WO2019126842A1

WO2019126842A1 - Therapeutic compounds and uses thereof

Info

Publication number: WO2019126842A1
Application number: PCT/AU2018/051409
Authority: WO
Inventors: Courtney HOLLIS; Nathan Kuchel; Rajinder Singh; Andrew Harvey; Thomas Avery; Florence CHERY; Jean-Marie Contreras; Julie GAY; Laetitia JUNG; Celine Michaut-Simon; Christophe Morice; Alexandre STEFFEN
Original assignee: Bionomics Limited
Priority date: 2017-12-27
Filing date: 2018-12-24
Publication date: 2019-07-04

Abstract

The present invention relates to compounds useful in the modulation of ion channel activity in cells. The invention also relates to use of these compounds in the treatment of pain, and pharmaceutical compositions containing these compounds and methods for their preparation.

Description

THERAPEUTIC COMPOUNDS AND USES THEREOF

FIELD

BACKGROUND

Voltage gated sodium channels are essential for the initiation and propagation of action potentials in excitable tissues such as muscle and nerve. To date 10 subtypes have been identified: Navl. l, Navl.2, Navl.3 and Navl.6 which occur in the CNS (and PNS), Navl.4 which is specific to skeletal muscle, Navl.5 in cardiac muscle and Navl.7-l.9 which are largely found in sensory neurones. Increased Navl.x channel activity leads to nerve hyper excitability and underlies a number of pathological conditions including: epilepsy (Navl.l and Navl.2), cardiac arrhythmia (Navl.5), myotonia (Navl.4) and chronic pain (Navl.7-Navl.9).

Sodium channel blockers are commonly used as analgesics and are represented across three drug classes: local anaesthetics, class I antiarrhythmic and antiepileptic drugs. Although generally well tolerated, these drugs exhibit poor Navl.x subtype selectivity and have a limited dose range due to side effects expected of interfering with CNS, cardiac and skeletal muscle sodium channel function including convulsions, ataxia, motor impairment, arrhythmias and paralysis. Despite their poor Navl.x selectivity, these drugs are nevertheless tolerated due to their relatively low potency for Navl.x channels in the resting (closed) state and greater potency for the inactivated state which commonly presides in Navl.x channels mediating pain signals. In addition to this “state-dependence”, the potency of local anaesthetic like compounds tends to increase with the frequency of channel opening (use-dependence) which again presides more in pathogenic states such as pain, epilepsy and ventricular fibrillation. Thus Navl.x blockers can exhibit functional selectivity as well as subtype selectivity. Navl.7 has recently gained much attention as a pain target due to genetic evidence linking mutations of this channel to pain syndromes. Gain of function mutations of Navl.7 are linked to two painful conditions, inherited erythromelalgia and paroxysmal extreme pain syndrome. On the other hand, rare loss of function mutations of Navl.7 result in congenital insensitivity to pain and anosmia. Navl.7 is distributed primarily in the peripheral nervous system in dorsal root and sympathetic ganglia where it plays a role in setting the threshold for action potential firing thus controlling sensory neuron sensitivity to incoming stimuli. The largely peripheral distribution of this channel contributes to its attractiveness as a pain target due to the added safety of not requiring CNS penetrance and hence lowering the potential for CNS related side effects.

Development of a potent and subtype selective Navl.7 inhibitor is expected to provide substantial benefit over existing analgesics targeting sodium channels which lack selectivity and consequently are associated with a range of dose limiting CNS and cardiovascular side effects. In addition to subtype selectivity, functional selectivity may be exploited by designing compounds which inhibit the inactivated state of Navl.7 which predominates in chronic pain and thus spares the normal non-pathogenic function of the channel.

There is still a need for improved and specific therapies for the treatment of pain.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I) and pharmaceutical compositions thereof. In certain embodiments compounds of formula (I) have utility in the treatment of pain disorders.

In one aspect, the invention provides compounds of formula (I)

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, wherein:

R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci_₆ alkyl, Ci_ ₆ haloalkyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₅-C₁₂ aryl, optionally substituted C₂-C₁₂ heterocyclyl; or R and R , together with the N to which they are attached, form an optionally substituted C₂-C₁₂ heterocyclyl or optionally substituted C₂-C₁₂ heteroaryl;

R is selected from hydrogen, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_ C₆ haloalkyl, optionally substituted Ci_C₆ alkoxy, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₃-C₇ cycloalkenyl, optionally substituted acyl, optionally substituted C₂-C₁₂ heterocyclyl or optionally substituted aryl;

Y is a divalent linker group selected from C₁-C₅ alkylene, -(CH₂)_x-0-(CH₂)_y-, -(CH₂)_X-S- (0¾)_g-, wherein x and y are each integers independently selected from 0, 1, 2, and 3; each R⁴ is independently selected from hydroxy, acyl, acyloxy, amino, thio, halogen, cyano, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl; or optionally substituted aryloxy;

R⁵ is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; and n is an integer selected from 0, 1, and 2.

In a further aspect, the invention provides compounds of formula (la):

R¹, R², R³, R⁴, Y and n are each as defined for compounds of formula (I) and; each R⁶ is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl;

h

each R is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl; or

R⁶ and R⁷ together form a group selected from C₃-C₁₂ cycloalkenyl, C₅-C₁₂ aryl, C₂-C₁₂ heterocyclyl, C₂-C₁₂ heteroaryl, each of which may be optionally substituted with one or more of Ci_C₆ alkyl, Ci-C₆ haloalkyl, OCi_C₆ alkyl, OCi_C₆ haloalkyl, C₃-C₁₂ aryl, hydroxyl, alkoxy, acyl, acyloxy, acylamino, sulfamoyl, nitro, amino, thio, halogen, and cyano; p is an integer selected from 0, 1, 2 and 3; and m is an integer selected from 0, 1 and 2.

In another embodiment which is relevant to compounds of formula (I) and (la); Y is -CH₂CH₂-.

In another embodiment which is relevant to compounds of formula (I) and (la); Y is -CH₂CH₂CH₂-.

In another embodiment which is also relevant to compounds of formula (I) and (la) R¹ is H and R² is H.

In another embodiment which is relevant to compounds of formula (I) and (la), Y is -CH₂CH₂- and R¹ and R² are both H.

In another embodiment which is relevant to compounds of formula (I) and (la); Y is -CH₂CH₂CH₂- and R¹ and R² are both H.

In another aspect, the present invention relates to pharmaceutical compositions comprising of at least one compound provided herein and a pharmaceutical carrier, excipient or diluent. The pharmaceutical composition can comprise one or more compounds described herein. It will be understood that compounds provided herein, useful in the pharmaceutical compositions and treatment methods disclosed below, can be pharmaceutically acceptable as prepared and used. In still a further aspect, the invention provides or relates to methods for preventing, treating or ameliorating a condition from among those listed herein, particularly pain disorders (including pain associated with cancer, surgery, and bone fracture, acute pain, inflammatory pain and neuropathic pain). Pain disorders for which the compounds of the invention may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain (e.g., toothache), cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout), headache, migraine and cluster headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.

In another aspect the invention provides methods for treating or preventing pain disorders, said method including the step of administering to a patient a compound of either formula (I) or formula (la) or the embodiments mentioned hereinbefore or after.

In an embodiment the invention relates to the treatment of chronic pain.

In an embodiment the invention relates to the treatment of neuropathic pain.

In an embodiment the invention relates to the treatment of inflammatory pain.

In an embodiment the invention relates to the treatment of cancer pain.

In an embodiment the invention relates to the treatment of trigeminal neuralgia, lower back pain, post- operative pain, toothache, arthritic pain (rheumatoid, osteoarthritis, gout), pain from irritable bowel, inherited erythromelalgia, paroxysmal extreme pain syndrome, post herpetic neuralgia (shingles), musculoskeletal pain, multiple sclerosis, sciatica, diabetic neuropathy, and HIV related neuropathy.

In a further embodiment the invention provides compounds to treat or prevent conditions resulting from membrane hyperexcitablility mediated by aberrant Nav channel activity for state and use- dependent Nav blockers; including:

^■ CNS conditions (for instance, epilepsy, anxiety, depression, bipolar);

^■ Cardiac conditions (for instance, arrhythmias, atrial and ventricular fibrillation); and

^■ Muscular (for instance, restless leg, tetanus).

In addition to methods of treatment set forth above, the present invention extends to the use of any of the compounds of the invention in the preparation of medicaments that may be administered for such treatments, as well as to such compounds for the treatments disclosed and specified. In additional aspects, the present invention is directed to methods for synthesising the compounds described herein, with representative synthetic protocols and pathways described below.

Accordingly, in certain embodiments it is an aim of the present invention to provide new compounds that can modulate the activity of at least one voltage -gated sodium ion channel and thus prevent or treat any conditions that may be causally related to aberrations in such acts.

Accordingly, the invention provides compounds that can treat or alleviate maladies or symptoms of same, such as pain, that may be causally related to the activation of a sodium channel.

In a further aspect the invention provides a method for treating or preventing conditions that may be casually related to the activation of at least one sodium channel, said method including the step of administering to a patient a compound of either formula (I) or formula (la) or the embodiments mentioned hereinbefore. In certain embodiments the compounds of the present invention display subtype and/or functional selectivity in relation to Navl.7 inhibition.

DETAILED DESCRIPTION

The term "alkyl" as used alone or in combination herein refers to a straight or branched chain saturated hydrocarbon group. The term "Ci-12 alkyl" refers to such a group containing from one to twelve carbon atoms and "lower alkyl" refers to Ci_₆ alkyl groups containing from one to six carbon atoms, such as methyl ("Me"), ethyl ("Et"), n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl and the like.

The term "cycloalkyl" refers to non-aromatic, saturated non-aromatic carbocycles. The term "C4- 9 cycloalkyl", for instance, refers to such a group having from 4 to 9 carbon atoms. Examples include cyclobutyl, cyclopentyl and cyclohexyl.

The term "alkenyl" refers to a straight or branched hydrocarbon containing one or more double bonds, preferably one or two double bonds. The term "C2-12 alkenyl", for instance, refers to such a group containing from two to twelve carbon atoms. Examples of alkenyl include allyl, 1- methylvinyl, butenyl, iso-butenyl, l,3-butadienyl, 3-methyl-2-butenyl, l,3-butadienyl, 1,4- pentadienyl, l-pentenyl, l-hexenyl, 3-hexenyl, l,3-hexadienyl, 1 ,4-hexadienyl and 1,3,5- hexatrienyl.

The term "cycloalkenyl" refers to cyclic alkenyl groups having a single cyclic ring or multiple condensed rings, and at least one point of internal unsaturation, preferably incorporating 4 to 11 carbon atoms. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl, indenyl and the like.

The term "alkynyl" refers to a straight or branched hydrocarbon containing one or more triple bonds, preferably one or two triple bonds. The term "C2-12 alkynyl", for instance, refers to such a group containing from two to twelve carbon atoms. Examples include 2-propynyl and 2- or 3- butynyl. The term "alkoxy" as used alone or in combination refers to a straight or branched chain alkyl group covalently bound via an oxygen linkage (-0-) and the terms "Ci_₆ alkoxy" and "lower alkoxy" refer to such groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.

The term "aryl" refers to carbocyclic (non -heterocyclic) aromatic rings or ring systems. The aromatic rings may be mono- or bi-cyclic ring systems. The aromatic rings or ring systems are generally composed of 5 to 10 carbon atoms. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like.

Aryl groups include phenyl, naphthyl, indenyl, azulenyl, fluorenyl or anthracenyl.

The term "heteroaryl" refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Preferably the heteroatom is nitrogen. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl, or benzofuranyl).

The term "heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring.

Examples of 5-membered monocyclic heterocyclyl and heteroaryl groups include furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4- oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3- and l,3,4-triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3- and l,3,4-thiadiazolyls). Examples of 6-membered monocyclic heterocyclyl and heteroaryl groups include pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, l,4-dioxanyl, morpholinyl, 1,4- dithianyl, thiomorpholinyl, piperazinyl, l,3,5-trithianyl and triazinyl.

Examples of 8, 9 and lO-membered bicyclic heterocyclyl and heteroaryl groups include 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl, pteridinyl and the like.

The terms "halo" and "halogen" refers to fluoro, chloro, bromo and iodo groups.

The term "halo alkyl" group has one or more of the hydrogen atoms on an alkyl group replaced with halogens. Notable examples are -CF₃ or -CF2H.

The term "aryloxy" refers to an aryl group as earlier described linked to the parent structure via an oxygen linkage (-0-). A notable example is phenoxy. Similarly, the term "heteroaryloxy" refers to a heteroaryl group as earlier described linked to the parent structure via an oxygen group. A notable example is a 4, 6 or 7-benzo[b]furanyloxy group.

The term "acyl" refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are described herein.

The term "oxyacyl" refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

The term "acylamino" refers to the group -NR”C(0)R” where each R” is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. The term "alkylene" refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH₂-), ethylene (-CH2CH2-), and the propylene isomers (e.g., -CH2CH2CH2- and - CH(CH₃)CH₂-), and the like.

The term “sulfamoyl” refers to the group -S(0)2NR”R” where each R” is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

The term“sulfonyl” refers to the group -S(0)₂R” where R” is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

The term "optionally substituted" means that a group may include one or more substituents. One or more hydrogen atoms on the group may be replaced by substituent groups independently selected from halogens (for example halo alkyl such as -CF3 or -CF₂H), Ci_₆ alkyl, C_2-6 alkenyl, C2-6 alkynyl, -(CH2)_VC3_₇ cycloalkyl, -(CH2)_VC4_₇ cycloalkenyl, -(CH₂)_V aryl, -(CH₂)_V heterocyclyl, -(CH₂)_V heteroaryl, -C₆H₄S(0)_qCi_₆ alkyl, -C(Ph)₃, -CN, -OR, -0-(CH₂)_1-6-R, -O- (CH₂)_I-6-OR, -0C(0)R, -C(0)R, -C(0)0R, -0C(0)NR'R",

NR'R", -NO2, -NRC(0)R, -NRC(0)NR'R", -NRC(S)NR'R", -NRS(0)₂R, -NRC(0)0R, -C(NR) NR'R", -C(=NOR')R, -C(=NOH)NR'R", -C(0)NR'R", -C(=NCN)-

NR'R", -C(=NR)NR'R", -C(=NR')SR", -NR'C(=NCN)SR", -C0NRS0₂R, -C(S)NR'R", - S(0)_qR, -SO2NRR", -S0₂NRC(0)R, -0S(0)₂R, -PO(OR)₂ and -N0₂;

where v is 0-6, q is 0-2 and each R, R' and R" is independently selected from H, Ci_₆ alkyl, C2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_4-7 cycloalkenyl, aryl, heterocyclyl, heteroaryl, Ci_₆ alkylaryl, Ci_₆ alkylheteroaryl, and Ci_₆ alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, Ci_₆ alkylaryl, Ci_₆ alkylheteroaryl, or Ci_ ₆ alkylheterocyclyl, may be optionally substituted with one to six of same or different groups selected from halogen, hydroxy, lower alkyl, lower alkoxy, -C0₂H, CF3, CN, phenyl, NH₂ and - N0₂; or when R' and R" are attached to the same nitrogen atom, they may, together with the atom to which they are attached, form a 5 to 7 membered nitrogen containing heterocyclic ring.

In an embodiment the optional substituents may be selected from: halogen (in particular, Cl, Br or F), Ci-₆ alkyl, Ci_₆ alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, Ci_₆ haloalkyl (in particular -CF₃), Ci_₆ haloalkoxy (such as -OCF₃), -OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, silyl, - NH₂, -NHC_I-4 alkyl, -N(C_M alkyl)₂, -CN, -N0₂, mercapto, -P=0(0H)(NH₂), -

S(0)₂NH₂, -S(0)₂NHC_I-4 alkyl, -S(0)₂N(C_I-4 alkyl)₂, Ci_₆ alkylcarbonyl, Ci_₆ alkoxycarbonyl, C0₂H, -S(0)R"' (where R'" is lower alkyl or cycloalkyl) and -S(0)₂R"' (where R'" is lower alkyl, cycloalkyl or OH).

Unless otherwise defined and only in respect of the ring atoms of non-aromatic carbocyclic or heterocyclic compounds, the ring atoms of such compounds may also be optionally substituted with one or two =0 groups, instead of or in addition to the above described optional substituents.

When the optional substituent is or contains an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group, the group may itself be optionally substituted with one to six of the same or different substituents selected from halogen, Ci_₆ alkyl, Ci_₆ alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, Ci_₆ haloalkyl (in particular -CF₃), Ci_₆ haloalkoxy (such as -OCF₃), -OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, -NH₂, -NHC_1-4 alkyl, -N(C_I-4 alkyl)₂, -CN, -N0₂, mercapto, -P=0(0H)(NH₂), -S(0)₂NH₂, -S(0)₂NHCi_₄ alkyl, -S(0)₂N(Ci_₄ alkyl)₂, Ci_₆ alkylcarbonyl, Ci_₆ alkoxycarbonyl, C0₂H, -S(0)R"' (where R'" is lower alkyl or cycloalkyl) and -S(0)₂R"' (where R'" is lower alkyl, cycloalkyl or OH).

As described above, in a first aspect, the invention provides compounds of formula (I)

In an embodiment, Y is a divalent linker group selected from, C₁-C₅ alkylene, -(CH₂)_x-0-(CH₂)_y- and, -(CH₂)_x-S-(CH₂)_y-. In an embodiment, x and y are each integers independently selected from 0, 1, 2, and 3. In one embodiment, x is 0. In another embodiment, x is 1. In another embodiment, x is 2. In another embodiment, x is 3. In one embodiment, y is 0. In another embodiment, y is 1. In another embodiment, y is 2. In another embodiment, y is 3. In an embodiment, Y is a divalent linker selected from C₁-C₃ alkylene, for instance, -CH₂-, -CH₂CH₂- or -CH₂CH₂CH₂-. In another embodiment, Y is -(CH₂)-0-(CH₂)-. In a further embodiment, Y is -(CH₂)-0-(CH₂)₂-. In yet another embodiment, Y is -S-(CH₂)-.

In an embodiment, R and R are independently selected from hydrogen, optionally substituted Ci_₆ alkyl, Ci_₆ haloalkyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₅-C₁₂ aryl, optionally substituted C₂-C₁₂ heterocyclyl, or R and R together with the N to which they are attached, form an optionally substituted C₂-C₁₂ heterocyclyl or optionally substituted C₂-C₁₂ heteroaryl. In one embodiment R and R are H. In another embodiment R and R are methyl. In a further embodiment R 1 is H and R2 is methyl. In another embodiment R 1 is propan-2-yl and

R 2 is H. In a further embodiment R 1 and R2 , together with the N to which they are attached, form an azetidine. In yet another embodiment, R and R together with the N to which they are attached, form a piperidine.

In an embodiment, R is selected from hydrogen, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted Ci_C₆ alkoxy, optionally substituted acyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₃-C₇ cycloalkenyl, optionally substituted C₂-C₁₂ heterocyclyl or optionally substituted aryl; In one embodiment, R is H. In another embodiment R 3 is Ci_C₆ alkyl. In another embodiment, R 3 is C₃-C₇ cycloalkyl. In a further embodiment, R is substituted Ci_C₆ alkyl.

In an embodiment, each R⁴ (when present) is independently selected from the group consisting of hydroxy, acyl, acyloxy, amino, thio, halogen, cyano, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_ C₆ dialkyl amino, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C2-C12 heterocyclyl, optionally substituted aryl, or optionally substituted aryloxy. In an embodiment, R⁴ is Ci-C₆ alkyl. In another embodiment, R⁴ is halo.

In an embodiment, n is selected from 0, 1, 2 and 3. In an embodiment, n is 0 (that is, unsubstituted). In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3.

In an embodiment, R⁵ is an optionally substituted heteroaryl-CH2-.

In an embodiment, R⁵ is an optionally substituted heterocyclyl-CH2-.

In an embodiment, R⁵ is an optionally substituted aryl-CH2-.

In an embodiment, R⁵ is an optionally substituted heteroaryl group. In another embodiment, R⁵ is an optionally substituted heteroaryl group, wherein the heteroaryl group is 5-membered or 6- membered. In another embodiment, R⁵ is an optionally substituted 5-membered heteroaryl group, selected from furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole and thiazole. In another embodiment, R⁵ is an optionally substituted 6-membered heteroaryl group selected from pyridine, pyrazine, pyrimidine, pyridazine and triazine. In another embodiment, R⁵ is an optionally substituted heteroaryl group, wherein the heteroaryl group is one or more fused 6- membered rings. In another embodiment, R⁵ is an optionally substituted heteroaryl group selected from quinoline, isoquinoline, quinoxaline and quinazoline. In another embodiment, R⁵ is an optionally substituted heteroaryl group, wherein the heteroaryl group has more than one heteroatom. In another embodiment, R⁵ is a monosubstituted heteroaryl group. In another embodiment, R⁵ is an optionally substituted heteroaryl group, wherein there is more than one substituent on the heteroaryl group. In another embodiment, R⁵ is an unsubstituted heteroaryl group. In an embodiment, R⁵ is an optionally substituted aryl group. In another embodiment, R⁵ is an optionally substituted aryl group, wherein the aryl group is one or more fused 6-membered rings. In another embodiment, R⁵ is a monosubstituted aryl group. In another embodiment, R⁵ is an optionally substituted aryl group, wherein there is more than one substituent on the aryl group. In another embodiment, R⁵ is an unsubstituted phenyl group. In another embodiment, R⁵ is an optionally substituted phenyl group. In another embodiment, R⁵ is an optionally substituted phenyl group, wherein the substituents are selected from H, halogen, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy, amino, acylamino, nitro, nitrile, silyl, sulfamoyl, aryl and heteroaryl. In another embodiment, R⁵ is an optionally substituted phenyl group, wherein the substituent is a halogen. In another embodiment, R⁵ is an optionally substituted phenyl group, wherein the substituent is an optionally substituted -OCi_C₆ alkyl. In another embodiment, R⁵ is an optionally substituted phenyl group, wherein the substituent is an optionally substituted haloalkyl. In another embodiment, R⁵ is an optionally substituted phenyl group, wherein the substituent is in the para position. In another embodiment, R⁵ is an optionally substituted phenyl group, wherein the substituent is in the meta position. In another embodiment, R⁵ is an optionally substituted phenyl group, wherein the substituent is in the ortho position.

In another embodiment, wherein R⁵ of Formula (I) is an optionally substituted phenyl group, there is provided compounds of formula (la):

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, wherein: R¹, R², R³, R⁴, Y and n are each as defined for compounds of formula (I) and; each R⁶ is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C2-C12 heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl; each R is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl; or

R⁶ and R⁷ together form a group selected from C₃-C₁₂ cycloalkenyl, C₅-C₁₂ aryl, C₂-C₁₂ heterocyclyl, C2-C12 heteroaryl, each of which may be optionally substituted with one or more of Ci_C₆ alkyl, Ci-C₆ haloalkyl, OCi_C₆ alkyl, OCi_C₆ haloalkyl, C₃-C₁₂ aryl, hydroxyl, alkoxy, acyl, acyloxy, acylamino, sulfamoyl, nitro, amino, thio, halogen, and cyano; p is an integer selected from 0, 1, 2 and 3; and m is an integer selected from 0, 1 and 2.

In an embodiment, each R⁶ is independently selected from hydrogen, hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heteroaryl.

h

In an embodiment, each R is independently selected from hydrogen, hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heteroaryl.

In another embodiment, R⁶ and R⁷ together form a group selected from C₃-C₁₂ cycloalkenyl, C₅- C₁₂ aryl, C₂-C₁₂ heterocyclyl, C₂-C₁₂ heteroaryl, each of which may be optionally substituted with one or more of Ci_C₆ alkyl, Ci-C₆ haloalkyl, OCi_C₆ alkyl, OCi_C₆ haloalkyl, C₃-C₁₂ aryl, hydroxyl, alkoxy, acyl, acyloxy, acylamino, sulfamoyl, nitro, amino, thio, halogen, and cyano.

With respect to formula (I) compounds disclosed herein the following combinations of any one or more of (i) to (v) are contemplated:

(i) R¹ and R² are H; or

R 1 and R 2 are methyl; or

R 1 is H and R 2 is methyl; or

R 1 is propan-2-yl and R 2 is H; or

R 1 and R 2 , together with the N to which they are attached, form an azetidine; or

R and R , together with the N to which they are attached, form a piperidine;

(ii) R³ is H; or

R is methyl; or

R is ethyl; or

R is methoxyethyl; or R is 2-methoxyethyl; or

R³ is propyl; or

R³ is propan-2-yl; or

R³ is cyclopropyl;

(iii) R⁴ is H; or

R⁴ is fluoro; or

R⁴ is chloro;

(iv) R⁵ is phenyl; or

R⁵ is fluoro phenyl; or

R⁵ is 2-fluoro phenyl; or

R⁵ is 3-fluoro phenyl; or

R⁵ is difluoro phenyl; or

R⁵ is 2, 3 -difluoro phenyl; or

R⁵ is 2, 5 -difluoro phenyl; or

R⁵ is 2,6-difluoro phenyl; or

R⁵ is 3, 5 -difluoro phenyl; or

R⁵ is difluoromethyl phenyl; or

R⁵ is 2-difluoromethyl phenyl; or

R⁵ is trifluoromethyl phenyl; or

R⁵ is 2- trifluoromethyl phenyl; or

R⁵ is 3 -trifluoromethyl phenyl; or

R⁵ is fluoro trifluoromethyl phenyl; or

R⁵ is 4-fluoro-2-trifluoromethyl phenyl; or

R⁵ is chloro phenyl; or

R⁵ is 2-chloro phenyl; or

R⁵ is 3 -chloro phenyl; or

R⁵ is chloro fluoro phenyl; or

R⁵ is 5-chloro-2-fluorophenyl; or

R⁵ is 3-chloro-4-fluoro phenyl; or R⁵ is 4-chloro-5-fluoro phenyl; or

R⁵ is 2-chloro-6-fluoro-phenyl; or

R⁵ is methoxy phenyl; or

R⁵ is 2-methoxy phenyl; or

R⁵ is 3 -methoxy phenyl; or

R⁵ is trifluoromethoxy phenyl; or

R⁵ is 2-trifluoromethoxy phenyl; or

R⁵ is 3 -trifluoromethoxy phenyl; or

R⁵ is 4-trifluoromethoxy phenyl; or

R⁵ is difluoromethoxy phenyl; or

R⁵ is 4-difluoromethoxy phenyl; or

R⁵ is fluoro-(trifluoromethoxy) phenyl; or

R⁵ is 5-fluoro-2-(trifluoromethoxy) phenyl; or

R⁵ is hydroxy phenyl; or

R⁵ is 3-hydroxy phenyl; or

R⁵ is 2,6-difluoro phenyl; or

R⁵ is methyl phenyl; or

R⁵ is 2-methyl phenyl; or

R⁵ is dimethyl phenyl; or

R⁵ is 2,6-dimethyl phenyl; or

R⁵ is propan-2-yl phenyl; or

R⁵ is 2-(propan-2-yl) phenyl; or

R⁵ is 3-(propan-2-yl) phenyl; or

R⁵ is naphthyl; or

R⁵ is 1 -naphthyl; or

R⁵ is 2-naphthyl; or

R⁵ is tetrahydronaphthyl; or

R⁵ is 5,6,7,8-tetrahydronaphthyl; or

R⁵ is thiophene; or

R⁵ is 3 -thiophene; or

R⁵ is phenol; or R⁵ is 3 -phenol; or

R⁵ is pyrazole; or

R⁵ is N-methyl pyrazole; or

R⁵ is 1 -N-methyl -4-pyrazole; or

R⁵ is benzopyrazole; or

R⁵ is N-methyl benzopyrazole; or

R⁵ is 1 -N-methyl -7-benzopyrazole; or

R⁵ is benzodioxyl; or

R⁵ is difluorobenzodioxyl; or

R⁵ is 2,2-difluorobenzodioxyl; or

R⁵ is indazolyl; or

R⁵ is lH-indazolyl; or

R⁵ is methyl-indazolyl; or

R⁵ is 1 -methyl- lH-indazol-7-yl; or

R⁵ is sulfamoyl phenyl; or

R⁵ is 4-sulfamoyl phenyl; or

R⁵ is benzo-N-methylsulfamoyl; or

R⁵ is 3-benzo-N-methylsulfamoyl; or

R⁵ is methyl benzoate; or

R⁵ is methyl-4-benzoate; or

R⁵ is benzamide; or

R⁵ is benz-3-amide;

(v) Y is -(CH₂)_2-; or

Y is -(CH₂)₃-; or

Y is -(CH₂)₄-; or

Y is -(CH₂)-0-(CH₂)-, or

Y is -(CH₂)-0-(CH₂)₂-, or

Y is -S-(CH₂)-.

In another embodiment a compound of Formula (I) is represented by the formula (lb):

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, wherein

R 1 R , and R 3 are as defined for compounds of formula (I) and;

R⁴ is H;

R⁶ is selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂- C₁₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl; and

R is selected from hydrogen, hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl.

In an embodiment and with reference to formula (lb):

R¹ and R² are both H. In an embodiment and with reference to formula (lb):

R³ is H or CH₃.

In an embodiment and with reference to formula (lb):

R³ is H.

In an embodiment and with reference to formula (lb):

R⁶ is halogen, Ci-C₆ haloalkyl, -OCi-C₆-alkyl or Ci-C₆ alkyl.

In an embodiment and with reference to formula (lb):

R⁶ is halogen, Ci-C₆ haloalkyl, or -OCi-C₆-alkyl.

In an embodiment and with reference to formula (lb):

R⁷ is H.

In an embodiment and with reference to formula (lb):

R⁶ is halogen, Ci-C₆ haloalkyl, or -OCi-C₆-alkyl; and

R⁷ is H.

In an embodiment and with reference to formula (lb):

R¹ and R² are both H;

R³ is H or CH₃;

R⁶ is halogen, Ci-C₆ haloalkyl, -OCi-C₆-alkyl or Ci-C₆ alkyl; and

R⁷ is H.

Representative compounds of formula (I), formula (la) and formula (lb) are shown in the Examples section.

The salts of the compounds of the invention are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.

It will be appreciated that the compounds of the invention, and the salts thereof, can be presented in the form of pharmaceutically acceptable derivatives. The term "pharmaceutically acceptable derivative" includes pharmaceutically acceptable esters, prodrugs, solvates and hydrates of the compounds of formula (I), or salts thereof. Pharmaceutically acceptable derivatives may include any pharmaceutically acceptable hydrate or any other compound or prodrug which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula (I), or an active metabolite or residue thereof.

The pharmaceutically acceptable salts include acid addition salts, base addition salts, and the salts of quaternary amines and pyridiniums. The acid addition salts are formed from a compound of the invention and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic, ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic, or tartaric acids. The counter ion of quaternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartrate. The base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium. Also, basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. The salts may be made in a known manner, for example by treating the compound with an appropriate acid or base in the presence of a suitable solvent.

The compounds of the invention may be in crystalline form and/or as solvates (e.g. hydrates) and it is intended that both forms be within the scope of the present invention. The term "solvate" is a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art.

The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphate esters and those formed from amino acids, preferably valine. Any compound that is a prodrug of a compound of the invention is within the scope and spirit of the invention.

The term "pharmaceutically acceptable ester" includes biologically acceptable esters of a compound of the invention such as sulphonic, phosphonic and carboxylic acid derivatives.

Thus, in another aspect of the invention, there is provided a prodrug or pharmaceutically acceptable ester of a compound of the invention or of a salt thereof.

It will be appreciated that the compounds of the invention may have at least one asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form. The invention extends to each of these forms individually and to mixtures thereof, including racemates. The isomers may be separated conventionally by chromatographic methods or by using a resolving agent. Alternatively the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. Where the compound has at least one carbon-carbon double bond, it may occur in Z- and E- forms with all isomeric forms of the compounds being included in the present invention. Furthermore, it will be appreciated that alicyclic compounds can also display cis trans isomerism. For example, where Y is -CH₂CH_2-, the compounds of formula (I) comprise a pyrrolidine which is capable of existing in more than one stereoisomeric form. In an embodiment, the substituents about the pyrrolidine may be in a c/.v-form. In another embodiment, the substituents about the pyrrolidine may be in a trans- form. In still other embodiments, the compound of formula (I) may be a mixture of cis- and trans- isomers. As noted above, it will be appreciated that the asymmetric centres of an alicyclic compound, such as a pyrrolidine for example, may also (or as an alternative) be assigned as R- or 5- to denote the relative stereochemistry.

The invention also includes where possible a salt or pharmaceutically acceptable derivative such as a pharmaceutically acceptable ester, solvate and/or prodrug of the aforementioned embodiments of the invention.

In another aspect of the invention, there is provided a pharmaceutical composition that comprises a therapeutically effective amount of one or more of the aforementioned compounds or pharmaceutically acceptable salts thereof, including pharmaceutically acceptable derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent.

In another aspect, the present invention provides pharmaceutical compositions for use as a sodium ion channel modulators, more particularly as pain relief agents, the composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable derivative thereof, and optionally a pharmaceutically acceptable carrier or diluent.

The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without another carrier) is surrounded by carriers.

The pharmaceutical compositions or formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.

The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, eg. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.

For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.

When desired, formulations adapted to give sustained release of the active ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

The amount of the compound of the invention to be administered may be in the range from about 10 mg to 2000 mg per day, depending on the activity of the compound and the disease to be treated.

Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.

The pharmaceutical preparations of the compounds according to the present invention may be co-administered with one or more other active agents in combination therapy. For example the pharmaceutical preparation of the active compound may be co-administered (for example, separately, concurrently or sequentially), with one or more other agents used to treat cognitive impairment or mood disorders such as acetylcholine esterase inhibitors, antipsycho tics, and antidepressants.

GENERAL SYNTHETIC SCHEMES AND DESCRIPTION

For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), methoxy (MeO), ethoxy (EtO), trimethylsilyl (TMS), tert-butyloxycarbonyl (Boc), and acetyl (Ac).

For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), ethanol (EtOH), diethyl ether (Et₂0), ethyl acetate (EtOAc), triethylamine (TEA), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), trifluoroethanol (TFE), dimethylformamide (DMF), sodium sulphate (NaoSCfl), tetrahydrofuran (THF), me/a-chloroperoxybenzoic acid (mCPBA), hexamethyldisilazane sodium salt (NaHMDS), 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), dimethylsulfoxide (DMSO), magnesium sulphate (MgS0₄), sodium hydrogen carbonate (NaHC0₃), tert-butanol (r-BuOH), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride salt (EDC1.HC1), tetra-n-butylammonium fluoride (TBAF), tetra-n-butylammonium bromide (TBAB), N,N-diisopropylethylamine (DIPEA), tert-butyldimethylsilyl (TBDMS), 1 -hydroxybenzotriazole (HOBt), trans- dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)4), tris(dibenzylideneacetone) dipalladium(O) (Pd2(dba)₃), tri-t-butyl phosphonium tetrafluoroborate (r-Bu₃PH.BF₄₎, 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), triphenylphosphine (PPh₃), diisopropyl azodicarboxylate (DIAD), pyridinium chlorochromate (PCC), borane dimethylsulfide (BMS), titanium isopropoxide (TiOiPr₄), sodium triacetoxyborohydride (NaBH(OAc)₃), sodium cyanoborohydride (NaBH₃(CN)), sodium borohydride (NaBH₄), ammonium chloride (NH₄Cl), chloroform (CHCl₃), manganese dioxide (MnCE), potassium carbonate (K₂C0₃), 1 ,2-dichloroethane (DCE), sodium azide (NaN₃), sodium nitrite (NaN(¾) and di-tert-butyl dicarbonate (B0C2O).

Unless otherwise stated the following generalisations apply.

The compounds of formula (I) have been named according to the standards used in the program ACD/ChemSketch 2012 from Advanced Chemistry Development Inc., ACD/Labs 2012 Release (File Version 14.01, Build 65894, 18 Sep 2013).

NMR, HPLC, MS and Mp data provided in the examples described below are registered on:

NMR: Agilent DD2 (500 MHz), Aglient DD2 (600 MHz) or Varian DD2 (300 MHz) using residual signal of deuterated solvent as internal reference. LCMS: Agilent Technologies LC/MS (1260 Infinity, 6120 Quadrupole LC/MS), column Zorbax SB-C8, 4.6 x l50mm, 5m, with mobile phase 80% ACN, 15% H₂0, 5% buffer (3: 1 MeOH/H₂0, 315 mg HC0₂NH₄, 1 mL AcOH) and MS detection (ESI method).

Mp: SRS OptiMelt - Automated Melting Point System

Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60F254 aluminium-backed plates which were visualised using fluorescence quenching under UV light or using an acidic anisaldehyde or a basic potassium permanganate dip. Flash chromatography was performed using either a Teledyne Isco CombiFlash Rf purification system using standard RediSep® cartridges or classically using conventional chromatographic equipment and techniques. Microwave irradiation was achieved using a CEM Explorer 48 Microwave Reactor. All reactions carried out using microwave irradiation were stirred.

Where necessary, anhydrous solvents were prepared using a Glascontour purification system or purchased from Sigma- Aldrich.

Scheme A

Scheme A outlines the synthesis of four isomeric intermediates, 7, 9, 10 and 11, which are accessible utilising enantiomerically pure lactam 1 or its enantiomer. Bromophenols of type 2, can be protected via treatment with TBDMSC1 in the presence of imidazole in DCE. It is conceivable that other bases and solvents can also be used such as TEA and DCM to affect TBDMS protection of the phenol. The resultant phenyl bromides, 3, can be treated with nBuLi in THF to yield substituted phenyl lithium intermediates which when reacted with lactams of type 1 give ketones of type 4. Alternatively, ketones of type 4 can be accessed via treatment of phenyl bromides of type 3 with magnesium in THF to give phenyl magnesium bromide intermediates which are then reacted with lactams of type 1. Subsequent cyclisation via imine formation can be affected by treatment with TFA in DCM to give imines of type 5 and 6. Foss of the TBDMS protecting group is occasionally observed at this point or following the subsequent reduction, which eliminates the requirement for the final deprotection step. Imines of type 5 and 6 can be reduced via hydrogenation in the presence of Pt0₂ in MeOH to give pyrrolidines of type 7 and 8. The reduction can also be performed via treatment with NaB¾ in MeOH. This method is particularly useful when R⁴ substituents which are sensitive to hydrogenation conditions, such as Cl, are present. Other sources of hydride or transition metal catalysts could be used to affect the reduction of the imine. If the TBDMS protecting group is still in place after the previous two steps it can be cleaved via treatment of 8 with TBAF in DCM to give pyrrolidines of type 7 and 9. Other methods of cleaving TBDMS protected phenols could be used and are outlined in Greene’s Protective Groups in Organic Synthesis (Fourth Edition) by Wuts P G M and Greene T W, New Jersey, John Wiley & Sons, Inc., 2007.

Scheme B

Scheme B outlines the synthesis of compounds of Formula (I). Amines of type 12, where R⁵ is optionally substituted aryl, heteroaryl or heterocyclyl, can be converted to azides of type 14 via diazotization with NaN0₂ and HC1 in THF at low temperatures followed by treatment with NaN₃. Azides of type 14 can also be accessed via copper mediated azide displacement of bromides of type 13, where R⁵ is as defined above, in the presence of sodium ascorbate and N,N’-DMED in EtOH/H₂0. Other bases and ligands can also be used such as NaOH and L- proline. Neat azides can be reacted with p-toluene sulfonyl cyanide at l00°C in a pressure vessel to give sulfonyl tetrazoles of type 15. Alternatively, sulfonyl tetrazoles of type 15 can be generated from isothiocyanates. Reaction of isothiocyanates of type 16, where R⁵ is optionally substituted aryl, heteroaryl or heterocyclyl, with NaN₃ in EtOH yields thiotetrazoles of type 17. Reaction of thiotetrazoles of type 17 with 4-iodotoluene in the presence of CuCl, K₂C0₃, and ethylenediamine in DMF yields p-toluene thiotetrazoles of type 18. Subsequent oxidation of p- toluene thiotetrazoles of type 18 with mCPBA in DCM gives sulfonyl tetrazoles of type 15. Other oxidants could also be used such as H₂0₂, NaOCl, dimethyldioxirane, Oxone® or KMn0₄. Sulfonyl tetrazoles of type 15 can be coupled with phenols of type 7, 9, 10 or 11 in the presence of a base to generate ethers of type 24. K₂C0₃ in DMF is indicated in Scheme B, however, alternative bases such as NaH or potassium /-butoxide could be used, as well as other solvents such as THF, to affect the transformation. Ethers of type 24 can be converted to compounds of Formula (I) via treatment with NH₃ in MeOH to produce primary amides or with methylamine or dimethylamine in THF to produce secondary and tertiary amides respectively. Alternatively, ethers of type 24 can be converted to compounds of Formula (I) by reaction with dimethylaluminium amides, which are easily prepared via treatment of primary or secondary amines with AlMe₃, in DCM to form secondary and tertiary amides.

Compounds of Formula (I) can also be accessed via bromotetrazoles of type 19. Reaction of isothiocyanates of type 16, where R⁵ is optionally substituted aryl, heteroaryl or heterocyclyl, with NaN₃ in EtOH yields thiotetrazoles of type 17. Treatment of the thiotetrazoles of type 17 with ZnBr and AcOOH in AcOH gives bromotetrazoles of type 19. Subsequent coupling of bromotetrazoles of type 19 with phenols of type 7, 9, 10 or 11 in a similar manner as described above for sulfonyl tetrazoles of type 15 generates ethers of type 24, which in turn are converted to compounds of Formula (I). Compounds of Formula (I) can also be accessed via chlorotetrazoles of type 23. Reaction of amines of type 12, where R⁵ is optionally substituted aryl, heteroaryl or heterocyclyl, with formic acid in the presence of I₂ yields formamides of type 20. Alternatively, ethyl formate can be used in exchange for I₂ in the formation of formamides. Treatment of formamides of type 20 with S0₂Cl₂ in SOCl₂ generates isocyanide dichlorides of type 22. Alternatively, isocyanide dichlorides of type 22 can be accessed through formamide dehydration of formamides of type 20 via treatment with POCl₃ and TEA in DCM to give isocyanides of type 21 and subsequent chlorination with S0₂Cl₂ in DCM. Reaction of isocyanide dichlorides of type 22 with NaN₃ in acetone/water gives chlorotetrazoles of type 23. Alternatively, chlorotetrazoles of type 23 can be accessed via reaction of isocyanide dichlorides of type 22 with NaN₃ in a biphasic mixture of toluene and water in the presence of TBAB. Subsequent coupling of chlorotetrazoles of type 23 with phenols of type 7, 9, 10 or 11 in a similar manner as described above for sulfonyl tetrazoles of type 15 generates ethers of type 24, which in turn are converted to compounds of Formula (I).

Scheme C

Scheme C outlines an alternative sequence of chemical transformations to achieve compounds of Formula (I). Phenols of type 7, 9, 10 or 11 can be converted to amides of type 25 via treatment with NH₃ in MeOH to form primary amides or by reaction with dimethylaluminium amides, which are easily prepared via treatment of primary or secondary amines with AlMe₃, in DCM to form secondary and tertiary amides. Secondary and tertiary amides can also be produced via reaction of phenols of type 7, 9, 10 or 11 with methylamine or dimethylamine respectively in THF (Scheme B). Subsequently, amides of type 25 can be coupled with tetrazoles of type 15, 19, or 23 in the presence of a base to generate compounds of Formula (I). K₂C0₃ in DMF is indicated in Scheme C, however, alternative bases such as NaH or potassium /-butoxide could be used, as well as other solvents such as THF, to affect the transformation.

Phenols of type 7, 9, 10 or 11 can also be Boc protected, to prevent degradation, via treatment with BocoO in the presence of NaHC0₃ and 'BLIOH in THF to give phenols of type 26. Subsequently, phenols of type 26 can be converted to amides in a similar manner as described above for phenols of type 7, 9, 10 or 11. Amides of type 27 can also be coupled with tetrazoles of type 15, 19, or 23 in the presence of a base to generate compounds of type 28 in a similar manner to amides of type 25 as described above. Finally, deprotection of compounds of type 28 via treatment with 4N HC1 in dioxane in MeOH leads to the formation of compounds of Formula

(I).

Scheme D

Scheme D outlines substitution on the basic nitrogen via reductive alkylation and amide formation. Methyl substitution can be affected via treatment of compounds of Formula (I) with formaldehyde, NaBH₃CN, and AcOH in MeOH. Ethyl substitution can be affected via treatment of compounds of Formula (I) with NaBH₄ in AcOH. Alternatively, ethyl substituted compounds can be obtained via treatment of compounds of Formula (I) with iodoethane in the presence of K2CO3 in DMF. Isopropyl substitution can be affected via treatment of compounds of Formula (I) with acetone, NaBH(OAc)₃, and AcOH in DCE. Cyclopropyl substituted compounds can be obtained via treatment of compounds of Formula (I) with ( 1 -ethoxycyclopropoxy)trimethylsilane in the presence of NaoSO^ AcOH, and NaBH₃CN in MeOH. The reducing agents NaBH₃CN, NaB¾, and NaBH(OAc)₃ can potentially be used interchangeably across the four reductive alkylation reactions. Substitution on the basic nitrogen is also possible via amide bond formation. Treatment of compounds of Formula (I) with acid chlorides, such as acetyl chloride, in the presence of TEA in DCM leads to the formation of tertiary amides.

Scheme E

Scheme E shows that substitution on the basic nitrogen can also be undertaken prior to the conversion of the terminal methyl ether group to an amide. Reaction of ethers of type 24 with alkyl bromides, such as 2-bromoethyl methyl ether as depicted in Scheme E, in the presence of K₂C0₃ in DMF leads to the formation of ethers of type 78. Ethers of type 78 can then be converted to compounds of Formula (I) via treatment with NH₃ in MeOH to produce primary amides or with methylamine or dimethylamine in THF to produce secondary and tertiary amides respectively. Alternatively, ethers of type 78 can be converted to compounds of Formula (I) by reaction with dimethylaluminium amides, which are easily prepared via treatment of primary or secondary amines with AlMe₃, in DCM to form secondary and tertiary amides. Scheme F

Scheme F outlines the synthesis of four phenols 37, 38, 39 and 40, which can be substituted for phenols 7, 9, 10 or 11 in Schemes B and C, previously described, to yield seven membered ring analogues. Diacids of type 29 can be converted to azepines of type 30 via a three step synthesis as described in New J. Chem., 38(12), 5905-5917; 2014. Azepines of type 30 are Boc protected via treatment with BocoO in the presence of NaHC0₃ and 'BuOH in THF to give azepines of type 31. Bromophenols of type 2 can be protected via treatment with TBDMSC1 in the presence of imidazole in DCE. Other bases and solvents can also be used such as TEA and DCM. The resultant phenyl bromides, 3, can be treated with /iBuLi in THF to yield substituted phenyl lithium intermediates which when reacted with azepines of type 31 give ketones of type 32. Alternatively, ketones of type 32 can be accessed via treatment of phenyl bromides of type 3 with magnesium in THF to give phenyl magnesium bromide intermediates which are then reacted with azepines of type 31. Subsequent cyclisation via imine formation can be affected by treatment with TFA in DCM to give imines of type 33 and 34. Loss of the TBDMS protecting group is occasionally observed at this point or following the subsequent reduction, which eliminates the requirement for the final deprotection step. Imines of type 33 and 34 can be reduced via hydrogenation in the presence of Pt0₂ in MeOH to give azepines of type 35 and 36. The reduction can also be performed via treatment with NaBH₄ in MeOH. If the TBDMS protecting group is still in place after the previous two steps it can be cleaved via treatment of 36 with TBAF in DCM to give phenols of type 35, which encapsulates isomers 37, 38, 39 and 40. Separation of isomers 37-40 could be achieved through classical separation methods where the isomers are diastereomers. Where the isomers are enantiomers chromatographic methods, such as chiral HPLC or SFC, could be employed. Alternatively, for the separation of enantiomers, classical methods such as derivatisation with chiral auxiliaries or the formation of chiral salts could be used. Separation of racemic mixtures 30 or 31 utilising the methods described above could also be achieved.

Scheme G

Scheme G outlines the synthesis of four phenols 49, 51, 52 and 53, which can be substituted for phenols 7, 9, 10 or 11 in Schemes B and C previously described to yield six membered morpholine ring analogues. Amino acids of type 41 can undergo reductive amination with 4- methoxybenzaldehyde in the presence of NaOH in water, followed by treatment with NaB¾, to give the para methoxy benzyl protected derivatives of type 42. Compounds of type 42 undergo cyclisation when treated with 2-chloroacetyl chloride in the presence of NaOH in water. Subsequent treatment with SOCl₂ in MeOH gives methyl ester oxomorpholine derivatives of type 43. Deprotection of compounds of type 43 is affected via treatment with ceric ammonium nitrate in a mixture of CH₃CN and water to give oxomorpholines of type 44. Oxomorpholines of type 44 are Boc protected via treatment with Boc₂0 in the presence of NaHC0₃ and 'BuOH in THF to give oxomorpholines of type 45. Bromophenols of type 2 can be protected via treatment with TBDMSC1 in the presence of imidazole in DCE. Other bases and solvents can also be used such as TEA and DCM. The resultant phenyl bromides, 3, can be treated with /iBuLi in THF to yield substituted phenyl lithium intermediates which when reacted with oxomorpholines of type 45 give ketones of type 48. Alternatively, ketones of type 48 can be accessed via treatment of phenyl bromides of type 3 with magnesium in THF to give phenyl magnesium bromide intermediates which are then reacted with oxomorpholines of type 45. Subsequent cyclisation via imine formation can be affected by treatment with TFA in DCM to give imines of type 47 and 48. Loss of the TBDMS protecting group is occasionally observed at this point or following the subsequent reduction, which eliminates the requirement for the final deprotection step. Imines of type 47 and 48 can be reduced via hydrogenation in the presence of Pt0₂ in MeOH to give oxomorpholines of type 49 and 50. The reduction can also be performed via treatment with NaB¾ in MeOH. If the TBDMS protecting group is still in place after the previous two steps it can be cleaved via treatment of 50 with TBAF in DCM to give phenols of type 49 and 51. Phenols 52 and 53 can be accessed via the use of the alternative isomer of amino acid 41 in the first step. Scheme H

Scheme H outlines the synthesis of derivatives of compounds of Formula (I) which have an oxazepan ring. Boc protected serine esters 55 can be reacted with propargyl bromides 54 in the presence of NaH in DMF to yield alkynes of type 56. Chlorotetrazoles of type 23, previously described, can be coupled with bromophenols of type 57 to give ethers of type 58. K₂C0₃ in DMF is indicated in Scheme H, however, alternative bases such as NaH or potassium /-butoxide could be used, as well as other solvents such as THF, to affect the transformation. Alkynes of type 56 and ethers of type 58 can then undergo Sonogashira coupling to produce alkynes of type 59. Pd(PPli3)Cl2, Cul, and TEA in THF is indicated in Scheme H, however, alternative catalysts such as Pd(PPh₃₎₄ and Pd₂(dba)₃ could be used, as well as other bases, such as DIPEA, and solvents such as dioxane and DMF, to affect the transformation. Compounds of type 59 can then be Boc deprotected via treatment with a methanolic solution of HC1, in EtOAc, generated from acetyl chloride in MeOH, to produce compounds of type 60. Compounds of type 60 can then undergo cyclisation via treatment with silver triflate in a suitable solvent such as DCM, THF or DMF to give cyclized compounds of type 61. Reduction of compounds of type 61 via hydrogenation give oxazepans of type 62. 5% Pt/C and EtOAc are indicated in Scheme H, however, other catalysts, such as 5% Pd/C, and solvents, such as MeOH and EtOH, could be substituted. Treatment of oxazepans of type 62 with NH₃ in MeOH yields isomeric oxazepans 63 and 64. Oxazepans 65 and 66 can be accessed via the use of the alternative isomer of Boc protected serine ester 55 in the first step.

Scheme I

76 77

Scheme I outlines the synthesis of four phenols 73, 75, 76 and 77, which can be substituted for phenols 7, 9, 10 or 11 in Schemes B and C, previously described, to yield six membered ring analogues. Piperidine acids of type 67 can be converted to piperidine methyl esters of type 68 via treatment with SOCl₂ in MeOH. Piperidines of type 68 are Boc protected via treatment with BocoO in the presence of TEA and DMAP in DCM to give piperidines of type 69. Bromophenols of type 2 can be protected via treatment with TBDMSC1 in the presence of imidazole in DCE. Other bases and solvents can also be used such as TEA and DCM. The resultant phenyl bromides, 3, can be treated with uBuLi in THF to yield substituted phenyl lithium intermediates which when reacted with piperidines of type 69 give ketones of type 70. Alternatively, ketones of type 70 can be accessed via treatment of phenyl bromides of type 3 with magnesium in THF to give phenyl magnesium bromide intermediates which are then reacted with piperidines of type 69. Subsequent cyclisation via imine formation can be affected by treatment with TFA in DCM to give imines of type 71 and 72. Loss of the TBDMS protecting group is occasionally observed at this point or following the subsequent reduction, which eliminates the requirement for the final deprotection step. Imines of type 71 and 72 can be reduced via hydrogenation in the presence of Pt0₃ in MeOH to give piperidines of type 73 and 74. The reduction can also be performed via treatment with NaB¾ in MeOH. If the TBDMS protecting group is still in place after the previous two steps it can be cleaved via treatment of 74 with TBAF in DCM to give phenols of type 73 and 75. Phenols 76 and 77 can be accessed via the use of the alternative isomer of piperidine acid 67 in the first step.

Scheme J

Formula (I)

Scheme J outlines a sequence of chemical transformations to achieve compounds of Formula (I) with piperidine ring systems. Phenols of type 73, 75, 76 or 77 can be converted to amides of type 79 via treatment with NH₃ in MeOH to form primary amides or by reaction with dimethylaluminium amides, which are easily prepared via treatment of primary or secondary amines with AlMe₃, in DCM to form secondary and tertiary amides. Subsequently, amides of type 79 can be coupled with tetrazoles of type 15, 19, or 23 in the presence of a base to generate compounds of Formula (I). K₂C0₃ in DMF is indicated in Scheme J, however, alternative bases such as NaH or potassium /-butoxide could be used, as well as other solvents such as THF, to affect the transformation. Futhermore methyl substitution of the basic nitrogen can be affected via treatment of compounds of Formula (I) with formaldehyde, NaBH₃CN, and AcOH in MeOH. Another variation is to add, remove or modify the substituents of the products and intermediates outlined in Schemes A-J to form new derivatives. This could be achieved by using standard techniques for functional group inter-conversion, well known in the industry, such as those described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations by Larock R C, New York, VCH Publishers, Inc., 1989. Affecting these modifications may require the use of protecting groups in order to obtain the desired compound. Protecting groups can be installed and removed using standard techniques, well known in the industry, such as those described in Greene’s Protective Groups in Organic Synthesis (Fourth Edition) by Wuts P G M and Greene T W, New Jersey, John Wiley & Sons, Inc., 2007.

The following examples are not intended to limit the invention which is described herein.

EXAMPLES

General Synthesis

General Procedure A (TBDMS protection of phenols): A solution of 4-bromophenol 2 (1 equiv.) and imidazole (2.4 equiv.) in DCE (0.58 M with respect to 4-bromophenol) was stirred at ambient temperature for 15 minutes. A solution of TBDMSC1 (1.1 equiv.) in DCE (2.1 M with respect to TBDMSC1) was added drop-wise which caused a precipitate to form. The reaction mixture was stirred at 90°C for 2.5 hours. The solid was filtered off and the filtrate washed with saturated NH₄CI solution. The organic phase was dried (MgS0₄), filtered and concentrated in vacuo to give crude product which was purified by column chromatography using silica gel to give the desired product, (4-bromophenoxy)-n?r/-butyldimethylsilane 3.

General Procedure B ( Reaction of substituted phenyl lithium with lactams): To a solution of (4-bromophenoxy)-n?r/-butyldimethylsilane 3 (1.1 equiv.) in anhydrous THF (0.63 M with respect to silane) at -78°C under a nitrogen atmosphere was added 2.0 M /iBuLi in hexane (1.05 equiv.) drop-wise. Once drop-wise addition was complete the mixture was then stirred at this temperature for 45 minutes. After this time the mixture was added drop-wise to a solution of methyl A-(fer/-butoxycarbonyl)pyroglutamate 1 (1 equiv.) in anhydrous THF (0.43 M with respect to glutamate) at -78°C under a nitrogen atmosphere. The mixture was then stirred at this temperature for 45 minutes and then warmed to -40°C and stirred at this temperature for 1 hour. Once complete the reaction mixture was quenched with saturated NH4CI solution and allowed to warm to ambient temperature. The mixture was then extracted with EtOAc and the combined organics were dried (MgS0₄), filtered and concentrated in vacuo. The crude material was further purified by column chromatography using silica gel to yield the desired product, 4.

General Procedure C ( Reaction of substituted phenyl magnesium with lactams): Prior to use magnesium was cleaned with 1 N HC1 and washed with water, THF and Et₂0. Magnesium (1 equiv.) was added to a three-necked flask and heated under vacuum. After cooling to ambient temperature, the vacuum was replaced by argon. (4-Bromophenoxy)-/er/-butyldimethylsilane 3 (1 equiv.) and iodine (0.02 equiv.) were added in solution in anhydrous THF (0.54 M with respect to silane) and the mixture was stirred at 70°C for 1 hour. The mixture was cooled to - 78°C, and l-(tert-butyl) 2-methyl-6-oxopiperidine- 1 ,2-dicarboxylate 69 (0.9 equiv.) in anhydrous THF (0.48 M with respect to dicarboxylate) was added dropwise. The mixture was stirred at -40°C for 1 hour before being allowed to reach ambient temperature. Upon completion the reaction was quenched with saturated NH4CI solution. The mixture was then extracted with EtOAc and the combined organics were dried (MgS0₄), filtered and concentrated in vacuo. The crude material was further purified by column chromatography using silica gel to yield the desired product, 70.

General Procedure D (Imine formation): To a solution of compound 4 or compound 70 (1 equiv.) in anhydrous DCM (0.17 M with respect to compound 4 or compound 70) was added TFA (12 equiv.) under a nitrogen atmosphere and the mixture stirred for 5 hours. Once complete the mixture was concentrated in vacuo, the crude yellow oil diluted with EtOAc, and the organics washed with saturated NaHC0₃ solution. The organics were then dried (MgS0₄), filtered and concentrated in vacuo to give a crude mixture of silyl deprotected (5 or 71) and silyl protected (6 or 72) imine products, which was utilised without further purification.

General Procedure E (Hydrogenation): A solution of the mixture of imines 5 and 6 or imines 71 and 72 in MeOH (45 ml for every 1 g of imine mixture) was degassed with anhydrous nitrogen for 30 minutes. After this time Pt0₂ (10 mg for every 1 g of imine mixture) was added and the mixture stirred under an atmosphere of hydrogen at 1 atmosphere until complete. Once complete the mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated in vacuo to give a crude mixture of pyrrolidines 7 and 8 or piperidines 73 and 74, which was utilised without further purification.

General Procedure F (TBDMS group removal): To a solution of the mixture of pyrrolidines 7 and 8 or piperidines 73 and 74 in DCM (10 ml for every 1 g of pyrrolidine or piperidine mixture) was added a 1.0 M solution of TB AF in THF ( 1 ml for every 1 g of pyrrolidine or piperidine mixture) portion-wise and the mixture stirred at ambient temperature for 3 hours. The reaction was monitored by TLC or LCMS and if any TBDMS protected starting material remained further 1.0 M solution of TBAF in THF was added to complete the deprotection of the phenol. Once complete water was added and the organics separated, the aqueous was further extracted with DCM and the combined organics were dried (MgS0₄), filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel to give pyrrolidine isomers 7 and 9 pure and distinct or piperidine isomers 73 and 75 pure and distinct.

Note: Pyrrolidines 7, 9, 10 and 11 and piperidines 73, 75, 76 and 77 should be stored below -4°C to prevent isomerisation.

General Procedure G (Azide formation): To a solution of bromide 13 (1 equiv.) in a mixture of EtOH and water 7:3 (0.54 M with respect to bromide) was added NaN₃ (2 equiv.), (+)-sodium-L- ascorbate (0.1 equiv.), N, A’-d i met h y 1 et h y 1 en ed i am i ne (0.3 equiv.) and Cul (0.2 equiv.). The mixture was then degassed with argon, the pressure vessel sealed, and in the absence of light heated to l00°C for 5 hours. After cooling to ambient temperature, EtOAc was added and the organic layer washed with water. The combined organics were dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was used without further purification or alternatively was purified by column chromatography over silica gel to afford azide 14.

General Procedure H (Azide formation): To a solution of amine 12 (1 equiv.) in a mixture of 6 N HC1 and THF 2: 1 (0.33 M with respect to amine) at 0°C was added NaN0₂ (1 equiv.) as an ice cold solution in water (2.7 M with respect to NaN0₂) dropwise, maintaining the internal temperature between 0-5 °C by occasional addition of ice to the reaction mixture. After complete addition the reaction was stirred for an additional 10 min at 0°C before dropwise addition of an ice cold solution of NaN₃ (1.2 equiv.) in water (3.2 M with respect to NaN₃). The reaction was then allowed to achieve ambient temperature over 1 hour. Once complete the reaction mixture was extracted with EtOAc and the organic extracts combined, dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was flushed through a short plug of silica (eluent 100% hexane or Et₂0), dried in vacuo and used as such for the subsequent reaction.

General Procedure I (p -Toluene sulfony l tetrazole formation): In a pressure vessel azide 14 (1 equiv.) and p-toluenesulfonyl cyanide (1 equiv.) were combined and the vessel sealed. The two reactants were heated at l00°C for 3 days. After cooling to ambient temperature, the residue was dissolved in minimal DCM and purified by column chromatography using silica gel to afford the p-toluenesulfonyl tetrazole 15.

General Procedure J (Thiotetrazole formation): To a solution of isothiocyanate 16 (1 equiv.) in EtOH (0.09 M with respect to isothiocyanate) was added NaN₃ (5 equiv.). The mixture was heated at l00°C for 3 hours. After cooling to ambient temperature 12 N HC1 (5.4 equiv.) was slowly added. The reaction mixture was concentrated in vacuo and then 1 N NaOH (3.7 equiv.) was added. The mixture was washed with EtOAc and the combined organic layers extracted with 1N NaOH. The organic phase was discarded and the combined aqueous extracts were treated with 12N HC1 until acidic. The acidic aqueous phase was then extracted with EtOAc and the organic extracts combined, dried (MgS0₄), filtered and concentrated in vacuo to afford thiotetrazole 17.

General Procedure K (p-Toluene thiotetrazole formation): To a solution of thiotetrazole 17 (1 equiv.) in DMF (0.32M with respect to thiotetrazole) was added 4-iodotoluene (1.1 equiv.), CuCl (0.2 equiv.), ethylenediamine (0.2 equiv.) and K₂C0₃ (2 equiv.). The reaction mixture was heated at 85°C under MW conditions for 4 hours. Upon completion the reaction mixture was quenched with saturated NH₄Cl solution and extracted with EtOAc. The extracts were combined, dried (MgS0₄), filtered and concentrated in vacuo. The crude material was purified by column chromatography using silica gel to afford the p-toluene thiotetrazole 18.

General Procedure L (p-Toluenesulfonyl tetrazole formation ): To a solution of p-toluene thiotetrazole 18 in DCM (0.12 M with respect to thiotetrazole) was added 75% m-CPBA (3 equiv.). The reaction mixture was stirred at ambient temperature for 18 hours. Upon completion the mixture was diluted with DCM and washed with 1 N NaOH solution. The organic phases were combined, dried (MgS0₄), filtered and concentrated in vacuo. The crude material was purified by column chromatography using silica gel to afford the p-toluenesulfonyl tetrazole 15.

General Procedure M (Bromotetrazole formation): To a solution of thiotetrazole 17 (1 equiv.) in acetic acid (0.28 M with respect to thiotetrazole) was added zinc bromide (2 equiv.) and the resultant mixture heated at 40°C. A solution of 39% peracetic acid in acetic acid (6 equiv.) was added dropwise and the mixture was heated at 80°C for 5 hours. After cooling to ambient temperature the reaction mixture was poured into water and the resultant precipitate filtered and dried to afford bromotetrazole 19.

General Procedure N (Phenyl formamide formation): A 20 mL glass vial was charged with amine 12 (1 equiv.), formic acid (6 equiv.) and iodine (~5 mmol%). The vial was sealed and heated to 70°C on a heater/shaker overnight. Once complete the reaction mixture was diluted with EtOAc and the organics washed with saturated NaoSoOs solution, saturated NaHC0₃ solution, water and brine, dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography over silica gel to afford formamide 20.

General Procedure O ( Isocyanide dichloride formation): To an ice cold solution of formamide 20 (1 equiv.) in SOCl₂ (6 equiv.) under nitrogen was added SO2CI2 (1.4 equiv.) drop-wise. The cooling bath was removed and the reaction warmed at 50°C overnight. Once complete the reaction mixture was concentrated in vacuo. The crude material was taken up in water and the pH adjusted to approximately 8 with saturated NaHC0₃ solution. The aqueous was then extracted with EtOAc, the extracts combined, dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was flushed through a short plug of silica (eluent 10% EtOAc/n-hexane), dried in vacuo and used as such for the subsequent reaction.

General Procedure P (Isocyanide formation): To a solution of formamide 20 (1 equiv.) in dry DCM (0.27 M with respect to formamide) and freshly distilled TEA (5 equiv.) under nitrogen was added freshly distilled POCl₃ (1.2 equiv.) drop-wise. The reaction was stirred at ambient temperature for 3 hours. Once complete the reaction mixture was quenched with brine and extracted with EtOAc. The extracts were combined and washed with 2 N HC1, saturated NaHC0₃ solution and brine, dried (MgS0₄), filtered and concentrated in vacuo. The crude material was flushed through a short plug of silica (eluent 75% DCM/n-hexane), dried in vacuo and used as such for the subsequent reaction.

General Procedure Q ( Isocyanide dichloride formation): To a solution of isocyanide 21 (1 equiv.) in dry DCM (0.55 M with respect to isocyanide) at -60°C under nitrogen was added freshly distilled SO2CI2 (1 equiv.) drop- wise. The reaction was allowed to gradually achieve ambient temperature over 2.5 hours. Once complete the reaction mixture was quenched with saturated NaHC0₃ solution and extracted with EtOAc. The extracts were combined, dried over (MgSOz_t), filtered and concentrated in vacuo. The crude material was passed through a short plug of silica (eluent 100% n-hexane), dried in vacuo and used as such for the subsequent reaction.

General Procedure R (Chlorotetrazole formation): To a solution of isocyanide dichloride 22 (1 equiv.) in acetone (0.46 M with respect to isocyanide dichloride) was added NaN₃ (1 equiv.) as a solution in water (1.38 M with respect to NaN₃). The reaction mixture was stirred at ambient temperature for 90 minutes. Once complete the acetone was removed in vacuo and the crude residue diluted with water and EtOAc. The layers were separated and the aqueous further extracted with EtOAc. The extracts were combined, dried (MgS0₄), filtered and concentrated in vacuo. The crude material was purified by column chromatography using silica gel to afford the chlorotetrazole 23.

General Procedure S (Phenol-tetrazole ether formation): To a solution of pyrrolidine 7, 9, 10, or 11 or pyrrolidinamide 25 or piperidinamide 79 (1 equiv.) in anhydrous DMF (0.18 M with respect to pyrrolidine or pyrrolidinamide or piperidinamide) was added tetrazole 15, 19, or 23 (1 equiv.) and K₂C0₃ (1.4 equiv.). The mixture was stirred at 60°C until complete, after which time the mixture was cooled to ambient temperature and poured into a saturated solution of NH₄CI and extracted with EtOAc. The combined organic extracts were washed with a saturated solution of NH₄CI, dried (MgSCF), filtered and concentrated in vacuo. The crude residue was purified by column chromatography using silica gel to afford the expected phenol-tetrazole ether 24 or compound of Formula (I).

General Procedure T (Primary amide formation): In a pressure vessel phenol-tetrazole ether 24 or 78 (1 equiv.) was solubilized in a 7 N solution of NH₃ in MeOH (0.09M with respect to phenol-tetrazole ether) and the vessel sealed. The mixture was stirred at ambient temperature for 20 hours, after this time the volatiles were removed in vacuo and the residue was purified by column chromatography using silica gel to afford compounds of Formula (I).

General Procedure U ( Secondary and tertiary amide formation ): A 20 mF glass vial was charged with phenol-tetrazole ether 24 or 78 (1 equiv.) and either a 2 M solution of methylamine or dimethylamine in THF (0.04 M with respect to phenol-tetrazole ether). The vial was sealed and the reaction was stirred at ambient temperature overnight. Upon completion the reaction mixture was concentrated in vacuo and the crude residue purified by column chromatography using silica gel to afford compounds of Formula (I).

General Procedure V (Tertiary amide formation): To a solution of pyrrolidine (2.1 equiv.) in dry DCM (0.20 M with respect to pyrrolidine) at -30°C under nitrogen was added a 2 M solution of trimethylaluminium in toluene (2 equiv.) drop wise. The mixture was allowed to achieve ambient temperature over 30 minutes before addition of phenol-tetrazole ether 24 or 78 (1 equiv.). The reaction mixture was stirred at 40°C for 20 hours. Upon completion the reaction was quenched with a 1 M solution of Rochelle’s salt and extracted with DCM. The extracts were combined, dried (MgSCF), filtered and concentrated in vacuo. The crude material was purified by column chromatography using silica gel to afford compounds of Formula (I). General Procedure W (Primary amide formation): In a pressure vessel pyrrolidine 7, 9, 10, or 11 or piperidine 73, 75, 76, or 77 (1 equiv.) was solubilized in a 7 N solution of NH₃ in MeOH (0.21 M with respect to pyrrolidine or piperidine) and the vessel sealed. The mixture was stirred at ambient temperature for 20 hours, after this time the volatiles were removed in vacuo and the residue was purified by column chromatography using silica gel to afford pyrrolidinamides 25 or piperidinamides 79.

General Procedure X ( Secondary and tertiary amide formation): A 2 M solution of trimethylaluminium in toluene (2.3 equiv.) was added to a mixture of a 2 M solution of methylamine or dimethylamine in THF (1 equiv.) and DCM (0.21 M with respect to trimethylaluminium). The mixture was stirred at ambient temperature for 15 minutes and pyrrolidine 7, 9, 10, or 11 (1 equiv.) was added. The reaction mixture was stirred at ambient temperature for 20 hours. Upon completion water was added and the mixture was extracted with DCM. The aqueous layer was acidified until pH 5 with 1 N HC1 and was then extracted with DCM. The organic phases were combined, dried (MgS0₄), filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel to afford the expected phenol pyrrolidinamide.

General Procedure Y (Boc protection of pyrrolidines): To a solution of pyrrolidine 7, 9, 10, or 11 (1 equiv.) in THF (0.11 M with respect to pyrrolidine) was added BocoO (2 equiv.), 5% aqueous NaHC0₃ solution (0.11 M with respect to pyrrolidine) and r-BuOH (0.11 M with respect to pyrrolidine). The mixture was stirred at ambient temperature for 20 hours. Upon completion the reaction mixture was quenched with water and extracted with EtOAc. The extracts were combined, dried (MgS0₄), filtered and concentrated in vacuo. The crude material was purified by column chromatography using silica gel to afford the Boc protected pyrrolidine 26.

General Procedure Z (Boc deprotection of pyrrolidinamides): To a solution of Boc protected pyrrolidinamide 28 (1 equiv.) in MeOH (0.05 M with respect to pyrrolidinamide) was added 4 N HC1 in dioxane (10 equiv.). The reaction mixture was stirred at ambient temperature overnight. Upon completion the reaction mixture was concentrated in vacuo. The crude residue was purified by column chromatography using silica gel to afford compounds of Formula (I). General Procedure AA (Reductive alkylation with aldehydes): To a solution of tetrazole pyrrolidinamide (1 equiv.) or tetrazole piperidinamide (1 equiv.) in anhydrous MeOH (0.02 M in with respect to tetrazole pyrrolidinamide or tetrazole piperidinamide) was added acetic acid (2.4 equiv.) and 37% formaldehyde in water (2.4 equiv.). The mixture was stirred at ambient temperature for 10 minutes and NaBH₃(CN) (2.4 equiv.) was added. The resultant reaction mixture was stirred at ambient temperature for 20 hours. Upon completion the reaction mixture was diluted with EtOAc and washed with saturated NaHC0₃ solution. The organic phase was dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography using silica gel to afford compounds of Formula (I).

General Procedure AB (Reductive alkylation with acetic acid): To a solution of tetrazole pyrrolidinamide (1 equiv.) in acetic acid (0.30 M in with respect to tetrazole pyrrolidinamide) was added NaBH₄ (4.7 equiv.) and the mixture stirred at ambient temperature. Once gas evolution had ceased the reaction mixture was stirred at 60°C for 2 hours. Upon completion the reaction mixture was quenched with saturated NaHC0₃ solution and Na₂C0₃ was added to until the mixture was basic. The resultant mixture was extracted with DCM and combined organics were dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography using silica gel to afford compounds of Formula (I).

General Procedure AC (Amine substitution): A 4 mF glass vial was charged with tetrazole pyrrolidinamide (1 equiv.), K₂C0₃ (1.3 equiv.), iodoethane (1.1 equiv.) and DMF (0.03 M with respect to pyrrolidinamide). The vial was sealed and heated at 60°C overnight. Upon completion the reaction mixture was quenched with saturated NaHC0₃ solution and extracted with EtOAc. The organic phase was dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography using silica gel to afford compounds of Formula (I).

General Procedure AD (Reductive alkylation with ketones): To a solution of tetrazole pyrrolidinamide (1 equiv.) in DCE (0.29 M with respect to tetrazole pyrrolidinamide) were added acetic acid (2 equiv.) and ketone (1.5 equiv.). The mixture was stirred at ambient temperature for 10 minutes and NaBH(OAc)₃ (1.6 equiv.) was added. After stirring for 3 hours at ambient temperature, the mixture was poured into a saturated solution of NaHC0₃ and extracted with DCM. The combined organic extracts were dried (MgS0₄), filtered and concentrated in vacuo to afford compounds of Formula (I).

General Procedure AE ( Reductive alkylation with (1-ethoxycyclopropyl) trimethylsilane): To a solution of tetrazole pyrrolidinamide (1 equiv.) in MeOH (0.03 M with respect to pyrrolidinamide) was added Na₂S0₄ (3 equiv.), (l-ethoxycyclopropoxy)trimethylsilane (4 equiv.), AcOH (7 equiv.) and NaBH₃(CN) (3.2 equiv). The reaction was warmed at 60°C overnight. Upon completion the reaction was concentrated in vacuo and the crude residue partitioned between saturated NaHC0₃ solution and EtOAc. The layers were separated and the aqueous further extracted with EtOAc. The extracts were combined, dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography using silica gel to afford compounds of Formula (I).

General Procedure AF (Tertiary amide formation): To a solution of tetrazole pyrrolidinamide (1 equiv.) in anhydrous DCM (0.05 M with respect to pyrrolidinamide) under nitrogen was added TEA (1.1 equiv.) followed by acetyl chloride (1 equiv.). The reaction was stirred at ambient temperature for 1 hour. Upon completion the reaction was quenched with saturated NH₄Cl solution and extracted with EtOAc. The extracts were combined, dried (MgS0₄) filtered and concentrated in vacuo. The crude residue was purified by column chromatography using silica gel to afford compounds of Formula (I).

General Procedure AG (Amine substitution ): A 4 mL glass vial was charged with phenol- tetrazole ether 24 (1 equiv.), K₂C0₃ (1.3 equiv) and anhydrous DMF (0.1 M with respect to phenol-tetrazole ether). To this was added 2-bromoethyl methyl ether (1 equiv.). The vial was sealed and the reaction warmed at 60°C overnight. Additional 2-bromoethly methyl ether (1 equiv.) was added and heating continued for a further 24 hours if required to achieve completion. Upon completion the reaction was diluted with EtOAc and the organics washed with water and brine, dried (MgS0₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography using silica gel to afford ethers of type 78. Intermediates in Table 1 were generated as described under General Procedure A (Scheme A) from commercially available 4-bromophenols 2.

Table 1.

Intermediates in Table 2 were generated as described under General Procedure B (Scheme A) or General Procedure C (Scheme I) from (4-bromophenoxy)-n?r/-butyldi methyl si lanes 3.

Table 2.

Intermediates in Table 3 were generated as described under General Procedure F (Scheme A or Scheme I) from pyrrolidine mixture of 7 and 8 or their enantiomers or from piperidine mixtures of 73 and 74 and their enantiomers.

Table 3.

Intermediates in Table 4 were generated as described under General Procedure G or H (Scheme B) from amines 12 or bromides 13.

Table 4.

Intermediates in Table 5 were generated as described under General Procedure I or L (Scheme B) from azides 14 or thiotetrazoles 18.

Table 5.

Intermediates in Table 6 were generated as described under General Procedure J (Scheme B) from isothiocyanates 16.

Table 6.

Intermediates in Table 7 were generated as described under General Procedure K (Scheme B) from thiotetrazoles 17.

Table 7.

Intermediates in Table 8 were generated as described under General Procedure M (Scheme B) from thiotetrazoles 17.

Table 8.

Intermediates in Table 9 were generated as described under General Procedure N (Scheme B) from amines 12. Table 9.

Intermediates in Table 10 were generated as described under General Procedure P (Scheme B) from formamides 20.

Table 10.

Intermediates in Table 11 were generated as described under General Procedure O or Q (Scheme B) from formamides 20 or isocyanides 21.

Table 11.

Intermediates in Table 12 were generated as described in General Procedure R (Scheme B) from isocyanide dichlorides 22.

Table 12.

Intermediates in Table 13 were generated as described under General Procedure S (Scheme B) from pyrrolidines 7, 9, 10 or 11 and tetrazoles 15, 19 or 23.

Table 13.

Intermediates in Table 14 were generated as described under General Procedure AG (Scheme E) from pyrrolidine esters 24.

Table 14.

Intermediates in Table 15 were generated as described under General Procedure W or General Procedure X (Scheme C or Scheme J) from pyrrolidines 7, 9, 10 or 11 or from piperidines 73, 75,

76 or 77.

Table 15.

Examples in Table 16 were generated as described under General Procedure T or General Procedure U or General Procedure V (Scheme B) from pyrrolidine esters 24.

Table 16.

Examples in Table 17 were generated as described under General Procedure S (Scheme C and Scheme J) from pyrrolidinamides 25 and piperidinamides 79.

Table 17.

Examples in Table 18 were generated as described under General Procedure AA or General Procedure AB or General Procedure AC or General Procedure AD or General Procedure AE or Gneral Procedure AG (Scheme D and Scheme J) from compounds of Formula (I).

Table 18

Example i: Cell lines

hNavl.7, hNavl.2blb2, hNavl.4, hNavl.5, rNavl.6blb2 were stably expressed in human embryonic kidney cells and kept under constant antibiotic selection. For in vitro assays, cells were maintained in appropriate growth medium at 37 °C and 5% CO 2 in a humidified incubator. Example ii: Electrophysiology

Navl.x expressing cells plated in T-25 flasks for 2-3 days prior to use and grown to 70-85% confluence were briefly trypsinized to obtain a single cell suspension of ~2-3 x 10⁶ cells/ml. All electrophysiological recordings were performed at ambient temperature (21-23 °C) using automated patch clamp (Patchliner, Nanion Technologies GmbH) in the whole -cell configuration using the following solutions: Internal solution contained (in mM): CsCl (50), NaCl (10), CsF (60), EGTA (20), HEPES (10), pH 7.2 KOH, 285 mOsmol.Kg ¹. External (bath) solution contained (in mM): NaCl (140), KC1 (4), MgCE (1), CaCE (2) D-Glucose monohydrate (5), HEPES (10), pH 7.4 NaOH, 298 mOsmol.kg ¹.

The following voltage protocols were used to assess different Navl.x channel states:

Resting state:

Cells were held at -120 mV and activated by 6 x 20 ms depolarising voltage pulses to -10 mV at a frequency of 0.1 Hz. Recordings were made initially in bath solution and 2-3 minutes after compound addition at increasing concentrations and steady state values were calculated from the 6^th pulse (P6). % resting state inhibition was calculated by (l-(P6drug/P6control))*l00%.

Inactivated state:

For each Navl.x channel, a steady state inactivation curve was obtained in order to calculate the voltage resulting in 50% channel inactivation (Vo.smact)· A 2 pulse protocol was then employed in which cells held at a voltage corresponding to 20 mV more negative to V0.5 inact were depolarised to -10 mV for 20 ms before returning to the previous holding voltage. This test pulse constituted Pl and represents 100% available (non- inactivated) Navl.x channels. The same cell was then depolarised for 8 s to a voltage corresponding to 7 mV more positive than Vo_.5mact in order to cause channel inactivation. Following a brief (2 ms) hyperpolarising voltage step to -120 mV (to reset the activation gate), cells were again subjected to a depolarising test pulse (P2) to -10 mV for 20 ms before returning to the holding potential. Each sequence was repeated 6 x at 30 s intervals. Using this protocol, control P2 current amplitudes (representing the % channels available following 8 s inactivation) was ~ 50% of control Pl current amplitude. 6 repetitions of this recording sequence were made in the control bath solution and then again 2 minutes after compound addition and thereafter at increasing compound concentrations. % inhibition was calculated by (l-(P2drug at repetition 6/P2control at repetition 6))* 100. Data were either presented as % block by a single concentration of drug or an estimated elC^o determined from 2- 3 drug concentrations which was determined by fitting data with a sigmoidal dose response curve (variable slope) using GraphPad Prism software (Version 6.0).

Compound preparation

All compounds were dissolved in DMSO to 20 irM initially. Subsequent dilutions in DMSO were made to achieve 200 x final bath concentrations. DMSO compound stocks were finally diluted 1/200 in bath solution just prior to assay resulting in a final DMSO concentration of 0.5% which was not found to affect control current amplitude.

Biology Section

Example iii: Formalin paw test

Male mice were injected subcutaneously (s.c.) with 25 mΐ of 2.5% formalin diluted in saline into the plantar surface of the left footpad and flinching (pain behaviour) was quantified using an automated nociception analyser from the university of California, San Diego (Yaksh et al 2001). A characteristic biphasic response in flinching behaviour was observed with Phase 1 flinching quantitated from 0-5 minutes and phase 2 flinching quantitated from 10 - 30 minutes post formalin. In general, animals were administered a single dose of compound 30 minutes prior to formalin via the oral route and treatment animals were scored for phase 1 and phase 2 cumulative flinching against appropriate vehicle treated controls. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A compound of formula (I):

R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci_₆ alkyl, Ci_ 6 haloalkyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₅-C₁₂ aryl, optionally substituted C₂-C₁₂ heterocyclyl; or R and R , together with the N to which they are attached, form an optionally substituted C₂-C₁₂ heterocyclyl or optionally substituted C₂-C₁₂ heteroaryl;

Y is a divalent linker group selected from C₁-C₅ alkylene, -(CH₂)_x-0-(CH₂)_y-, -(CH₂)_X-S- (CH₂)_y-, wherein x and y are each integers independently selected from 0, 1, 2, and 3; each R⁴ is independently selected from hydroxy, acyl, acyloxy, amino, thio, halogen, cyano, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl; or optionally substituted aryloxy; R⁵ is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; and n is an integer selected from 0, 1, and 2.

2. A compound according to claim 1 , wherein R⁵ is an optionally substituted aryl group.

3. A compound of formula (I) according claim 2, wherein the compound is a compound of formula (la):

R¹, R², R³, R⁴, Y and n are each as defined for compounds of formula (I) and; each R⁶ is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl; h

each R is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C₂-Ci₂ heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl; or

R⁶ and R⁷ together form a group selected from C₃-C_{| 2} cycloalkenyl, C₃-C_{| 2} aryl, C₂-Ci₂ heterocyclyl, C₂-Ci₂ heteroaryl, each of which may be optionally substituted with one or more of Ci_C₆ alkyl, Ci-C₆ haloalkyl, OCi_C₆ alkyl, OCi_C₆ haloalkyl, C₃-C_{| 2} aryl, hydroxyl, alkoxy, acyl, acyloxy, acylamino, sulfamoyl, nitro, amino, thio, halogen, and cyano; p is an integer selected from 0, 1, 2 and 3; and m is an integer selected from 0, 1 and 2.

4. A compound of formula (I) according to claim 1 wherein R⁵ is an optionally substituted heteroaryl group or an optionally substituted heterocyclyl group.

5. A compound according to claim 4 wherein R⁵ is selected from furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, quinoline, isoquinoline, quinoxaline and quinazoline.

6. A compound according to any one of the preceding claims wherein Y is a divalent linker selected from CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -(CH₂)-0-(CH₂)-, -(CH₂)-0-(CH₂)₂-, and -S-(CH₂)-.

7. A compound according to any one of the preceding claims whrein R 1 and R 2 are independently selected from hydrogen and optionally substituted Ci_C₆ alkyl or R 1 and R 2 together with the N to which they are attached, form an optionally substituted C₂-C₁₂ heterocyclyl or optionally substituted C₂-C₁₂ heteroaryl.

8. A compound according to any one of the preceding claims wherein R is selected from hydrogen, optionally substituted Ci_C₆ alkyl, optionally substituted C₃-C₇ cycloalkyl and optionally substituted Ci_C₆ alkoxy.

9. A compound according to any one of the preceding claims wherein each R⁴ is independently selected from optionally substituted Ci_C₆ alkyl and halogen.

10. A method of treating or preventing pain disorders, said method including the step of administering to a patient a compound of formula (I)

R is selected from hydrogen, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_ C₆ haloalkyl, optionally substituted Ci_C₆ alkoxy, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₃-C₇ cycloalkenyl, optionally substituted acyl, optionally substituted C₂-C₁₂ heterocyclyl or optionally substituted aryl; Y is a divalent linker group selected from C₁-C₅ alkylene, -(CH₂)_x-0-(CH₂)_y-, -(CtU S- (CH₂)_y-, wherein x and y are each integers independently selected from 0, 1, 2, and 3; each R⁴ is independently selected from hydroxy, acyl, acyloxy, amino, thio, halogen, cyano, optionally substituted Ci_C₆ alkyl, optionally substituted Ci_C₆ haloalkyl, optionally substituted -OCi_C₆ alkyl, optionally substituted -OCi_C₆ haloalkyl, optionally substituted Ci_C₆ alkyl amino, optionally substituted Ci_C₆ dialkyl amino, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₁₂ heterocyclyl, optionally substituted aryl; or optionally substituted aryloxy;

11. The method according to claim 10 wherein the pain disorder is pain associated with

cancer, surgery, bone fracture, acute pain, inflammatory pain or neuropathic pain.

12. Use of a compound of formula (I)

R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci_₆ alkyl, Ci_ 6 haloalkyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₅-C₁₂ aryl, optionally substituted C₂-C₁₂ heterocyclyl; or R 1 and R 2 , together with the N to which they are attached, form an optionally substituted C₂-C₁₂ heterocyclyl or optionally substituted C₂-C₁₂ heteroaryl;

R⁵ is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; and n is an integer selected from 0, 1, and 2; in the manufacture of a medicament for the treatment or prevention of pain disorders.

13. Use according to claim 10 wherein the pain disorder is pain associated with cancer,

surgery, bone fracture, acute pain, inflammatory pain or neuropathic pain.

14. A compound of formula (I)

R⁵ is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; and

n is an integer selected from 0, 1, and 2;

for use in the treatment or prevention of pain disorders.

14. A compound according to claim 13 wherein the pain disorder is pain associated with cancer, surgery, bone fracture, acute pain, inflammatory pain or neuropathic pain.