ES2599822T3 - Heterocyclic chromene-spirocyclic piperidin amides as ion channel modulators - Google Patents

Abstract

A compound of formula I: ** Formula ** or a pharmaceutically acceptable salt thereof, in which, independently for each case and optionally substituted with halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl as valence allows: A is ** Formula ** or is selected from a heteroaryl or heterocyclic group of the formula: ** Formula ** R1 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH , OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl O (CH2) 1-6-R8 in which up to two CH2 units can be replaced by O, CO, S, SO, SO2, NR7; R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, aryl, COOH, CH2CF3, CHF2, CF3, CN, OH, OR7, CON (R7) 2, SO2R7, SR7, SOR7, SO2N (R7) 2, O (CH2) 1-6-R8 in which up to two CH2 units may be replaced by O, CO, S, SO, SO2, CF2, or NR7; R3 is halo, C1-C6 alkyl or C3-C8 cycloalkyl, where up to two CH2 units can be replaced by O, CO, S, SO, SO2, or NR8; R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CHF2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl, or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S, SO, SO2, or NR7; R5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7 , NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl, or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three units of CH2 can be replaced with O, CO, S, SO, SO2, or NR7; R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SR7, SOR7, SO2R7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl, or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units can be replaced by O , CO, S, SO, SO2, or NR7; or two occurrences of R4 and R5, or R5 and R6, taken together with the carbons to which they are attached form a ring comprising up to 2 heteroatoms, optionally substituted with halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl , and alkyl; R7 is H, C1-C6 alkyl, CHF2, CF3, or C3-C8 cycloalkyl, or 2 R7 taken together with the atoms to which they are attached form a ring; R8 is H, CF3, CO2R7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N (R7) 2, NR7COR7, CON (R7) 2, CN, or SO2R7; X is N, S, or CR2 in which at least X is N; W is N or CH, in which up to 2 W are N; one line ------ marks a double bond optionally depending on the identity of X; m is an integer from 0 to 4 inclusive; n is an integer from 0 to 3 inclusive; and o is an integer from 0 to 4 inclusive.

Description

DESCRIPTION

Heterocyclic chromene-spirocyclic piperidin amides as ion channel modulators

 5

TECHNICAL FIELD OF THE INVENTION

[0001] The invention relates to compounds useful as ion channel inhibitors. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods for using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to the injured tissue. However, there are many conditions in which pain persists beyond its usefulness, or in which patients would benefit from pain inhibition. Voltage-dependent sodium channels are believed to play a critical role in pain signaling. This belief is based on the known functions of these channels in normal physiology, pathological states that arise from mutations in sodium channel genes, preclinical work in animal models of the disease, and the clinical utility of 20 channel modulating agents. of known sodium (Cummins, TR, Sheets, PL, and Waxman, SG, The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain 131 (3), 243 (2007); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics Expert Opin Investig Druggy 17 (12) 1849 (2008); Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities Curr Opin Pharmacol 8 (1) , 50 (2008)). 25

[0003] Voltage-dependent sodium channels (NAV) are key biological mediators of electrical signaling. NAVs are the main mediators of the rapid upward race of the action potential of many types of excitable cells (e.g., neurons, skeletal myocytes, cardiac myocytes), and therefore are critical for the initiation of signaling in cells (Hille , Bertil, Ion Channels of Excitable Membranes (3rd ed. Sinauer 30 Associates, Inc., Sunderland, MA, 2001)). Because of the role NAV plays in the initiation and propagation of neuronal signals, antagonists that reduce NAV currents can prevent or reduce neuronal signaling. Therefore NAV channels are considered possible targets in pathological conditions where reduced excitability is expected to relieve clinical symptoms, such as pain, epilepsy, and some cardiac arrhythmias (Chahine, M., Chatelier, A., Babich, O ., and Krupp, JJ, Voltage-gated sodium channels in neurological 35 disorders CNS Neurol Disord Drug Target 7 (2), 144 (2008)).

[0004] The NaVs form a subfamily of the ion-dependent voltage-dependent superfamily and comprise 9 isoforms, designated NaV 1,1-NaV 1,9. The tissue locations of the nine isoforms vary greatly. NaV 1.4 is the primary sodium channel of skeletal muscle, and NAV 1.5 is the primary sodium channel of cardiac myocytes. NaVs of 1.7, 1.8 and 1.9 are located primarily in the peripheral nervous system, while 1.1, 1.2, 1.3, and 1.6 are the neuronal channels of NAV found in the systems central and peripheral nervous. The functional behaviors of the nine isoforms are similar but different in the details of their voltage-dependent and kinetic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XL VII. Nomenclature and structure-function relationships of voltage-gated sodium channels. 45 Pharmacol Rev 57 (4), 397 (2005)).

[0005] NAV Channels have been identified as the main objective of some clinically useful pharmaceutical products that reduce pain (Cummins, TR, Sheets, PL, and Waxman, SG, The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain 131 (3), 243 (2007)). Local anesthetic drugs such as lidocaine 50 block pain by inhibiting navigation channels. These compounds provide excellent local pain reduction, but suffer the inconvenience of suppressing normal acute pain and sensory stimuli. The systemic administration of these compounds results in dose-limiting side effects that are generally attributed to the blockage of neuronal channels in the CNS (nausea, sedation, confusion, ataxia). Cardiac side effects may also occur, and in fact these compounds are also used as class 1 55 antiarrhythmics, presumably due to blockage of the NaV1.5 channels in the heart. Other compounds that have proven effective in reducing pain to act by blocking sodium channels such as carbamazepine, lamotragine, and tricyclic antidepressants (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action Eur J Pain have also been suggested. 6 Suppl A, 3 (2002); Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na + currents by antidepressant sertraline and paroxetine J Membr Biol 222 (2), 79 (2008)) .. These Compounds 60 are also dose limited by adverse effects similar to those observed with local anesthetics. It is expected that antagonists that specifically block only the critical isoform for nociception have increased efficacy, since the reduction of adverse effects caused by the block of channels outside the target should allow for greater dosing and therefore more complete blocking of target channel isoforms. 65

[0006] Four isoforms NaV, NaV 1.3, 1.7, 1.8, 1.9 and have been specifically indicated as likely targets for pain. NaV 1,3 is normally found in pain detecting dorsal root ganglion neurons (DRG) only at an early stage of development and is lost shortly after birth in both humans and rodents. However, lesions of the damaged nerve have been found to result in a return of NaV 1,3 channels to DRG neurons and this may contribute to abnormal signaling of pain in 5 different chronic pain conditions that result from nerve damage ( neuropathic pain). These data have led to the suggestion that pharmacological blockade of NAV 1,3 could be an effective treatment for neuropathic pain. In opposition to this idea, global genetic knockout of NAV 1.3 in mice does not prevent the development of allodynia in mouse models of neuropathic pain (Nassar, MA et al., Nerve injury induces robust allodynia and ectopic discharges in NaV 1, 3 null mutant mice Mol Pain 2, 33 (2006)). It is not yet known whether compensatory changes 10 in other channels allow for normal neuropathic pain in NaV 1,3 knockout mice, although it has been reported that NAV 1.1 knockout results in drastic upward regulation of NAV 1,3 . The reverse effect of the NAV 1.3 knockout could explain these results.

[0007] NaV 1,7, 1,8, and 1,9 are highly expressed in DRG neurons, including neurons whose axons 15 compensate for C fibers and Aδ nerve fibers that are thought to carry the most pain signals from the nocioceptive terminals to the central nervous. Equal expression of NaV 1.3, NAV 1.7 is increased after nerve injury and may contribute to neuropathic pain states. The localization of NaV 1,7, 1,8, and 1,9 in nocioceptors led to the hypothesis that reducing sodium currents through these channels can relieve pain. In fact, specific interventions that reduce the levels of these channels have proven effective in 20 animal pain models.

[0008] Specific reduction of NAV 1.7 in rodents by several different techniques has resulted in the reduction of pain behaviors observed in animal models. Injection of a NAV 1.7 viral antisense cDNA construct greatly reduces normal pain responses caused by inflammation or mechanical injury (Yeomans, DC et al., Decrease in inflammatory hyperalgesia by herpes vector-mediated knockdown of NaV 1.7 sodium channels in primary afferents Hum Gene Ther 16 (2), 271 (2005)). Similarly, a genetic reduction of NAV 1.7 in a subset of nociceptive neurons reduces acute and inflammatory pain in mouse models (Nassar, MA et al., Nociceptor-specific gene deletion reveals a major role for NaV 1.7 (PN1 ) in acute and inflammatory pain Proc Natl Acad Sci USA 101 (34), 12706 (2004)). Overall reduction of NAV 1.7 in mice carries 30 animals that die on the first day after birth. These mice are not introduced and this is the alleged cause of death.

[0009] Treatments that specifically reduce NaV 1.8 channels in rodent models effectively reduce pain sensitivity. Reduction of NaV 1.8 in rats by intrathecal injection of antisense oligodeoxynucleotides 35 reduces neuropathic pain behaviors, leaving the sensation of acute pain intact (Lai, J. et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1,8. Pain 95 (1-2), 143 (2002); Porreca, F. et al, A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3 / SNS and NaN / SNS2, in rat models of chronic pain Proc Natl Acad Sci USA 96 (14), 7640 (1999)). Global genetic knockout of NAV 1.8 in mice or specific destruction of neurons expressing NAV 1.8 40 greatly reduces the perception of acute, inflammatory, and visceral mechanical pain (Akopian, AN et al., The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurasci 2 (6), 541 (1999); Abrahamsen, B. et al, The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321 (5889), 702 (2008); Laird, JM, Souslova, V., wood, JN, and Cervero, F., Deficits in visceral pain and referred hyperalgesia in NaV 1.8 (SNS / PN3) -null mice. J Neurasci 22 (19), 8352 (2002)). In contrast to the antisense experiments in rats, genetic knockout mice appear to develop neuropathic pain behaviors normally after nerve injury (Lai, J. et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel , NaV1,8, Pain 95 (1-2), 143 (2002); Akopian, AN et al, The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurasci 2 (6), 541 (1999) ; Abrahamsen, B et al., The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321 (5889), 50 702 (2008) ;. Laird, JM, Souslova, V., wood, JN, and Cervero , F., Deficits in visceral pain and referred hyperalgesia in NaV 1.8 (SNS / PN3) -null mice. J Neurosci 22 (19), 8352 (2002)).

[0010] NaV 1.9 global knockout mice have reduced sensitivity to pain-induced inflammation, despite normal and neuropathic acute pain behaviors (Amaya, F. et al., The voltage-gated sodium 55 channel Na ( v) 1.9 is an effector of peripheral inflammatory pain hypersensitivity. J Neurosci 26 (50), 12852 (2006) ;. Priest, BT et al., Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV 1.9 to sensory transmission and nociceptive behavior Proc Natl Acad Sci USA 102 (26), 9382 (2005)). The reduction of the medulla of the NAV 1.9 had no apparent effect on the pain behavior in rats (Porreca, F. et al., A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3 / SNS and NaN / SNS2, in rat 60 models of chronic pain, Proc Natl Acad Sci USA 96 (14), 7640 (1999)).

[0011] The understanding of the role of NAV channels in human physiology and pathology has been greatly advanced by the discovery and analysis of naturally occurring human mutations. Nav 1.1 and NAV 1.2 mutations give rise to various forms of epilepsy (Fujiwara, T., Clinical spectrum of mutations in SCN1A gene: severe 65 myoclonic epilepsy in infancy and related epilepsies. Epilepsy Res 70 Suppl 1, S223 (2006 ); George, AL, Jr. Inherited disorders of voltage-gated sodium channels. J Clin Invest 115 (8), 1990 (2005); Misra, SN, Kählig, KM, and George,

AL, Jr., Impaired Nav1,2 function and reduced cell surface expression in benign familial neonatal-infantile seizures. Epilepsy 49 (9), 1535 (2008)). Mutations of NaV 1.4 cause muscle disorders such as congenital paramiotonia (Vicart, S., Sternberg, D., Fontaine, B., and Meola, G., Human skeletal muscle sodium channelopathies. Neurol Sci. Neurol Sci 26 (4) , 194 (2005)). NaV 1.5 mutations give rise to cardiac disorders such as Brugada syndrome and long QT syndrome (Bennett, PB, Yazawa, K., Makita, N., and George, AL, Jr., Molecular 5 mechanism for an inherited cardiac arrhythmia Nature 376 (6542), 683 (1995); Darbar, D. et al., Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation Circulation 117 (15), 1927 (2008); .. Wang, P. et al, SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome, Cell 80 (5), 805 (1995)).

[0012] Recent discoveries have shown that mutations in the gene encoding the NAV 1.7 10 channel (SCN9A) can cause both improved and reduced pain syndromes. The group work of Waxman et al has identified at least 15 mutations that give rise to a greater current through NAV 1,7 and are linked to congenital dominant pain syndromes. Mutations that lower the threshold of activation of NAV 1,7 cause inherited erythromyalgia (EMI). IEM patients have abnormal burning pain in their limbs. Mutations that interfere with the normal inactivation properties of NAV 1.7 lead to prolonged sodium currents and cause extreme paroxysmal pain disorder (PEPD). PepD patients exhibit symptoms of periocular, perimandibular, and rectal pain that progresses throughout life (Drenth, JP et al., SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol 124 (6) , 1333 (2005); Estacion, M. et al, NAV 1.7 NaV 1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms 20 of both disorders. J Neurosci

28 (43), 11079 (2008)).

[0013] NAV 1.7 null mutations in human patients have recently been described by several groups (Ahmad, 25 S. et al, A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet 16 (17), 2114 ( 2007) .; Cox, JJ et al, An SCN9A channelopathy causes congenital inability to experience pain. Nature 444 (7121), 894 (2006); Loss-of-function mutations in the NaV 1.7 gene underlie congenital indifference to pain in multiple human populations Clin Genet 71 (4), 311 (2007)). In all cases, patients showed congenital indifference to pain. These patients do not report pain under any circumstances. Many of these patients suffer serious injuries in early childhood, since they do not have the pain of protection, normal that helps prevent tissue damage and develop appropriate protective behaviors. Apart from the notable loss of reduced or absent pain and odor sensation (Goldberg, YP et al., Loss-of-function mutations in the NaV 1.7 gene congenital underlie indifference to pain in multiple human populations. Clin Genet 71 (4) , 311 (2007)), these patients seem completely normal. Despite the normally high expression of NAV 1.7 in sympathetic neurons (Toledo-35 Aral, JJ et al., Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci USA 94 (4), 1527 (1997)) and adrenal chromaffin cells (Klugbauer, N., Lacinová, L., Flockerzi, V., and Hofmann, and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells EMBO J 14 (6), 1084 (1995)), these patients of 1.7 null NAV show no signs of sympathetic neuroendocrine or nervous disorders.

[0014] Acquisition of NAV 1.7 function mutations that cause pain, together with loss of NAV 1.7 function of pain suppressing mutations, provide strong evidence that NAV 1.7 plays an important role. in the signaling of human pain. The relative good health of patients with zero NAV 1.7 indicates that the ablation of NAV 1.7 is well tolerated in these patients.

[0015] Unfortunately, the efficacy of sodium channel blockers that are currently used for the disease states described above has been largely limited by a number of side effects. These side effects include various CNS abnormalities, such as blurred vision, dizziness, nausea and sedation, as well as cardiac arrhythmias and potentially more life-threatening heart failure. Consequently, there remains a need to develop additional Na channel antagonists, preferably those with greater potency and fewer side effects.

[0016] US 2004/0266802 describes tricyclic compounds useful for the treatment of neuropathic pain and other CNS disorders.

SUMMARY OF THE INVENTION

[0017] It has now been found that the compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as voltage-dependent sodium channel inhibitors. These compounds have the general formula I:

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image 1

 5

 10

 fifteen

 twenty

 25

or a pharmaceutically acceptable salt thereof.

[0018] These pharmaceutically acceptable compounds and compositions are useful for treating or decreasing the severity of a variety of diseases, disorders or conditions, including, but not limited to, acute pain, chronic, neuropathic or inflammatory pain, arthritis, migraine, pain. Headed cluster, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, attica science, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION

[0019] In one aspect, the invention provides compounds of formula I: 40

image2

 Four. Five

 fifty

 55

 60

 65

or a pharmaceutically acceptable salt thereof,

in which, independently for each case and optionally substituted with halo, cyano, oxoalkoxy, hydroxyl, amino, nitro, aryl, haloalkyl and alkyl as the valence allows:

A is 5

image3

 10

 fifteen

or is selected from a heteroaryl or heterocyclic group of the formula:

image4

 twenty

 25

 30

 35

 40

 Four. Five

 fifty

 55

 60

 65

image5

 5

image6

 10

 fifteen

 twenty

 25

 30

 35

 40

 Four. Five

 fifty

 55

R1 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7) 2 , SO2N (R7) 2, CF3, OCF3,

OCHF2, heterocycloalkyl, aryl, heteroaryl O (CH2) 1-6-R8 in which up to two CH2 units may be replaced by O, CO, S, SO, SO2, or NMR7;

R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, aryl, COOH, OR7, CH2CF3, CHF2, CF3, 60 CN, CON (R7) 2, SO2R7, SR7, SOR7, SO2N ( R7) 2, O (CH2) 1-6-R8 in which up to two CH2 units may be replaced by O, CO, S, SO, SO2, CF2, or NR7;

R3 is halo, C1-C6 alkyl or C3-C8 cycloalkyl, where up to two CH2 units can be replaced by O, CO, S, SO, SO2, or NR8;

R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, 65 SOR7, CO2R7, NR7COR7, NR7CO2R7, CON ( R7) 2. SO2N (R7) 2, CHF2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl, or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units

they can be replaced by O, CO, S, SO, SO2, or NR7;

R5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7 , NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, CHF2, heterocycloalkyl, aryl, heteroaryl, or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three units of CH2 can be replaced with O, CO, S, SO, SO2 or NR7; 5

R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SR7, SO2R7, CO2R7, NR7COR7, NR7CO2R7, CON (R7) 2 , SO2N (R7) 2, CF3, OCF3, OCHF3, heterocycloalkyl; aryl, heteroaryl, or a linear, branched or cyclic (CH2) 1-8-R8 chain in which up to three CH2 units can be replaced with O, CO, S, SO, SO2 or NR7; or

two occurrences of R4 and R5, or R5 and R6, taken together with the carbons to which they are attracted form a ring comprising up to 2 heteroatoms, optionally substituted with halo, cyano, oxoalkoxy, hydroxyl, amino, nitro, aryl, haloalkyl, and alkyl;

R7 is H, C1-C6 alkyl, CHF2, CF3, or C3-C8 cycloalkyl, or 2 R7 taken together with the atoms to which they are attached form a ring;

R8 is H, CF3, CO2R7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N (R7) 2, NR7COR7, CON (R7) 2, CN, or SO2R7;

X is N, S, or CR2 where at least X is N;

W is N or CH, in which up to 2 W are N;

a line ---- marks a double bond optionally depending on the identity of X; m is an integer from 0 to 4 inclusive; twenty

n is an integer from 0 to 3 inclusive; Y

or is an integer from 0 to 4 inclusive.

[0020] For the purposes of this invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, Ed .: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

[0021] As described herein, the compounds of the invention may optionally be substituted with one or more substituents, such as generally illustrated above, or as exemplified by the classes, subclasses, and species of the invention. . The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". As described herein, the R1-R8 variables in formula I encompass specific groups, such as, for example, alkyl and aryl. Unless otherwise indicated, each of the specific groups for the R1-R8 variables may be optionally substituted with one or more substituents of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For example, an alkyl group may be optionally substituted with one or more of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, an aryl group may be optionally substituted with one or more of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. As one of ordinary skill in the art will recognize, the combinations of substituents provided for by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow their production, detection, and preferably recovery, purification, and use for one or more of the purposes described in this document. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when maintained at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least one week. When two alkoxy groups are attached to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atom to which they are attached.

[0022] In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the substitution of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents have been described above in the definitions and later in the description of the compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent 55 It can be the same or different in each position. A ring substituent, such as a heterocycloalkyl, may be attached to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, for example, both rings share a common atom. As one of ordinary skill in the art will recognize, the combinations of substituents provided for by this invention are those combinations that result in the formation of stable or chemically feasible compounds. 60

[0023] The phrase "up to", as used herein, refers to or any zero integer that is equal to or less than the number after the phrase. For example, "up to 3" means any of 0, 1, 2, and 3.

[0024] The term "aliphatic", "aliphatic group" or "alkyl" as used herein, means a linear (ie, unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or which contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups

They contain 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms, and in still other embodiments the aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups. The term "cycloaliphatic" or "cycloalkyl" means a monocyclic, bicyclic hydrocarbon, or a tricyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but is not aromatic and has a single point of attachment to the rest of the molecule In some embodiments, "cycloaliphatic" refers to a C3-C8 monocyclic or bicyclic C8-C12 hydrocarbon hydrocarbon that is fully saturated or that contains one or more unsaturation units, but is not aromatic, having a single point of attachment to the rest of the molecule in 10 where any individual ring in said bicyclic ring system has 3-7 members.

[0025] Unless otherwise specified, the term "heterocycle", "heterocyclyl", "heterocycloaliphatic", "heterocycloalkyl" or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or systems of tricyclic rings in which one or more ring atoms in one or more ring members is an independently selected heteroatom. The heterocyclic ring may be saturated or it may contain one or more unsaturated bonds. In some embodiments, the "heterocycle," "heterocyclyl," "heterocycloaliphatic," "heterocycloalkyl," or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 3 to 7 ring members. twenty

[0026] The term "heteroatom" means oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)). 25

[0027] The term "unsaturated," as used herein, means that a remainder has one or more units of unsaturation, but is not aromatic.

[0028] The term "alkoxy" or "thioalkyl," as used herein, refers to an alkyl group, as previously defined, attached to the main carbon chain through an oxygen atom ("alkoxy" ) or sulfur ("thioalkyl").

[0029] The term "aryl" used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen rings of 35 carbon atoms, in which at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 carbon atoms in the ring. The term "aryl" can be used interchangeably with the term "aryl ring".

[0030] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen members in the ring, in which at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic." Four. Five

[0031] The term "alkylidene chain" refers to a linear or branched carbon chain that can be completely saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.

 fifty

[0032] Unless otherwise indicated, the structures represented in this document are also intended to include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, the individual stereochemical isomers as well as the enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

[0033] Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Therefore, tautomers of the compounds of formula I are included within the scope of the invention.

[0034] In addition, unless otherwise indicated, the structures represented herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the compounds of formula I, wherein one or more hydrogen atoms are replaced deuterium or tritium, or one or more carbon atoms are substituted by a carbon enriched 13C or 14C are within the scope of this invention. Such compounds are useful, for example, as analysis tools, probes in biological assays, or sodium channel blockers with a better therapeutic profile.

[0035] In the formulas and drawings, a line that crosses a ring and attached to a group R as in

 5

image7

 10

 fifteen

 twenty

 25

it means that the group R can be attached to any carbon, or if appropriate, heteroatom such as N, of that ring as valence allows.

 30

[0036] Within a definition of a term such as, for example, R3, R4, R5 or R6, when a CH2 unit or, interchangeably, the methylene unit may be substituted by O, NR7, or S, understands that it includes any CH2 unit, including a CH2 within a terminal methyl group. For example, -CH2CH2CH2SH is within the definition of C1-C6 alkyl where up to two CH2 units may be replaced by S, because the CH2 unit of the terminal methyl group has been replaced by S. 35

[0037] In another embodiment, the invention relates to a compound of formula I and the concomitant definitions, in which all W are CH. In another embodiment, a W is N.

[0038] In another embodiment, the invention relates to a compound of formula I and the concomitant definitions, wherein R1 is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OR7, CON (R7) 2, OR (CH2) 1-6-R8 in which up to two CH2 units may be replaced by o, CO, S, SO, SO2, or NR7. In another embodiment, R1 is F, Cl, CH3, CN, OCH3, CH2OH, CH2N (CH3) 2, CH2NH2, CONHCH3, CON (CH3) 2, CH2OCH3.

[0039] In another embodiment, the invention relates to a compound of formula I and the concomitant definitions, wherein R2 is C1-C6 alkyl, C1-C6 alkoxy-haloalkyl, halo, CN, OR7, CF3, CON ( R7) 2, SO2R7 O (CH2) 1-6-R8 in which up to two CH2 units may be replaced by o, CO, S, SO, SO2, or NR7. In another embodiment, R2 is CH3, CF3, CHF2, C2H5, CH2OH, halo, CN, (CH2) 2OCH3, SO2CH3, SOCH3, CH2CF3, CH2NH2, CH2NHCOCH3, CH2NHCOH, COCH3, or CONHCH3.

 fifty

[0040] In another embodiment, the invention relates to a compound of formula I and the concomitant definitions, wherein R3 is C1-C6 alkyl. In another embodiment, R3 is methyl.

[0041] In another embodiment, the invention relates to a compound of formula I and the concomitant definitions, wherein m is 0, 1 or 2. In another embodiment, m is 0. 55

[0042] In another embodiment, the invention relates to a compound of formula I and the concomitant definitions, in which n is 0, 1 or 2. In another embodiment, n is 0. In another embodiment, n is 1.

[0043] In another embodiment, or is 0. 60

[0044] In another embodiment, R4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR7, CON (R7) 2, NR7SO2R7, SO2R7,

SOR7, SR7, CO2R7, NR7CO2R7, CF3, CHF2, OCF3, OCHF2, heteroaryl, or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S , SO, SO2, or NR7. In another embodiment, R4 is H, F, Cl, OH, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, CO2CH3, CH2OH, SO2CH3, CN, NHSO2CH3, 65 C2H5, OC2H5, OCF2CHFCl, OCH2CF3, O (CH2) 2CH3 , OCH (CH3) 2, O (CH2) 2OH, OCH2OCH3, SCH3, CON (CH3) 2, NHCO2tBu,

 5

image8

 10

[0045] In another embodiment, R5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR7, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, CON (R7) 2, SO2N (R7) 2 , CF3, OCF3, or a linear, branched or cyclic (CH2) 1-8-R8 chain in which up to three CH2 units can be replaced by o, CO, S, SO, SO2, or NR7. In another embodiment, R5 is H, F, Cl, CH3, C2H5, CH (CH3) 2, tBu, OH, OCH3, OC2H5, OCH (CH3) 2, CH2OH, CF3, OCF3, CN, CO2CH3, CONH2, N ( CH3) SO2CH3, SO2NH2 or SO2CH3.

[0046] In another embodiment, R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, SR7, SOR7, SO2R7, NR7COR7, SO2N (R7) 2, WITH ( R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, heteroaryl or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units can be replaced by o, CO, S, SO, 20 SO2, or NR7. In another embodiment, R6 is H, F, Cl, CH3, CF3, OCH3, OC2H5, CH2CH2OH, OCF3, OCHF2, SOCH (CH3) 2, SO2CH3, SO2CH (CH3) 2, SO2CHF2, SO2CF3, SO2C2H5, SO2CH2CH (CH3) 2, SO2tBu, OH, CN, CH2CH3, OCH2CF3, O (CH2) 2OH, NHC (= O) CH3, OCH2C (= O) NH2,

image9

 25

O (CH2) 2CH3, 30

image10

 35

O (CH2) 3OH, O (CH2) 2OCH3,

image11

 40

OR (CH2) 2OCF3,

 Four. Five

image12

 fifty

O (CH2) 2SO2CH3, tBu,

image13

 55

 60

 65

 5

image14

 10

OtBu,

 fifteen

image15

 twenty

O (CH2) 3OCH3, O (CH2) 2OC2H5, 25

image16

 30

O (CH2) 2N (CH3) 2,

 35

image17

 40

 Four. Five

OCH2Ph, SO2NHCH3, SO2N (CH3) 2, SO2NHCH2CH3, SO2N (CH3) CH (CH3) 2, SO2CH2CH2OH, CONHCH (CH3) 2 or OCH2CO2H. fifty

[0047] In another embodiment, two occurrences of R4 and R5 together with the carbons to which they are attached, form an optionally substituted ring comprising up to 2 heteroatoms. In another embodiment, two occurrences of R5 and R6 together with the carbons to which they are attached, form an optionally substituted ring comprising up to 2 heteroatoms. 55

[0048] In another embodiment, R4 is H. In another embodiment, R5 is halo, CF3, C1-C6 alkyl, or C1-C6 alkoxy. In another embodiment, R5 is C1-C6 alkoxy. In another embodiment, R6 is C1-C6 alkyl or C1-C6 alkoxy. In another embodiment, R6 is C1-C6 alkyl.

 60

[0049] In another embodiment, R4 is H; R5 is halo, CF3, C1-C6 alkyl, or C1-C6 alkoxy; and R6 is C1-C6 alkyl or C1-C6 alkoxy. In another embodiment, R4 is H, R5 is C1-C6 alkoxy, and R6 is C1-C6 alkyl.

[0050] In another embodiment, R4 is H, and R5 and R6 are alkoxy. In another embodiment, R4 is halo, R5 is H, and R6 is alkoxy. In another embodiment, R4 and R5 are H, and R6 is SO2R7. In another embodiment, R4 and R5 are H, and R6 is SO2NR7. 65

[0051] In another embodiment,

 5

image18

 10

is selected from: 15

 twenty

 25

 30

 35

 40

 Four. Five

 fifty

 55

 60

 65

image19

image20

image21

image22

image23

image24

image25

[0052] In another embodiment, the invention relates to a compound of formula I and the concomitant definitions, wherein A is heteroaryl or heterocyclic selected from:

image26

image27

image28

 5

 10

 fifteen

 twenty

 25

[0053] In another embodiment, the invention relates to a compound of formula I and the concomitant definitions, wherein the compound has the formula IA:

image29

 35

 40

 Four. Five

 fifty

where: 55

R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S, SO, SO2, or NR7; 60

R5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7 , NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units it can be substituted with O, CO, S, SO, SO2, or NR7; 65

R6

is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SR7, SOR7, SO2R7, CO2R7, NR7COR7, NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units can be replaced by O, CO , S, SO, SO2, or NR7; or 5

two occurrences of R4 and R5, or R5 and R6, taken together with the carbons to which they are attached form a ring comprising up to 2 heteroatoms, optionally substituted with halo, cyano, oxoalkoxy, hydroxyl, amino, nitro, aryl, haloalkyl and I rent.

 10

[0054] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, wherein R1 is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, CON (R7) 2, O (CH2 ) 1- 6-R8 in which up to two units of CH2 may be replaced by or NR7. In another embodiment, R1 is F, Cl, CN, CH3, CH2OH, CH2N (CH3) 2, CH2NH2, CONHCH3, CON (CH3) 2, CH2OCH3.

[0055] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, wherein R2 is C1-C6 alkyl, CN, CF3, CON (R7) 2, SO2R7, O (CH2) 1 -6-R8 where up to two CH2 units can be replaced with O or NR7. In another embodiment, R2 is CH3, CF3, CH2OH, CN, SO2CH3, SOCH3, CH2NH2, CH2NHCOCH3, CH2NHCOH, COCH3, or CONHCH3.

[0056] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, wherein R3 is C1-C6 alkyl or 2 occurrences of R3 taken together form a C3-C8 cycloalkyl group. In another embodiment, R3 is CH3. In another embodiment, 2 occurrences of R3 taken together form a C3-C8 cycloalkyl group.

[0057] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, wherein R4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR7, CHF2, CF3 , OCF3, OCHF2, SO2R7, SOR7, SR7, NR7CO2R7, heteroaryl, or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S, SO , SO2, or NR7. In another embodiment, R4 is H, F, Cl, OH, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, CO2CH3, CH2OH, SO2CH3, CN, NHCO2tBu, C2H5, OCF2CHFCl,

image30

 30

or

 35

image31

[0058] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, wherein R5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR7, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S, SO, SO2, or NR7. In another embodiment, R5 is H, F, Cl, CH3, C2H5, tBu, OH, OCH3, OC2H5, OCH (CH3) 2, CH2OH, CF3, OCF3, CN, CO2CH3, CONH2, N (CH3) SO2CH3, SO2NH2 or SO2CH3.

 Four. Five

[0059] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, wherein R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, SR7, SOR7, SO2R7, NR7COR7, SO2N (R7) 2, CF3, OCF3, heteroaryl, or a linear, branched or cyclic chain (CH2) 1-8-R8, in which up to three CH2 units can be replaced with O, CO, S, SO, SO2, or NR7. In another embodiment, R6 is H, F, CH3, CF3, OCH3, OCF3, SO2CH3, SO2C2H5, SO2CH (CH3) 2, SO2CH2CH (CH3) 2, SO2tBu, SO2CHF2, CN, CH2CH3, tBu, 50 CH2CH2OH, C (CH3 ) 2OH, OCH2CF3, O (CH2) 2OH, NHC (= O) CH3, OCH2C (= O) NH2,

image32

 55

image33

 60

O (CH2) 2CH3,

image34

 65

O (CH2) 3OH, O (CH2) 2OCH3,

image35

 5

image36

 10

OR (CH2) 2OCF3,

 fifteen

image37

 twenty

O (CH2) 2SO2CH3, tBu,

image38

 25

 30

 35

 40

 Four. Five

image39

 fifty

OtBu,

 55

image40

 60

O (CH2) 3OCH3, O (CH2) 2OC2H5,

O (CH2) 2N (CH3) 2,

image41

 5

 10

OCH2Ph, SO2NHCH3, SO2NHCH2CH3, SO2CH2CH2OH or OCH2CO2H.

[0060] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, in which m is 0 or 1. In another embodiment, m is 0.

[0061] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, in which n is 0, 1 or 2. In another embodiment, n is 0. In another embodiment, n is 1. In Another embodiment, n is 2.

 twenty

[0062] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, which is either 0, 1 or 2. In another embodiment, or is 0. In another embodiment, or is 1. In another embodiment, or is 2, and the two occurrences of R3 form a C3-C8 cycloalkyl group.

[0063] In another embodiment, the invention relates to a compound of formula IA and the concomitant definitions, in which

image42

 30

 35

is selected from:

 40

 Four. Five

 fifty

 55

 60

 65

image43

[0064] In another embodiment, the invention relates to a compound of formula I and concomitant definitions, wherein the compound has the formula IB:

    IB

where:

R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S, SO, SO2, or NR7; 5

R5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7 , NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units they can be substituted with O, CO, S, SO, SO2, or NR7; 10

R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SOR7, SO2R7, SR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S, SO, SO2, or NR7; or 15

two occurrences of R4 and R5, or R5 and R6, taken together with the carbons to which they are attached form a ring comprising up to 2 heteroatoms, optionally substituted with halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl.

 twenty

[0065] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, wherein R1 is halo or C1-C6 alkoxy. In another embodiment, R1 is F, Cl or OCH3.

[0066] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, wherein R2 is C1-C6 alkyl, CF3 O (CH2) 1-6-R8 in which up to two CH2 units they can be replaced by 25 O or NR7. In another embodiment, R2 is CH3, CF3, C2H5, CH2CF3, O (CH2) 2OCH3.

[0067] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, wherein R4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR7, CON (R7 ) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7CO2R7, CHF2, CF3, OCF3, OCHF2, heteroaryl, or a linear, branched or cyclic (CH2) 1-8-R8 chain in which 30 to three CH2 units they can be replaced with o, CO, S, SO, SO2, or NR7. In another embodiment, R4 is H, F, Cl, OH, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SO2CH3, CN, NHSO2CH3, C2H5, OC2H5, OCF2CHFCl, OCH2CF3, O (CH2) 2CH3, OCH2OCH3, OCH ( CH3) 2, O (CH2) 2OH, SCH3, CON (CH3) 2, NHCO2tBu,

 35

image44

 40

[0068] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, wherein R5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR7, CF3, OCF3 , SO2R7, SR7, SOR7, or a linear, branched or cyclic (CH2) 1-8-R8 chain in which up to three CH2 units can be replaced by O, CO, S, SO, SO2, or NR7. In another embodiment, R5 is H, F, Cl, CH3, CF3, OCH3, CH (CH3) 2, OCH2CH3, CH2OH, OCF3, CN, SO2CH3 or tBu. Four. Five

[0069] In another embodiment, R6 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR7, CON (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7CO2R7, CHF2, CF3 , OCF3, OCHF2, heteroaryl, or a linear, branched or cyclic (CH2) 1-8-R8 chain in which up to three CH2 units may be replaced by O, CO, S, SO, SO2, or NR7. In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, wherein R6 is H, F, Cl, OH, CH3, CF3, OCH3, OCF3, OCHF2, SOCH (CH3) 2, SO2CH3 , SO2CHF2, SO2CF3, SO2C2H5, SO2CH (CH3) 2, SO2CH2CH (CH3) 2, SO2tBu, SO2NHCH3, SO2N (CH3) 2, SO2NHCH2CH3, SO2N (CH3) CH (CH3) 2, CONHCH (CH3) O, CH2CH3, O2 ,

image45

 55

O (CH2) 2CH3, 60

image46

 65

O (CH2) 2OCH3, O (CH2) 2OCF3, tBu,

image47

 5

 10

 fifteen

OtBu,

image48

 twenty

 25

or OCH2Ph. 30

[0070] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, wherein two occurrences of R4 and R5 are both C1-C6 alkyl and together with the carbons to which they are attached, form a ring. optionally substituted comprising up to 2 heteroatoms. In another embodiment, two occurrences of R5 and R6 are both C1-C6 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

[0071] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, in which m is 0 or 1. In another embodiment, m is 0. In another embodiment, m is 1.

 40

[0072] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, in which n is 0, 1 or 2. In another embodiment, n is 1.

[0073] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, which is 0.

[0074] In another embodiment, the invention relates to a compound of formula IB and the concomitant definitions, in which

 fifty

image49

 55

is selected from:

 60

image50

[0075] In another embodiment, the invention relates to a compound selected from Table 1:

Table 1

image51

 5

 10

 fifteen

 twenty

 25

 30

[0076] In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

[0077] In another aspect, the invention relates to a method for inhibiting a voltage-dependent sodium ion channel in:

(a) a patient; or

(b) a biological sample;

 40

which comprises administration to the patient, or contacting the biological sample, with a compound of formula I or a pharmaceutical composition comprising a compound of formula I. In another embodiment, the voltage-dependent sodium ion channel is Nav 1 , 7.

[0078] In another aspect, the invention relates to a compound for use in the treatment or reduction of severity in a subject of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headaches, neuralgia of the Trigeminal, herpetic neuralgia, general neuralgia, epilepsy or epilepsy conditions, or conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome , incontinence, visceral pain, osteoarthritis pain, posterpatic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-surgical pain, pain cancer, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, angina induced by stress or exercise, palpitations, hypertension, migraine, or gastro-intestinal abormal motility.

 55

[0079] In another embodiment, said use of a compound is to treat or decrease the severity of femoral cancer pain; chronic non-malignant bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic; IBS pain; chronic and acute headache; migraine; tension headache, including cluster headaches; chronic and acute neuropathic pain, postherpatic neuralgia 60; diabetic neuropathy; HIV-related neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; neuropathic pain induced by radiotherapy; post-mastectomy pain; central pain; pain from spinal cord injury; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; 65 acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; Neck Pain; tendonitis; injury / exercise pain; acute visceral pain, abdominal pain;

pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; the hernias; chest pain, heart pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; caesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; the pain of acute shingles; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain, including sinus pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet disease pain; painful adiposis 5; phlebitic pain; Guillain-Barré pain; pain in the legs and feet in motion; Haglund's syndrome; erythromyalgia pain; Fabry disease pain; bladder and urogenital disease, including urinary incontinence; bladder hyperactivity; painful bladder syndrome; interstitial cystitis (HF); prostatitis; complex regional pain syndrome (CRPS), type I and type II; generalized pain, extreme paroxysmal pain, pruritus, tinnitus, or induced chest pain. 10

[0080] The compounds of the invention can be easily prepared using the following methods. Methods for preparing the compounds of the invention are illustrated below in Scheme 1 to Scheme 24.

General Scheme 1

 fifteen

image52

 twenty

 25

 30

 35

R is alkyl such as methyl

a) H +: protic acid such as acetic acid or para-toluene acid; b) diisobutylaluminum hydride, CH2Cl2.

 40

General Scheme 2

image53

 Four. Five

 fifty

 55

PG = protecting group such as BOC, benzyl, CBZ

H +: protic acid such as trifluoroacetic acid, para-toluene acid, propionic acid, or dichloroacetic acid.

 60

 65

General Scheme 3

image54

 5

 10

a) aqueous MOH (ie, NaOH, LiOH), water miscible polar solvent such as dioxane or THF; b) coupling agent (ie HATU), base (ie TEA, NH4Cl or NH3 in DMF or CH2Cl2; c) cyanuric chloride, DMF.

General Scheme 4

 twenty

image55

 25

 30

 35

a) POCl3, DMF; b) NaBH4, MeOH; c) Ac2O, base (Et3N), DMAP in THF; d) Pd / C, H + (i.e. acetic acid), a polar solvent (i.e., EtOAc).

General scheme 5 40

image56

 Four. Five

 fifty

 55

 60

a) 5- (trifluoromethyl) dibenzothiophene-5-io trifluoromethanesulfonate, K2CO3, DMF; b) protic acid (i.e., HCl, TFA), solvent (i.e., dioxane, CH2Cl2); c) CF3I, FeSO4 · 7H2O, H2SO4, H2O2, DMSO. 65

General scheme 6

image57

 5

 10

 fifteen

 twenty

a) H +: protic acid such as acetic acid or para-toluene acid; b) diisobutylaluminum hydride, CH2Cl2. 25

General Scheme 7

image58

 30

 35

PG = protecting group such as BOC, benzyl, CBZ 40

H +: protic acid such as trifluoroacetic acid, para-toluene acid, propionic acid, or dichloroacetic acid.

 Four. Five

 fifty

 55

 60

General Scheme 8

image59

 5

 10

 fifteen

 twenty

 25

 30

 35

R = benzyl, CO2Bn, BOC, COCH3, COCF3, COArile. 40

a) pyrrolidine, MeOH; b) BF3.OEt2, (ETO) 3CH, CH2Cl2; c) 1) HCl, dioxane; 2) NH2-NR2BOC; 3) R = BOC, HCl, dioxane; d) I2, acetone; e) 1) NH2-NHR2BOC, EtOH; 2) R = BOC, HCl, dioxane; f) NaH, HCO2Et; g) deprotection: R = benzyl or CO2Bn, Pd / C, H2; R = COCF3 or COCH3, NaOH, MeOH; R = BOC, HCl, dioxane.

R is not 45

BOC

 fifty

 55

 60

General Scheme 9

image60

 5

 10

 fifteen

 twenty

 25

 30

a) LDA, R'COH, THF; (R ’= aliphatic) b) oxidation (ie, Dess-Martin periodic) in CH2Cl2; c) NH2NR2BOC, para-toluene acid, EtOH; d) deprotection: Pd / C, H2; NaOH MeOH; HCl, dioxane.

General Scheme 10 35

image61

 40

 Four. Five

 fifty

 55

 60

R = benzyl, BOC, COCH3, COCF3, COArile.

a) MeMgX (X = Br, I); Et3N, THF; MeCOH; b) pyrrolidine, MeOH; c) NaH, HCO2Et; d) 1) NH2-NR2BOC, EtOH; 2) HCl, dioxane e) deprotection: Pd / C, H2; NaOH, MeOH; HCl, dioxane. 65

General Scheme 11

image62

 5

 10

 fifteen

 twenty

 25

 30

 35

 40

 Four. Five

 fifty

a) NH2OH H2O, MeOH b) p-TSCL, pyridine; c) NaOEt; toluene d) 1) R2COCl, Et3N, CH2Cl2; 2) Lawesson reagent, toluene; e) Deprotection: R = BOC: HCl, dioxane; f) R2CONH2, 180 ° C; g) Deprotection: R = CBZ; Pd / C, H2; NaOH, MeOH.

General Scheme 12 55

X = Cl, Br, I, OTf; M = B (OR) 2, ZnCl, MgBr

a) Pd (0) such as Pd (PPh3) 4, base such as Et3N or K2CO3 in a solvent such as THF, DMF or DCE, 80 ° C.

General Scheme 13

 5

image63

 10

 fifteen

 twenty

 25

a) protic acid (ie para-toluene sulfonic • H2O), DCE, 80 ° C; b) deprotection (ie R = BOC: HCl, dioxane).

 30

General Scheme 14

image64

 35

 40

a) RCO2H coupling agent (i.e., HATU, EDCI), base (i.e., TEA), polar aprotic solvent (i.e., DMF, CH2Cl2); b) RCOCl, base (ie TEA), polar aprotic solvent (i.e. DMF, CH2Cl2)

General Scheme 15

 fifty

R5 = benzyl, CO2Bn, BOC, COCH3, COCF3, COArile.

a) K2CO3, DMF; b) nBuLi, THF; c) R5 = BOC: protic acid (i.e., HCl, TFA), solvent (i.e. dioxane, MeOH, CH2Cl2); R5 = benzyl, CO2Bn: H2, Pd / C, the solvent (ie, MeOH, EtOH, iPrOH, EOAC); R5 = COCH3, COCF3: base (i.e., NaOH, K2CO3), solvent (i.e., MeOH, EtOH, water).

General Scheme 16 5

image65

 10

 fifteen

R5 = benzyl, CO2Bn, BOC, COCH3, COCF3, COArile.

a) chlorosufonyl isocyanate, THF; b) R5 = BOC: protic acid (i.e., HCl, TFA), solvent (i.e., dioxane, 20 MeOH, CH2Cl2); R5 = benzyl, CO2Bn: H2, Pd / C, the solvent (ie, MeOH, EtOH, iPrOH, EOAC); R5 = COCH3, COCF3: base (i.e., NaOH, K2CO3), solvent (i.e., MeOH, EtOH, water).

General Scheme 17

 25

image66

 30

 35

 40

R5 = BOC, benzyl, CO2Bn, COCH3, COCF3, COArile.

a) K2CO3, DMSO; b) nBuLi, THF; c) K2CO3, DMF; d) R5 = BOC: protic acid (i.e., HCl, TFA), solvent (i.e. dioxane, MeOH, CH2Cl2); R5 = benzyl, CO2Bn: H2, Pd / C, the solvent (ie, MeOH, EtOH, iPrOH, EOAC); R5 = COCH3, COCF3: base (i.e., NaOH, K2CO3), solvent (i.e., MeOH, EtOH, water).

 fifty

 55

 60

General Scheme 18

image67

 5

 10

 fifteen

 twenty

R5 = benzyl, CO2Bn, COCH3, COCF3, COArile. 25

a) POCl3, DMF; b) HO-NH2HCl, EtOH, NaOAc, H2O; c) R5 = benzyl, CO2Bn: H2, Pd / C, the solvent (ie, MeOH, EtOH, iPrOH, EOAC); R5 = COCH3, COCF3: base (i.e., NaOH, K2CO3), solvent (i.e., MeOH, EtOH, water).

General Scheme 19 30

image68

 35

 40

R5 = BOC, benzyl, CO2Bn, COCH3, COCF3, COArile; R6 = alkyl. Four. Five

a) 1) NCS, CH2Cl2, (R6) 2S or R6SCl; 2) oxidizing conditions (ie H2O2, AcOH, or mCPBA, CH2Cl2; b) R5 = BOC: protic acid (i.e., HCl, TFA), solvent (i.e., dioxane, MeOH, CH2Cl2); R5 = benzyl, CO2Bn: H2, Pd / C, the solvent (ie, MeOH, EtOH, iPrOH, EOAC); R5 = COCH3, COCF3: base (i.e., NaOH, K2CO3), solvent (i.e., MeOH, EtOH, water).

 fifty

General Scheme 20

image69

 55

 60

R = benzyl, CO2Bn, BOC, COCH3, COCF3 or COArilo.

a) H2NNHR2, solvent (for example, EtOH).

 65

General Scheme 21

image70

 5

 10

 fifteen

 twenty

a) acid (i.e., HCl), solvent (i.e., dioxane, toluene); b) NH2-NHR2, solvent (ie) EtOH.

General Scheme 22

 25

image71

 30

 35

 40

a) H +: protic acid such as acetic acid or para-toluene acid; b) BF3-OEt2, CH2Cl2; c) i) H2, Pd / C, the solvent (i.e. AcOH, MeOH), ii) BOC2O, base (i.e., Na2CO3), solvent (i.e., THF), iii) 5- (trifluoromethyl trifluoromethanesulfonate) ) dibenzothiophene-5-io, K2CO3, DMF; d) protic acid (i.e., HCl, TFA), solvent (i.e., dioxane, CH2Cl2).

 fifty

 55

 60

65

General Scheme 23

image72

 5

 10

 fifteen

 twenty

R5 = BOC, benzyl, CO2Bn, COCH3, COCF3, COArile; R6 = H, alkyl; X = Br, Cl

a) X = Br; NBS, solvent (ie CH2Cl2); X = Cl; NCS, solvent (ie CH2Cl2); b) catalyst (i.e., Pd2 (dba) 3-CHCl3), alkene (i.e. R6CH = CHOR7), ligand (i.e. tBu3P), base (i.e., men (Chex) 2), solvent (i.e. , dioxane); c) R5 = BOC: protic acid (i.e., HCl, TFA), solvent (i.e. dioxane, MeOH, CH2Cl2); R5 = benzyl, CO2Bn: H2, Pd / C, the solvent (ie, MeOH, EtOH, iPrOH, EOAC); R5 = COCH3, COCF3: base (i.e., NaOH, K2CO3), solvent (i.e., MeOH, EtOH, water).

[00105] Scheme 24 30

image73

 35

 40

R5 = BOC, benzyl, CO2Bn, COCH3, COCF3, COArile; R6 = alkyl, aryl.

a) acylating agent (for example: R6C (O) 2O, R6C (O) Cl), base (for example: pyridine, Et3N, or DBN), solvents (for example: CH2Cl2, DCE, or THF) or acylating agent ( for example: R6C (O) 2O), Lewis acid (for example: BF3.OEt2), base (for example: pyridine), solvents (for example: CH2Cl2); b) R5 = BOC: protic acid (i.e., HCl, TFA), solvent (i.e. dioxane, MeOH, CH2Cl2); R5 = benzyl, CO2Bn: H2, Pd / C, the solvent (ie, MeOH, EtOH, iPrOH, EOAC); R5 = COCH3, COCF3: base (i.e., NaOH, K2CO3), solvent (i.e., MeOH, EtOH, water).

Uses, Formulation and Administration 50

Pharmaceutically Acceptable Compositions

[0081] As discussed above, the invention provides compounds that are inhibitors of voltage-dependent sodium ion channels, and therefore the present compounds are useful for the treatment of diseases, disorders and conditions including, but not limited to acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression , myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence. Accordingly, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

 65

[0082] It will also be appreciated that certain of the compounds of the invention may exist in free form for treatment, or when appropriate, as a pharmaceutically acceptable derivative thereof. According to the

Invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a subject in need is able to provide, directly or indirectly, a compound as described otherwise, or a metabolite or residue thereof.

 5

[0083] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without toxicity, irritation, response. allergic and similar, and are consistent with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention which, upon administration to a receptor, is capable of providing, either directly or indirectly, a compound of this invention or a inhibitory active metabolite or residue thereof. As used herein, the term "inhibitory active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of a voltage-dependent channel of sodium ions.

[0084] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. 15 describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable carriers, non-toxic acid addition salts, are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, acid. Oxalic, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, canforate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepatoate, glucohepatoate, glucohepatoate, glucohepatoate, glucohepatoate, glucohepatoate , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, 25 lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, persulfate 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + salts (C1-4 alkyl) 4. This invention also provides for the quaternization of any group containing basic nitrogen of the 30 compounds described herein. Water or oil soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. 35

[0085] As described above, the pharmaceutically acceptable compositions of the invention further comprise a pharmaceutical carrier, adjuvant or vehicle, which, as used herein, includes any and all solvents, diluents, or other vehicle aids, liquid dispersion or suspension, active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as adapted to the particular dosage form desired to the surface. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) describes various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Except as long as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a harmful manner with any other component of the pharmaceutically acceptable composition, its use is contemplated than within the scope of this invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, mixtures of 50 partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica , magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, block polyethylene-polyoxypropylene polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; 55 tragacanth powder; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; agents such as magnesium hydroxide and aluminum hydroxide buffers; alginic acid; pyrogen free water; isotonic saline solution; Ringer's solution; ethyl alcohol, and 60 phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants They may also be present in the composition, according to the formulator's judgment.

 65

Uses of pharmaceutically acceptable compounds and compositions

[0086] In another aspect, a compound of the invention is provided for use in the treatment or reduction of the severity of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, neuralgia herpetic, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorder such as anxiety and depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, 5 incontinence, pain visceral, osteoarthritis pain, posterpatic neuralgia, diabetic neuropathy, radicular, sciatic pain, back pain, headache or neck pain, severe or treatment-resistant pain, nociceptive pain, breakthrough pain, post-surgical pain, or cancer pain .

[0087] In certain embodiments, a compound of the invention is provided for use in the treatment or decrease in the severity of stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress or exercise-induced angina, palpitations , hypertension, migraine, or aboriginal gastrointestinal motility.

[0088] In certain embodiments, a compound of the invention is provided for use in the treatment or decrease in the severity of acute, chronic, neuropathic pain or inflammatory pain. In certain other embodiments, a compound of the invention is provided for use in the treatment or reduction of the severity of root pain, sciatica, back pain, headache, or neck pain. In still other embodiments, a compound of the invention is provided for use in the treatment or reduction of the severity of severe or intractable pain, acute pain, post-surgical pain, back pain, tinnitus or cancer pain. twenty

[0089] In certain embodiments, a compound of the invention is provided for use in the treatment or reduction of the severity of femoral cancer pain; chronic non-malignant bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, including abdominal; pancreatic; 25 pain of IBS; chronic and acute headache; migraine; tension headache, including cluster headaches; chronic and acute neuropathic pain, including post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; neuropathic pain induced by chemotherapy; neuropathic pain induced by radiotherapy; post-mastectomy pain; central pain; 30 pain from spinal cord injury; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; Neck Pain; tendonitis; pain injuries / exercise; acute visceral pain, including abdominal pain;

pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chest pain, including heart pain; 35 pelvic pain, renal colic pain, acute obstetric pain, including labor pain; caesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, including endometriosis; the pain of acute shingles; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain, including sinus pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behçet's disease pain; painful adiposis; phlebitic pain; Guillain-Barré pain; pain in the legs and feet in motion; 40 Haglund syndrome; erythromyalgia pain; Fabry disease pain; bladder and urogenital disease, including urinary incontinence; bladder hyperactivity; painful bladder syndrome; interstitial cystitis (HF); or prostatitis; complex regional pain syndrome (CRPS), type I and type II; angina induced by pain.

[0090] In certain embodiments of the invention, an "effective amount" of the pharmaceutically acceptable compound or composition is effective in treating or decreasing the severity of one or more acute, chronic, neuropathic pain or inflammatory pain, arthritis, migraine that amount. , cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain , tinnitus or cancer pain.

[0091] The compounds and compositions, according to the use of the invention, can be administered using any amount and any route of effective administration to treat or decrease the severity of one or more of acute, chronic, neuropathic or inflammatory pain. , arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmias, movement disorders, neuroendocrine disorders , ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, 60 visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or intractable pain, pain Nociceptive, breakthrough pain, postsurgical pain, tinnitis or cancer pain. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The "unit dosage form" expression, as used herein, refers to a physically discrete unit of appropriate agent for the subject to be treated. It will be understood,

however, that the total daily use of the compounds and compositions of the invention will be decided by the attending physician within the scope of the medical trial. The specific effective dose level for any particular subject or organism will depend on a variety of factors including the disorder to be treated and the severity of the disorder; the activity of the specific compound employed; the specific composition used; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or coincident with the specific compound employed, and similar factors well known in medical techniques. The term "subject" or "patient", as used herein, means an animal, preferably a mammal, and more preferably a human being.

 10

[0092] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral spray. or nasal, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of from about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg , of the subject's body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0093] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl solubilize alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor, and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and perfuming agents.

[0094] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions 30 may be formulated according to the known technique using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion for injection in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose any mild fixed oil can be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0095] Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before of its use.

[0096] In order to prolong the effect of a compound of the invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the proportion of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by trapping the compound in liposomes or microemulsions that are compatible with body tissues.

 55

[0097] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax that are solid at room temperature but liquid at body temperature and will therefore melt in the rectal or vaginal cavity and release the active compound.

 60

[0098] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert or carrier such as sodium citrate or dicalcium phosphate and / or) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, 65 d) disintegrating agents such as agar-agar, calcium carbonate, starch Potato or tapioca, alginic acid, certain silicates, and sodium carbonate, agents e) solution retardants such as paraffin, f) accelerators

of absorption such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, stearate magnesium, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. 5

[0099] Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings such as enteric coatings 10 and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of inclusion compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0100] The active compounds may also be in microencapsulated form with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings such as enteric coatings, controlled release coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, compression lubricants and other compression aids a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the 25 dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of inclusion compositions that can be used include polymeric substances and waxes.

 30

[0101] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as required. Ophthalmic, formulation ear drops, and eye drops are also contemplated within the scope of this invention. Additionally, the invention contemplates the use of inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as required. Ophthalmic, formulation ear drops, and eye drops are also contemplated within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The speed can be controlled by providing a rate control membrane or by dispersing the compound in a polymer matrix or gel.

[0102] As described generally above, the compounds of the invention are useful as inhibitors of voltage-dependent sodium ion channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of Nav1,1, Nav1,2, Nav1,3, Nav1,4, Nav1,5, Nav1,6, Nav1,7, Nav1,8, or Nav1,9, and therefore, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or decreasing the severity of a disease, condition or disorder in which the activation or hyperactivity of one or more Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, NaV1.8 or 50 NaV1.9 is involved in the disease, condition or disorder. When the activation or hyperactivity of Nav1,1, Nav1,2, NaV1,3, Nav1,4, Nav1,5, Nav1,6, Nav1,7, NaV1,8, or NaV1,9 is involved in a particular disease, the condition or disorder, the disease, condition or disorder may also be referred to as a "Nav1,1, Nav1,2, Nav1,3, Nav1,4, Nav1,5, Nav1,6, Nav1,7, Nav1,8 or NaV1.9 mediated by the disease, condition or disorder. " Accordingly, in another aspect, the invention provides a compound for use in the treatment or reduction of the severity of a disease, condition or disorder in which the activation or hyperactivity of one or more of Nav 1,1, Nav1 , 2, NaV1,3, NAV1 0.4, Nav1.5, Nav1.6, Nav1.7, NaV1.8 or Nav1.9 is involved in the disease state.

[0103] The activity of a compound used in this invention as an inhibitor of Nav1,1, Nav1,2, Nav1,3, 60 Nav1,4, Nav1,5, Nav1,6, Nav1,7, Nav1,8, or Nav1,9 can be tested according to the methods described in general in the Examples of this document, or according to methods available to a person skilled in the art.

simultaneously with, before, or after, one or more other therapeutic agents or desired medical procedures. The particular combination of therapies (therapeutic products or procedures) to be used in a combination regimen 65 will take into account the compatibility of the desired therapeutic products and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed can achieve an effect

desired for the same disorder (for example, a compound of the invention can be administered simultaneously with another agent used to treat the same disorder), or they can achieve different effects (for example, control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, that is being treated." For example, exemplary additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as ethodolac, indomethacin, sulindac, tolmetin; naphthylalkanes such as nabumetone; oxicam such as Piroxicam; para-aminophenol derivatives, such as acetaminophen; propionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, sodium naproxen, oxaprozin; salicylates such as aspirin, choline and magnesium trisalicylate, diflunisal; phenamates such as meclofenamic acid and phenylamic acid; such as methazole; or opiates (narcotics) agonists (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine). Additionally, non-pharmacological analgesic approaches can be used in conjunction with the administration of one or more compounds of the invention. For example, anesthesiological (intraspinal infusion, neural blocade), neurosurgical (CNS pathway neurolysis), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal spine stimulation), physiological (physiotherapy, orthopedic devices, diathermy), or psychological (cognitive Hypnosis methods, biofeedback, or behavioral methods) approaches can also be used. Additional suitable therapeutic agents or approaches are generally described in The Merck Manual, Seventeenth Edition, Ed. Mark H. Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug Administration website, www.fda.gov . twenty

[0104] In another embodiment, additional suitable therapeutic agents are selected from the following:

(1) an opioid analgesic, for example, morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphane, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, nalloxone buprenorphine, butorphanol, nalbuphine or pentazocine;

(2) a non-steroidal anti-inflammatory drug (NSAID), for example, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, naproethane , nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetine or zomepiraco;

(3) a barbiturate sedative, for example, amobarbital, approbital, butabarbital, butabital, mefobarbital, metarbital, metohexital, pentobarbital, phenobartital, secobarbital, talbutal, teamillal or thiopental;

 35

(4) a benzodiazepine that has a sedative action, for example, chlordiazepoxide, chlorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

(5) a Hi antagonist that has a sedative action, for example, diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcycline; 40

(6) a sedative such as glutethimide, meprobamate, methaqualone or dicloralphenazone;

(7) a skeletal muscle relaxant, for example, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metocarbamol or orfrenadine; Four. Five

(8) an NMDA receptor antagonist, for example, dextromethorphan ((+) - 3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+) - 3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone , cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex (R), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including a NR2B 50 antagonist, for example, ifenprodil, traxoprodil or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl] -1-hydroxyethyl-3,4-dihydro-2 (1H) quinolinone ;

(9) an alpha-adrenergic agent, for example, doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1, 2,3,4 tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline;

(10) a tricyclic antidepressant, for example desipramine, imipramine, amitriptyline or nortriptyline;

(11) an anticonvulsant, for example, carbamazepine, lamotrigine, topiratmate or valproate; 60

(12) one of the tachykinin (NK) antagonist, in particular an NK-I antagonist of NK-3, NK-2 or, for example, ([Alpha] R, 9R) -7- [3,5-bis ( trifluoromethyloo) benzyl] -8.9, 10.11 tetrahydro-9-methyl-5- (4- methylphenyl) 7H- [1,4] diazocino [2,1-g] [1,7] inenaphthyride-6-13 -diona (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, 65 dapitant or 3 - [[2-methoxy-5- (trifluoromethoxy ) phenyl] methylamino] -2-phenylpiperidine (2S, 3S);

(13) a muscarinic antagonist, for example oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a selective COX-2 inhibitor, for example, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; 5

(15) a coal tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, raptoneprine, 10-peroneprinone, peroneprine , asenapine, lurasidone, amisulpiride, balaperidone, palindore, eplivanserine, osanetant, rimonabant, meclinertant, Miraxion (R) or sarizotan;

(17) a vanilloid receptor agonist (for example resiniferatoxin) or antagonist (for example capsazepine);

(18) a beta-adrenergic such as propranolol;

(19) a local anesthetic such as mexiletine; twenty

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, especially 5 HTI B / I D agonist such as eletriptan, sumatriptan, narrow atriptan, zolmitriptan or rizatriptan; 25

(22) a 5-HT2A receptor antagonist such as R (+) - alpha- (2,3-dimethoxy-phenyl) -1- [2- (4- fluorophenylethyl)] - 4-ridinemethanol over pipe (MDL- 100907 );

(23) an analgesic (nicotinic) cholinergic, such as ispronicline (TC-1734), (E) -N-methyl-4- (3-pyridinyl) -3-buten-30 1-amine (RJR-2403), ( R) -5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol (R);

(25) a PDEV inhibitor, such as 5- [2-ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl] -1-methyl-3-n-propyl-35 1,6-di- hydro- 7H-pyrazolo [4,3-d] pyrimidine-7-one (sildenafil), (6R, 12aR) - 2,3,6,7,12,12a-hexahydro-2-methyl-6- (3, 4- methylenedioxyphenyl) pyrazine [2 ', 1': 6.1] pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- (4 -ethyl-piperazine-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazine-4-one (vardenafil) , 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7 // - pyrazolo [4,3- < i] pyrimidine-7-one, 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl 3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4 , 3- <i] pvrimidm-7-40 one, 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-yl] -3-ethyl-2- [2-methoxyethyl] - 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7-one, 4 - [(3-chloro-4-methoxybenzyl) amino] -2 - [(2S) -2- (hydroxymethyl) pyrrolidine -1-yl] -N- (pyrimidine-2-ylmethyl) pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propi lo-6,7-dihydro-1 H -pyrazolo [4,3-d] pyrimidine-5-yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide; (Z) an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methyl gabapentin, (1 [alpha], 3 [alpha], 5 [alpha]) (3-amino-methyl-bicyclo [3.2. 0] hept-3-yl) acetic acid, (3S, 5R) -3-aminomethyl 5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) - 3-amino acid 5-methyl-octanoic acid, (2S, 4S) -4- (3-chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) - proline, [(1R, 5R, 6S) - 6 - (aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid, 3- (cyclohexylmethyl 1-aminomethyl) -4H [1, 2,4] oxadiazol-5-one, C- [1 - (I H- tetrazol-5-ylmethyl) cycloheptyl] -methylamine, (3S, 4S) - (1-aminomethyl-3,4-dimethyl-cyclopentyl) acetic acid (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid (3S, 5R) -3-amino-5-50 methyl-nonanoic acid, (3S, 5R) - 3-amino-5-methyl-octanoic acid, (3R, 4R, 5R) -3-amino-4, 5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-non-4,5-dimethyl-octanoic acid;

(26) a cannabinoid;

 55

(27) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

(28) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite of methylsertraline, fluoxetine, norfluoxetine (desmethyl metabolite of fluoxetine), fluvoxamine, paroxetine, citalopram, metabolite of citalopram desMetilocitalopram, limeopramine, phenylemoramine, phenylpramxamine , ifoxetine, cyanodotiepine, lytoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

(29) a norepinephrine (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, phezolamine, tomoxetine, mianserine, buproprion, hydroxybuproprion bupropion metabolite, nomifensin and viloxazine (vivaxazor) (especially Viloxazor) the reuptake of norepinephrine such as reboxetine, in particular (S, S) -reboxetine;

(30) a dual serotonin and norepinephrine reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine desmethyloclomipramine metabolite, duloxetine, milnacipran and imipramine;

(31) an inducible nitric oxide synthase (iNOS) such as S- [2 - [(1-iminoethyl) amino] ethyl] -L-5 homocysteine inhibitor, S- [2 - [(1-iminoethyl) amino] ethyl ] -4,4-dioxo-L-cysteine, S- [2 - [(1-iminoethyl) amino] ethyl] -2-methyl-L-cysteine, (2S, 5Z) -2-amino-2-methyl acid -7 - [(1-iminoethyl) amino] -5-heptenoic, 2 - [[(1R, 3S) -3-amino-4-hydroxy-1- (zolyl 5-thia -) - butylJthioJ-S-chloro- S -pyridinecarbonitril; 2 - [[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -4-robenzonitril chloride, (2S, 4R) -2-amino-4 - [[ 2-Chloro-5- (trifluoromethyl) phenyl] thio] -5-thiazolbutanol, 2 - [[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -6- (trifluoromethyl) -3 pyridinecarbonitrile, 2 - [[(1R, 3S) -3-amino-4-10 hydroxy-1- (5-thiazolyl) butyl] thio] -5-chlorobenzonitrile, N- [4- [2- (3-Chlorobenzylamino) ethyl] phenyl] thiophene-2-carboxamidine, or guanidinoethyldisulfide;

(32) an acetylcholinesterase inhibitor such as donepezil;

 fifteen

(33) a prostaglandin E2 subtype 4 (EP4) such as 7V antagonist - [({2- [4- (2-ethyl-4,6-dimethyl-1 H -imidazo [4,5-c] pyridine-1 yl)) phenyl] ethyl} amino) carbonyl] -4-methylbenzenesulfonamide or 4 - [(15) -1 - ({[5-chloro-2- (3- fluorophenoxy) pyridine-3-yl] carbonyl} amino) ethyl] benzoic acid;

(34) a B4 leukotriene antagonist; such as 1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) 20 cyclopentanecarboxylic (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- (4 - methoxyphenyl) -5E- hexenyl acid] oxyphenoxy] -valeric (ONO-4057) or DPC-11870,

(35) a 5-lipoxygenase inhibitor, such as zileuton, 6 - [(3-fluoro-5- [4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]) phenoxy -methyl] -1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6- (3-pyridylmethyl), 1,4-benzoquinone (CV-6504); (36) a sodium channel blocker, such as lidocaine;

(36) a 5-HT3 antagonist, such as ondansetron; and pharmaceutically acceptable salts and solvates thereof.

 30

[0105] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions currently described will vary from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. 35

[0106] The compounds of this invention or pharmaceutically acceptable compositions thereof can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the invention as described generally above, and in classes and subclasses here, and a vehicle suitable for coating said implantable device. In yet another aspect, the invention includes an implantable device coated with a composition comprising a compound of the invention as described generally above, and in classes and subclasses here, and a vehicle suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in United States Patents accordingly, the invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the invention as generally described above. , and in classes and subclasses herein, and a suitable vehicle for coating said implantable device. In yet another aspect, the invention includes an implantable device coated with a composition comprising a compound of the invention as described generally above, and in classes and subclasses here, and a vehicle 50 suitable for coating said implantable device. Suitable coatings and general preparation of coated implantable devices are described in US 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally also be covered by a suitable top layer of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0107] Another aspect of the invention relates to the use of a compound in the inhibition of one or more of Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7 , Nav1.8, or Nav1.9, the activity in a biological sample or a subject, which use comprises administration to the subject, or in contact with said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. 65

[0108] Inhibition of one or more of Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.8 or Nav1.9, the

Biological activity in one of the sample is useful for a variety of purposes that are known to one skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and the comparative evaluation of new sodium ion channel inhibitors.

 5

EXAMPLES

[0109] General methods. 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were obtained as solutions in tertiary acetonitrile deuterium (CD3CN), chloroform-d (CDCl3) or dimethylsulfoxide-D6 (DMSO). Mass spectra (MS) were obtained using an applied 10

Spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] salt

Step 1: 2- (1H-pyrrol-1-yl) phenol

 fifteen

[0110]

image74

 twenty

 25

[0111] A 5L 3-neck round bottom flask was equipped with a mechanical stirrer, a heating mantle, a water-cooled reflux condenser, a probe / controller temperature and a nitrogen inlet / outlet. The vessel was charged with (50 g, 0.46 mol) of 2-amino-phenol and acetic acid (750 ml) which provided a very dark solution. Stirring was started and the vessel was charged with 2,5-dimethoxytetrahydrofuran (59.4 ml, 0.458 mol) dropwise over 2 minutes. The dark mixture was then heated at 100 ° C for 15 min. The mixture was allowed to cool to room temperature and filtered through a bed of celite to remove residual solids. The filtrate 35 was concentrated under reduced pressure of azeotropic distillation with toluene. The residual oil was dissolved in ethyl acetate (1000 ml) and partitioned with water (500 ml). The organic layer was separated and washed with water (500 ml), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide 2- (1H-pyrrol-1-yl) phenol (54 g, 74%) as a dark oil. ESI-MS m / z calc. 159.1, found 160.2 (M + 1) +. Retention time: 2.67 minutes (3 minutes of execution). 1 H NMR (400 MHz, CDCl 3) δ 7.37-7.23 (m, 2H), 7.13-6.97 (m, 2H), 6.91 (t, J = 1.9 40 Hz, 2H ), 6.43 (t, J = 1.9 Hz, 2H), 5.35 (s, 1H).

3- (1H-Pyrrol-1-yl) pyridine-2-ol was also synthesized using the procedure described above.

Step 2: tert-butyl spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-methyl carboxylate

 Four. Five

[0112]

image75

 fifty

 55

A 5L 3-neck round bottom flask was equipped with a mechanical stirrer, an addition funnel, a probe / controller temperature and a nitrogen inlet / outlet. The vessel was charged under nitrogen with 2- (1 H -pyrrol-1-yl) phenol (40 g, 0.25 mol) and dichloromethane (800 ml). Stirring was started and the dark solution was charged with ethyl tert-butyl-4-oxopiperidine-1-carboxylate (55.1 g, 0.276 mol) added as a solid in one portion. An addition funnel was loaded with TFA (38.7 ml, 0.503 mol) which was subsequently added dropwise over 15 minutes. The dark mixture was continued stirring at room temperature for 5 hours at which time the contents of the reaction vessel were transferred to a separatory funnel and partitioned with water (500 ml). The organic layer was separated and washed with 1M NaOH (2 x 250 ml), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide a light amber oil (105 g). The material was purified by silica gel column flash chromatography (4: 1 Hex / EtOAc, 250 fractions of one ml) to provide (51 g, 60%) of tert-butyl spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-methyl carboxylate as

A light amber oil. ESI-MS m / z calc. 340.2, found 341.3 (M + 1) +. Retention time: 2.17 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.5 Hz, 1H), 7.19 to 7.13 (m, 1H), 07/10 to 07/01 (m, 3H), 6.34 (t, J = 3.1 Hz, 1H), 6.03 (d, J = 3.4 Hz, 1H), 4.02 (s, 2H), 3.30 (s, 2H), 2.14 -1.99 (m, 2H), 1.90 (td, J = 13.3, 4.9 Hz, 2H), 1.48 (s, 9H).

 5

Step 3: Spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] hydrochloride salt

[0113]

 10

image76

 fifteen

 twenty

[0114] A 5L 3-neck round bottom flask was equipped with a mechanical stirrer, an addition funnel, a temperature probe / controller and a nitrogen inlet / outlet. The vessel was charged under nitrogen with a light amber solution of tert-butyl spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1 'carboxylate and (50 g, 0.15 mol) and toluene (250 ml) of stirring was started and the addition funnel was charged with which it was added dropwise over 10 minutes resulting in a very dark solution (73 ml, 0, 29 mol) of 4M HCl in 1,4-dioxane. The mixture was continued stirring at room temperature for 1 h before the reaction mixture was filtered to remove residual solids. The filtrate was concentrated under reduced pressure to provide a solid that was triturated with diethyl ether (2 x 200 mL) and then dried under vacuum to provide (31 g, 76%) of spiro [benzo [b] pyrrolo [1,2 -d] [1,4] oxazine-4,4'-piperidine] in the form of a white solid. ESI-MS m / z calc. 30 240.1, found 241.3 (M + 1) +. Retention time: 1.21 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 9.45 (s, 2H), 7.76-7.62 (m, 1H), 7.55 (dd, J = 2.8, 1.3 Hz, 1H) , 7.23 to 7.8 (m, 3H), 6.31 (t, J = 3.2 Hz, 1H), 6.11 (dd, J = 3.4, 1.3 Hz, 1H), 3.29 to 3.13 ( m, 4H), 2.25 (td, J = 14.4, 5.0 Hz, 2H), 2.09 (d, J = 14.1 Hz, 2H).

[0115] The following compounds were prepared using the procedures described above: 7-fluorospiro 35 [benzo [b] Pyrolo [1,2-d] [1,4] oxazine-4,4'-piperidine]: ESI- MS m / z calc. 258.1 (-HCl), found 259.2 (M + 1) +. Retention time: 1.29 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 9.52 (s, 2H), 7.76 (dd, J = 8.9, 5.6 Hz, 1H), 7.58-7.54 (m, 1H) , 7.20 (dd, J = 9.6, 2.8 Hz, 1H), 6.97 (td, J = 8.7, 2.8 Hz, 1H), 6.31 (t, J = 3 , 2 Hz, 1H), 6.11 (dd, J = 3.4, 1.2 Hz, 1H), 3.30 to 3.14 (m, 4H), 2.28 (td, J = 14, 7, 5.5 Hz, 2H), 2.11 (d, J = 14.1 Hz, 2H) and 7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine -4 , 4'-piperidine]: ESI-MS m / z calc. 274.1 (-HCl), found 275.2 40 (M + 1) +. Retention time: 1.38 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 9.38 (s, 2H), 7.75 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 8.6, 2.2 Hz, 1H), 6.33 (t, J = 3.2 Hz, 1H ), 6.13 (d, J = 3.0 Hz, 1H), 3.30 to 3.11 (m, 4H), 2.32 - 2.17 (m, 2H), 2.10 (d, J = 14.1 Hz, 2H).

Spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -7-carbonitrile 45

Step 1: 1'-tert-Butyl spiro 7-methyl [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1 ', 7-dicarboxylate

[0116]

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[0117] Trifluoroacetic acid was added (3.15 g, 2.13 ml, 27.6 mmol) dropwise to a solution of methyl 3-hydroxy-4-pyrrol-1-yl-benzoate methyl (3, 00 g, 13.8 mmol) and ethyl tert-butyl 4-oxopiperidine -1-carboxylate (3.00 g, 15.2 mmol) in dichloromethane (60 ml) and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with water and 1N NaOH. The organics were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 0-30% EtOAc in hexanes. The pure fractions were combined and concentrated to give 1'-tert-butyl-methyl spiro 7 [benzo [b] pyrrolo [1,2-d]

[1,4] oxazine-4,4'-piperidine] -1 ', 7-dicarboxylate. ESI-MS m / z calc. 398.4, found 399.5 (M + 1) +. Retention time: 2.13 minutes (3 minutes of execution).

Step 2: 1 ′ - (tert-butoxycarbonyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -7-carboxylic acid 5

[0118]

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[0119] A solution of 1'-tert-butyl-methyl spiro 7 [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1 ', 7-dicarboxylate (3.5 g, 8.8 mmol) in LiOH (18 ml of 2.0 M, 35.1 mmol) and dioxane (18 ml) was stirred at 55 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was acidified with 1 N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give 1'- (tert-butoxycarbonyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'- piperidine] - 7-carboxylic acid that was used without further purification. ESI-MS m / z calc. 384.4, found 385.3 (M + 1) +. Retention time: 1.81 minutes (3 minutes of execution). 25

Step 3: tert-butyl-7 carbamoylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1’-methyl carboxylate

[0120] 30

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[0121] A solution of NH4Cl (1.4 ml, 40 mmol) and Et3N (5.6 ml, 40 mmol) in DMF (6 ml) was added to a solution of 1-tert-butoxycarbonylspiro [piperidine-4.4 '-pyrrolo [2,1-c] [1,4] benzoxazine] -7'-carboxylic acid (3.1 g, 8.0 mmol), HATU (3.3 g, 8.8 mmol) and Et3N ( 2.5 ml, 18 mmol) in DMF (6 ml). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated. Purification of the residue by silica gel chromatography eluting with 0-100% EtOAc in hexanes provided tert-butyl-7'carbamoylspiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine ] -1-carboxylate- (2.7 g, 89%). ESI-MS m / z calc. 383.4, found 384.7 (M + 1) +. Retention time: 1.60 minutes (3 minutes of execution).

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Step 4: tert-butyl-7 Cyanospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1’-methyl carboxylate

[0122]

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[0123] A solution of tert-butyl-7'-carbamoylspiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (2.7 g, 7 , 1 mmol) and cyanuric chloride (1.3 g, 7.1 mmol) in DMF (10 ml) was stirred at room temperature for 1 hour. The reaction was poured into water and the product was extracted in ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give a crude mixture that was purified by chromatography on silica gel eluting with 0-100% EtOAc in hexanes. The pure fractions were combined and concentrated to give 5 tert-butyl-7-Cyanoespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-carboxylate methyl (1.1 g, 44%). ESI-MS m / z calc. 365.4, found 366.3 (M + 1) +. Retention time: 2.00 minutes (3 minutes of execution).

Step 5: Spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -7-carbonitrile

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[0124]

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[0125] A solution of tert-butyl-7'-Cyanospiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (1.1 g, 3 , 1 mmol) in HCl in dioxane (3.1 mL of 4.0 M, 12 mmol) was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness to give spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -7-carbonitrile (880 mg, 94%). ESI-MS m / z calc. 265.3, found 266.1 (M + 1) +. Retention time: 25 0.92 minutes (3 minutes of execution).

Methyl spiro [benzo [b] pyrrolo [l, 2-d] [1,4] oxazine-4,4'-piperidine] -7-methyl carboxylate

[0126] 30

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[0127] A solution of 1'-tert-butyl-methyl spiro 7 [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1 ', 7-dicarboxylate (1.8 g, 4.5 mmol) in HCl (4.5 ml, 4.0 M in dioxanes, 18 mmol) was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give methyl spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -7-methyl carboxylate (1.5 g , quant). ESI-MS m / z calc. 298.3, found 299.5 (M + 1) +. Retention time: 1.06 minutes (3 minutes of execution).

1-Methylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine]

Step 1: 1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 50

[0128]

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[0129] To a solution at 0 ° C of spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] (HCl salt) (1.0 g, 3.6 mmol) in acetonitrile Dry (10 ml), under a nitrogen atmosphere, NaHCO3 (1.5 g, 18 mmol) was added followed by the dropwise addition of benzyl bromide (560 µl, 4.7 mmol). The cooling bath was removed. Water (25 ml) was then added, and the organic solvent was removed in vacuo. The product was extracted from the aqueous solution with EtOAc (3 x 150 ml). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (silica gel: 5-70% EtOAc in hexanes) to give 1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine- 4.4 'piperidine] 660 mg, 55%).

ESI-MS m / z calc. 330.4, found 331.5 (M + 1) +; Retention time: 1.23 minutes (3 minutes of execution).

Step 2: 1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbaldehyde

[0130] 5

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[0131] N, N-dimethylformamide (723 ml, 9.40 mmol), under a nitrogen atmosphere, was cooled to 0 ° C and POCl3 (876 µl, 9.40 mmol) dropwise. The reaction was stirred for 20 min at 0 ° C and a white solid formed. A solution of 1-bencilespiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] (2.07 g, 6.27 mmol) in dry DMF (15.5 ml) was added ) drop by drop and the cooling bath was removed. The reaction mixture was stirred for 2 hours at 50 ° C, then cooled to room temperature and poured onto ice. Sodium hydroxide (1 M) was added until the pH reached 10, then the solution was acidified to pH 6 with HCl 3. Then, the mixture was extracted with EtOAc. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel: 10 to 70% EtOAc in hexanes) to give 1'bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4.4 'piperidine] -1-carbaldehyde (1.94 g, 86%). ESI-MS m / z calc. 358.4, found 359.3 (M + 1) +; Retention time: 1.16 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 8.17 to 8.7 (m, 1H), 7.38-7.30 (m, 4H), 7.29 to 7.24 (m, 1H), 7.20 at 7.13 (m, 2H), 7.09 (m, 2H), 6.20 (d, J = 4.1 Hz, 1H), 3.59 (s, 2H), 2.76 (m, 2H) , 2.58-2.45 (m, 2H), 2.10-1.96 (m, 4H).

Step 3: (1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl) methanol 30

[0132]

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[0133] A solution of 1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbaldehyde (1.94 g, 45 5, 40 mmol) in methanol (40 ml) was cooled to 0 ° C. Sodium borohydride (409 mg, 10.8 mmol) was added in one portion and the cooling bath was removed. After stirring for 1 hour at room temperature, the reaction was diluted with saturated aqueous NaHCO3 (50 ml) and DCM (150 ml). The organic layer was separated and the aqueous layer was extracted twice more with DCM (150 ml). The organic layers were combined, dried, filtered and concentrated to give (1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1 -yl) methanol (1.66 g) as a white solid. The crude material was used in the next step without purification.

Step 4: (1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl) methyl acetate

[0134] 55

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[0135] A solution of (1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl) methanol (1.66 g, 4.60 mmol) and 4- (dimethylamino) pyridine (561 mg, 4.60 mmol) in dry THF (40 ml) was cooled to 0 ° C. Triethylamine (2.56 ml, 18.4 mmol) was added then added to the reaction mixture followed by the dropwise addition of acetic anhydride (1.27 ml, 13.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. It was then concentrated and purified by column chromatography (silica gel: 10 to 40% EtOAc in hexanes) to give (1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4 ] oxazine-4,4'-piperidine] -1-yl) methyl acetate (1.32 g, 61% yield in two steps). ESI-MS m / z calc. 402.5, found 403.7 (M + 1) +; Retention time: 1.31 minutes (3 minrun). 10

Step 5: 1-Methylspiro [benzo [b] pyrrolo [1,2-d [1,4] oxazine-4,4'-piperidine]]

[0136]

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[0137] To a solution of (1'-bencilespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl) methyl acetate (300 mg , 0.75 mmol) in ethyl acetate (30 ml) acetic acid (17 µl, 0.30 mmol) was added. The reaction was washed extensively with nitrogen and then 10% Pd / C (40 mg, 0.37 mmol) was added. The reaction was placed under hydrogen gas and stirred for 20 h at room temperature. The suspension was filtered through celite, concentrated, then purified by column chromatography (silica gel: 0.1 to 15% methanol in dichloromethane) to give 1-methylpyrro [benzo [b] pyrrolo [1,2 -d] [1,4] oxazine dine -4,4'-piperi-] (65 mg, 34%). ESI-MS m / z calc. 254.3, found 255.3 (M + 1) +; Retention time: 1.93 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.9 Hz, 1H), 7.16-6.99 (m, 3H), 6.03 (d, J = 3.2 Hz , 1H), 5.94 (d, J = 3.4 Hz, 1H), 3.14 (t, J = 12.2 Hz, 2H), 2.94 (d, J = 12.3 Hz, 2H), 2.56 (s, 3H), 2.19 (m, 1H), 2.04 (d, J = 12.7 Hz, 2H), 1.97-1.84 (m, 2H).

1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine]

Step 1: tert-butyl 1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-40 methyl carboxylate

[0138]

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tert-butyl spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-carboxylate ethyl (100 mg, 0.29 mmol), trifluoromethanesul-5- (trifluoromethyl fonate) ) dibenzothiophene-5 ium (300 mg, 0.73 mmol) and K2CO3 (110 mg, 0.76 mmol) were combined in N, N-dimethylformamide (1 ml). The reaction mixture was heated at 80 ° C for 16 hours. The reaction mixture was filtered and then purified by reverse phase HPLC 10 to 99% methanol in water to give the tert-butyl-1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-methyl carboxylate (57

mg, 48%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.22 to 7.3 (m, 3H), 6.79 (d, J = 3.9 Hz, 1H), 6.03 (d, J = 3.9 Hz, 1H), 4.27-3.75 (m, 2H), 3.39-3.10 (m, 2H), 2.13-1.96 ( m, 2H), 1.95-1.78 (m, 2H), 1.48 (s, 9H). ESI-MS m / z calc. 408.4, found 409.5 (M + 1) +; Retention time: 2.38 minutes (3 minutes of execution).

Step 2: 1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] hydrochloric acid 5

[0139]

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tert-butyl 1 '- (trifluoromethyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (30 mg, 0.074 mmol) was dissolved in chloride of hydrogen in dioxane (700 µl of 4.0 M, 2.8 mmol). The reaction mixture was allowed to stand for 20 minutes. The solvent was evaporated to give 1-spiro (trifluoromethyl) [benzo [b] pyrrolo [1,2-d] [1,4] oxazine eridine-4,4'-Pip] was then used hydrochloride without further purification (25 mg , 99%). 1 H NMR (400 25 MHz, DMSO) δ 9.23 (br s, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.40-7.19 (m, 3H), 7 , 05 (d, J = 3.9 Hz, 1H), 6.38 (d, J = 4.0 Hz, 1H), 3.42-3.04 (m, 4H), 2.37-2, 00 (m, 4H). ESI-MS m / z calc. 308.3, found 309.5 (M + 1) +; Retention time: 1.53 minutes (3 minutes of execution).

1- (Trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] sulfate

[0140]

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[0141] To spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] (5.20 g, 21.6 mmol) in DMSO (104 ml) H2SO4 (1 , 27 ml, 23.8 mmol) (note: exothermic), ferrous sulfate heptahydrate (6.5 ml of 1.0 M, 6.5 mmol) followed by CF3I (4.24 g, 21.6 mmol) by Slow bubbling through the solution and taking the difference in canister weight. The mixture was cooled with an ice-water bath before H2O2 (2.45 ml of 30% w / v, 21.6 mmol) was added dropwise over 10 min maintaining the temperature <23 ° C. The mixture was allowed to stir for 15 min before it was poured onto ice (250 g), producing a white precipitate. The suspension was stirred for 5 min and then the solid was collected by filtration. The off-white solid was collected in acetonitrile (150 ml) and heated at reflux for 1 h. The solvent was removed and the solid was recrystallized from EtOH (15 ml / g) and water (5 ml / g). The solid was collected and dried to give 1-spiro (trifluoromethyl) [benzo [b] Pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] sulfate (2.9 g , 33%). ESI-MS m / z calc. 308.1, found 309.1 (M + 1) +; Retention time: 1.23 minutes (3 minutes of 55 execution).

7-Chloro-1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine]

Step 1: tert-butyl 7-chloro-1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 60 1'carcarboxylate

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[0142]

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tert-butyl 7'-chlorospiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (370 mg, 1.0 mmol), potassium carbonate (360 mg, 2.6 mmol) and trifluoromethanesulfonate 5- (trifluoromethyl) dibenzothiophene-5-io (1.0 g, 2.5 mmol) were combined in N, N-dimethylformamide (3.7 ml). The reaction mixture was heated at 80 ° C for 90 minutes. Trifluoromethanesulfonate 5- (trifluoromethyl) dibenzothiophene-5-io (200 mg, 0.50 mmol) and potassium carbonate (69 mg, 0.50 mmol) were added and stirring was continued for an additional 40 minutes. The reaction mixture was partitioned between 50 ml of water and 50 ml of dichloromethane. The layers were separated and the organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a pale yellow solid. The crude material was purified on silica gel using a gradient of 0-5% ethyl acetate in hexanes to give tert-butyl-7-chloro-1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2- d] [1,4] oxazine-4,4'piperidine] 1'-methyl carboxylate (210 mg, 63%) as a white solid. 1 H NMR (400 MHz, CDCl 3) δ 7.58 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 7.06 (dd, J = 8 , 8, 2.4 Hz, 1H), 6.80 (d, 25 J = 3.9 Hz, 1H), 6.04 (d, J = 3.9 Hz, 1H), 4.07-3, 96 (m, 2H), 3.26 to 3.14 (m, 2H), 2.07-1.81 (m, 4H), 1.47 (s, 9H). ESI-MS m / z calc. 442.9, found 443.1 (M + 1) +; Retention time: 2.34 minutes (3 minutes of execution).

Step 2: 7-Chloro-1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] hydrochloric acid 30

[0143]

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tert-butyl 7-chloro-1- (trifluoromethyl) spiro [benzo [b] pyrrolo1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-methyl carboxylate (210 mg, 0, 14 mmol) was dissolved in HCl in dioxane (2.0 mL of 4.0 M, 8.0 mmol). The reaction mixture was allowed to stand for 30 minutes. Then, the reaction mixture was evaporated to dryness to give 1--7-chloro spiro (trifluoromethyl) [benzo [b] Pyrolo [1,2-d] [1,4] oxazine-4,4'-piperidine ] acid hydrochloric. ESI-MS m / z calc. 342.7, found 343.3 (M + 1) +; Retention time: 1.46 minutes (3 minutes of execution). fifty

2-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] and 3-methylpiro [benzo [b] pyrrolo [1,2-d] [1, 4] oxazine-4,4'-piperidine]

Step 1: 2- (3-methyl-1H-pyrrol-1-yl) phenol 55

[0144]

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[0145] Diisobutylaluminum (100 ml of 1.0 M, 100 mmol) was added dropwise to a solution of dimethyl 2-methylbutanedioate (7.6 g, 48 mmol) in dichloromethane (15 ml) at -78 ° C, and the solution was stirred for 1 h. A suspension of 2-aminophenol HCl salt (6.6 g, 45 mmol) in water (110 ml) was initially added dropwise with vigorous stirring, then in small portions. Halfway through the addition, the cooling bath was removed to help facilitate agitation. The mixture was stirred vigorously at room temperature overnight, then filtered over celite and the filter cake washed several times with dichloromethane. The filtrate was separated, and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organics were washed with brine (50 ml), dried over MgSO4, concentrated and purified by column chromatography (0-40% EtOAc / hexane) to give 2- (3-methylpyrrol-1-yl) phenol (3.7 g, 48%) as a yellow oil. ESI-MS m / z calc. 173.2, found 174.3 (M + 1) +; Retention time: 1.51 minutes (3 minutes of execution).

Step 2: tert-butyl 2-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-methyl carboxylate and tert-butyl 3-methylpyrro [ benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-methyl carboxylate

[0146]

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[0147] A 2- (3-methylpyrrol-1-yl) phenol (2.0 g, 12 mmol) and ethyl tert-butyl 4-oxopiperidine-1-carboxylate (2.5 g, 13 30 mmol) in dichloromethane (36 ml) under N2 was added dropwise at 0 ° C, dichloroacetic acid (1.9 ml, 23 mmol) for 5 min. The mixture was stirred at that temperature for 2 h, then kept at 5 ° C overnight. The mixture was washed with water (10 ml), 1 M NaOH (20 ml) and brine (10 ml), dried over MgSO4 and purified by column chromatography (0-30% ane EtOAc / hex) to give a mixture of product isomers (~ 2.7 g, 68%, 2: 1 NMR ratio). The mixture was subjected to SFC separation using ChiralPak OD-H (30% MeOH w / 0.1% 35 DEA, 70% CO2) to give the tert-butyl-3-methylpyrro [benzo [b] pyrrolo [1 , 2-d] [1,4] ox-azine-4,4'-piperidine] 1'-methyl carboxylate as the first elution fraction (1.0 g, 37%) and tert-butyl-2 'methylpyrro [ pyrrolo piperidine-4,4 '[2,1-c] [1,4] benzoxazine] -1-carboxylate methyl as the second elution fraction (0.40 g, 30%).

Step 3a: 3-methylpyrro [benzo [b] pyrrolo [1,2-d [1,4] oxazine-4,4'-piperidine]] hydrochloric acid 40

[0148]

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[0149] A tert-butyl-2 'methylstyrene [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (second 60 elution fraction from step 2 ) (0.40 g, 1.1 mmol) of hydrogen chloride in 1,4-dioxane (2.8 mL of 4.0 M, 11 mmol) was added and the mixture was stirred 1 h, then filtered and was rinsed with 1: 1 ether / isopropanol to give 2 'methylpyrro [piperidine-4,4'-pyrrolo [2,1 c] [1,4] benzoxazine] as a pink solid. ESI-MS m / z calc. 254.3, found 255.3 (M + 1) +; Retention time: 1.16 minutes (3 minutes of execution).

 65

Step 3b: 3-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] hydrochloric acid

[0150]

image96

 5

 10

[0151] For tert-butyl 3-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-methyl carboxylate (first elution peak of the step 2 (hydrogen chloride 1.0 g, 2.8 mmol) in 1,4-dioxane (7.0 mL of 4.0 15 M, 28 mmol) was added and the mixture was stirred 1 h, then filtered and rinsed with 1: 1 ether / isopropanol to give 3'-methylpyrro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] as a solid ESI-MS m / z calc pink 254.3, found 255.3 (M + 1) +; .. Retention time: 1.14 minutes (3 minutes of execution).

2'-Methylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 20

[0152]

image97

 25

 30

[0153] Trifluoroacetic acid (443 ml, 5.75 mmol) was added to a solution of 2-pyrrole-1-ylphenol (457 mg, 2.87 mmol) and 2-methyl-4-oxo-piperidine tert-butyl -1-methyl carboxylate (613 mg, 2.87 mmol) in dichloromethane (19 ml) and the solution was vigorously stirred for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3, and the organics were extracted with EtOAc (3 x 200 mL). The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel: 0-10% EtOAc in dichloromethane) to give the tert-butyl-2 'methylstyrene [benzo [b] pyrrolo [1,2-d] [1,4] oxazine- 4,4'-40 piperidine] 1'-methyl carboxylate as a brown oil. The crude residue was dissolved in a solution of HCl in dioxane (1.4 ml of 4.0 M, 5.6 mmol) and stirred for 30 min at room temperature. The volatiles were removed in vacuo and the residue was dissolved in diethyl ether. The solids were collected by filtration to provide 2'methylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] (386 mg, 46%) as a solid reddish of Brown color. ESI-MS m / z calc. 254.1, found 255.5 (M + 1) +; Retention time: 1.12 minutes (3 minutes of execution). Four. Five

8'-aza-spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,3'-bicyclo [3.2.1] octane]

Step 1: (1R, 5S) -8- (2,2,2-trifluoroacetyl) -8-azabicyclo [3.2.1] octan-3-one

 fifty

[0154]

image98

 55

 60

 65

[0155] A solution of (1S, 5R) -8-azabicyclo [3.2.1] octan-3-one (500 mg, 4.00 mmol) in pyridine (16 ml) was stirred in an ice bath and (2 , 2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (1.11 ml, 7.99 mmol) was added dropwise. The solution was gently heated to room temperature and stirred for 1 h. Then, the reaction was quenched with ice and extracted with EtOAc (3 x 100 ml). The organic layers were combined and washed with saturated aqueous NaHCO3, followed by 1M NaOH, and brine. The organic layer was dried over Na2SO4, filtered and concentrated to provide (1R, 5S) -8- (2,2,2-trifluoroacetyl) -8-azabicyclo [3.2.1] octan-3-one as an oil clear (620 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 5.08-4.94 (m, 1H), 4.79-4.67 (m, 1H), 2.87-2.63 (m, 2H), 2, 52 (d, J = 16.2 Hz, 2H), 2.35 - 2.08 (m, 2H), 2.01-1.86 (m, 1H), 1.85-1.73 (m, 1 HOUR).

Step 2: 2,2,2-trifluoro-1- (8'-azaspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,3'-bicyclo [3.2.1] octane ] -8'-il) 10 et- anone

[0156]

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 25

A solution of TFA (387 µL, 5.02 mmol) in dichloroethane (18 mL) was added to 2-pyrrole-1-ylphenol (401 mg, 2.52 mmol) and (1R, 5S) -8- (2, 2,2 trifluoroacetyl) -8-azabicyclo [3.2.1] octan-3-one (620 mg, 2.80 mmol). The solution was heated at 70 ° C overnight. The solvent was evaporated and the crude residue was purified by column chromatography (silica gel: 0-10% EtOAc in hexanes) to give 2,2,2-trifluoro-1- (8'-azaspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,3'-30 bicyclo [3.2.1] octane] -8'-yl) ethanone in the form of a transparent oil (469 mg, 46% ). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 7.5 Hz, 1H), 7.07-6.94 (m, 4H), 6.23 (t, J = 3.2 Hz , 1H), 5.87 (d, J = 3.4 Hz, 1H), 4.74 (d, J = 7.4 Hz, 1H), 4.42 (s, 1H), 2.50-2 , 34 (m, 2H), 2.34-2.16 (m, 3H), 2.16-1.89 (m, 3H). ESI-MS m / z calc. 362.4, found 363.3 (M + 1) +; Retention time: 2.07 minutes (3 minutes of execution).

 35

Step 3: 8'-aza-spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,3'-bicyclo [3.2.1] octane]

[0157]

 40

 Four. Five

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 55

[0158] To a solution of 2: 2,2,2-trifluoro-1- (8'-azaspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,3'-bicyclo [3.2.1] octane] -8'-yl) ethanone (469 mg, 1.29 mmol) in MeOH (5 mL) NaOH (1.3 mL of 2.0 M, 2.6 mmol) was added. The solution was heated at 70 ° C overnight. The reaction was then cooled to room temperature and the organics 60 were extracted with EtOAc (3 x 100 mL), combined, and dried over Na2SO4. Then, the organic layer was filtered and concentrated to provide 8'-azaspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,3'-bicyclo [3.2.1] octane] as an opaque oil with a quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.7 Hz, 1H), 7.09-6.96 (m, 4H), 6.26 (t, J = 3.2 Hz , 1H), 5.97 (d, J = 3.4 Hz, 1H), 3.58 (s, 2H), 2.40-2.29 (m, 2H), 2.21 to 2.15 (m, 2H) , 2.09 (dd, J = 15.0, 3.1 Hz, 2H), 1.86-1.77 (m, 2H). ESI-MS m / z calc. 266.3, found 267.3 (M + 1) +; Retention time: 1.04 65 minutes (3 minutes of execution).

Spiro [piperidine-4,6 '-pyrido [3,2-b] pyrrolo [1,2-d] [1,4] oxazine]

[0159]

 5

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 fifteen

[0160] A mixture of 2-pyrrole-1-ylpyridine-3-ol (1.00 g, 6.24 mmol), ethyl tert-butyl 4-oxopiperidine-1-carboxylate (1.24 g, 6.24 mmol), 4-methylbenzenesulfonic acid hydrate (119 mg, 0.625 mmol), molecular sieves (442 mg) and dichloroethane (8.9 ml) was heated at 130 ° C for 162 hours. The reaction was filtered and washed with dichloroethane. The solid was dissolved in MeOH and filtered through a plug of Celite. The solvent was evaporated under reduced pressure to provide spiro [piperidine-4,6 '-pyrido [3,2-b] pyrrolo [1,2-d] [1,4] oxazine] (1.4 g, 38% ). ESI-MS m / z calc. 241.1, found 242.5 (M + 1) +; Retention time: 1.10 minutes (4 min of execution).

9 '- (trifluoromethyl) spiro [piperidine-4,6'-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine]

 25

Step 1: Benzyl spiro [piperidine-4,6 '-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] -1-ethyl carboxylate

[0161]

 30

image102

 35

[0162] To a stirred solution of 3-pyrrol-1-ylpyridine-2-ol (481 mg, 3.00 mmol) and benzyl 4,4-dimethoxypiperidine-1-ethyl carboxylate (922 g, 3.3 mol) in CH2Cl2 (20 ml) at 40 ° C BF3 · OEt2 (407.3 µl, 3,300 mmol) was added dropwise. The reaction mixture was stirred at 40 ° C for 16 hours. The mixture was poured into a sat solution. here Na2CO3 and stirred for 5 min before it was extracted with EtOAc (3x). The organic layers were combined, washed with sat. here Na2CO3, water, brine, dried (Na2 SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc / CH2Cl2) to give benzyl [piperidine-4,6 '-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] -1-ethyl carboxylate as an oil. ESI-MS m / z calc. 375.2, found 376.5 (M + 1) +; 45 Retention time: 1.70 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 8.10 (dd, J = 7.7, 1.1 Hz, 1H), 8.00 (dd, J = 4.9, 1.5 Hz, 1H), 7 , 60-7.52 (m, 1H), 7.42-7.36 (m, 4H), 7.36-7.29 (m, 1H), 7.16 (dd, J = 7.8, 4.9 Hz, 1H), 6.33 (t, J = 3.2 Hz, 1H), 6.20 (d, J = 3.4 Hz, 1H), 5.11 (s, 2H), 3 , 97 (d br, J = 13.2 Hz, 2H), 3.28 (broad s, 2H), 1.98-1.92 (m, 4H).

 fifty

Step 2: tert-butyl spiro [piperidine-4,6 '-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] -1-ethyl carboxylate

[0163]

 55

image103

 60

[0164] A solution of spiro benzyl [piperidine-4,6 '-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] -1-ethyl carboxylate 65 (220 mg, 0.586 mmol), AcOH (33 µl, 0.59 mmol) and Pd / C (22 mg, 0.21 mmol) in MeOH (2 mL) was stirred under an H2 balloon for 6 hours. The mixture was filtered through celite and the fitrate evaporated to give spiro [piperidine-4,6'-

pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] (ESI-MS m ./calc z 241.1, found 242.5 (M + 1) +; retention time : 0.46 minutes (3 min of execution)). Then, the residue was taken up in THF (3 ml) before Na2CO3 was added (1.2 ml of 2.0 M, 2.4 mmol). Boc2O (156 mg, 0.70 mmol) was added and the mixture was stirred at room temperature for 12 hours. , N, N-dimethylethylenediamine (0.5 ml) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water and extracted with EtOAc (3x). The organics were combined, washed with 0.1 N HCl (3x), 5 brine, dried (Na2SO4) and filtered through a silica plug to give the tert-butyl-spiro [piperidine-4.6 ' -pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] -1-carboxylate (134 mg, 67%).

[0165] 1H NMR (400 MHz, DMSO) δ 8.18 to 8.13 (m, 1H), 8.12-8.00 (m, 1H), 7.69-7.56 (m, 1H), 7.32 -7.12 (m, 1H), 6.39 (dd, J = 5.8, 3.0 Hz, 1H), 6.33-6.20 (m, 1H), 3.94 (d, J = 11.9 Hz, 2H), 3.26 (s, 2H), 2.02 (wide s, 4H), 1.48 (d, J = 2.3 Hz, 9H). 10

Step 3: tert-Butyl 9 '- (trifluoromethyl) spiro [piperidine-4,6'-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] -1-ethyl carboxylate

[0166] 15

image104

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 25

[0167] A solution of tert-butyl-spiro [piperidine-4,6 '-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] -1-ethyl carboxylate (134 mg, 0.393 mmol) and 5- (trifluoromethyl) dibenzothiophene-5-io (99.4 mg, 0.393 mmol) in DMF (2 ml) was stirred at 30-80 ° C for 1.5 hours. The mixture was poured into water and extracted with EtOAc (3x). The organics were combined, washed with water and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc / hexanes) to give the tert-butyl-9 '- (trifluoromethyl) spiro [piperidine-4,6'-pyrido [2,3-b] pyrrolo [ 1,2-d] [1,4] oxazine] -1-ethyl carboxylate (83 mg, 56%). ESI-MS m / z calc. 409.2, found 410.5 (M + 1) +; Retention time: 1.92 minutes (3 minutes of execution). 35

Step 4: 9 '- (trifluoromethyl) spiro [piperidine-4,6'-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine]

[0168]

 40

image105

 Four. Five

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[0169] To a solution of tert-butyl-9 '- (trifluoromethyl) spiro [piperidine-4,6'-pyrido [2,3-b] pyrrolo [1,2-d] [1,4] oxazine] - 1-Carboxylate (83 mg, 0.20 mmol) in CH2Cl2 (3 ml) TFA (1.0 ml, 13 mmol) was added and the mixture was stirred at room temperature for 15 min before being evaporated to dryness. The residue was taken up in EtOAc and sat. here Na2CO3, the layers were separated, and the aqueous layer was extracted with EtOAc (2x). The organics were combined, washed with sat. here Na2CO3, brine, dried (Na2SO4) and evaporated to dryness to give 9 '- (trifluoromethyl) spiro [piperidine-pyrido 4,6'- [2,3-b] pyrrolo [1,2-d] [1 , 4] oxazine] as a solid pale yellow solid (59 mg). ESI-MS m / z calc. 309.1, found 310.3 (M + 1) +; Retention time: 1.32 minutes (3 minutes of execution).

7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbaldehyde 65

Step 1: 1- (7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1’il) -2,2,2-trifluoro

[0170]

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 10

[0171] To a solution of 7 'chlorospiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] (3.5 g, 11.3 mmol) in dry THF (70, 00 ml) at 0 ° C Et3N (6.27 ml, 45.0 mmol) was added dropwise followed by DMAP (1.374 g, 11.25 mmol). 15 (2,2,2 trifluoroacetyl) 2,2,2-trifluoroacetate (2.82 ml, 20.3 mmol) was added and the mixture was stirred for 8 h at room temperature. The solvent was removed and the residue was partitioned between sat. here NaHCO3 (50 ml) and DCM (250 MLL). The layers were separated and the aqueous phase was extracted with DCM (2 x 250 ml). The organics were combined, dried, filtered, purified by column chromatography (3-15% AcOEt in hexanes) to give 1- (7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1, 4] oxazine-4,4'-piperidine] 1'yl) -2,2,2-trifluoro (85%). ESI-MS m / z calc. 370.1, found 370.3 20 (M + 1) +; Retention time: 2.15 minutes (3 minutes of execution).

Step 2: 7-chloro-1 '- (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1- Hyde carbalde-

 25

[0172]

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 35

[0173] POCl3 (1.33 ml, 14.3 mmol) was added dropwise at 0 ° C under an atmosphere of N2 to dry DMF (1.1 ml, 14 mmol). The reaction mixture was left for 20 min at this temperature, which led to the formation of a white solid. A solution of 1- (7'-chlorospiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl) -2,2,2-trifluoro- Ethanone was added (353 mg, 9.535 mmol) in dry DMF (26.5 ml) dropwise and the cooling bath was removed. The reaction was allowed to stir at room temperature for 1 h. The mixture was poured onto ice and 1 M NaOH (25 ml) was added. The pH was adjusted to 7 with 3M HCl and the mixture was extracted with DCM three times. The combined organics were dried, filtered and concentrated. Column chromatography (5-30% AcOEt in hexanes) in residue 45 gave 7-chloro-1 '- (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolidone lo [1,2-d] [1, 4] oxazine-4,4'-piperidine] -1-carbaldehyde. ESI-MS m / z calc. 398.1, found 399.3 (M + 1) +; Retention time: 1.96 minutes (3 minutes of execution).

Step 3: 7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbaldehyde 50

[0174]

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[0175] For 7'-chloro-1- (2,2,2-trifluoroacetyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] 1'carbaldehyde (65 se added 510 mg, 1.28 mmol) dissolved in MeOH (5.1 ml) K2CO3 (371 mg, 2.69 mmol) in one portion at room temperature. Water (2 ml) was added, and the organic solvent was removed in vacuo. The mixture was extracted with DCM (3x10

ml) The organics were combined, dried, filtered and concentrated to give 7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbaldehyde in form of an oil yellow, which is used as such for the next stage. ESI-MS m / z calc. 302.1, found 303.3 (M + 1) +; Retention time: 1.07 minutes (3 minutes of execution).

 5

1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride Step 1: tert-butyl 4-oxospiro [chroman-2,4'-piperidine] 1'-carboxylate methyl

[0176]

 10

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[0177] To a solution of ethyl tert-butyl-4-oxopiperidine-1-carboxylate (93.7 g, 470 mmol) in pyrrolidine (56.0 ml, 673 mmol) and anhydrous MeOH (112 ml) was added 1 -ethanone (2-hydroxyphenyl) (56 ml, 468 mmol). The reaction mixture was stirred at 80 ° C for 2.5 hours. The methanol was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 ml), washed with 1 M aqueous HCl (1 x 150 ml) and brine (2 x 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a yellow oil. This oil was diluted with hexane (400 ml) and heated at 60 ° C until in solution. Once dissolved, the solution was allowed to cool to 25 ° C. The crystals were collected by vacuum filtration and washed with hexane to obtain methyl tert-butyl 4-oxospiro [eridine chromano-2,4'-Pip] 1'-carboxylate (105 g, 70%) as a light yellow solid . ESI-MS m / z calc. 317.2, found 318.2 (M + 1) +; Retention time: 1.78 minutes (3 minutes of execution). 1 H NMR (400 30 MHz, CDCl3)? 7.87 (dd, J = 7.8, 1.5 Hz, 1H), 7.55-7.45 (m, 1H), 7.10-6.90 (m, 2H), 3.95- 3.80 (m, 2H), 3.26 to 3.17 (m, 2H), 2.72 (s, 2H), 2.03 (d, J = 13.0 Hz, 2H), 1.68-1.58 (m, 2H), 1.46 (s, 9H).

[0178] The following compounds were synthesized using the procedure described above: tert-butyl 6-chloro-4-oxospiro [chroman-2,4'-piperidine] -1'-ethyl carboxylate: ESI-MS m / z calc. 351.1, found 352.4 35 (M + 1) +; Retention time: 3.13 minutes (4 min run) 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 2.7 Hz, 1H), 7.44 (dd, J = 8.8 , 2.7 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 3.92-3.83 (m, 2H), 3.24 to 3.13 (m, 2H), 2.71 (s, 2H), 2.01 (d, J = 12.7 Hz, 2H), 1.66-1.56 (m, 2H), 1.46 (s, 9H); tert-butyl 7-chloro-4-oxospiro- [chroman-2,4'-piperidine] 1’-ethyl carboxylate: ESI-MS m / z calc. 351.1, found 352.2 (M + 1) +; Retention time: 3.18 minutes (4 min of execution). 1 H NMR (400 MHz, CDCl 3) δ 7.80 (d, J = 8.4 Hz, 1 H), 7.03 (d, J = 1.8 Hz, 1 H), 6.99 (dd, J = 8 , 4, 1.9 Hz, 40 1H), 3.94-3.83 (m, 2H), 3.25 to 3.16 (m, 2H), 2.04-1.97 (m, 2H), 1.66 -1.56 (m, 2H), 1.46 (s, 9H); tert-butyl 6-methoxy-4-oxospiro [chroman-2,4'-piperidine] 1’-ethyl carboxylate: ESI-MS m / z calc. 347.2, found 348.4 (M + 1) +; Retention time: 3.07 minutes (4 min of execution). 1 H NMR (400 MHz, CDCl 3) δ 7.28 (dd, J = 16.3, 2.4 Hz, 1H), 7.11 (dd, J = 9.0, 2.6 Hz, 1H), 6 , 91 (dd, J = 9.0, 2.0 Hz, 1H), 3.90-3.84 (m, 2H), 3.80 (s, 3H), 3.26 to 3.15 (m, 2H), 2.69 (s, 2H), 2.07-1.97 (m, 2H), 1.64-1.52 (m, 2H), 1.46 (s, 9H). Four. Five

Step 2: 3- (diethoxymethyl) -4-oxospiro [chroman-2,4'-piperidine] 1’-methyl carboxylate

[0179]

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[0180] For triethyl orthoformate (85 ml, 510 mmol) in dry dichloromethane (460 ml) under nitrogen at -10 ° C, BF3OEt2 (65 ml, 510 mmol) was added dropwise. The solution was allowed to warm to 0 ° C and stirred for 10 minutes. The solution was cooled to -78 ° C before the slow dropwise addition of tert-butyl 4-oxospiro [chromane-2,4'-piperidine] - 65 methyl 1'-carboxylate (55 g, 170 mmol) in dichloromethane (25 ml). N-ethyl-N-isopropylpropan-2-amine (100 ml, 600 mmol) was added over a period of 30 minutes, and the mixture was slowly heated to 25 ° C and stirred thereto.

overnight temperature The reaction mixture was diluted with dichloromethane (500 ml) followed by a solution of saturated aqueous sodium bicarbonate (500 ml). The layers were separated, and the organic layer was washed with additional sodium bicarbonate (500 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-25% ethyl acetate in hexane) to provide tert-butyl-3- (diethoxymethyl) -4-oxo-spiro [chromane-2,4'-piperidine ] 1'-methyl carboxylate (72 g, 91%) 5 as an orange oil. ESI-MS m / z calc. 419.5, found 420.3 (M + 1) +; Retention time: 2.50 minutes (3 minutes of execution).

[0181] The following compounds were synthesized using the procedure described above: tert-butyl 6-chloro-3- (ethoxymethyl di -) - 4-oxospiro [chroman-2,4'-piperidine] 1'-ethyl carboxylate: ESI - MS m / z calc. 453.2, 10 found 454.4 (M + 1) +; Retention time: 3.41 minutes (4 min run); tert-butyl 7-chloro-3- (diethoxymethyl) -4-oxospiro [chroman-2,4'-piperid-ine] 1'-ethyl carboxylate: ESI-MS mlz calc. 453.2, found 454.3 (M + 1) +; Retention time: 2.41 minutes (3 minutes of execution); tert-butyl 3- (diethoxymethyl) -6-methoxy-4-oxospiro [chroman-2,4'-piperidine] 1'-ethyl carboxylate: ESI-MS m / z calc. 449.2, found 450.4 (M + 1) +; Retention time: 3.28 minutes (4 min of execution). fifteen

Step 3: 1-methyl-1H-pyro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride

[0182]

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 30

[0183] To methyl tert-butyl 3- (diethoxymethyl) -4-oxo-spiro [chromane-2,4'-piperidine] 1'-carboxylate (72 g, 160 mmol) hydrochloric acid (610 ml of 4 , 0 M, 2.5 mol). The reaction mixture was allowed to stir at 25 ° C for 2 hours. The solvent was removed in vacuo, and the solid obtained was subjected to azeotropic distillation with EtOH (3 x 700 ml). The resulting beige-white solid was dissolved in EtOH (685 ml) at 25 ° C before the addition of N-35 amino-N-methyl-carbamate tert-butyl (29 ml, 200 mmol). The solution was allowed to stir at 25 ° C overnight. To the thick beige-white suspension that formed was added hydrochloric acid (200 ml of 4.0 M, 800 mmol). The mixture was heated to 60 ° C to give a light yellow solution. After 1 hour at 60 ° C, a thick white suspension developed. The suspension was allowed to cool slowly to 25 ° C, and the solids were collected by vacuum filtration. The filter cake was rinsed with a solution of 10% EtOH in hexane (2 x 40,500 ml). The solid was placed in a vacuum oven overnight (20 mm Hg / 45 ° C). 1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydro- chloride (42 g, 78%) was obtained as an off-white solid. ESI-MS m / z calc. 255.3, found 256.3 (M + 1) +; Retention time: 1.30 minutes (3 minutes of execution). 1H NMR (400 MHz, MeOD) δ 7.82-7.76 (m, 1H), 7.61 (s, 1H), 7.40-7.34 (s, 1H), 7.22 to 7.14 (m, 2H), 4.19 (s, 3H), 3.52-3.42 (m, 2H), 3.41-3.33 (m, 2H), 2.39-2.07 (m, 4H) . Four. Five

[0184] The following compounds were synthesized using the procedure described above: 8-chloro-1-methyl-1 H- spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride: ESI-MS m / z calc. 289.1, found 290.3 (M + 1) +; Retention time: 1.29 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 7.74 (d, J = 2.4 Hz, 1 H), 7.43 (s, 1 H), 7.36 (dd, J = 8.7, 2.4 Hz , 1H), 7.21 (d, J = 8.7 Hz, 1H), 4.12 (s, 3H), 3.26 to 3.13 (m, 4H), 2.24 to 2.4 50 (m, 4H); 7-Chloro-1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride: ESI-MS m / z calc. 289.1, found 290.2 (M + 1) +; Retention time: 2.00 minutes (4 min of execution). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.3 Hz, 1H), 7.36 (s, 1H), 7.17-6.97 (m, 2H), 4.15 (s, 3H), 3.48-3.37 (m, 4H), 2.45-2.22 (m, 4H); 8-methoxy-1-methyl-1H-spiro [chromene [4,3-c] pyrazol 4,4'-piperidine] dihydrochloride: ESI-MS m / z calc. 285.2, found 286.5 (M + 1) +; Retention time: 1.14 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 55 1H), 7.12 (d, J = 2.7 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H) , 6.87-6.79 (m, 1H), 4.16 (s, 3H), 3.83 (s, 3H), 3.48-3.39 (m, 4H), 2.48-2 , 18 (m, 4H).

2-Methyl-2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] hydrate chloride

 60

Step 1: (Z) -3- (ethoxymethylene) spiro [chroman-2,4'-piperidine] -4-one

[0185]

 65

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 5

 10

[0186] For tert-butyl 3- (diethoxymethyl) -4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (33.0 g, 78.7 mmol) in toluene (73, 33 ml) acid hydrochloric acid (68.8 ml of 4.0 M in dioxane, 275 mmol) was added. The reaction mixture was heated at 60 ° C for 15 min. Most of the solvent was removed in vacuo, and the brown suspension was filtered using a medium frit. The solids were washed with 500 ml of toluene. The solids were dried to give 3-15 (ethoxymethylene) spiro [chroman-2,4'-piperidine] -4-one (15.4 g, 63%) (Z). ESI-MS m / z calc. 273.1, found 274.3 (M + 1) +; Retention time: 0.85 minutes (3 minutes of execution).

Step 2: 2-methyl-2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

 twenty

[0187]

image113

 25

 30

[0188] (Z) -3- (ethoxymethylene) spiro [chroman-2,4'-piperidine] -4-one (2.46 g, 7.94 mmol) in ethanol (24.6 ml) was treated with methylhydrazine (423 mL, 7.94 mmol). The reaction mixture was heated at 70 ° C for 1 h and then at 100 ° C for 10 min. The mixture was allowed to cool to room temperature overnight. The yellow solid was filtered off and washed with ethanol to give 2-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] (1.20 g, 74%). ESI-35 MS m / z calc. 255.1, found 256.3 (M + 1) +; Retention time: 0.65 minutes. 1H NMR (400 MHz, DMSO) δ 9.01 (s, 2H), 7.75 (s, 1H), 7.61 (dd, J = 7.5, 1.2 Hz, 1H), 7.28 to 7.20 (m, 1H), 7.10-6.99 (m, 2H), 3.89 (s, 3H), 3.28 to 3.18 (m, 4H), 2.18 to 2.2 (m, 4H).

2- (trifluoromethyl) -2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 40

Step 1: tert-butyl 1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’-methyl carboxylate

[0189]

 Four. Five

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 fifty

 55

[0190] A tert-butyl 3- (diethoxymethyl) -4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (15.1 g, 35.9 mmol) and hydrazine (1, 35 ml, 43.1 mmol) in EtOH (120 ml) was added hydrochloric acid (900 ml of 4.0 M in dioxanes, 3.6 mmol). The mixure was heated at 60 ° C for 2 h before it was cooled and the solvent was evaporated. The residue was purified by chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes to give 60 tert-butyl-spiro [1 H -chromen [4,3-c] pyrazol-4,4'-piperidine] 1'-methyl carboxylate (8.76 g, 71%). ESI-MS m / z calc. 341.2, found 342.3 (M + 1) +; Retention time: 1.69 minutes (3 minutes of execution).

Step 2: tert-Butyl 2- (bromodifluoromethyl) -2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'-carboxylate and tert-butyl 1- (bromodifluoromethyl) -1H spiro [ chromene [4,3-c] pyrazol-4,4'-piperidine] 1'-carboxylate 65

[0191]

image115

 5

 10

[0192] A solution of tert-butyl-spiro [1H-chromene [4,3-c] pyrazol-4,4'-piperidine] 1'-methyl carboxylate (1.80 g, 5.26 mmol) in DMF (4.4 ml) was cooled to 0 ° C. Sodium hydride (242 mg, 6.05 mmol) was added and the reaction mixture was stirred for 30 min. Dibromodifluoromethane (11.0 g, 4.78 ml, 52.6 mmol) was added and the reaction mixture was allowed to warm to room temperature for 2 h. The mixture was poured into water and extracted with dichloromethane. The organics were washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by chromatography on silica gel eluting with 100% dichloromethane until the first peak then eluted 0-10% ethyl acetate in dichloromethane to collect the second peak. Peak 1: tert-butyl 20 2- [bromine (difluoro) methyl] spiro [chromene [4,3-c] pyrazol-piperidine 4,4 '] 1'-methyl carboxylate (251 mg, 10%). ESI-MS m / z calc. 469.1, found 470.5 (M + 1) +; Retention time: 2.30 minutes (3 minutes of execution). Peak 2: tert-butyl 1- [bromine (difluoro) methyl] spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'-methyl carboxylate (200 mg, 8%). ESI-MS m / z calc. 469.1, found 470.3 / 472.3 (M + 1) +; Retention time: 1.69 minutes (3 minutes of execution). 25

Step 3: 2- (trifluoromethyl) -2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

[0193]

 30

image116

 35

 40

[0194] tert-butyl-2- [bromine (difluoro) methyl] spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1-methyl carboxylate (251 mg, 0.534 mmol) was dissolved in 2 -isopropoxypropane was added (377 µl) at 0 ° C before pyridine hydrofluoride (250 µl, 2.78 mmol). The reaction mixture was stirred for 15 min and oxomercury (98.3 45 mg, 0.454 mmol) was added in three portions. The reaction was heated to 25 ° C and stirred for 16 h. The reaction mixture was poured into water and extracted with dichloromethane. The organics were washed with sodium bicarbonate and brine, dried over sodium sulfate, and concentrated under reduced pressure to give a mixture of 2- (trifluoromethyl) 2H-spiro [chromene [4,3-c] pyramid zol-4 , 4 'piperidine] (. ESI-MS m / z calc 309.1, found 310.5 (M + 1) +; retention time: 1.22 minutes (3 min run)) and 1H-spiro [chromene [4,3-c] pyrazole 4,4'-piperidine]. fifty

[0195] 1- (trifluoromethyl) -1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] was also prepared using the procedure described above. ESI-MS m / z calc. 309.1, found 310.5 (M + 1) +; Retention time: 1.07 minutes (3 minutes of execution)

 55

1,3-dimethyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride

Step 1: 3- (1-hydroxyethyl) -4-oxospiro [chroman-2,4'-piperidine] 1’-carboxylate

[0196] 60

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 65

[0197] To a solution of N-isopropylpropan-2-amine (0.57 ml, 4.1 mmol) in THF (3.5 ml) was added a solution of n-butyllithium in hexane (2.6 ml 1.6 M, 4.1 mmol) dropwise at -78 ° C under Ar. The solution was allowed to stir at -20 ° C for 15 min and then cooled to -78 ° C. of methyl tert-butyl 4-oxospiro [chromane-2,4'-piperidine] 1'-carboxylate 5 (1.1 g, 3.5 mmol) in THF (3.5 mL) was added at -78 ° C followed by the addition of acetaldehyde (0.22 ml, 3.9 mmol) in THF (3 ml). The reaction was quenched with saturated aqueous ammonium chloride at -78 ° C, heated to 25 ° C and extracted with acatate acetate (2x). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. Purification by silica gel chromatography (20-30% ethyl acetate in hexane) provided 3- (1-hydroxyethyl) -4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (0, 80 g, 63%) 10 as a colorless oil. ESI-MS m / z calc. 361.2, found 362.5 (M + 1) +; Retention time: 1.79 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3)? 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.55-7.48 (m, 1H), 7.06-6.96 (m, 2H), 4.33- 4.23 (m, 1H), 4.10-3.93 (m, 1H), 3.88-3.67 (m, 1H), 3.41-3.27 (m, 1H), 3, 07-2.94 (m, 1H), 2.62 (d, J = 5.2 Hz, 1H), 2.45 (d, J = 8.5 Hz, 1H), 2.20-2.00 (m, 2H), 1.85-1.76 (m, 1H), 1.58-1.49 (m, 1H), 1.46 (s, 9H), 1.26 (t, J = 7 , 1 Hz, 1H) 1.13 (d, J = 6.6 Hz, 3H). fifteen

Step 2: tert-butyl 3-acetyl-4-oxospiro [chroman-2,4'-piperidine] 1’-carboxylate

[0198]

 twenty

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 25

[0199] A mixture of tert-butyl-3- (1-hydroxyethyl) -4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (600 30 mg, 1.66 mmol) and periodinan Dess-Martin (8.3 ml of 0.30 M, 2.5 mmol) was stirred at 25 ° C for 5 h. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3 (2x), 5% Na2S2O3 (2x), brine, dried over MgSO4, filtered and concentrated to dryness. Purification by silica gel chromatography provided tert-butyl 3-acetyl-4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (435 mg, 73%). ESI-MS m / z calc. 359.2, found 360.4 (M + 1) +; Retention time: 2.84 minutes (4 min of execution). 1H NMR 35 (400 MHz, CDCl3)? 7.86 (dd, J = 7.8, 1.5 Hz, 1H), 7.60-7.52 (m, 1H), 7.7 to 7.1 (m, 2H), 4.10-3.79 ( m, 2H), 3.76 (s, 1H), 3.29 to 3.3 (m, 2H), 2.27 (s, 3H), 2.10-1.85 (m, 3H), 1.68-1 , 58 (m, 1H), 1.47 (s, 9H).

Step 3: 1,3-dimethyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride

 40

[0200]

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 Four. Five

 fifty

[0201] A mixture of tert-butyl-3-acetyl-4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (250 mg, 0.70 mmol), tert-butyl N-amino- N-methylcarbamate (120 ml, 0.84 mmol) and p-toluene sulfonic monohydrate (27 mg, 0.14 mmol) in ethanol (8 ml) was heated at 80 ° C overnight. More tert-butyl-N-amino-N-methyl-55 carbamate (120 µl, 0.84 mmol) was added and the mixture was heated at 80 ° C for 6.5 h, then another portion of tert-butyl N-amino-N-methyl- methyl carbamate (120 µL, 0.84 mmol) was added and the mixture was heated at 80 ° C for 2 h. HCl (0.87 ml of 4.0 M in dioxane, 3.5 mmol) was added and the mixture was stirred at 80 ° C for 1 h. After cooling, the precipitate was collected by filtration and washed with cold EtOH to provide 1,3-dimethyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] di- (295 mg ,> 100%, may contain some methyl hydrazine HCl salt) 60 as a solid. ESI-MS m / z calc. 269.2, found 270.5 (M + 1) +; Retention time: 1.11 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) delta 7.71 (dd, J = 7.8, 1.3 Hz, 1H), 7.33-7.27 (m, 1H), 7.17 to 7.14 (m, 1H) , 7.11 to 7.5 (m, 1H), 4.02 (s, 3H), 3.28 to 3.15 (m, 4H), 2.40-2.30 (m, 2H), 2.23 (s, 3H), 2.07-1.97 (m 2H).

1H-Spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 65

Step 1: benzyl 4-oxospiro [chroman-2,4'-piperidine] 1’-methyl carboxylate

[0202]

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 10

[0203] A mixture of 1-ethanone (2-hydroxyphenyl) (50 g, 0.37 mol), methyl benzyl 4-oxopiperidine-1-carboxylate (94 g, 0.40 mol), pyrrolidine (61 ml, 0 , 73 mol) and methanol (24 ml) was heated at 80 ° C for 20 hours. After cooling to 15-25 ° C, the reaction mixture was diluted with ethyl acetate (1000 ml) and partitioned with 1M aqueous HCl (500 ml). The organic phase was washed with aqueous 1M HCl (2 x 500 ml), water (500 ml), saturated sodium chloride solution (500 ml), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate in hexane) provided benzyl 4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (105 g, 81% yield) Like a yellow oil ESI-MS m / z calc. 351.2, found 352.2 (M + 1) +; Retention time: 2.30 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3)? 7.88 (d, J = 7.8 Hz, 1H), 7.54-7.47 (m, 1H), 7.44-7.29 (m, 5H), 7.02 (dd, J = 14.8, 7.8 Hz, 2H), 5.16 (s, 2H), 4.10-3.90 (m, 2H), 3.36-3.24 (m, 2H), 2.73 (s, 2H), 2.12-2.00 (m, 2H), 1.71-1.58 (m, 2H).

Step 2: Benzyl 3- (diethoxymethyl) -4-oxospiro [chroman-2,4'-piperidine] 1’-methyl carboxylate 25

[0204]

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 35

[0205] To a solution of triethyl orthoformate (71 ml, 0.43 mol)] in dichloromethane (250 ml) at -10 ° C under nitrogen atmosphere was added boron trifluoride diethyl ether (54 ml, 0.43 mol) drop by drop for 30 minutes. The mixture was allowed to warm to 0 ° C and stirring was continued at 0 ° C for 15 minutes. Then, the mixture was cooled to -78 ° C and a solution of methyl benzyl 4-oxospiro [chroman-2,4'-piperidine] 1'-carboxylate (50 g, 0.14 mol) in dichloromethane (250 ml) was added dropwise over 1 hour, followed by N-ethyl-N-isopropylpropane-2-amine (87 ml, 0.50 mol) for 1 hour at -78 ° C. The mixture was continued stirring at -78 ° C for 30 minutes and then at 25 ° C for 15 hours. The reaction mixture was diluted with dichloromethane (750 ml) and then partitioned with saturated sodium bicarbonate solution (500 ml). The organic phase was washed with water (500 ml), saturated sodium chloride solution (500 ml), dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-50% ethyl acetate in hexane) provided benzyl 3- (diethoxymethyl) -4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (50 g, 78%) as a yellow oil. ESI-MS m / z calc. 50 453.2, found 408.5 (M + 1 OEt) +; Retention time: 2.08 minutes (3 minutes of execution).

Step 3: Benzyl 3- (hydroxymethylene) -4-oxospiro [chroman-2,4'-piperidine] 1’-methyl carboxylate

[0206] 55

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[0207] Iodine (2.88 g, 11.4 mmol) was added slowly to a solution of benzyl 3- (diethoxymethyl) -4-oxospiro 65

[chroman-2,4'-piperidine] 1'-methyl carboxylate (20.6 g, 45.4 mmol) in acetone (515 ml) and the mixture was stirred at 35 ° C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography of

silica gel (0-40% ethyl acetate in hexane) to give benzyl 3- (hydroxymethylene) -4-oxospiro [chroman-2,4'-piperidine] -1 'carboxylate (15.2 g, 88%) . ESI-MS m / z calc. 379.1, found 380.3 (M + 1) +; Retention time: 2.00 minutes (3 minutes of execution).

Step 4: Benzyl 1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’-methyl carboxylate 5

[0208]

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 fifteen

[0209] A solution of benzyl 3- (hydroxymethylene) -4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate 20 (1.95 g, 5.10 mmol) and hydrazine (161 ml, 5.10 mmol) in EtOH (39 ml) was stirred at room temperature for 1 hour and then at 50 ° C for 3 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (10-100% ethyl acetate in hexane) to give benzyl 1H-spiro [chromene- [4,3-c] pyrazole-4.4 '-piperidine] -1'-ethyl carboxylate (1.11 g, 58%). ESI-MS m / z calc. 375.2, found 376.3 (M + 1) +; Retention time: 1.71 minutes (3 minutes of execution). 25

Step 5: 1H-Spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

[0210]

 30

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 40

[0211] A mixture of spiro benzyl [1H-chromene [4,3-c] pyrazol-4,4'-piperidine] 1'-methyl carboxylate (1.11 g, 2.96 mmol) and palladium (10% by weight on carbon, 157 mg, 0.15 mmol) in MeOH (15 ml) was established under hydrogen (1 45 atm) and stirred vigorously at room temperature for 3 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated to give 1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] (570 mg, 80%). ESI-MS m / z calc. 241.1, found 242.5 (M + 1) +; Retention time: 0.42 minutes (3 minutes of execution).

1- (2-Methoxyethyl) -1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 50

Step 1: 3- (hydroxymethylene) -4-oxospiro [chroman-2,4'-piperidine] 1’-methyl carboxylate

[0212]

 55

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 65

[0213] NaH (1.89 g, 47.3 mmol) was added in small portions to a mixture of methyl tert-butyl-4-oxospiro [chroman-2,4'-piperidine] 1'-carboxylate (3, 0 g, 9.5 mmol), Et2O (75 ml) and MeOH (120 µl) at rt. The mixture was allowed to stir for 1 h before ethyl formate was added dropwise (9.2 ml, 110 mmol). The mixture was allowed to stir at 25 ° C overnight before it was quenched with 1M aqueous HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (0 to 100% ethyl acetate in hexanes) provided 3- (hydroxymethylene) -4-oxospiro [cro-man-2,4'-piperidine] 1'-methyl carboxylate (1.2 g, 36%) as a light yellow solid. ESI-MS m / z calc. 345.2, found 246.2 (M + 1-Boc) +; Retention time: 2.62 minutes (4 min of execution). 1 H NMR (400 MHz, CDCl 3) δ 15.13 (d, J = 8.3 Hz, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.88 (dd, J = 7 , 8, 1.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8, 2 Hz, 1H), 4.10-3.95 (m, 2H), 3.25 to 3.15 10 (m 2H), 2.15 (d, J = 12.7 Hz, 2H), 1.80-1, 66 (m, 2H), 1.47 (s, 9H).

Step 2: 1- (2-methoxyethyl) -1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

[0214] 15

[0215] A mixture of tert-butyl-3- (hydroxymethylene) -4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (200 mg, 0.58 mmol) and tert-butyl N- amino-N - (2-methoxyethyl) carbamate (130 mg, 0.70 mmol) was left in ethanol (5 ml) with stirring at rt for 2 h. A solution of hydrogen chloride in 1,4-dioxane (150 mL of 4.0 M, 0.60 mmol) was added and the mixture was stirred at 50 ° C for 1.5 h before it was concentrated in vacuo to give 1- (2-methoxyethyl) -1H-spiro [chromene [4,3-c] pyramid zol-4,4'-piperidine] (85 mg, 44%). ESI-MS m / z calc. 299.2, found 300.3 (M + 1) +; Retention time: 0.95 minutes (3 minutes of execution).

 25

1- (2,2,2-trifluoroethyl) -1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] and 2- (2,2,2-trifluoroethyl) - 2H-spiro [ chromene [4,3-c] pyrazol-4,4'-piperidine]

[0216]

 30

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 40

[0217] A mixture of tert-butyl-3- (hydroxymethylene) -4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (100 mg, 0.29 mmol) and 2.2.2 -trifluoroethylhydrazine (57 mg, 0.35 mmol) was left in ethanol (2.5 ml) with stirring at 25 ° C for 2 h. A solution of hydrogen chloride in 1,4-dioxane (72 ml of 4.0 M, 0.29 mmol) was added and the mixture was stirred at 50 ° C for 1.5 h before it was concentrated in vacuo to give a mixture of 1- (2, 2,2-trifluoroethyl) -1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] and 2- (2,2,2-trifluoroethyl) 2H -spiro [chromene [4,3-c] pyrazol-4,4'-45 piperidine] (60 mg, 58%). ESI-MS m / z calc. 323.1, found 324.2 (M + 1) +; Retention time: 1.11 minutes (3 minutes of execution).

(4-tert-Butyl-3-methoxyphenyl) (1-methyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone and (4-tert-butyl -3-methoxyphenyl) (2-methyl-2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'yl) methanone

Step 1: 1- (4-tert-Butyl-3-methoxybenzoyl) piperidine-4-one

[0218]

 55

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[0219] A solution of 4-tert-butyl-3-methoxybenzoyl chloride (650 mg, 4.2 mmol) in toluene (4.4 ml) and a solution of NaOH (1.1 ml of 4.0 M, 4.4 mmol) were added simultaneously dropwise to a solution of benzoyl 4-tert-butyl-3-methoxychloride (960 mg, 4.2 mmol) in NaOH (2.1 mL of 2.0 M, 4.2 mmol) at 25 ° C. The mixture was stirred for 90 min before the toluene was removed in vacuo. The alkaline phase was extracted with dichloromethane (3x). The organics were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 1- (4-tert-butyl-3- methoxybenzoyl) piperidine-4-one (1.2 g, 94 %). ESI-MS m / z calc. 289.2, found 290.3 (M + 1) +; Retention time: 1.60 minutes (3 minutes of execution).

Step 2: 1 ’- (4-tert-Butyl-3-methoxybenzoyl) spiro [chroman-2,4'-piperidine] -4-one

 twenty

[0220]

 25

 30

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 35

[0221] 1- (2-Hydroxyphenyl) ethanone (260 µl, 2.2 mmol) was added portionwise at room temperature to pyrrolidine (370 40 µl, 4.4 mmol) followed by addition in portions of 1- (4- tert-butyl-3-methoxy-benzoyl) piperidine-4-one (630 mg, 2.2 mmol). Anhydrous methanol (140 µl) was added and the suspension was heated at 80 ° C for 3 h. Then, the mixture was partitioned between ethyl acetate and 1M aqueous HCl. The layers were separated and the aqueous layer was discarded. Saturated aqueous sodium bicarbonate was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by cro-45 column chromatography (0-25% ethyl acetate / hexanes) to give 1 '- (4-tert-butyl-3-methoxybenzoyl) spiro [chroman-2,4'-piperidine] -4-one (840 mg, 94%) as a light yellow solid. ESI-MS m / z calc. 407.2, found 408.2 (M + 1) +; Retention time: 2.07 minutes (3 minutes of execution).

Step 3: 1 ’- (- Butyl-3-methoxybenzoyl 4-tert) -3- (hydroxymethylene) spiro [chroman-2,4'-piperidine] -4-one 50

[0222]

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 60

[0223] NaH (57 mg, 1.4 mmol) was added in small portions to a mixture of 1 '- (4-tert-butyl-3-methoxy-benzoyl) spiro [melena-2,4'-piperidine cro- ] - 4-one (250 mg, 0.61 mmol) in THF (2.5 ml) at 25 ° C. A solution of 65 ethyl formate (74 µl, 0.90 mmol) in THF (0.5 mL) was added and the mixture was allowed to stir at 25 ° C for 3 h before it was interrupted with 0, aqueous HCl 5 M. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x).

The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 1 '- (4-tert-butyl-3- methoxybenzoyl) -3- (hydroxymethylene) spiro [chroman-2,4' -piperidine] -4-one (50 mg, 19%) as an orange oil. ESI-MS m / z calc. 435.2, found 436.2 (M + 1) +; Retention time: 1.87 minutes (3 minutes of execution).

 5

Step 4: (4-tert-Butyl-3-methoxyphenyl) (1-methyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'yl) methanone and (4-tert -butyl-3-methoxyphenyl) (2-methyl-2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

[0224] 10

mixture of 1 '- (4-tert-butyl-3-methoxy-benzoyl) -3- (hydroxymethylene) spiro [chromane-2,4'-piperidine] -4-one (50 mg, 0.12 mmol) and methylhydrazine (6.7 ml, 0.13 mmol) in ethanol (1.6 ml) was allowed to stir at 25 ° C for 3 h. The mixture was filtered and then purified by reverse phase HPLC to provide (4-tert-butyl-3-methoxy-phenyl) - (2-spiro 15 methyl- [chromene [4,3-c] pyrazole-4.4 '-piperidine] 1'yl) methanone (8 mg, 15%) (peak 1) and (4-tert-butyl-3-methoxy-Phenyl) - (1-methylstyrene [chromene [4,3-c] pyrazole -4,4'-piperidine] 1'il) methanone (peak 2). (4-tert-Butyl-3-methoxy-Phenyl) - (2-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'yl) methanone: ESI-MS m / z calc. 445.2, found 446.3 (M + 1) +; Retention time: 1.87 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.2 to 7.20 (m, 1H), 7.17 to 7.10 (m, 1H ), 7.06-6.94 (m, 2H), 6.93-6.83 (m, 2H), 4.25 to 4.5 20 (m, 1H), 4.02-3.93 (m, 1H) , 3.85-3.75 (m, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.55-3.40 (m, 1H), 2.37-2 , 18 (m, 2H), 1.35 (s, 9H), 1.30 to 1.15 (m, 2H). (4-tert-Butyl-3-methoxy-phenyl) - (1-Methylspiro- [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'yl) methanone: ESI-MS m / z calc . 445.2, found 446.3 (M + 1) +; Retention time: 2.10 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.18 (t, J = 7.7 Hz , 1H), 7.08-6.88 (m, 3H), 6.84 (t, J = 7.5 Hz, 1H), 4.43-4.32 (m, 1H), 4.20 to 4.5 ( m, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.76-25 3.55 (m, 2H), 2.26 to 2.25 (m, 2H), 1.80- 1.50 (m, 2H), 1.36 (s, 9H).

(4-Methoxy-3- (trifluoromethyl) phenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’il) methanone

Step 1: 1- (4-methoxy-3- (trifluoromethyl) benzoyl) piperidine-4-one 30

[0225]

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 40

[0226] A solution of 4-methoxy-3- (trifluoromethyl) benzoyl (4.00 g, 16.8 mmol) in toluene (16 ml) and a solution of 45 NaOH (3.8 ml of 4.0 M, 15 mmol) were added simultaneously dropwise to a solution of piperidine-4,4-diol hydrochloride (2.30 g, 15.2 mmol) in NaOH (7.6 mL of 2.0 M, 15 mmol) at 25 ° C The mixture was stirred for 90 min before the toluene was removed in vacuo. The alkaline phase was extracted with dichloromethane (3 times). The organics were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to provide 1- (4-methoxy-3- (trifluoromethyl) benzoyl) piperidine-4-one (4.2 g, 91%) . ESI-MS m / z calc. 301.3, found 302.2 (M + 1) +. 50 Retention time: 0.95 minutes (3 minutes of execution). 1 H NMR (400 MHz, CDCl 3) δ 7.77 (d, J = 1.9 Hz, 1 H), 7.70 (dd, J = 8.6, 2.1 Hz, 1 H), 7.09 (d , J = 8.6 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 4H), 2.55 (s, 4H)

Step 2: 1 ’- (4-methoxy-3- (trifluoromethyl) benzoyl) spiro [chroman-2,4'-piperidine] -4-one

[0227]

 5

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 fifteen

[0228] 1- (2-Hydroxyphenyl) ethanone (1.80 g, 13.3 mmol) was added portionwise at 25 ° C to pyrrolidine (2.20 ml, 26.6 mmol) followed by addition in portions of 1 - (4-Methoxy-3 - (trifluoromethyl) benzoyl) piperidine-4-one (4.00 g, 13.3 mmol). Then, anhydrous methanol (868 µl) was added and the red suspension was heated at 80 ° C for 3 hours. The reaction was cooled to 25 ° C and stirred overnight. Ethyl acetate (5 ml) and 1 M and HCl (ac, 5 ml) were added. The aqueous layer was separated and discarded. 1M NaOH (aq, 5 ml) was added and the aqueous layer was separated and discarded. A brine solution (10 ml) was added and the aqueous layer was separated and discarded. The organic layer was dried over Na2SO4, filtered and the solvent evaporated to provide an oil. The crude oil was dissolved in dichloromethane and purified by column chromatography using 0-50% ethyl acetate / hexanes to provide 1 '- (4-methoxy-3- (trifluoromethyl) benzoyl) spiro [chroman-2,4' - piperidine] -4-one (4.4 g, 79%) as an off-white solid. ESI-MS m / z calc. 419.4, found 420.2 (M + 1) +. Retention time: 2.63 minutes (4 25 min of execution).

Step 3: (Z) -3- (hydroxymethylene) -1 ’- (4-methoxy-3- (trifluoromethyl) benzoyl) spiro [chroman-2,4'-piperidine] -4-one

[0229] 30

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 40

[0230] NaH (120 mg, 3.0 mmol) was added to a mixture of 1 '- (4-methoxy-3- (trifluoromethyl) benzoyl) spiro [chroman-2,4'-piperidine] -4-one ( 250 mg, 0.60 mmol) in diethyl ether (6.2 ml) at 0 ° C. MeOH (0.01 ml) was added and the mixture was allowed to warm to 25 ° C for 1 h. The mixture was cooled to 0 ° C before ethyl formate (600 ml, 7.4 mmol) was added slowly. The mixture was allowed to stir at 25 ° C overnight. The mixture was partitioned between ethyl acetate slowly and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (twice). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a crude mixture containing the desired product that was taken for the next step without further purification. ESI-MS m / z calc. 447.4, found 448.1 (M + 1) +. Retention time: 2.38 minutes (4 min of execution). fifty

Step 4: (4-methoxy-3- (trifluoromethyl) phenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

[0231] 55

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 65

Tert-butyl N-amino-N-methyl-carbamate (21 mg, 0.14 mmol) was added to a mixture of (Z) -3- (hydroxymethylene) -1 '- (4- methoxy-3- (trifluoromethyl) benzoyl) spiro [chroman-2,4'-piperidine] -4-one (53 mg, 0.12 mmol) in ethanol (1.6 ml) at 25 ° C. The mixture was allowed to stir at 25 ° C for 2 hours before hydrogen chloride, (150 µl of 4.0 M, 0.60 mmol) was added. The mixture was heated at 50 ° C for 1 h before it was cooled to 25 ° C and concentrated in vacuo. The residue was taken up in DMF and purified by reverse phase HPLC to give (4-methoxy-3- (trifluoromethyl) phenyl) (1-5 methyl-1H-spiro [chromene [4,3-c] pyrazole-4, 4 'piperidine] 1' il) methanone. ESI-MS m / z calc. 457.2, found 458.1 (M + 1) +. Tention Re-time: 2.66 minutes (4 min of execution). 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.43 (s, 1H), 7.3 6 (t, J = 7.2 Hz, 1H), 7.16 to 7.3 (m, 3H), 4.30 (s, 3H), 3.97 (s, 3H), 3.51 (s, 2H), 2.73 (s, 2H), 2.16 (s, 2H), 1.92 (s, 2H).

 10

(4-methoxy-3- (trifluoromethyl) phenyl) (1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’il) methanone

[0232]

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[0233] A mixture of 3- (hydroxymethylene) -1'- [4-methoxy-3- (trifluoromethyl) benzoyl] spiro [chromane-2,4'-piperidine] -4-one (54 mg, 0.12 mmol ) and hydrazine (3.8 µL, 0.12 mmol) in ethanol (1.7 mL) was allowed to stir for 1 hour at 25-25 ° C, then for 2.5 hours at 50 ° C. The mixture was cooled and then concentrated in vacuo. The residue was taken up in DMF and purified by reverse phase HPLC to give (4-methoxy-3- (trifluoromethyl) phenyl) (1H-spiro [chromene [4,3-c] pyrazole 4,4'-piperidine] 1 'il) methanone. ESI-MS m / z calc. 443.2, found 444.1 (M + 1) +; Retention time: 2.40 minutes (4 min of execution). 1 H NMR (400 MHz, CDCl 3) δ 9.15-8.90 (m, 1 H), 7.73 (s, 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.58 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.33-7.18 (m, 1H), 7.04 (dd, J = 18.8, 8.3 Hz, 2H), 6.91 (t, J = 7.5 30 Hz, 1H), 6.05-5.60 (m, 1H), 4.50-4.05 (m, 2H), 4, 08-3.55 (m, 3H), 3.97 (s, 3H), 2.50-2.32 (m, 2H).

1-ethyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

Step 1: tert-butyl 1,3-dioxoisoindolin-2-yl (ethyl) carbamate 35

[0234]

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 Four. Five

[0235] methyl tert-butyl N- (1,3-dioxoisoindolin-2-yl) carbamate (1.0 g, 3.8 mmol), iodoethane (460 µL, 5.7 mmol), potassium carbonate (2 , 1 g, 15 mmol), and triethyl ammonium benzyl bromide (210 mg, 0.80 mmol) were combined in acetonitrile (15 ml) and heated at 50 ° C for 48 h. The reaction mixture was diluted with water (30 ml) and extracted with ether (3 x 15 ml). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness. The crude material was purified by column

chromatography (0-20% ethyl acetate in hexanes) to provide tert-butyl-1,3-dioxoisoindolin-2-yl (ethyl) -carbamic (0.79 g, 71%). ESI-MS m / z calc. 290.1, found 291.3 (M + 1) +; Retention time: 1.64 minutes (3 minutes of execution). 1 H NMR (400 MHz, CDCl 3) δ 7.98-7.85 (m, 2H), 7.84-7.69 (m, 2H), 3.86-3.57 (m, 2H), 1, 52 (s, 3H), 1.32 (s, 6H), 1.27 to 1.4 (m, 3H). 55

Step 2: tert-butyl-1 ethylhydrazinecarboxylate

[0236]

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[0237] tert-butyl 1,3-dioxoisoindolin-2-yl (ethyl) -carbamic (790 mg, 2.7 mmol) in THF (16 ml) was cooled to 0 ° C and methylhydrazine (250 µL, 4.8 mmol) was added. The reaction mixture was heated to room temperature and stirred until all the starting material was consumed. The mixture was filtered through a bed of Celite and the solvent was evaporated. The residue was purified by column chromatography (0-10% methanol in dichloromethane) to provide 1-ethyl tert-butyl hydrazinecarboxylate (320 mg, 74%). Retention time: 1.13 minutes (3 minutes of execution).

Step 3: benzyl 1-ethyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-methyl carboxylate

 10

[0238]

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[0239] A mixture of tert-butyl-1-ethylhydrazinecarboxylate (320 mg, 2.0 mmol) and benzyl 3- (hydroxymethylene) -4-oxo-spiro [chromane-2,4'-piperidine] 1'-carboxylate methyl (770 mg, 2.0 mmol) was left in dichloroethane (5 mL) with stirring at 25 ° C with TFA (78 µl, 1.0 mmol) for 2 h. Once the LC / MS analysis showed complete imine formation, more TFA was added to deprotect the hydrazine and cycle the product. The reaction was diluted with dichloromethane, and aqueous sodium bicarbonate was added with stirring. The layers were separated and the organic extracts were further washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography (0 to 100% ethyl acetate in hexanes) to give benzyl 1-ethyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine ] -1'-methyl carboxylate (530 mg, 65%). ESI-MS m / z calc. 403.2, found 404.7 (M + 1) +; 30 retention time: 1.94 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.6 Hz, 1H), 7.40-7.29 (m, 4H), 7.29 to 7.19 (m, 2H), 7.10 -6.99 (m, 2H), 5.16 (s, 2H), 4.47 (q, J = 7.3 Hz, 2H), 4.15-3.95 (m, 2H), 3, 45-3.26 (m, 2H), 2.15 to 2.3 (m, 2H), 1.88-1.78 (m 2H), 1.54 (t, J = 7.3 Hz, 4H).

Step 4: 1-ethyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 35

[0240]

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 Four. Five

[0241] Benzyl 1-ethyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'-methyl carboxylate (530 mg, 1.3 mmol) was stirred in methanol ( 9.5 ml) with Pd / C (70 mg, 0.070 mmol) under a hydrogen atmosphere for 16 h. The reaction was filtered through a syringe filter and the solvent was evaporated to give 1-ethyl-1H-spiro [chromene [4,3-c ridine] pyrazole-4,4'-on pipe] (350 mg, 99 %). ESI-MS m / z calc. 269.2, found 270.5 (M + 1) +; Retention time: 0.80 minutes (3 minutes of execution).

 55

9-Aza-1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine].

Step 1: 1- (3-hydroxypyridin-2-yl) ethanone

[0242] 60

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[0243] A solution of MeMgBr (390 ml of 1.4 M in toluene / THF (75:25), 540 mmol) was heated to 60 ° C and a solution of 3-hydroxypyridine-2-carboxylic (15 g, 110 mmol) and triethylamine (15 ml, 110 mmol) in THF (75 ml) was added dropwise over 3 hours. Then, the resulting mixture was stirred for 2 hours at 60 ° C. The reaction mixture was cooled in an ice / brine bath and methyl formate (13 ml, 220 mmol) was added keeping the internal temperature below 20 ° C. The reaction mixture was acidified to pH 5-6 with 1M aqueous HCl, and the layers were separated, and the aqueous layer was extracted with ethyl acetate (3x). The organic phases were combined, washed with brine, dried over sodium sulfate and evaporated to dryness to provide 1-ethanone (3-hydroxypyridin-2-yl) (4.0 g, 27%). ESI-MS m / z calc. 137.1, found 138.3 (M + 1) +; Retention time: 0.62 minutes (3 minutes of execution).

 10

Step 2: tert-butyl 4 'oxo-3', 4'-dihydrospiro [piperidine-4,2 '-pyran [3,2-b] pyridine] -1-ethyl carboxylate

[0244]

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[0245] A solution of ethyl 1-ethanone (3-hydroxy-2-pyridyl) (2.4 g, 18 mmol), ethyl tert-butyl 4-oxopiperidine-1-carboxylate (3.5 g, 18 mmol) and Pyrrolidine (1.5 ml, 18 mmol) in MeOH (12 ml) was stirred at 80 ° C for 2 hours. After cooling to room temperature 1 M aqueous HCl was added until pH 4 was reached and the reaction mixture was stirred for another 30 minutes. The methanol was evaporated, the rest of the mixture was poured into water, and the pH was adjusted to pH 7 with saturated aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate (3x), washed with brine (3x), dried over sodium sulfate and evaporated to dryness. Purification by silica gel chromatography (50-100% ethyl acetate in hexane) provided tert-butyl 4 'oxo-3', 4'-dihydrospiro- [piperidine-4.2 '-35 pyran [3.2 -b] ethyl pyridine] -1-carboxylate (2.2 g, 40%) as an orange oil that solidified at rest. ESI-MS m / z calc. 318.2, found 319.3 (M + 1) +; Retention time: 1.16 minutes (3 minutes of execution).

Step 3: tert-butyl 3 '- (hydroxymethylene) -4'-oxo-3', 4'-dihydrospiro- [piperidine-4,2 '-pyran [3,2-b] pyridine] -1-carboxylate 40

[0246]

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[0247] To a suspension of sodium methoxide (594 mg, 11.0 mmol) in THF (5 ml) was added a suspension of 4'-oxo-3 ', 4'-dihydrospiro [piperidine-4.2 tert-butyl '- pyrano [3,2-b] pyridine] -1-ethyl carboxylate (1.0 g, 3.1 mmol) in THF (10 ml), followed by ethyl formate (2.5 ml, 31 mmol) and the reaction mixture was stirred at 25 ° C for 3 hours. Additional sodium methoxide (170 mg, 3.1 mmol) and ethyl formate (0.25 ml, 3.1 mmol) were added and the reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (4x). The aqueous layer was saturated with solid NaCl and extracted with ethyl acetate (5x). The organic layers were combined and dried over sodium sulfate. The precipitate formed was filtered and washed with ether (2x). The solid product was dissolved in hot dichloromethane / MeOH (1: 1) and filtered, and the filter cake was rinsed with additional hot dichloromethane / MeOH (1: 1) (4x) to dissolve the entire product and remove the sulfate from solid sodium The combined filtrates 65 were evaporated to provide tert-butyl-3 '- (hydroxymethylene) -4'-oxo-3', 4'-dihydrospiro- [piperidine-4,2 '-pyran [3,2-b] pyridine] -1 methyl carboxylate (560 mg, 52%) as a yellow solid. ESI-MS m / z calc. 346.2,

found 347.5 (M + 1) +; Retention time: 0.98 minutes (3 minutes of execution).

Step 4: 9-Aza-1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

[0248] 5

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[0249] tert-butyl 3 '- (hydroxymethylene) -4'-oxo-3', 4'-dihydrospiro- [piperidine-4,2 '-pyran [3,2-b] pyridine] -1-carboxy-late (160 mg, 0.46 mmol), tert-butyl N-amino-N-methyl-carbamate (68 mg, 0.46 mmol) and HCl in dioxane (0.64 ml of 4.0 M, 2.5 mmol ) in EtOH (1.6 ml) was heated at 50 ° C for 3 hours. Another portion of HCl in dioxane (0.64 ml of 4.0 M, 2.5 mmol) was added and the reaction mixture was stirred at 50 ° C for 4 hours. The reaction mixture was poured into saturated aqueous sodium carbonate and extracted with 10% MeOH in dichloromethane (3x). The organic phases were combined, dried over sodium sulfate and concentrated to give 9-aza-1-methyl-1 H-spiro [chromene [4,3-c] pyrazole 4,4'-piperidine]. ESI-MS m / z calc. 256.1, found 257.3 (M + 1) +; Retention time: 0.64 minutes (3 minutes of execution).

 25

2-Methylspiro [chromene [3,4-d] thiazol-4,4'-piperidine] hydrochloric acid

Step 1: (E) tert-Butyl 4- (hydroxyimino) spiro [chroman-2,4'-piperidine] 1’-methyl carboxylate

[0250] 30

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 40

of methyl tert-butyl 4-oxospiro [chroman-2,4'-piperidine] 1'-carboxylate (450 mg, 1.41 mmol) and hydroxylamine 50% by weight in water (940 µl of 50% w / v, 14 mmol) were combined in methanol (9.0 ml) and heated to reflux. After 24 hours, the reaction mixture was diluted with ethyl acetate and washed with water. The organics were dried over MgSO4, filtered and evaporated to dryness to give (E) tert-butyl-4- (hydroxyimino) spiro 45 [chroman-2,4'-piperidine] 1'-methyl carboxylate (450 mg, 98%) ESI-MS m / z calc. 332.4, found 333.3 (M + 1) +; Retention time: 1.68 minutes (3 minutes of execution).

Step 2: (E) tert-Butyl 4- (tosyloxyimino) spiro [chroman-2,4'-piperidine] 1’-methyl carboxylate

 fifty

[0251]

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[0252] A mixture of tert-butyl (4E) -4-hydroxyiminospiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (448 mg, 1.34 mmol) and 4-methylbenzene chloride (514 mg , 2.70 mmol) were stirred in pyridine (2.1 ml) at 0 ° C for 6 hours. The reaction mixture was poured onto ice and the mixture was extracted with ethly acetate. The organics were dried over sodium sulfate and evaporated to give (E) tert-butyl-4- (tosyloxyimino) spiro [chroman-2,4'-piperidine] 1'-methyl carboxylate (532 mg, 81%) . ESI-MS m / z calc. 486.2, found 487.5 (M + 1) +; Retention time: 2.20 minutes (3 minutes of execution).

Step 3: tert-butyl 3-amino-4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate 10

[0253]

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tert-butyl (4E) -4- (p-tolylsulfonyloxyimino) spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (3.36 g, 6.90 mmol) was dissolved in toluene (40 ml) and cooled in an ice bath. Sodium ethoxide (2.5 ml of 21% w / v, 7.6 mmol) was added dropwise and the reaction was allowed to warm to room temperature overnight. The reaction was filtered through a bed of Celite. The celite was washed with a 1 N solution of HCl and the resulting two layers separated. The aqueous layer was neutralized with 4M NaOH and extracted with ethyl acetate. The organics were dried over sodium sulfate and evaporated to give methyl tert-butyl-3-amino-4-oxospiro [chroman-2,4'-piperidine] 1'-carboxylate (33 mg, 1%). ESI-MS m / z calc. 332.4, found 333.7 (M + 1) +; Retention time: 1.14 minutes (3 minutes 40 of execution).

Step 4: 2-methylpyrro [chromene [3,4-d] thiazol-4,4'-piperidine]

[0254] 45

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tert-butyl 3-amino-4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (33 mg, 0.10 mmol), acetyl chloride (7.8 µl, 0.11 mmol), and N, N diethylethanamine (28 µl, 0.20 mmol) were combined in dichloromethane and stirred

for 30 minutes The reaction mixture was diluted with dichloromethane and washed with 1N HCl, a saturated solution of NaHCO3, and brine. The organics were dried over sodium sulfate and evaporated to dryness. The residue was stirred in toluene with the Lawesson reagent (40 mg, 0.10 mmol) at 70 ° C overnight. The reaction was diluted with dichloromethane and filtered through a celite pad. The filtrate was evaporated and stirred with HCl in dioxane (1.0 mL of 4.0 M, 4.0 mmol) for 1 h at room temperature. The reaction mixture was evaporated to dryness to produce 2-methylpyrro [chromene [3,4-d] thiazol-4,4'-piperidine] (27 mg, 20%). ESI-MS m / z calc. 272.4, found 273.1 (M + 1) +; Retention time: 1.05 minutes (3 minutes of execution).

1H-spiro [chromene [4,3-d imidazol-4,4'-piperidine]]

 10

[0255]

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[0256] Benzyl 3-amino-4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (600 mg, 1.64 mmol) was added portion-prudent formamide (3.0 ml, 75 mmol) and the mixture was heated at 180 ° C for 2 h. After cooling to room temperature, 3 ml of 1 N NaOH was added and the resulting solution was extracted with dichloromethane. The organic compounds were combined and washed with brine, dried over sodium sulfate, and evaporated to dryness. The crude material was filtered through silica gel eluting with 0-10% methanol in dichloromethane. The combined fractions were evaporated, and the residue (400 mg) was dissolved in methanol (5 ml). Pd / C (210 mg, 0.20 mmol) was added and the mixture was stirred under a hydrogen balloon. The reaction was filtered and the filtrate was evaporated to give [chromene [4,3-d] imidazole 4,4'-piperidine] 1H-spiro. ESI-MS m / z calc. 241.3, found 242.5 (M + 1) +; Retention time: 0.27 minutes (3 minutes of execution).

1-methyl-1H-spiro [chromene [4,3-b] pyrrole-4,4'-piperidine]

 40

Step 1: 2- (1-methyl-1H-pyrrol-2-yl) phenol

[0257]

 Four. Five

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[0258] 1-methyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrole (5.0 g, 24 mmol), tetrakis (triphenylphosphine) palladium (0 ) (1.4 g, 1.2 mmol), 2-bromophenol (4.2 g, 24 mmol), and potassium carbonate (24 mL of 2.0 M, 48 mmol) were combined in 1.2- dichloroethane (291 ml). The mixture was heated at 80 ° C for 16 h. The mixture was cooled to 25 ° C before it was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, and concentrated. Column chromatography (0 to 100% ethyl acetate / hexanes) in the residue gave 2-phenol (1-methylpyrrol-2-yl) (1.4 g, 34%). ESI-MS m / z calc. 173.2, found 174.2 (M + 1) +; Retention time: 1.76 minutes (3 minutes of execution). 60

Step 2: 1-methyl-1H-spiro [chromene [4,3-b] pyrrole-4,4'-piperidine]

[0259]

 65

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 10

[0260] A mixture of 2-phenol (1-methylpyrrol-2-yl) (1.20 g, 6.90 mmol), ethyl tert-butyl 4-oxopiperidine-1-carboxylate (1.38 g, 6, 93 mmol), 4-methylbenzenesulfonic acid hydrate (264 mg, 1.39 mmol), and dichloroethane (24 ml) was heated at 80 ° C for 2 h. HCl (1.7 ml of 4.0 M, 6.9 mmol) was added to the mixture and the mixture was allowed to stir at 50 ° C for 1 h. The mixture was cooled to 25 ° C and concentrated in vacuo. The residue was taken up in dichloromethane and washed with saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated. Column chromatography (0 to 100% ethyl acetate / hexanes) in the residue gave 1-methyl-1 H-spiro [chromene [4,3-b] Pyr-paper-4,4'-piperidine]. ESI-MS m / z calc. 254.3, found 255.2 (M + 1) +; Retention time: 1.51 minutes (3 minutes of execution).

 twenty

Spiro [piperidine-4,4'-pyrazolo [1,5-d] pyrido [2,3-b] [1,4] oxazine]

Step 1: 2-chloro-3- (1 H -pyrazol-1-yl) pyridine

[0261] 25

image150

 30

[0262] A solution of 2-chloro-3-fluoro-pyridine (1.3 g, 10.0 mmol), 1H-pyrazole (749 mg, 11.0 mmol) and K2CO3 (4.1 g, 35 30, 0 mmol) was stirred in DMF (15 ml) at 80 ° C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc (3x). The organics were combined, washed with water (3x), brine, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (5-30% EtOAc in hexanes) gave the desired product (0.7 g, 40%) as a white solid. ESI-MS m / z calc. 179.3, found 180.3 (M + 1) +. Retention time: 0.74 minutes (3 minutes of execution). 40

Step 2: tert-butyl spiro [piperidine-4,4'-pyrazolo [1,5-d] pyrido [2,3-b] [1,4] oxazine] -1-ethyl carboxylate

[0263]

 Four. Five

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 55

[0264] To a solution of 2-chloro-3-pyrazol-1-yl-pyridine (338 mg, 1.88 mmol) in THF (3.4 ml) a-78 butyl lithium was added ° C (979 µl 2.5 M, 2.45 mmol) dropwise over 5 minutes. The reaction mixture was then stirred at the temperature for 15 minutes before the addition of methyl tert-butyl 4-oxopiperidine-1-carboxylate (562.5 mg, 2.82 mmol). The reaction was allowed to reach 25 ° C, then heated at 70 ° C for 4 hours. The reaction mixture 60 was poured into water and extracted with EtOAc (3x). The organics were combined, washed with brine, dried (Na2SO4) and evaporated to dryness to give a crude mixture that was purified by column chromatography (5 to 30% EtOAc in hexanes) to give the title product (35 mg, 5%) that was used in the next stage without further purification. ESI-MS m / z calc. 342.2, found 343.3 (M + 1) +. Retention time: 1.46 minutes (3 minutes of execution). 65

Step 3: Spiro [piperidine-4,4'-pyrazolo [1,5-d] pyrido [2,3-b] [1,4] oxazine] hydrochloride

[0265]

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 10

[0266] To a solution of tert-butyl-spiro [piperidine-4,4'-pyrazolo [1,5-d] pyrido [2,3-b] [1,4] oxazine] -1-carboxylate ethyl (35 mg, 0.10 mmol) in CH2Cl2 (1 ml) and MeOH (0.1 ml) HCl in dioxane (256 µl of 4 M, 1.02 mmol) was added and the mixture was stirred at 40 ° C for 4 hours. The reaction mixture was evaporated and the hydrochloric acid salt of the product was used without further purification. ESI-MS m / z calc. 242.1, found 243.5 (M + 1) +. Retention time: 0.32 minutes (3 minutes of execution).

 twenty

Spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile]

Step 1: tert-butyl-1 Cyanospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1’-methyl carboxylate

 25

[0267]

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 35

[0268] For tert-butyl spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (54.6 g, 160.5 mmol) in THF (500 ml) at -75 ° C chlorosulfonyl isocyanate (17.5 ml, 200.6 mmol) in THF (100 ml) was added dropwise over a period of 30 minutes keeping the temperature below -70 ° C and the mixture was stirred at -40 75 ° C for 1 hr. To this DMF mixture (37.3 ml, 481.5 mmol) was added dropwise at -75 ° C and the mixture was heated to room temperature, stirring for a total of 2 h. The mixture was quenched with 1 L of 1 N NaOH and transferred to a separatory funnel with 500 ml of methyl ether-tert-butyl. The aqueous phase was separated and extracted with an additional 500 ml of methyl ether-tert-butyl. The combined organic phases were washed twice with 500 ml of brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude mixture that was purified by column chromatography with a gradient of 0 to 100% EtOAc / hexane. to give methyl tert-butyl-1-cyanospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-carboxylate (45 g, 76%) as an oil that crystallized on standing. ESI-MS m / z calc. 365.2, found 266.2 (M-Boc + 1) +. Retention time: 2.43 minutes (3 minutes of execution).

 fifty

Step 2: tert-butyl-1 Cyanospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1’-methyl carboxylate

[0269]

 55

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 65

[0270] To a mixture of tert-butyl-1'-Cyanospiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-carboxylate

ethyl (27.0 g, 73.9 mmol) in DCM (200 ml) TFA (28.5 ml, 369 mmol) was added. The mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the mixture was diluted with 200 ml of MTBE and neutralized with 175 ml of 2N NaOH. The layers were separated and the aqueous phase was extracted with 200 ml of MTBE. The combined organics were washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The residue solidified upon standing. The solids were suspended with 100 ml of MTBE and 200 ml of hexane. The precipitate 5 was collected in a Buchner funnel to give the tert-butyl-1-Cyanospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-carboxylate of methyl ESI-MS m / z calc. 265.1, found 266.2 (M + 1) +. Retention time: 1.21 minutes (3 minutes of execution).

[0271] 7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile and 7-fluorospiro [benzo [b] Pyrrolo [ 1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile was also prepared using the procedures described above.

9-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine]

Step 1: 3-methyl-2- (1H-pyrrol-1-yl) phenol

[0272]

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 25

[0273] A round bottom flask was charged with 2-amino-3-methyl-phenol (2.5 g, 20.3 mmol) and acetic acid (37.5 ml) to provide a very dark solution. Stirring was started and the vessel was charged with 2,5-dimethoxytetrahydrofuran (2.6 ml, 20.3 mmol) added dropwise clean over a period of 2 minutes. The dark mixture was then heated at 100 ° C for 3 h, after 80 ° C for 12 hours. The solvent was evaporated in vacuo and the crude residue was purified by column chromatography using a gradient of 0.5 to 50% EtOAc in 30 hexanes to yield 3-methyl-2- (1 H -pyrrol-1-yl) phenol ( 2.9 g, 83%). ESI-MS m / z calc. 173.1, found 174.3 (M + 1) +. Retention time: 1.31 minutes (3 minutes of execution).

Step 2: 9-methylpyrro [benzo [b] pyrrolo [1,2-d [1,4] oxazine-4,4'-piperidine]]

 35

[0274]

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 Four. Five

[0275] To a solution of 3-methyl-2- (1 H -pyrrol-1-yl) phenol (2.9 g, 16.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.6 g , 18.2 mmol) in dry dichloromethane (57.4 ml) TFA (2.5 ml, 33.1 mmol) was added over a period of 15 minutes and the reaction was stirred at 25 ° C for 12 hours. Another portion of TFA (2.5 ml, 33.1 mmol) was added at 25 ° C and the reaction was stirred for 2 hours after which time a third portion of TFA (2.55 ml, 33.1 was added) mmol) and the mixture was stirred at 25 ° C for an additional 12 hours. The reaction mixture was diluted with CH2Cl2 (350 ml) and washed with 1M NaOH (50 ml). The organic phase was dried with MgSO4, filtered, evaporated to dryness and the resulting residue was purified by chromatography on silica gel eluting with 0.5 to 40% MeOH in CH2Cl2 to yield 9-methyl- [benzo [b] spiro ] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] (2.0 g, 48%) obtained as a yellow oil. ESI-MS m / z calc. 254.1, found 255.3 (M + 1) +. Retention time: 1.08 minutes (3 minutes of execution).

8-fluoro-1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

 60

Step 1: tert-butyl 6-fluoro-4-oxospiro [chroman-2,4 'piperidine] -1'-methyl carboxylate

[0276]

 65

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 10

[0277] To a solution of ethyl tert-butyl-4-oxopiperidine-1-carboxylate (12.1 g, 60.9 mmol) in pyrrolidine (7.3 ml, 87.2 mmol) and anhydrous methanol (16, 5 ml) 1- (5-fluoro-2 hydroxy-phenyl) ethanone (9.3 g, 60.7 mmol) was added. The reaction mixture was stirred at 80 ° C for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 ml), washed with 1 N HCl (1 x 150 ml) and brine (2 x 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The oil was diluted with hexanes (400 ml) and heated at 60 ° C until in solution. Once dissolved, the solution was allowed to cool to 25 ° C. The crystals were collected by vacuum filtration, rinsed with hexanes to obtain tert-butyl 6-fluoro-4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (13.6 g, 67 %) as a light yellow solid. ESI-MS m / z calc. 335.2, found 336.7 (M + 1) +. retention time 1.85 minutes (3 minutes of execution).

 twenty

Step 2: 3- (diethoxymethyl) -6-fluoro-4-oxospiro [chroman-2,4'-piperidine] 1’-methyl carboxylate

[0278]

 25

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 35

[0279] For triethyl orthoformate (20.2 ml, 121.5 mmol) in dry dichloromethane (115 ml) under argon at -10 ° C, BF3.OEt2 (15.4 ml, 121.5 mmol) was added dropwise ). The solution was allowed to warm to 0 ° C and stirred for 10 minutes. Then, the solution was cooled to -78 ° C before the slow dropwise addition of tert-butyl 6-fluoro-4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (13 , 6 g, 40.5 mmol) in dichloromethane (10 ml). iPR2NEt (24.7 ml, 141.7 mmol) was added dropwise over 30 minutes, and the mixture was slowly heated to room temperature and stirred at 25 ° C for 2 hours. The reaction mixture was diluted with the addition of dichloromethane (200 µl) followed by a solution of saturated aqueous sodium bicarbonate (200 ml). The mixture was stirred in a separatory funnel and separated. The organic layer was washed with additional sodium bicarbonate solution (200 ml) and brine (200 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield a residue that was purified by silica gel column chromatography (0-25% EtOAc / hexanes gradient) to give the tert-butyl-3-45 ( diethoxymethyl) -6-fluoro -4-oxospiro [piperidine chroman-2,4 '] 1'-methyl carboxylate (3.9 g, 22%). ESI-MS m / z calc. 437.2, found 438.7 (M + 1) +. retention time 2.14 minutes (3 minutes of execution).

Step 3: 8-fluoro-1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

 fifty

[0280]

 55

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[0281] To a solution of tert-butyl-3- (diethoxymethyl) -6-fluoro-4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (2.6 g, 6, 0 mmol) in ethanol (20 ml) hydrochloric acid (22.5 ml of 4 M, 89.8 mmol) (4 M in dioxane) was added. The reaction mixture was allowed to stir at 25 ° C for 2 hours. The solvent was removed in vacuo, and the solid obtained was subjected to azeotropic distillation with ethanol (3 x 30 ml). The resulting beige-white solid was completely dissolved in ethanol (21 ml) at 25 ° C before the addition of tert-butyl N-amino-N-methyl-carbamate (1.1 5 ml, 7.2 mmol) . The solution was allowed to stir overnight. To the thick beige-white suspension that formed was added hydrochloric acid (7.5 mL of 4 M, 29.9 mmol) (4 M in dioxane). The mixture was heated to 60 ° C to give a light yellow solution. After 1 hour at 60 ° C, a thick white suspension developed. The suspension was allowed to cool slowly at 25 ° C for 4 hours, and the solids were collected by vacuum filtration. The cake was rinsed with a solution of 10% ethanol in hexanes (2x). Residual solvents were further removed under reduced pressure to provide 8-fluoro-1-methyl-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] (1.9 g, 92%). 1H NMR (400 MHz, DMSO) δ 7.59 (dd, J = 9.3, 2.8 Hz, 1H), 7.43 (s, 1H), 07/27 to 07/10 (m, 2H) , 4.12 (s, 3H), 3.28 to 3.11 (m, 4H), 2.59 (s, 1H), 2.22 to 2.2 (m, 4H). ESI-MS m / z calc. 273.1, found 274.1 (M + 1) +. retention time 0.84 minutes (3 minutes of execution).

 fifteen

1-Ethyl-8-fluoro-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

[0282]

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[0283] To a solution of methyl tert-butyl-3- (diethoxymethyl) -6-fluoro-4-oxo-spiro [chromane-2,4'-piperidine] 1'-carboxylate (1.3 g, 3 , 0 mmol) in ethanol (10.4 ml) hydrochloric acid (11.1 ml of 4 M, 44.6 mmol) (4 M in dioxane) was added. The reaction mixture was allowed to stir at 25 ° C for 2 hours. The solvent was removed in vacuo, and the solid obtained was subjected to azeotropic distillation with ethanol (3 x 30 ml). The resulting beige-white solid was completely dissolved in ethanol (10.40 ml) at 25 ° C before the addition of methyl tert-butyl N-amino-N-ethyl-carbamate (571.2 mg, 3, 6 mmol). The solution was allowed to stir at 25 ° C overnight. To the thick beige-white suspension that formed was added hydrochloric acid (3.7 ml of 4 M in dioxane, 14.9 mmol). The mixture was heated to 60 ° C to give a light yellow solution. After 1 hour at 60 ° C, a thick white suspension developed. The suspension was allowed to cool slowly at 25 ° C for 4 hours, and the solids were collected by vacuum filtration. The cake was rinsed with a solution of 10% EtOH in hexanes (2x). The residual solvent was further removed under reduced pressure to provide 1-ethyl-8-fluoro-spiro [chromene [4,3-c] pyrazol-4,4'-45 piperidine] (880 mg, 82%). ESI-MS m / z calc. 287.1, found 288.1 (M + 1) +. retention time 0.79 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) delta 7.52 (dd, J = 9.4, 2.8 Hz, 1H), 7.47 (s, 1H), 7.26 to 7.13 (m, 2H), 5.24 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.30 to 3.12 (m, 4H), 2.18 to 2.1 (m, 4H), 1.37 (t, J = 7, 2 Hz, 3H).

8-fluoro-2-methyl-2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 50

[0284]

 55

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[0285] For methyl tert-butyl 3- (diethoxymethyl) -6-fluoro-4-oxo-spiro [chromane-2,4'-piperidine] 1'-carboxylate (3.81 g, 8.71 mmol) is added hydrochloric acid (32.7 ml of 4.0 M in dioxane, 130 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed in vacuo, and the solid obtained was subjected to azeotropic distillation with EtOH (1 x 30 ml). The resulting solid was suspended in EtOH (30.5 ml) and treated with methylhydrazine (556 mL, 10.5 mmol) at 40 ° C for 4 h. The mixture was then heated at 80 ° C for 1 h resulting in a yellow solution with an off white precipitate. The solid was collected to give 8-fluoro-2-methyl-2H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] hydrochloride (798 mg, 26%). ESI-MS m / z calc. 273.1, found 274.5 (M + 1) +. retention time 0.83 minutes (3 minutes of execution). Note: The yellow mother liquor was evaporated to give a mixture of methyl regioisomers (1.71 g).

 10

Spiro [benzo [b] imidazo [1,2-d] [1,4] oxazine-4,4'-piperidine] dihydrochloride

Step 1: 1- (2-fluorophenyl) -1H-imidazole

[0286] 15

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[0287] 1,2-difluorobenzene (25 ml, 254.0 mmol), imidazole (15.6 g, 228.6 mmol), and potassium carbonate (70.2 g, 25 508.0 mmol) were suspended in dimethylsulfoxide (15 ml). The reaction mixture was heated at 110 ° C for 72 hours. The reaction mixture was then partitioned between ethyl acetate and was water and washed several times with a saturated aqueous solution of ammonium chloride to remove a small amount of di-imidazole material. The organic layer was then dried over sodium sulfate and evaporated to dryness to yield 1-imidazole (2-fluorophenyl) (430 mg, 1%) which was used without further purification. ESI-MS m / z calc. 162.1, found 163.3 (M + 1) +. 30 retention time 0.26 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 8.04 (s, 1 H), 7.69-7.62 (m, 1 H), 7.57 (s, 1 H), 7.54-7.45 (m, 2H), 7.41-7.33 (m, 1H), 7.13 (s, 1H).

Step 2: 4- (1- (2-fluorophenyl) -1H-imidazol-2-yl) -4-hydroxypiperidine-1-carboxylate tert-butyl

 35

[0288]

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 Four. Five

[0289] 1- (2-fluorophenyl) imidazole (484 mg, 2.99 mmol) was dissolved in tetrahydrofuran (5 ml) under an argon atmosphere. The reaction mixture was cooled to -78 ° C. N-Butyllithium (2.2 ml of 1.6 M, 3.58 mmol) in 50 hexanes was added slowly and the resulting mixture was stirred at -78 ° C for 1 hour. Then methyl tert-butyl 4-oxopiperidine-1-carboxylate (892.2 mg, 4.48 mmol) was added as a solution in tetrahydrofuran (2 ml). The reaction mixture was allowed to warm slowly to room temperature and stirred for 10 days. The crude material was evaporated to dryness and taken to the next stage without further purification. ESI-MS m / z calc. 361.2, found 362.1 (M + 1) +. retention time 1.12 minutes (3 minutes of execution). 55

Step 3: Spiro [benzo [b] imidazo [1,2-d] [1,4] oxazine-4,4'-piperidine]

[0290]

 60

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Methyl 4- [1- (2-fluorophenyl) imidazol-2-yl] -4-methyl hydroxy-piperidine-1-carboxylate (294 mg, 0.81 mmol) and K2CO3 (337 mg, 2 , 44 mmol) were heated at 110 ° C for 16 h in DMF (5 ml). The solvent was evaporated and the resulting material was partitioned between dichloromethane and water. The organics were separated and washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by column chromatography (0-50% ethyl acetate in hexanes) to give the tert-butyl-spiro [imidazo [2,1-c] [1,4] benzoxazine-4,4 ' -piperidine] -1 'methyl carboxylate (139 mg, 50%). ESI-MS m / z calc. 341.2, found 342.3 (M + 1) +. retention time 1.31 10 minutes (3 minutes of execution).

Step 4: Spiro [benzo [b] imidazo [1,2-d] [1,4] oxazine-4,4'-piperidine] dihydrochloride

[0291] 15

 twenty

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tert-butyl spiro [imidazo [2,1-c] [1,4] benzoxazine-4,4'-piperidine] 1'-methyl carboxylate (138 mg, 0.40 mmol) was stirred for 10 min in HCl 4 M in dioxane (2 ml of 4 M, 8.00 mmol). The reaction was evaporated to dryness to give the spiro [benzo [b] imidazo [1,2-d] [1,4] oxazine-4,4'-piperidine] dihydrochloride (97 mg, quantitative) which was used as follows stage without further purification. ESI-MS m / z calc. 241.1, found 242.3 (M + 1) +. retention time 0.40 minutes (3 minutes of execution).

7-fluoro-1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride 40

Step 1: tert-butyl 7-fluoro-4-oxospiro [chroman-2,4 'piperidine] 1’-methyl carboxylate

[0292]

 Four. Five

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[0293] To a solution of ethyl tert-butyl-4-oxopiperidine-1-carboxylate (7.5 g, 37.8 mmol) in pyrrolidine (4.5 ml, 54.1 mmol) and anhydrous methanol (10, 2 ml) 1- (4-fluoro-2-hydroxy-phenyl) ethanone (5.8 g, 37.6 mmol) was added. The reaction mixture was stirred at 80 ° C for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 ml), washed with 1 N HCl (1 x 150 ml) and brine (2 x 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The oil was diluted 60 with hexanes (400 ml) and heated at 60 ° C until in solution. Once dissolved, the solution was allowed to cool to 25 ° C. The crystals were collected by vacuum filtration, rinsing with hexanes to remove the tert-butyl 4-oxo-7-pyrrolidin-1-yl-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (8, 6 g), which was collected as a light yellow solid; ESI-MS m / z calc. 386.2, found 387.2 (M + 1) +; Retention time: 2.59 minutes (3 minutes of execution). The filtrate was concentrated and the residue was subjected to column chromatography (0 to 100% of ethyl acetate / hexanes) to give the tert-butyl-7-fluoro-4-oxo-spiro [chromane-2,4'- piperidine] -1'-ethyl carboxylate (2.7 g, 21%) as a light yellow solid; ESI-MS m / z calc. 335.2, found 336.2 (M + 1) +; Weather

Retention: 2.49 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.6, 6.7 Hz, 1H), 6.80-6.62 (m, 2H), 3.88 (d, J = 12.1 Hz, 2H), 3.21 (t, J = 12.0 Hz, 2H), 2.71 (s, 2H), 2.02 (d, J = 12.8 Hz, 2H), 1 , 62 (td, J = 14.1, 4.8 Hz, 2H), 1.46 (s, 9H).

Step 2: (Z) -terc-butyl 3- (ethoxymethylene) -7-fluoro-4-oxospiro [chroman-2,4'-piperidine] 1'-tert-5 butyl carboxylate and 3- (diethoxymethyl) -7 - fluoro-4-oxospiro [chroman-2,4'-piperidine] 1'-methyl carboxylate

[0294]

 10

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[0295] Triethyl orthoformate (4.0 ml, 24.1 mmol) in dry dichloromethane (23 ml) was added under 10 ° argon dropwise BF3.OEt2 (3.1 ml, 24.2 mmol). The solution was allowed to warm to 0 ° C and stirred for 10 minutes. Then, the solution was cooled to -78 ° C before the slow dropwise addition of tert-butyl 7-fluoro-4-oxo-spiro [chromane-2,4'piperidine] 1'-methyl carboxylate (2, 7 g, 8.0 mmol) in dichloromethane (1.2 ml). Diisopropylethylamine (4.9 ml, 28.2 mmol) was added for 10 minutes, and the mixture was slowly heated to 25 ° C and stirred at this temperature overnight. The reaction mixture was diluted with dichloromethane (500 ml) followed by a solution of saturated aqueous sodium bicarbonate (500 ml). The mixture was stirred in a separatory funnel and separated. The organic layer was washed with sodium bicarbonate (500 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-25% EtOAc / hexanes) to provide a mixture of tert-butyl (3Z) -3- (ethoxymethylene) -7-fluoro-4-oxo-spiro [Chroman-2, 4 'piperidine] 1'-methyl carboxylate (2.6 g, 82%) and 3- (ethoxymethyl di -) - 7-fluoro-4-oxo-spiro [chromane-2,4'- piperidine] -1'-carboxylate. ESI-MS m / z calc. 391.2, found 392.2 (M + 1) +; Retention time: 2.69 minutes (3 minutes of execution).

Step 3: 7-fluoro-1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride

[0296]

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 Four. Five

 fifty

[0297] For tert-butyl (3Z) -3- (ethoxymethylene) -7-fluoro-4-oxo-spiro [chromane-2,4'-piperidine] 1'-methyl carboxylate (2.6 g, 5, 9 mmol) was added hydrochloric acid (22.3 ml, 89.1 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25 ° C for 2 hours. The solvent was removed in vacuo, and the solid obtained was dissolved in EtOH (3 x 25 ml) and the solvent was evaporated to dryness. The resulting beige-white solid was completely dissolved in ethanol (21 ml) at 25 ° C before the addition of tert-butyl N-amino-N-methyl-carbamate (1.0 g, 7.1 mmol). Solution 55 was allowed to stir at 25 ° C overnight. To the thick beige-white suspension that formed, 4M hydrochloric acid in dioxane (7.4 mL, 29.7 mmol) was added. The mixture was heated to 60 ° C to give a light yellow solution. After 1 hour at 60 ° C, a beige-white and thick suspension developed. The suspension was allowed to cool slowly at 25 ° C for 1 hour, and the solids were collected by vacuum filtration. The cake was rinsed with a solution of 10% ethanol in hexanes (2x). The residual solvent was further removed under reduced pressure to provide 7-fluoro-1-methyl-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] dihydrochloride (1.4 g, 67%) as a solid light tan. ESI-MS m / z calc. 273.1, found 274.3 (M + 1) +; Retention time: 1.59 minutes (3 minutes of execution). 1H NMR (400 MHz, MeOD) δ 7.80 (dd, J = 8.7, 6.1 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.00 (dd , J = 9.8, 2.6 Hz, 1H), 6.91 (td, J = 8.6, 2.6 Hz, 1H), 4.14 (s, 3H), 3.53-3, 42 (m, 2H), 3.41-3.33 (m, 2H), 2.29 (d, J = 13.9 Hz, 2H), 2.23 to 2.11 (m, 2H). 65

1-Isopropyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

Step 1: benzyl 1-isopropyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’-methyl carboxylate

[0298]

 5

image169

 10

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mixture of tert-butyl N-amino-N-isopropyl-carbamate (530.4 mg, 3.0 mmol), (Z) benzyl 3- (hydroxymethylene) -4-oxospiro [chroman-2,4'-piperidine ] - 1'-Ethyl carboxylate (1.10 g, 2.9 mmol) and TFA (223.4 µl, 2.9 mmol) in dichloromethane (10 ml) was stirred for 2 h. The reaction was concentrated to 1/3 of the volume, then TFA (~ 1.5 ml) was added. The mixture was stirred for 30 min, then concentrated, neutralized with excess Et3N, re-concentrated and purified by column chromatography (0-60% EtOAc / hexanes) to give benzyl 1-isopropyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'carcarboxylate (1.1 g, 91%) as a pale yellow oil. ESI-MS m / z calc. 417.2, found 418.3 (M + 1) +; Retention time: 2.07 minutes (3 minutes of execution).

 25

Step 2: 1-isopropyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine]

[0299]

 30

image170

 35

 40

[0300] Benzyl 1-isopropylspiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'-methyl carboxylate (1.1 g, 2.6 mmol) was stirred in methanol (14.4 ml) with Pd / C (140.3 mg, 0.1318 mmol) under a hydrogen atmosphere for 16 h. The reaction was filtered through a syringe filter and the solvent was evaporated to give 1-isopropylspiro [chromene [4,3-c] pyrazol-4,4'-piperidine] (750 mg, 100%). ESI-MS m / z calc. 283.2, found 284.3 (M + 1) +; Retention time: 1.01 minutes (3 minutes of execution). Four. Five

7-Methylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile

Step 1: methyl tert-butyl-7 [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1’-methyl carboxylate 50

[0301]

 55

image171

 60

 65

[0302] To 5-methyl-2-pyrrole-1-yl-phenol (6.0 g, 33.6 mmol) in dichloromethane (75 ml) was added tert-butyl 4-oxopi-

ethyl peridine-1-carboxylate (6.61 g, 33.6 mmol) of trifluoroacetic acid then (3.1 ml, 40.3 mmol) and the mixture was stirred at room temperature for 5.5 hours. The solvent was evaporated and the crude residue was purified by column chromatography using a gradient of 0 to 100% dichloromethane in hexanes to give tert-butyl-7'-methylstyrene [piperidine-4,4'-pyrrolidone lo [2,1 -c] [1,4] benzoxazine] -1-ethyl carboxylate (7.1 g, 59%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.1 Hz, 1H), 7.12 to 7.9 (m, 1H), 6.88 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.29 (t, J = 3.2 Hz, 1H), 5 6.00-5.98 (m, 1H), 5.30 (s, 1H), 3, 97 (s, 2H), 3.26 (t, J = 12.2 Hz, 2H), 2.32 (s, 3H), 2.9 to 2.1 (m, 2H), 1.87 (dt, J = 13 , 3, 4.9 Hz, 2H), 1.48 (s, 9H). ESI-MS m / z calc. 354.4, found 355.5 (M + 1) +; retention time 2.28 minutes (3 minutes of execution).

Step 2: methyl tert-butyl 1-cyano-7-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-carboxylate 10 and 7- Methylespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile

[0303]

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tert-butyl 7'-methylpyrro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (5.0 g, 14.1 mmol) in THF ( 150 ml) at -78 ° C, chlorosulfonyl isocyanate (1.5 ml, 16.9 mmol) in THF (50 ml) was added dropwise over a period of 10 minutes. The mixture was stirred at that temperature during dropwise addition and the mixture was allowed to stir at room temperature overnight for 4 hours and then DMF (3.5 ml, 45.9 mmol). The mixture was concentrated, diluted with DCM (500 ml) and washed with sat. NaHO3 (200 ml), brine (200 ml), dried over MgSO4 and evaporated to yield a crude residue that was purified by column chromatography (50 to 100% dichloromethane / hexane) to give the tert-butyl-1 ' - (carbamoyl methoxysulfonili -) - 7'-methyl-spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate as a pale yellow oil (1, 3 g, 24%). 1H NMR (400 MHz, 30 CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.96-6.88 ( m, 2H), 6.05 (d, J = 4.0 Hz, 1H), 4.09-3.95 (m, 2H), 3.31 to 3.15 (m, 2H), 2.35 (s, 3H ), 2.04 (d, J = 14.0 Hz, 2H), 1.92-1.79 (m, 2H), 1.48 (s, 9H). ESI-MS m / z calc. 379.5, found 380.1 (M + 1) +; Retention time 2.20 minutes (3 min track), and 7-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile (0 , 5 g, 12%). 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.33 (d, J = 4.1 Hz, 1 H), 7.17 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 4.1 Hz, 1H), 3.26 to 3.9 (m, 35 4H) , 2.33 (s, 3H), 2.19 to 2.4 (m, 4H). ESI-MS m / z calc. 279.3, found 280.3 (M + 1) +; retention time 1.12 minutes (3 minutes of execution).

(1-Cyanospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -7-yl) methyl acetate

 40

Step 1: tert-butyl 7- (bromomethyl) -1-Cyanospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'carboxylate

[0304]

 Four. Five

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 55

tert-butyl 1'-cyano-7'-methyl-spiro [piperidine-4,4'-pyrrolo [2,1-c] 1,4] benzoxazine] -1-ethyl carboxylate (200 mg, 0.527 mmol), 1-bromopyrrolidine-2,5-dione (93.8 mg, 0.527 mmol), and 2- (1-cyano-1-methyl-ethyl) azo-2-methyl-propanonitrile (8.66 mg, 0.0527 mmol ) were combined in carbon tetrachloride (10 ml) and the mixture was heated at 60-80 ° C for 4 hours. The mixture was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (50 to 100% CH2Cl2 / hexanes) to give tert-butyl-7 '- (bromomethyl) 1' cyano-spiro [Pip eridine-4,4'-pyrrolo [2.1 c] [1,4] benzoxazine] -1-ethyl carboxylate (115 mg, 47%). ESI-MS m / z calc. 457.1, found 458.5 (M + 1) +; retention time 2.43 minutes (3 minutes of execution).

 65

Step 2: (1-Cyanospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -7-yl) methyl acetate

[0305]

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 5

 10

tert-butyl 7 '- (bromomethyl) 1' cyano-spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (33.0 15 mg, 0.0720 mmol) and potassium acetate (35.3 mg, 0.360 mmol) were combined in DMF (0.5 ml) and the mixture was stirred at 80 ° C for 18 hours. The mixture was taken up in NH4Cl (10 ml) and extracted with CH2Cl2 (10 ml). The solvent was removed under reduced pressure and the residue was purified by chromatrograpy column (0-10% EtOAc / CH2Cl2) to obtain tert-butyl 7 '- (acetoxymethyl) 1' cyano-spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (19.5 mg, 62%) as a clear oil. ESI-MS m / z calc. 437.2, found 438.5 (M + 1) +; retention time 20 2.05 minutes (3 minutes of execution). of tert-butyl 7 '- (acetoxymethyl) 1' cyano-spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate was dissolved in CH2Cl2 (se added 10 ml) before TFA (5.0 ml, 65 mmol). The solvent was removed under reduced pressure to give methyl (1'-Cyanoespiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -7'-yl) methyl acetate (15 mg, 62%) ESI-MS m / z calc. 337.1, found 338.3 (M + 1) +; retention time 1.16 minutes (3 minutes of execution). 25

7- (methoxymethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile

Step 1: 7-methyl-1 '- (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1- carbonitrile 30

[0306]

image175

 35

 40

[0307] To a solution of 7'methylspiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] 1'carbonitrile (250 mg, 0.885 45 mmol) in dichloromethane (5.0 ml) at 0 ° C triethylamine (374 µL, 2.69 mmol) and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (124 µl, 0,895 mmol) were added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (0 to 100% ethyl acetate / hexanes) to give 7'-methyl-1- (2,2,2-trifluoroacetyl) spiro [piperidine- 4,4 'pyrrolo [2,1-c] [1,4] benzox-azine] 1' carbonitrile (250 mg, 74%) ESI-MS m / z calc. 375.3, found 376.3 (M + 1) +; retention time 50 2.01 minutes (3 minutes of execution). 1 H NMR (400 MHz, CDCl 3) δ 8.01 (d, J = 8.8 Hz, 1 H), 6.99 (d, J = 4.0 Hz, 1 H), 6.96 (s, 1 H), 6.94 (d, J = 6.3 Hz, 1H), 6.07 (d, J = 4.0 Hz, 1H), 4.54-4.48 (m, 1H), 3.94 (d , J = 14.2 Hz, 1H), 3.71-3.62 (m, 1H), 3.34-3.25 (m, 1H), 2.36 (s, 3H), 2.20 ( d, J = 13.4 Hz, 2H), 1.66-1.45 (m, 2H).

Step 2: 7- (bromomethyl) -1 '- (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1 -55 carbonitrile

[0308]

 60

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 65

[0309] 7'-methyl-1- (2,2,2-trifluoroacetyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] 1'carbonitrile (250 mg, 0.666 mmol), 1-bromopyrrolidine-2,5-dione (119 mg, 0.666 mmol) and 2- (1-cyano-1-methyl-ethyl) panenitrile pro azo-2-5 methyl- (10.9 mg, 0.0666 mmol) were combined in carbon tetrachloride and the mixture was heated at 80 ° C for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give 7'- (bromomethyl) -1- (2,2,2-trifluoroacetyl) spiro [piperidine-4,4'-pyrrolo [2,1 c] [1,4] benzoxazine] 1'carbonitrile (53.2 mg, 18%).

 10

Step 3: 7- (methoxymethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile

[0310]

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 30

[0311] 7 '- (bromomethyl) -1-spiro (2,2,2-trifluoroacetyl) [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1' carbonitrile ( 53.2 mg, 0.117 mmol) was treated with sodium methoxide (36 mg, 0.67 mmol) at room temperature. The mixture was allowed to stir for 5 h at room temperature before it was concentrated under reduced pressure. The residue was taken up in acetate acetate, filtered, and concentrated to give 7'- (methoxymethyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzox-azine] -1 'carbonitrile (9.0 mg, 4%). ESI-MS m / z calc. 309.2, found 310.3 (M + 1) +; retention time 0.97 minutes (3 minutes of execution).

3-Methylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile 40

Step 1: 2,2,2-trifluoro-1- (3-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'il) ethanone

[0312]

 Four. Five

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 55

[0313] To a solution of 3'-methylspiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] (120 mg, 0.41 mmol), and Et3N (173 µl, 1.24 mmol) in dry dichloromethane (2.1 ml) at 0 ° C under N2, (2,2,2-trifluoroacetyl) oacetate 2,2,2-trifluor- (86 µl, 0.62 mmol) was added drop by drop. After 5 min, the cooling bath was removed and the mixture was stirred for 3 hours at 25 ° C. The solvent was removed under reduced pressure and the oily residue was purified by silica gel column chromatography eluting with 0.5 to 60% EtOAc in hexanes. The product 2,2,2-trifluoro-1- (3'-60 methylpyrro [pyrrolo piperidine-4,4 '[2,1-c] [1,4] benzoxazine] -1-yl) ethanone (95 mg, 66%) was isolated as a whitish solid foamy. ESI-MS m / z calc. 350.1, found 351.3 (M + 1) +; retention time 2.03 minutes (3 minutes of execution).

Step 2: 3-methyl-1 '- (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1 65 carbaldehyde

[0314]

image179

 5

 10

[0315] POCl3 (38 µl, 0.41 mmol) was added dropwise at 0 ° C under an atmosphere of N2 to DMF (32 µl, 0.41 mmol). The reaction was stirred for 30 min at this temperature and a white solid formed, to which a solution of 2,2,2-trifluoro-1- (3'-methylstyrene [piperidine-4,4'-) was slowly added. pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl) ethanone (95 mg, 0.27 mmol) in dry DMF (0.7 ml). The reaction was stirred for 4 h, poured onto ice, 0.8 ml of 1 M NaOH was added and the product was extracted with dichloromethane (3x5 ml). The organic phases were combined, washed with brine, dried, filtered and concentrated and the residue was purified by silica gel column chromatography eluting with 5-40% EtOAc in hexanes to yield 3-methyl-1. '- (2,2,2 trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbaldehyde (25 mg, 24%). ESI-MS m / z calc. 378.1, found 379.3 (M + 1) +; retention time 1.83 minutes (3 minutes of execution).

Step 3: 3-methyl-1 '- (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1- 25 carbonitrile

[0316]

 30

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 40

[0317] To a solution of 3'-methyl-1- (2,2,2-trifluoroacetyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1 ' -carbaldehyde (25 mg, 0.07 mmol) in ethanol (125 µl) at 60 ° C was added an aqueous solution of hydroxylamine hydrochloride (20.7 mg, 0.30 mmol) and sodium acetate (41.2 mg , 0.50 mmol) in water (125.0 µl). The solution was stirred at 60 ° C for 2 hours. The reaction was cooled to 25 ° C, addition of water and the precipitate that formed was collected by filtration. The solids were thoroughly washed with water and dried in vacuo, dissolved in Ac2O (119.1 µl, 1.26 mmol) and heated at 140 ° C for 5 h. The reaction was cooled to 25 ° C, poured onto ice, basified by the addition of solid NaHCO3 until foam formation no longer occurred and was extracted with dichloromethane (3x5 ml). The organic phases were combined, dried, filtered and concentrated to yield a residue that was purified by silica gel chromatography using a gradient of 0.5 to 45% EtOAc in hexanes to yield 3-50 methyl-1 ' - (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile (10 mg, 40%). ESI-MS m / z calc. 375.1, found 376.3 (M + 1) +; retention time 2.01 minutes (3 minutes of execution).

Step 4: 3-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile

 55

[0318]

image181

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 65

[0319] To a solution of 3'-methyl-1- (2,2,2-trifluoroacetyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1 ' -carbonitrile (10 mg, 0.027 mmol) in MeOH (159 µl) K2CO3 (7.7 mg, 0.056 mmol) was added in one portion at 25 ° C. Water (35 ml) was added, and the organics were removed in vacuo and the aqueous layer was extracted with dichloromethane (3x100 ml). The organic phases were combined, dried, filtered, concentrated to a white solid, which was used directly in the next step without further purification (7 mg, 93%).

9-fluorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile

[0320] Stage 1: 9-fluorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 10

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0 [0321] 3-fluoro-2- (1 H -pyrrol-1-yl) phenol (2.7 g, 16.6 mmol) and ethyl tert-butyl 4-oxopiperidine-1-carboxylate (3.3 g, 16.6 mmol) were dissolved in dry dichloromethane (53.6 ml). TFA (2.3 ml, 30.3 mmol) was added for 15 min and stirring was continued for 12 hours. Additional TFA (2.3 ml, 30.3 mmol) was added at 25 ° C. The reaction mixture was concentrated in vacuo and the residue was diluted with dichloromethane (350 ml) then washed with 1 M NaOH (2 x 50 ml), dried, filtered and evaporated to dryness. The resulting material was purified by chromatography on silica gel eluting with 0.5 to 40% MeOH in dichloromethane to give 9-fluorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4'-piperidine] (3.4 g, 86%). ESI-MS m / z calc. 258.1, found 259.1 (M + 1) +; retention time 0.90 minutes (3 minutes of execution).

Step 2: 2,2,2-trifluoro-1- (9-fluorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'il) ethanone 40

[0322]

 Four. Five

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[0323] To a cold solution of 9-fluorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] (3.1 g, 12.2 mmol) 55 in dry dichloromethane (54 ml) under N2 Et3N (5.1 ml, 36.6 mmol) and (2,2,2-trifluoroacetyl) 2,2,2 trifluoroacetate (2.5 ml, 18.3 mmol) were added successively ). The cooling bath was removed and the mixture was stirred overnight at room temperature. The mixture was concentrated, then purified by silica gel column chromatography eluting with 0.5 to 50% EtOAc in hexanes to yield 2,2,2-trifluoro-1- (9-fluorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'il) Ethoneone (2.2 g, 50%) as a white foamy solid. ESI-MS m / z calc. 354.1, 60 found 355.3 (M + 1) +; retention time 2.11 minutes (3 minutes of execution).

Step 3: 9-fluoro-1 '- (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1- carbaldehyde

 65

[0324]

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 10

[0325] POCl3 (282 µl, 3.0 mmol) was added dropwise at 0 ° C under an atmosphere of N2 to dry DMF (234 µl, 3.0 mmol). The reaction mixture was left for 20 min at this temperature, which led to the formation of a white solid. A solution of 2,2,2-trifluoro-1- (9'-fluorospiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl) ethanone (715 mg 2.0 mmol) dry DMF (5.4 ml) was added dropwise and the cooling bath was removed. The reaction was poured onto ice, 1M NaOH was added (5 ml), then the pH was adjusted to 7 with 2M HCl. The mixture was extracted with dichloromethane (3 x 10 ml). The organics were combined, dried with MgSO4, filtered and evaporated to yield a residue that was purified by silica gel column chromatography eluting with 5-30% EtOAc in hexanes to yield 9-fluoro-1 '- ( 2,2,2 trifluoroacetyl) spiro [benzo [b] Pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbaldehyde (770 mg, quant). ESI-MS m / z calc. 382.1, found 383.3 (M + 1) +; retention time 1.71 minutes 20 (3 minutes of execution).

Step 4: 9-fluoro-1 '- (2,2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1- carbonitrile

 25

[0326]

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 35

[0327] To a solution of 9'-fluoro-1- (2,2,2-trifluoroacetyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1 ' -40 carbaldehyde (715 mg, 1.9 mmol) in ethanol (3.5 ml) heated to 70 ° C was added an aqueous solution of hydroxylamine hydrochloride (587 mg, 8.4 mmol) and sodium acetate (1 , 16 g, 14.20 mmol) in water (3.6 ml). The mixture was heated at 60 ° C for 2 h. The mixture was cooled to 25 ° C, water was added and the precipitate formed was collected by filtration and washed thoroughly with water and dried under vacuum. The residue was dissolved in Ac2O (3.37 ml, 35.74 mmol) and heated at 140 ° C for 5 h. The reaction was cooled to 25 ° C, poured onto ice, basified by the addition of NaHCO3 (solid) until no foam formation was produced and extracted with dichloromethane (3 x 5 ml). The combined organic phases were dried, filtered and concentrated to yield a residue that was purified by silica gel chromatography (gradient: 0.5 to 45% EtOAc in hexanes) to give 9-fluoro-1 '- (2 , 2,2-trifluoroacetyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile (50 mg, 7%). ESI-MS m / z calc. 379.1, found 380.3 (M + 1) +; retention time 1.82 minutes (3 minutes of execution). fifty

Step 5: 9-fluorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-carbonitrile

[0328]

 55

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[0329] To a solution of 9'-fluoro-1- (2,2,2-trifluoroacetyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1 ' -carbonitrile (170 mg, 0.45 mmol) dissolved in MeOH (2.7 ml) K2CO3 (130 mg, 0.94 mmol) was added in one portion at room temperature. The reaction was monitored by LCMS until there was no starting material left. Water (10 ml) was added, and the organic solvent removed in vacuo. The product was extracted with dichloromethane (3 x 30 ml), the organic phases were combined, dried with sodium sulfate, filtered, concentrated to a white solid, which was used directly in the next step without further purification (104 mg , 82%). ESI-MS m / z calc. 283.1, found 284.1 (M + 1) +; retention time 0.94 minutes (3 minutes of execution).

1- (methylsulfonyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 10

Step 1: tert-butyl 1- (methylsulfonyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'carboxylate]

[0330]

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 30

[0331] To a solution of NCS (466 mg, 3.49 mmol) in dichloromethane (9.2 ml) at -10 ° C was added dimethyl sulfide (393.9 µL, 5.38 mmol) dropwise and The reaction mixture was stirred at this temperature for 10 min. The solution was cooled to -55 ° C and a spiro solution of tert-butyl [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (915 mg , 2.69 mmol) in dichloromethane (5 ml) was added dropwise over 10 min. The cooling bath was removed and the mixture was stirred until the solution reached 25 ° C. Water (10 ml) and EtOAc 35 (40 ml) were added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an orange oil (1.4 g) which was used in the next step without further purification. The oily orange residue obtained (1.4 g) was taken up in AcOH (5 ml), then H2O2 (671 µl of 30% w / v, 5.91 mmol) was added dropwise. After 15 min at 25 ° C, another portion of H2O2 (671 ml of 30% w / v, 5.91 mmol) was added dropwise and the reaction was monitored by HPLC until starting materials were cleared. EtOAc (50 ml) and saturated aqueous NaHCO3 (150 ml) were added and the product was carefully extracted (gas emission). The organic phase was washed with 150 ml of sat. Aq. NaHCO3, then with brine (50 ml). The organic phase was dried, filtered, concentrated under reduced pressure. Purification by silica gel column chromatography eluting with 5-100% EtOAc in hexanes provided tert-butyl-1'-Methylsulfinylspiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine ] -1-methyl carboxylate (276 mg, 0.68 mmol) that was collected in dry dichloromethane (1 ml). MCPBA 45 (116.0 mg, 0.67 mmol) was added at 25 ° C and the mixture was stirred for 1 h. Another 30 mg of mCPBA was added and after 30 min, saturated aqueous NaHCO3 (3 ml) was added and the product was extracted twice with dichloromethane (10 ml). The organic phases were combined, washed with brine, dried, filtered and concentrated to yield a residue that was purified by silica gel chromatography eluting with 5-100% EtOAc in hexanes. The desired product of tert-butyl 1'-Methylsulfonyl-spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate 50 (200 mg, 18% more 3 steps) was isolated as a yellow oil. ESI-MS m / z calc. 418.2, found 419.5 (M + 1) +; retention time 1.93 minutes (3 minutes of execution).

Step 2: 1- (methylsulfonyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine]

 55

[0332]

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 65

[0333] To a solution of tert-butyl-1'-methylsulfonylpyrro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (200 mg, 0, 48 mmol) in dry dichloromethane (1 ml) at 0 ° C TFA (147 µl, 1.91 mmol) was added. The cooling bath was removed and the mixture was stirred for 1.5 h at 25 ° C. The mixture was concentrated under reduced pressure and the residue obtained was taken up in dichloromethane (10 ml) and washed with saturated aqueous NaHCO3 (5 ml). The aqueous phase was extracted twice with dichloromethane (2x10 ml) and the organic phases were combined, dried, filtered and concentrated to yield 1'-methylsulfonylpyrro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] as a light yellow solid foam (150 mg, 99%). ESI-MS m / z calc. 318.1, found 319.3 (M + 1) +; retention time 10 0.93 minutes (3 minutes of execution).

[0334] 1- (Methylsulfinyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] was also prepared using the procedure previously described where only one aliquout of H2O2 It was used in step 1.

1- (Spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl) ethanone 15

Step 1: tert-butyl-1 bromospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1’-methyl carboxylate

[0335] 20

image189

 25

 30

[0336] For spiro of tert-butyl [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (13.2 g, 38.8 mmol) in CH2Cl2 (125 ml) at 0 ° C NBS (7.25 g, 40.7 mmol) in CH2Cl2 (25 ml) was added dropwise over 10 min. The mixture was stirred at 0 ° C for 5 min before it was diluted with 200 ml of 0.5 M Na2S2O3. The aqueous phase was removed and the organic phase was washed with 200 ml of brine. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-30% EtOAc / hexanes) to give the tert-butyl-1-bromoespiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4 'piperidine] 1'-methyl carboxylate. ESI-MS m / z calc. 418.1, found 419.0 (M + 1) +; Retention time: 2.29 minutes (3 minutes of execution).

Step 2: tert-butyl-1 acetylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'-40-methyl carboxylate

[0337]

 Four. Five

image190

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 55

[0338] To a solution of tert-butyl-1'-bromospiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (1.10 g, 2.60 mmol) and Pd2 (dba) 3 • CHCl3 (543 mg, 0.525 mmol) in 1,4-dioxane (4.4 ml) tri-tert-butyl phosphane (360 ml, 1.31 mmol), 1 was added -vinyloxybutane (3.55 ml, 26.2 mmol) and N cyclohexyl-N-methyl-cyclohexanamine (843 ml, 3.94 mmol). The mixture was heated at 80 ° C for 5 hours. The mixture was cooled to room temperature 60 before 1 N HCl (3 ml) was added and the mixture was stirred for 1 hour. The mixture was poured into water and extracted with ethyl acetate (4x). The organics were combined, washed with water (2x), brine and evaporated. The residue was purified by column chromatography (0-20% ethyl acetate in hexanes) to give the tert-butyl-1'-acetylspiro [piperidine-4,4'-pyrrolo [2,1 c] [1,4 ] benzoxazine] -1-methyl carboxylate (610 mg, 61%) as a yellow solid. ESI-MS m / z calc. 382.2, found 383.1 (M + 1) +; Tention Re-time: 1.97 minutes (3 minutes of execution). 1H NMR 65 (400 MHz, DMSO) δ 7.52 (dd, J = 8.1, 1.3 Hz, 1H), 7.35 (d, J = 4.1 Hz, 1H), 7.24 to 7.12 ( m, J = 9.4, 8.0, 1.6 Hz, 2H), 7.08-6.98 (m, 1H), 6.35 (d, J = 4.1 Hz, 1H), 3 , 88 (d br, J = 11.3 Hz, 2H), 3.13 (wide s, 2H), 2.49 (s, 3H), 1.92-1.76 (m,

4H), 1.41 (s, 9H).

Step 3: 1- (Spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl) ethanonehydrochloride

[0339] 5

image191

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 twenty

[0340] To a solution of tert-butyl-1'-acetylspiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-ethyl carboxylate (600 mg, 1, 57 mmol) in CH2Cl2 (6 mL) HCl in dioxane (3.9 mL of 4 M, 15.7 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness to give 1-spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzox-azine] 1'iletanone hydrochloride (499 mg, 99%) which It was used without further purification. ESI-MS m / z calc. 282.1, found 283.3 (M + 1) +; Retention time: 0.86 minutes (3 minutes of execution). 25

4- (2-Methoxyethoxy) -3-methylbenzoic acid

[0341]

 30

image192

 35

 40

[0342] To a solution of 4-hydroxy-3-methyl-benzoic acid (2.0 g, 13 mmol) in THF (24 ml) was added phonium tetrabutylphos- hydroxide (18 ml of 40% w / v, 26 mmol). The reaction mixture was cooled to 0 ° C in an ice-water bath and then 1-bromo-2-methoxy-ethane (1.8 g, 1.2 ml, 13 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was made acidic by the addition of 1M HCl and the reaction was extracted with ethyl acetate. The organics were dried over sodium sulfate and evaporated to give 180 mg of 4- (2-methoxyethoxy) -3-methylbenzoic acid (yield: 6%). ESI-MS m / z calc. 210.2, found 209.2 (M-H) -. Retention time: 0.96 minutes (3 minutes of execution).

[0343] The following compounds were synthesized using the procedures described above: 3-methyl-4-propoxybenzoic acid, 4- (2-isopropoxyethoxy) -3-methylbenzoic acid, and 4- (3-methoxypropoxy) -3-methylbenzoic acid. fifty

3-cyano-4- (2-methoxyethoxy) benzoic acid

[0344]

 55

image193

 60

 65

[0345] 3-cyano-4-fluorobenzoic acid (500 mg, 3.03 mmol), 2-methoxyethanol (461 mg, 6.06 mmol), and 60% w / w NaH (363

mg, 9.08 mmol) were combined in acetonitrile (15 ml) and the reaction mixture was heated at 70 ° C overnight. The reaction mixture was made acidic by the addition of 1N HCl and extracted with ethyl acetate. The organics were dried over sodium sulfate, evaporated and purified by column chromatography (0-10% methanol in dichloromethane) to give benzoic 3-cyano-4- (2-methoxyethoxy) (625 mg, 93%). 1 H NMR (400 MHz, CD 3 CN) δ 9.60 (s, 1 H), 8.26 (d, J = 1.9 Hz, 1 H), 8.22 (dd, J = 8.9, 2.2 Hz , 1H), 7.22 (d, J = 8.9 Hz, 1H), 4.34 (dd, J = 5.2, 3.7 Hz, 2H), 5 3.79 (dd, J = 5 , 2, 3.6 Hz, 2H), 3.41 (s, 3H).

[0346] The following compound was synthesized using the procedures described above: 3-cyano-4-propoxybenzoic acid.

3-methoxy-4- (2- (trifluoromethoxy) ethoxy) benzoic 10

Step 1: Methyl 3-methoxy-4- (2- (trifluoromethoxy) ethoxy) methyl benzoate

[0347]

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[0348] To sodium hydride (200 mg, 5.0 mmol) in DMF (6 ml) under N2 was added methyl benzoate 4-hydroxy-3-methoxy- (920 mg, 5.0 mmol) and the mixture was stirred for 10 min. Ethyl 2- (trifluoromethoxy) trifluoromethanesulfonate (prepared according to the procedure described by Blazejewski, et. Al. JOC, 2001, 66 (3), 1061-1063) (1.2 g, 25.6 mmol) was added dropwise and the solution was stirred at room temperature for 2 h, then at 50 ° C for 2 h. The mixture was concentrated to a solid, and the residue was taken up in 50 ml of DCM before it was washed with brine (20 ml), dried over MgSO4 and purified by column chromatography (0-25% EtOAc / hexane ) to give methyl 3-methoxy-4- (2- (trifluoromethoxy) ethoxy) methyl benzoate as a white solid. ESI-MS m / z calc. 294.1, found 295.3 (M + 1) +; Retention time: 1.63 minutes (3 minutes of execution). 30

Step 2: 3-methoxy-4- (2- (trifluoromethoxy) ethoxy) benzoic acid

[0349]

 35

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 40

[0350] Methyl 3-methoxy-4- (2- (trifluoromethoxy) ethoxy) benzoate (crude from Step 1) was dissolved in THF (5 ml) and a suspension of LiOH (550 mg, 23 mmol) in Water (5 ml) was added. The mixture was stirred vigorously and heated at 60 ° C for 6 h before it was concentrated to half the volume. Water (5 ml) was added and the mixture was extracted with diethyl ether (1 x 10 ml). The aqueous layer was acidified with 4 N HCl at pH 2. The resulting mixture was extracted with ethyl acetate (3 x 10 ml) and the combined organics were washed (1 x 10 ml of H2O, 1 x 10 ml of brine), dried over MgSO4 and evaporated to give 3-methoxy-4-(2- (trifluoromethoxy) ethoxy) benzoic acid (1.050 g, 82%) as a white solid. ESI-MS m / z calc. 280.1, found 281.3 (M + 1) +; Retention time: 1.34 minutes (3 minutes of execution).

3-methoxy-4- (2- (methylsulfonyl) ethoxy) benzoic

 55

Step 1: Methyl 4- (2-bromoethoxy) -3-methoxybenzoate

[0351]

 60

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[0352] To a solution of methyl 4-hydroxy-3-methoxy-benzoate methyl (2.0 g, 11 mmol) in acetone (330 ml) was added K2CO3 (6.1 g, 44 mmol) followed by 1, 2-dibromoethane (6.2 g, 2.8 ml, 33 mmol). The mixture was stirred for 2d at 75 ° C. The mixture was cooled to room temperature and the solids were removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography (10-25% ethyl acetate / hexanes) to give methyl 4- (2-bromoethoxy) -3-methoxybenzoate. ESI-MS m / z calc. 288.0, found 289.1 (M + 1) +; Retention time: 1.47 minutes (3 minutes of execution).

Step 2: 3-Methoxy-4- (2- (methylthio ethoxy)) benzoate acetate 10

[0353]

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[0354] To a solution of methyl 4- (2-bromoethoxy) -3-methoxybenzoate (258 mg, 0.892 mmol) in ethanol (2 ml) was added CH3SNa (81.3 mg, 1.16 mmol). The reaction mixture was stirred for 3 hours at 90 ° C before it was cooled to rt and concentrated. Column chromatography (5-25% ethyl acetate / hexanes) gave methyl 3-methoxy-4- (2- (methylthio) ethoxy) benzoate acetate. ESI-MS m / z calc. 270.1, found 271.5 (M + 1) +; Retention time: 1.61 minutes (3 minutes of execution). 25

Step 3: 3-methoxy-4- (2- (methylsulfonyl) ethoxy) benzoate acetate

[0355]

 30

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 35

[0356] mCPBA (91 mg, 0.53 mmol) was added to a solution of methyl 3-methoxy-4- (2- (methylthio) ethoxy) benzoate acetate (68 mg, 0.25 mmol) in DCM ( 3 ml) at 0 ° C. The ice bath was removed, and the mixture was allowed to stir at room temperature for 2 h. They were added to the mixture sat. here NaHO3 (2 ml) and DCM (3 ml). The layers were separated and the organic layer was washed with sat. here NaHCO3 (2 ml), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (5-70% ethyl acetate / hexanes) to give methyl 3-methoxy-4- (2- (methylosulfonyl) ethoxy) benzoate acetate. ESI-MS m / z calc. 302.1, found 303.5 (M + 1) +; Retention time: 1.21 minutes (3 minutes of execution). Four. Five

Step 4: 3-Methoxy-4- (2- (methylsulfonyl) ethoxy) benzoic acid

[0357]

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[0358] Ethyl 3-methoxy-4- (2- (methylsulfonyl) ethoxy) benzoate (30 mg, 0.099 mmol) was taken up in water (1.2 ml), 60 H2SO4 (200 ml, 3.8 mmol) , and AcOH (1,300 ml, 23 mmol). The mixture was heated at 90 ° C for 6 h before it was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (1-40% MeOH / DCM) to give 3-methoxy-4- (2- (methylsulfonyl) ethoxy) benzoic. ESI-MS m / z calc. 274.1, found 275.1 (M + 1) +; Retention time: 0.69 minutes (3 minutes of execution).

 65

3-carbamoyl-4-isopropoxybenzoic acid

[0359]

image200

 5

 10

[0360] 3-cyano-4-isopropoxy-benzoic (50 mg, 0.24 mmol), hydrogen peroxide (280 µl of 30% w / v, 2.4 mmol), and 10% NaOH (240 ml of 10% w / v, 0.61 mmol) and stirred at room temperature for 16 h. The mixture was acidified with 4M HCl and extracted with ethyl acetate (2 x 7 ml). The combined organics were washed with brine, dried over sodium sulfate and evaporated to give 3-carbamoyl-4-isopropoxy-benzoic acid (45 mg, 15 83%). ESI-MS m / z calc. 223.1, found 224.3 (M + 1) +; Retention time: 1.49 minutes (4 min of execution).

4-tert-butoxy-3-methoxybenzoic

Step 1: 4-tert-butoxy-3-methoxy-benzaldehyde 20

[0361]

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 30

[0362] 4-hydroxy-3-methoxy-benzaldehyde (500 mg, 3.29 mmol), Boc2O (1.74 g, 7.97 mmol), and Sc (OTf) 3 (0.080 g, 0.16 mmol) they were combined in dichloromethane (5 ml). The reaction mixture was allowed to stir at room temperature for 24 h. Water (5 ml) and dichloromethane (5 ml) were added and the two phases separated. The aqueous layer was extracted with dichloromethane (3 x 5 ml) and the combined organics were stirred with 10% aqueous potassium hydroxide until all remaining starting material was not observed in the organic phase (TLC, 40% acetate of ethyl in hexanes). The two phases were separated and then the dichloromethane layer was washed twice with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give 4-tert-butoxy-3- Methoxybenzaldehyde (130 mg, 19%) as a yellow oil. Rf = 0.66 (SiO2, 40% ethyl acetate in hexanes); ESI-MS m / z calc. 208.1, found 209.2 (M + 1) +. Retention time: 0.96 minutes (6 min walking).

Step 2: 3 butoxy 4-tert - methoxybenzoic

 Four. Five

[0363]

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[0364] 4-tert-Butoxy-3-methoxybenzaldehyde is suspended (130 mg, 0.62 mmol) in a mixture of dioxane (520 ml) and potassium hydroxide (6.5 ml of 0.20 M, 1.3 mmol). KMnO4 (150 mg, 0.93 mmol) was added and the reaction was vigorously stirred for 16 h. The reaction mixture was filtered and then concentrated to 3 ml. Hydrochloric acid (1 M, 4 ml) was added and the resulting precipitate was filtered (after standing for 15 minutes) and washed with 1 M 60 HCl and a small amount of water to give 4-tert-butoxy-3-methoxy-3-methoxy -benzoic acid (68 mg, 49%) as a white solid. Rf = 0.23 (SiO2, 40% ethyl acetate in hexanes); ESI-MS m / z calc. 224.1, found 225.2 (M + 1) +. Retention time: 1.66 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 12.80 (s, 1 H), 7.66-7.41 (m, 2 H), 7.09 (d, J = 8.8 Hz, 1 H), 3.78 (s, 3H), 1.32 (s, 9H).

[0365] The following compounds were synthesized using the procedures described above: -butyloxy-3-65 methyl-4-tert-benzoic acid from 4-hydroxy-3-methylbenzaldehyde, 2-fluoro-4,5-dimethoxybenzoic acid of 2 -fluoro- 4,5-dimethoxy benzaldehyde, 4-tert-butoxy-2-ethoxybenzoic acid from 4-hydroxy-2-methoxybenzaldehyde,

4-tert-Butoxy-2-fluor-2-fluoro-4-hydroxybenzaldehyde obenzoic acid, and 4-tert-butoxybenzoic acid from 4-hydroxybenzaldehyde.

2-fluoro-5-methoxy-4- (2-methoxyethoxy) benzoic acid

 5

Step 1: 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde

[0366]

 10

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[0367] AlCl3 (8.69 g, 65.2 mmol) was added to a solution of 2-fluoro-4,5-dimethoxy-benzaldehyde (2.00 g, 10.9 mmol) in DCM (100 ml) under an atmosphere of argon. The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was slowly quenched with water. The layers were separated and then the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over sodium sulfate and then evaporated to dryness to yield 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.82 g, 98%) as an off-white solid. ESI-MS m / z calc. 170.0, found 171.0 (M + 1) +. Retention time: 0.84 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 10.04 (s, 1 H), 7.22 (d, J = 6.7 Hz, 1 H), 6.73 (d, J = 11.9 Hz, 1 H), 3.81 (s, 3 H).

Step 2: 2-fluoro-5-methoxy-4- (2-methoxyethoxy) benzaldehyde 25

[0368]

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 35

[0369] 2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (0.500 g, 2.94 mmol) was dissolved in DMF (2.6 mL) containing Cs2CO3 (2.88 g, 8.82 mmol). 1-Bromo-2-methoxy-ethane (1.23 g, 828 ml, 8.82 mmol) was added and the reaction mixture was allowed to stir for 86 h. The reaction mixture was filitered and the filtrate evaporated to dryness to give 2-fluoro-5-methoxy-4-benzaldehyde (2-methoxyethoxy). ESI-MS m / z calc. 228.1, found 229.0 (M + 1) +. Retention time: 1.14 minutes (3 minutes of execution). 40

Step 3: 2-fluoro-5-methoxy-4- (2-methoxyethoxy) benzoic

[0370]

 Four. Five

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[0371] 2-Fluoro-5-methoxy-4- (2-methoxyethoxy) benzaldehyde (0.36 g, 1.6 mmol) was suspended in a mixture of oxane di- (1.5 ml) and KOH (16 ml 0.2 M, 3.2 mmol). KMnO4 (370 mg, 2.4 mmol) was added and the mixture was stirred vigorously for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated to 10 ml (blue solution). HCl (4 M, ~ 2 ml) was added and the resulting precipitate was filtered and washed with 1 M HCl and then with water (1.55 ml) to give 2-fluoro-methoxy-4-5 (2-methoxyethoxy) benzoic (300 mg, 78%) as a white solid. ESI-MS m / z calc. 244.1, found 245.1 (M + 1) +. Retention time: 1.01 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 12.96 (s, 1 H), 7.30 (d, J = 7.0 Hz, 1 H), 6.98 (d, J = 12.5 Hz, 1 H), 4.20 to 4.13 (m, 2H), 3.78 (s, 3H), 3.71-3.63 (m, 2H), 3.31 (s, 3H).

 60

4-tert-Butyl-3-cyanobenzoic acid

Step 1: Methyl 3-bromo-4-tert-butyl-benzoate

[0372] 65

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[0373] 4-tert-Butylbenzoic acid (3.00 g, 16.8 mmol) was mixed with nitric acid (11 ml), water (8.4 ml), glacial acetic acid (51 ml) and bromine (2, 9 g, 19 mmol) in a two-mouth flask containing an addition funnel and a reflux condenser. An aqueous solution of silver nitrate (2.9 g, 17 mmol) in water (8.5 ml) was added dropwise over 30 minutes with vigorous stirring. The mixture was stirred at room temperature for 16 h before it was poured into ice water. The solids were collected by vacuum filtration. The solids were collected in ethyl acetate and washed with water, then with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 3.2 g of a solid that was taken up in DMF (10 ml). To the solution was added potassium carbonate (4.7 g, 34 mmol) and methyl iodide (4.8 g, 34 mmol). The mixture was concentrated to dryness and the residue was dissolved in dichloromethane and washed with a solution of 1 N HCl, then with brine. The organics were dried over sodium sulfate and evaporated. The crude material was purified by column chromatography (0-10% ethyl acetate in hexanes) to give methyl 3-bromo-4-tert-butyl benzoate (2.26 g, 25%). 1 H NMR (400 MHz, CD 3 CN) δ 8.19 (d, J = 1.9 Hz, 1 H), 7.91 (dd, J = 8.3, 1.9 Hz, 1 H), 7.65 (d , J = 8.3 Hz, 1H), 3.89 (s, 3H), 1.54 (s, 9H). twenty

Step 2: Methyl 4-tert-butyl-3-cyanobenzoate

[0374]

 25

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[0375] Methyl 3-bromo-4-tert-butyl-benzoate methyl (2.26 g, 4.17 mmol) was dissolved in dry DMF (2.1 ml) before CuCN (821 mg, 9.17 mmol ) and NaCN (1.0 mg, 0.021 mmol), is additional. The mixture was washed thoroughly with nitrogen and stirred at 110 ° C for 24 h. The reaction mixture was diluted with ethyl acetate (70 ml) and washed with water. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography eluting with 0-10% ethyl acetate in hexanes to give methyl 4-tert-butyl-3-cyano-benzoate (390 mg, 43%). ESI-MS m / z calc. 217.1, found 218.5 (M + 1) +; Retention time: 2.07 minutes (3 minutes of execution). 1H NMR (400 MHz, CD3CN) δ 8.31 (d, J = 1.8 Hz, 1H), 8.16 (dd, J = 8.4, 2.0 Hz, 1H), 40 7.72 ( d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 1.55 (s, 9H).

Step 3: 4-tert-Butyl-3-cyanobenzoic acid

[0376] 45

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[0377] A mixture of methyl 4-tert-butyl-3-cyano-benzoate methyl (380 mg, 1.75 mmol), LiOH (3.5 mL of 2.0 M, 7.0 mmol) and 1, 4-dioxane (3.5 ml) was heated at 60 ° C for 2 h. The reaction mixture was made acidic and washed with dichloromethane (2 x 8 ml). The organics were combined, dried over sodium sulfate and evaporated to dryness to give 4-butyl-3-cyanobenzoic acid tert (348 mg, 98%). 1 H NMR (400 MHz, CD 3 CN) δ 9.77 (s, 1 H), 8.31 (d, J = 1.8 Hz, 1 H), 8.17 (dd, J = 8.4, 1.9 Hz , 1H), 7.71 (d, J = 8.4 Hz, 1H), 1.55 (s, 9H).

4-Cyano-3-methylbenzoic acid was also prepared using the procedures described above.

 60

(R) -3-Methoxy-4- (tetrahydrofuran-3-yloxy) benzoic acid

Step 1: (R) -Methyl 3-methoxy-4- (tetrahydrofuran-3-yloxy) benzoate

[0378] 65

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[0379] To a stirred solution of (3S) tetrahydrofuran-3-ol (403 mg, 4.57 mmol), methyl 4-hydroxy-3-methoxybenzoate (1.00 g, 5.49 mmol) and triphenylphosphane (1.44 g, 1.27 ml, 5.49 mmol) in THF (13 ml) at 0 ° C DIAD 10 (1.11 g, 1.06 ml, 5.49 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h, then at 55 ° C for 4 h. The mixture was diluted with EtOAc and washed with sat. here NaHCO3 (x2) and brine (x2). The organic layer was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield methyl (3) methoxy-4-benzoate (tetrahydrofuran-3-yloxy) (0, 97 g, 84%) as a viscous liquid. ESI-15 MS m / z calc. 252.1, found 253.3 (M + 1) +; Retention time: 1.72 minutes (3 minutes of execution).

Step 2: (R) -3-methoxy-4- (tetrahydrofuran-3-yloxy) benzoic acid

[0380] 20

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 25

[0381] A (R) -methyl 3-methoxy-4- (tetrahydrofuran-3-yloxy) benzoate (0.95 g, 3.8 mmol) dioxane (10 ml) and NaOH (10 ml, 1) were added M) and the mixture was heated at 80 ° C for 0.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in water and washed with EtOAc (x3). The aqueous layer was acidified and a solid formed. The aqueous layer (with the solid) was washed with EtOAc (x3). The combined organics were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give (R) -3-methoxy-4- (tetrahydrofuran-3-yloxy) benzoic acid (0.71 g, 79%) as a white solid. ESI-MS m / z calc. 238.1, found 239.3 (M + 1) +; Retention time: 1.21 minutes (4 min of execution). 1 H NMR (400 MHz, DMSO) δ 12.70 (s, 1 H), 7.54 (dd, J = 8.3, 1.4 Hz, 1 H), 7.46 (d, J = 1.3 35 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.13 to 5.2 (m, 1H), 4.04-3.62 (m, 7H), 2.40-2.12 (m, 1H), 2.10-1.86 (m, 1H).

[0382] The following compounds were synthesized using the procedures described above: (R) -4 - ((2,2-dimethyl-1,3-dioxolane-4-yl) methoxy) -3-methoxybenzoic, (S) -4 - ((2,2-Dimethyl-1,3-dioxolane-4-yl) methoxy) -3-methoxybenzoic identification action, and 4- (3-hydroxycyclopentyloxy) -3-methoxybenzoic acid.

 40

3-methoxy-4- (2-methoxy-2-methylpropoxy) benzoic acid

Step 1: Methyl 3-methoxy-4- (2-methyloxy) benzoate

[0383] 45

image211

 fifty

[0384] methyl methyl 3-methoxy-4- (2-methyloxyloxy) benzoate was synthesized using the procedure described above. ESI-MS m / z calc. 236.1, found 237.1 (M + 1) +; Retention time: 1.63 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 7.56 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.06 (d , J = 8.5 Hz, 1H), 5.07 (br s, 1H), 4.97 (br s, 1H), 4.55 (s, 2H), 3.83 (s, 3H), 3 , 82 (s, 3H), 1.78 (s, 3H).

Step 2: Methyl 3-methoxy-4- (2-methoxy-2-methylpropoxy) methyl benzoate 60

[0385]

 65

image212

 5

[0386] For methyl 3-methoxy-4- (2-methylaxyloxy) methyl benzoate (313 mg, 1.33 mmol) in MeOH (2.5 mL) 10 H2SO4 (71 µl, 1.3 mmol) was added and The mixture was heated in a microwave vial at 100 ° C for 15.5 h. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (0-30% ethyl acetate in hexane) to yield methyl 3-4-methoxy methyl benzoate (2-methoxy- 2-methyl-propoxy) (208 mg, 59%). ESI-MS m / z calc. 268.1, found 269.5 (M + 1) +; Retention time: 1.46 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.10 (d , J = 8.5 Hz, 1H), 15 3.90 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.17 (s, 3H), 1, 22 (s, 6H).

Step 3: 3-methoxy-4- (2-methoxy-2-methylpropoxy) benzoic acid

[0387] 20

image213

 25

[0388] Methyl 3-methoxy-4- (2-methoxy-2-methyl-propoxy) methyl benzoate (177 mg, 0.660 mmol), dioxane (1.9 ml) and 30 NaOH (1.8 ml of 1, 0 M, 1.8 mmol) were combined and the mixture was heated at 80 ° C for 15 min. The solvent was evaporated under reduced pressure and the crude mixture was dissolved in water. The mixture was extracted with EtOAc (3x). The aqueous layer was acidified with 1 N HCl before it was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give 3-methoxy-4- (2-methoxy-2-methyl-propoxy) benzoic acid (130 mg, 77%). ESI-MS m / z calc. 254.1, found 255.5 (M + 1) +; 35 retention time: 1.14 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 12.61 (s, 1 H), 7.54 (dd, J = 8.4, 1.9 Hz, 1 H), 7.45 (d, J = 1.8 Hz , 1H), 7.07 (d, J = 8.5 Hz, 1H), 3.89 (s, 2H), 3.81 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).

4 - ((1R, 2R) -2-Hydroxycyclopentyloxy) -3-methoxybenzoic acid

 40

Step 1: Methyl 4 - ((1R, 2R) -2-Hydroxycyclopentyloxy) -3-methoxybenzoate

[0389]

 Four. Five

image214

 fifty

 55

[0390] 6-Oxabicyclo [3.1.0] hexane (2.43 g, 2.50 ml, 28.9 mmol) was added dropwise to a stirred solution of methyl 4- hydroxy-3-methoxybenzoate ( 5.26 g, 28.9 mmol) and BF3 · OEt2 (410 mg, 369 ml, 2.89 mmol) in benzene (10 ml) at room temperature. The mixture was stirred at room temperature overnight before it was diluted with ethyl acetate and washed with 1N NaOH. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 0-100% EtOAc in hexanes to give methyl 4- ((1R, 2R) -2-clopentyloxy hydroxycy-) - 3-methoxybenzoate. ESI-MS m / z calc. 266.1, found 267.1 (M + 1) +; Retention time: 1.16 minutes (3 minutes of execution).

Step 2: 4 - ((1R, 2R) -2-Hydroxycyclopentyloxy) -3-methoxybenzoic acid 65

[0391]

image215

 5

 10

[0392] A solution of methyl 4 - [(1R, 2R) -2-hydroxycyclopentoxy] -3-methyl-methoxy-benzoate (2.8 g, 11 mmol) and LiOH (21 mL of 2.0 M, 42 mmol ) in dioxane (20 ml) was stirred at 50 ° C overnight. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was acidified with 1 N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give 4 - ((1R, 2R) -2-Loxy hydroxycyclopenty -) - 3-methoxybenzoic acid. ESI-MS m / z calc. 252.1, found 253.5 (M + 1) +; Retention time: 1.07 15 minutes (3 minutes of execution).

4- (2-methoxyethoxy) -3- (trifluoromethyl) benzoic acid

[0393] 20

image216

 25

 30

[0394] 3-methoxypropan-1-ol (217 mg, 2.40 mmol), 4-fluoro-3- (trifluoromethyl) benzoic acid (500 mg, 2.40 mmol), and NaH (240 mg, 6.0 mmol ) were combined in THF (10 ml) and DMF (1 ml) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between ethyl acetate and a 1M aqueous solution of hydrochloric acid. The layers were separated and then the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude material was purified by column chromatography using a gradient of 0-5% methanol in dichloromethane to yield 4- (3- methoxypropoxy) -3- (trifluoromethyl) benzoic acid (213 mg, 32%) as a white solid. . ESI-MS m / z calc. 278.1, found 279.3 (M + 1) +; Retention time: 1.38 minutes (3 minutes of execution).

[0395] 4-Propoxy-3- (trifluoromethyl) benzoic acid was prepared from 4-fluoro-3- (trifluoromethyl) benzoic acid and 3- fluoro-4- (2-methoxyethoxy) benzoic acid was prepared from 3,4 -difluorobenzoic acid using the procedure described above.

4- (2-hydroxypropan-2-yl) -3-methoxybenzoic acid

[0396] 45

image217

 fifty

 55

[0397] 4-Bromo-3-methoxy-benzoic acid (2.00 g, 8.67 mmol) was dissolved in THF (50 ml) and the solution was cooled to -78 ° C. n-BuLi in hexanes (7.6 ml of 2.5 M, 19 mmol) was added dropwise over 15 minutes. The reaction mixture was allowed to stir for 30 minutes at -78 ° C and then with acetone (640 µl, 8.9 mmol) was added dropwise. The reaction mixture was allowed to stir for 30 minutes at -78 ° C and then allowed to warm to room temperature. The reaction mixture was diluted with 100 ml of 1M aqueous sodium hydroxide. The organic layer was discarded and the aqueous layer was made acidic with 4M aqueous hydrochloric acid. Then, the aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was purified by column chromatography using a gradient of 0-5% of methanol in dichloromethane to give 4- (2-hydroxypropan-2-yl) -3-methoxybenzoic acid (618 mg, 34%). ESI-MS m / z calc. 210.1, found 209.1 (M-1) -; Retention time: 0.68 minutes (3 minutes of execution).

[0398] 4- (3-Hydroxyoxetane-3-yl) -3-methoxybenzoic acid was also prepared using the method described above. ESI-MS m / z calc. 224.1, found 223 (M-1) -; Retention time: 0.69 minutes (3 minutes of execution).

1- (2-Methoxyethyl) -2-oxo-1,2-dihydropyridine-4-carboxylic

 5

Step 1: 1- (2-Methoxyethyl) -2-oxo-1,2-dihydropyridine-4-carboxylate and 2- (2- methoxyethoxy) isonicotinate

[0399]

 10

image218

 fifteen

[0400] methyl 2-oxo-1H-pyridine-4-carboxylate ethyl (2.00 g, 13.1 mmol), K2CO3 (3.61 g, 26.1 mmol), THF (48 ml), DMF ( 38 ml) and 1-bromo-2-methoxy-ethane (3.63 g, 2.45 ml, 26.1 mmol) were combined and the mixture was stirred at 80 ° C for 2d. The reaction was filtered using ethyl acetate and the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (0 to 100% ethyl acetate in hexane) to give methyl 1-20 (2- Methoxyethyl) -2-oxo-1,2-dihydropyridine-4-carboxylate ethyl [(1.22 g, 44%), ESI-MS m / z calc. 211.1, found 212.3 (M + 1) +; Retention time: 0.57 minutes (3 minutes of execution); 1 H NMR (400 MHz, DMSO) δ 8.35 (d, J = 5.2 Hz, 1 H), 7.41 (d, J = 5.2 Hz, 1 H), 7.21 (s, 1 H), 4.47-4.36 (m, 2H), 3.89 (s, 3H), 3.71-3.64 (m, 2H), 3.30 (s, 3H)] and methyl 2- (2 -methoxyethoxy) isonicotinate [(405 mg), ESI-MS m / z calc. 211.1, found 212.1 (M + 1) +; Retention time: 1.04 minutes (3 minutes of execution); 1 H NMR (400 MHz, DMSO) δ 7.75 (d, J = 7.0 Hz, 1 H), 6.86 (s, 1 H), 25 6.55 (d, J = 7.0 Hz, 1 H) , 4.09 (t, J = 5.2 Hz, 2H), 3.85 (s, 3H), 3.58 (t, J = 5.2 Hz, 2H), 3.23 (s, 3H) ].

Step 2: 1- (2-methoxyethyl) -2-oxo-1,2-dihydropyridine-4-carboxylic acid

[0401] 30

image219

 35

[0402] Ethyl 1- (2-methoxyethyl) -2-oxo-pyridine-4-carboxylate ethyl (1.56 g, 7.39 mmol), dioxane (16 ml) and NaOH (20 ml of 1 M, 20 mmol) were combined and the mixture was heated at 80 ° C for 50 min. The solvent was evaporated under reduced pressure and the residue was dissolved in water before it was washed with EtOAc (3x). The aqueous layer was acidified with 1 N HCl and washed with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give 1- (2-methoxyethyl) -2-oxo-pyridine-4-carboxylic acid (1.0 g, 69%) as a solid White. ESI-MS m / z calc. 197.2, found 198.3 (M + 1) +; Retention time: 0.29 minutes (3 minutes of execution); 1 H NMR (400 MHz, DMSO) δ 13.59 (s, 1 H), 7.72 (d, J = 7.0 Hz, 1 H), 6.84 (d, J = 1.6 Hz, 1 H), 6.53 (dd, J = 7.0, 1.6 Hz, 1H), 4.08 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 5.2 Hz, 2H ), 3.23 (s, 3H). Four. Five

2- (2-methoxyethoxy) isonicotinic acid

[0403]

 fifty

image220

 55

[0404] Methyl 2- (2-methoxyethoxy) pyridine-4-carboxylate (562 mg, 2.66 mmol), dioxane (6 ml) and NaOH (7.1 ml of 1 M, 7.1 mmol) were combined and the mixture was heated at 80 ° C for 50 min. The solvent was evaporated under reduced pressure and the residue was dissolved in water before it was washed with EtOAc (3x). The aqueous layer was acidified with 1 N HCl and washed with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give 2- (2-methoxyethoxy) pyridine-4-carboxylic acid (457 mg, 87%) as a white solid. ESI-MS m / z calc. 197.2, found 198.3 (M + 1) +; Retention time: 0.66 minutes (3 minutes of execution); 1 H NMR (400 MHz, DMSO) δ 13.64 (s, 1 H), 8.32 (d, J = 5.2 Hz, 1 H), 7.39 (d, J = 5.2 Hz, 1 H), 7.18 (s, 1H), 4.51-4.27 (m, 2H), 3.78-3.54 (m, 2H), 3.30 (s, 3H). 65

4-tert-Butyl-3-hydroxybenzoic acid

[0405]

image221

 5

 10

[0406] To a stirring solution of 4-tert-butyl-3-methoxy-benzoic acid (400 mg, 1.92 mmol) in anhydrous DCM (9 ml) under N2 at -78 ° C was added BBR3 (5, 76 ml of 1 M in DCM, 5,763 mmol) drop by drop for 30 minutes. The mixture was allowed to stir at -78 ° C for 1 hour, allowed to warm to room temperature for 1 hour and then stirred at room temperature for 1 hour. The mixture was poured onto crushed ice and stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with DCM (3x). The combined organics were combined, dried over Na2SO4 and then concentrated under reduced pressure to give 4-tert-butyl-3-hydroxybenzoic acid. ESI-MS m / z calc. 194.1, found 195.1 (M + 1) +; Retention time: 1.45 minutes (3 minutes of execution); 1 H NMR (400 MHz, DMSO) δ 12.50 (s, 1 H), 9.71 (s, 1 H), 7.39 (d, J = 1.1 Hz, 1 H), 7.32 (dd, J = 8.0 Hz, 1.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 1.35 (s, 9H).

 twenty

4-ethyl-3-hydroxybenzoic acid

Step 1: 4-ethyl-3-methoxybenzoic acid

[0407] 25

image222

 30

[0408] A mixture of 4-bromo-3-methoxy-benzoic acid (2.49 g, 10.9 mmol) and Pd (dppf) Cl2 (158 mg, 0.216 mmol) was stirred in dioxane (25 ml) and Et2Zn ( 22 ml, 1 M in hexanes, 22 mmol) was added. The reaction mixture was heated 35 to 70 ° C for 1 h. The mixture was cooled to room temperature and quenched with MeOH (1.1 ml). The solution was diluted with ethyl acetate (20 ml) and washed with 1 N HCl (10 ml). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness to give 4-ethyl-3-methoxybenzoic acid. ESI-MS m / z calc. 180.1, found 179.1 (M-1) -; Retention time: 1.77 minutes (3 minutes of execution).

 40

Step 2: 4-ethyl-3- hydroxybenzoic acid

[0409]

 Four. Five

image223

 fifty

[0410] 4-ethyl-3-hydroxybenzoic acid was prepared using the method described above. ESI-MS m / z calc. 166.1, 55 found 167.1 (M + 1) +; Retention time: 1.09 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 12.62 (s, 1 H), 9.64 (s, 1 H), 7.37 (d, J = 1.5 Hz, 1 H), 7.33 (dd, J = 7.8.1.5Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 2.57 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7 , 5 Hz, 3H). 4-ethyl-3-methylbenzoic acid was also prepared using the procedures described above.

 60

3-methoxy-4- (1-methoxy-2-methyl-1-oxopropan-2-yl) benzoic

Step 1: methyl tert-butyl 4-bromo-3-methoxybenzoate

[0411] 65

image224

 5

[0412] MgSO4 (4.82 g, 40.0 mmol), DCM (40 ml) and H2SO4 (533 ml, 10.0 mmol) were combined at 0 ° C and the mixture was allowed to stir for 30 minutes at 0 ° C. 4-Bromo-3-methoxy-benzoic acid (2.31 g, 10.0 mmol) and 2-methyl-propan-2-ol (4.78 ml, 50.0 mmol) were added and the mixture was allowed to stir to ta for one night. The mixture was filtered to remove MgSO4 and the filtrate was washed with 1N NaOH. The layers were separated and the organic layer was dried over sodium sulfate and the solvent was removed to give 400 mg of methyl tert-butyl 4-bromo-3-methoxybenzoate. ESI-MS m / z calc. 286.0, found 287.0 (M + 1) +; Retention time: 3.11 minutes (4 min of execution).

Step 2: tert-butyl 3-methoxy-4- (1-methoxy-2-methyl-1-oxopropan-2-yl) benzoate

[0413]

image225

 twenty

 25

[0414] To a microwave vial was added ZnF2 (36 mg, 0.35 mmol) and Pd (tBu3P) 2 (7.2 mg, 0.014 mmol). The reaction vessel was purged with nitrogen for 10 minutes before methyl tert-butyl 4-bromo-3-methoxybenzoate (200 mg, 0.70 mmol) dissolved in DMF (2.5 ml) followed by (1- Methoxy-2-methyl-prop-1-enoxy) trimethyl-silane 30 (180 mg, 1.1 mmol). The reaction vessel was placed in an 80 ° C oil bath under a nitrogen atmosphere and the mixture was allowed to stir overnight. The mixture was allowed to cool to rt and filtered through a frit and washed with brine and EtOAc. The organics were separated and dried over sodium sulfate. The solvent was removed and the residue was taken to the next step without further purification. ESI-MS m / z calc. 308.2, found 309.4 (M + 1) +; Retention time: 3.12 minutes (4 min of execution). 35

Step 3: 3-methoxy-4- (1-methoxy-2-methyl-1-oxopropan-2-yl) benzoic acid

[0415]

 40

image226

 Four. Five

[0416] To the crude tert-butyl 3-methoxy-4- (1-methoxy-2-methyl-1-oxopropan-2-yl) benzoate from Step 2 was added DCM (1 50 ml) followed by TFA (540 ml , 7.0 mmol). The reaction was allowed to stir for 2 h before concentrating in vacuo. The residue was dissolved in DMF, filtered and purified by prep HPLC (MeOH: H2O, 1-99% in an HCl modifier) to give 3-methoxy-4- (1-methoxy-2-methyl-1-oxopropan - 2-yl) benzoic. ESI-MS m / z calc. 252.1, found 253.2 (M + 1) +; Retention time: 2.45 minutes (4 min of execution).

 55

3-fluoro-4- (oxetane-3-yloxy) benzoic acid

Step 1: Methyl 3-fluoro-4- (oxetane-3-yloxy) methyl benzoate

[0417] 60

 65

image227

 5

[0418] NaH (80 mg, 2.0 mmol) was added to a mixture of oxetane-3-ol (150 mg, 2.0 mmol) and DMF (2 ml) at 0 ° C. The reaction was allowed to stir before methyl was added 3,4-difluorobenzoate (170 mg, 1.0 mmol) 10 minutes. The reaction was then heated at 80 ° C overnight. The reaction was quenched with brine and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate and the solvent was removed to give methyl 3-fluoro-4- (oxetane-3-yloxy) methyl benzoate. ESI-MS mlz calc. 226.1, found 227.2 (M); Retention time: 2.36 minutes (4 min of execution).

 fifteen

Step 2: 3-fluoro-4- (oxetane-3-yloxy) benzoic acid

[0419]

image228

 twenty

 25

[0420] Crude methyl 3-fluoro-4- (oxetane-3-yloxy) benzoate from Step 1, MeOH (1 ml) and KOH (4.0 ml of 3.0 M, 12 mmol) were combined and the mixture was let stir for 3 ha rt. The mixture was extracted with EtOAc and the organic layer was discarded. Then, the aqueous layer was treated with 1 N HCl and the pH was adjusted to pH 3. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were dried over sodium sulfate and the solvent was removed. The crude acid was used without further purification. ESI-MS m / z calc. 212.1, found 213.0 (M + 1) +; Retention time: 1.65 minutes (4 min of execution).

3-Formyl-4- isopropoxybenzoic acid

 35

Step 1: Methyl 3-formyl-4-isopropoxybenzoate

[0421]

 40

image229

 Four. Five

[0422] A methyl 3-formyl-4-hydroxy-benzoate methyl (10.0 g, 55.5 mmol), potassium carbonate (30.7 g, 222 mmol) 50 and N, N-dimethylformamide (63 ml ) 2-iodopropane (11.1 ml, 111 mmol) was added. The mixture was heated at 60 ° C for 18 hours. The mixture was filtered using ethyl acetate (200 ml) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml) and washed with water (3 x 75 ml) and a saturated aqueous solution of sodium chloride (1 x 75 ml). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to provide methyl methyl 3-formyl-4-isopropoxy benzoate (98%) as a yellow viscous liquid. ESI-MS m / z calc. 222.2, found 223.3 (M + 1) +; Retention time: 1.51 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 10.35 (s, 1 H), 8.23 (d, J = 2.3 Hz, 1 H), 8.17 (dd, J = 8.8, 2.3 Hz , 1H), 7.39 (d, J = 8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H).

Step 2: 3-formyl-4-isopropoxybenzoic acid 60

[0423]

 65

image230

 5

 10

[0424] To a solution of the ester (from the previous step) in dioxane (4 ml) was added 2 ml of sodium hydroxide solution (5N). The reaction mixture was heated at 65 ° C for 4 hours. The reaction mixture was cooled to room temperature and diluted with 20 ml of water. The water layer was extracted with 20 ml portion of ethyl acetate (2x). The organic extracts were discarded and the aqueous layer was acidified with 1M HCl. The resulting product was extracted in ethyl acetate, dried over MgSO4, filtered, and evaporated to dryness to give 3-formyl-4-isopropoxy-benzoic acid (320 mg, 55% in 2 steps) as a white solid. . 1 H NMR (400 MHz, DMSO) δ 10.36 (s, 1 H), 8.23 (d, J = 2.5 Hz, 1 H), 8.15 (dd, J = 2.5, 8.9 Hz , 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.96-4.87 (m, 1H), 1.37 (d, J = 5.6 Hz, 6H).

4- (2-Cyanopropane-2-yloxy) -3-methoxybenzoic

 twenty

[0425]

image231

 25

[0426] A (250 ml) 3-neck-flask with oven-dried 4- (cyanomethoxy) -3-methoxy-benzoic acid (1.0 g, 4.8 mmol) and anhydrous THF (14 ml) cooled to -78 ° C KHMDS in toluene (29 ml of 0.5 M, 15 mmol) was added slowly. After 1 h, iodomethane (960 µL, 15 mmol) was added dropwise and the mixture was stirred at -78 ° C for 30 min. THF (14 ml) was added and the reaction was cooled to -78 ° C. KHMDS (19 ml of 0.5 M, 9.5 mmol) was added. After 1 h, iodomethane (640 µl, 10 mmol) was added and the reaction was stirred for 30 min at -78 ° C. The reaction was allowed to warm to room temperature overnight. The reaction was stopped with NH4Cl. The aqueous layer was separated and washed with ethyl acetate (x 3). The aqueous layer was acidified and extracted with ethyl acetate (x 3). The organic layer was dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to give a mixture of mono and di-alkylated products as observed by LCMS (negative mode). ESI-MS m / z calc. 235.4, found 234.1 (M-1) -. Retention time: 0.93 minutes (3 minutes of execution).

 40

2-cyano-4-isopropoxy-benzoic acid

Step 1: 2-Bromo-5-isopropoxybenzonitril

[0427]

 Four. Five

image232

 fifty

[0428] 2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken up in 55 dry DMF (12.5 ml) . 2-Iodopropane (2.00 ml, 20.2 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The mixture was diluted with ether (100 ml), filtered on celite and the filtrate was washed with water (3 x 50 ml) and brine (50 ml), dried over MgSO4, evaporated and purified by column chromatography ( 5-45% EtOAc / hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitril as a colorless oil. 1 H NMR (400 MHz, CDCl 3) δ 7.53 (d, J = 9.0 Hz, 1 H), 7.15 (d, J = 2.9 Hz, 1 H), 6.99 (dd, J = 9 , 0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 60 (d, J = 6.0 Hz, 6H). ESI-MS m / z calc. 239.0, found 240.1 (M + 1) +. Retention time: 1.81 minutes (3 minutes of execution).

Step 2: tert-butyl 2-cyano-4-isopropoxybenzoate

 65

[0429]

image233

 5

[0430] 2-Bromo-5-isopropoxybenzonitril was added (200 mg, 0.83 mmol) in dry THF (0.5 ml) to a solution of 10 lithium butyl (570 µl of 1.6 M, 0.91 mmol ) in dry THF (0.5 ml) at -65 ° C. The mixture was stirred for 15 minutes and then a solution of BOC anhydride (380 ml, 1.7 mmol) in dry THF (1 ml) was added and the reaction was stirred for an additional 15 min at this temperature. The cooling bath was removed and water (2 ml) was added. The solvent was removed in vacuo and the mixture was extracted with dichloromethane (5 ml). The organic layer was dried, filtered and concentrated to give a brown oil that was purified on silica gel chromatography using a gradient of 15-70% ethyl acetate in hexanes to give the tert-butyl-2-cyano- 4-isopropoxybenzoate (82 mg, 38%). ESI-MS m / z calc. 261.3, found 262.3 (M + 1) +. Retention time: 1.96 minutes (3 minutes of execution).

Step 3: 2-cyano-4-isopropoxybenzoic acid

 twenty

[0431]

image234

 25

 30

[0432] Trifluoroacetic acid (0.6 ml, 7.8 mmol) was added dropwise to a solution of 2-cyano-4-isopropoxy tert-butyl benzoate (82 mg, 0.31 mmol) in dichloromethane (0.6 ml) at 0 ° C under N2 atmosphere. After completing the addition, the cooling bath was removed and stirring was continued for an additional 2 h at 25 ° C. The solvent was removed under reduced pressure to give 2-cyano-4-isopropoxybenzoic acid that was used directly in the next step without further purification. 35

1-Methylindazol-7-carboxylic

[0433]

 40

image235

 Four. Five

[0434] Methyl 1-methylindazol-7-carboxylate methyl (1 g, 5.3 mmol) was suspended in a mixture of sodium hydroxide (12 mL of 1.0 M, 12 mmol) and 1,4-dioxane ( 8.7 ml). The reaction mixture was heated at 80 ° C for 30 minutes. The dioxane was evaporated and the aqueous layer was extracted with ethyl acetate three times and the extracts were discarded. The aqueous layer was acidified with 4M hydrochloric acid and then filtered and washed with 1M hydrochloric acid to give 1-methylindazole-7-carboxylic acid (0.9g, 97%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.31 (s, 1 H), 8.20 (s, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 4.18 (s, 3H).

 55

2,4-Diethoxy-3-methyl-benzoic

[0435]

image236

 60

 65

[0436] Methyl 2,4-dihydroxy-3-methyl-methyl benzoate (193 mg, 1.06 mmol) was dissolved in DMF (1 ml) containing cesium carbonate (1.03 g, 3.18 mmol) . Iodoethane (847 µL, 10.6 mmol) was added and the reaction mixture was allowed to stir for 86 hours. Then, the reaction mixture was filtered and evaporated to dryness. The crude material was dissolved in a mixture of dioxane (2 ml) and sodium hydroxide (1.1 ml of 1.0 M, 1.1 mmol). The reaction mixture was then heated at 80 ° C for 75 minutes. The dioxane was evaporated to dryness and the reaction mixture was made acidic with 4M hydrochloric acid. The aqueous layer was extracted 3 times with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and evaporated to dryness to yield 2,4-diethoxy-3-methyl-benzoic acid (189 mg, 80%) as a pale yellow solid which It was used without further purification. 1 H NMR (400 MHz, DMSO) δ 12.37 (s, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 4.08 (q, J = 6.9 Hz, 2H), 3.87 (q, J = 7.0 Hz, 2H), 2.06 (s, 3H), 1.36 (t, J = 6 , 9 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H). 10

4- (isopropylsulfonyl) -3-methylbenzoic acid

Step 1: 4- (isopropylthio) -3- methylbenzoic acid

 fifteen

[0437]

image237

 twenty

 25

[0438] Lithium butyl (16 ml of 1.6 M, 26 mmol) was added dropwise to a mixture of 4-bromo-3-methyl-benzoic acid (2.5 g, 12 mmol) and THF (63 ml) at -78 ° DO. The mixture was allowed to stir at -78 ° C for 30 minutes before a solution of 2-isopropyldisulfanylpropane (1.7 g, 12 mmol) in THF (2 ml) was added dropwise. The mixture was allowed to stir at -78 ° C for 30 min, then 30 min at RT. The reaction mixture was diluted with 100 ml of 1M aqueous sodium hydroxide. The organic layer was discarded and the aqueous layer was made acidic with 4M aqueous hydrochloric acid. Then, the aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was purified by column chromatography using a gradient of 0-5% MeOH in dichloromthane to give 4- (isopropylthio) -3-methylbenzoic acid (870 mg, 18%). MS m / z calc. 210.3, found 211.2 (M + 1) +. Retention time: 2.32 minutes (3 minutes of execution). 35

Step 2: 4- (isopropylsulfonyl) -3-methylbenzoic acid

[0439]

 40

image238

 Four. Five

[0440] 3-Chlorobenzenecarboperoxoic acid (930 mg, 4.2 mmol) was added to a mixture of 4- (isopropylthio) -3-met ylbenzoic acid (250 mg, 1.2 mmol) and dichloromethane (5.0 ml) at 25 ° C. The mixture was allowed to stir at 25 ° C for 50 2 h before concentrating in vacuo. The white solid material was collected in dichloromethane and subjected to column chromatography (0-2% MeOH / dichloromethane) to give 4-isopropyl-3-methyl-benzoic acid (90 mg, 31%) as a white solid. ESI-MS m / z calc. 242.3, found 243.2 (M + 1) +. Retention time: 1.57 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 13.50 (s, 1H), 8.50-7.66 (m, 3H), 3.50 -3.47 (m, 1H), 2.67 (s, 3H), 1.19 (d, J = 1.16 Hz, 6H). 55

3-methyl-4- (trifluoromethoxy) benzoic

[0441]

 60

image239

 65

[0442] A mixture of 3-bromo-4- (trifluoromethoxy) benzoic acid (923 mg, 3.24 mmol) and PdCl2 (dppf) (95 mg, 0.13 mmol) were stirred in 1,4-dioxane (9 ml) in a three-mouth flask in an argon atmosphere (a condenser was added to the flask). Dimethylcinc in toluene (3.2 ml of 2.0 M, 6.4 mmol) was added very slowly (Caution: the reaction was very exothermic) and the mixture was stirred at room temperature for 1 hour before it was heated to 5 70 ° C for 18 h. The mixture was cooled to room temperature before it was charged with additional dioxane (9 ml) and PdCl2 (dppf) (100 mg). The mixture was cooled to 0 ° C before additional dimethyl zinc in toluene (3.0 ml, 2.0 M) was added. The ice bath was removed and the mixture was heated at 70 ° C overnight. The mixture was cooled to room temperature and quenched with methanol (2 ml) very slowly. The solution was diluted with ethyl acetate and washed with 1 N HCl (3x). The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness to give 3-methyl-4- (trifluoromethoxy) benzoic (56%).

4-Methoxy-3,5-dimethyl-benzoic acid

Step 1: Methyl 4-hydroxy-3,5-dimethyl-benzoate 15

[0443]

image240

 twenty

 25

[0444] K2CO3 (3.0 g, 21 mmol) followed by iodomethane (1.2 ml, 20 mmol) were added to a solution of 4-benzyloxy 3,5-dimethyl-benzoic acid (5.0 g, 20 mmol) in DMF (100 ml) and the mixture was stirred at room temperature for 6 h. The solution was diluted with water and acidified with 1% aq. HCl The mixture was extracted with EtOAc (3 x 200 ml). The combined organics were washed with water (200 ml), dried over sodium sulfate, filtered, and concentrated. The residue was taken up in degassed 2-propanol (100 ml). Pd / C (10%, 500 mg) was added and the mixture was degassed again and filled with Ar. The mixture was introduced under an atmosphere of H2 (balloon) and stirred overnight. The solids were filtered off through Celite and the filtrate was concentrated in vacuo to provide methyl 4-hydroxy-3,5-dimethyl-methyl benzoate (91%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 7.56 (s, 2H), 3.76 (s, 3H), 3.38 (s, 9H), 2.19 (s, 6H). 35

Step 2: 4-methoxy-3,5-dimethyl-benzoic acid

[0445]

 40

image241

 Four. Five

[0446] Iodomethane (350 ml, 5.6 mmol) was added to a vigorously stirred suspension of methyl 4-hydroxy-3,5-dimethyl-methyl benzoate (0.50 g, 2.8 mmol) and K2CO3 ( 1.5 g, 11 mmol) in DMF (14 ml) and the mixture was stirred overnight at 60 ° C. The solution was cooled to room temperature and concentrated in vacuo. The residue was taken up in water and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organics were washed with water (300 ml) and dried over sodium sulfate, filtered and concentrated to provide the intermediate ester. The residue was taken up in EtOH (20 ml) and NaOH (1.4 ml of 2.0 M, 2.8 mmol) was added. The solution was heated at 60 ° C overnight. The solution was cooled to room temperature and the volatiles were removed in vacuo. The residue was taken up in water and extracted with EtOAc. The layers were separated and the organic extracts were discarded. The aqueous layer was acidified with 1 N aqueous HCl, and extracted with ethyl acetate (3 x 100 ml). The combined organics were dried over sodium sulfate, filtered and concentrated to provide 4-methoxy-3,5-dimethyl-benzoic acid (85%) as a white solid. (4-Isopropoxy-3,5-dimethylphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'yl) methanone was also prepared using the procedures described above . 60

1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0447]

 65

image242

 5

[0448] A solution of KOH (1.60 g, 28.5 mmol) was added to 2-oxo-1H-pyridine-3-carboxylic acid (2.00 g, 14.4 mmol) in methanol (20 ml) in water (3 ml) and the mixture was stirred vigorously until a thick suspension formed. Iodomethane (10 ml, 0.16 mmol) was added and the mixture was heated at reflux for 1.5 h. The mixture was concentrated to 1/3 of the volume and acidified to pH 1 with 6N HCl. The solids were filtered off and washed with water (3 x 2 ml) and acetonitrile (2 x 2 ml), and then dried in vacuo to give 1-methyl 2-oxo-pyridine-3-carboxylic acid as a white solid ESI-MS m / z calc 153.0, found 154.1 (M-1) -. Retention time: 0.65 minutes (3 minutes of execution). 1-Ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid was also synthesized using the procedure described above.

 fifteen

1-Isopropyl-2-oxo-pyridine-4-carboxylic acid

Step 1: Ethyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate

[0449] 20

image243

 25

[0450] To methyl 2-oxo-1H-pyridine-4-carboxylate (700 mg, 4.57 mmol) in dry DMF (4.4 ml), ground K2CO3 (2.53 g, 18.3 mmol) was added finely ) followed by 2-iodopropane (914 µl, 9.14 mmol). The mixture was heated at 60 ° C (external) for 1 h. The mixture was diluted with acetonitrile (10 ml) and filtered. The filtrate was evaporated on Celite and purified by column chromatography (0 to 100% EtOAc / DCM) to give methyl methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (230 mg). ESI-MS m / z calc 195.1, found 196.3 (M-1) -. Retention time: 1.09 minutes (3 minutes of execution). 35

Step 2: 1-isopropyl-2-oxo-pyridine-4-carboxylic acid

[0451]

 40

image244

 Four. Five

 fifty

[0452] To Methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (225 mg) was added NaOH (550 µl of 25% by weight, 4.3 mmol) and water (0.6 ml ). The mixture was stirred rapidly and heated at 50 ° C for 1 h. The mixture was cooled, acidified to pH 2 with 6 N aq. HCl and the solids were collected, rinsed with water and ACN (2x). The solid was dried in vacuo to give 1-isopropyl-2-oxo-pyridine-4-carboxylic acid as a white solid. ESI-MS m / z calc 181.2, found 182.3 (M-1) -. Retention time: 0.86 minutes (3 minutes of execution). 55

3-fluoro-4-isopropoxybenzoic acid

Step 1: Methyl 3-fluoro-4-isopropoxybenzoate

 60

[0453]

image245

 65

[0454] To methyl 3-fluoro-4-hydroxybenzoate (2.00 g, 11.8 mmol) in DMF (12.5 mL) K2CO3 (6.50 g, 47.0 mmol) was added followed by 2-iodopropane (2.35 ml, 23.5 mmol). The mixture was heated at 60 ° C for 1.5 h. The mixture was filtered using EtOAc and the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-fluoro-4-isopropoxybenzoate. ESI-MS m / z calc 212.1, found 213.3 (M + 1) +. Retention time: 1.70 minutes (3 minutes of execution). 10

Step 2: 3-fluoro-4-isopropoxybenzoic acid

[0455]

 fifteen

image246

 twenty

 25

[0456] Methyl 3-fluoro-4-isopropoxybenzoate (from step 1), 1,4-dioxane (31 ml) and NaOH (31 ml of 1.0 M, 31 mmol) were combined and the mixture was heated to 80 ° C for 20 min. The solvent was evaporated under reduced pressure. The crude mixture was dissolved in water and washed with EtOAc (3x). The combined organics are discarded. The aqueous layer was acidified and extracted with EtOAc (3x). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-fluoro-4-isopropoxy-benzoic acid (1.25 g, 72%) as a white solid. ESI-MS m / z 30 calc 198.1, found 199.3 (M + 1) +. Retention time: 1.34 minutes (3 minutes of execution). 2-Fluoro-4-isopropoxybenzoic acid and 4-isopropoxy-3-methylbenzoic acid were also prepared using the procedures described above.

4- (1-Hydroxypropan-2-yl) -3-methoxybenzoic acid 35

Step 1: benzyl 4-bromo-3-methoxybenzoate

[0457]

 40

image247

 Four. Five

 fifty

[0458] 4-Bromo-3-methoxy-benzoic acid (1.50 g, 6.49 mmol), K2CO3 (2.69 g, 19.5 mmol), and DMF (10 ml) were combined and the mixture was left under stirring for 10 minutes. Bromomethylbenzene (849 µL, 7.14 mmol) was added dropwise and the mixture was allowed to stir at rt for 1 h. The reaction mixture was quenched with brine and extracted with EtOAc (3x). The organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% -70% EtOAc in hexanes) to provide methyl benzyl 4-bromo-3-methoxybenzoate (91%). ESI-MS mlz calc 320.0, found 321.0 / 323.0 (M + 1) +. Retention time: 3.24 minutes (4 min of execution).

Step 2: Methyl benzyl 3-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate 60

[0459]

 65

image248

 5

 10

[0460] Pd (dppf) Cl2 (197 mg, 0.269 mmol), KOAc (1.06 g, 10.8 mmol), methyl benzyl 4-bromo-3-methoxybenzoate (865 mg, 2.69 mmol) , 4,4,5, 5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1,3,2-dioxaborolane (1.03 g, 4 , 04 mmol), and DMF (10 ml) and heated overnight at 100 ° C. The reaction mixture was quenched with brine and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (3% -80% EtOAc in hexanes) to give benzyl 3- methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) methyl benzoate (34%). ESI-MS m / z calc 368.2, found 369.3 (M + 1) +. Retention time: 2.09 minutes (3 minutes of execution).

 twenty

Step 3: 4- (1-hydroxypropan-2-yl) -3-methoxybenzoic acid

[0461]

 25

image249

 30

 35

[0462] Dichloro- [dicyclohexyl (phenyl) phosphaniumyl] -tritert-butylphosphaniumyl-palladium (981 mg, 0.155 mmol) and 2-bromoallyloxymethylbenzene (341 mg, 1.50 mmol) were dissolved in DMF (1 ml). A solution of methyl benzyl 3-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (1.11 g, 3.00 mmol) in DMF ( 3 ml) the mixture was added heated at 90 ° C for 3 h. Then, the mixture was filtered through celite using ethyl acetate. Then, the filtrate was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue from step 1 was taken up in isopropanol (2 ml) and added at 10% Pd / C (160 mg, 0.150 mmol). The vessel was purged with nitrogen and a hydrogen balloon was added and the reaction mixture was allowed to stir overnight. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was partitioned between 2M aqueous Na2CO3 and ethyl acetate. The layers were separated and the organic phase was discarded. To the aqueous phase 1 M HCl was added until the solution was pH 3. Then, the solution was extracted with EtOAc (3x) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to provide 4 - (1-hydroxypropan-2-yl) -3-methoxybenzoic. ESI-MS m / z calc 210.1, found 211.1 (M + 1) +. Retention time: 1.19 minutes (3 minutes of execution).

 fifty

5-Isopropoxyquinoline-8-carboxylic acid

Step 1: 5-Isopropoxyquinoline

[0463] 55

image250

 60

 65

[0464] To a mixture of quinoline-5-ol (2.00 g, 13.8 mmol) and K2CO3 (7.62 g, 55.1 mmol) in DMF (20 ml) was added 2-iodopropane (2, 76 ml, 27.6 mmol). The reaction mixture was heated at 80 ° C overnight before it was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc-Hex) to provide 5-Isopropoxyquinoline 5 (91%) as a light yellow oil. ESI-MS m / z calc 187.1, found 188.3 (M + 1) +. Retention time: 1.06 minutes (3 minutes of execution).

Step 2: 8-Bromo-5-isopropoxy-quinoline

 10

[0465]

image251

 fifteen

 twenty

[0466] To a solution of 5-Isopropoxyquinoline (1.87 g, 10.0 mmol) in acetonitrile (100 ml) was added NBS (1.78 g, 10.0 mmol) at 0 ° C. The mixture was stirred at rt for 2 h before the solvent was removed. The residue was partitioned between EtOAc and H2O. The layers were separated and the organic layer was washed with brine, dried over MgSO4 and concentrated. The crude material was purified by column chromatography (0-10% EtOAc-Hex) to provide 8-bromo-5-isopropoxyquinoline (92%) as a light brown solid. ESI-MS m / z calc 265.1, found 266.1 (M + 1) +. Retention time: 1.44 minutes (3 minutes of execution).

Step 3: 5-Isopropoxyquinoline-8-carboxylic acid 30

[0467]

image252

 35

 40

[0468] To a solution of 8-bromo-5-isopropoxyquinoline (133 mg, 0.500 mmol) in THF (2 ml) was added nBuLi (310 45 µl of 1.6 M, 0.50 mmol) dropwise at -78 ° C under Ar. The reaction mixture was stirred at -78 ° C for 30 min. The carbon dioxide was bubbled through the solution for 10 min. The mixture was quenched with a sat solution. here NH4Cl before it was extracted with EtOAc (2x). The aqueous layer was acidified with 6 N HCl at pH ~ 4 and extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness to give 5- Isopropoxyquinoline-8-carboxylic acid. ESI-MS m / z calc 231.1, found 50 232.1 (M + 1) +. Retention time: 1.28 minutes (3 minutes of execution).

4- (1-Cyano-1-methyl-ethoxy) -2-methoxy-benzoic acid

Step 1: Methyl 4-hydroxy-2-methoxy-benzoate 55

[0469]

image253

 60

 65

[0470] Thionyl chloride (953 ml, 13.1 mmol) was added dropwise to a solution of 4-hydroxy-2-methoxy-benzoic acid (733 mg, 4.36 mmol) in methanol (30 ml) at 0 ° C. The mixture was stirred at 50 ° C overnight. The mixture of

The reaction was concentrated and the residue was dissolved in water (40 ml). The solution was neutralized with saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to dryness to give methyl 4-hydroxy-2-methoxybenzoate (99%). ESI-MS m / z calc 182.1, found 183.1 (M + 1) +. Retention time: 0.73 minutes (3 minutes of execution).

 5

Step 2: Methyl 4- (cyanomethoxy) -2-methoxybenzoate

[0471]

 10

image254

 fifteen

[0472] Methyl 4-hydroxy-2-methoxy-benzoate methyl (0.790 g, 4.34 mmol), 2-bromo-acetonitrile (361 µl, 5.42 mmol), and potassium carbonate (900 mg, 6, 51 mmol) were combined in N, N-dimethylformamide (5 ml). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 ml of ethyl acetate and 20 ml of water. The layers were separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride (2x). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield methyl 4- (cyanomethoxy) -2-methoxybenzoate (99%) as a brown oil. ESI-MS m / z calc 221.1, found 222.1 (M + 1) +. Retention time: 1.08 minutes (3 minutes of execution). 25

Step 3: 4- (1-cyano-1-methyl-ethoxy) -2-methoxy-benzoate

[0473]

 30

image255

 35

[0474] 4- (Cyanomethoxy) -2-methoxy-benzoate methyl (960 mg, 4.34 mmol) was dissolved in tetrahydrofuran (1 ml) and N, N-dimethylformamide (4 ml). Sodium hydride (521 mg, 13.0 mmol) was added and the reaction mixture was allowed to stir for 5 min. Iodomethane (1.35 ml, 21.7 mmol) was added and the reaction mixture was allowed to stir 40 for 10 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate was dried over sodium sulfate, filtered and evaporated to dryness. The crude material was dissolved in tetrahydrofuran (10 ml) and cooled to -78 ° C under an argon atmosphere. LDA (2.2 ml of 2.0 M, 4.4 mmol) was added and the reaction mixture was stirred at 78 ° C for 45 minutes. Iodomethane (1.35 ml, 21.7 mmol) was added and the reaction mixture was allowed to slowly warm to room temperature. The reaction mixture was evaporated to dryness, and then partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed twice with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness. Then, the crude product was purified on 40 g of silica gel using a gradient of 0-30% ethyl acetate in hexanes to give methyl 4- (1-cyano-1-methyl-ethoxy) -2-methoxybenzoate (31 %). ESI-MS m / z calc 249.1, found 250.3 (M + 1) +. Retention time: 1.59 minutes (3 minutes of execution). fifty

Step 4: 4- (1-methyl-ethoxy-1-cyano) -2-methoxy-benzoic

[0475]

 55

image256

 60

 65

[0476] Methyl 4- (1-cyano-1-methyl-ethoxy) -2-methoxy-benzoate (340 mg, 1.36 mmol) was dissolved in tetrahydrofuran (5 ml) and water (5 ml). Lithium hydroxide (98 mg, 4.1 mmol) was added and the reaction mixture was heated at 65 ° C for 1

hour. The crude material was diluted with 10 ml of water and extracted twice with ether. The ether extracts were discarded and the aqueous layer was made acidic with 4M HCl. Then, the product was extracted into ethyl acetate, dried over sodium sulfate, filtered, and evaporated to dryness to give 4- (1-cyano-1-methyl-ethoxy) -2-methoxy-benzoic acid (78% ) as a solid pale yellow. ESI-MS m / z calc 235.1, found 236.1 (M + 1) +. Retention time: 1.29 minutes (3 minutes of execution). 5

4-Isopropylsulfinylbenzoic acid

Step 1: Ethyl 4-isopropylsulfanylbenzoate

 10

[0477]

image257

 fifteen

[0478] A mixture of 4-fluorobenzoate acetate (390 mg, 2.32 mmol) and isopropylsulfanylsodium (273 mg, 2.78 20 mmol) in DMF (2.5 ml) was heated at 80 ° C for 36 h. The reaction mixture was diluted with ethyl acetate before being washed with 1 N NaOH and then brine. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting with 50-100% ethyl acetate in hexanes to give 4-isopropylsulfanylbenzoate acetate (350 mg).

 25

Step 2: Ethyl-4 isopropylsulfanylbenzoate

[0479]

image258

 30

 35

[0480] A solution of 4-isopropylsulfanylbenzoate acetate (350 mg, 1.6 mmol) and H2O2 (180 ml of 30% w / v, 1.6 mmol) in AcOH (2 ml) was stirred at room temperature for 3 h. The mixture was poured into a sat solution. here 40 Na2CO3 and the pH was adjusted to 10 with solid Na2CO3. The mixture was extracted with EtOAc (3x). The organics were combined and washed with sat. here Na2CO3, water (2x), then with brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography (20-50% EtOAc in hexanes) to give 4-isopropylsulfanylbenzoate acetate (65%). ESI-MS m / z calc. 240.1, found 241.3 (M + 1) +. Retention time: 1.16 minutes (3 minutes of execution). Four. Five

Step 3: 4-Isopropylsulfinylbenzoic Acid

[0481]

image259

 fifty

 55

 [0482] To a stirred solution of 4-isopropylsulfanylbenzoate acetate (245 mg, 1.02 mmol) in EtOH (1 mL) at room temperature was added NaOH (300 mL of 5.0 M, 1.50 mmol) dropwise at drop and the mixture was stirred for 30 min. The pH of the mixure was adjusted to 2 with 1 N HCl before it was evaporated to dryness. The solids were collected in water, filtered, washed with water (2x), and dried to give 4-Isopropylsulfinylbenzoic acid (80%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 3.07-2.97 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H).

4- (tert-butylsulfonyl) benzoic acid 65

Step 1: 4- (tert-Butyl) benzoic acid

[0483]

image260

 5

 10

[0484] ethyl 4-fluorobenzoate (1.5 g, 8.9 mmol) and tert-butylsulfanylsodium (2.00 g, 17.8 mmol) were combined in N, N-dimethylformamide (10 ml). The reaction mixture was heated at 80 ° C for 2 hours. A large amount of precipitate formed and an additional 15 ml of N, N-dimethylformamide and the reaction mixture was stirred for 20 hours at 80 ° C. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was discarded, and the aqueous layer was made acidic with 4M hydrochloric acid. The water layer was extracted twice with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated to dryness to yield 4- (tert-butylthio) benzoic as a colorless oil. ESI-MS m / z calc. 210.3, found 211.1 (M + 1) +. Retention time: 1.74 minutes (3 minutes of execution).

Step 2: 4- (tert-butylsulfonyl) benzoic acid

[0485]

image261

 25

 30

[0486] 4- (tert-Butyl) benzoic acid (from Step 1) was dissolved in AcOH (10 ml) and hydrogen peroxide (5.0 ml of 30% w / w, 52 mmol) was added to the mixture of reaction. The resulting mixture was heated at 80 ° C for 2 hours. The reaction mixture was allowed to cool to room temperature, and diluted with 50 ml of water and 100 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid. The white solid was dissolved in dichloromethane and evaporated to dryness. The solid was then dried under vacuum for 16 hours to give 4-tert-butylsulfonylbenzoic acid (2.2 g, 92%) as a white solid. ESI-MS m / z calc. 242.1, found 243.1 (M + 1) +. Retention time: 1.15 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 8.18 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 7.6 Hz, 2H), 1.25 (s, 9H). 40

4- (ethylsulfonyl) benzoic acid was also synthesized using the procedures described above.

4- (isobutyl sulfonyl) benzoic acid

Step 1: 4- (isobutylthio) benzoate 45

[0487]

image262

 fifty

 55

[0488] K2CO3 (1.23 g, 8.92 mmol) was added to a mixture of methyl 4-sulfanylbenzoate (1.00 g, 5.95 mmol), 1-bromo-2-methyl-propane (970 µl, 8.92 mmol), and DMF (10 ml) at rt. The mixture was allowed to stir for 4 h at rt before the solids were filtered off. The solids were washed with ethyl acetate, and then discarded. The combined filtrates were partitioned between ethyl acetate (100 ml) and water (100 ml). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give methyl 4- benzoate (isobutylthio) (82%) as a clear oil. ESI-MS mlz calc. 224.1, found 225.2 (M + 1) +. Retention time: 1.59 minutes (3 minutes of execution).

Step 2: Methyl 4- (isobutyl sulfonyl) benzoate 65

[0489]

image263

 5

[0490] m-CPBA was added (3.59 g, 15.6 mmol) to a solution of methyl 4- benzoate (isobutylsulfanyl) (1.00 g, 10 4.46 mmol) in CH2Cl2 (20 mL) at rt. The mixture was allowed to stir for 2 h before concentrating in vacuo. Column chromatography (0 to 100% ethyl acetate / hexanes) in the residue gave methyl 4-benzoate (isobutyl sulfonyl). ESI-MS m / z calc. 256.1, found 257.2 (M + 1) +; Retention time: 1.96 minutes (3 minutes of execution). 1 H NMR (400 MHz, CDCl 3) δ 8.23 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 3.98 (s, 3H), 3.02 (d, J = 6.5 Hz, 2H), 2.25 (dp, J = 13.3, 6.6 Hz, 1H), 1.07 (d, J = 6.7 Hz, 6H ). fifteen

Step 3: 4- (isobutyl sulfonyl) benzoic acid

[0491]

 twenty

image264

 25

[0492] A mixture of methyl 4-isobutylsulfonylbenzoate (1.00 g, 3.90 mmol), NaOH (10 ml of 1.0 M, 10 mmol), and 30 1,4-dioxane (10 ml) was heated to 80 ° C for 1.5 h. The mixture was cooled to rt before it was concentrated in vacuo. The solid residue was taken up in water and washed with ethyl acetate, which is discarded. The aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate (2x). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (0 to 100% ethyl acetate / hexanes) in the residue gave 4- (isobutyl sulfonyl) benzoic acid (98%). ESI-MS m / z calc. 242.1, found 243.2 (M + 1) +; 35 retention time: 1.73 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 3.03 (d, J = 6 , 5 Hz, 2H), 2.27 (dt, J = 13.3, 6.6 Hz, 1H), 1.08 (d, J = 6.7 Hz, 6H).

3-ethoxy-2- fluorobenzoic acid

 40

Step 1: 1-ethoxy-2-fluorobenzene

[0493]

 Four. Five

image265

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 55

[0494] A mixture of 2-fluorophenol (8.6 g, 77 mmol), iodoethane (9.2 ml, 120 mmol) and potassium carbonate (21 g, 150 mmol) (fine powder) was stirred in acetone (100 ml) at 50 ° C overnight, then at room temperature for 24 h. The mixture was filtered on a pad of silica gel, and rinsed with ether. The solution was carefully concentrated (due to product volatility), then microfiltered to give 1-ethoxy-2-fluorobenzene (92%) as a yellow oil. 1H NMR (CDCl3, 500 MHz), delta 7.12-6.94 (m, 2H), 6.91-6.86 (m, 60 1H), 6.83-6.77 (m, 1H), 4.01 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).

Step 2: 3-ethoxy-2-fluorobenzoic

[0495] 65

image266

 5

[0496] To 1-ethoxy-2-fluorobenzene (1.0 g, 7.1 mmol) in THF (10 ml) at -78 ° C butyl lithium (4.5 ml of 1 was added dropwise) , 6 M, 7.2 mmol) followed by N '- (2-dimethylaminoethyl) -N, N, N'-trimethyl-ethane-1,2-diamine (1.2 g, 7.2 mmol). The mixture was stirred for 3 hours at -78 ° C before it was quickly transferred through large cannula to a mixture of crushed dry ice (freshly crushed under N2) in ether. The mixture was heated to RT, diluted with 30 ml of 2M HCl (aq.), Extracted with ethyl acetate (2 x 30 ml), washed with 10 ml of brine and dried over MgSO4 to give acid 3 -ethoxy-2-fluorobenzoic acid (65%) as a white solid. ESI-MS m / z calc. 184.1, found 185.1 (M + 1) +; Retention time: 1.04 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 7.42-7.30 (m, 2H), 7.20 to 7.16 (m, 1H), 4.12 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). fifteen

3- (hydroxymethyl) -4-isopropoxy-benzoic

Step 1: Methyl 3-formyl-4-isopropoxy-benzoate

 twenty

[0497]

image267

 25

 30

[0498] Methyl 3-formyl-4-isopropoxy-benzoate methyl (180 mg, 0.81 mmol) was dissolved in tetrahydrofuran (4.8 ml) and LiBH4 (35 mg, 1.6 mmol) was added. The reaction was stirred at room temperature for 30 minutes before it was quenched with methanol (3 ml). The reaction was neutralized by the addition of a saturated aqueous solution of sodium bicarbonate (3 ml) and then extracted with ethyl acetate (3 x 10 ml). The combined organics were washed with a saturated aqueous solution of sodium chloride (1 x 10 ml), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 3- (hydroxymethyl) -4-isopropoxy- methyl benzoate (99%) as a viscous liquid. ESI-MS m / z calc. 224.3, found 225.3 (M + 1) +; Retention time: 1.26 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 8.09 (s, 1 H), 7.89 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 5.25 (t, J = 5.6 Hz, 1H), 4.86-4.68 (m, 1H), 4.54 (d, J = 5.6 Hz, 2H), 3.87 (s , 3H), 1.35 (d, J = 6.0 Hz, 6H). 40

Step 2: 3- (hydroxymethyl) -4-isopropoxy-benzoic

[0499]

 Four. Five

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 55

[0500] To methyl 3- (hydroxymethyl) -4-methyl isopropoxy-benzoate (180 mg, 0.80 mmol) and 1,4-dioxane (1,895 ml) was added sodium hydroxide (2.1 ml of 1, 0 M, 2.1 mmol) and the mixture was heated at 80 ° C for 50 minutes. The solvent was evaporated under reduced pressure. The crude mixture was dissolved in water (10 ml) and washed with ethyl acetate (3 x 10 ml) which was discarded. The aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with aceatate acetate (3 x 10 ml). The combined organics were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 3- (hydroxymethyl) -4-isopropoxy-benzoic acid (89%) as a white solid. ESI-MS m / z calc. 210.2, found 211.3 (M + 1) +; Retention time: 1.01 minutes (3 minutes of execution).

3-methyl-4-methylsulfonyl-benzoic acid 65

[0501]

image269

 5

 10

 [0502] Thionyl chloride (3.55 ml, 48.7 mmol) was added dropwise to a solution of 4-fluoro-3-methyl-benzoic acid (2.50 g, 16.2 mmol) in methanol (102 ml) at 0 ° C. The mixture was stirred at 50 ° C for 2 hours. The reaction mixture was evaporated to dryness and then the crude ester was dissolved in N, N-dimethylformamide (10 ml). Sodium thiomethoxide (2.50 g, 35.7 mmol) was added and the reaction mixture was heated at 80 ° C for 15 hours. The reaction mixture was partitioned between 1M hydrochloric acid and ethyl acetate. The layers were separated and the organic layer was washed with 1M hydrochloric acid. The ethyl acetate layer was dried over sodium sulfate, filtered, and evaporated to dryness. The resulting acid and ester mixture was suspended in acetic acid (20 ml). Hydrogen peroxide (5.0 ml of 30% w / w) was added and the reaction mixture was heated at 80 ° C for 2 hours. The reaction mixture was diluted with water (20 ml) and the resulting mixture was extracted three times with 50 ml portions of ethyl acetate. The combined organics were evaporated to dryness and the residue was dissolved in tetrahydrofuran (10 ml). Water (10 ml) and lithium hydroxide (1.17 g, 48.7 mmol) were then added and the reaction mixture was heated at 65 ° C for 4 hours. The reaction mixture was diluted with water (20 ml) and the resulting mixture was extracted three times with 20 ml portions of ethyl acetate. The aqueous layer was made acidic with 6M aqueous hydrochloric acid and extracted 3 times with 50 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and evaporated to dryness to give 3-methyl-4-methylsulfonyl-benzoic acid (2.25 g, 72%) as a white solid. ESI-MS m / z calc. 214.0, found 215.0 (M + 1) +; Retention time: 0.97 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 13.48 (s, 1 H), 8.07-7.94 (m, 3 H), 3.27 (s, 3 H), 2.70 (s, 3 H).

4-isopropoxy-2,5-dimethylbenzoic acid

 30

Step 1: 1-iodo-4-isopropoxy-2,5-dimethylbenzene

[0503]

 35

image270

 40

[0504] K2CO3 (1.23 g, 8.87 mmol) followed by 2-iodopropane (806 µl, 8.06 mmol) were added to a solution of 4-iodo-2,5-dimethyl-phenol (1.00 g, 4.03 mmol) in DMF (40 ml) and the solution was heated at 50 ° C for 24 h. Then, the mixture was acidified with 1% aqueous HCl before it was extracted with EtOAc (3 x 100 ml). The combined organics were washed with 1 N NaOH (3 x 200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% ethyl acetate / hexanes) to provide 1-iodo-4-isopropoxy-2,5-dimethylbenzene (42%) as a yellow oil.

Step 2: 4-Isopropoxy-2,5-Ethylbenzoic Acid 50

image271

[0505]

 55

 60

[0506] A solution of 1-iodo-4-isopropoxy-2,5-dimethylbenzene (450 mg, 1.6 mmol) in THF (7.8 ml) was cooled to -78 ° C before nBuLi (620 ml, 2.5 M, 1.6 mmol was added dropwise). The mixture was allowed to warm to 0 ° C, then cooled to -78 ° C before it was added dropwise to a flask containing crushed CO2 and dried. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured onto ice and acidified with 1N HCl. The mixture was extracted with ethyl acetate (3x) and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to give 4-isopropoxy-2,5-dimethylbenzoic acid (67 mg, 10%). ESI-MS m / z

calc. 208.1, found 209.1 (M + 1) +; Retention time: 1.55 minutes (3 minutes of execution).

Spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl (4- (2,2,2-trifluoroethoxy) phenyl) methanone

[0507] 5

image272

 10

 fifteen

[0508] 4- (2,2,2-Trifluoroethoxy) benzoic acid (22 mg, 0.10 mmol), HATU (42 mg, 0.11 mmol), and DMF (0.8 ml) were combined and left SRIT at room temperature for 10 minutes. then, the spiro activated acid [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] (28 mg, 0.10 mmol) was added followed by the addition of Et3N (84 µl, 0.60 mmol). The reaction mixture was stirred at room temperature for 17 h before it was filtered and purified by prep-HPLC (5 mM HCl / H2O and MeOH) to provide spiro [benzo [b] pyrrolo [1,2-d]). [1,4] oxazine-4,4'-piperidine] 1'il (oethoxy 4- (2,2,2-trifluor-) phenyl) methanone. ESI-MS m / z calc. 442.2, found 443.4 (M + 1) +. Retention time: 2.05 minutes (4 min of execution).

(4- (isopropylsulfonyl) -3-methylphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

 25

[0509]

image273

 30

 35

[0510] Triethylamine (152 µl, 1.1 mmol) was added to a mixture of 1-methylpyrro [chromene [4,3-c] pyrazol-4,4'-Pip eridine] dihydrochloride (108 mg, 0, 33 mmol), 4 - (isopropylsulfonyl) -3-methylbenzoic acid (80 mg, 0.33 mmol), HATU (126 mg, 0.33 mmol), and dichloromethane (2 ml) at 25 ° C. The mixture was heated at 40 ° C for 3 h. The mixture was concentrated and the residue was purified by column chromatography (0-100% ethyl acetate / hexanes) to give (4- (propylsulfonyl iso-) -3-methylphenyl) (1-methyl-1H-spiro [ chromene [4,3-c] pyrazol-4,4'-piperidine] 1'yl) methanone (107 mg, 65%) as a white spongy solid. ESI-MS m / z calc. 479.6, found 480.3 (M + 1) +. Retention time: 2.24 minutes (3 minutes of execution).

 Four. Five

9-aza- (4-isopropoxy-3-methylphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’il) methanone

[0511]

image274

 fifty

 55

[0512] A solution of 9-aza-1-methyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] (64 mg, 0.19 mmol), 4-60 isopro- poxy-3 methyl-benzoic acid (45 mg, 0.23 mmol), HATU (89 mg, 0.23 mmol) and iPR2NEt (169 µl, 0.97 mmol) in DMF (0.5 mL) was stirred at temperature ambient for 16 hours. Purification by HPLC (10-90% MeOH in water (HCl modifier)) provided the product HCl salt. This material was taken up in EtOAc and washed with saturated aqueous Na2CO3 (2x), brine, dried over Na2SO4 and evaporated to dryness to give 9-aza- (4-isopropoxy-3-methylphenyl) (1-methyl-1H spiro - [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'yl) methanone (8 mg, 18%) 65 as a white solid. ESI-MS m / z calc. 432.2, found 433.5 (M + 1) +; Retention time: 1.91 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3)? 8.19 (dd, J = 4.7, 1.3 Hz, 1H), 7.47-7.21 (m, 4H), 7.14 (dd, J = 8.2,

4.7 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.75-4.48 (m, J = 12.0, 5.9 Hz, 1H), 4, 36 (s, J = 7.9 Hz, 3H), 3.44 (wide s, 2H), 2.22 (s, J = 7.5 Hz, 3H), 2.16 (wide s, 2H), 1.94 (wide s, 2H), 1.70 (wide s, 2H), 1.36 (d, J = 6.9 Hz, 6H).

[0513] The following compounds were prepared using procedures described above.

 5

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 65

(7-Chiorospiro [benzo [b] pyrrolo [1,2 d] [1,4] oxazine-4,4'-piperidine] -1'iI) (2-fluoro-5-methoxyphenyl) methanone

[0514]

image275

 5

 10

[0515] 7-Chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine 4,4'-piperidine] (62 mg, 0.20 mmol), 2-fluoro-5-methoxybenzoic acid (34 mg, 0.20 mmol), EDCI (38 mg, 0.20 mmol), and Et3N (56 µL, 0.40 mmol) were combined in DCM (1 ml) and the mixture was stirred for 6 h. The mixture was diluted with DCM and washed with 1N HCl, sat. here Baking soda and brine. The organics were dried over sodium sulfate and evaporated. The crude material was purified by chromatography on silica gel eluting with 0 40% ethyl acetate in hexanes to provide (7 chlorospiro [benzo [b] pyrrolo [1,2 d] [1,4] oxazine 4,4 'piperidine] 1'il) (2-fluoro-5-methoxyphenyl) methanone. ESI-MS m / z calc. 426.1, found 20 427.5 (M + 1). Retention time: 2.12 minutes (mm 3 stroke). 1 H NMR (400 MHz, CDCl 3) 6 7.26 (d, J = 8.4 Hz, IH), 7.13 7.07 (m, 2H), 7.05 6.96 (m, 2H), 6.94 6.85 (m, 2H), 6.33 (t, J = 3.2 Hz, IH), 6.08 5.98 (m, 20 IH), 4.69 (d, J = 13.1 Hz , IH), 3.80 (s, 3H), 3.63 3.44 (m, 2H), 3.33 (t, J = 12.8 Hz, IH), 2.19 (d, J = 13 , 8 Hz, IH), 2.09 1.96 (m, 2H), 1.60 (s, IH).

(4 (tert-butylsulfonyl) phenyl) (1- (trifluoromethyl) spiro- [benzo [b] pyrrolo [1,2 d] [1,4] oxazine-4,4'-piperidine] -1'iI) methanone

[0516]

image276

 30

 35

[0517] 1 '- (TrifluoroMethyl) spiro [piperidine 4,4' pyrrolo [2,1-c] [1,4] benzoxazine] (172 mg, 0.599 mmol), 4-tert-butylsulfonylbenzoic acid (176 mg, 0.727 mmol), 3- (ethyliminomethyleneamino) N, N-dimethyl-propane-1-amine hydrochloride 40 (150 mg, 0.783 mmol), and triethylamine (312 µL, 2.24 mmol) were combined in dichloromethane (3.4 ml ). The reaction mixture was allowed to stir for 72 hours at room temperature. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give the crude product. The crude material was purified by preparative reverse phase chromatography, using a gradient of 10 99% acetonitrile in water to produce (4-tert-butylsulfonylphenyl) [1 '(trifluoromethyl) spiro [piperidine 4.4' pyrrolo [2 , 1-c] [1,4] benzoxazine] -1-yl] methanone (49 mg, 16%) as a white solid. ESIMS m / z calc. 532.2, found 533.5 (M + 1). Retention time: 2.10 minutes (mm 3 stroke). 1H NMR (400 MHz, DMS0) δ 7.89 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8 , 0 Hz, IH), 7.35 7.25 (m, 2H), 7.25 7.16 (m, IH), 7.03 (d, J = 3.9 Hz, IH), 6.40 (d, J = 3.9 Hz, IH), 50 4.53 4.37 (m, IH), 3.57 3.14 (m, 3H), 2.17 1.78 (m, 4H), 1.26 (s, 9H).

[0518] The following compound was prepared using the procedures indicated above:

 55

 60

 65

 5

 (1-Methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) (m-tolyl) methanone

[0519]

image277

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 fifteen

[0520] 3-Methylbenzoyl chloride (14 mg, 0.09 mmol) was added to a mixture of 1-Methyl-1H-spiro [chromeno [4.3-20 c] pyrazol-4,4'-piperidine] dihydrate chloride (30 mg, 0.09 mmol), triethylamine (64 µL, 0.46 mmol), and DMF (0.7 mL) at 25 ° C. The mixture was allowed to stir at 50 ° C overnight before cooling to 25 ° C. The mixture was filtered and then purified by reverse phase HPLC to yield (1-Methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) (mtolyl) methanone ESI-MS m / z calc. 373.2, found 374.2 (M + 1) + Retention time: 2.04 minutes (4 mm run time). 25

[0521] The following compound was prepared using the procedures described above:

 Name of product

 Amine or Amine- HCI Acid Chloride

 (7-Chloro-1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) (2- (trifluoromethoxy) phenyl) methanone

 7-Chloro-1-methyl-1H-spiro [chromeno [4, 3-c] pyrazole-4,4'-piperidine] 2- (trifluoromethoxy) benzoyl chloride

 (8-Chloro-1-Methyl-I H- Spiro [chromeno [4,3-c] pyrazole-4,4'-piperidine] -I '-yl) (2- (trifluoromethoxy) phenyl) methanone

 8-Chloro-I - Methyl-I H-spiro [chromeno [4, 3- c] pyrazole-4,4'-piperidine] 2- (trifluoromethoxy) benzoyl chloride

 30

 35

 40

 Four. Five

(3-Fluoro-4-hydroxy-phenyl) - (1-methyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

[0522]

 fifty

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 55

A mixture of 1-methylospiro [chromene [4,3 c] pyrazol-4,4'-piperidine] bis hydrochloric acid (507 mg, 1.7 mmol), 3-60 fluoro-4-hydroxy-benzoic acid (271 mg , 1.7 mmol), triethylamine (727 µL, 5.2 mmol), and EDCI (333 mg, 1.7 mmol) in dichloromethane (10 mL) were stirred at room temperature for 16 hours. The reaction was diluted with dichloromethane and washed with HCl, saturated sodium bicarbonate solution, and brine. The organics were dried over sodium sulfate and evaporated. The crude material was purified by column chromatography eluting with 0-10% methanol in dichloromethane to yield (3-fluoro-4-hydroxy-phenyl) - (1-methyl-1H-spiro [chromene [4.3-65 c] pyrazol-4,4'-piperidine] -1'il) methanone (330 mg, 48%). ESI-MS m / z calc 393.4, found 394.3 (M + I) the retention time t: 1.39 minutes (3 mm RUN). 1 H NMR 55 (400 MHz, DMSO) 10.41 (s, IH), 7.73 (d, J = 7.7 Hz, IH), 7.46 (s,

IH), 7.32-7.23 (m, 2H), 7.15 7.04 (m, 3H), 6.98 (t, J = 8.5 Hz, IH), 4.10 (s, 3H), 3.52 3.19 (m, 4H), 1.99 1.85 (m, 4H).

[0523] The following compounds were prepared using the procedure described above:

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 Four. Five

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 (4-propoxy-3- (trifluoromethyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 ' -piperidine] - I '-YI) methanonabenzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) methanone

Step 1: (4-fluoro-3- (trifluoromethyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4 , 4'-piperidine] -1'-il) methanone 5

[0524]

image279

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[0525] Spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] (100 mg, 0.361 mmol), 4-fluoro-3- (trifluoromethyl) benzoic acid (75.2 mg, 0.361 mmol), and triethylamine (110 mg, 151 µl, 1.08 mmol) were combined in DMF (3 mL) and HATU (137 mg, 0.361 mmol) was added. The reaction was stirred at room temperature for 1 h and concentrated. The residue was purified by column chromatography (silica gel: 0-50% ethyl acetate in hexanes) (phenyl 4-fluoro-3-20 (trifluoromethyl)) to give (spiro [benzo [b] pyrrolo [1,2 -d] [1,4] oxazine-4,4'-piperidine] -1'-yl) methanone (113 mg, 73%). ESI-MS m / z calc. 430.1, found 431.1 (M + 1) +; Retention time: 2.24 minutes (4 min of execution).

Step 2: (4-propoxy-3- (trifluoromethyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4 , 4'-piperidine] - I '-YI) methanonabenzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'piperidine] -1'-yl) methanone

[0526]

image280

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 35

[0527] (4-fluoro-3- (trifluoromethyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4 , 4'-piperidine] -1'-yl) methanone (22 mg, 0.051 mmol), nPrOH (12 µl, 0.15 mmol), and NaH (60%, 6.1 mg, 0.15 mmol) were combined in acetonitrile (1 ml) and the reaction mixture was heated at 70 ° C for 1 husband. Reaction mixture 40 was filtered and purified by reverse phase HPLC to provide (4-propoxy-3- (trifluoromethyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine -4,4'-piperidine], 4] oxazine-4,4'-piperidine] - I'-YI) methanonabenzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'piperidine ] - 1'-il) methanone. ESI-MS m / z calc. 470.2, found 471.2 (M-1) -; Retention time: 2.83 minutes (4 min of execution).

[0528] The following compounds were synthesized using the procedures described above: (R) spiro 45 [benzo [b] pyrrolidone lo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1 ' il (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) methanone, (S) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'- piperidine], 4] oxazine-4, 4 'piperidine] -1'-yl (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) nyl Phe-) methanone, spiro [benzo [b] pyrrolo [1, 2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl (4 - ((tetrahydrofuran-2-yl) methoxy) -3 - (luoro Methyl trif-) phenyl) methanone, (4- (2- (dimethylamino) ethoxy) -3- (trifluoromethyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine -50 4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone, and (S) - (4- (2-methoxypropoxy) -3- (trifluoromethyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'yl) methanone.

2- (2-methoxy-4- (spiro [benzo [b] pyrrolo [1,2-d] [-4,4'-piperidine oxazine 1,4]] - 1’-ylcarbonyl) phenoxy) [acetic acid 55

Step 1: (4-hydroxy-3-methoxyphenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 ' -piperidine] -1'-il) methanone

[0529] 60

image281

 65

[0530] 4-Hydroxy-3-methoxy-benzoic acid (304 mg, 1.81 mmol) was stirred with thionyl chloride (645 mg, 395 µL, 5.42 mmol) in dichloromethane and 2 drops of DMF were added. After stirring for 2.5 h, excess thionyl chloride and dichloromethane were removed in vacuo. The residue was added to a mixture of spiro [piperidine-4,4'-pyrrolo [2,1 c] [1,4] benzoxazine] (500 mg, 1.81 mmol), 1,4-dioxane (6.5 ml), and triethylamine (760 mL, 5.42 mmol). The mixture was stirred for 18 hours at 90 ° C before it was cooled to room temperature and evaporated to dryness. The residue was dissolved in ethyl acetate, filtered and washed with 1N HCl (2x), a saturated sodium bicarbonate solution (2x), and brine. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography (0 to 100% EtOAc / hexane) to give (4-hydroxy-3-methoxyphenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine- 4,4'-piperidine], 4] oxazine -4,4'-piperidine] -1'-yl) methanone (394 mg, 56%). ESI-MS m / z calc. 390.2, found 391.2 (M + 1) +; Retention time: 2.56 minutes (4 min of execution). 10

Step 2: 2- (2-methoxy-4- (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 ' -piperidine] -1'-ylcarbonyl) phenoxy) acetate

[0531] 15

image282

 twenty

[0532] For (4-hydroxy-3-methoxyphenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 '-25 piperidine] -1'-yl) methanone (200 mg, 0.512 mmol), sodium iodide (38.4 mg, 0.256 mmol), Cs2CO3 (334 mg, 1.03 mmol), and DCE (5 , 0 ml) methyl 2-bromoacetate (49 µl, 0.51 mmol). The mixture was stirred at 60 ° C for 18 h. More methyl bromoacetate 2- (1.0 mmol) was added and the mixture was heated for 3 hours at 60 ° C. The mixture was cooled and then filtered. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel (0-30% ethyl acetate / DCM) to give 2- (2-methoxy-4- (spiro [benzo 30 [ b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] ox-azine-4,4'-piperidine] -1'-ylcarbonyl) phenoxy) ethyl acetate ( 140 mg, 59%). ESI-MS m / z calc. 462.2, found 463.5 (M + 1) +; Tention time: 2.68 minutes (4 min of execution).

Step 3: 2-acetic ((spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1 '-ylcarbonyl) phenoxy-4-2-methoxy) acetic acid 35

[0533]

image283

 40

 Four. Five

[0534] To a solution of 2- (2-methoxy-4- (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine- 4,4'-piperidine] -1'-nyl ylcarbo-) phenoxy) ethyl acetate (140 mg, 0.303 mmol) in THF (4 mL) LiOH (600 µl of 2.0 M, 1.2 mmol) was added and the mixture was stirred at room temperature for 19 h. The mixture was filtered and purified by HPLC using 5 mM HCl / water and MeOH to give 2- (2-methoxy-4- (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine- 4,4'-50 piperidine], 4] oxazine-4, 4'-piperidine] -1'-ylcarbonyl) phenoxy) acetic acid. ESI-MS m / z calc. 448.2, found 449.3 (M + 1) +; Retention time: 5.90 minutes (15 minutes of execution).

(3-methoxy-4- (2-methoxypropan-2-yl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone 55

Step 1: (4- (2-hydroxypropan-2-yl) -3-methoxyphenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] - 1'-yl) methanone

[0535] 60

image284

 65

[0536] 4- (1-Hydroxy-1-methyl-ethyl) -3-methoxy-benzoic acid (120 mg, 0.573 mmol), spiro [piperidine-4,4'-pyrrolo [2,1 c] [1, 4] benzoxazine] (167 mg, 0.573 mmol), triethylamine (320 µl, 2.29 mmol), and EDC (110 mg, 0.573 mmol) were combined in DCM (5.8 mL). The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of 5 sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to provide (4- (2-hydroxypropan-2-yl) -3-oxyphenyl met) (spiro [benzo [b] pyrrolo [1,2] -d] [1,4] oxazine-4,4'-piperidine] -1'-yl) methanone. ESI-MS m / z calc. 432.0, found 433.1 (M + 1) +; Retention time: 1.61 minutes (3 minutes of execution).

 10

Step 2: (3-methoxy-4- (2-methoxypropan-2-yl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] , 4] oxazine-4,4'-piperidine] -1'-yl) methanone

[0537]

 fifteen

image285

 twenty

[0538] (4- (2-hydroxypropan-2-yl) -3-methoxyphenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] 25 oxazine-4,4'-piperidine] -1'-yl) methanone (crude material from step 1) was dissolved in a mixture of THF (3 ml) and DMF (3 ml). NaH (28 mg, 0.69 mmol) was added and the reaction mixture was allowed to stir for 2 minutes. Then, MeI (54 µL, 0.86 mmol) was added and the reaction mixture was allowed to stir for 1 h. The reaction mixture was evaporated to dryness and the residue was suspended in 25 ml of dichloromethane. The suspension was washed twice with a 1M solution of hydrochloric acid, followed by two washes with a saturated aqueous solution of sodium bicarbonate, followed by two washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give the crude product. The crude material was purified by column chromatography using a gradient of 0-35% ethyl acetate in hexanes to give (3-methoxy-4- (2-methoxypropan-2-yl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] ox-azine-4,4'-piperidine] -1'-yl) methanone (94 mg, 35% in 2 steps). ESI-MS m / z calc. 446.2, found 447.5 (M + 1) +; Retention time: 7.60 minutes (15 35 minutes of execution). 1H NMR (400 MHz, DMSO) δ 7.68-7.65 (m, 1H), 7.50-7.49 (m, 1H), 7.40 (d, J = 7.9 Hz, 1H) , 7.17-6.98 (m, 5H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.49-4.34 (m, 1H), 3.83 (s, 3H), 3.80-3.41 (m, 3H), 3.13 (s, 3H), 2.11-1.81 (m, 4H) and 1.50 (s, 6H).

(7-Chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (3-methoxy-4- (3-methoxyoxetan-3 il) nyl) methanone Phe- was also prepared using the procedures described above. 40

(4-methoxy-3- (methylsulfonyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 ' -piperidine] -1'-il) methanone

Step 1: (4-fluoro-3- (methylsulfonyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] 45 oxazine- 4,4'-piperidine] -1'-yl) methanone

[0539]

 fifty

image286

 55

[0540] Spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] (257 mg, 0.928 mmol), 4-fluoro-3-methylsulfonyl-benzoic acid (203 mg, 0.928 mmol), triethylamine (518 µl, 3.71 mmol), and EDC (196 mg, 1.02 mmol) were combined in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 4 d. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give the crude product. The crude material was purified by column chromatography using a gradient of 0-75% ethyl acetate in hexanes to give (phenyl 4-fluoro-3-Methylsulfonyl-) spiro [piperidine-4,4'-pyrrolo [2,1- c] [1,4] benzoxazine] -1-yl-methanone (222 mg, 54%) as a colorless oil. ESI-MS m / z calc. 440.1, found 441.1 (M + 1) +; Retention time: 1.51 65 minutes (3 minutes of execution).

Step 2: (4-methoxy-3- (methylsulfonyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4 , 4'-piperidine] -1'-yl) methanone

[0541]

 5

image287

 10

[0542] (4-fluoro-3-methylsulfonyl-phenyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl-methanone (44 mg, 0, 10 mmol) and MeOH (12 µl, 0.30 mmol) were combined in DMF (1 ml). NaH (60%, 12 mg, 0.30 mmol) was added and the reaction mixture was stirred for 10 minutes. The mixture was filtered and purified by preparative reverse phase liquid chromatography using a gradient of 10-99% acetonitrile in water containing 5 mM hydrochloric acid to give (4-methoxy-3- (methylsulfonyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone. ESI-MS m / z calc. 452.1, found 453.5 (M + 1) +; Retention time: 1.78 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 7.87 (d, J = 2.0 Hz, 1H), 7.86-7.81 (m, 1H), 7.67 (d, 20 J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 07/22 to 07/02 (m, 3H), 6.28 (t, J = 3.1 Hz, 1H), 6.16 (d, J = 2.3 Hz, 1H), 4.52-4.18 (m, 1H), 4.00 (s, 3H), 3.58 (s, 3H), 3.28 (s, 3H), 1.98 (s, 4H).

[0543] The following compounds were synthesized using the procedures described above: (3- (methylsulfonyl) -4-poxyphenyl pro-) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4 , 4'-piperidine], 4] oxazine-4, 4'-piperidine] -1'-yl) methanone, (4-isopropoxy-3- (trifluoromethyl) benzoicoco3- (nyl Methylsulfo-) phenyl) (spiro [benzo 25 [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone, (4- ( isopentyloxy) -3- (Methylsulphonyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 ' -piperidine] -1'-yl) methanone, and (4- (2-methoxyethoxy) -3- (methylsulfonyl) phenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine- 4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone.

 30

(5- (hydroxymethyl) -2,4-dimethoxyphenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 '-piperidine] -1'-il) methanone

[0544]

 35

image288

 40

 Four. Five

[0545] 2,4-dimethoxy-5- (spiro [benzo [b] pyrrolo [1,2-d] [-4,4'-piperidine oxazine 1,4]] - 1'-ylcarbonyl) benzaldehyde (65 mg , 0.15 mmol) was suspended in MeOH (1 ml). NaBH4 (60 mg, 1.6 mmol) was added and the reaction mixture was allowed to stir for 15 minutes. The reaction mixture was filtered and purified by preparative reverse phase liquid chromatography using a gradient of 20 to 99% methanol in water containing no modifier to give (5- (hydroxymethyl) -2,4-dimethoxyphenyl) (spiro [ benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) methanone. 50 ESI-MS m / z calc. 434.2, found 435.5 (M + 1) +; Retention time: 1.63 minutes (3 minutes of execution).

(7-Chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1’-yl) (nyl 4-cyclopropyl-3-methoxyphe-) methanone

 55

[0546]

image289

 60

 65

[0547] Pd-Fibrecat (42 mg, 0.0065 mmol), (4-bromo-3-methoxyphenyl) (pyro-7 chloros- [benzo [b] pyrrolo [1,2-d] were added to a microwave vial ] [1, 4] oxazine-4,4'-piperidine] -1'-yl) methanone (63 mg, 0.13 mmol), acid

cyclopropyloboronic acid (17 mg, 0.19 mmol), DMF (0.7 ml), and K2CO3 (190 µl of 2.0 M, 0.39 mmol). The reaction vessel was purged with nitrogen and the mixture was heated at 120 ° C overnight. The mixture was filtered and purified by prep-HPLC HPLC (20 to 99% MeOH: H2O with HCl modifier) to give (7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4'-piperidine] -1'-yl) (4-cyclopropyl-3-methoxyphenyl) methanone. ESI-MS m / z calc. 448.2, found 449.4 (M + 1) +; Retention time: 3.32 minutes (4 min of execution). 5

(S) - (8-Chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (4- (2,3-dihydroxypropoxy ) -3-met oxyphenyl) methanone

[0548] 10

image290

 fifteen

[0549] (R) - (8-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (4 - ((2 , 2-dimethyl-1,3-dioxolane-4-yl) methoxy) -3-methoxyphenyl) methanone (41 mg, 0.076 mmol) and 4-methylbenzenesulfonic acid hydrate (2.9 mg, 20 0.015 mmol) were dissolved in MeOH (760 µl were added) and H2O (76 ml). The reaction mixture was heated at 80 ° C for 45 min. The mixture was filtered and the residue was purified by reverse phase HPLC using 5 mM HCl / H2O and MeOH to give (S) - (8-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (4- (2,3-dihydroxypropoxy) -3-methoxyphenyl) methanone. ESI-MS m / z calc. 498.2, found 499.3 (M + 1) +; Retention time: 4.72 minutes (15 minutes of execution). 25

[0550] The following compounds were synthesized using the procedures described above: (S) - (4- (2,3-poxy dihydroxypro -) - 3-methoxyphenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1, 4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone and (R) - (4- (2,3-di-hydroxypropoxy) -3-methoxyphenyl) (spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'- il) methanone.

 30

(4-ethyl-3-methoxyphenyl) (7- (hydroxymethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4, 4'-piperidine] -1'-

il) methanone

Step 1: Methyl 1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] 35 oxazine- 4,4'-piperidine] -7-carboxylate

[0551]

 40

image291

 Four. Five

[0552] A solution of 4-ethyl-3-methoxy-benzoic acid (450 mg, 2.5 mmol), HATU (940 mg, 2.5 mmol), methyl spiro [piperidine-4,4'-pyrrolo [2 , 1-c] [1,4] benzoxazine] -7'-methyl carboxylate (830 mg, 2.5 mmol) and Et3N (1.7 ml, 50 9.9 mmol) in DMF (8 ml) was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated to yield a crude mixture that was purified by chromatography on silica gel eluting with 0-30% EtOAc in hexanes to yield 1'- (4-ethyl-) methyl. 3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -7-methyl carboxylate (1.1 g, quant). ESI-MS m / z 55 calc. 460.5, found 461.5 (M + 1) +; Retention time: 2.08 minutes (3 minutes of execution).

Step 2: 1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4, 4'-piperidine] -7-carboxylic acid Identification action

 60

[0553]

 65

image292

 5

[0554] A solution of 1- (4-ethyl-3-methoxy-benzoyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -7'-carboxycarboxylate (1.1 g, 2.5 mmol) in LiOH (2.5 ml of 4.0 M, 9.9 mmol) and dioxane (5 ml) was stirred at 50 ° C for 1 hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous phase was acidified with 1 N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give a crude product that was used in the next step without further purification (0.60 g, 53%). ESI-MS m / z calc. 446.5, found 447.5 (M + 1) +; Retention time: 1.84 minutes (3 minutes of execution).

 fifteen

Step 3: (4-ethyl-3-methoxyphenyl) (7- (hydroxymethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine -4,4'-piperidine] - 1'- il) methanone

[0555]

 twenty

image293

 25

[0556] A 1- (4-ethyl-3-methoxy-benzoyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -7'-carboxylic acid (550 mg , 1.2 mmol) in tetrahydrofuran (2.2 ml) at 0 ° C triethylamine (200 µl, 1.4 mmol) of isobutyl chloroformate was then added (180 µL, 1.4 mmol). The mixture was stirred for 30 min and then filtered. The filtrate was added dropwise to a solution of sodium borohydride (70 mg, 1.8 mmol) in water (770 µl) at 0 ° C. The mixture was allowed to slowly reach room temperature before it was concentrated to 1/3 of the volume, diluted with ethyl acetate and washed with 1M HCl. The organics were dried over sodium sulfate, filtered and evaporated to give (4-ethyl-3-methoxyphenyl) (7- (hydroxymethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] 35 oxazine -4,4'-piperidine] -1'-yl) methanone (330 mg, 62%). ESI-MS m / z calc. 432.5, found 433.5 (M + 1) +; Retention time: 1.78 minutes (3 minutes of execution).

(4-ethyl-3-methoxyphenyl) (7- (methoxymethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4, 4'-piperidine] -1'-il) methanone 40

[0557]

image294

 Four. Five

 fifty

[0558] MeI (7.2 µL, 0.12 mmol) was added to a solution of (4-ethyl-3-methoxy-phenyl) - [7 '- (hydroxymethyl) spiro [Pip eridine-4,4'- pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl] methanone (50 mg, 0.12 mmol) and NaH (4.6 mg, 0.12 mmol) in DMF (1 ml) and It was stirred at room temperature for 1 hour. The reaction was filtered and purified by reverse phase LC-MS 55 (10-99% CH3CN / H2O). The pure fractions were combined and evaporated to give (4-ethyl-3-methoxyphenyl) (7- (Thyl methoxyme-) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4'-piperidine], 4] oxazine-4,4 'piperidine] -1'-yl) methanone. ESI-MS m / z calc. 446.5, found 447.5 (M + 1) +; Retention time: 2.11 minutes (3 minutes of execution).

 60

(7 - ((dimethylamino) methyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] - 1'-yl) (4-ethyl-3-phenyl methoxy) methanone

Step 1: 1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4, 4'-piperidine] -7-carbaldehyde 65

[0559]

image295

 5

 10

[0560] A solution of (4-ethyl-3-methoxy-phenyl) - [7 '- (hydroxymethyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] - 1-yl] methanone (270 mg, 0.62 mmol) and manganese dioxide (270 mg, 3.1 mmol) in dichloromethane (5 ml) was stirred at 60 ° C overnight. The reaction was filtered, evaporated and subjected to the next step without further purification. ESI-MS m / z calc. 430.5, found 431.7 (M + 1) +; Retention time: 2.01 minutes (3 minutes of execution). fifteen

Step 2: (7 - ((dimethylamino) methyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'- piperidine] -1'-yl) (4-ethyl 3- methoxyphenyl) methanone

[0561] 20

image296

 25

[0562] A solution of 1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] 30 oxazine-4,4'-piperidine] -7-carbald-ehyde (88 mg, 0.20 mmol) N, N-dimethylamine hydrochloride (83 mg, 1.0 mmol), Et3N (140 µl, 1.0 mmol ) and NaHB (OAc) 3 (130 mg, 0.60 mmol) in DMF (1 ml) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN / H2O) to yield (7 - ((dimethylamino) methyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (4-ethyl-3-methoxyphenyl) methanone. ESI-MS m / z calc. 459.6, found 460.5 (M + 1) +; Retention time: 1.40 minutes (3 35 minutes of execution).

1 '- (4-ethyl-3-methoxybenzoyl) -N, N-dimethylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine- 4,4'-piperidine] -7-carboxamide

 40

[0563]

image297

 Four. Five

 fifty

[0564] A solution of 1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine -4,4'-piperidine] -7-yl-acid carboxylate (40 mg, 0.09 mmol), HATU (34 mg, 0.090 mmol), N, N-dimethylamine hydrochloride (7.3 mg, 0.090 mmol ) and iPR2NEt (62 ml, 0.36 mmol) in DMF (1 ml) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% of CH3CN / H2O). The pure fractions were combined and evaporated to give 1 '- (4-ethyl-3-methoxybenzoyl) -N, N-dimethylspiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4'-piperidine], 4] oxazine-4,4 'piperidine] -7-carboxamide. ESI-MS m / z calc. 473.6, found 474.5 (M + 1) +; Retention time: 1.80 minutes (3 minutes of execution).

1 '- (4-ethyl-3-methoxybenzoyl) -N-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-60 4 , 4'-piperidine] -7-carboxamide

[0565]

 65

image298

 5

1 '- (3-Methoxybenzoyl-4-ethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 solution '-piperidine] -7-carboxylic acid (40 mg, 0.090 mmol), HATU (34 mg, 0.090 mmol), N-methylamine hydrochloride (6.0 mg, 0.090 mmol) and iPR2NEt (62 µl, 0.36 mmol ) in DMF (1 ml) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN / H2O). The pure fractions were combined and evaporated to give 1 '- (4-ethyl-3-methoxybenzoyl) -N-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4' -piperidine], 4] oxazine-4,4'-piperidine] -7-carboxamide. ESI-MS m / z calc. 459.5, found 460.5 (M + 1) +; Retention time: 1.73 minutes (3 minutes of execution).

 fifteen

(7- (aminomethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'- il) (nyl 4-ethyl-3-methoxyphe-) methanone

[0566]

 twenty

image299

 25

[0567] NaBH4 (17.7 mg, 0.47 mmol) was added slowly to a solution of 1- (4-ethyl-3-methoxybenzoyl) spiro 30 [piperidine 4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -7'-carbonitrile (20 mg, 0.050 mmol) and dichlorocobalt hexahydrate (22 mg, 0.090 mmol) in MeOH (1 ml) and stirred at room temperature for 10 minutes. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN / H2O) to give (7- (aminomethyl) spiro [benzo [b] pyrrolo [1,2-d] [1, 4] oxazine-4,4'-piperidine], 4] oxazine -4,4'-piperidine] -1'-yl) (4-ethy1-3-methoxyphenyl) methanone. ESI-MS m / z calc. 431.5, found 432.5 (M + 1) +; Retention time: 1.44 minutes (3 minutes of execution). 35

(4-Isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl) (1- (methylsulfonyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone

Step 1: (4-Isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl) (1- (methylthio) spiro [benzo [b] pyrrolo 40 [1,2-d] [1,4] oxazine-4,4 ' -piperidine], 4] oxazine ine-4,4'-piperid -] - 1'il) methanone

[0568]

 Four. Five

image300

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[0569] A solution of 1-chloropyrrolidine-2,5-dione (92 mg, 0.70 mmol) in dry dichloromethane (3.2 ml) was added dropwise at -10 ° C to a solution of Methylsulfanylmethane (82 µl, 1.1 mmol) in dry dichloromethane (800 ml) over a period of 5 minutes. The reaction was allowed to warm to room temperature and stirred for 30 minutes. Then, the mixture was cooled to -55 ° C and a solution of (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-phenyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [ 1,4] ben- zoxazine] -1-yl-methanone (210 mg, was added dropwise)

0.49 mmol) in dry dichloromethane (800 µl). The cooling bath was removed and the mixture gradually heated to room temperature and stirred overnight. The solvent was removed in vacuo and the pink residue obtained was dissolved in dry toluene (7 ml) and heated at 50 ° C for 5 minutes. The solvent was removed to give (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl) (1- (methylthio) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone (250 mg, 78%). ESI-MS m / z calc. 462.2, 5 found 463.5 (M + 1) +; Retention time: 2.43 minutes (3 minutes of execution).

Step 2: (4-Isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl) (1- (methylsulfonyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'- piperidine], 4] oxazine dine-4,4'-piperi -] - 1'il) methanone

 10

[0570]

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[0571] To a solution of (4-isopropoxy-3-methylphenyl) (1- (methylthio) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] , (250 mg, 0.54 mmol) in dry dichloromethane (2 ml) at 0 ° C, 3-chlorobenzene-carboperoxoic acid (93 mg, 0.54 mmol) was added After stirring 10 minutes at 0 ° C it was removed the cooling bath The reaction was diluted with dichloromethane (25 ml) and saturated sodium bicarbonate (10 ml) The organic layer was separated and the aqueous layer was extracted twice with dichloromethane (2 x 25 ml). The combined were washed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified by column chromatography (silica gel: 5-40% EtOAc in hexanes) then reverse phase HPLC 10 at 99% acetonitrile in water (HCl modifier) to give (4-isopropoxy-3-methylphenyl) (1- (methylsulfonyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4 , 4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) met 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 7.9 Hz, 1H), 7.31 to 7.21 (m, 4H), 7.21 to 7.13 (m, 2H), 6.84 (d , J = 8.7 Hz, 1H), 6.17 (d, J = 4.0 Hz, 1H), 4.65-4.52 (m, 1H), 4.25 40 (wide s, 2H) , 3.55-3.36 (m, 2H), 3.10 (s, 3H), 2.22 (s, 3H), 2.18-1.87 (m, 4H) and 1.36 (d , J = 6.0 Hz, 6H). ESI-MS m / z calc. 494.6, found 495.5 (M + 1) +; Retention time: 1.98 minutes (3 minutes of execution).

1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'- piperidine] -1-carbonitrile 45

Step 1: (Z) -1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1oxima carbaldehyde

image302

[0572] 50

 55

 60

 65

[0573] A solution of 1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine -4,4'-piperidine] -1-ehyde carbald- (950 mg, 2.21 mmol) in ethanol (4.7 ml) was heated to 60 ° C. Added one

solution of hydroxylamine hydrochloride (693 mg, 9.97 mmol) and sodium acetate (1.38 g, 16.8 mmol) in water (4.7 ml) to the carbaldehyde solution. The reaction mixture was heated at 70 ° C for 30 minutes before it was cooled to room temperature. Water was added and the product formed a white precipitate that was collected by filtration. The solids were washed with water and toluene, and dried under reduced pressure to give (Z) -1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1, 4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] oxime -1-carbaldehyde (847 5 mg).

Step 2: 1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4, 4'-piperidine] -1-carbonitrile

 10

[0574]

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[0575] Acetic anhydride (4.0 ml, 42 mmol) was added to (Z) -1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo 30 [1,2-d] [ 1, 4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] oxime -1-carbaldehyde (847 mg from the previous stage). The reaction mixture was heated at 140 ° C for 3.5 h, then cooled to room temperature and poured onto ice. Dichloromethane (30 ml) was added followed by sodium bicarbonate (0.7 g). Then, the organic phase was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried, filtered, and concentrated to give a yellow oil. The crude material was purified by column chromatography (silica gel: 5-45% EtOAc in hexanes) to give 1 '- (4-ethyl-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2 -d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1-carbonitrile (944 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 1H), 7.22 to 7.16 (m, 1H), 7.15 to 7.8 (m, J = 7.6 Hz, 3H), 7.00 (d, J = 4.0 Hz, 1H), 6.93-6.87 (m, 2H), 6.08 (d, J = 4.0 Hz, 1H), 4.64 (s , 1H), 3.83 (s, 3H), 3.65-3.14 (m, 3H), 2.62 (q, J = 7.5 Hz, 2H), 2.27-1.67 ( m, 4H), 1.16 (t, J = 7.5 Hz, 3H). ESI-MS m / z calc. 427.5, found 428.5 (M + 1) +; 40 retention time: 2.08 minutes (3 minutes of execution).

(1- (aminomethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'- il) (nyl 4-isopropoxy-3- (trifluoromethyl) benzoicoco3-Methylophe-) methanone

 Four. Five

[0576]

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[0577] To a solution of 1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4'-piperidine], 4] oxazine-4,4'-piperidine] -1-dichlorocobalt was added carbonitrile (255 mg,

0.572 mmol) in MeOH (15.3 ml) at 0 ° C (149 mg, 1.14 mmol) followed by the addition of NaBH4 (216 mg, 5.72 mmol). The reaction mixture was allowed to stir for 15 minutes at room temperature before it was cooled to 0 ° C and acidified with 1M HCl. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc (50 ml) and saturated aqueous NaHCO3 (15 ml). The aqueous phase was extracted with EtOAc (2 x 50 ml). The combined organic phases were dried with Na2SO4, filtered and concentrated to give (1- (aminomethyl) spiro [benzo [b] pyrrolo [1,2-5 d] [1,4] oxazine-4,4'-piperidine ], 4] oxazine-4,4'-piperidine] -1'-yl) (nyl 4-isopropoxy-3- (trifluoromethyl) benzoicoco3-Methylophe-) methanone (170 mg, 67%). ESI-MS m / z calc. 445.6, found 446.5 (M + 1) +; Retention time: 1.45 minutes (3 minutes of execution).

N - ((1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1, 10 4] oxazine-4,4' -piperidine], 4] oxazine-4,4'-piperidine] -1-yl) methyl) formamide

[0578]

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[0579] A solution of (1- (aminomethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'- Piperidine] -1'-yl) (4-isopropoxy 3- methylphenyl) methanone (60 mg, 0.13 mmol) in ethyl formate (109 ml, 1.35 mmol) was heated at 50 ° C overnight. The solvent was removed under reduced pressure and the product was purified by reverse phase HPLC 10 to 99% acetonitrile in water (HCl modifier) to give N - ((1 '- (4-isopropoxy-3- (trifluoromethyl) acid) benzoicoco3-methyl-benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl) methyl) 35 formamide. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.30 to 7.22 (m, 1H), 7.20 to 7.1 (m, 3H ), 6.83 (d, J = 8.1 Hz, 1H), 6.28 (d, J = 3.5 Hz, 1H), 5.99 (d, J = 3.6 Hz, 1H), 5.89 (s, 1H), 4.77 (d, J = 5.0 Hz, 2H), 4.62-4.52 (m, 1H), 3.50 (s, 2H), 2.21 (s, 3H), 2.17-1.78 (m, 4H), 1.70 (s, 2H), 1.36 (d, J = 6.0 Hz, 6H). ESI-MS m / z calc. 473.6, found 474.5 (M + 1) +; Retention time: 1.80 minutes (3 minutes of execution).

 40

N - ((1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'- piperidine], 4] oxazine-4,4'-piperidine] -L-yl) methyl) acetamide

[0580]

 Four. Five

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[0581] Crude (1- (aminomethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) (4-isopropoxy 3-methyl-phenyl) methanone (49 mg, 0.11 mmol) was dissolved in a solution of

Dry dichloromethane (0.5 ml) and pyridine (0.3 ml) and cooled to 0 ° C. Acetic anhydride (52 µL, 0.55 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched by the addition of methanol (0.5 ml), concentrated and purified by reverse phase HPLC [10 to 99% acetonitrile in water (modifying HCl)] to give N - ((1 ' - (4-Isopropoxy spiro-3-methylbenzoyl) [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1-yl) methyl) acetamide. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.9 Hz, 1H), 7.33-7.21 (m, 2H), 7.13 (d, J = 4.2 Hz , 2H), 07.10 to 07.02 (m, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.26 (d, J = 3.4 Hz, 1H), 5.99 ( d, J = 3.5 Hz, 1H), 5.68 (s, 1H), 4.71 (d, J = 4.7 Hz, 2H), 4.64-4.50 (m, 1H), 3.50 (s, 2H), 2.22 (s, 3H), 2.17-1.76 (m, 7H), 1.67 (s, 2H), 1.36 (d, J = 6, 0 Hz, 6H). ESI-MS m / z calc. 487.6, found 488.5 (M + 1) +; Retention time: 1.81 minutes (3 minutes of execution).

(7-Chloro-1- (hydroxymethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-10 piperidine ] -1'-yl) (3-methoxy-4- (trifluoromethyl-) phenyl) methanone

Step 1: 7-Chloro-1 '- (3-methoxy-4- (trifluoromethyl) benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] , 4] oxazine-4,4-piperi- eat] -1-carbaldehyde

 fifteen

[0582]

image307

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 25

[0583] POCl3 (150 µl, 1.5 mmol) was added dropwise at 0 ° C under an atmosphere of N2 to dry DMF (120 µl, 1.5 mmol). The reaction mixture was left for 20 min at this temperature, which led to the formation of a white solid. A solution of (7'-chloros-pyro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl) - [3--4-methoxy (trifluoromethyl) phenyl ] methanone (490 mg, 1.0 mmol) in dry DMF (3.7 ml) was added dropwise and the cooling bath was removed and stirring was continued for an additional hour. The mixture was poured onto ice-water, 1M NaOH (7 ml) was added and the pH was adjusted to 7 with 2M HCl. The reaction was extracted with dichloromethane (3 x 10 ml). The combined organics were dried with MgSO4, filtered and evaporated to yield a residue that was purified by silica gel chromatography eluting with 5-20% AcOEt in dichloromethane to give 7-chloro-1 '- (3-methoxy -4- (trifluoromethyl) benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine- 4,4'-piperidine] -1 -carbaldehyde (400 mg, 77%). ESI-MS m / z calc. 504.9, found 505.3 (M + 1) +; Retention time: 2.04 minutes (3 minutes of execution). 40

[0584] 1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) -9-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4 '-piperidine], 4] oxazine-4,4'-piperidine] -1-car - baldehyde was synthesized from (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl) (9-methylpyrro [benzo [b ] pyrrolo [1,2-d] [piperidine 1,4] oxazine-4,4 '] - 1'-yl) methanone by the procedure described above.

 Four. Five

Step 2: (7-Chloro-1- (hydroxymethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4 ' -piperidine] -1'-yl) (3-methoxy-4- (trifluoromethyl) phenyl) methanone

[0585]

 fifty

image308

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 60

[0586] Chloro-1 '- (3-methoxy-4- (trifluoromethyl) benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4 ] oxazine-4,4'-piperidine] -1-carbaldehyde (50 mg, 0.10 mmol) dissolved in dry THF (3 ml) was cooled to 0 ° C. NaBH4 (3.9 mg, 0.10 mmol) was added and stirring was continued for 30 min. The mixture was filtered through Celite, evaporated and purified by column chromatography (5-30% AcOEt in dichloromethane) to give (7-chloro-1- (hydroxymethyl) spiro [benzo [b] pyrrolo [1, 2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) (3-65 methoxy-4- (trifluoromethyl) phenyl) methanone . ESI-MS m / z calc. 506.9, found 507.0 (M + 1) +; Retention time: 1.96 minutes (3 minutes of execution).

7-Chloro-1 '- (3-methoxy-4- (trifluoromethyl) benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1-carbonitrile

[0587] 5

image309

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 fifteen

[0588] To a solution of 7-chloro-1 '- (3-methoxy-4- (trifluoromethyl) benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4 '-piperidine], 4] oxazine-4,4'-piperidine] -1-carbaldehyde (310 mg, 0.61 mmol) in ethanol (1.5 ml) was added an aqueous solution of hydroxylamine hydrochloride (190 mg, 2.7 mmol) and sodium acetate (380 mg, 4.6 mmol) in water (1.5 ml). The mixture was heated at 95 ° C for 2 hours. The reaction mixture was cooled to 25 ° C, water was added and the white precipitate that formed was collected by filtration, washed thoroughly with water and dried by azeotrope with toluene. The solid was dissolved in Ac2O (1.1 mL, 12 mmol) and heated at 140 ° C for 3.5 hours. The mixture was cooled to 25 ° C, poured on ice, diluted with dichloromethane (30 ml), and neutralized with NaHO3 (2 g). The organic phase was separated, and the aqueous phase was further extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried, filtered, concentrated to a yellow oil that was purified by column chromatography (silica gel, 5-30% EtOAc in hexanes) to give 7-chloro- 1 '- (3-Methoxy 4- (trifluoromethyl) benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine ridine-4, 4'-over pipe] -1-carbonitrile. 1 H NMR (400 MHz, CDCl 3) δ 8.06 (t, J = 10.1 Hz, 1 H), 7.70 (s, 1 H), 7.64 (dd, J = 8.6, 1.6 Hz , 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.7, 2.2 Hz, 1H), 7.03 (dd, J = 10, 4, 6.3 Hz, 2H), 6.13 (d, J = 4.0 Hz, 1H), 4.61 (s, 1H), 3.96 (d, J = 20.2 Hz, 3H) , 3.89-3.06 (m, 3H), 2.16-1.81 (m, 4H). ESI-MS m / z calc. 501.9, found 502.0 30 (M + 1) +; Retention time: 2.17 minutes (3 minutes of execution).

[0589] 1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine ], 4] oxazine-4,4'-piperidine] -9-carbonitrile was synthesized from 1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) spiro [benzo [b] pyrrolo [1] , 2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] ehyde -9-carbald- using the procedure described above. 35

(4-Isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl) (1H-spiro [chromene [3,4-d] imidazol-4,4'-piperidine] -1’-yl) methanone

[0590] 40

image310

 Four. Five

 fifty

mixture of 1 H-spiro [chromene [3,4-d] imidazol-4,4'-piperidine] (210 mg, 0.88 mmol), 4-isopropoxy-3- (trifluoromethyl) benzoicoco-3-methyl-benzoic acid ( 170 mg, 0.89 mmol), triethylamine (370 µl, 2.6 mmol), and EDCI (170 mg, 0.89 mmol) in dichloromethane (5 ml) was stirred for 16 h. The reaction mixture was diluted with dichloromethane and washed with 1 M HCl, saturated NaHCO3 solution, and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography eluting with 0-100% of methanol in dichloromethane to give (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl acid) (1H-spiro [chromene [3,4] -d] imidazol-4,4'-piperidine] -1'-yl) methanone (44 mg, 12%). ESI-MS m / z calc. 417.5, found 418.5 (M + 1) +; Retention time: 1.44 minutes (3 minutes of execution).

(4-Isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl) (1-methyl-1H-spiro [chromene [3,4-d] imidazol-4,4'-60 piperidine] -1'-yl) methanone and (4-Isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl) (3-methyl-3H-spiro [chromene [3,4-d] imidazol-4,4'-piperidine] -1'-yl) methanone

[0591]

 65

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 5

[0592] (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methylphenyl acid) (1H-spiro [chromene [3,4-d] imidazol-4,4'-10 piperidine] -1'-yl) methanone (44 mg, 0.11 mmol), iodomethane (20 µl, 0.32 mmol), and potassium carbonate (29 mg, 0.21 mmol) were stirred in DMF (1 ml) for 16 h. The reaction was filtered and evaporated. The crude material was purified by column chromatography eluting with 0-10% methanol in dichloromethane followed by reverse phase HPLC (gradient: 1-99% ACN in water with formic acid as modifier) to separate the two regioisomers. First of all eluting the product: ESI-MS m / z calc. 431.5, found 432.7 (M + 1) +; Retention time: 1.51 15 minutes (3 minutes of execution). Secondly eluting the product: ESI-MS m / z calc. 431.5, found 432.7 (M + 1) +; Retention time: 1.54 minutes (3 minutes of execution).

(4-Cyclopropyl-3-methoxy-phenyl) - (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1’-yl) methanone

 twenty

[0593]

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 30

Step 1: (4-Bromo-3-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1’-yl) methanone

[0594] To a 100 ml round bottom flask of 4-bromo-3-methoxy-benzoic acid (860 mg, 3.7 mmol), HATU (1.4 g, 3.7 mmol), DMF (6 ml) was added ) and triethylamine (1.4 ml, 10 mmol). The reaction mixture was allowed to stir for 10 minutes. 1-Methylspiro [chromene [4,3-c] pyrazol-4,4'-piperidine] (860 mg, 3.4 mmol) dissolved in DMF (6 ml) was added, and the mixture was allowed to stir at 25 ° C. After 2 h, the reaction was quenched with brine and extracted with ethyl acetate. The combined organic layers were washed with brine 3 times. The combined organic layer was dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (5-90% EtOAc: hexanes) to give (4-bromo-3-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazole- 40,4'piperidine] -1'-yl) methanone in the form of white foam. ESI-MS m / z calc. 467.1, found 468.2 (M + 1) +. Retention time: 3.04 minutes (4 min of execution).

Step 2: (4-cyclopropyl-3-methoxy-phenyl) - (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone 45

[0595]

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 55

[0596] Microwave (4-bromo-3-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-piperidine 4,4 '] - 1'-yl) were added to a microwave vial methanone (70 mg, 0.15 mmol), cyclopropylboronic acid (26 mg, 0.30 mmol), fiber cat (49 60 mg, 0.0075 mmol), DMF (0.7 ml), and K2CO3 (150 µl 3.0 M, 0.45 mmol). The vial was purged with nitrogen and heated at 120 ° C for 2 hours. The reaction was filtered and purified by HPLC (20-99%) MeOH: H2O. ESI-MS m / z calc. 429.2, found 430.4 (M + 1) +. Retention time: 2.95 minutes (4 min of execution).

(3-Methylbenzoimidazol-4-yl) - (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1’-yl) methanone 65

[0597]

image314

 5

 10

Step 1: (1H-benzo [d] imidazol-4-yl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

[0598] To a solution of 1-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] (211 mg, 0.830 mmol), zol-4-carboxylic acid 1H-benzimide- (134 mg , 0.830 mmol) and triethylamine (346 µL, 2.50 mmol) in dichloromethane (2 mL) HATU (314 mg, 0.830 mmol) was added in one portion and the mixture was stirred for 12 hours. The reaction mixture was treated with 1M NaOH (1 ml) for 10 minutes. Dichloromethane (5 ml) was added. The two layers were separated and the aqueous layer was extracted with dichloromethane (2 x 5 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated to yield a residue that was purified on silica using a gradient of 0.5 to 30% MeOH in dichloromethane to give (1H-benzo [ d] imidazol-4-yl) (1-methyl-1 H-spiro [chromene 20 [4,3-c] pyrazol-4,4'-piperid-ine] -1'-yl) methanone. ESI-MS m / z calc. 399.5, found 400.5 (M + 1) +. Retention time: 1.12 minutes (4 min of execution).

Step 2: (3-Methylbenzoimidazol-4-yl) - (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

[0599]

image315

 30

 35

[0600] To a solution of (1H-benzo [d] imidazol-4-yl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'- il) methanone (21 mg, 0.052 mmol) in dry THF (0.2 ml) was added under N2 NaH (1.9 mg, 0.079 mmol) at 0 ° C. After 30 min, MeI (3.3 µl, 0.052 mmol) was added and the mixture was stirred at 0 ° C for 1 h. The reaction mixture was quenched with water and the solvent was removed in vacuo to yield a residue. crude which was collected in methanol and purified by reverse phase HPLC to give (3-Methylbenzoimidazol-4-yl) - (1-methyl-1 H-spiro [chromene [4,3-c] pyrazole 4,4'-piperidine ] -1'-il) methanone. ESI-MS m / z calc. 413.5, found 414.5 (M + 1) +. Retention time: 1.13 minutes (3 minutes of execution). Four. Five

[4- (2-Hydroxy-1,1-dimethyl-ethyl) -3-methoxy-phenyl] - (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperi- eat] -1'-il) methanone

[0601] 50

image316

 55

 60

[0602] Difluorozinc (16 mg, 0.15 mmol) and Pd (tBu3P) 2 (7.6 mg, 0.015 mmol) were added to a microwave vial. The vial was capped and purged with nitrogen for 10 minutes. DMF (1 ml) was added and the reaction mixture was allowed to stir for 10 minutes. (4-Bromo-3-methoxyphenyl) (1-methyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-65 piperidine] -1'-yl) methanone (140 mg, 0.30 mmol) dissolved in DMF (0.5 ml) was added followed by trimethyl (2-methylprop-1-enoxy) lane Si- (83 µl, 0.45 mmol). The reaction vessel was placed in an oil bath maintained at 80 ° C

for 16 hours The reaction mixture was filtered, quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in MeOH (2 ml). NaBH4 (34 mg, 0.90 mmol) was added and the reaction mixture immediately turned yellow to brown. The mixture was filtered and purified by HPLC (1-99%) of MeOH: H2O to provide [4- (2-hydroxy-1,1-dimethyl-ethyl) -3-methoxy-phenyl] - (1-methyl- 1H- spiro [chromene [4,3-c] pyramid zol-4,4'-piperidine] -1'-yl) methanone. ESI-MS m / z calc. 5 461.5, found 462.2 (M + 1) +. Retention time: 2.73 minutes (4 min of execution).

[0603] 1 '- (4- (1-hydroxy-2-methyl-2-yl) -3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1, 4] oxazine-4, 4'-piperidine], 4] oxazine-4, ridine 4 'on pipe] -1-carbonitrile was synthesized from-1' - (4-bromo-3-methoxybenzoyl) spiro [benzo [b] pyrrolo [1, 2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine- 4,4'piperidine] -1-carbonitrile using the procedures described above. 10

(4-ethoxy-2-isopropoxy-phenyl) - (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

Step 1: (4-ethoxy-2-hydroxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1’-yl) methanone

 fifteen

[0604]

image317

 twenty

 25

[0605] In a vial, 4-ethoxy-2-hydroxy acid benzoic acid (0.40 mmol) was added followed by HATU (170 mg, 0.44 mmol), DMF (0.7 ml), and triethylamine (220 µl, 1.6 mmol). The mixture was stirred for 10 minutes before adding 1-methyl-1 H- [chromene [4,3-c] pyrazol-4,4'-piperidine] spiro (100 mg, 0.40 mmol). The reaction mixture was allowed to stir at 25 ° C for 12 hours before it was filtered and purified by HPLC (1-99%) of MeOH: H2O to give 30 (4-ethoxy-2-hydroxy phenyl) (1 -methyl-1H spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone (53 mg, 32%). ESI-MS m / z calc. 419.5, found 420.4 (M + 1) +. Retention time: 2.96 minutes (4 min of execution).

Step 2: (4-ethoxy-2-isopropoxy-phenyl) - (1-methyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone 35

[0606]

image318

 40

 Four. Five

[0607] To a vial containing a solution of (4-ethoxy-2-hydroxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-50 piperidine 4,4 '] - 1'- il) methanone (41 mg, 0.1 mmol) in DMF (0.8 ml) K2CO3 (69 mg, 0.5 mmol), and 2-iodopropane (15 ml, 0.15 mmol) was added. The mixture was stirred for 3 hours at 25 ° C. The crude reaction mixture was filtered and purified by HPLC (1-99%) of MeOH: H2O to give (4-ethoxy-2-isopropoxy-phenyl) - (1-methyl-1H-spiro [chromene [4.3] -c] pyrazole 4,4'-piperidine] -1'-yl) methanone (17 mg, 33%). ESI-MS m / z calc. 461.5, found 462.2 (M + 1) +. Retention time: 3.16 minutes (4 min of execution). 55

(2-Isopropoxy-4-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone was synthesized using the procedures described above. ESI-MS m / z calc. 447.2, found 448.4 (M + 1) +; Retention time: 3.03 minutes (4 min of execution).

[3- (hydroxymethyl) -4-isopropoxy-3- (trifluoromethyl) benzoicocophenyl acid] - (1-methyl-1H-spiro [chromene [4.3-60 c] pyrazol-4,4'-piperidine] -1 ' -il) methanone

Step 1: 2-isopropoxy-5- (1-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’carbonyl) benzaldehyde

[0608] 65

image319

 5

[0609] 1-Methylspiro [chromene [4,3-c] pyrazol-4,4'-piperidine] (250 mg, 0.76 mmol), 3-formyl-4-isopropoxy-3-10 (trifluoromethyl) acid benzoicocoacid benzoicoco (160 mg, 0.76 mmol), EDCI (160 mg, 0.84 mmol), and Et3N (430 µl, 3.1 mmol) were combined in dichloromethane (7.1 ml) and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with an M HCl 1 (x 2), a saturated aqueous solution of NaHCO3 (2 x) and a saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-15-30% ethyl acetate in dichloromethane) to produce 2-isopropoxy-5- (1-methylpyrro [chromene [4,3-c] pyrazole- 4,4'-piperidine] 1'carbonyl) benzaldehyde (117 mg, 34%) as a light yellow solid. ESI-MS m / z calc. 445.2, found 446.3 (M + 1) +; Retention time: 1.74 minutes (3 minutes of execution).

Step 2: [3- (hydroxymethyl) -4-isopropoxy-3- (trifluoromethyl) benzoicocophenyl acid] - (1-methyl-1H-spiro 20 [chromene [4,3-c] pyrazol-4,4'-piperid- ine] -1'-il) methanone

[0610]

image320

 25

 30

 35

[0611] 2-Isopropoxy-5- (1-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-carbonyl) benzaldehyde (110 mg, 0.25 mmol) was dissolved in THF (3 ml) and LiBH4 (11 mg, 0.50 mmol) were added. The reaction was stirred at room temperature for 1.5 h before being quenched with methanol (3 ml). The reaction was neutralized by the addition of a saturated sodium bicarbonate solution and extracted with ethyl acetate (3x). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate in hexane) to give [3- (hydroxymethyl) phenyl -4-isopropoxy] - (1-methylpyrro [chromene [4 , 3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone (74 mg, 65%) as a white solid. ESI-MS m / z calc. 447.5, found 448.3 (M + 1) +. Retention time: 1.59 minutes (3 minutes of execution).

 Four. Five

(7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (4- (2-hydroxyethyl) -3-methoxyphe- nyl) methanone

Step 1: 2- (4- (7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-ylcarbonyl) -2-methoxyphe- nyl) acetaldehyde 50

[0612]

image321

 55

 60

[0613] To a microwave vial was added Pd (tBu3P) 2 (128 mg, 0.250 mmol) and difluorozinc (259 mg, 2.50 mmol). The vial was capped and purged with nitrogen for 10 minutes. DMF (1 ml) was added and the mixture was stirred for 10 minutes. A solution of (4-bromo-3-methoxy-phenyl) - (7'-chlorospiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl) methanone ( 244 mg, 0.500 mmol) in DMF (1.5 ml) was added followed by trimethyl () vinyl silane (581 mg, 5.00 mmol). The reaction mixture was heated at 80 ° C for 1 h before it was quenched with brine and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate and the solvent was removed. The

crude reaction was purified by silica gel chromatography (5% -80% ethyl acetate / hexanes) to give 2- (4- (7-chlorospiro [benzo [b] pyrrolidone lo [1,2-d] [ 1,4] oxazine-4,4-pipendin] 1'ylcarbon-yl acetaldehyde) -2-methoxyphenyl).

Step 2: (7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (4- (2-hydroxyethyl) -3 phenyl -methoxy-) methanone 5

[0614]

image322

 10

 fifteen

[0615] A 2- (4- (7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] 1'ylcarbon-yl) -2 -methoxyphenyl ) Acetaldehyde (from Step 1) MeOH (1 ml) was added followed by NaBH4 (95 mg, 2.5 mmol) and the reaction was stirred for 30 minutes at room temperature. After 30 minutes, the mixture was filtered and the filtrate was purified by prep HPLC (1-99% MeOH: H2O) to give (7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (4- (2-hydroxyethyl) -3-methoxyphenyl) methanone (16 mg, 7%). ESI-MS m / z calc. 452.2, found 453.2 (M + 1) +. Retention time: 2.91 minutes (4.5 minutes of execution).

[0616] (7-Chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] -1'-yl) (3-fluoro-4- (1- hydroxy-2-Methylopropan-2-yl) phenyl) methanone [ESI-MS m / z calc. 468.2, found 469.4 (M + 1) +. Retention time: 3.06 minutes (4.5 min run)] and (7-chlorospiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine] - 1'-yl) (4- (1-hydroxy-2-methyl-2-yl) phenyl) methanone [/ z calc ESI-MS m. 450.2, found 451.2 (M + 1) +. Retention time: 9.72 minutes (15 min of 25 execution)] were prepared using the procedures described above.

(4- (isopropylsulfonyl) -3-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

 30

Step 1: (4- (isopropylthio) -3-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

[0617]

 35

image323

 40

[0618] (4-Bromo-3-methoxy-phenyl) - (1-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone (300 mg, 0, 64 45 mmol), diphenyl phosphate phane (22 mg, 0.038 mmol), palladium propane-2-thiol acetate (30 ml, 0.32 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4- il) (4.3 mg, 0.019 mmol), and sodium carbonate (680 mg, 6.4 mmol) were combined in 1,4-dioxane (1.3 ml). The reaction mixture was heated at 100 ° C for 4 hours. A second aliquot of propane 2-thiol (30 µl, 0.32 mmol) was added and the reaction mixture was stirred for 16 hours. The crude reaction mixture was filitered and then evaporated to dryness. The crude material was purified by column chromatography using a gradient of 0 to 100% ethyl acetate in dichloromethane to provide a mixture of (4- (isopropylthio) -3-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone and (4-bromo-3-methoxy-phenyl) - (1-methyl spiro- [chromene [4,3-c ] pyrazol-4, 4'-piperidine] -1'-yl) methanon.

Step 2: (4- (isopropylsulfonyl) -3-methoxyphenyl) (1-methyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] - 1'-55 yl) methanone

[0619]

image324

 60

 65

[0620] (4-Isopropylsulfanyl-3-methoxy-phenyl) - (1-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone (291 mg, 0, 6277 mmol) was dissolved in acetic acid (3 ml) and hydrogen peroxide (200 µl, 6.527 mmol) was added. The reaction mixture was heated at 80 ° C for 40 minutes before it was partitioned between ethyl acetate (15 ml) and water (10 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and then purified by column chromatography using a gradient of 0-5% og methanol in 5 dichloromethane to give (4-isopropyl-3 -methoxy-phenyl) - (1-Methylspiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone (51 mg, 24%) as a white solid. ESI-MS m / z calc. 495.2, found 496.5 (M + 1) +. Retention time: 1.52 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 7.83 (d, J = 8.0 Hz, 1 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.45 (s, 1 H), 7.34 (s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 to 7.6 (m, 2H), 4.45-4.31 (m, 1H), 4.10 (s, 3H), 3.97 (s, 3H), 3.68 (septet, J = 6.7 Hz, 1H), 3.59 -3.22 (m, 3H), 2.10-1.82 (m, 4H), 1.17 (d, J = 6.9 Hz, 10 6H).

[0621] (4- (tert-Butylsulfonyl) -3-methoxyphenyl) (1-methyl-1 H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone was also synthesized using the procedures described above. (4- (tert-Butylsulfonyl) -3-methylphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'yl) methanone and (4 - ( ethylsulfonyl) -3-methylphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone were synthesized from (4-bromo- phenyl 15 3-methyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-ilmetanone) using the procedures described above.

7-Chloro-1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methylbenzoyl) -N-methylpyrro [benzo [b] pyrrolo [1,2-d] [ine 1,4] oxazine-4,4 -piperid -] - 1-carboxamide 20

Step 1: 7-chloro-1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4'-piperidine], 4] oxazine-4,4'-piperidine] -1-carboxylic acid

[0622] 25

image325

 30

 35

[0623] To a solution of 7-chloro-1 ′ - (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) spiro [benzo

[b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'piperidine] -1-carbaldehyde (130 mg, 0.27 mmol) in Acetone (1.5 ml) was added a solution of potassium permanganate (43 mg, 16 µl, 0.27 mmol) in water (1.5 ml) and acetone (1.5 ml) dropwise at 0 ° C . The mixture was allowed to stir at room temperature for 2 h before it was concentrated on Celite from methanol. Column chromatography on the residue (0-40 20% EtOAc / CH2Cl2) gave 7-chloro-1'-spiro (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl acid [benzo [b] pyrrolo [1,2-d] [1,4] piperidine oxazine-4,4 '] - 1-carboxylic acid (13%).

Step 2: 7-Chloro-1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methylbenzoyl) -N-methylpyrro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4 , 4'-piperidine], 4] oxazine-4,4-Pip eridine] -1-carboxamide 45

[0624]

image326

 fifty

 55

[0625] 7-Chloro-1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-methyl-benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4, 4'-piperidine], 4] oxazine-4,4'-piperidine] -1-car-carboxylic acid (17 mg, 0.034 mmol), methanamine hydrochloride (2.3 mg, 0.034 mmol), and Et3N (19 µl, 0.14 mmol) were collected in dry dichloromethane (0.5 ml). HATU (13 mg, 0.034 mmol) was added and the mixture was allowed to stir for 15 min at room temperature. The mixture was purified by prep HPLC to provide 7-chloro-1 '- (4-isopropoxy-3- (trifluoromethyl) benzoicoco3-met ylbenzoyl) -N-methylstyrene [benzo [b] pyrrolo [1,2-d] [ 1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1-carboxamide. ESI-MS m / z calc. 507.2, found 508.0 (M + 1) +. Retention time: 1.92 minutes (3 minutes of 65 execution).

(2-Methoxy-4- (methylsulfonyl) phenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1’-yl) methanone

Step 1: (2-methoxy-4- (methylthio) phenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

 5

[0626]

image327

 10

 fifteen

[0627] A mixture of (4-fluoro-2-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone (500 mg, 1.23 mmol) and methanethiol (172 mg, 2.45 mmol) in DMF (5 ml) was heated at 80 ° C for 36 h. The reaction gave rise to the desired product as well as the O-demethylated version of the product. To the crude reaction mixture was added 3 eq of iodomethane to reMetiloate in the desired product. The reaction mixture was washed with 1 N HCl, sat. here NaHO3, and brine. The organics were dried over sodium sulfate and evaporated. The crude product was purified by column chromatography eluting with 50-100% ethyl acetate in hexanes to give (2-methoxy-4- (methylthio) phenyl) (1-methyl-1H-spiro [chromene [4.3] -c] pyrazole -4,4'-piperidine] -1'-25 yl) methanone (60%). ESI-MS m / z calc. 435.2, found 436.1 (M + 1) +. Retention time: 1.53 minutes (3 minutes of execution).

Step 2: (2-Methoxy-4- (methylsulfonyl) phenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone

[0628]

image328

 35

 40

 Four. Five

[0629] A mixture of (2-methoxy-4- (methylthio) phenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) Methanone (320 mg, 0.74 mmol) and 30% hydrogen peroxide (250 µl) in acetic acid (3 mL) was heated at 80 ° C for 45 min. The mixture was diluted with water and extracted with ethyl acetate. The organics were washed with sat. here NaHCO3 and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography eluting with 70 to 100% ethyl acetate in hexanes 50 to give (2-methoxy-4- (methyl sulfonyl) phenyl) (1-methyl-1H-spiro [chromene [4, 3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone. ESI-MS m / z calc. 467.2, found 468.2 (M + 1) +. Retention time: 1.29 minutes (3 minutes of execution). 1H NMR (400 MHz, DMSO) δ 7.76-7.70 (m, 1H), 7.63-7.41 (m, 4H), 7.28 (t, J = 7.7 Hz, 1H) , 7.18 - 7.04 (m, 2H), 4.46-4.35 (m, 1H), 4.14 to 4.5 (m, 3H), 3.98-3.90 (m, 3H), 3 , 53-3.36 (m, 1H), 3.28 (s, 3H), 3.30 to 3.14 (m, 2H), 2.09-1.77 (m, 4H). 55

[0630] (4- (Isopropylsulfonyl) -2-methoxyphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone was also synthesized using the procedures described above. (1-methyl-1H-spiro [chromene [4,3-c] pyramid zol-4,4'-piperidine] -1'-yl) (3-methyl-4- (methylsulfonyl) phenyl) methanone was synthesized from (nyl 4-fluoro-3-Methylophe-) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone using the procedures described above. 60

[0631] (4- (Isopropylsulfonyl) -2-methylphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone was synthesized at starting (4-fluoro-2-methylphenyl) (1-methyl-1H-spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-yl) methanone using the procedures above.

N, N-dimethyl-2- (1-methylspiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’carbonyl) benzamide 65

Step 1: 2- (1-Methylspiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1’carbonyl) benzoic acid

[0632]

image329

 5

 10

[0633] A mixture of methyl 2- (1-methylspiro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'-carbonyl) benzoate (500 mg, 1.17 mmol), NaOH (5.0 ml of 1.0 M, 5.0 mmol), and 1,4-dioxane (5 ml) was heated at 80 ° C for 1.5 h. The mixture was cooled to rt before it was concentrated in vacuo. The solid residue was taken up in water and washed with ethyl acetate, which is discarded. The aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate (2x). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2- (1-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'carbonyl) Benzoic acid (33 mg, 75%) as a white solid. ESI-MS m / z calc. 403.2, found 404.2 (M + 1) +; Retention time: 2.31 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 13.22 (s, 1 H), 7.93 (d, J = 7.7 Hz, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.65 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.36 (br s, 2H), 7.28 (t, J = 7.7 Hz, 1H), 7.08 (dd, J = 13.8, 6.3 Hz, 2H), 4.39 (br s, 1H), 4.10 (s, 3H), 03/30 at 03/12 (m, 2H), 2.05-1.86 (m, 4H), 1.85-1.74 (m, 1H).

 25

Step 2: N, N-dimethyl-2- (1-methylpyrro [chromene [4,3-c] pyrazol-4,4'-piperidine] 1'carbonyl) benzamide

[0634]

image330

 30

 35

 40

[0635] Et3N (170 µl, 1.2 mmol) was added to a mixture of 2- (1-methylpyrro [chromene [4,3-c] pyrazol 4,4'-piperidine-] - 1'-carbonyl) acid benzoicoco (100 mg, 0.25 mmol), N-methylmethanamine hydrochloride (30 mg, 0.37 mmol), EDCI (48 mg, 0.25 mmol), and CH2Cl2 (1.5 ml) at room temperature. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 and washed with 1N HCl. The layers were separated and the organic layer was washed with 1 N NaOH, and then with brine before it was dried over sodium sulfate and concentrated in vacuo to give N, N-45 dimethyl-2- (1-ylspiro met [ chromene [4,3-c] pyrazol-4,4'-piperidine] 1'carbonyl) benzamide (38 mg) as a white solid. ESI-MS m / z calc. 430.2, found 431.3 (M + 1) +; Retention time: 2.24 minutes (3 minutes of execution). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.7 Hz, 1H), 7.45-7.37 (m, 3H), 7.46-7.22 (m, 2H) , 7.30-7.21 (m, 1H), 7.13-7.00 (m, 2H), 4.52 (d, J = 13.5 Hz, 1H), 4.19 (s, 3H ), 3.74-3.51 (m, 2H), 3.31 (t, J = 11.9 Hz, 1H), 3.09 (s, 3H), 2.94 (s, 3H), 2.24 at 2.2 (m, J = 13.9 Hz, 2H), 2.02-1.76 (m, 2H). N-Isopropyl-4- (1-methyl-1H-spiro [chromene 50 [4,3-c] pyrazol-4,4'-piperidine] -1'-ylcarbonyl) benzamide was synthesized from 4- (1- methyl-1H spiro [chromene [4,3-c] pyrazol-4,4'-piperidine] -1'-ylcarbonyl) benzoic acid using the procedures described above.

(S) - (4- (tetrahydrofuran-3-ylsulfonyl) phenyl) (1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [piperidine 1,4] oxazine-4,4 '] - 1'-yl) methanone and (R) - (4- (tetrahydrofuran-3-ylsulfonyl) phenyl) (1- (trifluoromethyl) spiro [benzo [b] 55 pyrrolo [1,2-d] [1,4] oxazine -4,4'-piperidine], 4] oxazine-4,4'-piperidine] -1'-yl) methanone

[0636]

 60

 65

image331

 5

 10

 fifteen

[0637] (4- (tetrahydrofuran-3-ylsulfonyl) phenyl) (1- (trifluoromethyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4-on ridine pipe] -1'-il) methanone underwent chiral CFS (column: Phenomenex Lux cellulose-2 (250 x 10 mm), 5 mm; mobile phase: 40% IPA w / 0.2% DEA, 60% CO2; concentration: 30 mg / ml in MeOH; injection volume: 20 µl; pressure: 100 bar; detection wavelength: 254 nm) to give two peaks. For each enantiomer, the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 1 M aqueous hydrochloric acid (1 x 1 ml), a saturated aqueous solution of sodium bicarbonate (1 x 1 ml) and a saturated aqueous solution of sodium chloride (1 x 1 ml). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give [4 - [(3S) tetrahydrofuran-3-yl] sulfonylphenyl] - [1 '- (trifluoromethyl) spiro [piperidine-4 , 4 'pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl] methanone as a yellow solid (peak 1, stereochemistry was randomized): ESI-MS m / z calc. 546.1, found 547.2 (M + 1) +; Retention time: 1.93 minutes (3 minutes of execution); 1 H NMR (400 MHz, DMSO) δ 7.99 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8 , 0 Hz, 1H), 7.37-7.14 (m, 3H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H ), 4.53-4.36 (m, 1H), 4.33-4.19 (m, 1H), 4.08-3.94 (m, 1H), 3.91-3.58 (m , 3H), 3.56-3.16 (m, 3H), 2.19-1.82 (m, 6H) and [4 - [(3R) tetrahydrofuran-3-yl] sulfonylphenyl] - [1'- (trifluoromethyl) spiro [piperidine-4,4'-pyrrolo [2,1-c] [1,4] benzoxazine] -1-yl] methanone as a yellow solid (peak 2, stereochemistry was randomized): ESI-MS m / z calc. 546.1, found 547.2 (M + 1) +; Retention time: 1.93 minutes (3 minutes of execution); 1 H NMR (400 MHz, DMSO) δ 7.99 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8 , 2 Hz, 1H), 7.36-7.14 (m, 3H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H ), 4.54-4.36 (m, 1H), 4.33-4.17 (m, 1H), 4.09-3.95 (m, 1H), 3.90-3.59 (m , 3H), 3.58-3.12 (m, 3H), 2.24-1.77 (m, 6H).

 35

7- (hydroxymethyl) -1 '- (4- (isopropylsulfonyl) benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine- 4,4'-piperidine] -1-carbonitrile

[0638]

 40

image332

 Four. Five

 fifty

[0639] (1-cyano-1 '- (4- (isopropylsulfonyl) benzoyl) spiro [benzo [b] pyrrolo [1,2-d] [1,4] oxazine-4,4'-piperidine], 4] oxazine-4,4'-piperidine] -7 yl) ethyl acetate Thyl me- (16.2 mg, 0.0297 mmol) was treated with 1M LiOH (1 ml), THF (5 ml) and MeOH (1 ml ). The mixture was stirred at room temperature overnight. The volatiles were removed and the residue was neutralized with 1N HCl. The mixture was extracted with CH2Cl2 (2x). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7'- (hydroxymethyl) -1- (4-55 isopropylsulfonylbenzoyl) spiro [piperidine-4,4'-pyrrolo [2.1 c ] [1,4] benzoxazine] -1'-carbonitrile (11.3 mg, 75%). ESI-MS m / z calc. 505.58, found 506.5 (M + 1) +; retention time 1.49 minutes (3 minutes of execution). 1 H NMR (400 MHz, DMSO) δ 7.93 (dd, J = 8.2, 6.5 Hz, 3H), 7.73 (d, J = 8.3 Hz, 2H), 7.32 (d , J = 4.0 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 4.1 Hz, 1H ), 5.39-5.30 (m, 1H), 4.51 (s, 2H), 3.81-3.64 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.37 (m, 1H), 2.20 to 2.12 (m, 1H), 2.13 to 2.3 (m, 1H), 2.01 (t, J = 5.9 Hz, 1H), 1.57 (dd, J = 12.5, 6.2 Hz, 1H), 1.17 (d, 60 J = 6.8 Hz, 6H).

[0640] Table 2 below recites the analytical data for the compounds of Table 1.

 65

Table 2.

 Cmpd No.

 LC / MS M + 1 LC / RT min 1H NMR

 one

 523.25 2.48

 2

 436.08 2.13

 3

 430.70 1.61 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.27 -7.05 (m, 4H), 7.02 (dd, J = 7.0, 4.0 Hz, 1H), 6.10 (dd, J = 14.8, 3.9 Hz, 1H), 4.86-4.72 (m, 2H), 4.70-4.55 (m, 1H), 3.88 (d, J = 4.8 Hz, 3H), 3.62-3.51 ( m, 1H), 3.48-3.17 (m, 3H), 2.32-1.87 (m, 6H), 1.78-1.62 (m, 1H),

 4

 432.70 1.56

 5

 432.30 1.96

 6

 483.16 1.98

 7

 431.00 2.19

 8

 485.30 1.62

 9

 485.50 1.79 1H NMR (400 MHz, CDCl3) d 7.69-7.61 (m, 3H), 7.43 (d, J = 8.2 Hz, 2H), 7.23-7, 01 (m, 3H), 6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H), 4.92 (d, J = 8.0 Hz, 2H), 4.82 (d, J = 8.0 Hz, 2H), 4.66 (bs, 1H), 3.80-3.15 (m, 4H), 2.32 - 1.67 (m, 4),

 10

 462.20 3.16

 eleven

 533.50 2.13 1H NMR (400 MHz, DMSO) d 7.98 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.34-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H), 4.49-4.39 (m, 1H), 3.58-3.37 (m, 3H), 3.27 (d, J = 6.5 Hz, 2H), 2.17 - 1.96 (m, 4H), 1.93 - 1.80 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H),

 12

 563.40 1.91 1H NMR (400 MHz, DMSO) d 7.88 (d, J = 8.4 Hz, 2H), 7.61-7.53 (m, 3H), 7.36-7, 24 (m, 2H), 7.24-7.16 (m, 1H), 7.02 (d, J = 4.0 Hz, 1H), 6.41 (d, J = 4.0 Hz, 1H ), 4.55-4.34 (m, 1H), 3.62-3.38 (m, 2H), 3.29-3.06 (m, 1H), 2.22-1.79 (m , 4H), 1.34 (s, 6H),

 13

 462.50 1.98

 14

 429.30 1.51

 fifteen

 469.97 3.72

 16

 420.30 1.75

 17

 493.50 1.53 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.73 (t, J = 5.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.36-7.28 (m, 3H), 7.27-7.17 ( m, 1H), 6.47 (d, J = 4.0 Hz, 1H), 4.76-4.64 (m, 1H), 4.52-4.46 (m, 1H), 3.58 -3.14 (m, 4H), 2.85-2.76 (m, 2H), 2.15-2.00 (m, 3H), 1.98-1.84 (m, 1H),

 18

 448.34 1.83

 19

 534.50 1.64

 twenty

 491.14 2.03

 twenty-one

 445.08 2.10

 22

 424.10 1.77 1H NMR (400 MHz, CDCl3) d 12.26, 7.52, 7.26, 7.24, 7.09, 7.01, 6.99, 6.32, 6.30 , 6.01, 5.97, 5.94, 4.76, 4.73, 4.65, 4.61, 3.68, 3.65, 3.62, 3.51, 3.48, 3 , 44, 3.40, 3.37, 3.27, 3.25, 3.22, 2.30, 2.26, 2.21, 2.17, 2.13, 2.07, 2.01 , 1.99, 1.96, 1.91, 1.76, 1.73, 1.70, 1.59, 1.25, 0.07,

 2. 3

 473.30 1.83 1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.26 - 7.03 (m, 5H), 6.81 (dd, J = 7.0, 4.1 Hz, 1H), 6.06 (dd, J = 16.3, 3.9 Hz, 1H), 4.86-4.60 (m, 3H), 3.88 (s, 3H), 3.64-3.18 (m, 4H), 2.31-1.87 (m, 4H),

 24

 418.00 1.85

 25

 465.50 6.80

 26

 513.50 1.80

 27

 393.07 2.72

 28

 432.50 1.83 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.4 Hz, 1H), 7.47 (s, 1H), 7.42-7.36 (m, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.15-7.05 (m, 2H), 7.05-6.99 (m, 2H), 4.44-4 , 13 (m, 1H), 4.10 (s, 3H), 3.72-3.39 (m, 2H), 3.31-3.17 (m, 1H), 2.02-1.85 (m, 4H), 1.33 (s, 9H),

 29

 443.20 2.17

 30

 481.40 2.79

 31

 497.10 1.84

 32

 443.70 2.34 1H NMR (400 MHz, CDCl3) d 6.90-6.77 (m, 7H), 6.68-6.52 (m, 4H), 6.34 (d, J = 8 , 0 Hz, 1H), 5.85 (dd, J = 5.8, 2.9 Hz, 1H), 5.55 (d, J = 3.6 Hz, 1H), 4.44 (br s, 1H), 4.10 (d, J = 2.3 Hz, 1H), 3.79 (br s, 1H), 2.05-1.87 (m, 4H), 1.74 (d, J = 2.2 Hz, 3H), 1.61 (s, 3H), 1.11 (d, J = 2.3 Hz, 12H), 0.89 (dd, J = 6.0, 2.3 Hz, 6H),

 33

 444.17 2.42

 3. 4

 493.50 1.80

 35

 485.19 1.83

 36

 472.30 2.16

 37

 485.50 1.88

 38

 435.50 2.38

 39

 438.50 1.70 1H NMR (400 MHz, DMSO) d 7.72, 7.70, 7.52, 7.47, 7.45, 7.31, 7.31, 7.15, 7.14 , 7.13, 6.30, 6.30, 6.29, 6.14, 6.13, 6.10, 6.08, 5.76, 4.39, 4.35, 3.46, 3 , 34, 3.18, 3.14, 3.12, 2.89, 2.79, 2.77, 2.75, 2.73, 2.67, 2.50, 2.33, 2.02 , 1.98, 1.93, 1.90, 1.86, 1.83, 1.19, 1.17, -0.00,

 40

 443.00 1.78

 41

 453.50 1.78 1H NMR (400 MHz, DMSO) d 7.87 (d, J = 2.0 Hz, 1H), 7.86-7.81 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.22-7.02 (m, 3H), 6, 28 (t, J = 3.1 Hz, 1H), 6.16 (d, J = 2.3 Hz, 1H), 4.52-4.18 (m, 1H), 4.00 (s, 3H ), 3.58 (s, 3H), 3.28 (s, 3H), 1.98 (s, 4H),

 42

 446.00 1.99 1H NMR (400 MHz, CDCl3) d 8.18-8.12 (m, 1H), 7.26-7.13 (m, 5H), 7.07-6.96 (m , 2H), 6.15 - 6.10 (m, 1H), 4.61 (dt, J = 12.0, 6.0 Hz, 2H), 3.44 (s, 3H), 2.07 ( dt, J = 47.5, 23.6 Hz, 5H), 1.46-1.36 (m, 6H),

 43

 414.00 1.13

 44

 392.20 2.97

 Four. Five

 495.50 1.89 1H NMR (400 MHz, CDCl3) d 7.25 (d, J = 6.6 Hz, 1H), 7.14-7.07 (m, 3H), 7.04-6, 96 (m, 3H), 6.32 (t, J = 3.2 Hz, 1 H), 6.03 (dd, J = 3.5, 1.3 Hz, 1 H), 5.00 (d , J = 7.6 Hz, 2H), 4.86 (d, J = 7.6 Hz, 2H), 4.72 - 4.57 (m, 1H), 3.84 (s, 3H), 3 , 77 - 3.49 (m, 2H), 3.45 - 3.23 (m, 1H), 3.09 (s, 3H), 2.26 - 1.75 (m, 4H),

 Cmpd No.

 LC / MS M + 1 LC / RT min 1H NRM

 46

 509.00 1.67

 47

 462.30 2.46

 48

 463.50 1.88

 49

 507.50 1.56 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.1 Hz, 3H), 7.34 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.2 Hz, 2H), 7.28-7 , 18 (m, 1H), 6.47 (d, J = 4.0 Hz, 1H), 4.72-4.68 (m, 1H), 4.50-4.38 (m, 1H), 3.55-3.38 (m, 2H), 3.29-3.15 (m, 1H), 3.16-3.07 (m, 2H), 2.14-2.04 (m, 3H ), 1.95-1.86 (m, 1H), 0.90 (d, J = 6.2 Hz, 3H),

 fifty

 485.50 2.18 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 21.6, 8.1 Hz, 4H) , 7.20-7.05 (m, 3H), 6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H), 4.75- 4.55 (m, 1H), 4.44-4.40 (m, 1H), 3.81-3.20 (m, 3H), 2.28-1.72 (m, 7H), 0, 98 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H),

 51

 478.30 1.62

 52

 435.50 1.86

 53

 480.50 1.54 1H NMR (400 MHz, DMSO) d 7.79 (s, 1H), 7.76-7.69 (m, 2H), 7.66-7.42 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.17-7.03 (m, 2H), 4.50-4.37 (m, 1H), 4.10 (s, 3H) , 3.54-3.39 (m, 2H), 3.37-3.09 (m, 2H), 2.44-2.30 (m, 3H), 2.11-1.70 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H),

 54

 458.37 1.59 1H NMR (400 MHz, CDCl3) d 8.16-8.09 (m, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.25-7, 18 (m, 3H), 7.17-7.11 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H ), 4.66 (s, 1H), 3.98 (d, J = 11.1 Hz, 1H), 3.82-3.71 (m, 1H), 3.68 (d, J = 11, 1 Hz, 1H), 3.63 - 3.24 (m, 2H), 2.55 (s, 3H), 2.25 - 2.13 (m, 1H), 2.03 - 1.73 (m , 4H), 1.58 (s, 3H),

 55

 421.10 2.62

 56

 430.50 1.95

 57

 481.14 2.45

 58

 400.21 2.33

 59

 433.10 1.61

 60

 427.23 2.10

 61

 408.20 1.66

 62

 444.50 2.71

 63

 427.50 2.07 1H NMR (400 MHz, CDCl3) d 7.26 (d, J = 8.7 Hz, 1H), 7.13-7.06 (m, 4H), 7.02 (dd, J = 8.5, 2.2 Hz, 1 H), 6.99 - 6.93 (m, 1H), 6.34 (t, J = 3.2 Hz, 1H), 6.06 - 6, 01 (m, 1H), 4.61 (s, 1H), 3.92 (s, 3H), 3.73 (s, 1H), 3.49 (s, 1H), 3.36 (s, 1H ), 2.26-1.73 (m, 4H),

 64

 480.20 1.69

 65

 442.70 1.85 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.1 Hz, 1H), 7.47-7.30 (m, 4H), 7.26-7, 18 (m, 2H), 7.17-7.07 (m, 2H), 7.01 (t, J = 5.5 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H ), 4.67 (m,

 1H), 4.43 (m, 1H), 3.51 (m, 4H), 2.32-1.71 (m, 6H), 0.97 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H),

 Cmpd No.

 LC / MS M + 1 LC / RT min 1H NMR

 66

 448.50 3.26

 67

 494.30 2.33

 68

 501.30 2.06

 69

 471.19 2.83 H NMR (400.0 MHz, DMSO) d 7.76 - 7.65 (m, 3H), 7.50 - 7.49 (m, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.17-7.05 (m, 3H), 6.29 - 6.28 (m, 1H), 6.17 - 6.16 (m, 1H), 4, 61-4.18 (m, 1H), 4.12 (t, J = 6.2 Hz, 2H), 3.83-3.05 (m, 3H), 1.98 (s, 4H), 1 , 78-1.73 (m, 2H) and 0.99 (t, J = 7.4 Hz, 3H) ppm,

 70

 499.30 1.88

 71

 441.16 2.20

 72

 551.50 2.20 1H NMR (400 MHz, CDCl3) d 7.59 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.8, 2.3 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 6.98 (dd, J = 8.2, 1.8 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H) , 4.22-4.15 (m, 3H), 3.88 (s, 3H), 3.81-3.76 (m, 2H), 3.44 (s, 3H), 3.53-3 , 30 (m, 3H), 2.18-1.80 (m, 4H),

 73

 501.23 2.14

 74

 477.30 2.04

 75

 495.20 2.01

 76

 400.50 1.68 1H NMR (400 MHz, DMSO) d 9.75 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 3, 7 Hz, 1H), 7.31 (d, J = 4.1 Hz, 2H), 7.26 - 7.21 (m, 1H), 7.20 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 3.9 Hz, 1H), 3.08 (s, 1H) , 2.13 (s, 3H), 2.05-1.91 (m, 4H),

 77

 376.26 1.95

 78

 534.30 1.99 1H NMR (400 MHz, CDCl3) d 7.96 (d, J = 8.2 Hz, 2H), 7.87 (dd, J = 7.6, 1.4 Hz, 1H) , 7.64-7.58 (m, 3H), 7.37-7.29 (m, 1H), 7.13-7.01 (m, 2H), 4.67 (d, J = 12, 7 Hz, 1H), 3.75-3.58 (m, 1H), 3.58-3.49 (m, 1H), 3.47-3.33 (m, 1H), 2.32 (d , J = 12.4 Hz, 1H), 2.21 - 2.07 (m, 1H), 2.03 - 1.84 (m, 1H), 1.84 - 1.64 (m, 1H), 1.36 (s, 9H),

 79

 400.21 2.13

 80

 424.16 1.71

 81

 409.11 2.01

 82

 490.30 2.07

 83

 463.10 1.65

 84

 458.25 1.87

 85

 491.19 2.04

 86

 427.25 2.27

 87

 391.24 1.79

 88

 426.24 1.77

 89

 461.22 2.22

 90

 499.50 4.71

 91

 476.30 2.12

 92

 414.50 1.36

 93

 468.20 1.29 1H NMR (400 MHz, DMSO) d 7.76-7.70 (m, 1H), 7.63-7.41 (m, 4H), 7.28 (t, J = 7 , 7 Hz, 1H), 7.18-7.04 (m, 2H), 4.46-4.35 (m, 1H), 4.14-4.05 (m, 3H), 3.98 - 3.90 (m, 3H), 3.53-3.36 (m, 1H), 3.28 (s, 3H), 3.30-3.14 (m, 2H), 2.09-1, 77 (m, 4H),

 94

 462.20 1.71 1H NMR (400 MHz, DMSO) d 7.73 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 12.9 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1 H), 7.22-7.01 (m, 3H), 6.67-6.56 (m, 2H), 4.39 (d, J = 12, 8 Hz, 1H), 4.09 (s, 3H), 3.79 (s, 3H), 3.50-3.34 (m, 1H), 3.31-3.11 (m, 2H), 2.07 - 1.93 (m, 1H), 1.93 - 1.72 (m, 3H), 1.34 (s, 9H),

 95

 501.30 2.53

 96

 441.16 2.28

 97

 435.10 1.37

 98

 434.20 1.55

 99

 400.20 0.71 1H NMR (400 MHz, DMSO) d 8.62 (d, J = 6.8 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J = 7, 7 Hz, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.13 (d, J = 8, 1 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 6.8 Hz, 1H), 4.46 (d, J = 13.1 Hz , 1H), 4.10 (s, 3H), 3.52-3.13 (m, 3H), 2.13-1.75 (m, 4H),

 100

 438.50 1.36

 101

 458.34 1.64 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.21 (dd,

 J = 11.1, 4.2 Hz, 1H), 7.12 (dd, J = 13.0, 5.0 Hz, 2H), 7.01 (d, J = 4.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 4, 61 (d, J = 13.2 Hz, 1H), 3.88 (d, J = 1.0 Hz, 6H), 3.52 (s, 2H), 3.25 (t, J = 11.9 Hz, 1H), 2.15 (d, J = 14.1 Hz, 1H), 2.07 (s, 1H), 1.96 (t, J = 12.6 Hz, 2H), 1.64 ( s, 1H),

 102

 376.15 1.42

 103

 469.40 3.06

 104

 444.24 2.10

 105

 407.40 3.18

 106

 451.20 9.72

 107

 477.14 2.03

 108

 478.30 1.92 1H NMR (400 MHz, CDCl3) d 7.52, 7.49, 7.47, 7.33, 7.31, 7.29, 7.29, 7.27, 7.26 , 7.26, 7.23, 7.21, 7.19, 7.16, 7.14, 7.08, 7.04, 7.02, 6.99, 6.83, 6.64, 6 , 46, 5.30, 4.69, 4.66, 4.13, 3.99, 3.61, 3.58, 3.54, 3.51, 3.40, 3.36, 3.33 , 3.30, 3.27, 2.20, 2.17, 2.07, 2.04, 2.01, 1.97, 1.96, 1.94, 1.93, 1.91, 1 , 90, 1.76, 1.62, 1.57, 1.52,

 109

 404.30 2.33

 110

 430.27 2.43

 111

 423.24 2.07

 112

 461.50 2.68

 113

 411.20 1.45

 114

 475.30 1.78

 115

 418.00 1.83

 116

 493.25 2.19

 117

 436.50 1.80

 118

 457.23 2.52

 119

 452.30 1.16 1H NMR (400 MHz, DMSO) d 7.97 (s, 1H), 7.95-7.89 (m, 2H), 7.77-7.68 (m, 3H), 7.26-7.21 (m, 2H), 7.19-7.12 (m, 2H), 4.36-4.23 (m, 1H), 3.59-3.40 (m, 4H ), 2.18-2.00 (m, 3H), 1.99-1.87 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H),

 120

 438.50 1.73 1H NMR (400 MHz, CDCl3) d 7.54, 7.44, 7.42, 7.30, 7.28, 7.28, 7.23, 7.13, 7.12 , 7.12, 7.06, 7.05, 7.04, 7.03, 7.02, 6.55, 6.55, 6.37, 6.36, 6.36, 6.28, 6 , 28, 6.26, 6.26, 6.06, 6.05, 5.32, 5.30, 5.29, 5.27, 5.25, 5.23, 4.62, 4.59 , 3.76, 3.72, 3.63, 3.60, 3.57, 3.52, 3.51, 3.32, 3.28, 3.25, 2.22, 2.19, 2 , 12, 2.08, 2.03, 2.03, 1.98, 1.95, 1.91, 1.88, 1.65, 1.60, 1.55, 1.53, 1.39 , 1.38, 1.23, 1.22, 0.98,

 121

 474.28 1.81

 122

 544.24 2.13

 123

 505.10 2.06 1H NMR (400 MHz, DMSO) d 7.96 (d, J = 7.9 Hz, 1H), 7.62-7.49 (m, 3H), 7.35-7, 25 (m, 2H), 7.25-7.17 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.41 (d, J = 4.0 Hz, 1H ), 4.51-4.36 (m, 1H), 3.58-3.14 (m, 3H), 3.25 (s, 3H), 2.68 (s, 3H), 2.19 - 1.81 (m, 4H),

 124

 388.27 1.77

 125

 454.50 1.98 1H NMR (400 MHz, CDCl3) d 8.14, 8.12, 8.02, 7.52, 7.31, 7.26, 7.24, 7.21, 7.19 , 7.16, 7.14, 7.12, 7.03, 7.02, 6.81, 6.62, 6.44, 6.12, 6.11, 4.71, 3.97, 3 , 59, 3.56, 3.54, 3.50, 3.48, 3.42, 3.40, 3.33, 3.29, 3.26, 3.23, 2.96, 2.88 , 2.80, 2.21, 2.18, 2.14, 2.10, 2.06, 2.02, 1.97, 1.77, 1.57.0.94,

 126

 485.16 2.32

 127

 426.30 1.83

 128

 418.30 2.44

 129

 477.26 2.16

 130

 458.50 2.11

 131

 485.16 2.33

 132

 475.30 1.87

 133

 515.24 2.28

 134

 501.30 2.06

 135

 452.50 1.93

 136

 441.16 2.50

 137

 432.50 1.46

 138

 453.28 2.18

 139

 483.30 1.40

 140

 465.50 4.00

 141

 452.30 1.46 1H NMR (400 MHz, DMSO) d 7.96 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.46 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.15 - 7.05 (m, 2H), 4, 44-4.32 (m,

 1H), 4.10 (s, 3H), 3.61-3.36 (m, 2H), 3.26 (s, 3H), 2.68 (s, 3H), 2.11-1.81 (m, 5H),

 142

 465.40 3.02

 143

 458.10 2.66

 144

 462.19 2.11

 145

 442.18 2.57

 146

 478.30 2.22

 147

 410.50 1.55 1H NMR (400 MHz, CDCl3) d 7.42, 7.42, 7.40, 7.40, 7.24, 7.24, 7.23, 7.22, 7.17 , 7.12, 7.11, 7.09, 7.04, 6.94, 6.93, 6.86, 6.86, 6.84, 6.84, 6.73, 6.38, 6 , 30, 6.18, 6.17, 6.16, 6.11, 6.09, 6.07, 5.92, 5.91, 5.70, 4.51, 4.47, 3.60 , 3.42, 3.37, 3.33, 3.29, 3.25, 3.17, 3.14, 3.11, 2.89, 2.47, 2.02, 1.99, 1 , 94, 1.93, 1.89, 1.86, 1.62, 1.11, 1.08, 0.73, 0.71, 0.49, 0.47, 0.45, - 0, 00,

 148

 447.15 2.25

 149

 487.30 1.93

 150

 445.30 2.02 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.32-7.22 (m, 2H), 7.10-7.00 (m, 2H), 5.92 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 10.7 Hz, 1H), 4.29 (dq, J = 13.5, 6.6 Hz, 1H), 4.17 (s, 3H), 3.58 (s, 2H), 3.38 (t, J = 12.4 Hz, 1H), 2.29 - 2.13 (m, 1H), 2.08 - 1.90 (m, 1H) , 1.78 (s, 1H), 1.28 (d, J = 6.5 Hz, 7H),

 151

 547.20 1.93 1H NMR (400 MHz, DMSO) d 7.99 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.37-7.14 (m, 3H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H), 4.53-4.36 (m, 1H), 4.33-4.19 (m, 1H), 4.08-3.94 (m, 1H), 3.91 - 3.58 (m, 3H), 3.56-3.16 (m, 3H), 2.19 - 1.82 (m, 6H),

 152

 445.15 2.43

 153

 418.50 1.62 1H NMR (400 MHz, CDCl3) d 7.38 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.22-7.06 (m, 4H), 6.82 (d, J = 9.0 Hz, 1H), 4.56 (Sept, J = 5.8 Hz, 1H), 4, 43-3.76 (m, 2H), 3.65-3.37 (m, 2H), 2.36-2.15 (m, 2H), 2.21 (s, 3H), 2.14 - 2.00 (m, 2H), 1.33 (t, J = 10.2 Hz, 6H),

 154

 422.50 1.74 1H NMR (400 MHz, CDCl3) d 7.51, 7.49, 7.29, 7.28, 7.26, 7.14, 7.12, 7.11, 7.09 , 7.07, 7.05, 7.03, 7.01, 7.00, 5.30, 4.67, 4.50, 4.48, 4.46, 4.44, 3.99, 3 , 99, 3.64, 3.61, 3.57, 3.53, 3.50, 3.39, 3.35, 3.33, 3.29, 2.22, 2.19, 2.03 , 1.96, 1.92, 1.89, 1.77, 1.73, 1.57, 1.54, 1.52, 1.23, 1.21,

 155

 444.24 1.86

 156

 458.00 1.89 1H NMR (400 MHz, CDCl3) d 8.15 (d, J = 7.9 Hz, 1 H), 7.24 (t, J = 7.7 Hz, 1 H), 7 , 20 - 7.12 (m, 2H), 7.04 (d, J = 3.2 Hz, 2H), 6.99 (dd, J = 8.2, 1.5 Hz, 1H), 6, 89 (d, J = 8.2 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 4.59 (dt, J = 12.2, 6.1 Hz, 2H), 3.89 (s, 3H), 3.57 (d, J = 110.2 Hz, 2H), 2.82 (s, 3H), 2.38 - 1.77 (m, 5H), 1.40 (d, J = 6.0 Hz, 6H),

 157

 427.20 2.21

 158

 432.00 1.83 1H NMR (400 MHz, CDCl3) d 7.56 (d, J = 7.7 Hz, 1H), 7.33-6.98 (m, 5H), 6.73 (d, J = 9.0 Hz, 2H), 4.65 (d, J = 12.8 Hz, 1H), 4.55 (dt, J = 12.1, 6.1 Hz, 1H), 4.14 ( s, 3H), 3.62 - 3.24 (m, 3H), 2.32 (s, 3H), 2.26-1.60 (m, 5H), 1.32 (d, J = 6, 0 Hz, 6H),

 159

 373.20 2.99

 160

 402.50 1.76

 161

 457.50 2.19

 162

 416.21 2.31

 163

 411.20 2.08

 164

 503.30 2.06 1H NMR (400 MHz, DMSO)? 7.57 (d, J = 8.2 Hz, 1H), 7.38-7.24 (m, 2H), 7.24-7.17 (m, 1H), 6.98 (t, J = 22.1 Hz, 2H), 6.84 (d, J = 8.6 Hz, 1H), 6.40 (s, 1H), 4.46 (d, J = 12.7 Hz, 1H), 3 , 81 (d, J = 6.3 Hz, 6H), 3.75 (s, 3H), 3.36 (s, 2H), 3.15 (s, 1H), 1.94 (dd, J = 33.5, 13.8 Hz, 4H),

 165

 462.50 3.04

 166

 449.50 2.14

 167

 440.50 1.78 1H NMR (400 MHz, CDCl3) d 7.51, 7.49, 7.43, 7.42, 7.40, 7.38, 7.36, 7.31, 7.29 , 7.27, 7.26, 7.24, 7.21, 7.19, 7.12, 7.10, 7.07, 7.05, 7.03, 7.00, 6.76, 6 , 58, 6.56, 6.39, 4.66, 4.50, 4.48, 4.46, 4.44, 3.62, 3.59, 3.55, 3.52, 3.49 , 3.47, 3.45, 3.38, 3.33, 3.29, 2.18, 2.07, 2.04, 2.01, 1.97, 1.93, 1.91, 1 , 80, 1.76, 1.62, 1.60, 1.57, 1.54, 1.52, 1.23, 1.21, 1.19,

 168

 451.10 1.65 1H NMR (400 MHz, DMSO) d 7.71 (dd, J = 8.9, 5.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H) , 7.50 (dd, J = 2.9, 1.4 Hz, 1H), 7.11 (dd, J = 9.6, 2.8 Hz, 1H), 7.03 - 6.89 (m , 3H), 6.28 (t, J = 3.2 Hz, 1H), 6.19 (dd, J = 3.4, 1.4 Hz, 1 H), 4.53-4.24 (m , 1H), 3.83 (s, 3H), 3.71-3.36 (m, 3H), 2.05-1.83 (m, 4H), 1.48 (s, 6H),

 169

 456.50 1.71 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.35 - 6.92 (m, 7H), 4.43-4.29 (m, 1H), 4.10 (s, 3H), 3.87 (s, 3H), 3.65-3.19 (m, 3H), 2.11 - 1.80

 (m, 4H),

 170

 499.30 7.77

 171

 459.50 1.99

 172

 497.21 2.04

 173

 417.02 2.57

 174

 446.30 2.61

 175

 462.30 1.81

 176

 516.00 1.79

 177

 415.19 2.05

 178

 528.26 2.45

 179

 445.15 2.42

 180

 466.50 1.61

 181

 457.50 2.15

 182

 430.70 1.75

 183

 469.50 1.78

 184

 405.50 4.54 1H NMR (400 MHz, DMSO) d 7.66 (dd, J = 7.6, 1.4 Hz, 1H), 7.55 - 7.46 (m, 1H), 7, 42 (d, J = 8.7 Hz, 2H), 7.23-7.05 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H), 6.28 (t, J = 3.2 Hz, 1H), 6.22 - 6.14 (m, 1H), 4.93 - 4.81 (m, 1H), 4.50 - 4.06 (m, 1H), 4, 03 (t, J = 12.1, 7.2 Hz, 2H), 3.77-3.67 (m, 2H), 3.56-3.06 (m, 3H), 2.07-1, 78 (m, 4H),

 185

 446.08 2.33

 186

 399.23 2.13

 187

 420.30 1.55

 188

 432.20 1.76

 189

 439.14 2.03

 190

 448.30 2.35

 191

 503.30 2.06

 192

 423.20 2.18

 193

 465.50 2.27

 194

 444.50 1.73 1H NMR (400 MHz, CDCl3) d 7.58, 7.56, 7.52, 7.32, 7.31, 7.30, 7.29, 7.28, 7.26 , 7.23, 7.21, 7.19, 7.16, 7.14, 7.10, 7.07, 7.05, 7.03, 7.00, 6.84, 6.64, 6 , 46, 6.10, 4.68, 4.65, 4.16, 3.99, 3.64, 3.60, 3.58, 3.55, 3.49, 3.47, 3.39 , 3.36, 3.33, 3.30, 2.22, 2.19, 2.06, 1.97, 1.93, 1.90, 1.75, 1.62, 1.57, 1 , 53, 1.52, 1.25, 1.23, 1.21, 1.19,

 195

 489.30 1.70

 196

 493.50 1.74

 197

 430.50 4.47 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.32 (dd, J = 10.2, 4.1 Hz, 3H), 7.28-7.17 (m, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.48 ( d, J = 4.0 Hz, 1H), 4.88 (t, J = 5.5 Hz, 1H), 4.58-4.08 (m, 1H), 4.03 (t, J = 4 , 9 Hz, 2H), 3.72 (q, J = 10.1, 5.2 Hz, 2H), 3.67 - 3.09 (m, 3H), 2.15 - 1.80 (m, 4H),

 198

 510.50 2.31

 199

 200

 421.30 2.58

 201

 365.25 1.95

 202

 446.50 6.06 1H NMR (400 MHz, DMSO) d 7.73 (d, J = 6.8 Hz, 1H), 7.48 (s, 1H), 7.28 (t, J = 7, 3 Hz, 1H), 7.16 - 6.88 (m, 3H), 6.83 (s, 1H), 4.66 - 4.50 (m, 1H), 4.39 (d, J = 12 , 4 Hz, 1H), 4.09 (s, 3H), 3.42 (d, J = 12.2 Hz, 1H), 3.33 (s, 5H), 2.20 (s, 3H), 2.09 (s, 3H), 1.90 (dd, J = 32.3, 19.2 Hz, 4H), 1.27 (d, J = 6.0 Hz, 6H),

 203

 463.50 1.87

 204

 509.21 2.04

 205

 448.40 3.03

 206

 416.50 2.03 1H NMR (400 MHz, DMSO) d 9.43 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7 , 31 (d, J = 4.0 Hz, 2H), 7.26 - 7.21 (m, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.91 (dd, J = 8.1, 1.9 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 4.1 Hz, 1H), 5.76 ( s, 1H), 3.79 (s, 3H), 3.50 - 3.38 (m, 1 H), 3.30 - 3.17 (m, 1H), 2.09 - 1.92 (m , 4H),

 207

 539.50 1.95

 208

 428.50 1.97

 209

 464.30 1.72 1H NMR (400 MHz, DMSO) d 8.02 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.72-7.64 (m, 3H), 7.53-7.46 (m, 1H), 7.20-7.03 (m, 3H), 6.32-6.26 (m, 1H), 6.20-6.15 ( m, 1H), 4.58-4.27 (m, 1H), 3.64-3.14 (m, 3H), 2.15-1.83 (m, 5H), 0.55-0, 33 (m, 4H),

 210

 491.36 2.63

 211

 467.30 1.72

 212

 404.30 1.84

 213

 466.50 2.24

 214

 442.50 1.91

 215

 402.10 2.17

 216

 467.10 1.77

 217

 374.20 2.93

 218

 413.27 2.28

 219

 404.40 2.86

 220

 460.50 2.27 1H NMR (400 MHz, CDCl3) d 7.75 (d, J = 1.7, 1H), 7.60-7.51 (m, 2H), 7.27 (d, J = 8.5, 1H), 7.11 (d, J = 2.1, 2H), 7.02 (dd, J = 8.5, 2.2, 1H), 6.35 (t, J = 3.2, 1H), 6.05 (dd, J = 3.5, 1.3, 1H), 4.70-4.53 (m, 1H), 3.72-3.51 (m, 2H ), 3.44-3.23 (m, 1H), 2.28-1.77 (m, 4H), 1.53 (s, 9H),

 221

 389.50 2.00

 222

 407.28 2.20

 223

 517.20 2.34 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.1 Hz, 1H), 7.22-7.06 (m, 3H), 7.01 (d, J = 1.7 Hz, 1H), 6.98 (dd, J = 8.2, 1.7 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.81 ( d, J = 3.9 Hz, 1H), 6.05 (d, J = 3.9 Hz, 1H), 4.65 - 4.25 (m, 1H), 4.23 - 4.14 (m , 2H), 3.88 (s, 3H), 3.82-3.75 (m, 2H), 3.58-3.32 (m, 3H), 3.44 (s, 3H), 2, 20-1.80 (m, 4H),

 224

 415.50 1.47

 225

 424.10 1.72

 226

 411.30 1.20

 227

 424.10 1.73

 228

 523.70 6.06

 229

 399.23 2.25

 230

 418.50 1.40

 231

 486.48 1.57 1H NMR (400 MHz, DMSO) d 7.57 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.29 (q, J = 8.1 Hz, 2H), 7.20 (t, J = 6.7 Hz, 1H), 7.02 (d , J = 4.3 Hz, 1H), 6.42 (d, J = 3.9 Hz, 1H), 4.98 (s, 1H), 4.72 (t, J = 5.7 Hz, 1H ), 4.51-4.31 (m, 1H), 3.42 (s, 2H), 1.99 (s, 5H), 1.39 (s, 3H),

 232

 427.20 2.20

 233

 495.30 2.32

 2. 3. 4

 481.50 1.88

 235

 506.30 1.59

 236

 404.50 1.86

 237

 501.30 3.00

 238

 535.22 2.28 1H NMR (400 MHz, DMSO) d 7.80-7.67 (m, 3H), 7.56-7.47 (m, 1H), 7.37-7.26 (m , 2H), 7.14 (dd, J = 8.5, 2.3 Hz, 1H), 6.30 (t, J = 3.2 Hz, 1H), 6.23 - 6.14 (m, 1H), 4.76-4.06 (m, 3H), 3.82-3.40 (m, 5H), 3.23 (s, 3H), 2.13-1.83 (m, 6H) ,

 239

 403.18 2.79

 240

 450.30 1.45

 241

 345.50 1.84

 242

 396.00 2.91

 243

 479.30 1.53 1H NMR (400 MHz, DMSO) d 8.02 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7, 7 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.52-7.42 (m, 1H), 7.34-7.25 (m, 1H), 7, 16 - 7.02 (m, 2H), 4.47-4.29 (m, 1H), 4.10 (s, 3H), 3.60 - 3.22 (m, 3H), 2.15 - 1.80 (m, 5H), 0.53-0.33 (m, 4H),

 244

 506.24 2.45

 245

 508.00 1.92

 246

 436.50 1.81

 247

 433.30 1.92 1H NMR (400 MHz, DMSO) d 7.67 (d, J = 7.6 Hz, 1H), 7.56-7.43 (m, 1H), 7.19-7, 04 (m, 3H), 7.04-6.96 (m, 3H), 6.28 (t, J = 3.1 Hz, 1H), 6.22-6.10 (m, 1H), 4 , 64-4.53 (m, 1H), 4.52-3.92 (m, 1H), 3.77 (s, 3H), 3.61-3.09 (m, 3H), 1.96 (s, 4H), 1.26 (d, J = 6.0 Hz, 6H),

 248

 509.20 1.72

 249

 461.00 1.92 1H NMR (400 MHz, DMSO) d 7.83-7.64 (m, 3H), 7.53-7.46 (m, 1H), 7.33 (d, J = 8 , 7 Hz, 1H), 7.10 (dd, J = 9.6, 2.7 Hz, 1H), 7.00 - 6.88 (m, 1H), 6.28 (t, J = 3, 1 Hz, 1H), 6.19-6.13 (m, 1H), 4.58-4.16 (m, 1H), 3.94 (s, 3H), 3.56 (s, 3H), 2.05 - 1.79 (m, 4H),

 250

 478.10 1.83 1H NMR (400 MHz, CDCl3) d 7.61, 7.59, 7.52, 7.43, 7.38, 7.36, 7.31, 7.26, 7.15 , 7.14, 7.10, 7.09, 7.07, 7.07, 7.04, 6.99, 6.83, 6.82, 6.54, 6.39, 6.34, 6 , 23, 6.20, 6.18, 6.07, 6.06, 6.03, 4.61, 4.58, 3.72, 3.69, 3.56, 3.49, 3.38 , 3.25, 3.22, 3.19, 2.80, 2.19, 2.15, 2.07, 2.04, 2.01, 1.96, 1.89, 1.87, 1 , 59, 1.36, 1.25, 0.97,

 251

 418.20 1.89

 252

 440.19 2.18

 253

 480.30 2.25

 254

 389.50 5.76

 255

 419.30 1.64

 256

 448.50 1.70 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 0.5 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.15 - 6.96 (m, 5H), 4.60 (hept, J = 5.9 Hz, 1H), 4.51-4.05 ( m, 1H), 4.10 (s, 3H), 3.78 (s, 3H), 3.59-3.20 (m, 3H), 2.10-1.75 (m, 4H), 1 , 26 (d, J = 5.7 Hz, 6H),

 257

 435.50 2.21 1H NMR (400 MHz, CDCl3) d 7.31-7.24 (m, 1H), 7.21 (dd, J = 7.5, 1.2 Hz, 1H), 7, 17 (d, J = 7.5 Hz, 1H), 7.07-6.98 (m, 4H), 4.93-4.36 (m, 1H), 3.90 (s, 3H), 3 , 68-3.13 (m, 3H), 2.98 (s, 3H), 2.65 (q, J = 7.5 Hz, 2H), 2.27-1.98 (m, 4H), 1.19 (t, J = 7.5 Hz, 3H),

 258

 444.20 2.21

 259

 404.50 1.85

 260

 501.00 1.82

 261

 453.30 3.01

 262

 433.20 1.70 1H NMR (400 MHz, DMSO) d 7.76 (s, 1H), 7.59 (dd, J = 7.6, 1.6 Hz, 1H), 7.46 (s, 2H), 7.25 - 7.17 (m, 1H), 7.06 - 6.96 (m, 2H), 4.69 (dt, J = 12.1, 6.0 Hz, 1H), 4 , 31 (d, J = 12.7 Hz, 1H), 3.86 (s, 3H), 3.54 (s, 1H), 3.33 (t, J = 11.1 Hz, 1H), 2 , 35 (s, 3H), 2.09-1.99 (m, 2H), 1.90 (d, J = 11.2 Hz, 3H), 1.31 (d, J = 6.0 Hz, 7H),

 263

 499.30 7.77

 264

 359.00 1.95

 265

 479.00 2.06

 266

 481.50 1.91 1H NMR (400 MHz, DMSO) d 7.87 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.6, 2.2 Hz, 1H) , 7.67 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 (dd, J = 2.9, 1.3 Hz, 1H), 7.37 (d, J = 8 , 8 Hz, 1H), 7.20 - 7.03 (m, 3H), 6.28 (t, J = 3.2 Hz, 1H), 6.16 (dd, J = 3.4, 1, 3 Hz, 1H), 5.03-4.85 (m, 1H), 4.57-4.05 (m, 1H), 3.80-3.37 (m, 3H), 3.28 (s , 3H), 2.06 - 1.83 (m, 4H), 1.36 (d, J = 6.0 Hz, 6H)

 267

 464.50 2.13 1H NMR (400 MHz, DMSO) d 7.53 (s, 1H), 7.48 (dd, J = 9.5, 2.5 Hz, 1H), 7.28-7, 23 (m, 2H), 7.19-7.10 (m, 2H), 7.00-6.95 (m, 1H), 4.64 (sept, J = 6.0 Hz, 1H), 4 , 45 (q, J = 7.2 Hz, 2H), 4.34-4.10 (m, 1H), 3.87-3.39 (m, 2H), 3.32-3.08 (m , 1H), 2.15 (s, 3H), 2.00-1.83 (m, 4H), 1.37 (t, J = 7.2 Hz, 3H), 1.29 (d, J = 6.0 Hz, 6H),

 268

 431.15 2.18

 269

 505.30 2.68

 270

 517.50 1.98 1H NMR (400 MHz, DMSO) d 7.97 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.1 Hz, 1H), 7.34-7.25 (m, 2H), 7.25-7.17 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H), 4.52-4.37 (m, 1H), 3.61-3.38 (m, 2H), 3.29 - 3.13 (m, 1H), 2.97-2.86 (m, 1H), 2.18-198 (m, 3H), 1.95-1.84 (m, 1H), 1 , 19-1.11 (m, 2H), 1.11-1.01 (m, 2H),

 271

 433.50 1.25

 272

 404.50 1.98 1H NMR (400 MHz, CDCl3) d 7.73 (dd, J = 17.9, 8.3 Hz, 3H), 7.58 (t, J = 7.7 Hz, 1H) , 7.29 (d, J = 7.3 Hz, 2H), 7.13 (d, J = 1.7 Hz, 2H), 7.05 (dd, J = 8.5, 1.9 Hz, 1H), 6.37 (t, J = 3.1 Hz, 1H), 6.10 - 6.03 (m, 1H), 4.65 (br s, 1H), 3.60 (br s, 2H ), 3.36 (br s, 1H), 2.22 (br s, 1H), 2.07 (br s, 2H), 1.88 (br s, 1H), 1.62 (d, J = 2.4 Hz, 3H),

 273

 437.26 2.35

 274

 446.30 2.60 1H NMR (400 MHz, CDCl3) d 7.54 (dt, J = 3.0, 1.3 Hz, 1H), 7.31-7.20 (m, 3H), 7, 10 - 6.95 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 4.65 (br s, 1H), 4.56 (sept, J = 6.0 Hz, 1H), 4.08 (s, 3H), 3.70 - 3.21 (m, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 2.17 - 1.82 (m, 4H), 1.35 (d, J = 1.1 Hz, 3H), 1.34 (d, J = 1.1 Hz, 3H),

 275

 397.50 2.07 1H NMR (400 MHz, CDCl3) d 7.46-7.37 (m, 1H), 7.30-7.27 (m, 4H), 7.25-7.10 (m , 5H), 7.04 (dd, J = 8.5, 2.2 Hz, 1H), 6.36 (t, J = 3.2 Hz, 1H), 6.07 (d, J = 3, 2 Hz, 1H), 4.65 (br, s, 1H), 3.57 (br, dd, J = 43.9, 16.6 Hz, 2H), 3.35 (br, s, 1H), 2.20 (br, s, 1H), 2.06 (br, s, 2H), 1.87 (br, s, 1H), 1.59 (s, 6H),

 276

 448.10 1.54

 277

 447.15 2.32

 278

 502.50 1.97

 279

 547.20 1.93 1H NMR (400 MHz, DMSO) d 7.99 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 1 H), 7.36 - 7.14 (m, 3 H), 7.03 (d, J = 3.9 Hz, 1 H), 6.40 (d, J = 4.0 Hz, 1H), 4.54-4.36 (m, 1H), 4.33-4.17 (m, 1H), 4.09-3.95 (m, 1H), 3.90 - 3.59 (m, 3H), 3.58-3.12 (m, 3H), 2.24 - 1.77 (m, 6H),

 280

 444.10 2.40

 281

 448.50 1.70 1H NMR (400 MHz, DMSO) d 7.74 (s, 1H), 7.61-7.56 (m, 1H), 7.20 (td, J = 8.2, 1 , 5 Hz, 1H), 7.05-6.94 (m, 5H), 4.60 (hept, J = 5.6 Hz, 1H), 4.21 (s, 1H), 3.87 (s , 3H), 3.78 (s, 3H), 3.60-3.32 (m, 3H), 2.06-1.78 (m, 4H), 1.26 (d, J = 6.0 Hz, 6H),

 282

 499.30 1.84

 283

 460.20 2.51

 284

 426.30 1.67

 285

 436.00 1.86 1H NMR (400 MHz, CDCl3) d 8.15 (d, J = 7.9 Hz, 1H), 7.39 (ddd, J = 31.5, 15.1, 7.3 Hz, 3H), 7.19 (dt, J = 14.9, 8.2 Hz, 4H), 7.05 (d, J = 3.7 Hz, 1H), 6.76 (s, 0H), 6.58 (d, J = 7.0 Hz, 1H), 6.39 (s, 0H), 6.13 (d, J = 3.8 Hz, 1 H), 4.76 (d, J = 10.5 Hz, 1 H), 3.69-3.17 (m, 3H), 2.32-1.91 (m, 5H),

 286

 495.00 1.47

 287

 481.50 1.71 1H NMR (400 MHz, CDCl3) d 7.34-7.23 (m, 2H), 7.14-7.08 (m, 2H), 7.07-6.99 (m , 3H), 6.34 (t, J = 3.2 Hz, 1H), 6.04 (dd, J = 3.5, 1.3 Hz, 1H), 5.02 (d, J = 7, 2 Hz, 2H), 4.87 (d, J = 7.2 Hz, 2H), 4.75-4.51 (m, 1H), 3.91 (s, 3H), 3.82-3, 43 (m, 3H), 2.29-1.72 (m, 4H),

 288

 487.27 2.04

 289

 462.50 1.93 1H NMR (400 MHz, CDCl3) d 7.02 (dd, J = 8.6, 1.6 Hz, 1H), 6.83-6.78 (m, 4H), 6, 37 (d, J = 8.1 Hz, 1H), 6.21 - 6.14 (m, 2H), 4.12 (dt, J = 16.6, 6.0 Hz, 1H), 3.67 (t, J = 2.5 Hz, 3H), 3.38 (t, J = 2.5 Hz, 3H), 3.04 (s, 2H), 1.76 (s, 3H), 1.64 (s, 2H), 1.44 (s, 2H), 1.18 (d, J = 1.5 Hz, 3H), 0.94-0.85 (m, 6H),

 290

 402.60 2.71

 291

 537.50 2.20

 292

 460.50 1.76

 293

 460.50 1.46

 294

 474.30 2.38

 295

 426.00 2.12

 296

 511.00 1.73

 297

 476.30 5.18 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.2 Hz, 2H), 7.27 - 7 , 20 (m, J = 8.9, 4.5 Hz, 1H), 6.47 (d, J = 4.0 Hz, 1H), 4.46 (d, J = 12.8 Hz, 1H) , 3.59-3.38 (m, 3H), 3.23 (s br, 1H), 2.07 (sbr, 3H), 1.90 (d, J = 12.6 Hz, 1H), 1 , 17 (d, J = 6.8 Hz, 6H),

 298

 463.20 2.08

 299

 424.30 1.79

 300

 507.00 1.96

 301

 396.25 1.68

 302

 444.17 2.03

 303

 481.50 1.89

 304

 422.15 2.19

 305

 467.50 2.29

 306

 443.70 1.74 1H NMR (400 MHz, DMSO) d 7.85 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.45 (s, 1H), 7.37-7.25 (m, 2H), 7.14-7.05 (m, 2H), 4.90-4.81 (m, 1H), 4.40-4 , 22 (m, 1H), 4.10 (s, 3H), 3.63-3.42 (m, 2H), 3.30-3.18 (m, 1H), 2.07-1.81 (m, 4H), 1.34 (d, J = 6.0 Hz, 6H),

 307

 462.20 1.74

 308

 442.70 1.78

 309

 428.50 1.75

 310

 458.00 1.77 1H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.3 Hz, 1H), 7.26-7.12 (m, 4H), 7.03 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 6.12 ( d, J = 3.9 Hz, 1H), 4.75-4.47 (m, 4H), 3.90-3.50 (m, 3H), 3.33 (s, 1H), 2.21 (d, J = 9.7 Hz, 1H), 2.12 - 1.99 (m, 2H), 1.86 (s, 1H), 1.35 (d, J = 6.0 Hz, 6H) ,

 311

 507.30 1.67

 312

 485.20 2.22

 313

 462.20 1.62 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.29 (t, J = 7, 7 Hz, 1H), 7.16-6.99 (m, 4H), 6.95 (dd, J = 8.1, 1.5 Hz, 1H), 4.47-4.17 (m, 1H ), 4.10 (s, 3H), 3.77 (s, 3H), 3.72-3.33 (m, 3H), 2.10-1.81 (m, 4H), 1.29 ( s, 9H),

 314

 417.50 2.26

 315

 431.70 2.32

 316

 434.50 1.29

 317

 413.27 2.35

 318

 446.00 2.03 1H NMR (400 MHz, CDCl3) d 8.14 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 8.3 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.20 - 7.11 (m, 2H), 7.04 (d, J = 4.0 Hz, 1H), 6.74 (dd, J = 8.6, 2.0 Hz, 1H), 6.60 (dd, J = 11.9, 2.1 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 4, 71 (d, J = 13.0 Hz, 1H), 4.56 (dt, J = 12.1, 6.1 Hz, 1H), 3.59 (d, J = 6.8 Hz, 2H), 3.31 (t, J = 12.6 Hz, 1H), 2.29 - 1.82 (m, 5H), 1.36 (d, J = 6.0 Hz, 6H),

 319

 453.40 2.63

 320

 442.20 2.41

 321

 458.50 1.87 1H NMR (400 MHz, CDCl3) d 7.51, 7.49, 7.47, 7.45, 7.43, 7.42, 7.38, 7.36, 7.34 , 7.32, 7.30, 7.28, 7.26, 7.26, 7.24, 7.22, 7.13, 7.11, 7.07, 7.05, 7.04, 6 , 99, 5.30, 4.67, 4.50, 4.48, 4.46, 4.44, 3.62, 3.58, 3.55, 3.52, 3.37, 3.33 , 3.29, 2.23, 2.20, 2.03, 1.94, 1.90, 1.74, 1.57, 1.54, 1.53, 1.20,

 322

 411.10 1.47

 323

 427.70 1.24 1H NMR (400 MHz, DMSO) d 8.59 (bs, 3H), 8.00 (d, J = 7.9 Hz, 1 H), 7.63 (d, J = 8 , 4 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.36-7.29 (m, 3H), 7.29-7.16 (m, 1H), 6 , 48 (d, J = 4.1 Hz, 1H), 4.51-4.38 (m, 1H), 3.70-3.47 (m, 2H), 3.20 (s, 1H), 2.18-1.88 (m, 4H), 1.65 (s, 6H),

 324

 431.02 2.80

 325

 432.50 1.13

 326

 447.50 2.08

 327

 465.50 1.81 1H NMR (400 MHz, CDCl3) d 7.97-7.91 (m, 2H), 7.64-7.57 (m, 2H), 7.36 (d, J = 7 , 3 Hz, 1H), 7.16 - 7.13 (m, 1H), 7.11 - 7.01 (m, 3H), 6.36 - 6.29 (m, 1H), 6.07 - 5.99 (m, 1H), 4.71-4.59 (m, 1H), 3.70-2.27 (m, 3H), 2.33-1.75 (m, 4H), 1, 36 (s, 9H),

 328

 442.50 1.86 1H NMR (400 MHz, CDCl3) d 7.52, 7.49, 7.47, 7.26, 7.21, 7.15, 7.13, 7.10, 7.08 , 7.08, 7.07, 7.06, 7.04, 7.04, 7.02, 7.02, 4.66, 4.13, 3.99, 3.99, 3.81, 3 , 61, 3.58, 3.55, 3.48, 3.46, 3.44, 3.39, 3.36, 3.33, 3.30, 3.27, 2.21, 2.17 , 2.01, 1.97, 1.94, 1.93, 1.90, 1.89, 1.75, 1.73, 1.69, 1.62, 1.57, 1.53,

 329

 496.26 1.95

 330

 506.30 2.17

 331

 443.12 2.43

 332

 407.50 5.96

 333

 500.30 1.59

 334

 472.30 1.74 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.24 - 7.18 (m, 1H), 7.18 - 7.09 (m, 2H), 7.02 (d, J = 3.8 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.11 (d, J = 3.8 Hz, 1H), 4.64 (s, 1H), 3.91 - 3.26 (m, 4H), 2.26 - 1.77 (m, 6H), 1.61 (s, 6H),

 335

 477.22 2.26

 336

 496.20 1.42 1H NMR (400 MHz, DMSO) d 7.77-7.69 (m, 1H), 7.63-7.40 (m, 4H), 7.28 (t, J = 7 , 7 Hz, 1H), 7.18-7.02 (m, 2H), 4.41 (d, J = 12.1 Hz, 1H), 4.15 - 4.05 (m, 3H), 3 , 98-3.88 (m, 3H), 3.60-3.49 (m, 1H), 3.49-3.35 (m, 1H), 3.30-3.11 (m, 2H) , 2.10-1.76 (m, 4H), 1.22-1.14 (m, 6H),

 337

 480.30 2.10

 338

 442.70 2.13

 339

 433.50 2.40

 340

 444.50 1.70

 341

 479.30 2.16

 342

 459.20 2.68

 343

 404.07 1.95

 344

 495.20 1.49

 3. 4. 5

 440.12 2.32

 346

 418.27 1.54

 347

 471.20 2.52 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.1 Hz, 1 H), 7.21-7.05 (m, 4H), 6.97-6 , 89 (m, 2H), 6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H), 4.96 - 4.23 (m, 1 H), 3.84 (s, 3H), 3.64 - 3.14 (m, 3H), 2.64 (q, J = 7.5 Hz, 2H), 2.25 - 1.75 ( m, 4H), 1.17 (t, J = 7.5 Hz, 3H),

 348

 509.70 1.92

 349

 391.20 3.01

 350

 430.40 2.91

 351

 387.20 2.50

 352

 433.30 2.36 1H NMR (400 MHz, DMSO) d 7.66 (d, J = 7.7 Hz, 1H), 7.51-7.47 (m, 1H), 7.18-6, 95 (m, 6H), 6.28 (t, J = 3.1 Hz, 1H), 6.17 (d, J = 3.4 Hz, 1H), 4.58 - 4.04 (m, 1H ), 3.94 (t, J = 6.5 Hz, 2H), 3.78 (s, 3H), 3.59-3.13 (m, 3H), 2.03 - 1.86 (m, 4H), 1.73 (sextet, J = 6.8 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H),

 353

 426.20 2.97

 354

 422.19 2.00

 355

 450.30 1.53 1H NMR (400 MHz, DMSO)? 7.73 (d, J = 7.4 Hz, 1H), 7.46 (s, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.19-6.80 (m , 4H), 4.39 (s, 1H), 4.10 (s, 3H), 3.79 (d, J = 22.0 Hz, 9H), 3.42 (s, 1H), 3.27 - 3.14 (m, 1H), 1.92 (d, J = 49.8 Hz, 4H),

 356

 447.13 2.84

 357

 479.30 1.54 1H NMR (400 MHz, DMSO)? 7.96 (d, J = 7.9 Hz, 1H), 7.58 - 7.50 (m, 3H), 7.37 (d, J = 4.1 Hz, 1H), 7.25 - 7 , 13 (m, J = 9.4, 8.0, 1.6 Hz, 2H), 7.08 - 6.99 (m, 1H), 6.38 (d, J = 4.0 Hz, 1H ), 4.45 (d, J = 12.4 Hz, 1H), 3.47 (dd, J = 22.7, 14.5 Hz, 2H), 3.25 (s, 3H), 3.23 - 3.10 (m, 1H), 2.68 (s, 3H), 2.49 (s, 3H), 2.14-2.00 (m, 1H), 1.94 (s br, 2H) , 1.80 (d, J = 13.9 Hz, 1H),

 358

 420.17 1.59

 359

 431.00 2.31

 360

 453.30 1.75

 361

 428.10 2.54

 362

 476.20 2.95

 363

 490.30 1.86 1H NMR (400 MHz, CDCl3) d 8.13 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.2 Hz, 2H), 7.03 (d , J = 4.0 Hz, 1H), 6.11 (d, J = 3.9 Hz, 1H), 4.73-4.64 (m, 1H), 3.62-3.51 (m, 2H), 3.40-3.30 (m, 1H), 3.30-3.20 (m, 1H), 2.72 (s, 3H), 2.29-2.17 (m, 1H) , 2.12 - 1.97 (m, 2H), 1.87 - 1.75 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H),

 364

 458.50 1.58

 365

 448.20 1.74

 366

 509.50 1.86

 367

 447.50 2.22 1H NMR (400 MHz, CDCl3) d 7.72 (d, J = 10.5 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.33 - 7.25 (m, 3H), 7.13 (d, J = 1.9 Hz, 2H), 7.04 (dd, J = 8.5, 2.1 Hz, 1H), 6.36 (t, J = 3.1 Hz, 1H), 6.11-6.04 (m, 1H), 4.67 (s, 1H), 3.61 (br, s, 2H), 3.38 (br, s, 1H), 2.22 (br, s, 1H), 2.08 (br, s, 2H), 1.88 (br, s, 1 H), 1.60 (s, 5H),

 368

 490.30 2.07

 369

 430.70 1.81

 370

 466.10 3.39

 371

 363.50 1.89

 372

 460.30 2.18

 373

 374

 481.50 1.94

 375

 472.50 1.90 1H NMR (400 MHz, CDCl3) d 7.98 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J = 8, 4 Hz, 1H), 6.99 (d, J = 4.0 Hz, 1H), 6.96 (s, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.07 (d, J = 4.0 Hz, 1H), 4.67 (s, 2H), 4.66-4.60 (m, 1H) , 4.06 - 3.26 (m, 3H), 2.36 (s, 3H), 2.19 - 1.82 (m, 5H), 1.37 (d, J = 6.0 Hz, 6H ),

 376

 471.50 3.29

 377

 405.10 2.51

 378

 379

 445.50 1.50

 380

 467.31 2.27

 381

 426.12 1.68 1H NMR (400 MHz, CDCl3) 7.57 (dd, J = 7.7, 1.4 Hz, 1 H), 7.45-7.34 (m, 2H), 7, 33-7.17 (m, 4H), 7.14-7.00 (m, 2H), 6.58 (dd, J = 77.9, 70.8 Hz, 1H), 4.66 (t, J = 13.1 Hz, 1H), 4.16 (s, 3H), 3.68-3.51 (m, 1H), 3.43-2.27 (m, 2H), 2.26-2 , 15 (m, 1H), 2.13-1.99 (m, 1H), 1.99-1.88 (m, 1H), 1.82-1.66 (m, 1H),

 382

 462.50 1.85

 383

 408.50 1.62

 384

 391.30 1.38

 385

 427.25 2.45

 386

 429.20 2.00

 387

 486.20 2.05

 388

 444.10 1.65

 390

 443.12 2.21

 391

 532.20 1.71

 392

 502.00 2.20 1H NMR (400 MHz, CDCl3) d 8.06 (t, J = 10.1 Hz, 1H), 7.70 (s, 1H), 7.64 (dd, J = 8, 6, 1.6 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.7, 2.2 Hz, 1H), 7.03 ( dd, J = 10.4, 6.3 Hz, 2H), 6.13 (d, J = 4.0 Hz, 1H), 4.61 (s, 1H), 3.96 (d, J = 20 , 2 Hz, 3H), 3.89-3.06 (m, 3H), 2.16 - 1.81 (m, 4H),

 393

 434.50 1.91

 394

 451.30 7.62

 395

 417.50 2.30

 396

 406.20 1.19 1H NMR (400 MHz, DMSO) d 9.44 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7 , 29 (t, J = 7.7 Hz, 1H), 7.16 - 7.05 (m, 2H), 7.00 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.10 (s, 3H), 4.18-4.02 (m, 1H), 3.79 (s, 3H), 3.54-3.25 (m, 3H), 2.06-1.78 (m, 4H),

 397

 407.24 2.16

 398

 490.50 1.47

 399

 447.50 7.60 H NMR (400.0 MHz, DMSO) d 7.68 - 7.65 (m, 1H), 7.50 - 7.49 (m, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.17-6.98 (m, 5H), 6.29 - 6.28 (m, 1H), 6.18-6.17 (m, 1H), 4, 49-4.34 (m, 1H), 3.83 (s, 3H), 3.80-3.41 (m, 3H), 3.13 (s, 3H), 2.11-1.81 ( m, 4H) and 1.50 (s, 6H) ppm,

 400

 465.21 2.23

 401

 420.00 1.89 1H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.1 Hz, 1H), 7.76-7.67 (m, 1H), 7.58-7, 49 (m, 2H), 7.38-7.32 (m, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.20-7.13 (m, 2H), 7 , 04 (d, J = 3.9 Hz, 1H), 6.12 (s, 1H), 4.72 (s, 1H), 3.37 (dd, J = 46.1, 33.5 Hz, 3H), 2.20 (s, 1H), 1.96 (dd, J = 56.3, 18.6 Hz, 3H),

 402

 453.28 2.25

 403

 490.40 3.05

 404

 543.00 1.75

 405

 376.50 1.43

 406

 444.40 1.51 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.25 - 7.19 (m, 1H), 7.17 - 7.11 (m, 2H), 7.02 (d, J = 3.9 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.66 (s, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.65 ( d, J = 11.1 Hz, 1H), 3.49 (s, 1H), 3.33 (s, 1H), 2.10 (s, 1H), 1.84 (s, 4H), 1, 53 (s, 3H),

 407

 497.50 2.03

 408

 486.35 1.70 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 8.5 Hz, 1H), 7.25-7.17 (m, 3H), 7.18-7, 10 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.66 (s, 1H), 3.74 (dd, J = 103.4, 60.3 Hz, 4H), 2.23 (s, 3H), 2.02 (dd, J = 92.2, 67.9 Hz, 5H), 1.61 (s, 6H),

 409

 412.50 1.69

 410

 446.50 6.31 1H NMR (400 MHz, CDCl3) d 7.50 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.29 - 7.22 (m, 3H), 7.11-7.02 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 4.56 (sept, J = 6.1 Hz, 1H), 4, 50 (s, 1H), 4.48 (q, J = 7.3 Hz, 2H), 3.84 (s, 1H), 3.48 (s, 2H), 2.21 (s, 3H), 2.10 (s, 1H), 1.90 (s, 2H), 1.75 (s, 1H), 1.55 (t, J = 7.3 Hz, 3H), 1.35 (d, J = 6.0 Hz, 6H),

 411

 518.30 1.55

 412

 432.30 1.76

 413

 534.50 2.07

 414

 433.70 1.91

 415

 417.13 2.89

 416

 460.00 2.08

 417

 481.20 3.03

 418

 432.50 1.29 1H NMR (400 MHz, CDCl3) d 7.64 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.29-7.23 (m, 3H), 7.10-7.02 (m, 2H), 4.93 (d, J = 7.0 Hz, 2H), 4.83 (d, J = 7.0 Hz, 2H), 4.60 (bs, 1H), 4.15 (s, 3H), 3.80 - 3.21 (m, 4H ), 2.29-1.44 (m, 4H),

 419

 426.50 7.85 H NMR (400.0 MHz, DMSO) d 7.93 (d, J = 1.7 Hz, 1H), 7.73 (m, 1H), 7.68 - 7.63 ( m, 2H), 7.50 (m, 1H), 7.17-7.05 (m, 3H), 6.29 (t, J = 3.2 Hz, 1H), 6.16 (dd, J = 1.3, 3.4 Hz, 1H), 4.48-4.34 (m, 1H), 3.59-3.41 (m, 2H), 3.23 (m, 1H), 2, 10-1.85 (m, 4H) and 1.48 (s, 9H) ppm,

 420

 464.20 2.38

 421

 411.23 2.18

 422

 430.70 1.77

 423

 480.30 2.31

 424

 489.50 2.04 1H NMR (400 MHz, CDCl3) d 7.71-7.59 (m, 2H), 7.23-7.06 (m, 5H), 6.81 (d, J = 3 , 9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H), 4.63 (s, 1H), 3.68 (s, 1H), 3.56 (s, 1H), 3.31 (s, 1H), 2.16 (s, 1H), 2.03-1.90 (m, 1H), 1.82 (d, J = 21.3 Hz, 1H), 1.64 (s, 6H),

 425

 448.50 1.32

 426

 490.30 1.83 1H NMR (400 MHz, CDCl3) d 8.13 (d, J = 7.4 Hz, 1H), 7.76 (d, J = 9.1 Hz, 2H), 7.43 - 7.36 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.0 Hz, 2H), 7.03 (d, J = 3.9 Hz, 1H), 6.14 - 6.06 (m, 1H), 4.76 (d, J = 13.5 Hz, 1H), 3.52 (t, J = 12.1 Hz, 1H), 3.41-3.24 (m, 2H), 3.24-3.16 (m, 1H), 2.44 (d, J = 13.7 Hz, 3H), 2.25 (d , J = 15.6 Hz, 1H), 2.10 - 1.95 (m, 3H), 1.84 - 1.73 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H),

 427

 476.30 2.12

 428

 489.25 1.95

 429

 446.20 2.49

 430

 418.30 1.90

 431

 506.50 1.49 1H NMR (400 MHz, DMSO) d 7.93 (dd, J = 8.2, 6.5 Hz, 3H), 7.73 (d, J = 8.3 Hz, 2H) , 7.32 (d, J = 4.0 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 4.1 Hz, 1H), 5.39-5.30 (m, 1H), 4.51 (s, 2H), 3.81-3.64 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.37 (m, 1H), 2.20-2.11 (m, 1H), 2.13-2.03 (m, 1H), 2.01 (t , J = 5.9 Hz, 1H), 1.57 (dd, J = 12.5, 6.2 Hz, 1H), 1.17 (d, J = 6.8 Hz, 6H),

 432

 411.23 2.18

 433

 404.20 1.75

 434

 443.20 2.12

 435

 466.50 1.72

 436

 490.30 1.90 1H NMR (400 MHz, CDCl3) d 8.13 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.26 - 7.21 (m, 1H), 7.15 (t, J = 7.2 Hz, 2H), 7.03 (d, J = 4.0 Hz, 1H), 6.11 (d, J = 4.0 Hz, 1H), 4.69 (d, J = 11.9 Hz, 1H), 3.66 - 3.48 (m, 2H), 3.40 - 3.28 (m, 1H), 3.00 (d, J = 6.5 Hz, 2H), 2.30 - 2.16 (m, 2H), 2.12-1 , 98 (m, 2H), 1.88 - 1.75 (m, 1H), 1.08 (s, 3H), 1.07 (s, 3H)

 437

 475.30 1.76

 438

 444.20 5.86 1H NMR (400 MHz, CDCl3) d 8.24 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 8.7, 2.9 Hz, 1H), 7.21 - 7.05 (m, 3H), 6.80 ( d, J = 3.9 Hz, 1H), 6.08 (d, J = 3.9 Hz, 1H), 4.65 (d, J = 12.3 Hz, 1H), 4.10 (d, J = 12.5 Hz, 1H), 3.90 (s, 3H), 3.61 (t, J = 13.0 Hz, 1H), 3.33 (t, J = 12.4 Hz, 1H) , 2.23 - 1.98 (m, J = 17.2 Hz, 4H),

 439

 412.30 1.35

 440

 490.30 1.84 1H NMR (400 MHz, CDCl3) d 8.00 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 4.0 Hz, 1H), 6.94 (d, J = 10.0 Hz, 2H), 6.09 (d , J = 4.0 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H), 3.65 - 3.47 (m, 2H), 3.34 (t, J = 12, 1 Hz, 1H), 3.21 (dt, J = 13.7, 6.9 Hz, 1H), 2.36 (s, 3H), 2.29 - 2.16 (m, 1H), 2, 11 - 1.95 (m, 2H), 1.90 - 1.71 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H),

 441

 457.27 2.43

 442

 430.40 2.95

 443

 417.50 1.86

 444

 400.00 1.35

 445

 485.50 1.75 1H NMR (400 MHz, CDCl3) d 8.59, 8.57, 7.52, 7.31, 7.26, 7.23, 7.22, 7.21, 7.16 , 7.14, 7.13, 7.11, 7.09, 7.01, 6.99, 6.97, 6.93, 6.15, 4.74, 4.70, 4.14, 4 , 12, 4.10, 4.08, 3.51, 3.29, 3.08, 2.21, 2.17, 2.08, 2.07, 2.05, 2.04, 2.01 , 1.61, 1.56, 1.51, 1.47, 1.45, 1.44,

 446

 458.50 1.78

 447

 432.50 1.46

 448

 431.20 2.24 1H NMR (400 MHz, CDCl3) d 7.56 (d, J = 7.7 Hz, 1H), 7.45-7.37 (m, 3H), 7.46-7, 22 (m, 2H), 7.30-7.21 (m, 1H), 7.13-7.00 (m, 2H), 4.52 (d, J = 13.5 Hz, 1H), 4 , 19 (s, 3H), 3.74-3.51 (m, 2H), 3.31 (t, J = 11.9 Hz, 1H), 3.09 (s, 3H), 2.94 ( s, 3H), 2.24 - 2.02 (m, J = 13.9 Hz, 2H), 2.02 - 1.76 (m, 2H),

 449

 463.50 1.98

 450

 414.25 2.26

 451

 463.30 2.27 1H NMR (400 MHz, CDCl3) d 7.49 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.29 (dd, J = 11.7, 6.5 Hz, 4H), 7.12 (d, J = 1.8 Hz, 2H), 7.04 (dd, J = 8.5, 2.1 Hz, 1H), 6.36 (t, J = 3.2 Hz, 1H), 6.07 (d, J = 3.3 Hz, 1H), 4.65 (br s, 1H), 3.62 (br s, 2H), 3.36 (br s, 1H), 2.21 (br s, 1H), 2.08 (br s, 2H), 1.87 (br s, 1H), 1.62 (s , 2H),

 452

 444.10 1.79

 453

 418.10 2.33

 454

 460.50 1.44

 455

 472.00 1.63 1H NMR (400 MHz, CDCl3) d 8.63 (s, 1 H), 7.83 (dd, J = 8.1, 1.6 Hz, 1H), 7.70 (d , J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.17 (tt, J = 15.4, 7.6 Hz, 3H), 6.84 (d, J = 3.9 Hz, 1H), 6.08 (d, J = 3.9 Hz, 1H), 4.65 (d, J = 20.8 Hz, 1H), 3.68 (s , 2H), 3.37 (s, 1H), 2.82 (s, 1H), 2.30-1.99 (m, 3H), 1.90 (s, 1H), 1.58 (s, 6H),

 456

 505.30 1.96 1H NMR (400 MHz, DMSO) d 7.96 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.34-7.17 (m, 3H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H), 4.51-4.37 (m, 1H), 3.62-3.11 (m, 3H), 3.35 (q, J = 7.3 Hz, 2H), 2.19 - 1.75 (m, 4H), 1.12 (t, J = 7.3 Hz, 3H),

 457

 472.25 1.52

 458

 459.50 2.01

 459

 429.50 2.30

 460

 429.30 1.57

 461

 394.10 1.76

 462

 458.50 1.68 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.18 - 7.09 (m, 2H), 7.01 (d, J = 4.0 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 5.70-5.30 (m, 2H), 4.63 (s, 2H), 3.68 - 3.23 (m, 2H), 2.27 (s, 3H), 2.21-2.02 (m, 2H), 1.99-1.74 (m, 2H),

 463

 429.30 1.53

 464

 418.30 2.38

 465

 404.30 1.67

 466

 449.10 1.41

 467

 418.30 1.95

 468

 462.30 2.33

 469

 508.30 1.58

 470

 406.20 2.80

 471

 461.22 2.52

 472

 524.30 2.18

 473

 432.70 1.60

 474

 435.50 1.63

 475

 427.50 2.12 1H NMR (400 MHz, CDCl3) d 7.26 (d, J = 8.4 Hz, 1H), 7.13-7.07 (m, 2H), 7.05-6, 96 (m, 2H), 6.94-6.85 (m, 2H), 6.33 (t, J = 3.2 Hz, 1H), 6.08-5.98 (m, 1H), 4 , 69 (d, J = 13.1 Hz, 1H), 3.80 (s, 3H), 3.63 - 3.44 (m, 2H), 3.33 (t, J = 12.8 Hz, 1H), 2.19 (d, J = 13.8 Hz, 1H), 2.09 - 1.96 (m, 2H), 1.60 (s, 1 H),

 476

 408.40 2.86

 477

 443.10 2.62

 478

 423.50 2.17 1H NMR (400 MHz, CDCl3) d 7.30 (dt, J = 8.4, 6.8 Hz, 3H), 7.12 (d, J = 2.0 Hz, 2H) , 7.01 (ddd, J = 20.7, 10.7, 4.8 Hz, 4H), 6.36 (t, J = 3.1 Hz, 1H), 6.06 (d, J = 2 , 9 Hz, 1H), 4.65 (br s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.71 (br s, 1H), 3.55 (br s, 1H), 3.33 (br s, 1H), 2.19 (br s, 1H), 2.05 (br s, 2H), 1.86 (br s, 1H), 1.62 (br s, 3H), 1.44 (t, J = 7.0 Hz, 3H),

 479

 486.00 2.03 1H NMR (400 MHz, CDCl3) d 8.10 (dd, J = 9.0, 5.2 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.03 (dd, J = 10.3, 6.1 Hz, 2H), 6.94 - 6.82 (m, 2H), 6.11 (d, J = 4.0 Hz, 1H), 4.61 (s, 1H), 3.95 (s, 3H), 3.49 (s, 3H), 2.03 (d, J = 66.9 Hz, 4H ),

 480

 456.50 1.82

 481

 437.00 2.05 1H NMR (400 MHz, CDCl3) d 8.16 - 7.94 (m, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.17-7.10 (m, 1H), 7.10-7.00 (m, 2H), 6.93 (d, J = 4.0 Hz, 1H ), 6.02 (d, J = 4.0 Hz, 1H), 4.60 (d, J = 10.9 Hz, 1H), 3.51 (s, 2H), 3.41 - 3.08 (m, 1H), 2.13 (d, J = 11.5 Hz, 1H), 1.95 (s, 3H), 1.78 (d, J = 8.8 Hz, 1H),

 482

 481.50 2.23

 483

 533.50 2.10 1H NMR (400 MHz, DMSO) d 7.89 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.25 - 7.16 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H), 4.53-4.37 (m, 1H), 3.57-3.14 (m, 3H), 2.17 - 1.78 (m, 4H), 1.26 (s, 9H),

 484

 477.22 2.20

 485

 432.50 1.96 1H NMR (400 MHz, CDCl3) d 8.15, 8.13, 7.54, 7.28, 7.26, 7.24, 7.22, 7.17, 7.16 , 7.14, 7.12, 7.04, 7.03, 7.02, 7.00, 6.97, 6.95, 6.12, 4.76, 4.73, 4.16, 4 , 14, 4.13, 4.11, 3.55, 3.31, 2.24, 2.20, 2.07, 2.05, 2.03, 2.02, 2.00, 1.99 , 1.63, 1.58, 1.54, 1.49, 1.48, 1.46,

 486

 436.50 1.46

 487

 443.70 1.83

 488

 497.50 1.78

 489

 423.30 6.50

 490

 456.00 2.20 1H NMR (400 MHz, CDCl3) d 7.28-7.22 (m, 2H), 7.18 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 3.7 Hz, 1H), 7.03 (dd, J = 13.1, 7.9 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.18 ( d, J = 4.0 Hz, 1H), 4.57 (dt, J = 12.1, 6.0 Hz, 2H), 3.43 (d, J = 6.4 Hz, 3H), 2, 70 (s, 3H), 2.22 (d, J = 3.5 Hz, 3H), 2.05 (t, J = 15.1 Hz, 5H), 1.36 (d, J = 6.0 Hz, 7H),

 491

 374.20 2.04

 492

 467.20 2.50 1H NMR (400 MHz, DMSO) d 7.71 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.6, 2.2 Hz, 1H), 7.07 - 6.95 (m, 3H), 6.30 ( t, J = 3.1 Hz, 1H), 6.20 (d, J = 3.3 Hz, 1H), 4.63 - 4.07 (m, 1H), 3.94 (t, J = 6 , 5 Hz, 2H), 3.79 (s, 3H), 3.59-3.14 (m, 3H), 2.08 - 1.86 (m, 4H), 1.73 (sextet, J = 7.0 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H),

 493

 451.23 2.25

 494

 453.30 1.40 1H NMR (400 MHz, DMSO) d 7.84 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.48 (s, 1H), 7.46 (s, 1H), 7.33-7.25 (m, 1H), 7.15-7, 04 (m, 2H), 4.45-4.34 (m, 1H), 4.10 (s, 3H), 3.61-3.21 (m, 3H), 2.44 (s, 3H) , 2.08-1.82 (m, 4H),

 495

 465.50 4.00

 496

 420.30 3.60 1H NMR (400 MHz, DMSO) d 7.73 (dd, J = 7.7, 1.1 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.33-7.25 (m, 1H), 7.16 - 7.04 (m, 2H), 6.99 (d, J = 8.7 Hz, 2H ), 4.88 (t, J = 5.4 Hz, 1H), 4.49-4.16 (m, 1H), 4.10 (s, 3H), 4.03 (t, J = 4, 9 Hz, 2H), 3.77-3.67 (m, 2H), 3.66-3.18 (m, 3H), 2.02-1.83 (m, 4H),

 497

 481.10 2.03 1H NMR (400 MHz, DMSO) d 7.71 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 2.8, 1.3 Hz, 1H) , 7.41 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 8.6, 2.3 Hz, 1H), 7.05 (d, J = 1.3 Hz, 1H), 7.01 (dd, J = 7.8, 1.3 Hz, 1H), 6.30 (t, J = 3.2 Hz, 1H), 6.20 (dd, J = 3.5, 1.2 Hz, 1H), 4.55 - 4.25 (m, 1H), 3.83 (s, 3H), 3.74 - 3.39 (m, 3H), 3.13 (s, 3H), 2.06 - 1.86 (m, 4H), 1.50 (s, 6H),

 498

 505.30 2.56 1H NMR (400 MHz, CDCl3) d 7.59 (d, J = 8.8 Hz, 1H), 7.18-7.10 (m, 2H), 7.07 (dd, J = 8.8, 2.4 Hz, 1H), 6.96-6.87 (m, 2H), 6.81 (d, J = 3.6 Hz, 1H), 6.07 (d, J = 3.8 Hz, 1H), 4.92-4.24 (m, 1H), 3.85 (s, 3H), 3.66-3.03 (m, 3H), 2.64 (q, J = 7.5 Hz, 2H), 2.31-1.75 (m, 4H), 1.18 (t, J = 7.5 Hz, 3H),

 499

 404.27 1.44

 500

 418.40 3.93

 501

 481.50 4.04

 502

 424.30 1.63 1H NMR (400 MHz, CDCl 3) d 8.24, 7.04, 7.02, 6.84, 6.82, 6.69, 6.65, 6.64, 6.61 , 6.56, 6.46, 6.45, 6.38, 6.38, 6.36, 6.36, 6.25, 6.22, 5.90, 5.70, 5.69, 5 , 68, 5.51, 5.49, 5.44, 5.43, 5.30, 5.28, 5.22, 4.02, 3.99, 3.36, 3.10, 2.97 , 2.92, 2.86, 2.84, 2.74, 2.69, 2.66, 2.63, 1.99, 1.92, 1.86, 1.81, 1.76, 1 , 71, 1.60, 1.54, 1.50, 1.45, 1.44, 1.41, 1.38, 1.26, 1.21, 0.79, -1.64,

 503

 483.97 3.83

 504

 516.00 1.88 1H NMR (400 MHz, CDCl3) d 8.38 (d, J = 8.1 Hz, 1H), 8.19-8.09 (m, 1H), 7.97 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.19-7.11 (m, 2H), 7, 03 (d, J = 4.0 Hz, 1H), 6.13 (d, J = 4.0 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H), 3.86 - 3.28 (m, 3H), 3.20 (s, 3H), 2.11 (d, J = 50.6 Hz, 16H), 1.99 - 1.79 (m, 2H),

 505

 503.95 4.25

 506

 418.50 1.47 1H NMR (400 MHz, CDCl3) d 7.64-7.50 (m, 3H), 7.44 (t, J = 12.1 Hz, 2H), 7.33-7, 21 (m, 2H), 7.06 (dd, J = 15.7, 8.0 Hz, 2H), 4.60 (m, 1H), 4.17 (s, 3H), 3.82-3 , 49 (m, 2H), 3.43 (m, 1H), 2.33-1.69 (m, 5H), 1.59 (s, 6H),

 507

 463.00 1.34

 508

 469.50 1.86 1H NMR (400 MHz, CDCl3) d 7.96 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 22.7 Hz, 1H), 7.11 - 7.01 (m, 4H), 6.92 (t, J = 3.8 Hz, 1H), 6.12 (d, J = 3.3 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H), 3.69-3.46 (m, 2H), 3.40 - 3.27 (m, 1H), 3.21 (dt, J = 13.7, 6.8 Hz, 2H), 2.15 (d, J = 56.6 Hz, 4H), 1.54 (s, 1H), 1.31 (d , J = 6.9 Hz, 8H),

 509

       1H NMR (400 MHz, DMSO) d 8.00 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.58 - 7.50 (m , J = 8.6 Hz, 2H), 7.35 (d, J = 4.0 Hz, 1H), 7.34 - 7.28 (m, J = 4.1 Hz, 2H), 7.28 - 7.20 (m, 1H), 6.48 (d, J = 4.0 Hz, 1H), 4.45 (d, J = 12.5 Hz, 1H), 3.59 - 3.42 ( m, J = 20.8 Hz, 2H), 3.25 (s, 3H), 3.19 (br d, 1H), 2.68 (s, 3H), 2.16-2.00 (m, J = 22.8 Hz, 3H), 1.90 (d, J = 13.1 Hz, 1H),

 510

 408.26 1.60

 511

 428.50 2.07

 512

 449.00 3.32

 513

 457.50 1.82 1H NMR (400 MHz, CDCl3) d 8.04 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.3 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 4.1 Hz, 2H), 7.13 (d, J = 1.9 Hz, 2H), 7.04 (dd , J = 8.5, 1.8 Hz, 1H), 6.36 (t, J = 3.1 Hz, 1H), 6.07 (d, J = 3.4 Hz, 1H), 4.67 (br s, 1H), 3.59 (br s, 2H), 3.38 (br s, 1H), 3.10 (s, 3H), 2.22 (br s, 1H), 2.06 ( br s, 2H), 1.89 (br s, 1H), 1.62 (s, 4H),

 514

 488.00 1.79 1H NMR (400 MHz, CDCl3) d 7.41 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 7.19 - 7.02 (m, 3H), 6.83 (d, J = 8.1 Hz, 1H), 6.26 (d, J = 3.4 Hz, 1H), 5.99 (d, J = 3.5 Hz, 1H), 5.68 (s, 1H), 4.71 (d, J = 4.7 Hz, 2H), 4.57 (dt, J = 12.0, 6.1 Hz, 2H), 4.00-3.30 (m, 3H), 2.23 (s, 3H), 2.20 - 1.75 (m, 4H), 1.36 (d, J = 6.0 Hz , 6H),

 515

 492.20 2.44

 516

 414.50 1.58 1H NMR (400 MHz, DMSO) d 7.99 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.38 - 7.13 (m, 6H), 6.50 (t, J = 4.4 Hz, 1H), 5.15 (t, J = 5.3 Hz, 1H), 4.52 (d, J = 5.4 Hz, 3H), 3.53-3.03 (m, 4H), 2.23-1.66 (m, 6H),

 517

 446.14 2.39

 518

 478.20 2.62

 519

 418.00 1.81 1H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.1 Hz, 1H), 7.38-7.31 (m, 1H), 7.23 (dd, J = 8.7, 6.6 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.04 (d, J = 4.0 Hz, 1H), 6.82 - 6.71 (m, 2H), 6.11 (dd, J = 10.3, 4.0 Hz, 1H), 4.79 (d, J = 13.3 Hz, 1H), 3.88 (d, J = 7.4 Hz, 3H), 3.62-3.24 (m, 3H), 2.31-2.17 (m, 1H), 2.17-1.81 (m, 3H),

 520

 394.30 1.83

 521

 467.30 1.47 1H NMR (400 MHz, DMSO) d 7.85 (d, J = 8.1 Hz, 2H), 7.79-7.52 (m, 4H), 7.46 (s, 1 H), 7.33-7.25 (m, 1H), 7.15-7.04 (m, 2H), 4.46-4.32 (m, 1 H), 4.10 (s, 3H), 3.64-3.20 (m, 3H), 2.81 (q, J = 7.2Hz, 2H), 2.09-1.81 (m, 4H), 0.98 (t, J = 7.2Hz, 3H),

 522

 476.30 1.80 1H NMR (400 MHz, CDCl3) d 8.09 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.41 (s, 1H), 7.40 (d,

 J = 7.0 Hz, 1H), 7.00 (d, J = 4.0 Hz, 1H), 6.95 (s, 1H), 6.94 (d, J = 10.2 Hz, 1H) , 6.09 (d, J = 4.0 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 3.65-3.53 (m, 2H), 3.32 ( t, J = 12.6 Hz, 1H), 3.09 (s, 3H), 2.75 (s, 3H), 2.36 (s, 3H), 2.27-2.17 (m, 1H ), 2.11 - 1.96 (m, 2H), 1.86-1.75 (m, 1H),

 523

 467.50 1.43 1H NMR (400 MHz, DMSO) d 7.85 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.64-7.55 (m, 2H), 7.49 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.25 - 7.16 (m, 1H), 7.06 - 6.94 (m , 2H), 4.33 (d, J = 11.7 Hz, 1H), 3.88 (s, 3H), 3.62-3.48 (m, 1 H), 3.48-3.34 (m, 2H), 2.60 (s, 3H), 2.46 (d, J = 4.9 Hz, 3H), 2.10 - 1.98 (m, 1H), 1.97-1, 82 (m, 3H),

 524

 432.50 1.18

 525

 432.70 1.51

 526

 458.28 1.76

 527

 463.10 1.68

 528

 458.50 1.80 1H NMR (400 MHz, CDCl3) d 7.52, 7.50, 7.33, 7.30, 7.29, 7.27, 7.24, 7.22, 7.17 , 7.15, 7.12, 7.08, 7.07, 7.05, 7.01, 6.84, 6.65, 6.47, 4.69, 4.65, 4.51, 4 , 49, 4.47, 4.45, 4.00, 3.65, 3.61, 3.58, 3.56, 3.51, 3.50, 3.48, 3.46, 3.40 , 3.36, 3.34, 3.30, 2.23, 2.19, 2.07, 2.02, 1.98, 1.97, 1.94, 1.93, 1.91, 1 , 76, 1.63, 1.61, 1.58, 1.55, 1.53, 1.23, 1.22, 1.20,

 529

 465.10 2.37

 530

 484.50 5.64

 531

 501.30 2.01 1H NMR (400 MHz, DMSO) d 7.57 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.36-7.25 (m, 3H), 7.20 (t, J = 7.7 Hz, 1H), 7.04-6.95 (m, 2H), 6.41 (d, J = 3.9 Hz, 1H), 5, 11-5.03 (m, 1H), 4.71-4.62 (m, 1H), 4.48 (s, 2H), 4.43-4.02 (m, 1H), 3.88- 3.12 (m, 3H), 2.09-1.87 (m, 4H), 1.27 (d, J = 6.0 Hz, 6H),

 532

 467.20 2.19

 533

 462.30 2.44

 534

 439.28 2.04

 535

 483.10 1.47 1H NMR (400 MHz, DMSO) d 8.12 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.47 (dd, J = 44.9, 6.9 Hz, 1H), 7.38-7.24 (m, 2H), 7.20 (t, J = 7.0 Hz, 1H), 7.02 ( d, J = 4.0 Hz, 1H), 6.70-6.57 (m, 1H), 6.40 (t, J = 4.6 Hz, 1H), 4.57-4.36 (m , 1H), 3.66-3.36 (m, 4H), 3.29-3.17 (m, 2H), 3.18-3.01 (m, 1H), 2.13 (dd, J = 25.2, 12.5 Hz, 1H), 2.08 - 1.97 (m, 2H), 1.97-1.77 (m, 5H),

 536

 444.50 2.18 1H NMR (400 MHz, DMSO) d 7.93 (d, J = 1.8, 1H), 7.75-7.69 (m, 2H), 7.64 (d, J = 8.3, 1H), 7.50 (dd, J = 2.8, 1.3, 1H), 7.09 (dd, J = 9.6, 2.8, 1H), 6.94 ( td, J = 8.7, 2.8, 1H), 6.29 (t, J = 3.2, 1H), 6.17 (dd, J = 3.4, 1.3, 1H), 4 , 46-4.34 (m, 1H), 3.62-3.40 (m, 2H), 3.29-3.16 (m, 1H), 2.15-1.83 (m, 4H) , 1.46 (s, 9H),

 537

 448.20 2.00

 538

 431.20 2.08

 539

 504.24 2.09

 540

 507.50 1.56 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.70 -7.64 (m, 3H), 7.37-7.28 (m, 3H), 7.26-7.18 (m, 1H), 6.47 (d, J = 4.0 Hz, 1H ), 4.52-4.35 (m, 2H), 3.60-3.12 (m, 5H), 2.85-2.75 (m, 2H), 2.15-2.02 (m , 3H), 1.95-1.85 (m, 1H), 1.56-1.46 (m, 2H),

 541

 532.30 1.95 1H NMR (400 MHz, DMSO) d 8.03 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 8, 0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.37-7.11 (m, 3H), 7.03 (d, J = 3.7 Hz, 1H) , 6.41 (d, J = 3.7 Hz, 1H), 4.55-4.36 (m, 1H), 3.64-3.13 (m, 3H), 2.20-1.81 (m, 5H), 0.54-0.33 (m, 4H),

 542

 454.19 1.58

 543

 480.30 2.24 1H NMR (400 MHz, DMSO) d 7.90 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.46 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.09 (dd, J = 16.6, 8.0 Hz, 2H), 4.38 (d, J = 11.4 Hz, 1H), 4.10 (s, 3H), 3.58-3.46 (m, 2H), 3.08 (d, J = 6.1 Hz, 2H), 2.65 (s, 3H), 2.08 - 1.79 (m, 4H), 1.18 (s, 3H), 1.16 (s, 3H),

 544

 436.50 1.88 1HNMR (400MHz, MeOD) d7.70 (d, J = 8.0Hz, 1H), 7.48 (d, J = 4.6Hz, 1H), 7.36-7.22 ( m, 2H), 7.22-7.04 (m, 4H), 5.11-5.01 (m, 1H), 4.03-3.96 (m, 3H), 3.71-3, 37 (m, 4H), 2.24 - 2.13 (m, 1H), 2.13 - 1.89 (m, 3H), 1.62 - 1.53 (m, 6H),

 545

 418.20 2.33

 546

 388.19 1.76

 547

 493.50 2.16

 548

 441.31 1.30

 549

 490.00 1.85

 550

 494.22 1.77

 551

 429.70 2.15

 552

 454.50 1.65

 553

 448.50 4.80

 554

 495.00 1.94

 555

 429.70 2.27 1H NMR (400 MHz, CDCl3) d 7.22 (d, J = 7.4 Hz, 1H), 7.16 (s, 2H), 7.04 - 6.84 (m, 7H), 6.21 (t, J = 3.2 Hz, 1H), 5.89 (d, J = 3.4 Hz, 1H), 4.82 (br, s, 1H), 4.12 ( br, s, 1H), 3.75 (s, 3H), 2.54 (q, J = 7.5 Hz, 2H), 2.45 - 1.84 (m, 8H), 1.48 (s , 4H), 1.07 (t, J = 7.5 Hz, 3H),

 556

 453.30 1.84

 557

 510.30 2.27

 558

 520.50 1.95 1H NMR (400 MHz, DMSO) d 7.84 (d, J = 7.9 Hz, 1H), 7.63-7.54 (m, 2H), 7.49 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.25 - 7.17 (m, 1H), 7.03 (d , J = 3.9 Hz, 1H), 6.42 (d, J = 4.0 Hz, 1H), 4.45 (d, J = 10.7 Hz, 1H), 3.61 - 3.40 (m, 2H), 3.27-3.14 (m, 1H), 2.60 (s, 3H), 2.45 (d, J = 4.9 Hz, 3H), 2.17-1, 95 (m, 3H), 1.95-1.81 (m, 1H),

 559

 458.50 1.79

 560

 392.26 1.64

 561

 457.10 2.35

 562

 384.10 2.16

 563

 379.50 2.01

 564

 442.20 6.16 1H NMR (400 MHz, CDCl3) d 8.41 (s, 1H), 7.71-7.58 (m, 3H), 7.22-7.04 (m, 3H), 6.80 (d, J = 3.9 Hz, 1H), 6.07 (d, J = 3.9 Hz, 1H), 4.67 (d, J = 13.3 Hz, 1H), 3, 99 (d, J = 12.8 Hz, 1H), 3.65-3.52 (m, 1H), 3.33 (td, J = 13.0, 2.9 Hz, 1H), 2.71 (q, J = 7.6 Hz, 2H), 2.18 (d, J = 15.2 Hz, 1H), 2.13 - 1.98 (m, 3H), 1.27 (t, J = 7.6 Hz, 3H),

 565

 419.50 1.32 1H NMR (400 MHz, CDCl3) d 7.58, 7.56, 7.53, 7.51, 7.41, 7.39, 7.27, 7.26, 7.25 , 7.24, 7.08, 7.05, 7.04, 7.01, 6.99, 6.53, 6.27, 6.25, 5.29, 5.27, 5.26, 5 , 24, 5.22, 4.56, 4.52, 4.33, 4.15, 4.14, 3.95, 3.68, 3.65, 3.62, 3.59, 3.50 , 3.48, 3.46, 3.44, 3.35, 3.32, 3.29, 3.16, 3.14, 2.95, 2.21, 2.18, 2.11, 2 , 07, 2.00, 1.94, 1.90, 1.86, 1.83, 1.80, 1.58, 1.37, 1.35, 1.22, 1.20, 1.18 , 0.06,

 566

 428.20 5.72 1H NMR (400 MHz, CDCl3) d 8.41 (s, 1H), 7.77-7.56 (m, 3H), 7.24-7.05 (m, 3H), 6.80 (d, J = 3.9 Hz, 1H), 6.08 (d, J = 3.9 Hz, 1H), 4.76-4.61 (m, 1H), 4.05-3 , 91 (m, 1H), 3.69-3.52 (m, 1H), 3.43-3.24 (m, 1H), 2.39 (s, 3H), 2.28-1.98 (m, 4H),

 567

 465.10 1.88 1H NMR (400 MHz, DMSO) d 7.71 (dd, J = 9.0, 5.6 Hz, 1H), 7.50 (dd, J = 2.8, 1.3 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 9.6, 2.7 Hz, 1H), 7.05 (d, J = 1 , 2 Hz, 1H), 7.01 (dd, J = 7.9, 1.2 Hz, 1H), 6.99-6.90 (m, 1H), 6.28 (t, J = 3, 2 Hz, 1H), 6.18 (dd, J = 3.6, 1.3 Hz, 1H), 4.52-4.26 (m, 1H), 3.83 (s, 3H), 3, 70-3.40 (m, 3H), 3.13 (s, 3H), 2.06-1.85 (m, 4H), 1.50 (s, 6H),

 568

 457.10 2.81

 569

 450.40 2.51

 570

 458.50 6.03

 571

 444.40 1.51 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.24-7.19 (m, 1H), 7.17-7.10 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.67 (s, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.64 ( d, J = 11.1 Hz, 1H), 3.60 - 3.23 (m, 2H), 2.07 (s, 2H), 1.88 (s, 4H), 1.53 (s, 3H ),

 572

 501.30 1.82

 573

 431.14 2.94

 574

 458.25 1.77

 575

 441.20 2.18

 576

 469.50 1.79

 577

 509.13 1.78

 578

 439.24 1.99

 579

 451.30 1.76 1H NMR (400 MHz, CDCl3) d 7.97-7.91 (m, 2H), 7.64-7.59 (m, 2H), 7.39-7.32 (m , 1H), 7.17 - 7.13 (m, 1H), 7.11 - 7.00 (m, 3H), 6.34 (t, J = 3.2 Hz, 1H), 6.06 - 6.00 (m, 1H), 4.71-4.59 (m, 1H), 3.70-3.31 (m, 3H), 3.27-3.14 (m, 1H), 2, 29 - 1.76 (m, 4H), 1.31 (d, J = 6.9 Hz, 6H),

 580

 499.50 1.58

 581

 452.00 1.89

 582

 466.30 1.52 1H NMR (400 MHz, DMSO) d 7.96 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.59 - 7.45 (m, 3H), 7.29 (t, J = 7.7 Hz, 1H), 7.17-7.04 (m, 2H), 4.54-4.33 (m, 3H ), 3.61-3.36 (m, 3H), 3.26 (s, 3H), 2.68 (s, 3H), 2.10-1.80 (m, 4H), 1.38 ( t, J = 7.2 Hz, 3H),

 583

 432.70 1.54

 584

 520.30 1.96

 585

 449.30 5.90

 586

 496.50 1.52 1H NMR (400 MHz, DMSO) d 7.83 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 - 7.06 (m, 2H), 4.45-4.31 (m, 1H), 4.10 (s, 3H), 3.97 (s, 3H), 3.68 (septet, J = 6 , 7 Hz, 1H), 3.59 - 3.22 (m, 3H), 2.10 - 1.82 (m, 4H), 1.17 (d, J = 6.9 Hz, 6H),

 587

 468.10 2.70

 588

 483.70 4.21

 589

 544.20 1.95

 590

 520.30 1.93 1H NMR (400 MHz, DMSO) d 7.85 (d, J = 8.2 Hz, 2H), 7.72-7.65 (m, 3H), 7.58 (d, J = 8.0 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.25 - 7.17 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H ), 6.40 (d, J = 4.0 Hz, 1H), 4.52-4.38

 (m, 1H), 3.60-3.12 (m, 3H), 2.80 (q, J = 7.2 Hz, 2H), 2.15-1.80 (m, 4H), 0, 98 (t, J = 7.2 Hz, 3H),

 591

 400.31 1.17

 592

 479.30 1.82

 593

 458.20 2.41 1H NMR (400 MHz, CDCl3) d 7.56 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.33 - 7.20 (m, 3H), 7.18 - 6.99 (m, 3H), 6.93 (t, J = 9.3 Hz, 1H), 4.67 (t, J = 15.1 Hz, 1H), 4.54-4.29 (m, 2H), 4.15 (s, 3H), 3.71-3.48 (m, 1H), 3.48-3.23 (m, 2H), 2.20 (t, J = 11.8 Hz, 1H), 2.10 - 1.64 (m, 3H),

 594

 494.50 1.76 1HNMR (400MHz, MeOD) d8.01 (d, J = 8.4Hz, 2H), 7.76 (d, J = 8.4Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7 , 13 (t, J = 7.6 Hz, 1H), 5.18-5.01 (m, 1H), 3.75-3.62 (m, 1H), 3.62-3.40 (m , 4H), 2.19 - 1.89 (m, 4H), 1.58 (d, J = 3.8 Hz, 6H), 1.29 (d, J = 6.9 Hz, 6H),

 595

 400.30 1.30

 596

 463.00 1.86

 597

 411.20 2.12

 598

 432.50 1.47

 599

 436.00 1.86

 600

 414.34 1.45

 601

 470.29 2.20

 602

 461.50 3.23

 603

 430.27 2.39

 604

 500.29 1.99

 605

 423.50 2.17 1H NMR (400 MHz, DMSO) d 7.71 (dd, J = 8.5, 4.5 Hz, 1H), 7.52 (d, J = 4.6 Hz, 1H) , 7.37-7.23 (m, 2H), 7.20-7.01 (m, 3H), 6.35-6.26 (m, 1H), 6.18 (dd, J = 9, 0, 2.4 Hz, 1H), 4.57-4.39 (m, 1H), 3.78-3.65 (m, J = 9.6 Hz, 3H), 3.54-3.11 (m, 3H), 2.25 (s, 3H), 2.12-1.80 (m, 4H),

 606

 483.70 4.20

 607

 481.00 1.49

 608

 432.70 1.89

 609

 467.50 1.93

 610

 446.30 1.97

 611

 431.06 2.72

 612

 465.10 2.01

 613

 466.30 4.17

 614

 471.30 1.62

 615

 511.24 2.14

 616

 509.32 2.04

 617

 466.30 2.30

 618

 479.30 7.06 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.2 Hz, 1H), 7.46-7.34 (m, 2H), 7.30 (t, J = 7.0 Hz, 1H), 7.25 - 7.05 (m, 4H), 6.81 (d, J = 3.5 Hz, 1H), 6.56 (dd, J = 77.9 , 70.7 Hz, 1H), 6.11 - 6.02 (m, 1H), 4.72 (d, J = 10.8 Hz, 1H), 3.63 - 3.20 (m, 3H) , 2.26 - 1.93 (m, 4H), 1.60 (s, 1H),

 619

 444.10 1.85

 620

 420.10 1.83

 621

 519.50 6.38

 622

 458.50 1.66

 623

 460.20 2.52

 624

 427.23 2.05

 625

 362.23 1.69

 626

 474.30 1.64

 627

 423.24 2.12

 628

 501.10 2.35

 629

 443.60 2.94

 630

 411.23 2.13

 631

 489.50 2.62

 632

 493.50 1.89

 633

 442.50 1.70

 634

 505.50 1.90

 635

 453.20 2.91

 636

 478.10 6.14

 637

 448.50 1.43

 638

 416.21 2.36

 639

 461.22 2.40

 640

 487.40 1.57 1H NMR (400 MHz, DMSO) d 7.57 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.34 - 7.26 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 4.0 Hz, 1H), 6.42 (d, J = 4.0 Hz, 1H), 4.98 (s, 1H), 4.72 (t, J = 5.9 Hz, 1H), 4 , 41 (s, 2H), 3.44-3.39 (m, 2H), 2.19-1.83 (m, 5H), 1.39 (s, 3H),

 641

 450.50 2.48

 642

 391.24 2.03

 643

 480.20 1.70 1H NMR (400 MHz, DMSO) d 7.90 (d, J = 8.1 Hz, 2H), 7.77-7.70 (m, 3H), 7.46 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.14-7.04 (m, 2H), 4.46-4.33 (m, 1H), 4.10 (s , 3H), 3.61-3.47 (m, 3H), 2.10-1.76 (m, 4H), 1.26 (s, 9H),

 644

 414.50 1.51

 645

 427.23 2.02

 646

 450.30 1.50 1H NMR (400 MHz, DMSO)? 7.76 (d, J = 29.4 Hz, 1H), 7.59 (dd, J = 7.5, 1.4 Hz, 1H), 7.24 - 7.16 (m, 1H), 7 , 07 - 6.90 (m, 3H), 6.84 (d, J = 8.6 Hz, 1H), 4.14 (d, J = 35.3 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 6H), 3.76 (d, J = 4.8 Hz, 3H), 3.31 (d, J = 13.6 Hz, 2H), 1.89 (dd, J = 46.8, 33.8 Hz, 4H),

 647

 447.50 2.07

 648

 487.10 2.63

 649

 388.27 1.74

 650

 436.30 1.83

 651

 411.10 1.53

 652

 411.20 1.42

 653

 478.20 2.59

 654

 488.20 1.81

 655

 442.00 2.19 1H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.0 Hz, 1H), 7.27-7.20 (m, 3H), 7.19-7, 12 (m, 2H), 7.04 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 4.74-4.25 (m, m, 2H), 3.44 (m, 3H), 2.22 (s, 3H), 2.20-1.75 (m, 4H) , 1.36 (d, J = 6.0 Hz, 6H),

 656

 472.39 2.29

 657

 411.27 2.10

 658

 486.20 2.24 1H NMR (400 MHz, DMSO) d 7.57 (d, J = 8.1 Hz, 1H), 7.50-7.42 (m, 2H), 7.30 (dtd, J = 9.3, 8.0, 1.5 Hz, 2H), 7.25 - 7.17 (m, 1H), 7.01 (d, J = 4.0 Hz, 1H), 6.41 (d, J = 4.0 Hz, 1H), 4.69 (hept, J = 6.1 Hz, 1H), 4.44 (d, J = 12.9 Hz, 1H), 3.93 (d , J = 12.3 Hz, 1H), 3.31-3.13 (m, 1H), 2.34 (s, 3H), 2.11-1.83 (m, 4H), 1.32 ( t, J = 10.2 Hz, 6H),

 659

 422.04 1.92

 660

 453.50 1.67

 661

 407.50 2.03

 662

 484.20 2.05

 663

 492.30 1.82

 664

 474.32 1.78

 665

 452.00 2.04

 666

 450.10 1.09

 667

 472.22 1.61

 668

 478.30 2.02

 669

 447.50 2.11

 670

 410.50 1.59 1H NMR (400 MHz, CDCl3) d 7.74, 7.73, 7.52, 7.42, 7.41, 7.39, 7.39, 7.28, 7.26 , 7.10, 7.10, 7.04, 7.04, 7.02, 7.01, 6.56, 6.53, 6.34, 6.34, 6.33, 6.03, 6 , 02, 4.12, 3.58, 3.48, 2.16, 2.12, 2.01, 1.97, 1.94, 1.57,

 671

 386.30 1.59 1H NMR (400 MHz, DMSO) d 9.84 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.37-7.28 (m, 5H), 7.27-7.19 (m, 1H), 6.79 (d, J = 8.5 Hz, 2H), 6.48 (d, J = 4.0 Hz, 1H), 2, 11 - 1.89 (m, 4H),

 672

 390.21 1.57 1H NMR (400 MHz, CDCl3) d 7.56 (d, J = 7.7 Hz, 1H), 7.43-7.19 (m, 4H), 6.89-7, 16 (m, 3H), 6.92 (d, J = 8.3 Hz, 1H), 4.67 (m, 1H), 4.16 (d, J = 2.0 Hz, 3H), 3, 86 (d, J = 4.5Hz, 3H), 3.66-3.28 (m, 3H), 2.19 (d, J = 14.1Hz, 1H), 2.06-1.59 (m , 3H),

 673

 424.30 1.88

 674

 422.50 1.72

 675

 506.30 1.87 1H NMR (400 MHz, DMSO) d 7.84 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.65 - 7.43 (m, 2H), 7.34 - 7.25 (m, 2H), 7.25 - 7.17 (m, 1H), 7.03 (d, J = 4.0 Hz, 1H ), 6.41 (d, J = 4.0 Hz, 1H), 4.51-4.38 (m, 1H), 3.61-3.12 (m, 3H), 2.44 (s, 3H), 2.16-1.82 (m, 4H),

 676

 451.50 2.46

 677

 474.00 1.79 1H NMR (400 MHz, CDCl3) d 8.23 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8, 3 Hz, 2H), 7.20 - 7.04 (m, 3H), 6.83 (d, J = 8.1 Hz, 1H), 6.28 (d, J = 3.5 Hz, 1H) , 5.99 (d, J = 3.6 Hz, 1H), 5.89 (s, 1H), 4.77 (d, J = 5.0 Hz, 2H), 4.57 (dt, J = 12.1, 6.0 Hz, 2H), 3.50 (s, 3H), 2.21 (s, 3H), 2.00 (t, J = 23.8 Hz, 4H), 1.36 ( d, J = 6.0 Hz, 6H),

 678

 475.30 1.69

 679

 510.00 1.91

 680

 490.50 1.49

 681

 481.50 2.23

 682

 485.50 2.07

 683

 479.30 1.78

 684

 500.00 1.77 1H NMR (400 MHz, CDCl3) d 8.39 (d, J = 8.1 Hz, 1H), 8.18-8.10 (m, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.24 (dd, J = 14.9, 7.2 Hz, 1H), 7.19-7.11 (m, 2H ), 7.03 (d, J = 4.0 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 4.68 (s, 1H), 3.59 (s, 2H ), 3.38 (d, J = 14.2 Hz, 1H), 2.81 (s, 1H), 2.77 (s, 3H), 2.35 - 1.96 (m, 6H), 1 , 95-1.70 (m, 2H),

 685

 549.60 1.87 1H NMR (400 MHz, DMSO) d 7.89 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.36 - 7.14 (m, 3H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H), 5.14-4.98 (m, 1H), 4.55-4.36 (m, 1H), 3.58-3.37 (m, 4H), 3.30 - 3.10 (m, 1H), 2.20-1.77 (m, 4H), 1.21 (s, 6H),

 686

 472.00 2.00 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 7.9 Hz, 1H), 7.33 (dd, J = 11.7, 4.1 Hz, 3H) , 7.23 (dt, J = 8.7, 4.5 Hz, 1H), 7.04 (dd, J = 14.8, 4.9 Hz, 2H), 6.48 (d, J = 4 , 1 Hz, 1H), 3.77 (s, 3H), 3.47 - 3.21 (m, 98H), 2.52 (dd, J = 11.8, 10.2 Hz, 24H), 2 , 02 (s, 5H), 1.29 (s, 9H),

 687

 688

 481.40 2.79

 689

 432.70 1.90

 690

 495.18 1.93

 691

 435.28 2.40

 692

 408.26 1.75

 693

 523.50 6.07

 694

 448.50 1.93

 695

 519.26 2.42

 696

 541.21 2.20

 697

 437.50 2.00 1H NMR (400 MHz, DMSO) d 7.71 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 2.9, 1.3 Hz, 1H) , 7.29 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.14 (dd, J = 8.6, 2.3 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.30 (t, J = 3.2 Hz, 1H), 6.20 (dd, J = 3.4, 1.3 Hz, 1H ), 4.51-4.30 (m, 1H), 3.82 (s, 3H), 3.67-3.41 (m, 2H), 3.29-3.15 (m, 1H) , 2.58 (q, J = 7.5 Hz, 2H), 2.06 - 1.86 (m, 4H), 1.13 (t, J = 7.5 Hz, 3H),

 698

 472.30 2.03

 699

 408.50 1.81

 700

 390.50 3.87

 701

 388.30 2.40

 702

 426.20 2.99

 703

 439.21 2.15

 704

 450.20 1.83 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.37 (t, J = 8, 2 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.6 Hz , 1H), 6.94 - 6.91 (m, 1H), 6.90 (s, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.10 (s, 3H) , 3.58-3.43 (m, 1H), 3.42-3.38 (m, 1H), 3.31-3.20 (m, 1H), 2.07-1.97 (m, 1H), 1.97-1.80 (m, 3H), 1.35 (s, 9H),

 705

 454.50 1.88 1H NMR (400 MHz, MeOD) d 7.70 (d, J = 7.2 Hz, 1H), 7.56-7.45 (m, 2H), 7.43-7, 33 (m, 2H), 7.34-7.26 (m, 2H), 7.20-7.08 (m, 2H), 7.08-6.65 (m, 1H), 5.14- 5.00 (m, 1H), 3.71-3.55 (m, 1H), 3.49-3.36 (m, 3H), 2.24-1.88 (m, 4H), 1, 62 - 1.52 (m, 6H),

 706

 454.50 1.90

 707

 413.20 1.86

 708

 413.27 2.45

 709

 432.30 2.01

 710

 432.40 3.14

 711

 432.70 1.62 1H NMR (400 MHz, CDCl3) d 7.57 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.32-7.20 (m, 2H), 7.06 (dd, J = 15.4, 7.8 Hz, 2H), 4.60 ( m, 1H), 4.42 (m, 1H), 4.18 (s, 3H), 3.80-2.26 (m, 3H), 2.32-1.71 (m, 7H), 0 , 96 (d, 6.2 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H),

 712

 501.30 2.55

 713

 460.50 1.75

 714

 467.30 1.53 1H NMR (400 MHz, CDCl3) d 7.84 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.30-7.23 (m, 2H), 7.11-7.03 (m, 2H), 4.77-4.49 (m, 1H ), 4.16 (s, 3H), 3.77-3.31 (m, 3H), 2.73 (s, 6H), 2.34-1.71 (m, 4H),

 715

 434.17 2.23

 716

 462.20 2.73

 717

 417.50 6.92

 718

 410.50 1.65 1H NMR (400 MHz, CDCl3) d 8.85, 7.52, 7.34, 7.33, 7.33, 7.32, 7.31, 7.30, 7.29 , 7.28, 7.26, 7.11, 7.11, 7.10, 7.09, 7.04, 7.04, 7.02, 7.02, 6.61, 6.59, 6 , 35, 6.34, 6.33, 6.16, 6.14, 6.13, 6.11, 6.04, 6.03, 6.02, 4.64, 4.63, 4.61 , 3.97, 3.70, 3.66, 3.64, 3.64, 3.61, 3.60, 3.58, 3.57, 3.56, 3.55, 3.52, 3 , 49, 3.39, 3.38, 3.35, 3.35, 3.34, 3.33, 3.32, 3.31, 3.30, 3.27, 3.27, 2.25 , 2.22, 2.15, 2.14, 2.11, 2.08, 2.08, 2.02, 2.01, 2.00, 1.99, 1.98, 1.95, 1 , 94, 1.93, 1.92, 1.91, 1.90, 1.88, 1.87, 1.85, 1.83, 1.81, 1.80, 1.78, 1.76 , 1.75, 1.70, 1.14,

 719

 415.26 1.98

 720

 465.18 2.20

 721

 491.50 1.83 1H NMR (400 MHz, CDCl3) d 8.13 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.3 Hz, 2H), 7.02 (d , J = 4.0 Hz, 1H), 6.11 (d, J = 4.0 Hz, 1H), 4.75-4.63 (m, 1H), 4.26 (d, J = 7, 6 Hz, 1H), 3.65-3.54 (m, 2H), 3.54-3.46 (m, 1H), 3.42-2.27 (m, 1H), 2.32-2 , 16 (m, 1H), 2.14-1.95 (m, J = 10.9 Hz, 2H), 1.91-1.77 (m, 1H), 1.11 (d, J = 6 , 5 Hz, 6H),

 722

 471.50 1.96 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.22-7.03 (m, 3H), 6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H), 4.65 (s, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.84 - 3.16 (m, 5H), 2.31 - 1.67 (m, 6H), 1.66-1.47 (m, 9H),

 723

 509.60 3.38

 724

 409.50 2.06 1H NMR (400 MHz, DMSO) d 7.71 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 2.9, 1.4 Hz, 1H) , 7.36 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 8.6, 2.3 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.30 (t, J = 3.2 Hz, 1H), 6.21 (dd, J = 3.4, 1.3 Hz, 1H ), 4.49-4.33 (m, 1H), 3.79 (s, 3H), 3.60-3.15 (m, 3H), 2.12-1.80 (m, 4H),

 725

 463.50 1.98

 726

 472.50 1.58

 727

 447.10 2.63 H NMR (400.0 MHz, DMSO) d 7.68 - 7.65 (m, 1H), 7.50 - 7.48 (m, 1H), 7.19 - 6.90 (m, 6H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.60-4.10 (m, 1H), 3.98-3 , 08 (m, 6H), 1.96 (s, 4H) and 1.29 (s, 9H) ppm,

 728

 424.50 1.66 1H NMR (400 MHz, CDCl3) d 7.56, 7.55, 7.54, 7.54, 7.37, 7.37, 7.36, 7.35, 7.31 , 7.26, 7.24, 7.08, 7.08, 7.01, 7.01, 6.99, 6.98, 6.33, 6.32, 6.31, 6.27, 6 , 25, 6.23, 6.07, 6.06, 5.30, 4.66, 4.63, 4.02, 3.58, 3.45, 3.42, 3.32, 3.29 , 3.26, 2.17, 2.14, 2.10, 2.09, 2.07, 2.04, 2.01, 1.59, 1.37, 1.35, 1.33, 1 , 21, 1,19, 0,07,

 729

 493.25 2.22

 730

 420.30 1.73

 731

 509.50 2.11

 732

 443.40 6.14 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.1 Hz, 1H), 7.15 (ddd, J = 26.0, 23.5, 13.3 Hz, 5H), 6.81 (d, J = 2.7 Hz, 1H), 6.72 (s, 1H), 6.06 (s, 1H), 3.47 (d, J = 19.7 Hz, 3H), 2.23 (s, 3H), 2.08 (s, 2H), 2.02 - 1.79 (m, 2H),

 733

 446.00 1.45

 734

 473.30 4.94

 735

 417.00 2.24

 736

 488.30 1.85

 737

 451.30 2.51

 738

 422.50 1.70 1H NMR (400 MHz, CDCl3) d 7.57, 7.55, 7.52, 7.31, 7.29, 7.27, 7.26, 7.26, 7.23 , 7.13, 7.11, 7.09, 7.06, 7.05, 7.03, 7.01, 6.99, 6.97, 6.95, 4.67, 4.64, 4 , 15, 4.13, 4.11, 4.09, 3.94, 3.61, 3.50, 3.49, 3.47, 3.45, 3.34, 2.22, 2.18 , 2.04, 2.01, 1.98, 1.97, 1.94, 1.93, 1.91, 1.90, 1.78, 1.57, 1.48, 1.46, 1 , 44, 1.25, 1.22, 1.21, 1.19,

 739

 427.18 2.21

 740

 426.00 1.42

 741

 410.30 1.60 1H NMR (400 MHz, CDCl3) d 7.52, 7.38, 7.36, 7.28, 7.26, 7.10, 7.09, 7.04, 7.03 , 7.02, 7.01, 6.55, 6.35, 6.34, 6.33, 6.21, 6.19, 6.03, 6.03, 5.30, 4.60, 4 , 56, 4.13, 4.11, 3.67, 3.60, 3.56, 3.29, 3.26, 3.23, 2.20, 2.17, 2.08, 2.05 , 1.96, 1.87, 1.55, 1.28, 1.26,

 742

 480.50 1.90 1H NMR (400 MHz, DMSO) d 7.52 (s, 1H), 7.48 (dd, J = 9.4, 2.3 Hz, 1H), 7.20-7, 09 (m, 2H), 7.02 (s, 1H), 6.99 (s, 2H), 4.60 (hept, J = 5.8 Hz, 1H), 4.45 (q, J = 7 , 2 Hz, 2H), 4.36-4.18 (m, 1H), 3.76 (s, 3H), 3.70-3.39 (m, 2H), 3.28-3.13 ( m, 1H), 2.02 - 1.84 (m, 4H), 1.37 (t, J = 7.2 Hz, 3H), 1.26 (d, J = 6.0 Hz, 6H),

 743

 515.20 2.33

 744

 442.18 2.52

 745

 446.50 5.70 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.29 (t, J = 7, 7 Hz, 1H), 7.16-7.05 (m, 4H), 4.31 (s, 1H), 4.23-4.16 (m, 1H), 4.10 (s, 3H), 3.44 (d, J = 53.4 Hz, 2H), 2.23 (s, 6H), 1.92 (d, J = 6.6 Hz, 4H), 1.24 (d, J = 6 , 1 Hz, 6H),

 746

 404.70 1.35 1H NMR (400 MHz, CDCl3) d 7.57 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.33 - 7.11 (m, 4H), 7.10-7.02 (m, 2H), 4.78-4.65 (m, 3H), 4.15 (s, 3H), 3.57-3 , 48 (m, 1H), 3.45-3.31 (m, 2H), 2.33 (d, J = 21.1 Hz, 3H), 2.26-2.19 (m, 1H), 2.04-1.88 (m, 2H), 1.84-1.64 (m, 2H),

 747

 450.30 1.47

 748

 420.26 1.77

 749

 429.50 2.02

 750

 432.30 2.22

 751

 539.50 6.58

 752

 480.30 2.05 1H NMR (400 MHz, CDCl3) d 7.87 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 11.1 Hz, 1H), 7.47 - 7.35 (m, 2H), 7.35 - 7.25 (m, 2H), 7.21 (t, J = 8.7 Hz, 1H), 7.11-6.98 (m, 2H ), 6.58 (t, J = 74.7 Hz, 1H), 4.78-4.62 (m, 1H), 3.71-3.51 (m, 1H), 3.47-3, 26 (m, 2H), 2.37-2.22 (m, 1H), 2.16-1.81 (m, 3H),

 753

 427.25 2.39

 754

 446.30 2.46

 755

 472.00 2.10

 756

 512.21 1.83

 757

 480.22 1.51

 758

 473.50 4.90

 759

 539.50 2.07

 760

 522.24 1.80

 761

 448.30 1.70

 762

 428.50 1.71 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 7.29-7.09 (m, 3H), 7.01 (t, J = 5.6 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.67 (m, 1H), 3.74 (m, 1H), 3.49 (m, 1H), 3.32 (m, 1H), 1.75-2, 25 (m, 4H), 1.73 (s, 1H), 1.58 (s, 6H),

 763

 408.24 1.83

 764

 417.13 2.89

 765

 427.25 2.67

 766

 406.50 1.84

 767

 479.30 1.49

 768

 511.50 1.69

 769

 432.50 2.00 1H NMR (400 MHz, CDCl3) d 8.19-8.02 (m, 1H), 7.29-6.89 (m, 10H), 6.09 (t, J = 3 , 5 Hz, 1H), 4.74 (d, J = 13.4 Hz, 1H), 4.49-3.96 (m, 2H), 3.69 - 3.26 (m, 3H), 3 , 24 (d, J = 13.2 Hz, 1H), 2.21 (d, J = 15.7 Hz, 2H), 2.10 - 1.87 (m, 2H), 1.74 (d, J = 12.5 Hz, 0H), 1.55 (d, J = 3.0 Hz, 1H), 1.38 (td, J = 6.9, 3.7 Hz, 3H),

 770

 446.30 2.05 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 11.0 Hz, 3H), 7.14 (ddd, J = 18.7, 16.0, 7.7 Hz, 4H), 6.99 (dt, J = 22.4, 5.5 Hz, 3H), 6.11 (s, 1H), 4.73 (d, J = 10.9 Hz, 1H), 4.60-4.46 (m, 1H), 3.52 (s, 2H), 3.28 (s, 1H), 2.22 (s, 0H), 2.28 - 2.12 (m, 1H), 2.13 - 1.90 (m, 3H), 1.55 (s, 1H), 1.36 (d, J = 6 , 0 Hz, 5H),

 771

 420.30 1.63

 772

 773

 408.22 1.74

 774

 404.30 1.63

 775

 515.50 2.14

 776

 401.22 2.21

 777

 469.40 2.92

 778

 527.30 6.81

 779

 414.25 2.43

 780

 469.50 2.15 1H NMR (400 MHz, CDCl3) d 7.74 (s, 1H), 7.66 (dd, J = 8.6, 1.7 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.10-6.97 (m, 5H), 6.29 (t, J = 3.2 Hz, 1H), 6.01-5.94 (m, 1H ), 4.88 (br, s, 1H), 4.13 (br, s, 1H), 3.92 (s, 3H), 2.59 - 2.15 (m, 5H), 2.06 ( br, s, 3H), 1.57 (s, 3H),

 781

 476.30 1.64 1H NMR (400 MHz, CDCl3) d 8.22-8.05 (m, 1H), 7.50 (q, J = 8.2 Hz, 4H), 7.27-7, 19 (m, 4H), 7.19-7.09 (m, 2H), 7.01 (t, J = 6.2 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H ), 4.67 (s, 1H), 4.31-4.12 (m, 1H), 3.62 (d, J = 39.1 Hz, 2H), 3.33 (s, 1H), 2 , 72 (d, J = 20.1 Hz, 3H), 2.12 (d, J = 47.3 Hz, 2H), 2.01 (s, 4H), 1.82 (t, J = 13, 7 Hz, 4H), 1.58 (d, J = 20.4 Hz, 3H),

 782

 458.50 1.55 1H NMR (400 MHz, CDCl3) d 8.15-8.07 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.25-7, 16 (m, 3H), 7.16-7.08 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H ), 4.74-4.57 (m, 1H), 4.00 (d, J = 11.1 Hz, 1H), 3.85-3.71 (m, 1H), 3.69 (d, J = 11.1 Hz, 1H), 3.63 - 3.23 (m, J = 86.9 Hz, 2H), 2.56 (s, 3H), 2.23-2.07 (m, 2H ), 1.99 - 1.72 (m, 5H), 1.58 (s, 3H),

 783

 497.50 2.02

 784

 462.50 1.67 1H NMR (400 MHz, CDCl3) d 8.21-8.06 (m, 1H), 7.84-7.80 (m, 2H), 7.48-7.35 (m , 1H), 7.29-7.18 (m, 1H), 7.19-7.08 (m, 2H), 7.02 (d, J = 3.9 Hz, 1H), 6.12- 6.08 (m, 1H), 4.75 (d, J = 13.8 Hz, 1H), 3.57-3.48 (m, 1H), 3.42 - 3.21 (m, 2H) , 3.05 (s, 3H), 2.44 (d, J = 13.0 Hz, 3H), 2.28-2.21 (m, 1H), 2.15 - 1.88 (m, 2H ), 1.84-1.69 (m, 1H),

 785

 544.20 1.95

 786

 431.15 2.18

 787

 431.19 2.17

 788

 476.40 3.02

 789

 460.50 1.46

 790

 395.11 1.86

 791

 449.10 2.35 H NMR (400.0 MHz, DMSO) d 7.67 - 7.65 (m, 1H), 7.50 - 7.49 (m, 1H), 7.17 - 6.99 (m, 6H), 6.29-6.26 (m, 1H), 6.18-6.17 (m, 1H), 4.35 (s, 1H), 4.12-4.10 (m , 2H), 3.82-3.78 (m, 3H), 3.67-3.65 (m, 2H), 3.40 (s, 3H), 3.33-3.30 (m, 3H ) and 1.95 (s, 4H) ppm,

 792

 451.30 1.98

 793

 471.30 1.88

 794

 521.30 1.84 1H NMR (400 MHz, DMSO) d 7.97 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.34-7.16 (m, 3H), 7.03 (d, J = 4.0 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H), 4.90 (t, J = 4.9 Hz, 1H), 4.52-4.37 (m, 1H), 3.75-3.65 (m, 2H), 3.58-3.36 (m, 4H), 3.28-3.15 (m, 1H), 2.20-1.77 (m, 4H),

 795

 457.00 2.13

 796

 450.50 1.52

 797

 388.30 2.41

 798

 415.19 2.09

 799

 452.00 2.01

 800

 450.27 1.76

 801

 418.50 1.75 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.29 (t, J = 7, 8 Hz, 1H), 7.13 (s, 4H), 4.33 (s, 1H), 4.10 (s, 3H), 3.68 (s, 5H), 2.25 (s, 6H) , 2.07 (s, 1H), 1.91 (s, 4H),

 802

 432.70 3.15

 803

 435.50 7.08

 804

 537.50 2.08 1H NMR (400 MHz, DMSO) d 7.93 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.58 (dd, J = 9.0, 5.2 Hz, 1H), 7.29 (dd, J = 9.1, 2.7 Hz, 1H), 7.10 (td, J = 8.7, 2 , 9 Hz, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.41 (d, J = 3.9 Hz, 1H), 4.54-4.37 (m, 1H ), 3.64-3.16 (m, 4H), 2.18-1.81 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H),

 805

 472.30 3.09

 806

 434.20 1.94

 807

 422.04 1.88

 808

 491.15 1.91

 809

 404.20 1.77

 810

 442.50 2.02 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.6 Hz, 1H), 7.46-7.38 (m, 4H), 7.22 (t, J = 7.3 Hz, 1H), 7.16 - 7.11 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 5.19 (d, J = 11.0 Hz, 2H), 4.97 (s, 1H), 3.83 - 3.25 (m, 3H), 2.26 - 1.79 (m, 5H), 1.60 (s, 6H),

 811

 426.10 1.68

 812

 451.20 2.38 1H NMR (400 MHz, DMSO) d 7.71 (dd, J = 8.9, 5.6 Hz, 1H), 7.53-7.47 (m, 1H), 7, 11 (dd, J = 9.6, 2.6 Hz, 1H), 7.05 - 6.98 (m, 3H), 6.94 (td, J = 8.8, 2.7 Hz, 1H) , 6.28 (t, J = 3.1 Hz, 1H), 6.18 (d, J = 3.4 Hz, 1H), 4.58-4.02 (m, 1H), 3.94 ( t, J = 6.5 Hz, 2H), 3.79 (s, 3H), 3.59-3.09 (m, 3H), 2.06 - 1.86 (m, 4H), 1.73 (sextet, J = 6.8 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H),

 813

 518.50 1.80

 814

 458.28 2.17

 815

 483.50 1.97 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.1 Hz, 1 H), 7.53-7.35 (m, 4H), 7.23-7 , 03 (m, 3H), 6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H), 4.64 (bs, 1H), 4 , 03 (d, J = 8.3 Hz, 1H), 3.81-3.23 (m, 3H), 2.32-1.70 (m, 5H), 1.29 - 1.05 (m , 1H), 0.72-0.28 (m, 4H),

 816

 399.26 1.67

 817

 431.70 2.10

 818

 485.00 2.38

 819

 521.00 1.85 1H NMR (400 MHz, CDCl3) d 8.59 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8, 5 Hz, 1H), 7.24 (t, J = 7.2 Hz, 2H), 7.19 - 7.12 (m, 2H), 7.04 (d, J = 8.5 Hz, 1H) , 6.15 (d, J = 4.1 Hz, 1H), 4.57 (s, 1H), 3.94 (s, 3H), 3.47 (s, 3H), 3.08 (s, 3H), 2.27-1.67 (m, 4H),

 820

 491.30 1.57

 821

 466.30 2.21

 822

 462.50 2.09

 823

 454.33 2.16

 824

 495.50 1.60

 825

 463.50 2.20

 826

 468.00 1.98

 827

 447.50 1.54 1H NMR (400 MHz, CDCl3) d 7.35 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 2.8, 1.3 Hz, 1H), 7.11 - 6.99 (m, 5H), 6.33 (t, J = 3.2 Hz, 1H), 6.04 ( dd, J = 3.5, 1.3 Hz, 1H), 5.02 (d, J = 7.2 Hz, 2H),

 4.86 (d, J = 7.1 Hz, 2H), 4.72 - 4.54 (m, 1H), 3.90 (s, 3H), 3.78 - 3.24 (m, 3H) , 2.35-1.76 (m, 4H),

 828

 444.30 2.54

 829

 505.50 1.89

 830

 419.20 1.66

 831

 420.30 1.75

 832

 520.30 1.98 1H NMR (400 MHz, CDCl3) d 8.10 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.17 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 4.0 Hz , 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.75-4.63 (m, 1H), 4.45 (s, 2H), 3.64-3.46 ( m, 2H), 3.43 (s, 3H), 3.41-3.29 (m, 1H), 3.26-3.17 (m, 1H), 2.29-2.19 (m, 1H), 2.10 - 1.99 (m, 2H), 1.81 (s, 1H), 1.31 (d, J = 6.9 Hz, 6H),

 833

 407.15 2.20

 834

 433.20 1.72

 835

 495.21 1.93

 836

 513.50 8.20

 837

 461.50 1.88

 838

 458.50 5.96

 839

 428.00 2.08 1H NMR (400 MHz, CDCl3) d 8.05 (d, J = 8.0 Hz, 1H), 7.18-7.02 (m, 4H), 6.95 (d, J = 4.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.03 (d, J = 4.0 Hz, 1H), 4.59 (s, 1H) , 3.78 (s, 3H), 3.37 (d, J = 81.3 Hz, 3H), 2.57 (q, J = 7.5 Hz, 2H), 2.35-1.60 ( m, 4H), 1.11 (t, J = 7.5 Hz, 3H),

 840

 547.50 5.88 1H NMR (400 MHz, DMSO) d 8.08-7.93 (m, 2H), 7.84-7.69 (m, 2H), 7.57 (d, J = 8 , 1 Hz, 1H), 7.38-7.12 (m, 3H), 7.11 - 6.96 (m, 1H), 6.48 - 6.31 (m, 1H), 4.53 - 4.18 (m, 2H), 4.07-3.97 (m, 1H), 3.88-3.71 (m, 2H), 3.69-3.59 (m, 1H), 3 , 60-3.37 (m, 2H), 3.31-3.13 (m, 1H), 2.23-1.78 (m, 6H),

 841

 416.50 1.84

 842

 450.97 3.18

 843

 450.97 3.12

 844

 505.30 5.49 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.73 - 7.60 (m, 3H), 7.34 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.2 Hz, 2H), 7.27-7.20 ( m, 1H), 6.47 (d, J = 4.0 Hz, 1H), 4.57-4.36 (m, 1H), 3.60-3.37 (m, 2H), 3.28 - 3.09 (m, 1H), 2.18-1.77 (m, 4H), 1.10 (s, 9H),

 845

 408.20 2.19

 846

 473.30 1.83 1H NMR (400 MHz, DMSO) d 7.57 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.38 - 7.16 (m, 3H), 7.01 (d, J = 4.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.41 (d, J = 4.0 Hz, 1H), 4.88 (t, J = 5.5 Hz, 1H), 4.49 - 4.09 (m, 1H), 4.03 (t, J = 4.9 Hz, 2H), 3.80-3.66 (m, 2H), 3.66-3.15 (m, 3H), 2.15-1.80 (m, 4H),

 847

 848

 433.50 1.78

 849

 427.50 1.50 1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.65 (dd, J = 8, 2, 2.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.18-7.03 (m, 3H), 6.95 (d, J = 4.0 Hz, 1H), 6.03 (d, J = 4.0 Hz, 1H), 4.69-4.48 (m, 1H), 3.81-3.11 (m, 3H), 2.24 - 1.72 (m, 4H), 1.31 (s, 9H),

 850

 447.30 2.07

 851

 530.00 1.82 1H NMR (400 MHz, CDCl3) d 7.29 (d, J = 5.9 Hz, 3H), 7.12 (d, J = 2.1 Hz, 2H), 7.09 - 6.99 (m, 3H), 6.91 (d, J = 8.2 Hz, 1H), 6.36 (t, J = 3.2 Hz, 1H), 6.06 (d, J = 3.2 Hz, 1H), 4.61 (s, 1 H), 4.48 (t, J = 5.3 Hz, 2H), 3.89 (s, 3H), 3.88-3.28 (m, J = 5.2 Hz, 5H), 3.24 (q, J = 7.4 Hz, 2H), 3.20 (s, 3H), 2.82 (s, 2H), 2.12 -1.75 (m, 4H), 1.41 (t, J = 7.3 Hz, 2H),

 852

 431.70 2.38

 853

 420.50 1.38 1H NMR (400 MHz, CDCl3) d 7.57 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.35 - 7.21 (m, 3H), 7.17 (t, J = 7.9 Hz, 1H), 7.13-7.00 (m, 2H), 4.88-4.80 (m, 1H ), 4.77 - 4.54 (m, 2H), 4.15 (d, J = 3.1 Hz, 3H), 3.90 (d, J = 11.6 Hz, 3H), 3.72 - 3.24 (m, 3H), 2.32 - 1.60 (m, 5H)

 854

 441.50 1.30 1H NMR (400 MHz, DMSO) d 9.30 (bs, 1H), 9.14 (bs, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7 , 45 (d, J = 8.6 Hz, 2H), 7.37-7.29 (m, 3H), 7.28-7.16 (m, 1H), 6.93 (d, J = 8 , 6 Hz, 2H), 6.47 (d, J = 4.0 Hz, 1H), 5.17-5.09 (m, 1H), 4.49-4.40 (m, 3H), 4 , 04-3.95 (m, 3H), 2.12-1.90 (m, 4H),

 855

 449.10 2.22 1H NMR (400 MHz, DMSO) d 7.71 (dd, J = 8.9, 5.6 Hz, 1H), 7.49 (dd, J = 2.8, 1.3 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.10 (dd, J = 9.6, 2.8 Hz, 1H), 7.01 (d, J = 1 , 3 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.28 (t, J = 3.2 Hz, 1H), 6.18 (dd, J = 3.4, 1, 2 Hz, 1H), 4.51-4.26 (m, 1H), 3.84 (s, 3H), 3.73-3.40 (m, 3H), 2.05-1.85 (m , 4H), 1.34 (s, 9H),

 856

 394.50 1.39 1H NMR (400 MHz, DMSO) d 10.41 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7 , 32 - 7.23 (m, 2H), 7.15-7.04 (m, 3H), 6.98 (t, J = 8.5 Hz, 1H), 4.10 (s, 3H), 3.52-3.19 (m, 4H), 1.99-1.85 (m, 4H),

 857

 477.00 2.04 1H NMR (400 MHz, DMSO) d 7.77 (d, J = 8.6 Hz, 1H), 7.74-7.67 (m, 2H), 7.56-7, 50 (m, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.31-7.27 (m, 1H), 7.14 (dd, J = 8.8, 2, 0 Hz, 1H), 6.30 (t, J = 2.6 Hz, 1H), 6.22 - 6.16 (m, 1H), 4.65-4.21 (m, 1 H), 3 , 94 (s, 3H), 3.74-3.38 (m, 3H), 2.06-1.83 (m, 4H),

 858

 443.12 2.15

 859

 452.30 1.46 1H NMR (400 MHz, DMSO) d 7.96 (d, J = 8.0 Hz, 2H), 7.79-7.68 (m, 3H), 7.46 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.16-7.03 (m, 2H), 4.47-4.32 (m, 1H), 4.10 (s , 3H), 3.62-3.20 (m, 3H), 3.35 (q, J = 7.4Hz, 2H), 2.10-1.82 (m, 4H), 1.12 (t , J = 7.3Hz, 3H),

 860

 430.70 1.77

 861

 413.27 2.23

 862

 471.19 1.69

 863

 474.50 1.81

 864

 442.50 1.53 1H NMR (400 MHz, CDCl3) d 8.17-8.03 (m, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.41 (t, J = 9.3 Hz, 2H), 7.25 - 7.18 (m, 1H), 7.18 - 7.08 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H ), 6.09 (d, 4.0 Hz, 1H), 4.95 (d, J = 7.3 Hz, 2H), 4.82 (d, 7.3 Hz, 2H), 4.67 ( bs, 1H), 3.81-3.21 (m, 4H), 2.34-1.50 (m, 4H),

 865

 418.00 2.02 1H NMR (400 MHz, CDCl3) d 8.20-8.08 (m, 1H), 7.45 (s, 1H), 7.32-7.21 (m, 4H), 7.16 (dd, J = 7.0, 5.5 Hz, 2H), 7.04 (d, J = 4.0 Hz, 1H), 6.13 (d, J = 4.0 Hz, 1H ), 4.67 (s, 1H), 3.98-3.04 (m, 3H), 2.42 (s, 3H), 2.33-1.71 (m, 5H),

 866

 434.20 1.93

 867

 414.50 1.47 1H NMR (400 MHz, DMSO) d 8.10 (s, 1H), 7.76-7.69 (m, 2H), 7.55-7.42 (m, 2H), 7.28 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7, 07 (t, J = 7.6 Hz, 1H), 4.63-4.31 (m, 1H), 4.09 (s, 3H), 4.08 (s, 3H), 3.64-3 , 19 (m, 3H), 2.18-1.67 (m, 4H),

 868

 390.30 2.35

 869

 490.00 1.82

 870

 413.30 2.19 1H NMR (400 MHz, CDCl3) d 7.46-7.27 (m, 7H), 7.12 (d, J = 2.1 Hz, 2H), 7.04 (dd, J = 8.5, 2.2 Hz, 1H), 6.36 (t, J = 3.2 Hz, 1H), 6.07 (d, J = 3.4 Hz, 1H), 5.32 ( s, 1H), 4.65 (br, s, 1H), 3.64 (br, s, 2H), 3.35 (br, s, 1H), 2.20 (br, s, 1H), 2 , 05 (br, s, 2H), 1.86 (br, s, 1H), 1.59 (s, 6H)

TESTS FOR THE DETECTION AND MEASUREMENT OF COMPOSITE NAV INHIBITION PROPERTIES

E-VIPR optical potential membrane test method with electrical stimulation

 5

[0641] Sodium channels are voltage dependent proteins that can be activated by inducing membrane voltage changes by applying electric fields. The electrical stimulation instrument and the methods of use are described in Ion Channel Assay Methods PCT / US01 / 21652, and are called E-VIPR. The instrument comprises a microtiter plate controller, an optical system to excite the coumarin dye while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current or voltage control amplifier, and a device to insert electrodes into well. Under the integrated control of the computer, this instrument passes protocols of electrical stimuli programmed by the user to the cells within the wells of the microtiter plate.

[0642] 24 hours before the E-VIPR assay, HEK cells expressing the human NaV subtype, such as NAV 1.7, are seeded in 384 well coated poly-lysine plates at 15,000-20,000 cells per well. Other subtypes are carried out in an analogous manner on a cell line that expresses the VL of interest. HEK cells are cultured in media (exact composition is specific for each cell type and the NAV subtype) supplemented with 10% FBS (fetal bovine serum, qualified; GibcoBRL # 16140-071) and 1% Pen-Strep (penicillin- streptomycin; GibcoBRL # 15140-122). The cells are grown in ventilated plug flasks, in 90% humidity and 10% CO2, at 100% confluence. They are usually divided by trypsinization 1:10 or 1:20, 20 depending on the programming needs, and grown for 2-3 days before the next split.

Reagents and Solutions:

[0643] 25

100 mg / ml Pluronic F-127 (Sigma # P2443), in dry DMSO

Composite Plates: 384 well bottom round plate, for example Corning 384 round bottom polypropylene wells # 3656 30

Cell Plates: 384 well treated tissue culture plate, for example Greiner # 781091-1B

10 mM DiSBAC6 (3) (Aurora # 00-100-010) in dry DMSO

 35

10 mM CC2-DMPE (Aurora # 00-100-008) in dry DMSO

200 mM ABSC1 on H20

[Bathroom buffer1. 10 mM glucose (1.8 g / L), magnesium chloride (anhydrous), 1 mM (0.095 g / L), calcium chloride, 2 40 mM (0.222 g / L), 10 mM HEPES (2.38 g / L), potassium chloride, 4.5 mM (0.335 g / L), sodium chloride 160mm (9.35g / L).

Hexil staining solution: Bath buffer1 + 0.5% β-cyclodextrin (do this before use, Sigma # C4767), 8 µM CC2-DMPE + 2.5 µM DiSBAC6 (3). To make the volume 10% solution of Pluronic F127 Stock 45 equal to the volumes of CC2-DMPE + DiSBAC6 (3) is added. The order of preparation is first to mix Pluronic and CC2-

DMPE, then add DiSBAC6 (3), while a vortex is performed, then add Bath1 + β-cyclodextrin.

Test Protocol:

 5

[0644]

1) Pre-point Compounds (in pure DMSO) on composite plates. Vehicle control compounds (pure DMSO), positive control (20 mM mother of DMSO tetracaine, 125 µM final in the assay) and assays are added to each well at 160x of desired final concentration in pure DMSO. Final composite plate volume will be 80 µl 10 (intermediate dilution 80 times from 1 µl point of DMSO; 160 times final dilution after transfer to cell plate). The final concentration of DMSO in all test wells is 0.625%.

2) Prepare Hexil Staining Solution.

 fifteen

3) Prepare cell plates. On the day of the test, the medium is aspirated and the cells are washed three times with 100 µl of Bath solution1, maintaining 25 µl of residual volume in each well.

4) 25 µl are distributed per well of hexyl dye solution in cell plates. Incubate for 20-35 minutes at room temperature or environmental conditions. twenty

5) 80 µl are distributed per well in 1 Composite Bath plates. Yellow-17 acid (1 mM) is added and potassium chloride can be altered from 4.5 to 20 mm, depending on the NAV test subtype and sensitivity.

6) Wash cell plates three times with 100 µl per well of Bath1, leaving 25 µl of residual volume. Then, transfer 25 ul per well of plates composed of cell plates. Incubate for 20-35 minutes at room temperature / environmental condition.

7) Read Plate in E-IPR. Use the controlled current amplifier to deliver stimulation wave pulses for typically 9 seconds and a scanning speed of 400 Hz. A pre-stimulus recording is performed for 0.5 seconds to obtain the baseline of unstimulated intensities. . The stimulation waveform is applied for 9 seconds, followed by 0.5 seconds of post-stimulation recording to examine relaxation at rest. The stimulation waveform of the electrical stimulation is specific for each cell type and the magnitude, duration and frequency of the applied current may vary to provide an optimal test signal. 35

Analysis of data

[0645] Data are analyzed and reported as normalized ratios of background emission intensities measured in the 460 nm and 580 nm channels. Background intensities are subtracted from each test channel. Background intensities 40 are obtained by measuring the emission intensities during the same time periods of test wells treated identically in which there are no cells. The answer as a function of time is reported below, as the relationships obtained using the following formula:

(intensity 460 nm - background 460 nm) 45

R (t) = --------------------------------------------

(intensity 580 nm - background 580 nm)

 fifty

[0646] The data is further reduced by calculating the initial (Ri) and final (Rf) ratios. These are the average relationship values during part or all of the period prior to stimulation, and during sample points during the stimulation period. The response to the stimulus R = Rf / Ri is then calculated and expressed as a function of time. 55

[0647] control responses are obtained by performing tests in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). The responses to the negative (N) and positive (P) controls are calculated as above. The antagonistic activity of compound A is defined as:

 60

where R is the proportion response of the test compound

ELECTROPHYSIOLOGICAL TESTS FOR NAV ACTIVITY AND INHIBITION OF COMPOUNDS OF

TEST

[0648] Zonal impingement electrophysiology was used to evaluate the efficacy and selectivity of sodium channel blockers in neurons of the root dorsal ganglion. Rat neurons were isolated from dorsal root ganglia and maintained in culture for 2 to 10 days in the presence of NGF (50 ng / ml) (culture media consisted of NeurobasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8-12 µm in diameter) have been visually identified and probed with thin-tip glass electrodes connected to an amplifier (Axon Instruments). The "voltage setting" mode has been used to evaluate the IC50 of the compound holding cells at - 60 mV. In addition, the "current clamp" mode has been used to test the efficacy of the compounds in blocking the potential generation action in response to current injections. The results of these experiments have contributed to the definition of the efficacy profile of the compounds.

Essays of works of Ion.

 fifteen

[0649] Sodium currents were recorded using the automated zone clamp system, Ion Works (Molecular Devices Corporation, Inc.). Cells expressing the navigation subtypes are collected from tissue culture and suspended at 0.5-4 million cells per ml Bath1. The Ion Works instrument measures changes in sodium currents in response to the voltage setting applied in a manner similar to the traditional zonal clamp test, except in a 384-well format. Users of the ion works, the 20 dose-response ratios were determined in the depolarization voltage setting mode of the cell from the specific experiment clamping potential at a test potential of approximately 0 mV before and after the addition of the test compound. The influence of the compound on the currents is measured in the test potential.

 25

1-benzazepine-2-one binding assay

[0650] The sodium channel inhibition properties of the compounds of the invention can also be determined by test methods described in Williams, BS et al., "Characterization of a New Class of Potent Inhibitors of the Voltage-Gated Sodium Channel NaV 1.7, "Biochemistry, 2007, 46, 14693-14703. 30

[0651] The exemplified compounds of Table 1 herein are active against one or more sodium channels as measured using the assays described hereinbefore as presented in Table 3.

Table 3. 35

image333

 5

 10

 fifteen

 twenty

 25

 30

 35

 40

 Four. Five

 fifty

[0652] Many modifications and variations of the embodiments described in this document can be made without

depart from the scope, as is evident to those skilled in the art. The specific embodiments described herein are offered by way of example only.

 55

 60

 65

Claims (12)

Claims 1. A compound of formula I: image 1  5  10  fifteen  twenty  25 or a pharmaceutically acceptable salt thereof, in which, independently for each case and optionally substituted with halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl as valence allows: A is image2  35  40 or is selected from a heteroaryl or heterocyclic group of the formula: image3  Four. Five  fifty  55  60  65 image4  5  10  fifteen  twenty  25  30  35  40  Four. Five R1 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7) 2 , SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl O (CH2) 1-6-R8 in which up to two CH2 units can be replaced by O, CO, S, SO, SO2, NR7 ; R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, aryl, COOH, CH2CF3, CHF2, CF3, CN, OH, 50 OR7, CON (R7) 2, SO2R7, SR7, SOR7, SO2N (R7) 2, O (CH2) 1-6-R8 in which up to two CH2 units can be replaced by O, CO, S, SO, SO2, CF2, or NR7; R3 is halo, C1-C6 alkyl or C3-C8 cycloalkyl, where up to two CH2 units can be replaced by O, CO, S, SO, SO2, or NR8; R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, 55 SOR7, CO2R7, NR7COR7, NR7CO2R7, CON ( R7) 2, SO2N (R7) 2, CHF2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl, or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S, SO, SO2, or NR7; R5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7 , NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, 60 heterocycloalkyl, aryl, heteroaryl, or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three units CH2 can be replaced with O, CO, S, SO, SO2, or NR7; R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SR7, SOR7, SO2R7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl, or a linear, branched or cyclic chain (CH2) 1-8-R8 in which up to three CH2 units can be replaced by O, CO, S, SO, SO2, or NR7; or two occurrences of R4 and R5, or R5 and R6, taken together with the carbons to which they are attached form a ring comprising up to 2 heteroatoms, optionally substituted with halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl; R7 is H, C1-C6 alkyl, CHF2, CF3, or C3-C8 cycloalkyl, or 2 R7 taken together with the atoms to which they are attached form a ring; R8 is H, CF3, CO2R7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N (R7) 2, NR7COR7, CON (R7) 2, CN, or SO2R7; X is N, S, or CR2 in which at least X is N; W is N or CH, in which up to 2 W are N; 10 one line ------ marks a double bond optionally depending on the identity of X; m is an integer from 0 to 4 inclusive; n is an integer from 0 to 3 inclusive; Y or is an integer from 0 to 4 inclusive.  fifteen 2. The compound of claim 1, wherein all the W's are CH. 3. The compound of claim 1 or 2, wherein image5  twenty  25 is selected from: image6  30  35  40  Four. Five  fifty  55  60  65 4. The compound of claim 1, wherein A is heteroaryl or heterocyclic, is selected from: 5. The compound of claim 1, wherein the compound has the formula IA: where: image7  5  10  fifteen  twenty  25 R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units can be replaced with or, CO, S, SO, SO2, or NR7; R5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR7, N (R7) 2, 30 NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic (CH2) 1-8-R8 chain in which up to three units of CH2 can be substituted with O, CO, S, SO, SO2, or NR7; R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SOR7, SO2R7, SR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units can be replaced with or , CO, S, SO, SO2, or NR7; or two occurrences of R4 and R5, or R5 and R6, taken together with the carbons to which they are attached form a ring comprising up to 2 heteroatoms, optionally substituted with halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. 40 6. The compound of claim 5, wherein image8  Four. Five  fifty is selected from:  55  60  65 image9  5  10  fifteen 7. The compound of claim 1, wherein the compound has the formula IB: image10  25  30  35  40 where:  Four. Five R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units can be replaced with O, CO, S, SO, SO2, or NR7; R5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR7, N (R7) 2, 50 NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic (CH2) 1-8-R8 chain in which up to three units of CH2 can be substituted with O, CO, S, SO, SO2, or NR7; R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR7, N (R7) 2, NR7SO2R7, SOR7, SO2R7, SR7, CO2R7, NR7COR7, NR7CO2R7, CON (R7 ) 2, SO2N (R7) 2, CF3, OCF3, OCHF2, heterocycloalkyl, aryl, heteroaryl or a linear, branched or cyclic (CH2) chain 1-8-R8 in which up to three CH2 units can be replaced with O , CO, S, SO, SO2, or NR7; or two occurrences of R4 and R5, or R5 and R6, taken together with the carbons to which they are attached form a ring comprising up to 2 heteroatoms, optionally substituted with halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. 60 8. The compound of claim 7, wherein  65 is selected from: 9. A compound selected from the following: image11  5  10  fifteen  twenty  25  30  35 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 40, and a pharmaceutically acceptable carrier. 11. A compound or composition of any one of claims 1 to 10, for use in a method of treating or decreasing the severity in a subject of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headaches, Trigeminal neuralgia, herpetic neuralgia, general neuralgia, 45 epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, bowel syndrome irritable, incontinence, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-surgical pain, 50 cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotro lateral sclerosis physics, stress or exercise induced by angina pectoris, palpitations, hypertension, migraine, or abnormal gastrointestinal motility. 12. The compound or composition for use according to claim 11, wherein said method is used to treat or reduce the severity of femoral cancer pain; chronic non-malignant bone pain; Rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic; IBS pain; chronic and acute headache; migraine; tension headache, including cluster headaches; chronic and acute neuropathic pain, post-60 herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; proximal and distal ectopic discharges; radiculopathy; Chemotherapy-induced neuropathic pain; induced by radiotherapy of neuropathic pain; post-mastectomy pain; central pain; pain from spinal cord injury; post-stroke pain; thalamic pain; complex regional pain syndrome; 65 phantom pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; Neck Pain; tendonitis; pain / exercise injuries; pain acute visceral, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, heart pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; caesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; the pain of acute shingles; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain, including sinus pain, dental pain; multiple sclerosis pain (MS); pain in depression; 5 leprosy pain; Behcet disease pain; painful adiposis; phlebitic pain; Guillain-Barré pain; pain in the legs and feet in motion; Haglund's syndrome; erythromelalgia pain; Fabry disease pain; bladder and urogenital disease, including urinary incontinence; bladder hyperactivity; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; generalized pain, extreme paroxysmal pain, pruritus, tinnitus, or pain induced by angina.  fifteen  twenty  25  30  35  40  Four. Five  fifty  55  60  65