The present invention relates to sulfonylureas and sulfonylthioureas comprising a 5-membered heteroaryl group substituted with a monovalent heteroaryl-containing group. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP3.

CROSS-REFERENCE TO RELATED APPLICATION

FIELD OF THE INVENTION

The present invention relates to sulfonylureas and sulfonylthioureas comprising a 5-membered heteroaryl group substituted with a monovalent heteroaryl-containing group, and to associated salts, solvates, prodrugs and pharmaceutical compositions. The present invention further relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.

BACKGROUND

The NOD-like receptor (NLR) family, pyrin domain—containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activity is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.

NLRP3 is an intracellular signalling molecule that senses many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerises to form a large aggregate known as an ASC speck. Polymerised ASC in turn interacts with the cysteine protease caspase-1 to form a complex termed the inflammasome. This results in the activation of caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1β and IL-18 (termed pro-IL-1β and pro-IL-18 respectively) to thereby activate these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC speck can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death.

Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2 resulting in its degradation and allowing the release of IL-1α. In human cells caspase-1 may also control the processing and secretion of IL-37. A number of other caspase-1 substrates such as components of the cytoskeleton and glycolysis pathway may contribute to caspase-1-dependent inflammation.

NLRP3-dependent ASC specks are released into the extracellular environment where they can activate caspase-1, induce processing of caspase-1 substrates and propagate inflammation.

Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1β signalling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergise with IL-23 to induce IL-17 production by memory CD4 Th17 cells and by γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also synergise to induce IFN-γ production from memory T cells and NK cells driving a Th1 response.

The inherited CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a critical component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of a number of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.

A role for NLRP3 in diseases of the central nervous system is emerging, and lung diseases have also been shown to be influenced by NLRP3. Furthermore, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using Nlrp3−/−mice, but there have also been insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes mellitus (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, resulting in cell death and inflammation.

Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits IL-1β production at micromolar concentrations in response to the activation of NLRP3 but not NLRC4 or NLRP1. Other previously characterised weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene and dimethyl sulfoxide (DMSO), although these agents have limited potency and are nonspecific.

Current treatments for NLRP3-related diseases include biologic agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologic agents have been used in clinical trials for other IL-1β-associated diseases.

Some diarylsulfonylurea-containing compounds have been identified as cytokine release inhibitory drugs (CRIDs) (Perregaux et al.; J. Pharmacol. Exp. Ther. 299, 187-197, 2001). CRIDs are a class of diarylsulfonylurea-containing compounds that inhibit the post-translational processing of IL-1β. Post-translational processing of IL-1β is accompanied by activation of caspase-1 and cell death. CRIDs arrest activated monocytes so that caspase-1 remains inactive and plasma membrane latency is preserved.

There is a need to provide compounds with improved pharmacological and/or physiological and/or physicochemical properties and/or those that provide a useful alternative to known compounds.

SUMMARY OF THE INVENTION

A first aspect of the invention provides a compound of formula (I):

wherein:Q is selected from O or S;R1is a 5-membered heteroaryl group substituted with at least one group RX, wherein RXis any monovalent group comprising a heteroaryl group, and wherein the 5-membered heteroaryl group of R1may optionally be further substituted; andR2is a cyclic group substituted at the α-position, wherein R2may optionally be further substituted;provided that the compound is not:

In the context of the present specification, a “hydrocarbyl” substituent group or a hydrocarbyl moiety in a substituent group only includes carbon and hydrogen atoms but, unless stated otherwise, does not include any heteroatoms, such as N, O or S, in its carbon skeleton. A hydrocarbyl group/moiety may be saturated or unsaturated (including aromatic), and may be straight-chained or branched, or be or include cyclic groups wherein, unless stated otherwise, the cyclic group does not include any heteroatoms, such as N, O or S, in its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups/moieties and combinations of all of these groups/moieties. Typically a hydrocarbyl group is a C1-C20hydrocarbyl group. More typically a hydrocarbyl group is a C1-C15hydrocarbyl group. More typically a hydrocarbyl group is a C1-C10hydrocarbyl group. A “hydrocarbylene” group is similarly defined as a divalent hydrocarbyl group.

An “alkyl” substituent group or an alkyl moiety in a substituent group may be linear (i.e. straight-chained) or branched. Examples of alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups/moieties. Unless stated otherwise, the term “alkyl” does not include “cycloalkyl”. Typically an alkyl group is a C1-C12alkyl group. More typically an alkyl group is a C1-C6alkyl group. An “alkylene” group is similarly defined as a divalent alkyl group.

An “alkenyl” substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds. Examples of alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4-hexadienyl groups/moieties. Unless stated otherwise, the term “alkenyl” does not include “cycloalkenyl”. Typically an alkenyl group is a C2-C12alkenyl group. More typically an alkenyl group is a C2-C6alkenyl group. An “alkenylene” group is similarly defined as a divalent alkenyl group.

An “alkynyl” substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds. Examples of alkynyl groups/moieties include ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups/moieties. Typically an alkynyl group is a C2-C12alkynyl group. More typically an alkynyl group is a C2-C6alkynyl group. An “alkynylene” group is similarly defined as a divalent alkynyl group.

A “cyclic” substituent group or a cyclic moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated (including aromatic) and may include one or more heteroatoms, e.g. N, O or S, in its carbon skeleton. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups as discussed below. A cyclic group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic. Typically, a cyclic group is a 3- to 12-membered cyclic group, which means it contains from 3 to 12 ring atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms.

A “heterocyclic” substituent group or a heterocyclic moiety in a substituent group refers to a cyclic group or moiety including one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, O or S, in the ring structure. Examples of heterocyclic groups include heteroaryl groups as discussed below and non-aromatic heterocyclic groups such as azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl and thiomorpholinyl groups.

A “cycloalkyl” substituent group or a cycloalkyl moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl substituent group or moiety may include monocycle, bicyclic or polycyclic hydrocarbyl rings.

A “cycloalkenyl” substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon-carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex-1,3-dien-1-yl. Unless stated otherwise, a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.

An “aryl” substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring. The term “aryl” includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless stated otherwise, the term “aryl” does not include “heteroaryl”.

A “heteroaryl” substituent group or a heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety. The term “heteroaryl” includes monocyclic aromatic heterocycles and polycyclic fused ring aromatic heterocycles wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic. Examples of heteroaryl groups/moieties include the following:

wherein G=O, S or NH.

For the purposes of the present specification, where a combination of moieties is referred to as one group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl.

Typically, the compounds of the present invention comprise at most one quaternary ammonium group such as —N+(Rβ)3or —N+(Rβ)2—.

Where reference is made to a —Rα—C(N2)Rβgroup, what is intended is:

Alternately in the optionally substituted groups or moieties defined immediately above, each —Rβmay be independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group, or any two —Rβattached to the same nitrogen atom may, together with the nitrogen atom to which they are attached, form a C2-C7cyclic group, wherein any —Rβmay optionally be substituted with one or more C1-C4alkyl, C1-C4haloalkyl, C3-C7cycloalkyl, C3-C7halocycloalkyl, —O(C1-C4alkyl), —O(C1-C4haloalkyl), —O(C3-C7cycloalkyl), —O(C3-C7halocycloalkyl), halo, —OH, —NH2, —CN, —C≡CH, oxo (═O), or 4- to 6-membered heterocyclic group.

More typically, in an optionally substituted group or moiety:(i) each hydrogen atom may optionally be replaced by a group independently selected from halo; —CN; —NO2; —N3; —Rβ; —OH; —ORβ; —Rα-halo; —Rα—CN; —Rα—NO2; —Rα—N3; —Rα—Rβ; —Rα—OH; —Rα—ORβ; —SH; —SRβ; —SORβ; —SO2H; —SO2Rβ; —SO2NH2; —SO2NHRβ; —SO2N(Rβ)2; —Rα—SH; —Rα—SRβ; —Rα—SORβ; —Rα—SO2H; —Rα—SO2Rβ; —Rα—SO2NH2; —Rα—SO2NHRβ; —Rα—SO2N(Rβ)2; —NH2; —NHRβ; —N(Rβ)2; —Rα—NH2; —Rα—NHRβ; —Rα—N(Rβ)2; —CHO; —CORβ; —COOH; —COORβ; —OCORβ; —Rα—CHO; —Rα—CORβ; —Rα—COOH; —Rα—COORβ; or —Rα—OCORβ; and/or(ii) any two hydrogen atoms attached to the same carbon atom may optionally be replaced by a π-bonded substituent independently selected from oxo (═O), ═S, ═NH or ═NRβ; and/or(iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or moiety, may optionally be replaced by a bridging substituent independently selected from —O—, —S—, —NH—, —N(Rβ)— or —Rα—;wherein each —Rα— is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or —Rβgroups; andwherein each —Rβis independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group, and wherein any —Rβmay optionally be substituted with one or more C1-C4alkyl, C1-C4haloalkyl, C3-C7cycloalkyl, —O(C1-C4alkyl), —O(C1-C4haloalkyl), —O(C3-C7cycloalkyl), halo, —OH, —NH2, —CN, —C≡CH, oxo (═O), or 4- to 6-membered heterocyclic group.

Alternately in the optionally substituted groups or moieties defined immediately above, each —Rβmay be independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group, or any two —Rβattached to the same nitrogen atom may, together with the nitrogen atom to which they are attached, form a C2-C7cyclic group, wherein any —Rβmay optionally be substituted with one or more C1-C4alkyl, C1-C4haloalkyl, C3-C7cycloalkyl, C3-C7halocycloalkyl, —O(C1-C4alkyl), —O(C1-C4haloalkyl), —O(C3-C7cycloalkyl), —O(C3-C7halocycloalkyl), halo, —OH, —NH2, —CN, —C≡CH, oxo (═O), or 4- to 6-membered heterocyclic group.

More typically, in an optionally substituted group or moiety:

(i) each hydrogen atom may optionally be replaced by a group independently selected from halo; —CN; —Rβ; —OH; —ORβ; —Rα-halo; —Rα—CN; —Rα—Rβ; —Rα—OH; —Rα—ORβ; —SRβ; —SORβ; —SO2H; —SO2Rβ; —SO2NH2; —SO2NHRβ; —SO2N(Rβ)2; —Rα—SRβ; —Rα—SORβ; —Rα—SO2H; —Rα—SO2Rβ; —Rα—SO2NH2; —Rα—SO2NHRβ; —Rα—SO2N(Rβ)2; —NH2; —NHRβ; —N(Rβ)2; —Rα—NH2; —Rα—NHRβ; —Rα—N(Rβ)2; —CHO; —CORβ; —COOH; —COORβ; —OCORβ; —Rα—CHO; —Rα—CORβ; —Rα—COOH; —Rα—COORβ; or —Rα—OCORβ; and/or(ii) any two hydrogen atoms attached to the same carbon atom may optionally be replaced by a π-bonded substituent independently selected from oxo (═O), ═S, ═NH or ═NRβ; and/or(iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or moiety, may optionally be replaced by a bridging substituent independently selected from —O—, —S—, —NH—, —N(Rβ)— or —Rα—;wherein each —Rα— is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or —Rβgroups; andwherein each —Rβis independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group, and wherein any —Rβmay optionally be substituted with one or more C1-C4alkyl, halo, —OH, or 4- to 6-membered heterocyclic group.

Alternately in the optionally substituted groups or moieties defined immediately above, each —Rβmay be independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group, or any two —Rβattached to the same nitrogen atom may, together with the nitrogen atom to which they are attached, form a C2-C7cyclic group, wherein any —Rβmay optionally be substituted with one or more C1-C4alkyl, C1-C4haloalkyl, halo, —OH, or 4- to 6-membered heterocyclic group.

Unless stated otherwise, any divalent bridging substituent (e.g. —O—, —S—, —NH—, —N(Rβ)—, —N(O)(Rβ)—, —N+(Rβ)2— or —Rα—) of an optionally substituted group or moiety (e.g. R1) must only be attached to the specified group or moiety and may not be attached to a second group or moiety (e.g. R2), even if the second group or moiety can itself be optionally substituted.

The term “halo” includes fluoro, chloro, bromo and iodo.

Unless stated otherwise, where a group is prefixed by the term “halo”, such as a haloalkyl or halomethyl group, it is to be understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without the halo prefix. For example, a halomethyl group may contain one, two or three halo substituents. A haloethyl or halophenyl group may contain one, two, three, four or five halo substituents. Similarly, unless stated otherwise, where a group is prefixed by a specific halo group, it is to be understood that the group in question is substituted with one or more of the specific halo groups. For example, the term “fluoromethyl” refers to a methyl group substituted with one, two or three fluoro groups.

Unless stated otherwise, where a group is said to be “halo-substituted”, it is to be understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group said to be halo-substituted. For example, a halo-substituted methyl group may contain one, two or three halo substituents. A halo-substituted ethyl or halo-substituted phenyl group may contain one, two, three, four or five halo substituents.

Unless stated otherwise, any reference to an element is to be considered a reference to all isotopes of that element. Thus, for example, unless stated otherwise any reference to hydrogen is considered to encompass all isotopes of hydrogen including deuterium and tritium.

Where reference is made to a hydrocarbyl or other group including one or more heteroatoms N, O or S in its carbon skeleton, or where reference is made to a carbon atom of a hydrocarbyl or other group being replaced by an N, O or S atom, what is intended is that:

is replaced by

—CH2— is replaced by —NH—, —O— or —S—;—CH3is replaced by —NH2, —OH or —SH;—CH═ is replaced by —N═;CH2═ is replaced by NH═, O═ or S═; orCH≡ is replaced by N≡;
provided that the resultant group comprises at least one carbon atom. For example, methoxy, dimethylamino and aminoethyl groups are considered to be hydrocarbyl groups including one or more heteroatoms N, O or S in their carbon skeleton.

Where reference is made to a —CH2— group in the backbone of a hydrocarbyl or other group being replaced by a —N(O)(Rβ)— or —N+(Rβ)2— group, what is intended is that:—CH2— is replaced by

or—CH2— is replaced by

In the context of the present specification, unless otherwise stated, a Cx-Cygroup is defined as a group containing from x to y carbon atoms. For example, a C1-C4alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms. Optional substituents and moieties are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituents and/or containing the optional moieties. For the avoidance of doubt, replacement heteroatoms, e.g. N, O or S, are not to be counted as carbon atoms when calculating the number of carbon atoms in a Cx-Cygroup. For example, a morpholinyl group is to be considered a C4heterocyclic group, not a C6heterocyclic group.

For the purposes of the present specification, where it is stated that a first atom or group is “directly attached” to a second atom or group it is to be understood that the first atom or group is covalently bonded to the second atom or group with no intervening atom(s) or group(s) being present. So, for example, for the group —(C═O)N(CH3)2, the carbon atom of each methyl group is directly attached to the nitrogen atom and the carbon atom of the carbonyl group is directly attached to the nitrogen atom, but the carbon atom of the carbonyl group is not directly attached to the carbon atom of either methyl group.

As stated, R1is a 5-membered heteroaryl group substituted with at least one group RX, wherein RXis any monovalent group comprising a heteroaryl group, and wherein the 5-membered heteroaryl group of R1may optionally be further substituted.

For the purposes of the present specification, where it is stated that a substituent, group or moiety “is a” specific group, it is to be understood that the specific group is directly attached to the remainder of the molecule, i.e. via a covalent bond with no intervening atom(s) or groups being present. Thus, in the first aspect of the invention, where it is stated that “R1is a 5-membered heteroaryl group” it is to be understood that a ring atom of the 5-membered ring of the 5-membered heteroaryl group is directly attached to the sulfur atom of the sulfonyl group, with no intervening atom(s) or groups being present. Similarly, where it is stated that “R2is a cyclic group”, it is to be understood that a ring atom of the cyclic group is directly attached to the nitrogen atom of the (thio)urea group, with no intervening atom(s) or groups being present. For the avoidance of doubt, R1is not attached to the sulfur atom of the sulfonyl group via the group RXor any optional substituent.

Conversely, in the first aspect of the invention, where it is stated that “RXis any monovalent group comprising a heteroaryl group”, it is to be understood only that the group RXincludes a heteroaryl group; such a group RXmay further comprise additional atoms, groups or moieties, which may connect the heteroaryl group of RXto the 5-membered heteroaryl group of R1.

The group RXmay contain a single heteroaryl group or more than one heteroaryl group. Typically the group RXcontains a single heteroaryl group.

In one embodiment, the 5-membered heteroaryl group of R1is monocyclic. In such an embodiment, the groups RXand, if present, any optional further substituents are monovalent, but may be or include cyclic groups. Examples of monocyclic 5-membered heteroaryl groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl groups.

In another embodiment, R1is:

wherein:V is independently selected from C and N, and W, X, Y and Z are each independently selected from N, O, S, NH and CH, provided that at least one of V, W, X, Y and Z is N, O, S or NH;m is 1, 2, 3 or 4;n is 0, 1, 2 or 3;each RXis independently selected from any RXas defined herein; andeach RYis independently selected from any monovalent optional substituent as defined herein.

As will be understood, ring A is a 5-membered heteroaryl group.

For the purposes of the present specification, where it is stated that W, X, Y or Z may be NH or CH, it is to be understood that this refers to W, X, Y and Z before possible substitution with RXor RYis considered. Thus, where it is stated that W, X, Y or Z may be NH, it is to be understood that W, X, Y or Z may be NH, or N—RXor N—RYafter substitution is considered. Similarly, where it is stated that W, X, Y or Z may be CH, it is to be understood that W, X, Y or Z may be CH, or C—RXor C—RYafter substitution is considered.

Typically, in any embodiment where W, X, Y or Z is NH, the NH is substituted, either by RXor RY.

Typically, V is C.

Typically, m is 1 or 2 and n is 0, 1 or 2. More typically, m is 1 and n is 0, 1 or 2. More typically still, m is 1 and n is 0 or 1.

Typically, at least two of V, W, X, Y and Z are C or CH. More typically, three of V, W, X, Y and Z are C or CH. For example, where V is C, two of W, X, Y and Z may be CH.

In one embodiment, the 5-membered heteroaryl group of R1contains at least one nitrogen atom in the 5-membered ring structure. For instance, in the above embodiment at least one of V, W, X, Y and Z may be N or NH. Typically, V is C and at least one of W, X, Y and Z is N or NH. Examples of 5-membered heteroaryl groups that contains at least one nitrogen atom in the 5-membered ring structure include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl groups.

More typically, the 5-membered heteroaryl group of R1contains at least two nitrogen atoms in the 5-membered ring structure. For example, in the above embodiment at least two of V, W, X, Y and Z may be N or NH. More typically still, V is C and at least two of W, X, Y and Z are N or NH.

In one embodiment, the 5-membered heteroaryl group of R1contains only carbon and nitrogen atoms in the 5-membered ring structure. For example, in the above embodiment, V may be independently selected from C and N, and W, X, Y and Z may each be independently selected from N, NH and CH, provided that at least one of V, W, X, Y and Z is N or NH. Typically, in such an embodiment, V is C. Typically, at least two of V, W, X, Y and Z are N or NH. More typically, two of V, W, X, Y and Z are N or NH. Typically, one of X and Y is NH and one of X and Y is CH. Most typically, ring A is an imidazolyl or pyrazolyl group. For example, in one embodiment V is C, X is CH, Y is NH, one of W and Z is CH and one of W and Z is N. In another embodiment, V is C, X is NH, Y is CH, one of W and Z is CH and one of W and Z is N.

Where m is 1, in a typical embodiment R1is:

wherein V, W, X, Y, Z, RX, RYand n are as defined above. Typically in such an embodiment, n is 0 or 1. More typically, R1is:

In one embodiment, RXis R10-L-, wherein:L is a bond or an alkylene, alkenylene or alkynylene group, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted; andR10is a heteroaryl group, wherein the heteroaryl group may optionally be substituted.

Typically, L is a bond or an alkylene or an alkenylene group, wherein the alkylene or alkenylene group may optionally include one or more heteroatoms N or O in its carbon skeleton, and wherein the alkylene or alkenylene group may be optionally substituted. More typically, L is a bond or an alkylene group, wherein the alkylene group may optionally include one or two heteroatoms N or O in its carbon skeleton, and wherein the alkylene group may be optionally substituted.

Where L is substituted, typically it is substituted with one or more substituents independently selected from halo, —CN, —OH, —NH2, oxo (═O) and ═NH. More typically, where L is substituted, it is substituted with one or more substituents independently selected from halo, —CN, —OH, —NH2and oxo (═O). Most typically, where L is substituted, it is substituted with one or more substituents independently selected from fluoro, chloro and oxo (═O).

In one embodiment, L contains only atoms selected from the group consisting of carbon, hydrogen, nitrogen, oxygen and halogen atoms.

In another embodiment, L does not contain an amide group. In a further embodiment, L does not contain a carbonyl group.

For the purposes of the present specification, an “amide group” is considered to be any group comprising the structure:

Typically, L is a bond or contains from 1 to 10 atoms other than hydrogen or halogen. More typically, L is a bond or contains from 1 to 6 atoms other than hydrogen or halogen. More typically still, L is a bond or contains from 1 to 5 atoms other than hydrogen or halogen.

More typically, L is a bond or a —CH2—, —N(Me)—CO— or —CH2N(Me)—CO— group. Most typically, L is a bond or a —CH2— or —CH2N(Me)—CO— group.

In one embodiment, R10is an imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, or thiadiazolyl group, any of which may optionally be substituted.

In one embodiment, the heteroaryl group of R10is unsubstituted.

Where the heteroaryl group of R10is substituted, typically it is substituted with one or more groups independently selected from halo, —OH, —NH2, —CN, —R20, —OR20, —NHR20or —N(R20)2, wherein each R20is independently selected from a C1-C4alkyl, C1-C4alkenyl or C1-C4alkynyl group, any of which may optionally be halo-substituted. More typically, the heteroaryl group of R10is unsubstituted or substituted with one or more chloro, fluoro and/or methyl groups, wherein any methyl group may optionally be substituted with one or more fluoro and/or chloro groups.

In one embodiment, RXis an optionally substituted heteroarylalkyl group. For example, RXmay be R10-L-, wherein R10is as defined above and L is an optionally substituted alkylene group.

In one embodiment, RXis:

wherein:T is O, S or NR101;R101is hydrogen or a C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl, or C3-C4halocycloalkyl group;each R102is independently selected from hydrogen or a halo, C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl, or C3-C4halocycloalkyl group; andL2is a straight chained or branched C1-C4alkylene group, where the alkylene group may optionally include one heteroatom N or O in its carbon skeleton, and wherein the alkylene group may optionally be substituted with one or more halo and/or oxo (═O) groups.

Typically in such an embodiment:R101is a methyl, ethyl, n-propyl, isopropyl or cyclopropyl group, all of which may optionally be substituted with one or more fluoro and/or chloro groups;each R102is independently selected from hydrogen or a methyl group, wherein the methyl group may optionally be substituted with one or more fluoro and/or chloro groups; andL2is a straight chained or branched C1-C3alkylene group, where the alkylene group may optionally include one heteroatom N or O in its carbon skeleton, and wherein the alkylene group may optionally be substituted with a single oxo (═O) group and/or with one or more fluoro and/or chloro groups.

Most typically in such an embodiment:R101is a methyl group;each R102is hydrogen; andL2is a straight chained or branched C1-C3alkylene group, where the alkylene group may optionally include one heteroatom N in its carbon skeleton, and wherein the alkylene group may optionally be substituted with a single oxo (═O) group.

In one embodiment, RXcontains only atoms selected from the group consisting of carbon, hydrogen, nitrogen, oxygen and halogen atoms.

In one embodiment, RXdoes not contain an amide group. In a further embodiment, RXdoes not contain a carbonyl group.

In one embodiment, RXcontains from 5 to 20 atoms other than hydrogen or halogen. More typically, RXcontains from 5 to 14 atoms other than hydrogen or halogen. More typically still, RXcontains from 5 to 11 atoms other than hydrogen or halogen.

In one embodiment, RXis selected from the group consisting of:

Alternatively, the 5-membered heteroaryl group of R1may be further substituted with one, two or three substituents independently selected from halo; —CN; —Rβ; —OH; —ORβ; —Rα—halo; —Rα—CN; —Rα—Rβ; —Rα—OH; —Rα—ORβ; —SRβ; —SORβ; —SO2H; —SO2Rβ; —SO2NH2; —SO2NHRβ; —SO2N(Rβ)2; —Rα—SRβ; —Rα—SORβ; —Rα—SO2H; —Rα—SO2Rβ; —Rα—SO2NH2; —Rα—SO2NHRβ; —Rα—SO2N(Rβ)2; —NH2; —NHRβ; —N(Rβ)2; —Rα—NH2; —Rα—NHRβ; —Rα—N(Rβ)2; —CHO; —CORβ; —COOH; —COORβ; —OCORβ; —Rα—CHO; —Rα—CORβ; —Rα—COOH; —Rα—COORβ; or —Rα—OCORβ;wherein each —Rα— is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or —Rβgroups; andwherein each —Rβis independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group, and wherein any —Rβmay optionally be substituted with one or more C1-C4alkyl, halo, —OH, or 4- to 6-membered heterocyclic group.

Typically, where the 5-membered heteroaryl group of R1is further substituted with one or more optional substituents RY, RYis a monovalent group. Typically, where RYis a monovalent group, RYcontains from 1 to 11 atoms other than hydrogen or halogen. More typically, RYcontains from 1 to 8 atoms other than hydrogen or halogen. Most typically, RYcontains from 1 to 6 atoms other than hydrogen or halogen.

In one embodiment, each RYis a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Where the hydrocarbyl group of RYis optionally substituted, typically it is substituted with one or more groups independently selected from halo, —CN, —OH, —NH2, oxo (═O) and ═NH.

Typically, each RYis a saturated hydrocarbyl group, e.g. a C1-C6saturated hydrocarbyl group, wherein the saturated hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the saturated hydrocarbyl group may optionally be substituted with one or more groups independently selected from halo, —CN, —OH, —NH2and oxo (═O), and wherein the saturated hydrocarbyl group may optionally include one or two heteroatoms N or O in its carbon skeleton.

More typically, each RYis independently selected from a C1-C6alkyl or C3-C6cycloalkyl group, wherein any C1-C6alkyl or C3-C6cycloalkyl group may optionally be substituted with one or more fluoro, chloro, —CN, —OH, —NH2, —OMe, —NHMe and/or —NMe2groups, wherein any methyl group may optionally be substituted with one or more fluoro and/or chloro groups.

More typically still, each RYis independently selected from a C1-C4alkyl or C3-C4cycloalkyl group, wherein any C1-C4alkyl or C3-C4cycloalkyl group may optionally be substituted with one or more fluoro and/or chloro groups.

Most typically each RYis independently selected from a methyl, ethyl, isopropyl or cyclopropyl group.

In one aspect of any of the above embodiments, R1contains from 10 to 30 atoms other than hydrogen. More typically, R1contains from 10 to 25 atoms other than hydrogen. More typically, R1contains from 10 to 20 atoms other than hydrogen. More typically, R1contains from 10 to 17 atoms other than hydrogen.

In one aspect of any of the above embodiments, R1contains from 10 to 25 atoms other than hydrogen or halogen. More typically, R1contains from 10 to 20 atoms other than hydrogen or halogen. More typically still, R1contains from 10 to 17 atoms other than hydrogen or halogen.

R2is a cyclic group substituted at the α-position, wherein R2may optionally be further substituted. For the avoidance of doubt, it is noted that it is a ring atom of the cyclic group of R2that is directly attached to the nitrogen atom of the urea or thiourea group, not any substituent.

In one embodiment of the first aspect of the invention, R2is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α-position, and wherein R2may optionally be further substituted. Typically, R2is a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the heteroaryl group is substituted at the α-position, and wherein R2may optionally be further substituted. Typically, R2is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α and α′ positions, and wherein R2may optionally be further substituted. Typically, R2is a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the heteroaryl group is substituted at the α and α′ positions, and wherein R2may optionally be further substituted. For example, R2may be a phenyl group substituted at the 2- and 6-positions or a phenyl group substituted at the 2-, 4- and 6-positions.

As used herein, the nomenclature α, β, α′, β′ refers to the position of the atoms of a cyclic group, such as —R2, relative to the point of attachment of the cyclic group to the remainder of the molecule. For example, where —R2is a 1,2,3,5,6,7-hexahydro-s-indacen-4-yl moiety, the α, β, α′ and β′ positions are as follows:

For the avoidance of doubt, where it is stated that a cyclic group, such as an aryl or a heteroaryl group, is substituted at the α and/or α′ positions, it is to be understood that one or more hydrogen atoms at the α and/or α′ positions respectively are replaced by one or more substituents, such as any optional substituent as defined above. Unless stated otherwise, the term “substituted” does not include the replacement of one or more ring carbon atoms by one or more ring heteroatoms.

In another embodiment, R2is a cyclic group substituted at the α and α′ positions, wherein R2may optionally be further substituted. For example, R2may be a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group substituted at the α and α′ positions.

In any of the above embodiments, typical substituents at the α and/or α′ positions of the parent cyclic group of R2comprise a carbon atom. For example, typical substituents at the α and/or α′ positions may be independently selected from —R4, —OR4and —COR4groups, wherein each R4is independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group and wherein each R4is optionally further substituted with one or more halo groups. More typically, the substituents at the α and/or α′ positions are independently selected from alkyl and cycloalkyl groups, such as C3-C6branched alkyl and C3-C6cycloalkyl groups, e.g. isopropyl, cyclopropyl, cyclohexyl or t-butyl groups, wherein the alkyl and cycloalkyl groups are optionally further substituted with one or more fluoro and/or chloro groups.

In one aspect of any of the above embodiments, each substituent at the α and α′ positions comprises a carbon atom.

Other typical substituents at the α and/or α′ positions of the parent cyclic group of R2may include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings which are fused to the parent cyclic group across the α,β and/or α′,β′ positions respectively. Such fused cyclic groups are described in greater detail below.

In one embodiment, R2is a fused aryl or a fused heteroaryl group, wherein the aryl or heteroaryl group is fused to one or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings, wherein R2may optionally be further substituted. Typically, a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α,β positions. Typically, the aryl or heteroaryl group is also substituted at the α′ position, for example with a substituent selected from —R4, —OR4and —COR4, wherein each R4is independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group and wherein each R4is optionally further substituted with one or more halo groups. Typically in such an embodiment, R2is bicyclic or tricyclic.

More typically, R2is a fused phenyl or a fused 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group is fused to one or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings, wherein R2may optionally be further substituted. Typically, a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 5- or 6-membered heteroaryl group across the α,β positions so as to form a 4- to 6-membered fused ring structure. Typically, the phenyl or the 5- or 6-membered heteroaryl group is also substituted at the α′ position, for example with a substituent selected from —R4, —OR4and —COR4, wherein each R4is independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group and wherein each R4is optionally further substituted with one or more halo groups. Typically in such an embodiment, R2is bicyclic or tricyclic.

In another embodiment, R2is a fused aryl or a fused heteroaryl group, wherein the aryl or heteroaryl group is fused to two or more independently selected cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings, wherein R2may optionally be further substituted. Typically, the two or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are each ortho-fused to the aryl or heteroaryl group, i.e. each fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring has only two atoms and one bond in common with the aryl or heteroaryl group. Typically, R2is tricyclic.

In yet another embodiment, R2is a fused aryl or a fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α,β positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α′,β′ positions, wherein R2may optionally be further substituted. Typically in such an embodiment, R2is tricyclic.

More typically, R2is a fused phenyl or a fused 5- or 6-membered heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 5- or 6-membered heteroaryl group across the α,β positions so as to form a first 4- to 6-membered fused ring structure, and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 5- or 6-membered heteroaryl group across the α′,β′ positions so as to form a second 4- to 6-membered fused ring structure, wherein R2may optionally be further substituted. Typically in such an embodiment, R2is tricyclic.

In one embodiment, —R2has a formula selected from:

wherein:A1and A2are each independently selected from an optionally substituted alkylene or alkenylene group, wherein one or more carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or more heteroatoms N, O or S;each Rais independently selected from —Raa, —ORaaor —CORaa;each Rbis independently selected from hydrogen, halo, —NO2, —CN, —Raa, —ORaaor —CORaa;provided that any Raor Rbthat is directly attached to a ring nitrogen atom is not halo, —NO2, —CN, or —ORaa;each Rcis independently selected from hydrogen, halo, —OH, —NO2, —CN, —Rcc, —ORcc, —CORcc, —COORcc, —CONH2, —CONHRccor —CON(Rcc)2;each Raais independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or a 3- to 7-membered cyclic group, wherein each Raais optionally substituted; andeach Rccis independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or a 3- to 7-membered cyclic group, or any two Rccattached to the same nitrogen atom may, together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclic group, wherein each Rccis optionally substituted.

Typically, any ring containing A1or A2is a 5- or 6-membered ring. Typically, A1and A2are each independently selected from an optionally substituted straight-chained alkylene group or an optionally substituted straight-chained alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms independently selected from nitrogen and oxygen. More typically, A1and A2are each independently selected from an optionally substituted straight-chained alkylene group, wherein one carbon atom in the backbone of the alkylene group may optionally be replaced by an oxygen atom. Typically, no heteroatom in A1or A2is directly attached to another ring heteroatom. Typically, A1and A2are unsubstituted or substituted with one or more substituents independently selected from halo, —OH, —CN, —NO2, C1-C4alkyl, C1-C4haloalkyl, —O(C1-C4alkyl) or —O(C1-C4haloalkyl). More typically, A1and A2are unsubstituted or substituted with one or more fluoro and/or chloro groups. Where R2contains both A1and A2groups, A1and A2may be the same or different. Typically, A1and A2are the same.

Where Raais a substituted C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl group, typically the C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl group is substituted with one or more (e.g. one or two) substituents independently selected from halo, —OH, —CN, —NO2, —O(C1-C4alkyl) or —O(C1-C4haloalkyl).

Where Raais a substituted 3- to 7-membered cyclic group, typically the 3- to 7-membered cyclic group is substituted with one or more (e.g. one or two) substituents independently selected from halo, —OH, —NH2, —CN, —NO2, —B1, —OB1, —NHB1, —N(B1)2, —CONH2, —CONHB1, —CON(B1)2, —NHCOB1, —NB1COB1, or —B11—;wherein each B1is independently selected from a C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, or two B1together with the nitrogen atom to which they are attached may form a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, wherein any B1may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB12, —NHB12or —N(B12)2;wherein each B11is independently selected from a C1-C8alkylene or C2-C8alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms N and/or O, and wherein the alkylene or alkenylene group may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB12, —NHB12or —N(B12)2; andwherein each B12is independently selected from a C1-C3alkyl or C1-C3haloalkyl group. Typically, any divalent group —B11— forms a 4- to 6-membered fused ring.

Typically, each Rais —Raa. More typically, each Rais independently selected from a C1-C6alkyl (in particular C3-C6branched alkyl) or C3-C6cycloalkyl group, wherein each Rais optionally further substituted with one or more halo groups. More typically, each Rais independently selected from a C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl or C3-C4halocycloalkyl group. Where a group Rais present at both the α- and α′-positions, each Ramay be the same or different. Typically, each Rais the same.

Typically, each Rbis independently selected from hydrogen or halo. More typically, each Rbis hydrogen.

Typically, each Rcis independently selected from a C1-C4alkyl or C3-C6cycloalkyl group, or any two Rccattached to the same nitrogen atom may, together with the nitrogen atom to which they are attached, form a 3- to 6-membered saturated heterocyclic group, wherein each Rccis optionally substituted. Where Rccis substituted, typically Rccis substituted with one or more halo, —OH, —CN, —NO2, —O(C1-C4alkyl) or —O(C1-C4haloalkyl) groups. More typically, each Rcis independently selected from a C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl or C3-C4halocycloalkyl group.

In one embodiment, —R2has a formula selected from:

In one embodiment, —R2has a formula selected from:

wherein A1and A2are each independently selected from an optionally substituted alkylene or alkenylene group, wherein one or more carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein Reis hydrogen or any optional substituent. Reand any optional substituent attached to A1or A2may together with the atoms to which they are attached form a further fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which may itself be optionally substituted. Similarly, any optional substituent attached to A1and any optional substituent attached to A2may also together with the atoms to which they are attached form a further fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which may itself be optionally substituted.

Typically, A1and A2are each independently selected from an optionally substituted straight-chained alkylene group or an optionally substituted straight-chained alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms independently selected from nitrogen and oxygen. More typically, A1and A2are each independently selected from an optionally substituted straight-chained alkylene group, wherein one carbon atom in the backbone of the alkylene group may optionally be replaced by an oxygen atom. Typically, no heteroatom in A1or A2is directly attached to another ring heteroatom. Typically, A1and A2are unsubstituted or substituted with one or more halo, hydroxyl, —CN, —NO2, —B3or —OB3groups, wherein B3is a C1-C4alkyl group which may optionally be halo-substituted. More typically, A1and A2are unsubstituted or substituted with one or more halo, hydroxyl, —CN, —B3or —OB3groups, wherein B3is a C1-C4alkyl group which may optionally be halo-substituted. More typically, A1and A2are unsubstituted or substituted with one or more fluoro and/or chloro groups. Where R2contains both A1and A2groups, A1and A2may be the same or different. Typically, A1and A2are the same.

In a further embodiment, —R2has a formula selected from:

Yet other typical substituents at the α-position of the parent cyclic group of R2may include monovalent heterocyclic groups and monovalent aromatic groups, wherein a ring atom of the heterocyclic or aromatic group is directly attached via a single bond to the α-ring atom of the parent cyclic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the parent cyclic group may optionally be further substituted. Such R2groups are described in greater detail below.

In one embodiment, the α-substituted parent cyclic group of R2is a 5- or 6-membered cyclic group, wherein the cyclic group may optionally be further substituted. In one embodiment, the α-substituted parent cyclic group of R2is an aryl or a heteroaryl group, all of which may optionally be further substituted. In one embodiment, the α-substituted parent cyclic group of R2is a phenyl or a 5- or 6-membered heteroaryl group, all of which may optionally be further substituted. In one embodiment, the α-substituted parent cyclic group of R2is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl or oxadiazolyl group, all of which may optionally be further substituted. In one embodiment, the α-substituted parent cyclic group of R2is a phenyl or pyrazolyl group, both of which may optionally be further substituted. In a further embodiment, the α-substituted parent cyclic group of R2is a phenyl group, which may optionally be further substituted.

In one embodiment, the α-substituted parent cyclic group of R2is substituted at the α and α′ positions, and may optionally be further substituted. For example, the α-substituted parent cyclic group of R2may be a phenyl group substituted at the 2- and 6-positions or a phenyl group substituted at the 2-, 4- and 6-positions.

In one embodiment, R2is a parent cyclic group substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the parent cyclic group may optionally be further substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is a phenyl or a 5- or 6-membered heterocyclic group, all of which may optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanyl, 1,3-oxathiolanyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,4-dioxanyl, thianyl, morpholinyl, thiomorpholinyl or 1-methyl-2-oxo-1,2-dihydropyridinyl group, all of which may optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanyl, 1,3-oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, 1,4-dioxanyl, morpholinyl or thiomorpholinyl group, all of which may optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, piperidinyl or tetrahydropyranyl group, all of which may optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, tetrahydropyranyl or 1-methyl-2-oxo-1,2-dihydropyridinyl group, all of which may optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is a phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl or tetrahydropyranyl group, all of which may optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is a phenyl, pyridinyl, pyrimidinyl or pyrazolyl group, all of which may optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is an unsubstituted phenyl, pyridinyl, pyrimidinyl or pyrazolyl group. In one embodiment, the monovalent heterocyclic group at the α-position is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, all of which may optionally be substituted. In one embodiment, the monovalent heterocyclic group at the α-position is an unsubstituted pyridin-3-yl group or an optionally substituted pyridin-4-yl group.

For any of these monovalent heterocyclic or aromatic groups at the α-position mentioned in the immediately preceding paragraph, the monovalent heterocyclic or aromatic group may optionally be substituted with one or two substituents independently selected from halo, —OH, —NH2, —CN, —NO2, —B4, —OB4, —NHB4, —N(B4)2, —CONH2, —CONHB4, —CON(B4)2, —NHCOB4, —NB4COB4, or —B44—;wherein each B4is independently selected from a C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, or two B4together with the nitrogen atom to which they are attached may form a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, wherein any B4may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB45, —NHB45or —N(B45)2;wherein each B44is independently selected from a C1-C8alkylene or C2-C8alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms N and/or O, and wherein the alkylene or alkenylene group may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB45, —NHB45or —N(B45)2; andwherein each B45is independently selected from a C1-C3alkyl or C1-C3haloalkyl group.

Typically, any divalent group —B44— forms a 4- to 6-membered fused ring.

In one embodiment, the monovalent heterocyclic or aromatic group at the α-position is a phenyl, pyridinyl, pyrimidinyl or pyrazolyl group, all of which may optionally be substituted with one or two substituents independently selected from halo, —OH, —NH2, —CN, —B4, —OB4, —NHB4or —N(B4)2, wherein each B4is independently selected from a C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl group all of which may optionally be halo-substituted. In one embodiment, the monovalent heterocyclic group at the α-position is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, all of which may optionally be substituted with one or two substituents independently selected from halo, —OH, —NH2, —CN, —B4, —OB4, —NHB4or —N(B4)2, wherein each B4is independently selected from a C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl group all of which may optionally be halo-substituted. In one embodiment, the monovalent heterocyclic group at the α-position is an unsubstituted pyridin-3-yl group or a pyridin-4-yl group optionally substituted with one or two substituents independently selected from halo, —OH, —NH2, —CN, —B4, —OB4, —NHB4or —N(B4)2, wherein each B4is independently selected from a C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl group all of which may optionally be halo-substituted.

In one embodiment, R2is a parent cyclic group substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the parent cyclic group may optionally be further substituted. In one embodiment, such further substituents are in the α′ position of the α-substituted parent cyclic group of R2. Such further substituents may be independently selected from halo, —R, —OR6or —COR6groups, wherein each R6is independently selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group and wherein each R6is optionally further substituted with one or more halo groups. Typically, such further substituents on the α-substituted parent cyclic group of R2are independently selected from halo, C1-C6alkyl (in particular C3-C6branched alkyl) or C3-C6cycloalkyl groups, e.g. fluoro, chloro, isopropyl, cyclopropyl, cyclohexyl or t-butyl groups, wherein the alkyl and cycloalkyl groups are optionally further substituted with one or more fluoro and/or chloro groups.

In one embodiment, —R2has a formula selected from:

wherein R7is C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl or C3-C6halocycloalkyl, R8is a 5- or 6-membered, optionally substituted heterocyclic or aromatic group, and Rgis hydrogen, halo, —OH, —NO2, —CN, —Rgg, —ORgg, —CORgg, —COORgg, —CONH2, —CONHRggor —CON(Rgg)2, wherein each —Rggis independently selected from C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl and C3-C4halocycloalkyl. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —NO2, —B5, —OB5, —NHB5, —N(B5)2, —CONH2, —CONHB5, —CON(B5)2, —NHCOB5, —NB5COB5, or —B55—;wherein each B5is independently selected from a C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, or two B5together with the nitrogen atom to which they are attached may form a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, wherein any B5may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB56, —NHB56or —N(B56)2;wherein each B55is independently selected from a C1-C8alkylene or C2-C8alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms N and/or O, and wherein the alkylene or alkenylene group may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB56, —NHB56or —N(B56)2; andwherein each B56is independently selected from a C1-C3alkyl or C1-C3haloalkyl group.

Typically, any divalent group —B55— forms a 4- to 6-membered fused ring. Typically, R7is C1-C4alkyl, R8is a 5- or 6-membered, optionally substituted heterocyclic or aromatic group, and Rgis hydrogen, halo, —CN, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl or halocyclopropyl. More typically, R7is C1-C4alkyl, R8is a 5- or 6-membered, optionally substituted heterocyclic or aromatic group, and Rgis hydrogen or halo. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —B5, —OB5, —NHB5or —N(B5)2, wherein each B5is independently selected from a C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl group all of which may optionally be halo-substituted.

wherein R8is a 5- or 6-membered, optionally substituted heterocyclic or aromatic group. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —NO2, —B6, —OB6, —NHB6, —N(B6)2, —CONH2, —CONHB6, —CON(B6)2, —NHCOB6, —NB6COB6, or —B66—;wherein each B6is independently selected from a C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, or two B6together with the nitrogen atom to which they are attached may form a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, wherein any B6may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB67, —NHB67or —N(B67)2;wherein each B66is independently selected from a C1-C8alkylene or C2-C8alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms N and/or O, and wherein the alkylene or alkenylene group may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB67, —NHB67or —N(B67)2; andwherein each B67is independently selected from a C1-C3alkyl or C1-C3haloalkyl group.

Typically, any divalent group —B66— forms a 4- to 6-membered fused ring. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —B6, —OB6, —NHB6or —N(B6)2, wherein each B6is independently selected from a C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl group all of which may optionally be halo-substituted.

In one embodiment, R2is a parent cyclic group substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the parent cyclic group may optionally be further substituted. The further substituents on the α-substituted parent cyclic group of R2also include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings which are fused to the α-substituted parent cyclic group of R2. Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused to the α-substituted parent cyclic group of R2, i.e. each fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring has only two atoms and one bond in common with the α-substituted parent cyclic group of R2. Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused to the α-substituted parent cyclic group of R2across the α′,β′ positions.

In one embodiment, —R2has a formula selected from:

wherein R8is a 5- or 6-membered, optionally substituted heterocyclic or aromatic group, and Rhis hydrogen, halo, —OH, —NO2, —CN, —Rhh, —ORhh, —CORhh, —COORhh, —CONH2, —CONHRhhor —CON(Rhh)2, wherein each —Rhhis independently selected from C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl and C3-C4halocycloalkyl. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —NO2, —B7, —OB7, —NHB7, —N(B7)2, —CONH2, —CONHB7, —CON(B7)2, —NHCOB7, —NB7COB7, or —B77—;wherein each B7is independently selected from a C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, or two B7together with the nitrogen atom to which they are attached may form a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, wherein any B7may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB78, —NHB78or —N(B78)2;wherein each B77is independently selected from a C1-C8alkylene or C2-C8alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms N and/or O, and wherein the alkylene or alkenylene group may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB78, —NHB78or —N(B78)2; andwherein each B78is independently selected from a C1-C3alkyl or C1-C3haloalkyl group.

Typically, any divalent group —B77— forms a 4- to 6-membered fused ring. Typically, Rhis hydrogen, halo, —CN, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl or halocyclopropyl. More typically, Rhis hydrogen or halo. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —NO2, —B7, —OB7, —NHB7or —N(B7)2, wherein each B7is independently selected from a C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl group all of which may optionally be halo-substituted.

In one embodiment, —R2has a formula selected from:

wherein R8is a 5- or 6-membered, optionally substituted heterocyclic or aromatic group. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —NO2, —B8, —OB8, —NHB8, —N(B8)2, —CONH2, —CONHB8, —CON(B8)2, —NHCOB8, —NB8COB8, or —B88—;wherein each B8is independently selected from a C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, or two B8together with the nitrogen atom to which they are attached may form a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, wherein any B8may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB89, —NHB89or —N(B89)2;wherein each B88is independently selected from a C1-C8alkylene or C2-C8alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms N and/or O, and wherein the alkylene or alkenylene group may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB89, —NHB89or —N(B89)2; andwherein each B89is independently selected from a C1-C3alkyl or C1-C3haloalkyl group.

Typically, any divalent group —B88— forms a 4- to 6-membered fused ring. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —B8, —OB8, —NHB8or —N(B8)2, wherein each B8is independently selected from a C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl group all of which may optionally be halo-substituted.

wherein R8is a 5- or 6-membered, optionally substituted heterocyclic or aromatic group, and Riis hydrogen, halo, —OH, —NO2, —CN, —Rii, —ORii, —CORii, —COORii, —CONH2, —CONHRiior —CON(Rii)2, wherein each —Riiis independently selected from C1-C4alkyl, C1-C4haloalkyl, C3-C4cycloalkyl and C3-C4halocycloalkyl. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —NO2, —B9, —OB9, —NHB9, —N(B9)2, —CONH2, —CONHB9, —CON(B9)2, —NHCOB9, —NB9COB9, or —B99—;wherein each B9is independently selected from a C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, or two B9together with the nitrogen atom to which they are attached may form a 4- to 6-membered heterocyclic group containing one or two ring heteroatoms N and/or O, wherein any B9may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB98, —NHB98or —N(B98)2;wherein each B99is independently selected from a C1-C8alkylene or C2-C8alkenylene group, wherein one or two carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or two heteroatoms N and/or O, and wherein the alkylene or alkenylene group may optionally be halo-substituted and/or substituted with one or two substituents independently selected from —OH, —NH2, —OB98, —NHB98or —N(B98)2; andwherein each B98is independently selected from a C1-C3alkyl or C1-C3haloalkyl group.

Typically, any divalent group —B99-forms a 4- to 6-membered fused ring. Typically, Riis hydrogen, halo, —CN, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl or halocyclopropyl. More typically, Riis hydrogen or halo. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, —OH, —NH2, —CN, —NO2, —B9, —OB9, —NHB9or —N(B9)2, wherein each B9is independently selected from a C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl group all of which may optionally be halo-substituted.

In the embodiment directly above, where a group or moiety is optionally substituted with one or more halo groups, it may be substituted for example with one, two, three, four, five or six halo groups.

In one aspect of any of the above embodiments, R2contains from 10 to 50 atoms other than hydrogen. More typically, R2contains from 10 to 40 atoms other than hydrogen. More typically, R2contains from 10 to 35 atoms other than hydrogen. Most typically, R2contains from 12 to 30 atoms other than hydrogen.

In one aspect of any of the above embodiments, R2contains from 5 to 30 atoms other than hydrogen or halogen. More typically, R2contains from 7 to 25 atoms other than hydrogen or halogen. More typically, R2contains from 9 to 20 atoms other than hydrogen or halogen. Most typically, R2contains from 12 to 18 atoms other than hydrogen or halogen.

Q is selected from O or S. In one embodiment of the first aspect of the invention, Q is O.

In one aspect of any of the above embodiments, the compound of formula (I) has a molecular weight of from 250 to 2000 Da. Typically, the compound of formula (I) has a molecular weight of from 300 to 900 Da. More typically, the compound of formula (I) has a molecular weight of from 350 to 600 Da.

A second aspect of the invention provides a compound selected from the group consisting of:

A third aspect of the invention provides a pharmaceutically acceptable salt, solvate or prodrug of any compound of the first or second aspect of the invention.

The compounds of the present invention can be used both in their free base form and their acid addition salt form. For the purposes of this invention, a “salt” of a compound of the present invention includes an acid addition salt. Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-sulfonic, naphthalene-2-sulfonic or camphorsulfonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). The acid addition salt may be a mono-, di-, tri- or multi-acid addition salt. A preferred salt is a hydrohalogenic, sulfuric, phosphoric or organic acid addition salt. A preferred salt is a hydrochloric acid addition salt.

Where a compound of the invention includes a quaternary ammonium group, typically the compound is used in its salt form. The counter ion to the quaternary ammonium group may be any pharmaceutically acceptable, non-toxic counter ion. Examples of suitable counter ions include the conjugate bases of the protic acids discussed above in relation to acid-addition salts.

The compounds of the present invention can also be used both, in their free acid form and their salt form. For the purposes of this invention, a “salt” of a compound of the present invention includes one formed between a protic acid functionality (such as a carboxylic acid group) of a compound of the present invention and a suitable cation. Suitable cations include, but are not limited to lithium, sodium, potassium, magnesium, calcium and ammonium. The salt may be a mono-, di-, tri- or multi-salt. Preferably the salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably the salt is a mono- or di-sodium salt or a mono- or di-potassium salt.

Preferably any salt is a pharmaceutically acceptable non-toxic salt. However, in addition to pharmaceutically acceptable salts, other salts are included in the present invention, since they have potential to serve as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable salts, or are useful for identification, characterisation or purification of the free acid or base.

The compounds and/or salts of the present invention may be anhydrous or in the form of a hydrate (e.g. a hemihydrate, monohydrate, dihydrate or trihydrate) or other solvate. Such other solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.

In some embodiments of the present invention, therapeutically inactive prodrugs are provided. Prodrugs are compounds which, when administered to a subject such as a human, are converted in whole or in part to a compound of the invention. In most embodiments, the prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect. Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound or to otherwise alter the properties of the compound. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to produce the active compound. The present invention also encompasses salts and solvates of such prodrugs as described above.

The compounds, salts, solvates and prodrugs of the present invention may contain at least one chiral centre. The compounds, salts, solvates and prodrugs may therefore exist in at least two isomeric forms. The present invention encompasses racemic mixtures of the compounds, salts, solvates and prodrugs of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of this invention, a “substantially enantiomerically pure” isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2%, and most typically less than 0.5% by weight.

The compounds, salts, solvates and prodrugs of the present invention may contain any stable isotope including, but not limited to12C,13C,1H,2H (D),14N,15N,16O,17O,18O,19F and127I, and any radioisotope including, but not limited to1C,14C,3H (T),13N,15O,18F,123I,124I,125I and131I.

The compounds, salts, solvates and prodrugs of the present invention may be in any polymorphic or amorphous form.

A fourth aspect of the invention provides a pharmaceutical composition comprising a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, and a pharmaceutically acceptable excipient.

Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Aulton's Pharmaceutics—The Design and Manufacture of Medicines”, M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier, 4thEd., 2013.

Pharmaceutically acceptable excipients including adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

In one embodiment, the pharmaceutical composition of the fourth aspect of the invention additionally comprises one or more further active agents.

In a further embodiment, the pharmaceutical composition of the fourth aspect of the invention may be provided as a part of a kit of parts, wherein the kit of parts comprises the pharmaceutical composition of the fourth aspect of the invention and one or more further pharmaceutical compositions, wherein the one or more further pharmaceutical compositions each comprise a pharmaceutically acceptable excipient and one or more further active agents.

A fifth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine, and/or for use in the treatment or prevention of a disease, disorder or condition. Typically, the use comprises the administration of the compound, salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the use comprises the co-administration of one or more further active agents.

The term “treatment” as used herein refers equally to curative therapy, and ameliorating or palliative therapy. The term includes obtaining beneficial or desired physiological results, which may or may not be established clinically. Beneficial or desired clinical results include, but are not limited to, the alleviation of symptoms, the prevention of symptoms, the diminishment of extent of disease, the stabilisation (i.e., not worsening) of a condition, the delay or slowing of progression/worsening of a condition/symptoms, the amelioration or palliation of the condition/symptoms, and remission (whether partial or total), whether detectable or undetectable. The term “palliation”, and variations thereof, as used herein, means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering a compound, salt, solvate, prodrug or pharmaceutical composition of the present invention. The term “prevention” as used herein in relation to a disease, disorder or condition, relates to prophylactic or preventative therapy, as well as therapy to reduce the risk of developing the disease, disorder or condition. The term “prevention” includes both the avoidance of occurrence of the disease, disorder or condition, and the delay in onset of the disease, disorder or condition. Any statistically significant (p≤0.05) avoidance of occurrence, delay in onset or reduction in risk as measured by a controlled clinical trial may be deemed a prevention of the disease, disorder or condition. Subjects amenable to prevention include those at heightened risk of a disease, disorder or condition as identified by genetic or biochemical markers. Typically, the genetic or biochemical markers are appropriate to the disease, disorder or condition under consideration and may include for example, inflammatory biomarkers such as C-reactive protein (CRP) and monocyte chemoattractant protein 1 (MCP-1) in the case of inflammation; total cholesterol, triglycerides, insulin resistance and C-peptide in the case of NAFLD and NASH; and more generally IL1β and IL18 in the case of a disease, disorder or condition responsive to NLRP3 inhibition.

A sixth aspect of the invention provides the use of a compound of the first or second aspect, or a pharmaceutically effective salt, solvate or prodrug of the third aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition. Typically, the treatment or prevention comprises the administration of the compound, salt, solvate, prodrug or medicament to a subject. In one embodiment, the treatment or prevention comprises the co-administration of one or more further active agents.

A seventh aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby treat or prevent the disease, disorder or condition. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more further active agents. Typically, the administration is to a subject in need thereof.

An eighth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in the treatment or prevention of a disease, disorder or condition in an individual, wherein the individual has a germline or somatic non-silent mutation in NLRP3. The mutation may be, for example, a gain-of-function or other mutation resulting in increased NLRP3 activity. Typically, the use comprises the administration of the compound, salt, solvate, prodrug or pharmaceutical composition to the individual. In one embodiment, the use comprises the co-administration of one or more further active agents. The use may also comprise the diagnosis of an individual having a germline or somatic non-silent mutation in NLRP3, wherein the compound, salt, solvate, prodrug or pharmaceutical composition is administered to an individual on the basis of a positive diagnosis for the mutation. Typically, identification of the mutation in NLRP3 in the individual may be by any suitable genetic or biochemical means.

A ninth aspect of the invention provides the use of a compound of the first or second aspect, or a pharmaceutically effective salt, solvate or prodrug of the third aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition in an individual, wherein the individual has a germline or somatic non-silent mutation in NLRP3. The mutation may be, for example, a gain-of-function or other mutation resulting in increased NLRP3 activity. Typically, the treatment or prevention comprises the administration of the compound, salt, solvate, prodrug or medicament to the individual. In one embodiment, the treatment or prevention comprises the co-administration of one or more further active agents. The treatment or prevention may also comprise the diagnosis of an individual having a germline or somatic non-silent mutation in NLRP3, wherein the compound, salt, solvate, prodrug or medicament is administered to an individual on the basis of a positive diagnosis for the mutation. Typically, identification of the mutation in NLRP3 in the individual may be by any suitable genetic or biochemical means.

A tenth aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the steps of diagnosing of an individual having a germline or somatic non-silent mutation in NLRP3, and administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to the positively diagnosed individual, to thereby treat or prevent the disease, disorder or condition. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more further active agents. Typically, the administration is to a subject in need thereof.

In general embodiments, the disease, disorder or condition may be a disease, disorder or condition of the immune system, the cardiovascular system, the endocrine system, the gastrointestinal tract, the renal system, the hepatic system, the metabolic system, the respiratory system, the central nervous system, may be a cancer or other malignancy, and/or may be caused by or associated with a pathogen.

It will be appreciated that these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive. In this regard any particular disease, disorder or condition may be categorized according to more than one of the above general embodiments. A non-limiting example is type I diabetes which is an autoimmune disease and a disease of the endocrine system.

In one embodiment of the fifth, sixth, seventh, eighth, ninth or tenth aspect of the invention, the disease, disorder or condition is responsive to NLRP3 inhibition. As used herein, the term “NLRP3 inhibition” refers to the complete or partial reduction in the level of activity of NLRP3 and includes, for example, the inhibition of active NLRP3 and/or the inhibition of activation of NLRP3.

There is evidence for a role of NLRP3-induced IL-1 and IL-18 in the inflammatory responses occurring in connection with, or as a result of, a multitude of different disorders (Menu et al., Clinical and Experimental Immunology, 166: 1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

NLRP3 has been implicated in a number of autoinflammatory diseases, including Familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al., Eur. J. Immunol., 40: 595-653, 2010). In particular, NLRP3 mutations have been found to be responsible for a set of rare autoinflammatory diseases known as CAPS (Ozaki et al., J. Inflammation Research, 8:15-27, 2015; Schroder et al., Cell, 140: 821-832, 2010; and Menu et al., Clinical and Experimental Immunology, 166: 1-15, 2011). CAPS are heritable diseases characterized by recurrent fever and inflammation and are comprised of three autoinflammatory disorders that form a clinical continuum. These diseases, in order of increasing severity, are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile cutaneous neurological articular syndrome (CINCA; also called neonatal-onset multisystem inflammatory disease, NOMID), and all have been shown to result from gain-of-function mutations in the NLRP3 gene, which leads to increased secretion of IL-1β.

The inflammasome, and NLRP3 specifically, has also been proposed as a target for modulation by various pathogens including viruses such as DNA viruses (Amsler et al., Future Virol. (2013) 8(4), 357-370).

NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al., Clinical and Experimental Immunology 166: 1-15, 2011; and Masters Clin. Immunol. 2013). For example, several previous studies have suggested a role for IL-1β in cancer invasiveness, growth and metastasis, and inhibition of IL-1β with canakinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomised, double-blind, placebo-controlled trial (Ridker et al. Lancet, S0140-6736(17)32247-X, 2017). Inhibition of the NLRP3 inflammasome or IL-1β has also been shown to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al. Oncol Rep. 2016; 35(4): 2053-64). A role for the NLRP3 inflammasome has been suggested in myelodysplastic syndromes (Basiorka et al. Blood. 2016 Dec. 22; 128(25):2960-2975) and also in the carcinogenesis of various other cancers including glioma (Li et al. Am J Cancer Res. 2015; 5(1): 442-449), inflammation-induced tumours (Allen et al. J Exp Med. 2010; 207(5): 1045-56 and Hu et al. PNAS. 2010; 107(50): 21635-40), multiple myeloma (Li et al. Hematology 2016 21(3): 144-51), and squamous cell carcinoma of the head and neck (Huang et al. J Exp Clin Cancer Res. 2017 2; 36(1): 116). Activation of the NLRP3 inflammasome has also been shown to mediate chemoresistance of tumour cells to 5-Fluorouracil (Feng et al. J Exp Clin Cancer Res. 2017 21; 36(1): 81), and activation of NLRP3 inflammasome in peripheral nerve contributes to chemotherapy-induced neuropathic pain (Jia et al. Mol Pain. 2017; 13:1-11).

NLRP3 has also been shown to be required for the efficient control of viral, bacterial, fungal, and helminth pathogen infections (Strowig et al., Nature, 481:278-286, 2012).

Accordingly, examples of diseases, disorders or conditions which may be responsive to NLRP3 inhibition and which may be treated or prevented in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention include:

In one embodiment, the disease, disorder or condition is selected from:(i) inflammation;(ii) an auto-immune disease;(iii) cancer;(iv) an infection;(v) a central nervous system disease;(vi) a metabolic disease;(vii) a cardiovascular disease;(viii) a respiratory disease;(ix) a liver disease;(x) a renal disease;(xi) an ocular disease;(xii) a skin disease;(xiii) a lymphatic condition;(xiv) a psychological disorder;(xv) graft versus host disease; and(xvi) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

In another embodiment, the disease, disorder or condition is selected from:(i) cancer;(ii) an infection;(iii) a central nervous system disease;(iv) a cardiovascular disease;(v) a liver disease;(vi) an ocular diseases; or(vii) a skin disease.

More typically, the disease, disorder or condition is selected from:(i) cancer;(ii) an infection;(iii) a central nervous system disease; or(iv) a cardiovascular disease.

In a further typical embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that may be treated or prevented in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention include inflammatory responses occurring in connection with, or as a result of:

In one embodiment of the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is an autoinflammatory disease such as cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor antagonist (DIRA), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still's disease (AOSD), haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), or sideroblastic anaemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD).

Examples of diseases, disorders or conditions which may be responsive to NLRP3 inhibition and which may be treated or prevented in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention are listed above. Some of these diseases, disorders or conditions are substantially or entirely mediated by NLRP3 inflammasome activity, and NLRP3-induced IL-1β and/or IL-18. As a result, such diseases, disorders or conditions may be particularly responsive to NLRP3 inhibition and may be particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention. Examples of such diseases, disorders or conditions include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS), systemic juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing polychondritis, Schnitzler's syndrome, Sweet's syndrome, Behcet's disease, anti-synthetase syndrome, deficiency of interleukin 1 receptor antagonist (DIRA), and haploinsufficiency of A20 (HA20).

Moreover, some of the diseases, disorders or conditions mentioned above arise due to mutations in NLRP3, in particular, resulting in increased NLRP3 activity. As a result, such diseases, disorders or conditions may be particularly responsive to NLRP3 inhibition and may be particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention. Examples of such diseases, disorders or conditions include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal onset multisystem inflammatory disease (NOMID).

An eleventh aspect of the invention provides a method of inhibiting NLRP3, the method comprising the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to inhibit NLRP3.

In one embodiment of the eleventh aspect of the present invention, the method comprises the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, in combination with one or more further active agents.

In one embodiment of the eleventh aspect of the present invention, the method is performed ex vivo or in vitro, for example in order to analyse the effect on cells of NLRP3 inhibition.

In another embodiment of the eleventh aspect of the present invention, the method is performed in vivo. For example, the method may comprise the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby inhibit NLRP3. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more further active agents. Typically, the administration is to a subject in need thereof.

Alternately, the method of the eleventh aspect of the invention may be a method of inhibiting NLRP3 in a non-human animal subject, the method comprising the steps of administering the compound, salt, solvate, prodrug or pharmaceutical composition to the non-human animal subject and optionally subsequently mutilating or sacrificing the non-human animal subject. Typically, such a method further comprises the step of analysing one or more tissue or fluid samples from the optionally mutilated or sacrificed non-human animal subject. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more further active agents.

A twelfth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in the inhibition of NLRP3. Typically, the use comprises the administration of the compound, salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the compound, salt, solvate, prodrug or pharmaceutical composition is co-administered with one or more further active agents.

A thirteenth aspect of the invention provides the use of a compound of the first or second aspect of the invention, or a pharmaceutically effective salt, solvate or prodrug of the third aspect of the invention, in the manufacture of a medicament for the inhibition of NLRP3. Typically, the inhibition comprises the administration of the compound, salt, solvate, prodrug or medicament to a subject. In one embodiment, the compound, salt, solvate, prodrug or medicament is co-administered with one or more further active agents.

In any embodiment of any of the fifth to thirteenth aspects of the present invention that comprises the use or co-administration of one or more further active agents, the one or more further active agents may comprise for example one, two or three different further active agents.

The one or more further active agents may be used or administered prior to, simultaneously with, sequentially with or subsequent to each other and/or to the compound of the first or second aspect of the invention, the pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or the pharmaceutical composition of the fourth aspect of the invention. Where the one or more further active agents are administered simultaneously with the compound of the first or second aspect of the invention, or the pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, a pharmaceutical composition of the fourth aspect of the invention may be administered wherein the pharmaceutical composition additionally comprises the one or more further active agents.

In one embodiment of any of the fifth to thirteenth aspects of the present invention that comprises the use or co-administration of one or more further active agents, the one or more further active agents are selected from:

It will be appreciated that these general embodiments defined according to broad categories of active agents are not mutually exclusive. In this regard any particular active agent may be categorized according to more than one of the above general embodiments. A non-limiting example is urelumab which is an antibody that is an immunomodulatory agent for the treatment of cancer.

In some embodiments, the one or more alkylating agents may comprise an agent capable of alkylating nucleophilic functional groups under conditions present in cells, including, for example, cancer cells. In some embodiments, the one or more alkylating agents are selected from cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In some embodiments, the alkylating agent may function by impairing cell function by forming covalent bonds with amino, carboxyl, sulfhydryl, and/or phosphate groups in biologically important molecules. In some embodiments, the alkylating agent may function by modifying a cell's DNA.

In some embodiments, the one or more anti-metabolites may comprise an agent capable of affecting or preventing RNA or DNA synthesis. In some embodiments, the one or more anti-metabolites are selected from azathioprine and/or mercaptopurine.

In some embodiments, the one or more plant alkaloids and/or terpenoids may prevent microtubule function. In some embodiments, the one or more plant alkaloids and/or terpenoids are selected from avincaalkaloid, a podophyllotoxin and/or a taxane. In some embodiments, the one or morevincaalkaloids may be derived from the Madagascar periwinkle,Catharanthus roseus(formerly known asVinca rosea), and may be selected from vincristine, vinblastine, vinorelbine and/or vindesine. In some embodiments, the one or more taxanes are selected from taxol, paclitaxel, docetaxel and/or ortataxel. In some embodiments, the one or more podophyllotoxins are selected from an etoposide and/or teniposide.

In some embodiments, the one or more topoisomerase inhibitors are selected from a type I topoisomerase inhibitor and/or a type II topoisomerase inhibitor, and may interfere with transcription and/or replication of DNA by interfering with DNA supercoiling. In some embodiments, the one or more type I topoisomerase inhibitors may comprise a camptothecin, which may be selected from exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In some embodiments, the one or more type II topoisomerase inhibitors may comprise an epipodophyllotoxin, which may be selected from an amsacrine, etoposid, etoposide phosphate and/or teniposide.

In some embodiments, the one or more mTOR (mammalian target of rapamycin, also known as the mechanistic target of rapamycin) inhibitors are selected from rapamycin, everolimus, temsirolimus and/or deforolimus.

In some embodiments, the one or more STING (Stimulator of interferon genes, also known as transmembrane protein (TMEM) 173) agonists may comprise cyclic di-nucleotides, such as cAMP, cGMP, and cGAMP, and/or modified cyclic di-nucleotides that may include one or more of the following modification features: 2′-O/3′—O linkage, phosphorothioate linkage, adenine and/or guanine analogue, and/or 2′-OH modification (e.g. protection of the 2′-OH with a methyl group or replacement of the 2′-OH by —F or —N3).

In some embodiments, the one or more cancer vaccines are selected from an HPV vaccine, a hepatitis B vaccine, Oncophage, and/or Provenge.

In some embodiments, the one or more antibiotics may comprise one or more cytotoxic antibiotics. In some embodiments, the one or more cytotoxic antibiotics are selected from an actinomycin, an anthracenedione, an anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and/or chlofazimine. In some embodiments, the one or more actinomycins are selected from actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In some embodiments, the one or more antracenediones are selected from mitoxantrone and/or pixantrone. In some embodiments, the one or more anthracyclines are selected from bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and/or valrubicin.

Unless stated otherwise, in any of the fifth to thirteenth aspects of the invention, the subject may be any human or other animal. Typically, the subject is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse, etc. Most typically, the subject is a human.

Typically, the mode of administration selected is that most appropriate to the disorder, disease or condition to be treated or prevented. Where one or more further active agents are administered, the mode of administration may be the same as or different to the mode of administration of the compound, salt, solvate, prodrug or pharmaceutical composition of the invention.

For oral administration, the compounds, salts, solvates or prodrugs of the present invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lozenges, as a powder or granules, or as an aqueous solution, suspension or dispersion.

Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose. Corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatine. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/or dissolving tablets.

Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

Powders or granules for oral use may be provided in sachets or tubs. Aqueous solutions, suspensions or dispersions may be prepared by the addition of water to powders, granules or tablets.

Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavouring agents, colouring agents and/or preservatives.

For parenteral use, the compounds, salts, solvates or prodrugs of the present invention will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride or glucose. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate. The compounds of the invention may also be presented as liposome formulations.

For ocular administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in a form suitable for topical administration, e.g. as eye drops. Suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels and ocular inserts. Alternatively, the compounds, salts, solvates or prodrugs of the invention may be provided in a form suitable for other types of ocular administration, for example as intraocular preparations (including as irrigating solutions, as intraocular, intravitreal or juxtascleral injection formulations, or as intravitreal implants), as packs or corneal shields, as intracameral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations.

For transdermal and other topical administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches.

Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.

The dose of the compounds, salts, solvates or prodrugs of the present invention will, of course, vary with the disorder, disease or condition to be treated or prevented. In general, a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day. The desired dose may be presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day. The desired dose may be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.

For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention.

By way of example, combinations of aspects and embodiments that are typical of the present invention include the following.

In a first combination, a compound of the first aspect of the invention is provided wherein the 5-membered heteroaryl group of R1is monocyclic and contains at least one nitrogen atom in the 5-membered ring structure, and wherein R2is a cyclic group substituted at the α and α′ positions, wherein R2may optionally be further substituted.

In a second combination, a compound of the first aspect of the invention is provided wherein the 5-membered heteroaryl group of R1is monocyclic and contains only carbon and nitrogen atoms in the 5-membered ring structure, and wherein R2is a cyclic group substituted at the α and α′ positions, wherein R2may optionally be further substituted.

In a third combination, a compound of the first aspect of the invention is provided wherein RXcontains only atoms selected from the group consisting of carbon, hydrogen, nitrogen, oxygen and halogen atoms, and wherein R2is a cyclic group substituted at the α and α′ positions, wherein R2may optionally be further substituted.

In a fourth combination, a compound of the first aspect of the invention is provided wherein RXcontains from 5 to 11 atoms other than hydrogen or halogen, and wherein R2is a cyclic group substituted at the α and α′ positions, wherein R2may optionally be further substituted.

In a fifth combination, a compound of the first aspect of the invention is provided wherein:Q is O;R1is

In a sixth combination, a compound of the first aspect of the invention is provided wherein:Q is O;R1is

wherein:V and X are independently selected from C and N, and W, Y and Z are each independently selected from N, NH and CH, provided that at least two of V, W, X, Y and Z are N or NH and at least two of V, W, X, Y and Z are C or CH;n is 0 or 1;RXis:

wherein:T is O, S or NR101;R101is a methyl, ethyl, n-propyl, isopropyl or cyclopropyl group, all of which may optionally be substituted with one or more fluoro and/or chloro groups;each R102is independently selected from hydrogen or a methyl group, wherein the methyl group may optionally be substituted with one or more fluoro and/or chloro groups;L2is a straight chained or branched C1-C3alkylene group, where the alkylene group may optionally include one heteroatom N or O in its carbon skeleton, and wherein the alkylene group may optionally be substituted with a single oxo (═O) group and/or with one or more fluoro and/or chloro groups;RYis selected from a C1-C4alkyl or C3-C4cycloalkyl group, wherein the C1-C4alkyl or C3-C4cycloalkyl group may optionally be substituted with one or more fluoro and/or chloro groups; andR2is:

wherein A1and A2are each independently selected from a straight-chained alkylene group, wherein one carbon atom in the backbone of the alkylene group may optionally be replaced by an oxygen atom, wherein any ring containing A1or A2is a 5- or 6-membered ring, wherein A1and A2are unsubstituted or substituted with one or more fluoro and/or chloro groups, and Reis hydrogen or halo.

A seventh combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, wherein the 5-membered heteroaryl group of R1is monocyclic and contains at least one nitrogen atom in the 5-membered ring structure, for use in medicine.

Typically, in any of the above exemplary combinations, Q is O.

Typically, in any of the above exemplary combinations, R2is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α and α′ positions, and wherein R2may optionally be further substituted.

Typically, in any of the above exemplary combinations, R2contains from 7 to 25 atoms other than hydrogen or halogen.

Typically, in any of the above exemplary combinations, RXcontains from 5 to 11 atoms other than hydrogen or halogen.

As will be appreciated the above combinations are exemplary only and other combinations of aspects and embodiments, including combinations of the above combinations, may readily be envisaged.

All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

EXPERIMENTAL METHODS

Nuclear Magnetic Resonance

NMR spectra were recorded at 300, 400 or 500 MHz. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Spectra were recorded using one of the following machines:a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe,a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control,a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™,an Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, indirect detection probe and direct drive console including PFG module, oran Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.
LC-MS

Reversed Phase HPLC Conditions for the LCMS Analytical Methods

Reversed Phase HPLC Conditions for the UPLC Analytical Methods

Preparative Reversed Phase HPLC General Methods

SYNTHESIS OF INTERMEDIATES

A solution of BuLi (100 mL, 250 mmol, 2.5M in hexanes) was added slowly to a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (36.2 g, 238 mmol) in THF (500 mL) keeping the temperature below −65° C. The mixture was stirred for 1.5 hours, then sulfur dioxide was bubbled through for 10 minutes. The mixture was allowed to warm to room temperature, the solvent evaporated and the residue triturated with TBME (300 mL) and filtered. The solid was washed with TBME and isohexane and dried to afford the crude title compound (54.89 g, 99%).

NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (20 g, 90 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 hours, quenched with water (100 mL), and then partitioned between DCM (300 mL) and water (200 mL). The organic phase was washed with water (200 mL), dried (MgSO4), filtered and evaporated to ˜50 mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature, and then partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1M HCl (2×250 mL), water (250 mL), dried (MgSO4), filtered, and evaporated to afford the crude title compound (41.02 g, 97%) as a brown oil.

A mixture of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (41 g, 87 mmol) and aq 1M HCl (30 mL) in THF (300 mL) and MeOH (50 mL) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue partitioned between EtOAc (400 mL) and aq 1M HCl (200 mL). The organic layer was washed with 10% brine (200 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with TBME, filtered and dried to afford the title compound (24.87 g, 69%) as an off white solid.

K2CO3(0.535 g, 3.87 mmol) was added to a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.5 g, 1.290 mmol) and 2-(chloromethyl)pyrimidine hydrochloride (0.213 g, 1.290 mmol) in DMF (8 mL). The reaction mixture was heated to 70° C. and stirred for 16 hours. Then the reaction mixture was washed with saturated brine (3×20 mL), the washings were combined and extracted with DCM (3×20 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-100% EtOAc/isohexane), then purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane and 0-10% MeOH/DCM) to afford the title compound (62 mg, 6%) as a yellow oil.

N,N-Bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (60 mg, 0.079 mmol) was dissolved in DCM (1 mL) and TFA (1 mL) was added. The solution was stirred for 16 hours. The reaction mixture was concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The crude product was purified by chromatography on silica gel (12 g column, 0-5% MeOH/DCM) to afford the title compound (16 mg, 84%) as a brown solid.

Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-(chloromethyl)oxazole to afford the title compound (523 mg, 83%) as a colourless crystalline solid.

Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(oxazol-2-ylmethyl)-1H-pyrazole-3-sulfonamide to afford the title compound (146 mg, 59%) as a colourless crystalline solid.

Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-(chloromethyl)-1-methyl-1H-imidazole, HCl salt to afford the title compound (270 mg, 37%) as a yellow oil.

Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-3-sulfonamide to afford the title compound (105 mg, 85%) as a yellow oil.

Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-bromopyridine to afford the title compound (210 mg, 83%) as an oil.

Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(pyridin-2-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (82 mg, 67%) as a white solid.

Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-bromothiazole to afford the title compound (169 mg, 84%) as an oil.

Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(thiazol-2-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (45 mg, 34%) as a white solid.

3-Bromopyridine (130 μL, 1.349 mmol) and N1,N2-dimethylethane-1,2-diamine (15 μL, 0.139 mmol) were added to a suspension of N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step C) (495 mg, 1.278 mmol), K2CO3(350 mg, 2.53 mmol) and CuI (15 mg, 0.079 mmol) in dry DMF (8 mL). The resulting mixture was heated to 140° C. (bath temperature) for 3 days. The mixture was cooled to room temperature, diluted with EtOAc (50 mL) and filtered through Celite®. The solution was concentrated in vacuo to give a brown oil, which was purified by chromatography on silica gel (40 g column 0-50% EtOAc/isohexane) to afford the title compound as a colourless oil (127 mg, 20%).

Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(pyridin-3-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (51 mg, 86%) as a white solid.

2 M Sodium tert-butoxide in THF (1.005 mL, 2.009 mmol) was added to a solution of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (0.5 g, 1.914 mmol) in THF (15 mL) and stirred at room temperature for 1 hour to give a white suspension. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.419 g, 2.105 mmol) in THF (5 mL) was added and stirred at room temperature overnight. The resultant colourless precipitate was collected by filtration, washing with THF (4 mL), and dried in vacuo to afford the title compound (930 mg, 91%) as a colourless solid.

Ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (3.15 g, 6.24 mmol) was dissolved in MeOH (20 mL), 2 M aqueous NaOH (3.12 mL, 6.24 mmol) was added and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (2.80 g, 99%) as a colourless solid.

To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in EtOAc (90 mL) was added dropwise a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in EtOAc (45 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 3 hours and upon cooling was filtered and concentrated in vacuo to afford the title compound as a brown oil (756 mg, 100%). The crude product was used directly in the next step without further purification.

PREPARATION OF EXAMPLES

Sodium tert-butoxide (2M in THF) (0.033 mL, 0.066 mmol) was added to a solution of 1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1) (15 mg, 0.063 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (14 mg, 0.070 mmol) was added and the reaction mixture was stirred at room temperature overnight. Volatiles were evaporated and the crude product was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (3.5 mg, 13%) as a white solid.

Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(oxazol-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P2) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (27 mg, 25%) as a white solid.

Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P3) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (34 mg, 21%) as a white solid.

Sodium tert-butoxide (2 M in THF) (0.103 mL, 0.206 mmol) was added to a solution of 1-(pyridin-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate P4) (44 mg, 0.196 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (41 mg, 0.206 mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. EtOAc (6 mL) was added and the suspension stirred for 1 hour, filtered, and washed with EtOAc (1 mL). The collected solid was dried under reduced pressure to afford the title compound (15 mg, 16%) as a white solid.

Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyridin-2-yl)-H-pyrazole-3-sulfonamide, sodium salt (Example 4) from 1-(thiazol-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate P5) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (16 mg, 24%) as a white solid.

Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(pyridin-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P6) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (16 mg, 17%) as a white solid.

HATU (58 mg, 0.151 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P7) (65 mg, 0.145 mmol) and N-methyl-1-(thiazol-2-yl)methanamine (19 mg, 0.151 mmol) in DMF (1 mL) and stirred for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (18 mg, 26%) as a white solid.

Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-N-(thiazol-2-ylmethyl)-1H-pyrazole-5-carboxamide (Example 7) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P7) and N-methyl-1-(1-methyl-H-imidazol-2-yl)methanamine to afford the title compound (11 mg, 13%) as a white solid.

Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-N-(thiazol-2-ylmethyl)-1H-pyrazole-5-carboxamide (Example 7) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P7) and N-methylthiazol-2-amine to afford the title compound (4 mg, 7%) as a white solid.

It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1ρ) from the cell.

THP-1 Cells: Culture and Preparation

THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma #S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma #P4333) in 10% Fetal Bovine Serum (FBS) (Sigma #F0804). The cells were routinely passaged and grown to confluency (˜106cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma #T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma #L4524) to give a 1 μg/ml Final Assay Concentration (FAC). 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

The following method step-by-step assay was followed for compound screening.1. Seed THP-1 cells (25,000 cells/well) containing 1.0 μg/ml LPS in 40 μl of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317)2. Add 5 μl compound (8 points half-log dilution, with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells3. Incubate for 3 hrs at 37° C. and 5% CO24. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells5. Incubate for 1 hr at 37° C. and 5% CO26. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant7. Then add 50 μl of resazurin (Sigma #R7017) (FAC 100 M resazurin in RPMI medium without FBS) and incubate plates for a further 1-1.5 h at 37° C. and 5% CO28. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm9. IC50data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)
96-Well Plate Map

The results of the pyroptosis assay performed are summarised in Table 1 below as THP IC50.

Human Whole Blood IL1β Release Assay

For systemic delivery, the ability to inhibit NLRP3 when the compounds are present within the bloodstream is of great importance. For this reason, the NLRP3 inhibitory activity of a number of compounds in human whole blood was investigated in accordance with the following protocol.

Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel.1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585)2. Add 10 μl compound (8 points half-log dilution with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells3. Incubate for 3 hrs at 37° C., 5% CO24. Add 10 μl nigericin (Sigma #N7143) (10 μM FAC) to all wells5. Incubate for 1 hr at 37° C., 5% CO26. At the end of the incubation period, spin plates at 300×g for 5 mins to pellet cells and remove 20 μl of supernatant and add to 96-well v-bottom plates for IL-1β analysis (note: these plates containing the supernatants can be stored at −80° C. to be analysed at a later date)7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000)8. IC50data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

The results of the human whole blood assay are summarised in Table 1 below as HWB IC50.

As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in the human whole blood assay.

It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.