+1)，484(M+23)。

example 19.1

The compounds listed in the table below were synthesized using a similar procedure as described in example 19. As indicated above, the compound numbers listed below do not correspond to the compound numbers provided in the general reaction formulae above.

Example 20

Synthesis of 1 '-pentyl-7H-spiro [ furo [3, 4-f ] [1, 3] benzodioxol-5, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 1, with non-critical changes, 3-hydroxy-3- [6- (hydroxymethyl) -1, 3-benzodioxol-5-yl is used]-1-pentyl-1, 3-dihydro-2H-indol-2-one instead of 1- (2-cyclopropylethyl) -3- (6-hydroxy-1, 3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-dihydro-2H-indol-2-one, the title compound (45%) was obtained as a colorless solid: melting point 113-;¹H NMR(300MHz，CDCl₃)7.24-7.33(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)175.9，148.7，148.1，143.6，133.7，132.1，130.3，129.8，125.3，125.0，123.1，113.5，109.1，108.7，101.9，101.7，88.7，74.4，40.0，29.7，29.0，25.3，13.3；MS(ES+)m/z352.1(M+1)。

example 21

Synthesis of 1 '-pentylspiro [ indeno [5, 6-d ] [1, 3] dioxole-5, 3' -indol ] -2 ', 7 (1' H, 6H) -dione

From [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl]To a solution of acetic acid (0.28g, 0.73mmol) was added a drop of DMF and oxalyl chloride (0.32mL, 3.7mmol) in toluene (10 mL). The mixture was stirred at ambient temperature overnight and concentrated to dryness in vacuo to give a brown oil. This material was dissolved in dichloromethane (15.0mL) and tin (IV) chloride (0.07mL, 0.57mmol) was added at 0 deg.C. The mixture was stirred at ambient temperature overnight and the reaction was quenched with ice water. The mixture was poured into water (100mL) 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 in vacuo. The residue was subjected to flash column chromatography to give the title compound (0.09g, 67%) as a white solid: ¹H NMR(300MHz，CDCl₃)7.31(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)201.4，177.5，154.8，151.8，149.6，143.1，132.5，131.6，128.9，123.4，123.2，108.9，103.5，102.6，102.5，53.8，47.7，40.5，29.0，27.1，22.3，14.0；MS(ES+)，m/z386.1(M+23)，364.1(M+1)。

Example 22

Synthesis of 1-pentyl-6 'H-spiro [ indole-3, 5' -naphtho [2, 3-d ] [1, 3] dioxole ] -2, 8 '(1H, 7' H) -dione

Following the procedure as described in example 21, with non-critical changes, 3- [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl]Propionic acid instead of [3- (1, 3-benzodioxol-5-yl) -2-keto-1-pentyl-2, 3-dihydro-1H-indol-3-yl]Acetic acid to obtain the title compound (32%) as a white solid:¹H NMR(300MHz，CDCl₃)7.57(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)195.4，177.4，152.3，148.0，142.7，138.9，133.6，128.8，128.4，124.1，122.9，108.9，106.9，106.6，101.9，51.7，40.2，33.1，32.8，29.0，27.1，22.3，14.0；MS(ES+)m/z400.1(M+23)，378.1(M+1)。

example 23

Synthesis of 1 '-pentyl-6, 7-dihydrospiro [ indeno [5, 6-d ] [1, 3] dioxole-5, 3' -indol ] -2 '(1' H) -one

1' -pentylspiro [ indeno [5, 6-d ]][1，3]Dioxole-5, 3' -indoles]-2′，A mixture of 7 (1' H, 6H) -dione (0.04g, 0.11mmol), triethylsilane (1.50mL), and trifluoroacetic acid (2.00mL, excess) was stirred at ambient temperature overnight. The mixture was concentrated to dryness in vacuo. Flash column chromatography of the residue was performed to give the title compound (0.02g, 47%) as an oil:¹H NMR(300MHz，CDCl₃)7.25(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)179.5，147.9，147.0，142.9，138.2，136.7，134.7，128.1，123.5，122.6，108.3，105.3，103.6，101.2，59.9，40.0，38.3，31.6，29.0，27.1，22.6，14.0；MS(ES+)m/z 372.1(M+23)，350.1(M+1)。

example 24

Synthesis of 1-pentyl-7 ', 8' -dihydro-6 'H-spiro [ indole-3, 5' -naphtho [2, 3-d ] [1, 3] dioxol ] -2(1H) -one

Following the procedure as described in example 23, with non-critical changes, 1-pentyl-6 'H-spiro [ indole-3, 5' -naphtho [2, 3-d ] was used][1，3]Dioxoles]-2, 8 ' (1H, 7 ' H) -dione instead of 1 ' -pentylspiro [ indeno [5, 6-d ]][1，3]Dioxole-5, 3' -indoles]-2 ', 7 (1' H, 6H) -dione to give the title compound (69%) as an oil:¹H NMR(300MHz，CDCl₃)7.25(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)180.3，146.7，146.1，142.4，137.3，131.6，127.8，127.8，124.1，122.5，109.0，108.3，107.3，100.7，52.0，40.0，34.0，29.4，29.1，27.1，22.4，18.8，14.0；MS(ES+)m/z364.1(M+1)。

example 25

Synthesis of 8 ', 8' -difluoro-1-pentyl-7 ', 8' -dihydro-6 'H-spiro [ indole-3, 5' -naphtho [2, 3-d ] [1, 3] dioxol ] -2(1H) -one

1-pentyl-6 'H-spiro [ indole-3, 5' -naphtho [2, 3-d ]][1，3]Dioxoles]A mixture of-2, 8 '(1H, 7' H) -dione (0.02g, 0.05mmol), bis (2-methoxyethyl) aminosulfur trifluoride (0.50mL) and 1 drop of ethanol was stirred in a Teflon bottle at 85 ℃ for 72 hours and the reaction was quenched by slow addition of water. The mixture was poured into water (100mL) 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 in vacuo. The residue was subjected to flash column chromatography to give the title compound (0.01g, 47%) as an oil:¹H NMR(300MHz，CDCl₃)7.57(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)；¹³CNMR(75MHz，CDCl₃)195.4，177.4，152.3，148.0，142.7，138.9，133.6，128.8，128.4，124.1，122.9，108.9，106.9，106.6，101.9，51.7，40.2，33.1，32.8，29.0，27.1，22.3，14.0；MS(ES+)m/z422.2(M+23)，380.2(M+1)。

example 26

Synthesis of 7-hydroxy-1 '-pentyl-6, 7-dihydrospiro [ indeno [5, 6-d ] [1, 3] dioxole-5, 3' -indol ] -2 '(1' H) -one

From 1-pentyl-6 'H-spiro [ indole-3, 5' -naphtho [2, 3-d ]][1，3]Dioxoles]To a solution of-2, 8 '(1H, 7' H) -dione (0.20g, 0.55mmol) in methanol (10.0mL) was added sodium borohydride (0.03g, 0.83 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, and poured into water (100mL) 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 in vacuo. Flash column chromatography of the residue was performed to give the title compound (0.18g, 90%) as an oil:¹H NMR(300MHz，CDCl₃)7.36-7.29(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)；¹³CNMR(75MHz，CDCl₃)180.5，148.9，148.5，143.7，140.5，136.9，132.1，128.7，123.7，123.3，108.8，105.7，103.2，101.5，74.8，59.6，40.4，28.9，27.0，22.3，14.0；MS(ES+)m/z 388.4(M+23)。

example 27

Synthesis of 7-methoxy-1 '-pentyl-6, 7-dihydrospiro [ indeno [5, 6-d ] [1, 3] dioxole-5, 3' -indol ] -2 '(1' H) -one

From 7-hydroxy-1' -pentyl-6, 7-dihydrospiro [ indeno [5, 6-d ]][1，3]Dioxole-5, 3' -indoles]To a solution of-2 '(1' H) -one (0.05g, 0.14mmol) in THF (10.0mL) was added sodium hydride (0.01mg, 0.21mmol) at 0 deg.C. The reaction mixture was stirred for half an hour, then methyl iodide (0.50mL) was added. The mixture was stirred at ambient temperature for 2 hours, then poured into water (100mL) 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 in vacuo. Flash column chromatography of the residue was performed to give the title compound (0.03g, 57%) as an oil: ¹H NMR(300MHz，CDCl₃)7.26-7.18(m，1H)，6.98-6.82(m，4H)，6.10(s，1H)，5.88(s，2H)，5.26(t，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)178.3，148.9，148.4，142.4，136.8，136.6，135.1，128.1，123.1，122.6，108.5，105.0，103.2，101.5，82.7，57.9，55.6，43.4，40.3，29.1，27.2，22.4，14.0：MS(ES+)m/z402.4(M+23)。

Example 28

Synthesis of 1 '-pentyl-6, 7-dihydro-5H-spiro [1, 3-dioxolo [4, 5-g ] isoquinoline-8, 3' -indol ] -2 ', 5 (1' H) -dione

1' -pentylspiro [ indeno [5, 6-d ]][1，3]Dioxole-5, 3' -indoles]A mixture of-2 ', 7 (1' H, 6H) -dione (0.10g, 0.28mmol), sodium azide (0.09g, 1.40mmol) and trifluoroacetic acid (2.00mL) was stirred at 50 ℃ overnight. The mixture was poured into water (100mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuoConcentrating to dryness. The residue was subjected to flash column chromatography to give the title compound (0.08g, 74%) as a white solid:¹H NMR(300MHz，CDCl₃)7.60(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)175.8，165.2，151.6，147.9，141.7，134.3，130.9，129.0，124.5，123.2，122.9，109.0，108.5，105.4，101.9，51.9，48.2，40.4，29.1，27.1，22.3，14.0；MS(ES+)m/z379.3(M+1)。

example 29

Synthesis of 2 '-keto-1' -pentyl-N-pyridin-2-yl-1 ', 2' -dihydrospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 '-indole ] -4' -carboxamide

In the 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]A mixture of-2 '(1' H) -one (0.28g, 0.65mmol), tetrakis (triphenylphosphine) palladium (0) (0.08g, 10 mol%), triethylamine (0.33g, 0.50mL, 3.25mmol) and 2-aminopyridine (0.12g, 1.30mmol) in N, N-dimethylformamide (5.00mL) was sparged with carbon monoxide (40 psi). The reaction mixture was heated at 80 ℃ for 16 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0mL), washed with water (3 × 20.0mL), brine (2 × 20.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography to give the title compound (0.04g, 14%) as a solid: ¹H NMR(300MHz，CDCl₃)8.52(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)；¹³CNMR(75MHz，CDCl₃)177.5，158.2，156.7，149.2，143.5，142.1，132.2，132.0，131.9，131.8，129.6，128.6，128.4，121.8，118.2，110.7，102.0，101.4，93.9，79.5，77.2，58.5，40.6，29.0，27.0，22.3，14.0；MS(ES+)m/z473.2(M+2)。

Example 29.1

Synthesis of N- (3-methoxyphenyl) -2 '-keto-1' -pentyl-1 ', 2' -dihydrospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 '-indole ] -4' -carboxamide

Following the procedure described in example 29, and making non-critical changes, using 3-methoxyaniline instead of 2-aminopyridine, the title compound was obtained (20%) as a colorless solid: melting point 173-175 ℃;¹H NMR(300MHz，CDCl₃)7.42(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)177.8，165.1，159.9，149.3，143.6，143.5，142.1，138.1，134.5，129.7，129.5，127.9，122.4，118.3，112.2，110.7，110.5，105.6，101.9，101.6，94.3，79.2，58.3，55.3，40.5，28.9，26.9，22.3，13.9；MS(ES+)m/z501.5(M+1)。

example 30

Synthesis of 2 '-keto-1' -pentyl-1 ', 2' -dihydrospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 '-indole ] -4' -carbonitrile

4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]A mixture of-2 '(1' H) -one (0.10g, 0.23mmol), tris (dibenzylideneacetone) dipalladium (0) (0.21g, 0.23mmol) and 2- (di-t-butylphosphino) biphenyl (0.07, 0.23mmol), tributyltin cyanide (0.07g, 0.23mmol) and potassium cyanide (0.02g, 0.23mmol) was purged with nitrogen and anhydrous acetonitrile (10.0mL) was added. The reaction mixture was refluxed for 16 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0mL), washed with water (20.0mL), brine (20.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo. The brown residue was subjected to column chromatography, eluting with ethyl acetate/hexane (65%) to give the title compound (0.03g, 33%) which was recrystallized from ether to obtain a colorless solid: melting point 128-129 ℃; ¹H NMR(300MHz，CDCl₃)9.10(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)176.5，157.1，149.5，143.5，142.4，135.4，129.7，128.3，126.4，116.3，114.8，112.3，108.8，102.2，93.7，78.7，58.3，40.6，28.9，26.7，22.2，13.9；MS(ES+)m/z377.5(M+1)。

Example 31

Synthesis of 1 '-hexylspiro [1, 3-dioxolo [4, 5-g ] chromene-8, 3' -indol ] -2 ', 6 (1' H, 7H) -dione

In acetic acid 2- (1-hexyl-3- (6-hydroxybenzo [ d ]][1，3]Dioxolen-5-yl) -2-ketoindolin-3-yl ester (0.19g, 0.43mmol) in THF: H₂To a solution in O (2: 1) was added lithium hydroxide (0.04g, 0.86 mmol). The mixture was stirred at ambient temperature for 4 hours. The organic solvent was removed in vacuo and the aqueous residue was adjusted to pH 2 and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo and the residue was subjected to column chromatography, eluting with 25% ethyl acetate/hexanes to give the title compound (0.09g, 53%) as a white solid:¹H NMR(300MHz，CDCl₃)7.33(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)175.9，165.8，148.3，147.2，144.6，142.6，129.9，129.6，123.8，123.4，114.7，109.2，105.1，101.9，99.8，49.6，40.3，37.2，31.2，27.2，26.4，22.4，13.9；MS(ES+)m/z 394.5(M+1)。

example 32

Synthesis of 1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Reacting 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]A mixture of-2 '(1' H) -one (0.10g, 0.27mmol) and palladium on carbon (0.09g, 0.01mmol) in methanol/ethyl acetate (1/1, 4.00mL) was stirred under hydrogen at atmospheric pressure for 16H. The solvent is evaporated and the black residue is subjected to column chromatography (ethyl acetate/hexane, 1- 6) To give the title compound (0.08g, 97%) as a white solid:¹H NMR(300MHz，CDCl₃)7.30(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)177.2，160.7，142.5，132.8，129.7，129.0，128.8，123.9，123.3，123.1，121.3，110.4，108.6，58.1，40.4，29.0，27.2，22.3，14.0；MS(ES+)m/z308.5(M+1)。

example 33

Synthesis of 6-phenylamino-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

In 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]To a solution of-2 '(1' H) -one (0.08g, 0.19mmol) in dry toluene (4.00mL) were added aniline (0.03g, 0.29mmol), xanthhphos (0.02g, 0.03mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.02g, 0.02 mmol). The reaction mixture was refluxed for 16 hours, cooled to ambient temperature, and concentrated to dryness in vacuo. The black residue was subjected to column chromatography (ethyl acetate/hexane, 1/7) to give the title compound (0.05g, 62%) as a yellow oil:¹H NMR(300MHz，CDCl₃)7.40-7.25(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)，1.45-130(m，4H)，0.92(t，3H)；MS(ES+)m/z399.5(M+1)。

example 34

Synthesis of 6-morpholin-4-yl-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one (1: 1)

Following the procedure as described in example 33, and making non-critical changes, using morphine instead of aniline, the title compound (42%) was obtained as a brown oil:¹H NMR(300MHz，CDCl₃)7.32(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)177.5，162.2，153.4，142.6，132.9，128.7，123.9，123.4，123.0，120.1，108.9，108.5，97.9，80.3，66.9，57.7，49.4，40.3，29.0，27.1，22.4，14.0；MS(ES+)m/z393.5(M+1)。

example 35

Synthesis of 6-amino-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

A.6- [ (diphenylmethylene) amino group]-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole ]Synthesis of (E) -2 '(1' H) -one

To a solution of 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one (0.10g, 0.26mmol) in anhydrous toluene (5.00mL) were added benzophenone imine (0.09g, 0.52mmol), sodium tert-butoxide (0.03g, 0.36mmol), tris (dibenzylideneacetone) dipalladium (0) (0.01g, 0.07mmol) and (. + -.) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (0.12g, 0.19 mmol). The reaction mixture was refluxed for 16 hours, cooled to ambient temperature, diluted with dichloromethane (50.0mL) and filtered through a bed of celite. The filtrate was concentrated to dryness in vacuo to afford the title compound, which was used in the next step without purification.

B.6-amino-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]Synthesis of (E) -2 '(1' H) -one

In 6- [ (diphenylmethylene) amino group]-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]To a solution of-2 '(1' H) -one in anhydrous tetrahydrofuran (4.00mL) was added 10% aqueous hydrochloric acid (2.00 mL). The reaction mixture was stirred for 15 minutes, diluted with aqueous sodium bicarbonate (5.00mL), and extracted with ethyl acetate (3X 25.0 mL). The combined organic solutions were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.02g, 24% yield) as a yellow oil: ¹H NMR(300MHz，CDCl₃)7.26(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)；¹³CNMR(75MHz，CDCl₃)177.8，171.2，162.1，148.7，142.5，133.1，128.6，127.8，123.9，123.7，123.0，118.5，108.5，108.4，97.2，80.2，77.6，77.4，77.2，76.8，64.0，60.4，57.6，40.3，29.7，29.0，27.1，22.6，22.4，22.1，19.1，14.2，14.0，13.7；MS(ES+)m/z323.5(M+1)。

Example 36

Synthesis of 1 '-pentyl-6-phenoxyspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

In 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]To a solution of (E) -2 '(1' H) -one (0.08g, 0.19mmol) in anhydrous dioxane (4.00mL) were added copper iodide (0.01g, 0.01mmol), N-dimethylglycine hydrochloride (0.01g, 0.01mmol), cesium carbonate (0.17g, 0.52mmol), and phenol (0.03g, 0.32 mmol). The resulting mixture was refluxed under nitrogen for 16 hours, diluted with dichloromethane (50.0mL), and filtered through a bed of celite. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/6) to give the title compound (0.07g, 87%) as a colorless oil:¹H NMR(300MHz，CDCl₃) 7.36-7.28(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/z400.5(M+1)。

example 37

Synthesis of 1 '-pentyl-6-pyridin-3-ylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Reacting 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]A mixture of-2 '(1' H) -one (0.08g, 0.19mmol), pyridine-3-boronic acid (0.05g, 0.41mmol), palladium acetate (0.002g, 0.07mmol), tri-p-tolylphosphine (0.0015g, 0.005mmol), 2M sodium carbonate (1.00mL) and 1, 2-dimethoxyethane (9.00mL) at reflux and N₂The mixture was heated for 16 hours. The solvent was evaporated and the black residue was extracted with ethyl acetate (4 × 15.0 mL). The combined organic material was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 4/1) to give the title compound (0.07g, 67% yield), As a white solid:¹H NMR(300MHz，CDCl₃)8.60(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)176.9，161.6，149.5，147.3，142.6，139.9，136.4，135.6，133.4，130.1，129.2，124.9，121.7，119.5，110.3，109.7，107.7，80.1，57.8，42.3，28.8，27.1，22.3，14.85；MS(ES+)m/z385.5(M+1)。

example 38

Synthesis of 1 '-pentyl-6-pyridin-4-ylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 37, and making non-critical changes, using 4-pyridineboronic acid alkane instead of 3-pyridineboronic acid, the title compound (38%) was obtained as a white solid: melting point 107-;¹H NMR(300MHz，CDCl₃)8.64-8.58(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/z385.5(M+1)。

example 39

Synthesis of 6- (methylsulfonyl) -1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Reacting 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]A mixture of-2 '(1' H) -one (0.60g, 1.55mmol), sodium methanesulfinate (0.19g, 1.86mmol), copper iodide (0.03g, 0.16mmol) and L-proline (0.04g, 0.31mmol) in dimethylsulfoxide (3.00mL) in N₂And heating at 100 deg.C for 2 days. The reaction mixture was diluted with water (50.0mL) and extracted with ethyl acetate (4X 15.0 mL). The combined organic material was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/3) to give the title compound (0.03g, 46%) as a pale yellow oil:¹H NMR(300MHz，CDCl₃)7.46-7.48(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)176.1，161.2，142.6，142.1，135.4，131.5，129.5，124.3，124.0，123.5，120.7，109.5，109.0，80.5，57.7，44.5，40.6，29.0，27.1，22.3，14.0；MS(ES+)m/z386.5(M+1)。

example 40

Synthesis of 1 '-pentyl-6- (phenylsulfonyl) spiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 39, and making non-critical changes, using sodium phenylsulfinate instead of sodium methanesulfinate, the title compound (50%) was obtained as a yellow oil:¹HNMR(300MHz，CDCl₃)7.94-7.88(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)176.1，161.2，143.2，142.5，141.2，134.9，133.3，129.4，129.3，127.8，124.1，124.0，123.5，121.1，109.8，108.9，80.5，57.7，40.5，29.0，27.1，22.3，14.0；MS(ES+)m/z448.5(M+1)。

EXAMPLE 41

Synthesis of 1 '-pentyl-5-phenoxyspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 36, with non-critical changes, 5-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole was used]-2 '(1' H) -one instead of 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]-2 '(1' H) -one to give the title compound (10% yield) as a colorless oil:¹HNMR(300MHz，CDCl₃)7.32-7.10(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/z400.4(M+1)。

example 42

Synthesis of 1 '- (benzhydryl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) spiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Reacting 5-bromo-1' - (benzhydryl) spiro [1 ]-benzofuran-3, 3' -indoles]A mixture of-2 ' (1 ' H) -one (3.00g, 6.22mmol), bis (pinacol) diboron (1.80g, 7.09mmol), (1, 1 ' -bis (diphenylphosphino) ferrocene) dichloropalladium (II) (o.45g, 9 mol%) and potassium acetate (5.49g, 56.0mmol) in anhydrous dimethylsulfoxide (40.0mL) at 100 ℃ and N₂Stirred for 16 hours. The reaction mixture was diluted with water (600 mL). The aqueous mixture was extracted with ethyl acetate (3X 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 (1.00g, 30%) as a white solid: ¹H NMR(300MHz，CDCl₃)7.68(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/z530.32(M+1)。

Example 43

Synthesis of 1 '- (benzhydryl) -5-hydroxyspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

1 '- (diphenylmethyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) spiro [ 1-benzofuran-3, 3' -indole]A mixture of-2 '(1' H) -one (4.50g, 8.50mmol), hydrogen peroxide (4.86mL, 30% solution, 42.5mmol), sodium hydroxide (16.38mL, 10% solution, 40.82mmol) in methanol was stirred at 0 ℃ for 30 min and at ambient temperature for 16H. 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 (3X 250 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was triturated with hexanes (20.0mL) followed by ether (15.0mL) to give the title compound (3.20g, 90%) as whiteSolid:¹HNMR(300MHz，CDCl₃)7.45-7.38(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/z420.23(M+1)。

example 44

Synthesis of 5-hydroxy spiro [ 1-benzofuran-3, 3 ' -indole ] -2 ' (1 ' H) -one

Following the procedure as described in example 1.28, with non-critical changes, 1 '- (benzhydryl) -5-hydroxyspiro [ 1-benzofuran-3, 3' -indole was used]-2 '(1' H) -one instead of 1 '- (diphenylmethyl) -5' -methyl spiro [ furo [2, 3-f ] ][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one to obtain the title compound (48%) as a white solid:¹H NMR(300MHz，DMSO-d₆)10.58(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/z254.2(M+1)。

example 45

Synthesis of 2 '-keto-1', 2 '-dihydrospiro [ 1-benzofuran-3, 3' -indol ] -5-yl trifluoromethanesulfonate:

in 5-hydroxy spiro [ 1-benzofuran-3, 3' -indole]-2 '(1' H) -one (0.18g, 0.70mmol) with trifluoromethanesulfonic anhydride (0.26g, 0.91mmol) in bisTo the mixture in methyl chloride (5.00mL) was added triethylamine (0.14g, 1.93mmol) at 0 ℃. The reaction mixture was stirred at ambient temperature for 16 hours and diluted with dichloromethane (100 mL). After washing with a saturated aqueous solution of sodium chloride (2X 20.0mL), 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 (0.07g, 25%) as a pale yellow solid:¹H NMR(300MHz，CDCl₃)7.92(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

Synthesis of 2 ' -keto-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } -1 ', 2 ' -dihydrospiro [ 1-benzofuran-3, 3 ' -indol ] -5-yl trifluoromethanesulfonate

In trifluoromethanesulfonic acid 2 '-keto-1', 2 '-dihydrospiro [ 1-benzofuran-3, 3' -indole]To a mixture of the-5-yl ester (0.42g, 1.10mmol) and sodium hydroxide (0.07g, 1.65mmol) in N, N-dimethylformamide (5.00mL) was added 2- (bromomethyl) -5- (trifluoromethyl) furan (0.50g, 2.20mmol) at 0 ℃. The reaction mixture was stirred at ambient temperature for 16 hours and diluted with ethyl acetate (200 mL). After washing with a saturated aqueous solution of sodium chloride (2X 20.0mL), 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 (0.47g, 80%) as a clear oil: ¹H NMR(300MHz，CDCl₃)7.34(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/z534.4(M+1)。

Example 47

Synthesis of 5-pyridin-3-yl-1 '- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 4.2, with non-critical changes, 2 '-keto-1' - { [5- (trifluoromethyl) -2-furyl ] was used]Methyl } -1 ', 2 ' -dihydrospiro [ 1-benzofuran-3, 3 ' -indole]-5-yl trifluoromethanesulfonate in place of 2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole)]-1 ' (2 ' H) -yl) -N- (2-fluorophenyl) acetamide and pyridine-3-boronic acid instead of pyrimidine-5-boronic acid to give 5-pyridin-3-yl-1 ' - { [5- (trifluoromethyl) -2-furyl]Methyl } spiro [ 1-benzofuran-3, 3' -indole]-2 '(1' H) -one (74%) as a white solid, which was treated with HCl in ether to obtain the title compound: melting point 98-100 deg.C;¹H NMR(300MHz，CD₃OD)8.96(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)；¹³CNMR(75MHz，CD₃OD)175.7，161.3，151.1，142.1，140.2，138.6，137.5，137.4，130.0，129.4，128.1，127.5，125.6，125.5，122.3，122.1，120.8，111.4，111.3，109.7，108.1，107.7，78.7，58.3，34.9；MS(ES+)m/z463.1(M+1)。

example 48

Synthesis of 1 '-pentyl-5-pyridin-3-ylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4.2, with non-critical changes, 5-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole was used]-2 ' (1 ' H) -one instead of 2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole) ]-1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide, and pyridine-3-boronic acid instead of pyrimidine-5-boronic acid, the title compound (70%) was obtained as a white solid:¹H NMR(300MHz，CDCl₃)8.55(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/z385.5(M+1)。

example 49

Synthesis of 1 '-pentyl-5-pyrimidin-5-ylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4.2, with non-critical changes, 5-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole was used]-2 ' (1 ' H) -one instead of 2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole)]-1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide to obtain the title compound (40%) as a white solid: melting point 115-;¹H NMR(300MHz，CDCl₃)9.08(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/z386.4(M+1)。

example 50

Synthesis of 1 '-pentyl-5-pyridin-4-ylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4.2, with non-critical changes, 5-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole was used]-2 ' (1 ' H) -one instead of 2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole)]-1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide, and pyridine-4-boronic acid instead of pyrimidine-5-boronic acid, the title compound (95%) was obtained as a white solid: ¹H NMR(300MHz，CDCl₃)8.55-8.47(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/z385.5(M+1)。

Example 51

Synthesis of 2 ' -keto-1 ' -pentyl-1 ', 2 ' -dihydrospiro [ 1-benzofuran-3, 3 ' -indole ] -5-carbonitrile

Following the procedure as described in example 30, with non-critical changes, 5-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole was used]-2 '(1' H) -one instead of 4 '-bromo-1' -pentylspiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one to obtain the title compound (78%) as a white solid:¹H NMR(300MHz，CDCl₃)7.51(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)176.2，164.1，142.6，134.8，131.4，130.8，129.6，127.8，123.9，123.5，118.8，111.5，109.1，104.7，80.6，57.3，40.6，29.0，27.1，22.3，14.0；MS(ES+)m/z333.5(M+1)。

example 52

Synthesis of N- (2-fluorophenyl) -2- (2 '-keto-5-pyridin-3-ylspiro [ 1-benzofuran-3, 3' -indol ] -1 '(2' H) -yl) acetamide

Following the procedure as described in example 37, with non-critical changes, 2- (5-bromo-2 '-ketospiro [ 1-benzofuran-3, 3' -indole was used]-1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide in place of 6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indole]-2 '(1' H) -one to give the title compound (55% yield) as a white solid: melting point 98-100 deg.C;¹H NMR(300MHz，CDCl₃)8.60-8.53(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)177.9，164.8，160.9，154.2，151.0，147.1，141.7，134.2，131.7，131.5，129.9，129.4，129.1，125.1，124.6，124.5，124.2，124.0，122.5，122.2，115.1，114.8，111.0，109.1，80.0，58.1，44.6；MS(ES+)m/z 466.4(M+1)。

example 53

Synthesis of 1 '- [ (5-fluoro-1H-benzimidazol-2-yl) methyl ] spiro [ furo [2, 3-f ] [1, 3] benzodioxol-7, 3' -indol ] -2 '(1' H) -one

Reacting (2' -ketospiro [ furo [2, 3-f ] ][1，3]Benzodioxole-7, 3' -indoles]A mixture of (2, 1) acetic acid (0.50g, 1.47mmol) and 4-fluorobenzene-1, 2-diamine (0.15g, 1.18mmol) in dry toluene (20.0mL) in N₂Reflux overnight. The reaction mixture was diluted with water (250mL) and extracted with ethyl acetate (2X 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/1) to give the title compound (0.13g, 22%): melting point 138-;¹H NMR(300MHz，CDCl₃)7.47-7.39(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)；¹³CNMR(75MHz，CDCl₃)179.2，161.3，158.1，156.2，149.2，149.1，142.5，141.2，131.5，129.5，124.4，124.0，118.0，111.6，111.2，109.9，103.1，101.7，93.5，80.5，58.5，38.9；MS(ES+)m/z430.2(M+1)。

example 54

Synthesis of 1 '- (benzhydryl) -5-pyridin-3-ylspiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one

Following the procedure as described in example 4.2, with non-critical changes, 5-bromo-1 '- (benzhydryl) spiro [ 1-benzofuran-3, 3' -indole was used]-2 ' (1 ' H) -one instead of 2- (4 '-bromo-5, 6-difluoro-2 '-ketospiro [ 1-benzofuran-3, 3' -indole]-1 '(2' H) -yl) -N- (2-fluorophenyl) acetamide, and pyridine-3-boronic acid instead of pyrimidine-5-boronic acid, the title compound (74%) was obtained as a white solid: melting point 204-;¹H NMR(300MHz，CDCl₃)8.62-8.46(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/z481.5(M+1)。

example 55

Synthesis of tert-butyl 3- (2 '-keto-1', 2 '-dihydrospiro [ 1-benzofuran-3, 3' -indol ] -5-yl) piperidine-1-carboxylate

A.5-piperidin-3-ylspiro [ 1-benzofuran-3, 3' -indoles]-synthesis of 2 '(1' H) -ketones:

following the procedure as described in example 1.28, and making non-critical changes, 1 ' - (benzhydryl) -5-pyridin-3-ylspiro [ 1-benzofuran-3, 3 ' -indol ] -2 ' (1 ' H) -one was used instead of 1 ' - (benzhydryl) -5 ' -methylspiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3 ' -indol ] -2 ' (1 ' H) -one to obtain the title compound, which was used in the next step.

B.3- (2 '-keto-1', 2 '-dihydrospiro [ 1-benzofuran-3, 3' -indole)]Synthesis of tert-butyl (5-yl) piperidine-1-carboxylate

From 5-piperidin-3-ylspiro [ 1-benzofuran-3, 3' -indoles]To a mixture of-2 '(1' H) -one, triethylamine (0.95g, 9.36mmol) in dry dichloromethane (15.0mL) was added di-tert-butyl dicarbonate (1.02g, 4.68mmol) at 0 ℃. The reaction mixture was stirred at ambient temperature and under N₂Stirring downStir overnight, dilute with dichloromethane (100mL), and filter through celite. The filtrate was concentrated to dryness in vacuo. The brown residue was subjected to column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.50g, 40%) as a white solid: melting point 120-; ¹HNMR(300MHz，CDCl₃)7.82(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/z443.4(M+1)。

Example 56

Synthesis of tert-butyl 3- (2 ' -keto-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } -1 ', 2 ' -dihydrospiro [ 1-benzofuran-3, 3 ' -indol ] -5-yl) piperidine-1-carboxylate

Following the procedure as described in preparation 1A, with non-critical changes, 3- (2 '-keto-1', 2 '-dihydrospiro [ 1-benzofuran-3, 3' -indole)]Tert-butyl-5-yl) piperidine-1-carboxylate instead of 4-bromoindole and 2- (bromomethyl) -5- (trifluoromethyl) furan instead of 1-bromopentane to give the title compound (10%) as a white solid: melting point is 59-61 ℃;¹H NMR(300MHz，CDCl₃)7.34-7.23(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

Synthesis of 5-pyridin-4-yl-1 '- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ 1-benzofuran-3, 3' -indol ] -2 '(1' H) -one hydrochloride

Following the procedure as described in example 4.2, with non-critical changes, 2 '-keto-1' - { [5- (trifluoromethyl) -2-furyl ] was used]Methyl } -1 ', 2 ' -dihydrospiro [ 1-benzofuran-3, 3 ' -indole]-5-yl trifluoromethanesulfonate in place of 2- (4 ' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3 ' -indole)]-1 ' (2 ' H) -yl) -N- (2-fluorophenyl) acetamide with pyridine-4-boronic acid instead of pyrimidine-5-boronic acid to obtain 5-pyridin-4-yl-1 ' - { [5- (trifluoromethyl) -2-furyl ] acetamide ]Methyl } spiro [ 1-benzofuran-3, 3' -indole]-2 '(1' H) -one as a white solid, which was treated with HCl in ether to afford the title compound (54%): melting point is 108-110 ℃;¹H NMR(300MHz，CDCl₃)8.57-8.47(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)，5.11-4.83(m，3H)，4.75(d，1H)；¹³C NMR(75MHz，CDCl₃)176.2，164.3，156.7，151.5，141.5，140.8，131.5，131.1，130.7，129.8，127.7，124.3，124.1，123.4，123.1，112.9，112.2，110.0，109.4，80.9，57.5，37.3；MS(ES+)m/z466.4(M+1)。

example 58

Synthesis of 5-methoxy-1 '-methyl spiro [ 1-benzofuran-3, 3' -indole ] -2 '(1' H) -one

In 5-hydroxy spiro [ 1-benzofuran-3, 3' -indole]-2 '(1' H) -one (0.10g, 0.39mmol), triphenylphosphine (0.20g, 0.76mmol) and formazanTo a mixture of alcohol (0.05g, 1.6mmol) in dry tetrahydrofuran was added diethyl azodicarboxylate (0.14g, 0.80mmol) at 0 ℃. The reaction mixture was brought to ambient temperature and N₂Stirred for 16 h and concentrated to dryness in vacuo. The brown residue was subjected to column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.02g, 14% yield) as a yellow solid: melting point is 159-161 ℃;¹H NMR(300MHz，CDCl₃)7.32(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

Synthesis of N- [2- (2 '-ketospiro [ furo [2, 3-f ] [1, 3] benzodioxole-7, 3' -indol ] -1 '(2' H) -yl) ethyl ] -2- (trifluoromethoxy) benzamide

Following the procedure as described in example 17, with non-critical changes, 1' - (2-aminoethyl) spiro [ furo [2, 3-f ] was used][1，3]Benzodioxole-7, 3' -indoles ]-2 ' (1 ' H) -one instead of 1 ' - (3-aminopropyl) spiro [ furo [2, 3-f ]][1，3]Benzodioxole-7, 3' -indoles]-2 '(1' H) -one, and 2- (trifluoromethoxy) benzoyl chloride instead of 3-chlorothiophene-2-carbonyl chloride, the title compound (91%) was obtained as a colorless solid: melting point 183-184 deg.C;¹H NMR(300MHz，CDCl₃)7.86-7.83(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)178.2，165.0，155.9，148.8，145.9，142.3，141.9，132.4，132.1，131.3，129.2，127.6，127.3，124.0，123.6，121.2，121.1，119.2，108.7，103.0，101.4，93.6，80.4，58.2，39.5，38.2；MS(ES+)m/z513.4(M+1)。

biological assay

Every technique is known in the art for detecting the activity of the compounds of the present invention. In order that the invention described herein may be more fully understood, the following biological assays are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

Biological example 1

Guanidine influx assay (in vitro assay)

This example describes an in vitro assay for detecting and dissecting the challenge of a test agent against human or rat sodium channels stably expressed in endogenous or recombinant cells. This assay can also be used to determine the IC-50 of sodium channel blocking compounds. The assay is based on Reddy n.l., et al, J Med Chem, (1998), 41 (17): 3298-302 by the guanidine flux assay.

The guanidine influx assay is a radiotracer flux assay to determine the ion flux activity of sodium channels in a high throughput microplate-based format. The measurement utilizes ¹⁴The C-guanidine hydrochloride is combined with various known sodium channel modulators to determine the potency of the test agent. Potency was determined by IC-50 calculation. Selectivity (also referred to as "selectivity profiling") is measured by comparing the potency of a compound for the channel of interest to its potency against other sodium channels.

Each test agent is assayed for cells expressing a channel of interest. Voltage-gated sodium channels are TTX sensitive or insensitive. This property is useful when evaluating the activity of a channel of interest, when it is in a mixed pool with other sodium channels. Table 1 below summarizes cell lines that may be used to screen for specific channel activity in the presence or absence of TTX.

TABLE 1

It is also possible to use recombinant cells expressing these sodium channels. The cloning and propagation of recombinant cells is known to those skilled in the art (see, e.g., Klugbauer, N, et al., EMBO J. (1995), 14 (6): 1084-90 and Lossin, C.et al., Neuron (2002), 34, pp.877-884).

Cells expressing the channel of interest are cultured according to the supplier's instructions or, in the case of recombinant cells, in the presence of a selective growth medium such as G418 (Gibco/Invitrogen). Cells were dissociated from the plates with enzyme solution (1X) trypsin/EDTA (Gibco/Invitrogen) and analyzed for density and viability using a hemocytometer (Neubauer). Dissociated cells were washed and resuspended in their medium, then placed in a Scintiplate (Beckman Coulter Inc.) (approximately 100,000 cells/well) and incubated at 37 ℃/5% CO ₂And incubating for 20-24 hours. After washing vigorously with low-sodium HEPES-buffered saline solution (LNHBSS) (150mM choline chloride, 20nM HEPES (Sigma), 1mM calcium chloride, 5mM potassium chloride, 1mM magnesium chloride, 10mM glucose), the agent diluted with LNHBSS (different concentrations of the test agent can be used) was added to each well. The activation/radiolabelling mix contained aconitine (Sigma) with 14C-guanidine hydrochloride (ARC).

After the test agent and the activation/radiolabelling mixture were added to the cells, the scientiplates were incubated at ambient temperature. After incubation, the scientiplates were washed thoroughly with LNHBSS supplemented with guanidine (Sigma). The scientiplates were dried and then counted using a Wallac MicroBetaTrilux (Perkin-Elmer Life Sciences). By targeting intracellular events expressing different sodium channels¹⁴The amounts of C-guanidine are compared to determine the ability of the test agent to block sodium channel activity. Based on this data, various computational methods, as set forth further in this specification, can be used to determine whether a test agent is selective for a particular sodium channel.

The IC-50 values of the test agent for a particular sodium channel can be determined using the general methods described above. The IC-50 can be determined using the following method: using a 3, 8, 10, 12 or 16 point curve repeated two or three times, starting at 1, 5 or 10 μ M, serial dilutions were made to reach final concentrations in the sub nM, nM and low μ M ranges. Typically, the midpoint concentration of the test agent is set at 1. mu.M, and higher or lower half-diluted serial concentrations (e.g., 0.5. mu.M; 5. mu.M and 0.25. mu.M; 10. mu.M and 0.125. mu.M; 20. mu.M, etc.) are used. The IC-50 curve was calculated using a 4-parameter Logistic model or Sigmoidal dose-response model (fit ═ a + ((B-a)/(1+ ((C/x) ^ D))).

By dividing the IC-50 value of the test sodium channel by a reference sodium channel such as Na_V1.5 to calculate the fold selectivity, selectivity factor or selectivity fold.

Biological example 2

Electrophysiological assay (in vitro assay)

Cells expressing the channel of interest were grown in DMEM growth medium (Gibco) containing 0.5mg/mL G418, +/-1% PSG and 10% heat-inactivated fetal bovine serum at 37 ℃ and 5% CO₂And (5) culturing. Cells were placed on 10mm petri dishes for electrophysiological recording.

Whole cell recordings were performed by the established whole cell voltage clamp method (Bean et al, op.cit.) using an Axopatch 200B amplifier and claudex software (Axon Instruments, Union City, CA). All experiments were performed at ambient temperature. The electrodes were fire ground to withstand 2-4Mohm voltage error and the capacitive artefacts were minimized by successive resistive and capacitive compensation, respectively. Data were acquired at 40kHz and filtered at 5 kHz. The external (bath) solution comprises: NaCl (140mM), KCl (5mM), CaCl at pH 7.4₂(2mM)，MgCl₂(1mM), HEPES (10 mM). The inner (pipette) solution contained (in mM): NaCl (5), CaCl at pH 7.2₂(0.1)，MgCl₂(2)，CsCl(10)，CsF(120)，HEPES(10)，EGTA(10)。

To evaluate the compoundsSteady-State affinity (K, respectively) for resting and inactive states of the channel _rAnd K_i) The voltage was depolarized at-60 to +90mV using a 12.5ms test pulse from a-110 mV clamp potential to establish a current-voltage relationship (I-V curve). The voltage near the peak of the I-V curve (-30 to 0mV) was used as the test pulse throughout the remainder of the experiment. The steady state failure (availability) curve was then established by measuring the activated current during the 8.75ms test pulse after applying a 1s conditioning pulse to a potential in the range-110 to-10 mV. To monitor the channel at steady state, a single "diary" profile with a clamp potential of-110 mV was established to record the quiescent current (10ms test pulse), the current after rapid failure (-5 ms pre-pulse at 80 to-50 mV followed by 10ms test pulse), and the current during various clamp potentials (35ms ramped to the test pulse level). Compounds were applied during "diary" profiling and blockade was monitored at 15s intervals.

After the compounds reached equilibrium, the voltage dependence of steady state failure in the presence of the compounds was determined. Compounds that block resting states of the channel will reduce the current caused by all clamped potentials during the test pulse, while compounds that block failure states primarily will reduce the current caused by more depolarized potentials during the test pulse. Current at rest (I) _{At rest}) With current (I) during a failure state_{Fail to work}) Is used to calculate the steady state affinity of the compound. Based on the Michaelis-Menton inhibition model, K_rAnd K_iAre calculated to respectively cause I_{At rest}Or I_{Fail to work}50% inhibition of the desired compound concentration.

V_maxFor inhibition rate, h is the Hill coefficient (for the interaction site), K_mIs the Michaelis-Menten constant, and [ drug]Is the concentration of the test compound. In I_{At rest}Or I_{Fail to work}50% inhibition (1/2V)_max) In the following, the first and second parts of the material,the drug concentration is numerically equal to K_mAnd are each approximately K_rAnd K_i。

Biological example 3

Sodium channel blocker induced analgesia

Thermally induced Tail Flick reaction time (Tail flash Latency) test

In this test, the analgesia effect resulting from administration of the compounds of the invention was observed by thermally induced tail flicks in mice. The test included a heat source consisting of a projector with a focused beam of light and irradiated the tail of the test mouse at a single point. The tail flick response time to the response to noxious thermal stimuli, i.e. the response time from the application of radiant heat to the dorsal surface of the tail to the occurrence of tail flick, was evaluated prior to drug treatment and measured and recorded at 40, 80, 120 and 160 minutes.

For the first part of the study, 65 animals were evaluated for baseline tail flick response times for two consecutive days once a day. These animals were then randomly assigned to one of 11 different treatment groups including vehicle control group, morphine control group and 9 compounds administered intramuscularly at 30 mg/kg. Following dosing, the animals were closely monitored for signs of toxicity including tremor or seizure, hyperactivity, shallow, rapid or inhibited breathing and inability to clean. The optimal incubation time for each compound was determined by regression analysis. The analgesia activity of the test compounds was expressed as a percentage of the maximal possible effect (% MPE) and was calculated using the formula:

wherein:

post-dose response time-the response time after each individual animal received the drug before the tail moves away from the heat source (tail flick).

Pre-dose response time-the response time before tail-flick off the heat source before each individual animal received the drug.

Cutoff time (10s) is the maximum time of exposure to the heat source.

Acute pain (formalin test)

The formalin test is used as an animal model for acute pain. In the formalin test, animals were habituated briefly to the plexiglas laboratory for 20 minutes the day before the experimental day. On the day of the experiment, animals were randomly injected with the test substance. At 30 minutes post-dose, 50 μ L of 10% formalin was injected subcutaneously onto the plantar surface of the left hind paw of the rat. Video data was taken starting immediately after formalin administration for 90 minutes.

Images were taken using the Actimetrix Limelight software, which stored the file with the extension of the. The video was then analyzed using The behavioral analysis software "The Observer 5.1" (Version 5.0, Noldus Information Technology, Wageningen, The Netherlands). Video analysis was performed by observing animal behavior and scoring each term according to type and defining the duration of the behavior (Dubuisson and Dennis, 1977). The behavior of scoring includes: (1) normal behavior, (2) no weight is applied to the paw, (3) the paw is lifted, (4) the paw is licked/bitten or grabbed. Lifting, paying attention to, or excessively licking, biting, and grasping the injected paw showed a painful response. If both jaws were placed on the floor without showing significant attention, excessive lick, bite or grab of the injected jaws, an analgesic response or protective effect from the compound is indicated.

Analysis of formalin test data was based on two factors: (1) the highest percent inhibition possible (% MPIE) and (2) pain score. The% MPIE was calculated by a series of steps, where the first step was to sum the length of time of abnormal behavior (behaviors 1, 2, 3) for each animal. A single value for the vehicle group was obtained by averaging all scores within the vehicle treatment group. MPIE values were calculated for each animal as follows:

MPIE (%) 100- [ (sum of treatments/average support value) × 100% ]

The pain score is calculated from the weighted scale described above. The duration of the activity was multiplied by a weight (scale of reaction severity) and divided by the total length of time observed to determine the pain rating for each animal. This calculation is represented by the following equation:

pain rating ═ 0(To) +1(T1) +2(T2) +3(T3) ]/(To + T1+ T2+ T3)

The compounds of the present invention have been shown to be effective in the range of 30mg/kg to 0.1 mg/kg.

CFA-induced chronic inflammatory pain

In this test, allodynia to the touch (tactle allodynia) was assessed by a calibrated von Frey filament method. After one full week of acclimation to the animal feeding facility, 150 μ L of "freund's complete adjuvant" (CFA) emulsion (CFA suspended in oil/saline (1: 1) emulsion at a concentration of 0.5 mg/mL) was injected subcutaneously onto the plantar surface of the rat's left hindpaw under mild isoflurane (isoflurane) anesthesia. Animals were allowed to recover from anesthesia and all animals were evaluated for baseline thermal and mechanical nociceptive thresholds one week after CFA administration. All animals were habituated to the experimental facility for 20 minutes the day before the start of the experiment. Test and control substances are administered to animals and nociceptive thresholds are measured at defined time points after administration to determine the analgesic response to each of the six available therapeutic agents. The time points used were predetermined to show the highest analgesic effect of each compound tested.

The Hargreaves test was used to evaluate the thermal nociception threshold of the animals. The animals were placed in a plexiglas box on an elevated glass platform with a heating unit. The glass platform was thermostatically controlled at a temperature of about 30 ℃ for all tests. After the animals were placed in the box, they were allowed to acclimate for 20 minutes until they stopped all exploratory activities. A radiant heat beam was applied to the plantar surface of the hind paw from below the glass platform using a model 226 plantar/caudal stimulator analgesic meter (IITC, Woodland Hills, CA). The idle and active intensities of the heat source were set to 1 and 45, respectively, during all experiments, and a 20 second cutoff time was used to avoid tissue damage.

After the Hargreaves test, the threshold of response of the animals to tactile stimuli was measured using an Electrovonfrey pain measuring instrument model 2290 (IITCLifeScience, Woodland Hills, Calif.). The animals were placed in a raised plexiglas box set on the surface of the wire mesh. After 10 minutes of acclimation, pre-calibrated Von Frey filaments were applied perpendicularly to the plantar surface of both paws of the animal, in increasing order, starting from 0.1g of filament, applying sufficient force to produce a slight flexion of the filament with respect to the paw. The test was continued until the filament was measured to have the lowest force inducing a rapid paw flick, or the stopping force reached about 20 g. This stopping force is used because it represents about 10% of the animal's body weight and it serves to prevent lifting of the entire limb due to the use of stiffer filaments, which would alter the nature of the stimulus. The compounds of the invention were shown to be effective in the range of 30mg/kg to 0.1 mg/kg.

Nociceptive post-operative model

Hypoalgesia caused by an in-plane incision in the paw was measured in this model by applying an increasing tactile stimulus to the paw until the animal retracted its paw from the applied stimulus. After the animals were anesthetized under 3.5% isoflurane administered through the nose cone, a 1cm longitudinal incision was made in the plantar position of the left hind paw, using a No. 10 scalpel blade, penetrating the skin and fascia, starting at 0.5 cm near the edge of the heel, extending toward the toes. After incision, the skin was closed with 2, 3-0 sterile suture. The injured site was coated with polyspirorin (Polysporin) and betadine (betadine). The animals were returned to their original cages overnight.

Withdrawal thresholds for tactile stimulation of both operated (ipsilateral) and non-operated (contralateral) paws of the animals can be measured using an Electrovonfrey pain measuring instrument model 2290 (IITC Life Science, Woodland Hills, CA). The animals were placed in a raised plexiglas box set on the surface of the wire mesh. After at least 10 minutes of acclimation, pre-calibrated Von Frey filaments were applied perpendicularly to the plantar surface of both paws of the animal, in increasing order, starting from 10g of filament, applying sufficient force to produce a slight flexion of the filament with respect to the paw. The test was continued until the lowest force at which the filament caused rapid retraction of the jaws was measured, or when a cutoff force of about 20g was reached. This stopping force is used because it represents approximately 10% of the animal's body weight and it serves to prevent lifting of the entire limb due to the use of stiffer filaments, which would alter the nature of the stimulus.

The compounds of the present invention were shown to be effective in the range of 30mg/kg to 0.1 mg/kg.

A neuropathic pain model; chronic compression injury

Briefly, in the middle of the thigh of the left hind leg of the animal, a 10 gauge scalpel blade was used to penetrate the skin and fascia, resulting in an approximately 3cm incision. The left sciatic nerve was exposed by blunt dissection through the biceps femoris muscle, and careful manipulation was performed to minimize bleeding. Four loose ligatures were performed at 1 to 2mm intervals along the sciatic nerve using 4-0 non-degradable sterile sutures. The loose strapping force needs to be tight enough to induce a slight compression of the sciatic nerve when viewed under a 4-fold magnification dissecting microscope. In the simulated animals, the left sciatic nerve was exposed without further treatment. The antibacterial ointment was applied directly to the wound, and the muscle was sutured using a sterile suture. You apply you iodine on and around the muscle and then use the surgical clamp to tighten the skin.

The threshold response of animals to tactile stimuli was measured using an Electrovonfrey pain measuring instrument model 2290 (IITC Life Science, Woodland Hills, Calif.). The animals were placed in a raised plexiglas box set on the surface of the wire mesh. After 10 minutes of acclimation, a pre-calibrated Von Frey filament was applied perpendicularly to the plantar surface of both paws of the animal, in increasing order, starting from 0.1g of filament, applying sufficient force to cause a slight bending of the filament relative to the paw. The test was continued until the lowest force at which the filament caused rapid retraction of the jaws was measured, or when a cutoff force of about 20g was reached. This cutoff force is used because it represents approximately 10% of the animal's body weight and it serves to prevent the entire limb from rising due to the use of stiffer filaments, which would alter the nature of the stimulus. The compounds of the present invention were shown to be effective in the range of 30mg/kg to 0.1 mg/kg.

The Hargreaves test was used to evaluate the thermal nociception threshold of the animals. After the tactile threshold measurement, the animal is placed in a plexiglas box above a raised glass platform with a heating unit. The glass platform was thermostatically controlled at a temperature of about 24 to 26 ℃ for all tests. After the animals were placed in the box, they were allowed to acclimate for 10 minutes until they stopped all exploratory activities. A radiant heat beam was applied to the plantar surface of the hind paw from below the glass platform using a model 226 plantar/caudal stimulator analgesia meter (IITC, Woodland Hills, CA). The idle and active intensities of the heat source were set to 1 and 55, respectively, during all trials, 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 was confirmed by the following test. Administration of a solution of aconitine (2.0 μ g/kg) dissolved in physiological saline via vein caused arrhythmia. The test compound of the present invention was administered intravenously 5 minutes after administration of aconitine. Evaluation of antiarrhythmic activity was performed by measuring the time from administration of aconitine to occurrence of extra-systolic (ES), and the time from administration of aconitine to occurrence of Ventricular Tachycardia (VT).

Rats anesthetized with isoflurane (2% 1/4 to 1/3) were subjected to an tracheotomy, first making an incision in the neck region, then separating the trachea and making a 2mm incision, so that the endotracheal tube was inserted 2cm into the trachea, so that the opening of the tube was located just at the top of the mouth. The cannula was secured with sutures and connected to the ventilator during the experiment.

Then, an incision (2.5 cm) was made in the femoral region and the femoral vessels were isolated using a blunt dissection probe. Two femoral veins were cannulated, one continuously dosed with pentobarbital anesthetic (0.02-0.05mL) and one for infusion and injection of drugs and carriers. The femoral artery was cannulated with a blood pressure gel catheter of a transmitter.

The ECG leads are connected to the pectoral muscle in the II lead position (/ upper right heart-white lead, and/lower left heart-red lead). The lead is fixed by a suture.

All surgical areas were covered with gauze wetted with 0.9% saline. Saline (1-1.5mL, 0.9% solution) was provided to wet the post-operative area. The ECG of the animals was equilibrated with ventilation for at least 30 minutes.

The arrhythmia is induced by infusing aconitine with 2 mug/Kg/min for 5 min. During this period, the ECG is recorded and continuously monitored. Intravenous bolus injections (10, 30 or 100. mu.g/kg) of the test compounds of the invention resulted in complete return to normal baseline ECG.

The compounds of the invention, when tested in this model, therefore show antiarrhythmic activity.

Biological example 5

Ischemia-induced arrhythmia assay

Rodent models of ventricular arrhythmias, in the acute cardiac resuscitation paradigm, have been used to test potential agents for atrial and ventricular arrhythmias in humans. Cardiac ischemia, which causes myocardial infarction, is a common cause of morbidity and mortality. The ability of a compound to prevent ischemia-induced ventricular tachycardia and fibrillation is the accepted model for determining the efficacy of a compound in a clinical setting for atrial and ventricular tachycardia and fibrillation.

Arrhythmia was first induced by pentobarbital (intraperitoneally) and maintained by iv bolus. The trachea of male SD rats was intubated and manually ventilated with room air at a stroke volume of 10mL/kg, 60 beats/min. The right femoral artery and vein were cannulated with PE50 catheter for recording mean arterial blood pressure (MAP), and intravenous administration of the compounds, respectively.

The chest was opened between the 4 th and 5 th ribs, creating a 1.5cm opening for visualization of the heart. Each rat was placed on the notched platform and the chest was opened by attaching a metal button to the rib cage. The suture needle was used to penetrate the ventricle immediately below the elevated atrium and exit the ventricle in a downward diagonal direction, thus obtaining a > 30% to < 50% Occlusion Zone (OZ). The outlet position is 0.5cm below the junction of the aorta and the left ventricle. The suture is tightened so that a loose loop (obturator) is formed around one of the branches of the artery. The chest is then closed, leaving the ends of the occlusion exposed outside the chest.

Electrodes were placed in lead II location (right atrium to apical) for ECG measurements as follows: one electrode was inserted into the right anterior paw and the other electrode into the left posterior paw.

Body temperature, MAP, ECG and heart rate were continuously recorded throughout the experiment. When the key parameters are stable, recording is carried out for 1-2 minutes to establish a reference value. Once the baseline value is established, infusion of the compound of the invention or the control substance is initiated. After 5 minutes of compound or control infusion, sutures were tightened to ligate LCA and cause ischemia in the left ventricle. After ligation, recording of critical parameters was continued for 20 minutes unless the MAP reached a critical level of 20-30mmHg for at least 3 minutes, in which case recording was stopped as the animal would be declared dead and then sacrificed. Compounds of the invention prevent arrhythmia and maintain a near normal MAP and HR capability score and compare to control groups.

The compounds of the invention, when tested in this model, demonstrated the ability to prevent ischemia-induced ventricular tachycardia and fibrillation.

*****

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications cited in this specification and/or listed in the application data sheet, are incorporated herein by reference, in their entirety.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims (4)

1. A compound, a stereoisomer, enantiomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

1'- (2-cyclopropylethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4' -bromo-1 ' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

(2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) acetic acid ethyl ester;

spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1'- [3- (benzyloxy) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4',7' -dichloro-1 '-pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

4 '-bromospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

4' -bromo-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -2' (1' H) -one;

5 '-methyl spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

Ethyl (4 '-bromo-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) acetate;

ethyl (4 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) acetate;

ethyl (5 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) acetate;

7 '-fluorospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

(2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) acetic acid;

n- (4-chlorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-fluorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-butyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

1'- (2-keto-2-piperidin-1-ylethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

N-butyl-N-methyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) -N-phenylacetamide;

n- (4-fluorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-fluorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-chlorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-fluorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-ethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (4-ethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-methylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 3-dimethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N- (3, 5-dimethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) -N-pentylacetamide;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) -N-propylacetamide;

n-isopropyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-methylbutyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-isobutyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-hexyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-cyclohexyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-cyclopentyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-heptyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N- (2-chlorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 6-dimethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-methoxyphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- [ (5-methyl-2-furyl) methyl ] -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-ethyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-methyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-fluorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- [2- (3-methoxyphenyl) ethyl ] -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-ethoxyethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N- (4-methoxybenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 4-dimethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-isopropoxypropyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-furylmethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (cyclohexylmethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-fluoro-2-methylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (4-methoxyphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-cyclobutyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 5-difluorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N-benzyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (cyclopropylmethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N-butyl-N-ethyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-octyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3, 3-dimethylbutyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (4-chloro-2-methylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-methoxyphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-fluoro-4-methylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3, 4-dimethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N- (3-chlorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-methoxybenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3, 4-difluorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-methylbenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-methoxybenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (4-isopropylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 3-difluorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) -N- (tetrahydrofuran-2-ylmethyl) acetamide;

n- [2- (4-methylphenyl) ethyl ] -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N- [2- (3-chlorophenyl) ethyl ] -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (4-cyanophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 3-dihydro-1H-inden-1-yl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-methoxyethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- [2- (4-methoxyphenyl) ethyl ] -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-cyanoethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 4-dichlorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3, 5-difluorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 4-difluorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N- (2-methylbenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3, 4-difluorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 5-difluorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) -N, N-dipropylacetamide;

n, N-dibutyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 6-difluorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- [2- (methylthio) phenyl ] -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-isopropylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (4-bromophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N- (4-chlorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 4-dichlorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3, 5-dichlorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n, N-diethyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-methyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) -N-phenylacetamide;

n- (4-hydroxybutyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-allyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-fluoro-5-methylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (1, 3-benzodioxol-5-ylmethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) acetamide;

N-cyclopropyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-cyclopropylethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3, 4-dichlorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 3-dichlorobenzyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2, 5-dimethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3, 4-dichlorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n, N-dimethyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n-methyl-2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) -N- (2-phenylethyl) acetamide;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) -N- (2-phenylpropyl) acetamide;

N- [ (1R) -1-cyclohexylethyl ] -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- [ (1S) -1-cyclohexylethyl ] -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) -N- (2-piperidin-1-ylethyl) acetamide;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) -N- [3- (trifluoromethyl) phenyl ] acetamide;

n- (3-cyanophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

1'- (2-morpholin-4-yl-2-ketoethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) -N- (2-phenylethyl) acetamide;

n- (4-bromo-2-chlorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-biphenyl-4-ylethyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) acetamide;

1 '-prop-2-yn-1-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2-ethoxyethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (2E) -pent-2-en-1-yl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-hex-5-en-1-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (cyclobutylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-pent-2-yn-1-ylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (5-chloropentyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (4-fluorobutyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (5-methylhexyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (3Z) -4-methylhexan-3-en-1-yl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2-bromoethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

5- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) valeronitrile;

1'- [2- (2-methoxyethoxy) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (cyclopropylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (4,4, 4-trifluorobutyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

diethyl [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] phosphonate;

1'- [ (2,2,3, 3-tetrafluorocyclobutyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (benzyloxy) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-allylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2-ethylbutyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (4-methylpentyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3-methylbut-2-en-1-yl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-pent-4-en-1-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

4- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) butanenitrile;

1'- [ (2-methylcyclopropyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3-cyclopropyl propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-hexylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (2-cyclopropyl-6-hydroxypyrimidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (2-methylcyclopropyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3-cyclopropyl propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-butylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'[4- (trifluoromethoxy) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1 '-propylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4' -bromo-1 ' -methyl spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4- [ (4' -bromo-2 ' -ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1' (2' H) -yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester;

ethyl 5- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) pentanoate;

ethyl 4- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) butanoate;

1'- (3-chloropropyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (cyclohexylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (methylsulfonyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3-hydroxypropyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propanal;

2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3 '-indole ] -4' -carbonitrile;

5, 6-difluoro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

5-fluoro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

5-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

5-chloro-6-fluoro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

6-methoxy-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

6-chloro-5-fluoro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1 '-pentyl-5- (trifluoromethyl) spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

5, 6-dichloro-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

6-bromo-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

5-bromospiro [ 1-benzofuran-3, 3' -indol ] -2' (1' H) -one;

6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indol ] -2' (1' H) -one;

ethyl (4' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3' -indol ] -1' (2' H) -yl) acetate;

(6-chloro-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1'(2' H) -yl) acetic acid methyl ester;

(5, 6-difluoro-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1'(2' H) -yl) acetic acid ethyl ester;

2- (4' -bromo-5, 6-difluoro-2 ' -ketospiro [ 1-benzofuran-3, 3' -indol ] -1' (2' H) -yl) -N- (2-fluorophenyl) acetamide;

2- (6-chloro-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

2- (5, 6-difluoro-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

2- (5-bromo-2 '-ketospiro [ 1-benzofuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

6-phenylamino-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

6-morpholin-4-yl-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

6-amino-1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1 '-pentyl-6-phenoxyspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1 '-pentyl-6-pyridin-4-ylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

6- (methylsulfonyl) -1 '-pentylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1 '-pentyl-6- (benzenesulfonyl) spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1 '-pentyl-5-phenoxyspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

5-hydroxy spiro [ 1-benzofuran-3, 3' -indol ] -2' (1' H) -one;

trifluoromethanesulfonic acid-2 '-keto-1', 2 '-dihydrospiro [ 1-benzofuran-3, 3' -indol ] -5-yl ester;

1 '-pentyl-5-pyridin-3-ylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1 '-pentyl-5-pyrimidin-5-ylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1 '-pentyl-5-pyridin-4-ylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

2' -keto-1 ' -pentyl-1 ',2' -dihydrospiro [ 1-benzofuran-3, 3' -indole ] -5-carbonitrile;

n- (2-fluorophenyl) -2- (2 '-keto-5-pyridin-3-ylspiro [ 1-benzofuran-3, 3' -indol ] -1'(2' H) -yl) acetamide;

3- (2 '-keto-1', 2 '-dihydrospiro [ 1-benzofuran-3, 3' -indol ] -5-yl) piperidine-1-carboxylic acid tert-butyl ester;

5-methoxy-1 '-methyl spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

(4 '-bromo-6, 6-dimethyl-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) acetic acid ethyl ester;

ethyl (2 '-keto-6, 7-dihydro-5H-spiro [ indeno [5,6-b ] furan-3, 3' -indol ] -1'(2' H) -yl) acetate;

ethyl (2-keto-5 ',6',7',8' -tetrahydrospiro [ indole-3, 3' -naphtho [2,3-b ] furan ] -1(2H) -yl) acetate;

6, 7-dihydrospiro [ benzo [1,2-b:4,5-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

(2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -1' (2' H) -yl) acetic acid ethyl ester;

(2 '-keto-6, 7-dihydro-5H-spiro [ indeno [5,6-b ] furan-3, 3' -indol ] -1'(2' H) -yl) acetic acid;

(4 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) acetic acid;

(4 '-bromo-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) acetic acid;

(5 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) acetic acid;

(2-keto-5 ',6',7',8' -tetrahydrospiro [ indole-3, 3' -naphtho [2,3-b ] furan ] -1(2H) -yl) acetic acid;

(2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -1' (2' H) -yl) acetic acid;

n- (2-fluorophenyl) -2- (2 '-keto-6, 7-dihydro-5H-spiro [ indeno [5,6-b ] furan-3, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-fluorophenyl) -2- (2-keto-5 ',6',7',8' -tetrahydrospiro [ indole-3, 3' -naphtho [2,3-b ] furan ] -1(2H) -yl) acetamide;

2- (4 '-bromo-6, 6-dimethyl-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

2- (4 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

2- (5 '-chloro-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

2- (4 '-fluoro-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

2- (4 '-bromo-2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

n- (2-fluorophenyl) -2- (2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -1' (2' H) -yl) acetamide;

2- (4' -fluoro-7 ' -methyl-2 ' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -1' (2' H) -yl) -N- (2-fluorophenyl) acetamide;

4' - [6- (dimethylamino) pyridin-3-yl ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (3, 5-dimethoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-fluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3, 5-dichlorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - [4- (dimethylamino) phenyl ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - (3,4, 5-trimethoxyphenyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3 '-indol ] -4' yl) benzonitrile;

4' -dibenzo [ b, d ] furan-4-yl-1 ' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (1-benzyl-1H-pyrazol-4-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (2-methoxypyrimidin-5-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (2, 4-dimethoxypyrimidin-5-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3 '-indol ] -4' yl) benzamide;

4' - {4- [ (dimethylamino) methyl ] phenyl } -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (1-benzofuran-2-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (6-methoxypyridin-3-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

n, N-dimethyl-4- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3 '-indol ] -4' yl) benzamide;

4' -dibenzo [ b, d ] thiophen-4-yl-1 ' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

3- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3 '-indol ] -4' yl) benzonitrile;

1' -pentyl-4 ' -pyridin-3-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-fluoro-4-methoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - [2- (trifluoromethoxy) phenyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - [3, 5-bis (trifluoromethyl) phenyl ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - [4- (trifluoromethyl) pyridin-3-yl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (2-fluoro-5-methoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-ethoxy-3-fluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (1-benzothien-2-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' -isobutyl-1 ' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - [4- (trifluoromethoxy) phenyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (5-fluoro-2-methoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (1, 3-benzodioxol-5-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' -phenylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - [2- (trifluoromethyl) phenyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-chlorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (2, 3-dihydro-1, 4-benzodioxol-6-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' -quinolin-3-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3, 5-difluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' -isoquinolin-4-yl-1 ' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (6-methoxypyridin-2-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (1H-indol-5-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

n- [2- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3 '-indol ] -4' yl) phenyl ] acetamide;

4' - (4-fluoro-2-methylphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' -quinolin-6-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

n- [4- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3 '-indol ] -4' yl) phenyl ] methanesulfonamide;

4' - (5-chloro-2-methoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - [3- (trifluoromethoxy) phenyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - (4-phenoxyphenyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (2, 4-dimethoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-furyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3, 4-dimethoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

n- [4- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3 '-indol ] -4' yl) phenyl ] acetamide;

1' -pentyl-4 ' - [ (E) -2-phenylvinyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (4-methoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (6-fluoropyridin-3-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-chloro-4-fluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-chlorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (1-benzothien-3-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - (2-phenoxyphenyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-isopropoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - [ (E) -2- (4-fluorophenyl) vinyl ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (6-fluoropyridin-2-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - [1- (benzenesulfonyl) -1H-indol-3-yl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (3-fluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-acetylphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (2-furyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-methylphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (1-methyl-1H-pyrrol-3-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (2, 5-difluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (2-fluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (2-chlorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (2, 4-difluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-morpholin-4-ylphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

5-methoxy-3- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3 '-indol ] -4' yl) -1H-indole-1-carboxylic acid tert-butyl ester;

1' -pentyl-4 ' -pyrimidin-5-yl spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4- [2- (2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3 '-indol ] -4' yl) phenyl ] piperazine-1-carboxylic acid tert-butyl ester;

4' - (2-methoxypyridin-3-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (5-methoxypyridin-3-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-butoxy-3-fluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' -pyridin-4-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' -phenoxazin-4-yl spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - [ (1Z) -3-chloroprop-1-en-1-yl ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - (3-thienyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (2, 3-dimethoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-butylphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-fluoro-5-methoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - [ 3-fluoro-4- (pentyloxy) phenyl ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (2-butoxy-5-fluorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-butoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-butoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-isobutoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - { 2-chloro-4- [ (3, 5-dimethoxybenzyl) oxy ] phenyl } -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - [4- (benzyloxy) -3-chlorophenyl ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (1-methyl-1H-indol-5-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (4-methoxypyridin-3-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - [ (6-methoxypyridin-3-yl) amino ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4'- (3-furyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4 '-dibenzo [ b, d ] furan-4-yl spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4 '-pyrimidin-5-ylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1' -methyl-4 ' -pyrimidin-5-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-furyl) -1' -methylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (6-fluoropyridin-3-yl) -1' -methylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' - (2-cyclopropylethyl) -4' -quinolin-3-ylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - [ (6-methoxypyridin-3-yl) amino ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - [ (3, 5-difluorophenyl) amino ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - [ (4, 6-dimethylpyridin-2-yl) amino ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - [ (4-methyl-1, 3-thiazol-2-yl) amino ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' -bromo-1 ' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4 '-morpholinyl-1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (4-methylpiperazin-1-yl) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

1 '-pentyl-4' - (pyrimidin-4-ylamino) -6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

1 '-pentyl-4' - (pyridin-3-ylamino) -6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (4-chloro-2- (trifluoromethyl) phenylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

1 '-pentyl-4' - (pyrimidin-2-ylamino) -6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (benzo [ d ] [1,3] dioxol-5-ylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (3-fluorophenylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (naphthalen-2-ylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (2-methoxyphenyl amino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (4-methylthiazol-2-ylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (4, 6-dimethylpyridin-2-ylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (3, 5-difluorophenylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (6-methoxypyridin-3-ylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

1 '-pentyl-7H-spiro [ furo [3,4-f ] [1,3] benzodioxol-5, 3' -indol ] -2'(1' H) -one;

2 '-keto-1' -pentyl-N-pyridin-2-yl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3 '-indole ] -4' -carboxamide;

n- (3-methoxyphenyl) -2 '-keto-1' -pentyl-1 ',2' -dihydrospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3 '-indole ] -4' -carboxamide;

2- (5, 6-difluoro-2 ' -keto-4 ' -pyrimidin-5-ylspiro [ 1-benzofuran-3, 3' -indol ] -1' (2' H) -yl) -N- (2-fluorophenyl) acetamide;

2- (6, 6-dimethyl-2 '-keto-4' -pyrimidin-5-yl-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) -N- (2-fluorophenyl) acetamide;

n- (2-fluorophenyl) -2- (2 '-keto-4' -pyrimidin-5-yl-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-methylbutyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n, N-diisopropyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N-butyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-pentylbenzamide;

n-hexyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-propylbenzamide;

n-isopropyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-heptyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- [2- (piperidin-1-ylcarbonyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

n-isobutyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-methoxypropyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (3-ethoxypropyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N-hexyl-N-methyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-isopropoxypropyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-ethoxyethyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-methyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-ethyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2,2, 2-trifluoroethyl) benzamide;

n- [2- (diethylamino) ethyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (3, 3-dimethylbutyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-ethylbutyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxyethyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-cyanoethyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- {2- [ (4-pyrimidin-2-ylpiperazin-1-yl) carbonyl ] benzyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2- { [4- (1, 3-benzodioxol-5-ylmethyl) piperazin-1-yl ] carbonyl } benzyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [2- (morpholin-4-ylcarbonyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

n- [3- (dimethylamino) propyl ] -N-methyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (3-methylbutyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n, N-diisopropyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-butyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-pentylbenzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-propylbenzamide;

n-isopropyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- [3- (piperidin-1-ylcarbonyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

n-isobutyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-hexyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N-heptyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-methoxypropyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (diethylamino) ethyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-methyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-ethyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-ethoxypropyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N-hexyl-N-methyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-isopropoxypropyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (2-ethoxyethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-ethylbutyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxyethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- [3- (morpholin-4-ylcarbonyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (4-pyrimidin-2-ylpiperazin-1-yl) carbonyl ] benzyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (4-methylpiperazin-1-yl) carbonyl ] benzyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

n- (3, 3-dimethylbutyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-cyanoethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-butyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- [4- (piperidin-1-ylcarbonyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

n, N-diisopropyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-pentylbenzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-propylbenzamide;

n-isopropyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-isobutyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-hexyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-heptyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-methoxypropyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- [2- (diethylamino) ethyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-methyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-ethyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-ethoxypropyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-methylpentyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2,2, 2-trifluoroethyl) benzamide;

N-hexyl-N-methyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-isopropoxypropyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (2-ethoxyethyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-ethylbutyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxyethyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-cyanoethyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [3- (dimethylamino) propyl ] -N-methyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-chlorophenyl) ethyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-phenylbenzamide;

n- (3-fluorophenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (4-chlorobenzyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclohexyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclopentyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-fluorophenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-fluorobenzyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-chlorophenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-fluorophenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-ethylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-ethylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (3-methylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 3-dimethylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3, 5-dimethylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-chlorobenzyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 6-dimethylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxyphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-methylphenyl) ethyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (tetrahydrofuran-2-ylmethyl) benzamide;

N, N-dibenzyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (3-phenylpropyl) benzamide;

n- [2- (3-chlorophenyl) ethyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-fluorophenyl) ethyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-fluorobenzyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-methoxybenzyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (cyclopropylmethyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (cyclohexylmethyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (2-furylmethyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 4-dimethylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-cyanophenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3, 5-dichlorophenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-fluoro-2-methylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-methoxyphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (5-chloro-2-methylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [3- (trifluoromethyl) phenyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (pyridin-4-ylmethyl) benzamide;

n-cyclobutyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 2-diphenylethyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2-pyrrolidin-1-ylethyl) benzamide;

n- [ (1-ethylpyrrolidin-2-yl) methyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2-piperidin-1-ylethyl) benzamide;

n- (2-morpholin-4-ylethyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [ (1S) -1-cyclohexylethyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (2-fluoro-5-methylphenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 4-difluorophenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (4-propylphenyl) benzamide;

n- (3, 3-diphenylpropyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 5-difluorobenzyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2-thienylmethyl) benzamide;

n- [ 4-chloro-2- (trifluoromethyl) phenyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-methoxyphenyl) ethyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (3, 5-dichlorobenzyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-chlorobenzyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [2- (2-thienyl) ethyl ] benzamide;

n- (2, 3-dihydro-1H-inden-1-yl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [4- (trifluoromethyl) benzyl ] benzamide;

n- [ 4-fluoro-2- (trifluoromethyl) phenyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (pyridin-3-ylmethyl) benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [2- (trifluoromethyl) benzyl ] benzamide;

N- (3-methylpyridin-2-yl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (1-benzylpiperidin-4-yl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [2- (trifluoromethyl) phenyl ] benzamide;

n- [ (1R) -1-cyclohexylethyl ] -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (6-methoxypyridin-3-yl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-1, 3-thiazol-2-ylbenzamide;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-1,3, 4-thiadiazol-2-ylbenzamide;

n- (4, 6-dimethylpyridin-2-yl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (2, 3-dihydro-1H-inden-5-yl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-2-adamantyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-1-adamantyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-1-naphthyl-2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3, 5-difluorophenyl) -2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (3-chlorophenyl) ethyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-phenylbenzamide;

n- (3-fluorophenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (4-chlorobenzyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-fluorobenzyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-chlorophenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-fluorophenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-ethylphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-ethylphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-methylphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 3-dimethylphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (3, 5-dimethylphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclohexyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclopentyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxybenzyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxyphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclopropyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 4-dimethylphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (tetrahydrofuran-2-ylmethyl) benzamide;

N, N-dibenzyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [3- (trifluoromethyl) phenyl ] benzamide;

n- (4-methoxybenzyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3, 5-dichlorophenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-pyridin-3-ylbenzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (pyridin-4-ylmethyl) benzamide;

n- (2-furylmethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-fluoro-2-methylphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (cyclopropylmethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-methoxyphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclobutyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-fluorophenyl) ethyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (cyclohexylmethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-methylphenyl) ethyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-benzyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (1-benzylpiperidin-4-yl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- [2- (4-methoxyphenyl) ethyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2-piperidin-1-ylethyl) benzamide;

n- (1-cyclohexylethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2-thienylmethyl) benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (4-propylphenyl) benzamide;

n- (2, 4-difluorobenzyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3, 5-difluorophenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 3-dihydro-1H-inden-5-yl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [4- (trifluoromethyl) benzyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [2- (2-thienyl) ethyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (pyridin-3-ylmethyl) benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [2- (trifluoromethyl) benzyl ] benzamide;

n- [2- (4-chlorophenyl) ethyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2-pyrrolidin-1-ylethyl) benzamide;

n- (3-methylpyridin-2-yl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-1, 3-benzodioxol-5-yl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (2-morpholin-4-ylethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-1, 3-thiazol-2-ylbenzamide;

n- (6-methoxypyridin-3-yl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3, 5-dichlorobenzyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-1-naphthyl-3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4, 6-dimethylpyridin-2-yl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-pyrimidin-4-ylbenzamide;

n- (5-methyl-1, 3-thiazol-2-yl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (4-methylbenzyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [3- (1H-imidazol-1-yl) propyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (5-cyclopropyl-1, 3, 4-thiadiazol-2-yl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-1,3, 4-thiadiazol-2-ylbenzamide;

n- (4-morpholin-4-ylphenyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [ (1-ethylpyrrolidin-2-yl) methyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 2-diphenylethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-fluorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (3-fluorobenzyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-chlorobenzyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-chlorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-fluorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-ethylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-ethylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-methylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3, 5-dimethylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (2, 3-dimethylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclohexyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclopentyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxybenzyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 6-dimethylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxyphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclopropyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-phenylbenzamide;

n- (2, 4-dimethylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (tetrahydrofuran-2-ylmethyl) benzamide;

n, N-dibenzyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [3- (trifluoromethyl) phenyl ] benzamide;

n- (4-methoxybenzyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3, 5-dichlorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-pyridin-3-ylbenzamide;

n- (4-cyanophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (pyridin-4-ylmethyl) benzamide;

N- [2- (3-chlorophenyl) ethyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-furylmethyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (3-fluoro-2-methylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (cyclopropylmethyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-methoxyphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-cyclobutyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 2-diphenylethyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-fluorophenyl) ethyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (cyclohexylmethyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-fluoro-4-methylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-methylphenyl) ethyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-benzyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- [4- (morpholin-4-ylcarbonyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

n- (1-benzylpiperidin-4-yl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [2- (4-methoxyphenyl) ethyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [2- (trifluoromethyl) phenyl ] benzamide;

N- [ 4-chloro-2- (trifluoromethyl) phenyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [ 4-fluoro-2- (trifluoromethyl) phenyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [ (1S) -1-cyclohexylethyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- [ (1R) -1-cyclohexylethyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 4-difluorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 3-dihydro-1H-inden-1-yl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2-thienylmethyl) benzamide;

n- [ (1-ethylpyrrolidin-2-yl) methyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (4-propylphenyl) benzamide;

n- (2, 5-difluorobenzyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 3-dihydro-1H-inden-5-yl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2, 5-difluorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [4- (trifluoromethyl) benzyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [2- (2-thienyl) ethyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (pyridin-3-ylmethyl) benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- [2- (trifluoromethyl) benzyl ] benzamide;

N- [2- (4-chlorophenyl) ethyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N- (2-pyrrolidin-1-ylethyl) benzamide;

n- (3-methylpyridin-2-yl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-1, 3-benzodioxol-5-yl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-morpholin-4-ylethyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- {4- [ (4-pyrimidin-2-ylpiperazin-1-yl) carbonyl ] benzyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-1, 3-thiazol-2-ylbenzamide;

n- (6-methoxypyridin-3-yl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- (3, 5-dichlorobenzyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-1-naphthyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- (4- { [4- (1, 3-benzodioxol-5-ylmethyl) piperazin-1-yl ] carbonyl } benzyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

n- (4, 6-dimethylpyridin-2-yl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -N-pyrimidin-4-ylbenzamide;

n- (5-methyl-1, 3-thiazol-2-yl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-cyano-6-fluorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-methylbenzyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- [3- (1H-imidazol-1-yl) propyl ] -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-morpholin-4-ylphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- {4- [ (4-methylpiperazin-1-yl) carbonyl ] benzyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

n- (5-cyclopropyl-1, 3, 4-thiadiazol-2-yl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

methyl 2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzoate;

methyl 3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzoate;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzoic acid methyl ester;

1'- (benzhydryl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1' - (benzhydryl) -5' -methyl spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

2- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzoic acid;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzoic acid;

1'- (4-fluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-benzylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3, 5-difluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3-nitrobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3-fluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzonitrile;

1'- [4- (1H-pyrazol-1-yl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (biphenyl-4-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4' - [ (2' -ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1' (2' H) -yl) methyl ] biphenyl-2-carbonitrile;

1'- (biphenyl-2-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (benzhydryl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (4-fluoro-3-methylbenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (5-fluoro-2-methylbenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2, 5-difluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [4- (1H-pyrrol-1-yl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (1H-pyrrol-1-yl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (4-chlorophenoxy) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 2-fluoro-3- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 2-fluoro-6- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 3-fluoro-4- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 4-fluoro-3- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 2-fluoro-5- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 4-fluoro-2- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 5-fluoro-2- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 2-fluoro-4- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2, 3-difluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ (1-bromo-2-naphthyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (1-naphthylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ 3-fluoro-5- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2, 4-difluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2, 6-difluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3-methoxybenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [4- (1H-1,2, 4-triazol-1-yl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [4, 4-bis (4-fluorophenyl) butyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2-chloro-4-fluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [2- (trifluoromethoxy) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (trifluoromethoxy) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1' - (2, 3-difluorobenzyl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5,4-b '] difuran-3, 3' -indole ]2'(1' H) -one;

1' - (4-methoxybenzyl) -5, 6-dihydrospiro [ benzo [1, 2-b: 5,4-b '] difuran-3, 3' -indole ]2'(1' H) -one;

4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzoic acid;

5-bromo-1 '- (benzhydryl) spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1'- (benzhydryl) -6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1'- (4-methoxybenzyl) -6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1'- (benzhydryl) -5-hydroxyspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1'- (benzhydryl) -5-pyridin-3-ylspiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1' - (benzhydryl) -5, 5-dimethyl-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -2' (1' H) -one;

2-methyl-1 '-pentylspiro [ furo [2,3-f ] [1,3] benzothiazol-7, 3' -indol ] -2'(1' H) -one;

1' - (benzhydryl) -6, 7-dihydrospiro [ benzo [1,2-b:4,5-b ' ] difuran-3, 3' -indol ] -2' (1' H) -one;

1' - (benzhydryl) -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -2' (1' H) -one;

1'- [2- (diethylamino) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [2- (pyridin-2-ylamino) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [2- (bipyridin-2-ylamino) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (cyclopropylmethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (4-fluorobenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (4-chlorophenyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (pentylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-ethoxyethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3-methoxypropyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3-methylbutyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3-ethoxypropyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2, 2-dimethylpropyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

3- { [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] amino } propionitrile;

1'- {3- [ (2,2, 2-trifluoroethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (cyclopropylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (cyclobutylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-cyclopropylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (isobutylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (hexylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (heptylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (isopropylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (tetrahydrofuran-2-ylmethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (benzylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-phenylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (dibenzylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (propylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (3-fluorophenyl) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3-phenylpropyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2, 2-diphenylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (4-methylphenyl) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (3-chlorophenyl) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-pyridin-4-ylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (pyridin-4-ylmethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (4-fluorophenyl) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (pyridin-2-ylmethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [ (1R) -1-cyclohexylethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-furylmethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (4-chlorobenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (4-methoxybenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3-isopropoxypropyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (2-fluorophenyl) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3, 3-dimethylbutyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (cyclohexylmethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [ (1S) -1-cyclohexylethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-piperidin-1-ylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-pyrrolidin-1-ylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-morpholin-4-ylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (cyclohexylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (cyclopentylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-chlorobenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (dibutylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (dipropylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (dimethylamino) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (diethylamino) ethyl ] (methyl) amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (diisopropylamino) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (diisopropylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (methylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (ethylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ bis (2-methoxyethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-fluorobenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3, 5-difluorobenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [3- (dimethylamino) propyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (diethylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (octylamino) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (1-methylbutyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ butyl (methyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-isopropoxyethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2, 4-difluorobenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-methylbenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3-fluorobenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2, 6-difluorobenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (1, 2-dimethylpropyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (1-methylpyrrolidin-2-yl) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-pyridin-3-ylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (1-methyl-2-phenylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [2- (2-chlorophenyl) ethyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-cyclohexylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-pyridin-2-ylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (2-biphenyl-4-ylethyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3-morpholin-4-ylpropyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3- { [ (5-methyl-2-furyl) methyl ] amino } propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- {3- [ (3-methylbenzyl) amino ] propyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3-aminopropyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2-aminoethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

3-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] thiophene-2-carboxamide;

N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] cyclopropanecarboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] cyclobutanecarboxamide;

2-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] nicotinamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] cyclopentanecarboxamide;

2, 2-dimethyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] propionamide;

2- (4-methoxyphenyl) -N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

4-tert-butyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

3, 3-dimethyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] butanamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] biphenyl-4-carboxamide;

3-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -1-benzofuran-2-carboxamide;

2- (benzyloxy) -N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2-furancarboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indole ] -1'(2' H) -yl) propyl ] -1, 3-benzodioxol-5-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] quinoline-2-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2-phenylacetamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] piperidine-1-carboxamide;

2-methoxy-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

4- (dimethylamino) -N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

4-ethoxy-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

2-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] butanamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2-phenoxyacetamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] quinoxaline-2-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] cyclohexanecarboxamide;

4-fluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

2-ethyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] butanamide;

2- (4-fluorophenyl) -N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

6-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] nicotinamide;

2-fluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2-phenylcyclopropanecarboxamide;

4-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

1- (4-fluorophenyl) -5-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -1H-pyrazole-4-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -1-benzofuran-5-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -2,1, 3-benzoxadiazole-5-carboxamide;

2, 4-dichloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

1-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -1H-1,2, 3-benzotriazole-5-carboxamide;

5-fluoro-2-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

2-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] isonicotinamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2, 3-dihydro-1, 4-benzodioxan-6-carboxamide;

5-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] isoxazole-3-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -1-benzofuran-2-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -1-benzothiophene-2-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2, 3-dihydro-1, 4-benzodioxan-2-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -4- (1H-pyrazol-1-yl) benzamide;

1, 3-dimethyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -1H-pyrazole-5-carboxamide;

4-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -3, 4-dihydro-2H-1, 4-benzoxazine-7-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] quinoxaline-6-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2, 3-dihydro-1-benzofuran-2-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -2, 3-dihydro-1-benzothiophene-5-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2- (trifluoromethoxy) benzamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] pentanamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] heptanamide;

3-cyclopentyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] propionamide;

9-keto-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] -9H-fluorene-4-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -4- (trifluoromethyl) benzamide;

2, 5-difluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

2, 5-dimethyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -3-furancarboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -4-phenoxybutyramide;

4-fluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2- (trifluoromethyl) benzamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2- (2-thienyl) acetamide;

2-chloro-5-fluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2-naphthamide;

2- (4-chlorophenoxy) -N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

2, 4-dimethoxy-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

2-nitro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

2- (4-chlorophenyl) -3-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] butanamide;

4-amino-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

3, 4-dimethoxy-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -5H-dibenzo [ b, f ] azepin-5-carboxamide;

N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] adamantane-1-carboxamide;

2- [ (2-isopropyl-5-methylcyclohexyl) oxy ] -N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -3, 5-bis (trifluoromethyl) benzamide;

2- (2, 5-dimethoxyphenyl) -N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

2-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

3-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

4-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] hexanamide;

2, 6-difluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

2-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2, 5-bis (trifluoromethyl) benzamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indole ] -1'(2' H) -yl) propyl ] pyrrolidine-1-carboxamide;

2-bromo-2, 2-difluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

2,3, 5-trifluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

5-fluoro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2- (trifluoromethyl) benzamide;

5-chloro-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2- (trifluoromethyl) benzamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] thiophene-2-carboxamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] morpholine-4-carboxamide;

2- (1-naphthyl) -N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] acetamide;

2-methyl-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] propionamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -N-propionylpropanamide;

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -4-pentylbenzamide;

4,7, 7-trimethyl-3-keto-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2-ketobicyclo [2.2.1] heptane-1-carboxamide;

2-bromo-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

3-cyano-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

4-cyano-N- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] benzamide;

n- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -2- (trifluoromethoxy) benzamide;

1- (4-fluorophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1-benzyl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- (4-phenoxyphenyl) urea;

1-butyl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1-cyclohexyl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1-ethyl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1-isopropyl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3-propylurea;

1-tert-butyl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1-cyclopentyl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3-pentylurea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3-phenylurea;

1- (2-furylmethyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1-hexyl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

ethyl N- ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) glycinate;

1- (3-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

n- ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) - β -alanine ethyl ester;

1- (4-cyanophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

n- ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) benzamide;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- (2-phenylethyl) urea;

1- (4-methylbenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2-methylbenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-ethylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3-methoxyphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2-fluoro-5-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3-fluoro-4-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-chlorophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

2-methacrylic acid-2- [ ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) amino ] ethyl ester;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- (1,1,3, 3-tetramethylbutyl) urea;

ethyl 4- [ ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) amino ] butanoate;

1- [4- (cyanomethyl) phenyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2, 3-dihydro-1H-inden-5-yl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3-acetylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-acetylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-isopropylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2-methoxybenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-methoxybenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-methoxy-2-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-chloro-2-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3-chloro-4-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3-chloro-2-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (5-chloro-2-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2-chlorobenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (1-naphthyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2-naphthyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3-chloro-2-fluorophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- (5,6,7, 8-tetrahydronaphthalen-1-yl) urea;

1- (4-tert-butylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-butylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (4-ethylphenyl) ethyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2, 3-dihydro-1, 4-benzodioxan-6-yl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

Methyl 4- [ ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) amino ] benzoate;

1- (2-ethoxybenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3, 4-dimethoxyphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3, 5-dimethoxyphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3-chloro-4-methoxyphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [4- (difluoromethoxy) phenyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (difluoromethoxy) phenyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- [3- (trifluoromethyl) phenyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- [2- (trifluoromethyl) phenyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- [4- (trifluoromethyl) phenyl ] urea;

1- (3, 4-dichlorophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2, 3-dichlorophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3, 5-dichlorophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

ethyl 4- [ ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) amino ] benzoate;

ethyl 2- [ ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) amino ] benzoate;

1- [2- (1, 3-benzodioxol-5-yl) ethyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

2-methyl-3- [ ({ [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] amino } carbonyl) amino ] benzoic acid methyl ester;

1- (4-butoxyphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2-methoxy-4-nitrophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1-biphenyl-2-yl-3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [ 4-methyl-3- (trifluoromethyl) phenyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2, 4-dichlorobenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- [2- (trifluoromethoxy) phenyl ] urea;

1- [ 4-fluoro-2- (trifluoromethyl) phenyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (5-tert-butyl-2-methoxyphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (3, 5-dimethoxyphenyl) ethyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (9H-fluoren-2-yl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (9H-fluoren-9-yl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- (3,4, 5-trimethoxyphenyl) urea;

1- (benzhydryl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- (2-phenoxyphenyl) urea;

1- (2-biphenyl-4-ylethyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -3- (3,4, 5-trimethoxybenzyl) urea;

1- (2-nitrophenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (1, 3-benzodioxol-5-yl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [4- (dimethylamino) phenyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2-fluorobenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (4-fluoro-3-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (3-fluorobenzyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (cyclohexylmethyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- (2-methylphenyl) -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

1- [4- (6-methyl-1, 3-benzothiazol-2-yl) phenyl ] -3- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] urea;

2- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) propyl ] -1H-isoindole-1, 3(2H) -dione;

2- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -1H-isoindole-1, 3(2H) -dione;

4 '-bromo-1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

5' -fluoro-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

5' -methyl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

5-bromo-1 '- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

4' -methoxy-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

7' -fluoro-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1'- { [1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazol-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- { [6- (trifluoromethyl) pyridin-3-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (6-chloropyridin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (tetrahydro-2H-pyran-2-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (tetrahydrofuran-2-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2, 3-dihydro-1, 4-benzodioxan-2-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (7-methoxy-2-keto-2H-1, 4-benzoxazin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (5-methyl-2-phenyl-2H-1, 2, 3-triazol-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3, 4-dihydro-2H-1, 5-benzodioxoheptacycloalken-7-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (1H-1,2, 3-triazol-4-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -1H-1,2, 3-triazole-5-carboxylic acid ethyl ester;

1- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) ethyl ] -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester;

1'- (1, 3-thiazol-4-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ (5-chloro-1-benzothien-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-2-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-4-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-3-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [2- (1H-pyrrol-1-yl) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- { [ 4-chloro-2- (trifluoromethyl) quinolin-6-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (2-methyl-1, 3-thiazol-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (1, 3-benzothiazol-2-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2,1, 3-benzothiadiazol-4-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2,1, 3-benzothiadiazol-5-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (1-methyl-1H-1, 2, 3-benzotriazol-5-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (1H-pyrrol-1-yl) propyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (3-methyl-5-phenylisoxazol-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (7-methoxy-2-keto-2H-chromen-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [2- (2,5, 5-trimethyl-1, 3-dioxan-2-yl) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ (6-fluoro-4H-1, 3-benzodioxol-8-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (5-phenyl-1, 3-oxazol-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (1, 3-benzodioxol-5-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '(piperidin-4-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'[ (1-methylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'[ (1-ethylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'[ (1-cyclohexylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'{ [ 1-cyclopropylmethyl) piperidin-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'[ (1-cyclopentylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'{ [1- (pyridin-3-ylmethyl) piperidin-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'{ [1- (3-methylbutyl) piperidin-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'{ [1- (1-ethylpropyl) piperidin-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'[ (1-cyclobutylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'[ (1-isopropylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'{ [1- (pyridin-2-ylmethyl) piperidin-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'{ [1- (2-thienylmethyl) piperidin-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- ({1- [3- (methylthio) propyl ] piperidin-4-yl } methyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'{ [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- { [1- (3, 3-dimethylbutyl) piperidin-4-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

7' -fluoro-1 ' - [ (1-isopropylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one hydrochloride;

1'- [ (6-methylpyridin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- [ (6-methoxypyridin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (6-chloropyridin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- { [6- (dimethylamino) pyridin-3-yl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- [ (6-morpholin-4-ylpyridin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- [ (6-pyrrolidin-1-ylpyridin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- [ (5-methylisoxazol-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' indol ] -2'(1' H) -one;

1'- (tetrahydro-2H-pyran-4-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'(2,1, 3-benzooxadiazol-5-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'[ (1-methyl-1H-benzotriazol-6-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4- [ (2' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -1' (2' H) -yl) methyl ] piperidine 1-carboxylic acid tert-butyl ester;

1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indole ]2' (1' H) -one hydrochloride;

4' -bromo-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4 '-bromo-1' - { [5- (trifluoromethyl) -2-furyl ] methyl } -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

1'- [ (3, 5-dimethylisoxazol-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2-furylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (1,2, 4-oxadiazol-3-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- { [5- (3-chlorophenyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (2-isopropyl-1, 3-oxazol-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (1-methyl-1H-benzoimidazol-2-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (2-keto-1, 3-benzothiazol-3 (2H) -yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1' - [ (5-chloro-2-thienyl) methyl ] -5' -fluorospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1'- [ (5-chloro-2-furyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (4-hydroxy-1, 2,2,6, 6-pentamethylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- { [5- (2-chlorophenyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (5-methyl-2-furyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (5-bromo-2-furyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (5-chloro-2-thienyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- { [ 3-hydroxy-5- (trifluoromethyl) -2-thienyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1' - ((5- (2- (trifluoromethyl) phenyl) furan-2-yl) methyl) -6H-spiro [ benzofuran [6,5-d ] [1,3] dioxolane-7, 3' -indol ] -2' -one;

1'[ (2-chloro-1, 3-thiazol-5-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- { [5- (trifluoromethyl) -2-thienyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- { [ 3-methoxy-5- (trifluoromethyl) -2-thienyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4' -methyl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

5' -methyl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1'- ({5- [4- (trifluoromethyl) phenyl ] -1,2, 4-oxadiazol-3-yl } methyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2-thienylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

5- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] thiophene-2-carbonitrile;

5- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) methyl ] -2-furancarbonitrile;

1'- { [5- (methylsulfonyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (6-keto-1, 6-dihydropyridin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (1-methyl-6-keto-1, 6-dihydropyridin-3-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (5-chloro-1, 3, 4-thiadiazol-2-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (1-pyridin-2-ylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (1-phenyl-2-ylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-2-ylmethyl) -6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- (2-piperidin-1-ylethyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

4- [2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) ethyl ] piperidine-1-carboxylic acid tert-butyl ester;

1'- (2-piperidin-4-ylethyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- [2- (1-cyclopentylpiperidin-4-yl) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- [2- (1-isopropylpiperidin-4-yl) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- [2- (1-cyclobutyl-piperidin-4-yl) ethyl ] spiro [ furo [2,3f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- {2- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl ] ethyl } spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

1'- (3-pyrrolidin-1-ylpropyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3-piperidin-1-ylpropyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1' - [ (5-fluoro-1H-benzoimidazol-2-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one 4' - (6-methoxypyridin-3-yl) -1' - { [5- (trifluoromethyl) -2-furanyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - [6- (dimethylamino) pyridin-3-yl ] -1' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4'- (3-furyl) -1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-2-ylmethyl) -4' -pyrimidin-5-yl-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

4 '-pyridin-3-yl-1' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

4'- (3-furyl) -1' - { [5- (trifluoromethyl) -2-furyl ] methyl } -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

4' -quinolin-3-yl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4 '-pyrimidin-5-yl-1' - { [5- (trifluoromethyl) -2-furyl ] methyl } -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b '] difuran-3, 3' -indol ] -2'(1' H) -one;

4- [ (2' -keto-4 ' -pyrimidin-5-yl spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1' (2' H) -yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester;

4- [ (5, 5-dimethyl-2 ' -keto-5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -1' (2' H) -yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester;

5, 5-dimethyl-1 ' - (piperidin-4-ylmethyl) -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -2' (1' H) -one hydrochloride;

5, 5-dimethyl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -2' (1' H) -one;

5, 5-dimethyl-1 ' - (pyridin-3-ylmethyl) -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -2' (1' H) -one hydrochloride;

5, 5-dimethyl-1 ' - (pyridin-2-ylmethyl) -5, 6-dihydrospiro [ benzo [1,2-b:5,4-b ' ] difuran-3, 3' -indol ] -2' (1' H) -one hydrochloride;

5-bromo-1 '- [ (5-chloro-2-thienyl) methyl ] spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-3-ylmethyl) -6- (trifluoromethoxy) spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one hydrochloride;

6- (trifluoromethoxy) -1'- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one;

2' -keto-1 ' - { [5- (trifluoromethyl) -2-furanyl ] methyl } -1',2' -dihydrospiro [ 1-benzofuran-3, 3' -indol ] -5-yl trifluoromethanesulfonate;

5-pyridin-3-yl-1 '- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one hydrochloride;

3- (2' -keto-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } -1',2' -dihydrospiro [ 1-benzofuran-3, 3' -indol ] -5-yl) piperidine-1-carboxylic acid tert-butyl ester;

5-pyridin-4-yl-1 '- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ 1-benzofuran-3, 3' -indol ] -2'(1' H) -one hydrochloride;

1 '-pentyl-6, 7-dihydrospiro [ indeno [5,6-d ] [1,3] dioxol-5, 3' -indol ] -2'(1' H) -one;

1-pentyl-7 ',8' -dihydro-6 'H-spiro [ indole-3, 5' -naphtho [2,3-d ] [1,3] dioxol ] -2(1H) -one;

7-methoxy-1 '-pentyl-6, 7-dihydrospiro [ indeno [5,6-d ] [1,3] dioxol-5, 3' -indol ] -2'(1' H) -one;

1 '-pentylspiro [ indeno [5,6-d ] [1,3] dioxole-5, 3' -indole ] -2',7(1' H,6H) -dione;

1-pentyl-6 'H-spiro [ indole-3, 5' -naphtho [2,3-d ] [1,3] dioxole ] -2,8'(1H,7' H) -dione;

8',8' -difluoro-1-pentyl-7 ',8' -dihydro-6 'H-spiro [ indole-3, 5' -naphtho [2,3-d ] [1,3] dioxol ] -2(1H) -one;

1 '-pentyl-6, 7-dihydro-5H-spiro [1, 3-dioxolo [4,5-g ] isoquinoline-8, 3' -indole ] -2',5(1' H) -dione; and

1 '-hexylspiro [1, 3-dioxolo [4,5-g ] chromene-8, 3' -indole ] -2',6(1' H,7H) -dione.

2. The compound of claim 1, a stereoisomer, enantiomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

1 '-pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2-keto-2-piperidin-1-ylethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) -N-phenylacetamide;

n- (4-fluorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (2-fluorophenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (4-ethylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

n- (3-methylphenyl) -2- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) acetamide;

2- (2' -ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1' (2' H) -yl) N- [ 2-ethoxyethyl ] -2- (2' -oxol o l) acetamide;

4' - [6- (dimethylamino) pyridin-3-yl ] -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' -dibenzo [ b, d ] furan-4-yl-1 ' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' - (2-methoxypyrimidin-5-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' -pyridin-3-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-chlorophenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' -quinolin-3-ylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-fluoro-2-methylphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (3-furyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (6-fluoropyridin-3-yl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4' - (4-isopropoxyphenyl) -1' -pentylspiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' -pyrimidin-5-yl spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

1' -pentyl-4 ' - (3-thienyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4'- (3-furyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4' - [6- (dimethylamino) pyridin-3-yl ] -1' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2' (1' H) -one;

4 '-pyrimidin-5-ylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4' -quinolin-3-yl-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4 '-morpholinyl-1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

1 '-pentyl-4' - (pyrimidin-2-ylamino) -6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

4'- (benzo [ d ] [1,3] dioxol-5-ylamino) -1' -pentyl-6H-spiro [ benzofuro [6,5-d ] [1,3] dioxol-7, 3 '-indolin ] -2' -one;

n- (3-ethoxypropyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (4-methoxybenzyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-ethoxyethyl) -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

N- [2- (4-fluorophenyl) ethyl ] -3- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- (4-fluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3, 5-difluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (cyclopropylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-2-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-4-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (pyridin-3-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (1, 3-benzothiazol-2-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (2,1, 3-benzothiadiazol-5-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ 2-fluoro-6- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 4-fluoro-3- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [ 2-fluoro-5- (trifluoromethyl) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2, 3-difluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2, 4-difluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (1, 3-benzodioxol-5-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- (3-cyclopropyl propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-hexylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

7' -fluoro-1 ' - [ (1-isopropylpiperidin-4-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one hydrochloride;

1'- (2-chloro-4-fluorobenzyl) spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (3-cyclopropyl propyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1 '-butylspiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [2- (trifluoromethoxy) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- [3- (trifluoromethoxy) benzyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one;

1'- (2,1, 3-benzoxadiazol-5-ylmethyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (1-methyl-1H-benzotriazol-6-yl) methyl ] spiro [ furo-2, 3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

4' -bromo-1 ' - { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

4' -bromo-1 ' -methyl spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2' (1' H) -one;

1'- [ (5-chloro-2-thienyl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [ (5-chloro-1, 3, 4-thiadiazol-2-yl) methyl ] spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one;

1'- [2- (1-cyclopentylpiperidin-4-yl) ethyl ] spiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -2'(1' H) -one hydrochloride;

n- (3-fluorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n-butyl-4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-fluorophenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

n- (2-methoxyphenyl) -4- [ (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxole-7, 3' -indol ] -1'(2' H) -yl) methyl ] benzamide;

1'- (3-hydroxypropyl) spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one; and

n- [3- (2 '-ketospiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -1'(2' H) -yl) propyl ] -2- (trifluoromethoxy) benzamide.

3. The compound of claim 2, a stereoisomer, enantiomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1'- { [5- (trifluoromethyl) -2-furyl ] methyl } spiro [ furo [2,3-f ] [1,3] benzodioxol-7, 3' -indol ] -2'(1' H) -one.

4. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1 to 3, a stereoisomer, enantiomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.