Novel sulfonamide carboxamide compounds

Abstract

The present invention relates to compounds of formula (I): wherein Q is selected from O or S; r1 is a non-aromatic heterocyclic group comprising at least one ring nitrogen atom, where R1 is attached to the sulfur atom of the sulfonylurea group via a ring carbon atom, and where R1 may optionally be substituted; and R2 is a cyclic group substituted in the alpha position, wherein R2 may optionally be further substituted. The invention also relates to salts, solvates and prodrugs of such compounds; pharmaceutical compositions comprising such compounds; and to the use of such compounds in the treatment and prophylaxis of medical conditions and diseases, most particularly in the treatment and prophylaxis of medical conditions and diseases by inhibition of NLRP3.

Description

[0001] This application is a divisional application of patent application No. 201880044712.X, filed on July 4, 2018, entitled “Novel Sulfonylurea Carboxamide Compounds”. TECHNICAL FIELD

[0002] The present invention relates to sulfonylureas and sulfonylthioureas comprising a non-aromatic heterocyclic group comprising at least one ring nitrogen atom and further comprising a second cyclic group substituted in the alpha position, and to related salts, solvates, prodrugs, and pharmaceutical compositions. The invention also relates to the use of such compounds in the treatment of medical conditions and diseases, most especially in the treatment and prevention of medical conditions and diseases by inhibition of NLRP3. BACKGROUND

[0003] 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 genetic disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease, and atherosclerosis.

[0004] NLRP3 is an intracellular signaling 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 polymerizes to form large aggregates known as ASC specks. Polymerized ASC in turn interacts with the cysteine protease caspase-1 to form a complex known as the inflammasome. This leads to activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (referred to as pro-IL-1β and pro-IL-18, respectively) to thereby activate these cytokines. Caspase-1 also mediates a form of inflammatory cell death known as pyroptosis. ASC specks can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death.

[0005] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted out of the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Despite its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarm molecule such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and allowing the release of IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. Many other caspase-1 substrates such as cytoskeletal proteins and components of the glycolytic pathway can lead to caspase-1 -dependent inflammation.

[0006] 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.

[0007] 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 signaling induces secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Th17 cells and by gd T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also synergize to induce IFN-γ production by memory T cells and NK cells that drive Th1 responses.

[0008] The genetic 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 key component of the inflammatory process. NLRP3 is also implicated in the pathogenesis of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0009] The role of NLRP3 in central nervous system diseases is emerging and lung diseases have been shown to be affected by NLRP3. In addition, NLRP3 plays a role in the development of liver diseases, kidney diseases, and aging. Many of these associations were made using Nlrp3 - / - mouse models, but there is also an understanding of specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1 β signaling, leading to cell death and inflammation.

[0010] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits IL-1 β production in response to activation of NLRP3, but not NLRC4 or NLRP1, at micromolar concentrations. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β- nitrostyrene, and dimethyl sulfoxide (DMSO), but these agents have limited potency and are non-specific.

[0011] 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-1 β 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-1 β related diseases.

[0012] Some diaryl sulfonylurea 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 diaryl sulfonylurea containing compounds that inhibit the post-translational processing of IL-1 β. The post-translational processing of IL-1 β is accompanied by activation of caspase-1 and cell death. CRIDs prevent activated monocytes from allowing caspase-1 to remain inactive and retain the plasma membrane latency.

[0013] Certain sulfonylurea-containing compounds are also disclosed as inhibitors of NLRP3 (see, e.g., Baldwin et al., J. Med. Chem., 59(5), 1691-1710, 2016; and WO 2016 / 131098 Al, WO 2017 / 129897 Al, WO 2017 / 140778 Al, WO 2017 / 184604 Al, WO 2017 / 184623 Al, WO 2017 / 184624 Al, and WO 2018 / 015445 Al).

[0014] There is a need to provide compounds with improved pharmacological and / or physiological and / or physiochemical properties and / or to provide compounds that are useful alternatives to known compounds. SUMMARY

[0015] A first aspect of the application provides a compound of formula (I):

[0016]

[0017] wherein:

[0018] Q is selected from O or S;

[0019] R 1 is a non-aromatic heterocyclic group containing at least one ring nitrogen atom, wherein R 1 is attached to the sulphur atom of the sulfonylurea group via a ring carbon atom, and wherein R 1 may optionally be substituted; and

[0020] R 2 is a cyclic group substituted in the alpha position, wherein R 2 may optionally be further substituted.

[0021] In the context of the present specification, a "hydrocarbyl" substituent group or hydrocarbyl moiety in a substituent group includes only carbon and hydrogen atoms, but does not include any heteroatoms such as N, O or S in its carbon backbone, unless otherwise specified. Hydrocarbyl groups / moieties can be saturated or unsaturated (including aromatic), and can be straight-chain or branched-chain, or be or include cyclic groups, wherein the cyclic groups do not include any heteroatoms such as N, O or S in their carbon backbone, unless otherwise specified. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups / moieties, and combinations of all such groups / moieties. Typically, a hydrocarbyl group is a C1-C 20 hydrocarbyl group. More typically, a hydrocarbyl group is a C1-C 15 hydrocarbyl group. More typically, a hydrocarbyl group is a C1-C 10 hydrocarbyl group. An "hydrocarbylene" group is similarly defined as a divalent hydrocarbyl group.

[0022] In the context of this specification, unless otherwise stated, an "alkyl" substituent group or an alkyl moiety in a substituent group may be linear or branched. Examples of alkyl groups / moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and n-pentyl groups / moieties. Unless otherwise stated, the term "alkyl" does not include "cycloalkyl". Typically, an alkyl group is C1-C 12 Alkyl groups. More typically, the alkyl group is a C1-C6 alkyl group. An "alkylene" group is similarly defined as a divalent alkyl group.

[0023] 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 otherwise indicated, the term "alkenyl" does not include "cycloalkenyl". Typically, alkenyl groups are C2-C 12 Alkenyl groups. More typically, alkenyl groups are C2-C6 alkenyl groups. An "alkenylene" group is similarly defined as a divalent alkenyl group.

[0024] An "alkynyl" substituent group or alkynyl moiety of 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, propynyl, but-1-ynyl, and but-2-ynyl. Typically, an alkynyl group is C2-C 12 Alkynyl groups. More typically, alkynyl groups are C2-C6 alkynyl groups. An "alkynylene" group is similarly defined as a divalent alkynyl group.

[0025] The cyclic moiety in a "cyclic" substituent group or a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring can be saturated or unsaturated (including aromatics) and can include one or more heteroatoms such as N, O or S in its carbon backbone. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic groups, aryl and heteroaryl groups as discussed below. Cyclic groups can be monocyclic, bicyclic (for example, bridging, condensed or spiral) or polycyclic. Typically, cyclic groups are 3 to 12 yuan of cyclic groups, meaning that they contain 3 to 12 ring atoms. More typically, cyclic groups are 3 to 7 yuan of monocyclic groups, meaning that they contain 3 to 7 ring atoms.

[0026] As used herein, when a cyclic group is described as monocyclic, it is understood that the cyclic group is not occluded by a divalent bridging substituent (e.g., -O-, -S-, -NH-, -N(R)-, or -NH-). β )-or-R α-) substitution so as to form a bridged, fused, or spiro substituent. However, unless otherwise indicated, a substituted monocyclic group can be substituted with one or more monovalent cyclic groups. Similarly, when a group is stated to be bicyclic, it is understood that the cyclic group, including any bridging, fused, or spiro divalent bridging substituents connecting the cyclic groups, but not including any monovalent cyclic substituents, is bicyclic.

[0027] A "heterocyclo" moiety in a substituent group or substituent group means a cyclic group or portion that includes one or more carbon atoms and one or more heteroatoms, e.g., N, O, or S, in a ring structure. Examples of heterocyclo groups include heteroaryl groups as discussed below and non-aromatic heterocyclo groups such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, thietanyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, thianyl, and dioxanyl groups.

[0028] A "cycloalkyl" moiety in a substituent group or substituent group means a saturated hydrocarbyl ring containing, e.g., 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a cycloalkyl substituent group or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0029] A "cycloalkenyl" moiety in a substituent group or substituent group means a non-aromatic unsaturated hydrocarbyl ring having one or more carbon-carbon double bonds and containing, e.g., 3 to 7 carbon atoms. Examples include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohex-1,3-dien-1-yl. Unless otherwise specified, a cycloalkenyl substituent group or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0030] An "aryl" moiety in a substituent group or substituent group means an aromatic hydrocarbyl ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic, fused ring aromatic hydrocarbons in which all of the fused ring systems (excluding any ring systems that are part of or formed by an optional substituent) are aromatic. Examples of aryl groups / moieties include phenyl, naphthyl, anthryl, and phenanthryl. Unless otherwise specified, the term "aryl" does not include "heteroaryl."

[0031] A "heteroaryl" moiety in a substituted group or substituent group refers to an aromatic heterocyclic group or moiety. The term "heteroaryl" includes both monocyclic aromatic heterocycles and polycyclic fused ring aromatic heterocycles, where all of the fused ring systems (excluding any ring systems that are part of or formed by an optional substituent) are aromatic. Examples of heteroaryl groups / moieties include the following:

[0032]

[0033] where G = O, S or NH.

[0034] Unless otherwise indicated, when a cyclic group or moiety is stated to be non-aromatic such as a cycloalkyl, cycloalkenyl, or non-aromatic heterocyclic group, it is understood that the group or moiety (excluding any ring systems that are part of or formed by an optional substituent) is non-aromatic. Similarly, when a cyclic group or moiety is stated to be aromatic such as an aryl or heteroaryl group, it is understood that the group or moiety (excluding any ring systems that are part of or formed by an optional substituent) is aromatic. In general, a cyclic group or moiety is considered to be non-aromatic when it does not have any tautomers that are aromatic. In general, a cyclic group or moiety is considered to be aromatic when it has tautomers that are aromatic, even if it has tautomers that are not aromatic.

[0035] For the purposes of the present specification, when a combination of moieties is referred to as a group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl, the moiety last mentioned contains the atom(s) linking the group to the remainder of the molecule. An example of an arylalkyl group is benzyl.

[0036] For the purposes of the present specification, in an optionally substituted group or moiety:

[0037] (i) each hydrogen atom can be optionally replaced by a group independently selected from halo; -CN; -NO2; -N3; -R β ; -OH; -OR β ; -R α -halo; -R α -CN; -R α -NO2; -R α -N3; -R α -R β ; -R α -OH; -R α -OR β ; -SH; -SR β ; -SOR β ; -SO2H; -SO2R β ; -SO2NH2; -SO2NHRβ ;-SO2N(R β )2;-R α -SH;-R α -SR β ;-R α -SOR β ;-R α -SO2H;-R α -SO2R β ;-R α -SO2NH2;-R α -SO2NHR β ;-R α -SO2N(R β )2;-Si(R β )3;-O-Si(R β )3;-R α -Si(R β )3;-R α -O-Si(R β )3;-NH2;-NHR β ;-N(R β )2;-N(O)(R β )2;-N + (R β )3;-R α -NH2;-R α -NHR β ;-R α -N(R β )2;-R α -N(O)(R β )2;-R α -N + (R β )3;-CHO;-COR β ;-COOH;-COOR β ;-OCOR β ;-R α -CHO;-R α -COLOR β ;-R α -COOH;-R α -COOR β ;-R α -OCOR β ;-C(=NH)R β ;-C(=NH)NH2;-C(=NH)NHR β ;-C(=NH)N(R β )2;-C(=NR β )R β ;-C(=NRβ )NHR β ;-C(=NR β )N(R β )2;-C(=NOH)R β ;-C(N2)R β ;-R α -C(=NH)R β ;-R α -C(=NH)NH2;-R α -C(=NH)NHR β ;-R α -C(=NH)N(R β )2;-R α -C(=NR β )R β ;-R α -C(=NR β )NHR β ;-R α -C(=NR β )N(R β )2;-R α -C(=NOH)R β ;-R α -C(N2)R β ;-NH-CHO;-NR β -CHO;-NH-COR β ;-NR β -COR β ;-CONH2;-CONHR β ;-CON(R β )2;-R α -NH-CHO;-R α -NR β -CHO;-R α -NH-COR β ;-R α -NR β -COR β ;-R α -CONH2;-R α -CONHR β ;-R α -CON(R β )2;-O-R α -OH;-O-R α -OR β ;-O-R α -NH2;-O-R α -NHR β ;-O-R α -N(R β)2; -O-R α -N(O)(R β )2; -O-R α -N + (R β )3; -NH-R α -OH; -NH-R α -OR β ; -NH-R α -NH2; -NH-R α -NHR β ; -NH-R α -N(R β )2; -NH-R α -N(O)(R β )2; -NH-R α -N + (R β )3; -NR β -R α -OH; -NR β -R α -OR β ; -NR β -R α -NH2; -NR β -R α -NHR β ; -NR β -R α -N(R β )2; -NR β -R α -N(O)(R β )2; -NR β -R α -N + (R β )3; -N(O)R β -R α -OH; -N(O)R β -R α -OR β ; -N(O)R β -R α -NH2; -N(O)R β -R α -NHR β ; -N(O)R β -R α -N(R β )2; -N(O)R β -R α -N(O)(R β )2; -N(O)R β -R α-N + (R β )2-R + (R β )2-R α (R + )2-R β (R α )2-R β (R + )2-R β (R α )2-R + (R β )2-R α (R β )2-R + (R β )2-R α (R β )2-R + (R β )2-R α (R β )2-R

[0038] (ii) any two hydrogen atoms attached to the same atom can optionally be replaced by a p-bonded substituent independently selected from oxo (=0), =S, =NH or =NR β ; and / or

[0039] (iii) any two hydrogen atoms attached to the same or different atoms (within the same optionally substituted group or moiety) can optionally be replaced by a bridging substituent independently selected from -0-, -S-, -NH-, -N=N-, -N(R β )-, -N(O)(R β )-, -N + (R β )2- or -R α -;

[0040] wherein each -R α - is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group can optionally be replaced by one or more heteroatoms N, O or S, wherein one or more -CH2- groups in the backbone of the alkylene, alkenylene or alkynylene group can optionally be replaced by one or more -N(O)(R β )- or -N + (R β )2- groups, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups are substituted; and

[0041] wherein each -R β is independently selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C2-C7cyclic group, or where any two or three -R β groups attached to the same nitrogen atom can form a C2-C7cyclic group, and wherein any -R β may be optionally 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), -CO(C1-C4alkyl), -CO(C1-C4haloalkyl), -COO(C1-C4alkyl), -COO(C1-C4haloalkyl), halo, -OH, -NH2, -CN, -CºCH, oxo (=O), or 4- to 6-membered heterocyclic group.

[0042] In general, the compounds of the present application comprise at least one quaternary ammonium group, such as -N + (R β )3or -N + (R β )2-.

[0043] When referring to -R α -C(N2)R β groups, it is intended to mean:

[0044]

[0045] In general, in an optionally substituted group or moiety:

[0046] (i) each hydrogen atom can be optionally replaced by a group independently selected from halo; -CN; -NO2; -N3; -R β ; -OH; -OR β ; -SH; -SR β ; -SOR β ; -SO2H; -SO2R β ; -SO2NH2; -SO2NHR β ; -SO2N(R β )2; -R α -SH; -R α -SR β ; -R α -SOR β ; -R α -SO2H; -R α -SO2Rβ ; -R α ; -R α ; -R β ; -R α ; -R β ; -R β ; -R β ; -R α ; -R α ; -R β ; -R α ; -R β ; -R β ; -R β ; -R β ; -R α ; -R α ; -R β ; -R α ; -R α ; -R β ; -R α ; -R β ; -R β ; -R β ; -R β ; -R β ; -R β ; -R β ; -R α ; -R α ; -R β ; -R α ; -R β ; -R α ; -R β ; -R β ; -R α ; -R α ; -R β ; -R α ; -R β ; -R α ; -R α ; -R β ; -R α ; -R α ; -R β ; -R α ; -R β ; -R α ; -Rα -OR β ; -NH-R α -NH2; -NH-R α -NHR β ; -NH-R α -N(R β )2; -NR β -R α -OH; -NR β -R α -OR β ; -NR β -R α -NH2; -NR β -R α -NHR β ; -NR β -R α -N(R β )2; a C3-C7cycloalkyl group optionally substituted with one or more C1-C3alkyl or C1-C3haloalkyl groups; a C3-C7cycloalkenyl group optionally substituted with one or more C1-C3alkyl or C1-C3haloalkyl groups; or a 3- to 7-membered non-aromatic heterocyclyl group optionally substituted with one or more C1-C6alkyl or C1-C3haloalkyl groups; and / or

[0047] (ii) any two hydrogen atoms attached to the same carbon atom can optionally be replaced by a p-bonded substituent independently selected from oxo (=0), =S, =NH or =NR β ; and / or

[0048] (iii) any two hydrogen atoms attached to the same or different atoms (within the same optionally substituted group or moiety) can optionally be replaced by a bridging substituent independently selected from -0-, -S-, -NH-, -N(R β )- or -R α -;

[0049] wherein each -R α - is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group can optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -R β groups; and

[0050] wherein each -R βindependently selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C2-C6cyclic group, and wherein any -R β optionally substituted with one or more C1-C3alkyl, C1-C3haloalkyl, C3-C7cycloalkyl, -O(C1-C3alkyl), halo, -CN, -CºCH, or oxo (=0) groups.

[0051] Generally, in an optionally substituted group or moiety:

[0052] (i) each hydrogen atom can be optionally replaced by a group independently selected from halo; -CN; -NO2; -N3; -R β ; -OH; -OR β ; -SH; -SR β ; -SOR β ; -SO2H; -SO2R β ; -SO2NH2; -SO2NHR β ; -SO2N(R β )2; -R α -SH; -R α -SR β ; -R α -SOR β ; -R α -SO2H; -R α -SO2R β ; -R α -SO2NH2; -R α -SO2NHR β ; -R α -SO2N(R β )2; -NH2; -NHR β ; -N(R β )2; -R α -NH2; -R α -NHR β ; -R α -N(R β )2; -CHO; -COR β ; -COOH; -COOR β ; -OCOR β ; -R α -CHO; -R α -COR β ; -R α -COOH; -R α -COOR β ; -R α -OCOR β ; -NH-CHO; -NR β-CHO; -NH-COR β ; -NR β -COR β ; -CONH2; -CONHR β ; -CON(R β )2; -R α -NH-CHO; -R α -NR β -CHO; -R α -NH-COR β ; -R α -NR β -COR β ; -R α -CONH2; -R α -CONHR β ; -R α -CON(R β )2; C3-C7cycloalkyl optionally substituted with one or more C1-C3alkyl or C1-C3haloalkyl groups; C3-C7cycloalkenyl optionally substituted with one or more C1-C3alkyl or C1-C3haloalkyl groups;

[0053] and / or

[0054] (ii) any two hydrogen atoms attached to the same carbon atom can optionally be replaced by a π-bonded substituent independently selected from (oxo) =0, =S, =NH or =NR β ; and / or

[0055] (iii) any two hydrogen atoms attached to the same or different atoms (within the same optionally substituted group or moiety) can optionally be replaced by a bridging substituent independently selected from -0-, -S-, -NH-, -N(R β )- or -R α -;

[0056] wherein each -R α 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, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted with one or more halo and / or -R β groups;

[0057] wherein each -R β is independently selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group, and wherein any -R βoptionally substituted with one or more C1-C3 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, -0(C1-C3 alkyl), halo, -CN, -CºCH, or oxo (=0) groups;

[0058] wherein each -R δ is independently selected from a C1-C6 alkyl or C1-C3 haloalkyl group;

[0059] wherein each m is independently selected from 1, 2, or 3; and

[0060] wherein each n is independently selected from 1, 2, or 3.

[0061] Typically, a substituted group comprises 1, 2, 3, or 4 substituents, more typically 1, 2, or 3 substituents, more typically 1 or 2 substituents, and more typically 1 substituent.

[0062] Unless otherwise specified, any divalent bridging substituent (e.g., -0-, -S-, -NH-, -N(R 1 )-, -N(O)(R β )-, -N β (R + )2- or -R β -) of an optionally substituted group or moiety (e.g., R α ) must only connect the specified group or moiety and can not connect a second group or moiety (e.g., R 2 ), even if the second group or moiety can itself be optionally substituted.

[0063] The term “halo” includes fluoro, chloro, bromo, and iodo.

[0064] Unless otherwise specified, any reference to an element is a reference to all isotopes of the element. Thus, for example, unless otherwise specified, any reference to hydrogen is a reference to all isotopes of hydrogen, including deuterium and tritium.

[0065] When referring to a hydrocarbyl group or other group that includes one or more heteroatoms N, O, and S in its carbon backbone, or when referring to a carbon atom of a hydrocarbyl group or other group that is replaced by an N, O, or S atom, it is intended that:

[0066] is replaced by ;

[0067] -CH2- is replaced by -NH-, -O-, or -S-;

[0068] -CH3 is replaced by -NH2, -OH, or -SH;

[0069] -CH= is replaced by -N=;

[0070] CH2= is replaced by NH=, O= or S=; or

[0071] CH≡ is replaced by N≡;

[0072] provided that the resulting group contains at least one carbon atom. For example, methoxy, dimethylamino and aminoethyl groups are considered to be hydrocarbyl groups that include one or more heteroatoms N, O or S in their carbon backbone.

[0073] when referring to a -CH2- group in the backbone of a hydrocarbyl group or other group that is replaced by a -N(O)(R β )- or -N + (R β )2- group, it is intended that:

[0074] -CH2- is replaced by ; or

[0075] -CH2- is replaced by .

[0076] In the context of the present specification, unless otherwise indicated, a C x -C y group is defined as a group containing x to y carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing 1 to 4 carbon atoms. When calculating the total number of carbon atoms in a parent group that is substituted with optional substituents and / or contains optional moieties, the optional substituents and moieties are not counted. To avoid doubt, when calculating the number of carbon atoms in a C x -C y group, a replacement heteroatom such as N, O or S is not counted as a carbon atom. For example, a morpholino group is considered to be a C4 heterocyclic group, not a C6 heterocyclic group.

[0077] For purposes of the present specification, when a first atom or group is stated to be "directly connected" to a second atom or group, it is understood that the first atom or group is covalently bonded to the second atom or group without an intervening atom or group. Thus, for example, for the group (C=0)N(CH3)2, the carbon atom of each methyl group is directly connected to the nitrogen atom, and the carbon atom of the carbonyl group is directly connected to the nitrogen atom, but the carbon atom of the carbonyl group is not directly connected to the carbon atom of either methyl group.

[0078] R 1 is a non-aromatic heterocyclic group that can be optionally substituted. To avoid doubt, it is noted that the sulfur atom of R 1 is a ring atom of the non-aromatic heterocyclic group that is directly connected to the sulfonylurea group (not any optional substituents).

[0079] R 1R is a non-aromatic heterocyclic group, which can be monocyclic, bicyclic (including bridged, fused and spiro), tricyclic or polycyclic. Bicyclic, tricyclic and polycyclic ring structures can be partially aromatic. To avoid doubt, it is stated that when R 1 is a partially aromatic bicyclic, tricyclic or polycyclic group, the sulfur atom directly attached to the sulfurylurea group is in a non-aromatic ring. To avoid doubt, it is also stated that when R 1 is a bicyclic, tricyclic or polycyclic group, the at least one ring nitrogen atom of R 1 is in a non-aromatic ring, but not necessarily in the non-aromatic ring of R 1 that is directly attached to the sulfur atom of the sulfurylurea group. In one embodiment, when R 1 is a bicyclic, tricyclic or polycyclic group, the at least one ring nitrogen atom of R 1 is in the non-aromatic ring of R 1 that is directly attached to the sulfur atom of the sulfurylurea group. 1

[0080] Typically, R 1 is monocyclic or bicyclic. In one embodiment, R 1 is a 4-, 5-, 6- or 7-membered monocyclic ring or a 7-, 8-, 9- or 10-membered bicyclic ring, wherein R 1 may optionally be substituted. In one embodiment, R 1 is a 4-, 5- or 6-membered monocyclic ring or a 7-, 8-, 9- or 10-membered bicyclic ring, wherein R 1 may optionally be substituted.

[0081] The non-aromatic heterocyclic group of R 1 may be fully saturated or partially saturated. In one embodiment, the non-aromatic heterocyclic group of R 1 is fully saturated.

[0082] In one embodiment, the non-aromatic heterocyclic group of R 1 is monocyclic. When the non-aromatic heterocyclic group of R 1 is monocyclic, it can optionally be substituted with any monovalent substituent or any divalent π-bonded substituent (such as those defined above), but can not be substituted with a divalent bridging substituent (e.g., -0-, -S-, -NH-, -N(R β )- or -R α ) so as to form a bridging, fused or spiro substituent. Examples of monocyclic non-aromatic heterocyclic groups include:

[0083]

[0084]

[0085] R​1 The non-aromatic heterocyclic group may contain one or more double bonds in the heterocyclic ring, provided that the heterocyclic ring is non-aromatic. 1 The non-aromatic heterocyclic group does not have any tautomers that are aromatic.

[0086] The following aromatic heterocyclic groups are considered because they have aromatic tautomers:

[0087]

[0088] For the avoidance of doubt, the term "non-aromatic heterocyclic group" does not exclude heterocyclic groups or moieties that have aromatic character solely by virtue of meso charge separation. For example, consider the following non-aromatic heterocyclic group, as it has no aromatic tautomers:

[0089]

[0090] The last tautomer shown is not considered because of the meso charge separation.

[0091] In one embodiment, R 1 The non-aromatic heterocyclic group is monocyclic and is selected from:

[0092]

[0093] where R 1 Such non-aromatic heterocyclic R 1 The group is attached to the sulfur atom of the sulfonylurea group via any suitable ring carbon atom. 1 The non-aromatic heterocyclic group is monocyclic and is selected from:

[0094] When at least one ring nitrogen atom adjacent to the carbonyl group is substituted, such that R 1 The non-aromatic heterocyclic group does not have any tautomers that are aromatic.

[0095] In another embodiment, R 1 The non-aromatic heterocyclic group may be substituted with one or more fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings such that the resulting group is bicyclic, tricyclic or polycyclic. 1 The non-aromatic heterocyclic group may be optionally replaced by -R α -substituted. The resulting group may optionally be further substituted with any monovalent substituent or any divalent π-bonded substituent (such as those defined above). Typically in this embodiment, the resulting group is bicyclic or tricyclic, most typically bicyclic. Examples of such resulting bicyclic groups include:

[0096]

[0097] wherein each X is independently CH2, NH, O, or S, and each Y is independently CH or N, and wherein R 1 the at least one ring nitrogen atom of R 1 is in the non-aromatic ring directly attached to the sulfur atom of the sulfonylurea group. 1 the at least one ring nitrogen atom of R

[0098] In one embodiment, the non-aromatic heterocyclic group of R 1 is a fused bicyclic ring. For example, the non-aromatic heterocyclic group of R 1 may be:

[0099] wherein R 1 may optionally be substituted. Such a non-aromatic heterocyclic R 1 group is attached to the sulfur atom of the sulfonylurea group through any suitable ring carbon atom.

[0100] In another embodiment, the non-aromatic heterocyclic group of R 1 is a bridged bicyclic ring. For example, the non-aromatic heterocyclic group of R 1 may be:

[0101] wherein R 1 may optionally be substituted. Such a non-aromatic heterocyclic R 1 group is attached to the sulfur atom of the sulfonylurea group through any suitable ring carbon atom.

[0102] In another embodiment, the non-aromatic heterocyclic group of R 1 is a spiro bicyclic ring. For example, the non-aromatic heterocyclic group of R 1 may be:

[0103] wherein R 1 may optionally be substituted. Such a non-aromatic heterocyclic R 1 group is attached to the sulfur atom of the sulfonylurea group through any suitable ring carbon atom.

[0104] In one embodiment, the non-aromatic heterocyclic group of R 1 is selected from:

[0105]

[0106] wherein R 1Such non-aromatic heterocyclic R 1 The group is attached to the sulfur atom of the sulfonylurea group via any suitable non-aromatic ring carbon atom. 1 The non-aromatic heterocyclic group is selected from:

[0107] When at least one ring nitrogen atom adjacent to the carbonyl group is substituted, such that R 1 The non-aromatic heterocyclic group does not have any tautomers that are aromatic.

[0108] In one embodiment, R 1 The non-aromatic heterocyclic group is selected from:

[0109]

[0110] where R 1 Such non-aromatic heterocyclic R 1 The group is attached to the sulfur atom of the sulfonylurea group via any suitable ring carbon atom. 1 The non-aromatic heterocyclic group is selected from:

[0111] When at least one ring nitrogen atom adjacent to the carbonyl group is substituted, such that R 1 The non-aromatic heterocyclic group does not have any tautomers that are aromatic.

[0112] In one embodiment, R 1 The non-aromatic heterocyclic group is selected from:

[0113]

[0114] where R 1 Such non-aromatic heterocyclic R 1 The group is attached to the sulfur atom of the sulfonylurea group via any suitable non-aromatic ring carbon atom. 1 The non-aromatic heterocyclic group is selected from:

[0115] When at least one ring nitrogen atom is substituted, such that R 1 The non-aromatic heterocyclic group does not have any tautomers that are aromatic.

[0116] In one embodiment, R 1 The non-aromatic heterocyclic group is selected from:

[0117]

[0118] where R 1may optionally be substituted or further substituted. Such non-aromatic heterocyclic R 1 groups are attached through any suitable ring carbon atom to the sulfur atom of the sulfonylurea group.

[0119] R 1 is a non-aromatic heterocyclic group containing at least one ring nitrogen atom. In one embodiment, R 1 contains one, two or three ring nitrogen, oxygen or sulfur atoms. In another embodiment, R 1 contains one or two ring nitrogen or oxygen atoms. In another embodiment, R 1 contains one or two ring nitrogen atoms. In another embodiment, R 1 contains one ring nitrogen atom.

[0120] R 1 may optionally be substituted by one or more substituents such as those defined above.

[0121] In one embodiment, R 1 is substituted by one or more (such as one, two or three) substituents independently selected from halo; -CN; -NO2; -N3; -R β ; -OH; -OR β ; -R α halo; -R α -CN; -R α -NO2; -R α -N3; -R α -R β ; -R α -OH; -R α -OR β ; -SH; -SR β ; -SOR β ; -SO2H; -SO2R β ; -SO2NH2; -SO2NHR β ; -SO2N(R β )2; -R α -SH; -R α -SR β ; -R α -SOR β ; -R α -SO2H; -R α -SO2R β ; -R α -SO2NH2; -R α -SO2NHR β ; -R α -SO2N(R β )2; -Si(R β)3; -O-Si(R β )3; -R α -Si(R β )3; -R α -O-Si(R β )3; -NH2; -NHR β ; -N(R β )2; -N(O)(R β )2; -N + (R β )3; -R α -NH2; -R α -NHR β ; -R α -N(R β )2; -R α -N(O)(R β )2; -R α -N + (R β )3; -CHO; -COR β ; -COOH; -COOR β ; -OCOR β ; -R α -CHO; -R α -COR β ; -R α -COOH; -R α -COOR β ; -R α -OCOR β ; -C(=NH)R β ; -C(=NH)NH2; -C(=NH)NHR β ; -C(=NH)N(R β )2; -C(=NR β )R β ; -C(=NR β )NHR β ; -C(=NR β )N(R β )2; -C(=NOH)R β ; -C(N2)R β ; -R α -C(=NH)R β ; -R α -C(=NH)NH2; -R α -C(=NH)NHR β ; -R α -C(=NH)N(R β )2; -R α -C(=NR β )Rβ ;-R α -C(=NR β )NHR β ;-R α -C(=NR β )N(R β )2;-R α -C(=NOH)R β ;-R α -C(N2)R β ;-NH-CHO;-NR β -CHO;-NH-COR β ;-NR β -COR β ;-CONH2;-CONHR β ;-CON(R β )2;-R α -NH-CHO;-R α -NR β -CHO;-R α -NH-COR β ;-R α -NR β -COR β ;-R α -CONH2;-R α -CONHR β ;-R α -CON(R β )2;-O-R α -OH;-O-R α -OR β ;-O-R α -NH2;-O-R α -NHR β ;-O-R α -N(R β )2;-O-R α -N(O)(R β )2;-O-R α -N + (R β )3;-NH-R α -OH;-NH-R α -OR β ;-NH-R α -NH2;-NH-R α -NHR β ;-NH-R α -N(R β )2;-NH-R α -N(O)(R β)2; -NR α -R + -N β (R β )2; -NR α -R β -OH; -NR α -R β -OR β ; -NR α -R β -NH2; -NR α -R β -NHR β ; -NR α -R β -N(R β )2; -NR α -R β -N(O)(R β )2; -NR α -R + -N β (R β )3; -N(O)R α -R β -OH; -N(O)R α -R β -OR β ; -N(O)R α -R β -NH2; -N(O)R α -R β -NHR β ; -N(O)R α -R β -N(R β )2; -N(O)R α -R β -N(O)(R β )2; -N(O)R α -R + -N β (R + )3; -N β (R α )2-R + -OH; -N β (R α )2-R β -OR + ; -N β (R α )2-R + -NH2; -N β (R α )2-R β -NHR + ; -Nβ )2-R α -N(R β )2; or -N + (R β )2-R α -N(O)(R β )2;

[0122] Each of these -R α - is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains 1 to 6 atoms in its main chain, wherein one or more carbon atoms in the main chain of the alkylene, alkenylene or alkynylene group may be optionally replaced by one or more heteroatoms N, O or S, wherein one or more -CH2- groups in the main chain of the alkylene, alkenylene or alkynylene group may be optionally replaced by one or more -N(O)(R β )-or-N + (R β )2-group, and wherein the alkylene, alkenylene or alkynylene group may be optionally replaced by one or more halo groups and / or -R β group substitution; and

[0123] Each of these -R β independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, or any two or three -R β Together with the nitrogen atom to which it is attached, it can form a C2-C7 cyclic group, wherein any -R β It may be optionally substituted by one or more of the following: C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), -O(C3-C7 halocycloalkyl), -CO(C1-C4 alkyl), -CO(C1-C4 haloalkyl), -COO(C1-C4 alkyl), -COO(C1-C4 haloalkyl), halo, -OH, -NH2, -CN, -C≡CH, oxo (=O) or a 4- to 6-membered heterocyclic group.

[0124] Usually, R 1 One or more ring nitrogen atoms are substituted by such a substituent.

[0125] In another embodiment, R 1 Substituted with one or more (such as one, two or three) substituents independently selected from the group consisting of: halo; -CN; -NO2; -N3; ​​-R β ;-OH;-OR β; -SH; -SR β ; -SO2R β ; -NH2; -NHR β ; -N(R β )2; -CHO; -COR β ; -COOH; -COOR β ; -OCOR β ; -R α -CHO; -R α -COR β ; -R α -COOH; -R α -COOR β ; -R α -OCOR β ; -NH-CHO; -NR β -CHO; -NH-COR β ; -NR β -COR β ; -CONH2; -CONHR β ; -CON(R β )2; -R α -NH-CHO; -R α -NR β -CHO; -R α -NH-COR β ; -R α -NR β -COR β ; -R α -CONH2; -R α -CONHR β ; -R α -CON(R β )2; -O-R α -OH; -O-R α -OR β ; -O-R α -NH2; -O-R α -NHR β ; -O-R α -N(R β )2; -NH-R α -OH; -NH-R α -OR β ; -NH-R α -NH2; -NH-R α -NHR β ; -NH-R α -N(R β )2; -NR β -R α-OH; -NR β -R α -OR β ; -NR β -R α -NH2; -NR β -R α -NHR β ; -NR β -R α -N(R β )2; C3-C7cycloalkyl optionally substituted with one or more C1-C3alkyl or C1-C3haloalkyl groups; C3-C7cycloalkenyl optionally substituted with one or more C1-C3alkyl or C1-C3haloalkyl groups; 3- to 7-membered non-aromatic heterocyclic group optionally substituted with one or more C1-C6alkyl or C1-C3haloalkyl groups; oxo (=0); or C1-C4alkylene bridge;

[0126] wherein each -R α 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 can optionally be replaced by one or more heteroatoms N, O, or S, and wherein the alkylene, alkenylene, or alkynylene group can optionally be substituted with one or more halo and / or -R β groups; and

[0127] wherein each -R β is independently selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C2-C6cyclic group, and wherein any -R β may optionally be substituted with one or more C1-C3alkyl, C1-C3haloalkyl, C3-C7cycloalkyl, -0(C1-C3alkyl), halo, -CN, -CºCH, or oxo (=0) groups.

[0128] Typically, R 1 is substituted on one or more ring nitrogen atoms with such a substituent.

[0129] In another embodiment, R 1 one or more (such as one, two, or three) substituents independently selected from halo; -CN; -NO2; -N3; -R β ; -OH; -OR β ; -SH; -SR β ; -SO2R β ; -NH2; -NHR β ; -N(R β)2; -CHO; -COR β ; -COOH; -COOR β ; -OCOR β ; -R α -CHO; -R α -COR β ; -R α -COOH; -R α -COOR β ; -R α -OCOR β ; -NH-CHO; -NR β -CHO; -NH-COR β ; -NR β -COR β ; -CONH2; -CONHR β ; -CON(R β )2; -R α -NH-CHO; -R α -NR β -CHO; -R α -NH-COR β ; -R α -NR β -COR β ; -R α -CONH2; -R α -CONHR β ; -R α -CON(R β )2; C3-C7cycloalkyl optionally substituted with one or more C1-C3alkyl or C1-C3haloalkyl groups; C3-C7cycloalkenyl optionally substituted with one or more C1-C3alkyl or C1-C3haloalkyl groups;

[0130] oxo (=0); or C1-C4alkylene bridge;

[0131] wherein each -R α is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 carbon atoms in its backbone, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted with one or more halo and / or -R β groups;

[0132] wherein each -R β is independently selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6cyclic group, and wherein any -R βoptionally substituted with one or more C1-C3alkyl, C1-C3haloalkyl, C3-C7cycloalkyl, -0(C1-C3alkyl), halo, -CN, -CºCH, or oxo (=0) groups;

[0133] wherein each -R δ is independently selected from a C1-C6alkyl or C1-C3haloalkyl group;

[0134] wherein each m is independently selected from 1, 2, or 3; and

[0135] wherein each n is independently selected from 1, 2, or 3.

[0136] Typically, R 1 is substituted on one or more ring nitrogen atoms with such a substituent.

[0137] In another embodiment, R 1 is substituted with one or more (such as one, two, or three) substituents independently selected from halo; -CN; -N3; -R β ; -SO2R β ; -NH2; -NHR β ; -N(R β )2; -R α -NH2; -R α -NHR β ; -R α -N(R β )2; -CHO; -COR β ; -COOR β ; -OCOR β ; -R α -CHO; -R α -COR β ; -R α -COOR β ; -R α -OCOR β ; -NH-CHO; -NR β -CHO; -NH-COR β ; -NR β -COR β ; -CONH2; -CONHR β ; -CON(R β )2;

[0138] or oxo (=0);

[0139] wherein each -R α - is independently selected from a C1-C3alkylene group;

[0140] wherein each -R β is independently selected from a C1-C6alkyl or C3-C6cycloalkyl group, and wherein any -R β may be optionally substituted with one or more C3-C6cycloalkyl, -0(C1-C3alkyl), halo, -CN, or -C≡CH groups;

[0141] wherein each -R δ is independently selected from a C1-C6alkyl group;

[0142] wherein each m is independently selected from 1 or 2; and

[0143] wherein each n is independently selected from 1 or 2.

[0144] Typically, R 1 is substituted on one or more ring nitrogen atoms with such a substituent.

[0145] In one embodiment, R 1 is substituted with one or more (such as one, two, or three) substituents independently selected from halo; C1-C6alkyl; C1-C6haloalkyl; C2-C6alkenyl; C2-C6haloalkenyl; C2-C6alkynyl; C2-C6haloalkynyl; -R 5 -CN; -R 5 -N3; -R 5 -NO2; -R 5 -N(R 6 )2; -R 5 -OR 6 ; -R 5 -SR 6 ; -R 5 -Si(R 6 )3; -R 5 -O-Si(R 6 )3; -R 5 -COR 6 ; -R 5 -COOR 6 ; -R 5 -CO-R 5 -OR 6 ; -R 5 -CON(R 6 )2; -R 5 -CO-R 5 -N(R 6 )2; -R 5 -C(=NR 6 )R 6 ; -R 5 -C(=NR 6 )N(R 6 )2; -R5 -C(=NOH)R 6 ; -R 5 -SO2R 6 ; -R 5 -phenyl; -R 5 -(Het);

[0146] oxo (=0); -CH2CH2-; -CH2CH2CH2-; -CH2CH2CH2CH2-; -CH=CH-CH=CH2-; or -R 5 -(C3-C6cycloalkyl), wherein the C3-C6cycloalkyl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl; wherein

[0147] R 5 is independently selected from a bond or C1-C5alkylene;

[0148] R 6 is independently selected from hydrogen, C1-C5alkyl, C1-C5haloalkyl, C3-C6cycloalkyl, -CO-(C1-C3alkyl), -COO-(C1-C4alkyl), or benzyl;

[0149] Het is selected from a pyridinyl, 2-oxo-l,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, or diaziridinyl group, each of which can be optionally substituted with one or two substituents independently selected from halo, C1-C4alkyl, C2-C4alkenyl, or C2-C4alkynyl;

[0150] X is selected from O, S, SO, or SO2;

[0151] m is 1, 2, or 3;

[0152] n is 1, 2, or 3; and

[0153] p is 0, 1, or 2.

[0154] Typically, R 1 is substituted on one or more ring nitrogen atoms with such a substituent.

[0155] In one embodiment, R 1 is substituted on one or more (such as one, two, or three) ring nitrogen atoms with a substituent independently selected from halo; C1-C6alkyl; C1-C6haloalkyl; C2-C6alkenyl; C2-C6haloalkenyl; C2-C6alkynyl; C2-C6haloalkynyl; -R 5 -CN; -R 5 -N3; -R 5 -NO2; -R 5-N(R 6 )2; -R 5 -OR 6 ; -R 5 -SR 6 ; -R 5 -Si(R 6 )3; -R 5 -O-Si(R 6 )3; -R 5 -COR 6 ; -R 5 -COOR 6 ; -R 5 -CO-R 5 -OR 6 ; -R 5 -CON(R 6 )2; -R 5 -CO-R 5 -N(R 6 )2; -R 5 -C(=NR 6 )R 6 ; -R 5 -C(=NR 6 )N(R 6 )2; -R 5 -C(=NOH)R 6 ; -R 5 -SO2R 6 ; -R 5 -phenyl; -R 5 -(Het);

[0156] oxo (=0); -CH2CH2-; -CH2CH2CH2-; -CH2CH2CH2CH2-; or -R 5 -(C3-C6cycloalkyl), wherein the C3-C6cycloalkyl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl; wherein

[0157] R 5 is independently selected from a bond or C1-C5alkylene;

[0158] R 6 is independently selected from hydrogen, C1-C5alkyl, C1-C5haloalkyl, C3-C6cycloalkyl, -CO-(C1-C3alkyl), -COO-(C1-C4alkyl), or benzyl;

[0159] Het is selected from a pyridyl, 2-oxo-l,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, or diaziridinyl group, each of which can be optionally substituted with one or two substituents independently selected from halo, C1-C4alkyl, C2-C4alkenyl, or C2-C4alkynyl;

[0160] X is selected from O, S, SO, or SO2;

[0161] m is 1, 2, or 3;

[0162] n is 1, 2, or 3; and

[0163] p is 0, 1, or 2.

[0164] In one embodiment, R 1 substituted on one or more (such as one, two, or three) ring nitrogen atoms with a substituent independently selected from halo; C1-C6alkyl; C1-C6haloalkyl; C2-C6alkenyl; C2-C6haloalkenyl; C2-C6alkynyl; C2-C6haloalkynyl; -R 5 -CN; -R 5 -N3; -R 5 -NO2; -R 5 -N(R 6 )2; -R 5 -OR 6 ; -R 5 -COR 6 ; -R 5 -COOR 6 ; -R 5 -CO-R 5 -OR 6 ; -R 5 -CON(R 6 )2; -R 5 -CO-R 5 -N(R 6 )2; -R 5 -SO2R 6 ; -R 5 -phenyl; -R 5 -pyridyl; -R 5 -(C3-C6cycloalkyl);

[0165] oxo (=0); -CH2CH2CH2-; or -CH2CH2CH2CH2-; wherein

[0166] R 5 is independently selected from a bond or C1-C5alkylene;

[0167] R6 is independently selected from hydrogen, C1-C5alkyl, C1-C5haloalkyl, C3-C6cycloalkyl, -CO-(C1-C3alkyl), or benzyl;

[0168] m is 1, 2 or 3; and

[0169] n is 1, 2 or 3.

[0170] In one embodiment, R 1 In one or more (such as one, two or three) ring carbon atoms is substituted with a substituent independently selected from oxo (=0); -CH2CH2-; -CH2CH2CH2-; -CH2CH2CH2CH2-; -CH=CH-CH=CH2-; -OR 7 or -CON(R 7 )2; wherein R 7 is independently selected from hydrogen or C1-C3alkyl.

[0171] In one embodiment, R 1 In one or more (such as one, two or three) ring carbon atoms is substituted with a substituent independently selected from oxo (=0); -CH2CH2CH2-; -CH2CH2CH2CH2-; or -CH=CH-CH=CH2-.

[0172] In one aspect of any of the above embodiments, R 1 contains 4 to 25 atoms other than hydrogen. More typically, R 1 contains 4 to 20 atoms other than hydrogen. More typically, R 1 contains 4 to 17 atoms other than hydrogen.

[0173] R 2 is a cyclic group which is substituted in the alpha position, wherein R 2 may optionally be further substituted. To avoid doubt, it is noted that R 2 is the ring atom of the cyclic group which is directly attached to the nitrogen atom of the urea or thiourea group (not any substituent).

[0174] In one embodiment of the first aspect of the application, R 2 is an aryl or heteroaryl group, wherein the aryl or the heteroaryl group is substituted in the alpha position, and wherein R 2 may optionally be further substituted. Typically, R 2 is a phenyl or 5- or 6-membered heteroaryl group, wherein the phenyl or the heteroaryl group is substituted in the alpha position, and wherein R 2 may optionally be further substituted. Typically, R 2is an aryl or heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the a and a' positions, and wherein R 2 may optionally be further substituted. Typically, R 2 is a phenyl or 5 or 6 membered heteroaryl group, wherein the phenyl or the heteroaryl group is substituted at the a and a' positions, and wherein R 2 may optionally be further substituted. For example, R 2 may be a phenyl group substituted at the 2 and 6 positions or a phenyl group substituted at the 2, 4 and 6 positions.

[0175] As used herein, the designations a, b, a', b' refer to the position of an atom of a cyclic group (such as -R 2 ) relative to the point of attachment of the cyclic group to the remainder of the molecule. For example, when -R 2 is a 1,2,3,5,6,7-hexahydro-s-indacen-4-yl moiety, the a, b, a' and b' positions are as follows:

[0176]

[0177] In another embodiment, R 2 is a cyclic group substituted at the a and a' positions, wherein R 2 may optionally be further substituted. For example, R 2 may be a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group substituted at the a and a' positions.

[0178] In any of the above embodiments, typical substituents at the a and / or a' positions of the parent cyclic group of R 2 comprise carbon atoms. For example, typical substituents at the a and / or a' positions of the parent cyclic group of R 2 may be independently selected from the group consisting of -R 4 , -OR 4 and -COR 4 groups, wherein each R 4 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and wherein each R 4 is optionally further substituted by one or more halo groups. More typically, the substituents at the a and / or a' positions are independently selected from alkyl and cycloalkyl groups, such as C3-C6 branched alkyl and C3-C6 cycloalkyl groups, for example isopropyl, cyclopropyl, cyclohexyl or tert-butyl groups, wherein the alkyl and cycloalkyl groups are optionally further substituted by one or more fluoro and / or chloro groups.

[0179] In one aspect of any of the above embodiments, each substituent at the a and a' positions comprises a carbon atom.

[0180] In one embodiment, -R 2 has a formula selected from the group consisting of:

[0181]

[0182] wherein R 8 and R 9 are independently selected from the group consisting of C1-C4 alkyl, and X is hydrogen or halo.

[0183] Typically, -R 2 has a formula selected from the group consisting of:

[0184]

[0185] In R 2 the alpha and / or alpha' position of the parent cyclic group, other typical substituents can include a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl, or heteroaryl ring fused to the parent cyclic group at the alpha, beta and / or alpha', beta' positions, respectively. Such fused cyclic groups are described in more detail below.

[0186] In one embodiment, R 2 is a fused aryl or 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 R 2 may optionally be further substituted.

[0187] In another embodiment, R 2 is a fused aryl or 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 R 2 may 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 shares only two atoms and one bond with the aryl or heteroaryl group. Typically, R 2 is tricyclic.

[0188] In another embodiment, R 2 is a fused aryl or fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl, or heteroaryl ring is fused to the aryl or heteroaryl group at the alpha, beta position and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl, or heteroaryl ring is fused to the aryl or heteroaryl group at the alpha', beta' position, wherein R 2 may optionally be further substituted.

[0189] In one embodiment, -R2 has a formula selected from the group consisting of:

[0190]

[0191] wherein A 1 and A 2 are 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 can optionally be replaced by one or more heteroatoms N, O, or S, and wherein B 1 is hydrogen or any optional substituent. The A 1 or A 2 B 1 and any optional substituent can together with the atom(s) to which they are attached form a further fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl, or heteroaryl ring, which can itself be optionally substituted. Similarly, any optional substituent attached to A 1 and any optional substituent attached to A 2 can also together with the atom(s) to which they are attached form a further fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl, or heteroaryl ring, which can itself be optionally substituted.

[0192] Typically, B 1 is hydrogen or a halo, hydroxyl, -CN, -NO2, -B 2 or -OB 2 group, wherein B 2 is a C1-C4 alkyl group which can optionally be substituted with halo.

[0193] Typically, any ring containing A 1 or A 2 is a 5- or 6-membered ring. Typically, A 1 and A 2 are unsubstituted or substituted with one or more halo, hydroxyl, -CN, -NO2, -B 3 or -OB 3 group, wherein B 3 is a C1-C4 alkyl group which can optionally be substituted with halo.

[0194] In another embodiment, -R 2 has a formula selected from the group consisting of:

[0195]

[0196] Typically, -R 2 has the formula:

[0197]

[0198] In R 2Other typical substituents for the alpha position of the parent cyclic group of R 2 are monovalent heterocyclic groups and monovalent aromatic groups, wherein a ring atom of the heterocyclic or aromatic group is directly connected to the alpha ring atom of the parent cyclic group via a single bond, wherein the heterocyclic or aromatic group can optionally be substituted, and wherein the parent cyclic group can optionally be further substituted. Such R

[0199] In one embodiment, R 2 is a 5- or 6-membered cyclic group, wherein the cyclic group can optionally be further substituted. In one embodiment, R 2 is an aryl or heteroaryl group, all of which can optionally be further substituted. In one embodiment, R 2 is a phenyl or 5- or 6-membered heteroaryl group, all of which can optionally be further substituted. In one embodiment, R 2 is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, or oxadiazolyl group, all of which can optionally be further substituted. In one embodiment, R 2 is a phenyl group, which can optionally be further substituted.

[0200] In one embodiment, R 2 is a parent cyclic group that is substituted at the alpha and alpha' positions, and can optionally be further substituted. For example, R 2 is a phenyl group that is substituted at the 2 and 6 positions or a phenyl group that is substituted at the 2, 4, and 6 positions.

[0201] In one embodiment, R 2substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the alpha position is a phenyl or 5- or 6-membered heterocyclic group, all of which can be optionally substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the alpha position is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, azetidinyl, 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 can be optionally substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the alpha position is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, piperidinyl, or tetrahydropyranyl group, all of which can be optionally substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the alpha position is a phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or tetrahydropyranyl group, all of which can be optionally substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the alpha position is a phenyl, pyridyl, pyrimidinyl, or pyrazolyl group, all of which can be optionally substituted with one or two substituents independently selected from halo, -OH, -NH2, -CN, -NO2, -B 4 , -OB 4 , -NHB 4 , or -N(B 4 )2, wherein B 4 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl group, all of which can be optionally halo substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the alpha position is an unsubstituted phenyl, pyridyl, pyrimidinyl, or pyrazolyl group. In one embodiment, the monovalent heterocyclic group at the alpha position is a pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl group, all of which can be optionally substituted with one or two substituents independently selected from halo, -OH, -NH2, -CN, -NO2, -B 4 , -OB 4 , -NHB 4 , or -N(B 4 )2, wherein B 4 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl group, all of which can be optionally halo substituted.independently selected from all optionally halo-substituted C1-C4alkyl, C2-C4alkenyl, or C2-C4alkynyl groups. In one embodiment, the monovalent heterocyclic group at the alpha 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, -NO2, -B 4 , -OB 4 , -NHB 4 , or -N(B 4 )2, wherein B 4 is independently selected from all optionally halo-substituted C1-C4alkyl, C2-C4alkenyl, or C2-C4alkynyl groups. Alternatively, any of these monovalent heterocyclic groups at the alpha position can optionally be substituted with one or two substituents independently selected from halo, -OH, -NH2, -CN, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, -OB 8 , or -N(B 8 )2, wherein B 8 is independently selected from optionally halo-substituted C1-C4alkyl.

[0202] In one embodiment, R 2 is a parent cyclic group substituted at the alpha position with a monovalent heterocyclic group or a monovalent aromatic group, wherein the heterocyclic or aromatic group can optionally be substituted, and wherein the parent cyclic group can optionally be further substituted. In one embodiment, such further substituents are in the alpha' position of the alpha-substituted parent cyclic group of R 2 . Such further substituents can be independently selected from halo, -R δ , -OR δ , or -COR δ groups, wherein each R δ is independently selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C2-C6cyclic groups, and wherein each R δ is optionally further substituted with one or more halo groups. Typically, such further substituents on the alpha-substituted parent cyclic group of R 2 are independently selected from halo, C1-C6alkyl (particularly C3-C6branched alkyl), or C3-C6cycloalkyl groups, e.g., fluoro, chloro, isopropyl, cyclopropyl, cyclohexyl, or tert-butyl groups, wherein the alkyl and cycloalkyl groups are optionally further substituted with one or more fluoro and / or chloro groups.

[0203] In one embodiment, -R 2 has a formula selected from:

[0204]

[0205] wherein R 10 is C1-C4 alkyl, R 11 is a 5- or 6-membered optionally substituted heterocyclic or aromatic group, and X is hydrogen or halo. In one embodiment, the optional substituents on the heterocyclic or aromatic group are selected from halo, -OH, -NH2, -CN, -NO2, -B 5 , -OB 5 , -NHB 5 , or -N(B 5 )2, wherein B 5 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl group, all of which can optionally be substituted with halo. Alternatively, the optional substituents on the heterocyclic or aromatic group are selected from halo, -OH, -NH2, -CN, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, -OB 8 , or -N(B 8 )2, wherein B 8 is independently selected from a C1-C4 alkyl group, optionally substituted with halo.

[0206] Typically, -R 2 has a formula selected from:

[0207]

[0208] wherein R 11 is a 5- or 6-membered optionally substituted heterocyclic or aromatic group. In one embodiment, the optional substituents on the heterocyclic or aromatic group are selected from halo, -OH, -NH2, -CN, -NO2, -B 6 , -OB 6 , -NHB 6 , or -N(B 6 )2, wherein B 6 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl group, all of which can optionally be substituted with halo. Alternatively, the optional substituents on the heterocyclic or aromatic group are selected from halo, -OH, -NH2, -CN, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, -OB 8 , or -N(B 8 )2, wherein B 8 is independently selected from a C1-C4 alkyl group, optionally substituted with halo.

[0209] In one embodiment, R 2is a parent cyclic group substituted at the α position by a monovalent heterocyclic group or a monovalent aromatic group, wherein the heterocyclic or aromatic group may be optionally substituted, and wherein the parent cyclic group may be optionally further substituted. 2 Further substituents on the α-substituted parent cyclic group may include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings, which may be fused to R 2 Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is ortho-fused to R 2 The α-substituted parent cyclic group, i.e., each fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring and R 2 The α-substituted parent cyclic groups have only two atoms and one bond in common. Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is ortho-fused to R in the α', β' position. 2 The α-substituted parent cyclic group.

[0210] In one embodiment, -R 2 Having a formula selected from the following:

[0211]

[0212] where R 11 is a 5- or 6-membered optionally substituted heterocyclic or aromatic group. In one embodiment, the optional substituents on the heterocyclic or aromatic group are selected from halo, -OH, -NH2, -CN, -NO2, -B 7 、-OB 7 、-NHB 7 or -N(B 7 )2, where B 7 are independently selected from C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl groups, all of which may be optionally substituted with halo. Alternatively, the optional substituents on the heterocyclic or aromatic group are selected from halo, -OH, -NH2, -CN, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, -OB 8 or -N(B 8 )2, where B 8 Independently selected from C1-C4 alkyl groups which may be optionally substituted with halo.

[0213] In one embodiment, R 2 is phenyl or a 5- or 6-membered heteroaryl group (such as phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl); wherein

[0214] (i) phenyl or a 5- or 6-membered heteroaryl group is substituted at the α position by a substituent selected from: -R 4 、-OR4 and -COR 4 wherein R 4 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or a C2-C6cyclic group, and wherein R 4 is optionally substituted by one or more halo groups; and

[0215] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted at the a' position by a substituent selected from -R 14 , -OR 14 and -COR 14 wherein R 14 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or a C2-C6cyclic group, and wherein R 14 is optionally substituted by one or more halo groups; and

[0216] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically by one, two or three substituents independently selected from halo, -NO2, -CN, -COOR 15 , -CONH2, -CONHR 15 or -CON(R 15 )2, wherein each -R 15 is independently selected from C1-C4alkyl or C1-C4haloalkyl groups); or

[0217] (ii) the phenyl or 5- or 6-membered heteroaryl group is substituted by a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused at the a, b positions to the parent phenyl or 5- or 6-membered heteroaryl group and which is optionally substituted by one or more halo groups; and

[0218] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted at the a' position by a substituent selected from -R 4 , -OR 4 and -COR 4 wherein R 4 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or a C2-C6cyclic group, and wherein R 4 is optionally substituted by one or more halo groups; and

[0219] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically by one or two substituents independently selected from halo, -NO2, -CN, -COOR 15 , -CONH2, -CONHR 15 or -CON(R 15 )2, wherein each -R 15independently selected from C1-C4 alkyl or C1-C4 haloalkyl groups); or

[0220] (iii) the phenyl or 5- or 6-membered heteroaryl group is substituted with a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring fused in the α,β positions to the parent phenyl or 5- or 6-membered heteroaryl group and which is optionally substituted with one or more halo groups; and

[0221] the phenyl or 5- or 6-membered heteroaryl group is substituted with a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring fused in the α', β' positions to the parent phenyl or 5- or 6-membered heteroaryl group and which is optionally substituted with one or more halo groups; and

[0222] Optionally, the phenyl group is further substituted (typically with substituents independently selected from the group consisting of halo, -NO2, -CN, -COOR 15 , -CONH2, -CONHR 15 or-CON(R 15 )2, where each -R 15 independently selected from C1-C4 alkyl or C1-C4 haloalkyl groups); or

[0223] (iv) phenyl or a 5- or 6-membered heteroaryl group substituted at the α position by a monovalent heterocyclic group or a monovalent aromatic group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may be optionally substituted by one or two substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, -R 12 -OR 13 、-R 12 -N(R 13 )2. -R 12 -CN or -R 12 -C≡CR 13 , and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to an alpha ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R 12 are independently selected from a bond or a C1-C3 alkylene group; and R 13 are independently selected from hydrogen or C1-C3 alkyl or C1-C3 haloalkyl groups; and

[0224] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position by a substituent selected from: —R 4 、-OR 4 and-COR 4 , where R 4is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and wherein R 4 is optionally substituted with one or more halo groups; and

[0225] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically by one, two or three substituents independently selected from the group consisting of halo, -NO2, -CN, -COOR 15 , -CONH2, -CONHR 15 or-CON(R 15 )2, where each -R 15 independently selected from C1-C4 alkyl or C1-C4 haloalkyl groups); or

[0226] (v) phenyl or a 5- or 6-membered heteroaryl group substituted at the α position by a monovalent heterocyclic group or a monovalent aromatic group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may be optionally substituted by one or two substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, -R 12 -OR 13 、-R 12 -N(R 13 )2. -R 12 -CN or -R 12 -C≡CR 13 , and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to an alpha ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R 12 are independently selected from a bond or a C1-C3 alkylene group; and R 13 are independently selected from hydrogen or C1-C3 alkyl or C1-C3 haloalkyl groups; and

[0227] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring fused in the α', β' positions to the parent phenyl or 5- or 6-membered heteroaryl group and which is optionally substituted with one or more halo groups; and

[0228] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically by one or two substituents independently selected from the group consisting of halo, -NO2, -CN, -COOR 15 、-CONH2、-CONHR 15 or-CON(R 15 )2, where each -R 15 independently selected from C1-C4 alkyl or C1-C4 haloalkyl groups).

[0229] In the embodiments immediately above, when a group or moiety is optionally substituted by one or more halo groups, it may, for example, be substituted by one, two, three, four, five or six halo groups.

[0230] In one aspect of any one of the above embodiments, R 2 contains 15 to 50 atoms. More typically, R 2 contains 20 to 40 atoms. Most typically, R 2 contains 25 to 35 atoms.

[0231] In another aspect of any one of the above embodiments, R 2 contains 10 to 50 atoms other than hydrogen. More typically, R 2 contains 10 to 40 atoms other than hydrogen. More typically, R 2 contains 10 to 35 atoms other than hydrogen. Most typically, R 2 contains 12 to 30 atoms other than hydrogen.

[0232] Q is selected from O or S. In one embodiment of the first aspect of the application, Q is O.

[0233] In a particular embodiment, the present application provides a compound of formula (I), wherein:

[0234] Q is O;

[0235] R 1 is a non-aromatic heterocyclic group selected from:

[0236]

[0237] wherein R 1 is attached to the sulphur atom of the sulphonylurea group via a non- aromatic ring carbon atom, and wherein R 1 may optionally be substituted; and

[0238] R 2 is a phenyl or 5 or 6 membered heteroaryl group; wherein

[0239] (i) the phenyl or 5 or 6 membered heteroaryl group is substituted at the alpha position by a substituent selected from -R 4 , -OR 4 and -COR 4 wherein R 4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and wherein R 4 is optionally substituted by one or more halo groups; and

[0240] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position by a substituent selected from: —R 14 、-OR 14 and-COR 14 , where R 14 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and wherein R 14 is optionally substituted with one or more halo groups; and

[0241] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically by one, two or three substituents independently selected from the group consisting of halo, -NO2, -CN, -COOR 15 、-CONH2、-CONHR 15 or-CON(R 15 )2, where each -R 15 independently selected from C1-C4 alkyl or C1-C4 haloalkyl groups); or

[0242] (ii) the phenyl or 5- or 6-membered heteroaryl group is substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring fused in the α,β positions to the parent phenyl or 5- or 6-membered heteroaryl group and which is optionally substituted with one or more halo groups; and

[0243] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position by a substituent selected from: —R 4 、-OR 4 and-COR 4 , where R 4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and wherein R 4 is optionally substituted with one or more halo groups; and

[0244] Optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically by one or two substituents independently selected from the group consisting of halo, -NO2, -CN, -COOR 15 、-CONH2、-CONHR 15 or-CON(R 15 )2, where each -R 15 independently selected from C1-C4 alkyl or C1-C4 haloalkyl groups); or

[0245] (iii) the phenyl or 5- or 6-membered heteroaryl group is substituted with a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring fused in the α,β positions to the parent phenyl or 5- or 6-membered heteroaryl group and which is optionally substituted with one or more halo groups; and

[0246] the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically by one, two or three substituents independently selected from halo, -N02, -CN, -COOR

[0247] optionally, the phenyl group is further substituted (typically by a substituent independently selected from halo, -N02, -CN, -COOR 15 , -CONHR 15 or -CON(R 15 )2, wherein each -R 15 is independently selected from a C1-C4 alkyl or C1-C4 haloalkyl group); or

[0248] (iv) the phenyl or 5- or 6-membered heteroaryl group is substituted at the alpha position by a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group can optionally be substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 haloalkyl, -R 12 -OR 13 , -R 12 -N(R 13 )2, -R 12 -CN or -R 12 -C≡CR 13 , and wherein the ring atoms of the monovalent heterocyclic or aromatic group are directly connected to the alpha ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R 12 is independently selected from a bond or a C1-C3 alkylene group; and R 13 is independently selected from hydrogen or a C1-C3 alkyl or C1-C3 haloalkyl group; and

[0249] optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted at the alpha' position by a substituent selected from -R 4 , -OR 4 and -COR 4 , wherein R 4 is selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and wherein R 4 is optionally substituted by one or more halo groups; and

[0250] optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically by one, two or three substituents independently selected from halo, -N02, -CN, -COOR 15, -CONH2, -CONHR 15 or -CON(R 15 )2, wherein each -R 15 is independently selected from a C1-C4alkyl or C1-C4haloalkyl group); or

[0251] (v) the phenyl or 5- or 6-membered heteroaryl group is substituted at the alpha position with a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group is optionally substituted with one or two substituents independently selected from halo, C1-C3alkyl, C1-C3haloalkyl, -R 12 -OR 13 , -R 12 -N(R 13 )2, -R 12 -CN or -R 12 -C≡CR 13 , and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly connected to the alpha ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R 12 is independently selected from a bond or a C1-C3alkylene group; and R 13 is independently selected from hydrogen or a C1-C3alkyl or C1-C3haloalkyl group; and

[0252] optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl, or heteroaryl ring that is fused at the alpha', beta' positions to the parent phenyl or 5- or 6-membered heteroaryl group and which is optionally substituted with one or more halo groups; and

[0253] optionally, the phenyl or 5- or 6-membered heteroaryl group is further substituted (typically with one or two substituents independently selected from halo, -NO2, -CN, -COOR 15 , -CONH2, -CONHR 15 or -CON(R 15 )2, wherein each -R 15 is independently selected from a C1-C4alkyl or C1-C4haloalkyl group);

[0254] provided that when the non-aromatic heterocyclic group of R 1 is selected from:

[0255] at least one ring nitrogen atom adjacent to the carbonyl group is substituted.

[0256] In this particular embodiment just above, when a group or moiety is optionally substituted with one or more halo groups, it can be for example substituted with one, two, three, four, five or six halo groups.

[0257] In this particular embodiment just above, R 2 The parent phenyl or 5- or 6-membered heteroaryl group can be selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0258] In this particular embodiment just above, R 1 may be optionally substituted with one or more (such as one, two or three) substituents independently selected from halo; C1-C6alkyl; C1-C6haloalkyl; C2-C6alkenyl; C2-C6haloalkenyl; C2-C6alkynyl; C2-C6haloalkynyl; -R 5 -CN; -R 5 -N3; -R 5 -NO2; -R 5 -N(R 6 )2; -R 5 -OR 6 ; -R 5 -SR 6 ; -R 5 -Si(R 6 )3; -R 5 -O-Si(R 6 )3; -R 5 -COR 6 ; -R 5 -COOR 6 ; -R 5 -CO-R 5 -OR 6 ; -R 5 -CON(R 6 )2; -R 5 -CO-R 5 -N(R 6 )2; -R 5 -C(=NR 6 )R 6 ; -R 5 -C(=NR 6 )N(R 6 )2; -R 5 -C(=NOH)R 6 ; -R 5 -SO2R 6 ; -R 5 -phenyl; -R 5 -(Het);

[0259] Oxo (=O); -CH2CH2-; -CH2CH2CH2-; -CH2CH2CH2CH2-; -CH=CH-CH=CH2-; or -R 5 -(C3-C6 cycloalkyl), wherein the C3-C6 cycloalkyl group is optionally substituted with one or two substituents independently selected from C1-C3 alkyl; wherein

[0260] R 5 independently selected from a bond or a C1-C5 alkylene group;

[0261] R 6 Independently selected from hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 cycloalkyl, -CO-(C1-C3 alkyl), -COO-(C1-C4 alkyl) or benzyl;

[0262] Het is selected from a pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl or diazirinyl group, each of which may be optionally substituted with one or two substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl;

[0263] X is selected from O, S, SO or SO2;

[0264] m is 1, 2, or 3;

[0265] n is 1, 2 or 3; and

[0266] p is 0, 1 or 2.

[0267] Usually, R 1 It is substituted by such a substituent on one or more (such as one, two or three) ring nitrogen atoms.

[0268] In one aspect of any one of the above embodiments, the molecular weight of the compound of formula (I) is 250 to 2000 Da. Typically, the molecular weight of the compound of formula (I) is 280 to 900 Da. More typically, the molecular weight of the compound of formula (I) is 310 to 550 Da.

[0269] A second aspect of the present invention provides a compound selected from the group consisting of:

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309] A third aspect of the application provides a pharmaceutically acceptable salt, solvate or prodrug of any of the compounds of the first or second aspects of the application.

[0310] The compounds of the application can be used in their free base form and in their acid addition salt form. For the purposes of the present application, "salts" of the compounds of the application include acid addition salts. The 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 (e.g. hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (e.g. nitric, perchloric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (e.g. propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or embonic acid), organic sulphonic acids (e.g. methanesulphonic, trifluoromethanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, benzenesulphonic, p-toluenesulphonic, naphthalene-2-sulphonic or camphorsulphonic acid) or amino acids (e.g. ornithine, glutamic acid or aspartic acid). The acid addition salts can be mono-, di-, tri- or poly-acid addition salts. Preferred salts are hydrohalogenic, sulphonic, phosphoric or organic acid addition salts. Preferred salts are hydrochloric acid addition salts.

[0311] When the compounds of the application include a quaternary ammonium group, typically the compounds are used in the form of their salts. The counter-ion of the quaternary ammonium group can 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.

[0312] The compounds of the present application can also be used in their free acid form and in their acid salt form. For the purposes of the present application, "salts" of the compounds of the present application include salts formed between the protonic acid functionality (such as a carboxylic acid group) of the compounds of the present application and a suitable cation. Suitable cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium, and ammonium. The salt can be a mono-, di-, tri-, or polysalt. 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.

[0313] Preferably, any salt is a pharmaceutically acceptable, non-toxic salt. However, in addition to pharmaceutically acceptable salts, other salts useful in the present application are included as they can serve as intermediates for further, for example, pharmaceutically acceptable salts, purification or preparation, or can be useful in the identification, characterization, or purification of the free acid or base.

[0314] The compounds and / or salts of the present application can be anhydrous or in the form of a hydrate (e.g., a hemihydrate, monohydrate, dihydrate, or trihydrate) or other solvate. Such solvates can be formed with common organic solvents including, but not limited to, alcoholic solvents such as methanol, ethanol, or isopropanol.

[0315] In some embodiments of the present application, there is provided a treatment of an inactive prodrug. A prodrug is a compound that, when administered to a subject, such as a human, is converted completely or partially to a compound of the present application. In most embodiments, a prodrug is a pharmacologically inactive chemical derivative that can be converted in vivo to an active drug molecule to exert a therapeutic effect. Any of the compounds described herein can be administered in the form of a prodrug to increase the activity, bioavailability, or stability of the compound or otherwise modify 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 yield the active compound. The present application also encompasses salts and solvates of such prodrugs, as described above.

[0316] The compounds, salts, solvates, and prodrugs of the present application can contain at least one chiral center. The compounds, salts, solvates, and prodrugs can therefore exist in at least two isomeric forms. The present application encompasses the racemic mixtures of the compounds, salts, solvates, and prodrugs of the present application as well as the isomers that are enriched and substantially enantiomerically pure. For the purposes of the present application, an "substantially enantiomerically pure" isomer of a compound comprises less than 5% by weight, more typically less than 2% by weight, and most typically less than 0.5% by weight of the other isomer of the same compound.

[0317] The compounds, salts, solvates, and prodrugs of the present application can contain: any stable isotope, including but not limited to12 C, 13 C, 1 H, 2 H(D), 14 N, 15 N, 16 O, 17 O, 18 O, 19 F and 127 I; and any radioisotopes, including but not limited to 11 C, 14 C, 3 H(T), 13 N, 15 O, 18 F, 123 I, 124 I, 125 I and 131 I.

[0318] The compounds, salts, solvates and prodrugs of the application can be in any polymorphic or amorphous form.

[0319] The fourth aspect of the application provides a pharmaceutical composition comprising a compound of the first or second aspect of the application, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the application, and a pharmaceutically acceptable excipient.

[0320] Suitable pharmaceutical formulations are selected and prepared according to conventional pharmaceutical principles, as described, for example, in "Aulton's Pharmaceutics - The Design and Manufacture of Medicines", M.E. Aulton and K.M.G. Taylor, Churchill Livingstone Elsevier, 4thEdition, 2013.

[0321] Pharmaceutically acceptable excipients (including adjuvants, diluents or carriers) that can be used in the pharmaceutical compositions of the application are those conventionally used in the art of pharmaceutical formulation and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, aluminium oxide, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0322] In one embodiment, the pharmaceutical composition of the fourth aspect of the invention further comprises one or more additional active agents.

[0323] In another embodiment, the pharmaceutical composition of the fourth aspect of the invention may be provided as 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 additional pharmaceutical compositions, wherein the one or more additional pharmaceutical compositions each comprise a pharmaceutically acceptable excipient and one or more additional active agents.

[0324] The fifth aspect of the present invention provides the compound of the first or second aspect of the present invention, or the pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the present invention, or the pharmaceutical composition of the fourth aspect of the present invention, which is used in medicine and / or for treating or preventing a disease, disorder or condition. Typically, the purposes include administering the compound, salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the purposes include co-administering one or more additional active agents.

[0325] As used herein, the term "treatment" refers equally to curative therapy and improvement or palliative therapy. The term includes obtaining beneficial or desired physiological results, which may or may not be clinically established. Beneficial or desired clinical results include, but are not limited to, relief of symptoms, prevention of symptoms, reduction of disease extent, stabilization of the patient's condition (i.e., no worsening), delay / slowing of progression / worsening of the patient's condition / symptoms, improvement or alleviation of the patient's condition / symptoms and alleviation (whether partial or total), whether detectable or undetectable. As used herein, the term "alleviation" and variations thereof mean that the degree of physiological condition or symptoms and / or the reduction of undesirable manifestations and / or the time course of progression are slowed or prolonged compared to when the compound, salt, solvate, prodrug or pharmaceutical composition of the present invention is not administered. As used herein, the term "prevention" relates to preventive or prophylactic therapy, as well as therapies that reduce the risk of developing a disease, disorder or condition. The term "prevention" includes avoiding the occurrence of a disease, disorder or condition, and delaying the onset of a disease, disorder or condition. Any statistically significant (p≤0.05) avoidance of occurrence, delay of onset, or reduction in risk as measured by controlled clinical trials can be considered as prevention of a disease, disorder, or condition. Subjects suitable for prevention include subjects at elevated risk of a disease, disorder, or condition as identified by genetic or biochemical markers. Typically, genetic or biochemical markers are suitable for the disease, disorder, or condition under consideration, and may include, for example, inflammatory biomarkers such as: in the case of inflammation, C-reactive protein (CRP) and monocyte chemoattractant protein 1 (MCP-1); in the case of NAFLD and NASH, total cholesterol, triglycerides, insulin resistance, and C-peptide; and more generally, in the case of a disease, disorder, or condition that responds to NLRP3 inhibition, IL1β and IL18.

[0326] A sixth aspect of the application provides 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 administration of the compound, salt, solvate, prodrug or medicament to a subject. In one embodiment, the treatment or prevention comprises co-administration of one or more additional active agents.

[0327] A seventh aspect of the application provides a method of treating or preventing 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, thereby treating or preventing the disease, disorder or condition. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, the administration is to a subject in need thereof.

[0328] An eighth aspect of the application provides a compound of the first or second aspect of the application, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the application, or a pharmaceutical composition of the fourth aspect of the application, for use in treating or preventing a disease, disorder or condition in an individual, wherein the individual has a germline or somatic non-silent mutation in NLRP3. The mutation can be, for example, a gain-of-function mutation or other mutation that results in increased NLRP3 activity. Typically, the use comprises administration of the compound, salt, solvate, prodrug or pharmaceutical composition to the individual. In one embodiment, the use comprises co-administration of one or more additional active agents. The use can also comprise diagnosing an individual having a germline or somatic non-silent mutation in NLRP3, wherein the compound, salt, solvate, prodrug or pharmaceutical composition is administered to the individual based on a positive diagnosis of the mutation. Typically, the identification of a mutation in NLRP3 in an individual can be by any suitable genetic or biochemical means.

[0329] A ninth aspect of the application provides 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 treating or preventing a disease, disorder or condition in an individual, wherein the individual has a germline or somatic non-silent mutation of NLRP3. The mutation can be, for example, a gain-of-function mutation or other mutation that results in increased NLRP3 activity. Typically, the treating or preventing comprises administering the compound, salt, solvate, prodrug or medicament to the individual. In one embodiment, the treating or preventing comprises co-administering one or more additional active agents. The treating or preventing can also comprise diagnosing an individual having a germline or somatic non-silent mutation of NLRP3, wherein the compound, salt, solvate, prodrug or medicament is administered to the individual based on the positive diagnosis of the mutation. Typically, the identification of the mutation of NLRP3 in the individual can be by any suitable genetic or biochemical means.

[0330] A tenth aspect of the application provides a method of treating or preventing a disease, disorder or condition, the method comprising the steps of: diagnosing an individual having a germline or somatic non-silent mutation of NLRP3, and administering to the positively diagnosed individual 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, thereby treating or preventing the disease, disorder or condition. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, the administering is to a subject in need thereof.

[0331] In general embodiments, the disease, disorder or condition can be of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, hepatic system, metabolic system, respiratory system, central nervous system, can be a cancer or other malignancy, and / or can be caused by or associated with a pathogen.

[0332] It will be appreciated that these general embodiments defined according to the broad disease, disorder and condition categories are not mutually exclusive of one another. In this regard, any particular disease, disorder or condition can be classified 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.

[0333] In one embodiment of the fifth, sixth, seventh, eighth, ninth or tenth aspect of the application, the disease, disorder or condition is responsive to NLRP3 inhibition. As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction in the level of NLRP3 activity and includes, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0334] There is evidence that NLRP3-induced IL-1 and IL-18 play a role in a large number of different conditions or in the inflammatory responses that occur as a result thereof (Menu et al., Clinical and Experimental Immunology, 166: 1-15, 2011; Strowig et al., Nature, 481: 278-286, 2012).

[0335] NLRP3 is 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), Swerdorf 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 cause a group 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 include three autoinflammatory disorders that form a clinical continuum. In order of increasing severity, these diseases are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurological cutaneous articular syndrome (CINCA; also known as neonatal-onset multisystem inflammatory disease, NOMID), and all have been shown to be caused by gain-of-function mutations in the NLRP3 gene, which cause increased secretion of IL-1β.

[0336] Many autoimmune diseases have been shown to involve NLRP3, including multiple sclerosis, type 1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), Behcet's disease, Sjogren's syndrome, macrophage activation syndrome (Masters Clin. Immunol. 2013; Braddock et al., at. Rev. Drug Disc. 2004 3: 1-10; Inoue et al., Immunology 139: 11-18; Coll et al., Nat. Med. 2015 21(3):248-55; and Scott et al., Clin. Exp. Rheumatol 2016 34(1):88-93), systemic lupus erythematosus (Lu et al., J Immunol. 2017 198(3): 1119-29), and systemic sclerosis (Artlett et al., Arthritis Rheum. 2011; 63(11):3563-74). NLRP3 has also been shown to be involved in many pulmonary diseases, including chronic obstructive pulmonary disease (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184:42-54, 2014 and Kim et al., Am J Respir Crit Care Med. 2017 196(3):283-97). NLRP3 has also been proposed to play a role in many central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain damage caused by pneumococcal meningitis (Walsh et al., Nature Reviews, 15:84-97, 2014, and Dempsey et al., Brain. Behav. Immun. 2017 61:306-316), intracranial aneurysms (Zhang et al., J. Stroke & Cerebrovascular Dis. 2015 24; 5:972-979), and traumatic brain injury (Ismael et al., J Neurotrauma. 2018 Jan 2).NRLP3 activity has also been shown to be involved in various metabolic diseases, including type 2 diabetes (T2D), atherosclerosis, obesity, gout, pseudogout, metabolic syndrome (Wen et al., Nature Immunology, 13:352-357, 2012; Duewell et al., Nature, 464:1357-1361, 2010; Strowig et al., Nature, 481:278-286, 2012) and nonalcoholic liver fibrosis (Mridha et al., J Hepatol. 2017 66(5):1037-46). NLRP3 has also been proposed to play a role in atherosclerosis, myocardial infarction (van Hout et al., Eur. Heart J 2017 38(11):828-36), heart failure (Sano et al., J AM. Coll. Cardiol. 2018 71(8):875-66), aortic aneurysm and dissection (Wu et al., Arterioscler. Thromb. Vase. Biol. 2017 37(4):694-706) and other cardiovascular events (Ridker et al., N Engl J Med., doi: 10.1056 / NEJMoa1707914, 2017) via IL-1 beta.Other diseases in which NLRP3 has been implicated include: ocular diseases such as wet and dry age-related macular degeneration (Doyle et al., Nature Medicine, 18:791-798, 2012 and Tarallo et al., Cell 2012 149(4):847-59), diabetic retinopathy (Loukovaara et al., Acta Ophthalmol. 2017; 95(8):803-808), and optic nerve injury (Puyang et al., Sci Rep. 2016 Feb 19; 6:20998); liver diseases including non-alcoholic liver fibrosis (NASH) (Henao-Mejia et al., Nature, 482: 179-185, 2012); inflammatory responses of the lung and skin (Primiano et al., J Immunol. 2016 197(6):2421-33), including contact hypersensitivity (such as bullous pemphigoid (Fang et al., J Dermatol Sci. 2016; 83(2): 116-23)), atopic dermatitis (Niebuhr et al., Allergy 2014 69(8): 1058-67), hidradenitis suppurativa (Alikhan et al., 2009 J Am Acad Dermatol 60(4):539-61), acne vulgaris (Qin et al., J Invest. Dermatol. 2014 134(2):381-88), and sarcoidosis (Jager et al., Am J Respir Crit Care Med 2015 191:A5816); inflammatory responses of the joints (Braddock et al., Nat. Rev. Drug Disc., 3:1-10, 2004); amyotrophic lateral sclerosis (Gugliandolo et al., Inflammation 2018 41(1):93-103); cystic fibrosis (Iannitti et al., Nat. Commun. 2016 7:10791); stroke (Walsh et al., Nature Reviews, 15:84-97, 2014); chronic kidney disease (Granata et al., PLoS One 2015 10(3):e0122272); and inflammatory bowel diseases including ulcerative colitis and Crohn’s disease (Braddock et al., Nat. Rev. Drug Disc., 3:1-10, 2004, Neudecker et al., J Exp. Med. 2017 214(6):1737-52, and Lazaridis et al., Dig. Dis. Sci. 2017 62(9):2348-56).It has been found that NLRP3 inflammasome is activated in response to oxidative stress and UVB irradiation (Schroder et al., Science, 327: 296-300, 2010). It has also been shown that NLRP3 is involved in inflammatory hyperalgesia (Dolunay et al., Inflammation, 40: 366-386, 2017).

[0337] It has also been proposed that inflammasomes and especially NLRP3 are targets modulated by various pathogens including viruses such as DNA viruses (Amsler et al., Future Virol. (2013) 8(4), 357-370).

[0338] NLRP3 is also 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 that IL-1 β has been shown to play a role in cancer invasiveness, growth and metastasis and in the inhibition of IL-1 β with canakinumab reduced the incidence of lung cancer and overall cancer mortality in a randomized, double-blind, placebo-controlled trial (Ridker et al. Lancet, S0140-6736(17)32247-X, 2017). Inhibition of NLRP3 inflammasome or IL-1 β was also shown to suppress the proliferation and migration of lung cancer cells in vitro (Wang et al. Oncol Rep. 2016; 35(4):2053-64). The role of NLRP3 inflammasome has been suggested in myelodysplastic syndromes (Basiorka et al. Blood. 2016 Dec 22; 128(25): 2960-2975); and in the carcinogenic effects of various other cancers, including glioma (Li et al. Am J Cancer Res. 2015; 5(1): 442-449), inflammation-induced tumors (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 head and neck squamous cell carcinoma (Huang et al. J Exp Clin Cancer Res. 2017 2; 36(1): 116). Activation of NLRP3 inflammasome was also shown to mediate chemoresistance of tumor cells to 5-fluorouracil (Feng et al. J Exp Clin Cancer Res. 2017 21; 36(1): 81), and activation of NLRP3 inflammasome in peripheral nerves resulted in chemotherapy-induced neuropathic pain (Jia et al. Mol Pain. 2017; 13: 1-11).

[0339] NLRP3 has also been shown to be required for effective control of viral, bacterial, fungal and helminth pathogen infections (Strowig et al., Nature, 481 :278-286, 2012).

[0340] Examples of diseases, disorders or conditions that can be responsive to NLRP3 inhibition and that can be treated or prevented in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspects of the application include:

[0341] (i) inflammation, including inflammation due to an inflammatory condition such as an autoinflammatory disease, inflammation due to a symptom of a non-inflammatory condition, inflammation due to an infection, or inflammation secondary to trauma, injury, or autoimmunity;

[0342] (ii) an autoimmune disease, such as acute disseminated encephalomyelitis, Addison’s disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, celiac disease, Crohn’s disease, diabetes mellitus type 1 (T1D), Goodpasture’s syndrome, Graves’ disease, Guillain-Barre syndrome (GBS), Hashimoto’s disease, idiopathic thrombocytopenic purpura, Kawasaki’s disease, lupus erythematosus (including systemic lupus erythematosus (SLE)), multiple sclerosis (MS) (including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing remitting multiple sclerosis (RRMS)), myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord’s thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still’s disease, unresponsive gouty arthritis, Reiter’s syndrome, Sjogren’s syndrome, systemic sclerosis systemic connective tissue disease, Takayasu’s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener’s granulomatosis, alopecia areata, Behcet’s disease, Chagas disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Sjogren’s syndrome, macrophage activation syndrome, Blau syndrome, vitiligo, or vulvodynia;

[0343] (iii) cancer, including lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia (including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)), adrenal cancer, anal cancer, basal and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ivan family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, gliomas, Hodgkin lymphomas, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumor, lymphoma (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymic cancer, thyroid cancer (including anaplastic thyroid cancer), uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilm's tumor;

[0344] (iv) infections, including viral infections (e.g., from influenza virus, immunodeficiency virus (HIV), alphavirus (such as Chikungunya virus and Ross River virus), flavivirus (such as Dengue virus and Zika virus), herpesvirus (such as Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxvirus (such as vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenovirus (such as adenovirus 5), or papillomavirus);bacterial infections (e.g., from Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi, or Yersinia pestis); fungal infections (e.g., from Candida species or Aspergillus species); protozoal infections (e.g., from Plasmodium, Babesia, Naegleria, Entamoeba, Leishmania, or Trypanosoma);Worm infections (e.g. from schistosomes, roundworms, tapeworms or flukes); and prion infections;

[0345] (v) central nervous system diseases such as Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, intracranial aneurysm, traumatic brain injury and amyotrophic lateral sclerosis;

[0346] (vi) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout and pseudogout;

[0347] (vii) cardiovascular diseases such as hypertension, ischaemia, reperfusion injury (including post-MI ischaemic reperfusion injury), stroke (including ischaemic stroke), transient ischaemic attack, myocardial infarction (including recurrent myocardial infarction), heart failure (including congestive heart failure and ejection fraction preserved heart failure), embolism, aneurysm (including abdominal aortic aneurysm) and pericarditis (including Dressler's syndrome);

[0348] (viii) respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma (such as allergic asthma and steroid-resistant asthma), asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis and idiopathic pulmonary fibrosis;

[0349] (ix) liver diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) including later stage fibrosis F3 and F4 stages, alcoholic fatty liver disease (AFLD) and alcoholic steatohepatitis (ASH);

[0350] (x) kidney diseases including chronic kidney disease, oxalosis, nephrocalcinosis, glomerulonephritis and diabetic nephropathy;

[0351] (xi) eye diseases including diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic nerve damage, dry eye and glaucoma;

[0352] (xii) skin diseases including dermatitis (such as contact dermatitis and atopic dermatitis), contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-induced skin diseases and acne aggregrans;

[0353] (xiii) lymphatic conditions such as lymphangitis and Castleman's disease;

[0354] (xiv) psychological disorders such as melancholy and psychological stress;

[0355] (xv) Graft versus host disease;

[0356] (xvi) allodynia, including mechanical allodynia; and

[0357] (xvii) any disease in which it has been determined that the individual carries a germline or somatic non-silent mutation in NLRP3.

[0358] In one embodiment, the disease, disorder or condition is selected from:

[0359] (i) cancer;

[0360] (ii) infection;

[0361] (iii) central nervous system disease;

[0362] (iv) cardiovascular disease;

[0363] (v) liver disease;

[0364] (vi) ocular disease; or

[0365] (vii) skin disease.

[0366] More generally, the disease, disorder or condition is selected from:

[0367] (i) cancer;

[0368] (ii) infection;

[0369] (iii) central nervous system disease; or

[0370] (iv) cardiovascular disease.

[0371] In one embodiment, the disease, disorder or condition is selected from:

[0372] (i) acne vulgaris;

[0373] (ii) atopic dermatitis;

[0374] (iii) Alzheimer's disease;

[0375] (iv) amyotrophic lateral sclerosis;

[0376] (v) age-related macular degeneration (AMD);

[0377] (vi) anaplastic thyroid cancer;

[0378] (vii) cryopyrin-associated periodic syndromes (CAPS);

[0379] (viii) contact dermatitis;

[0380] (ix) cystic fibrosis;

[0381] (x) congestive heart failure;

[0382] (xi) chronic kidney disease;

[0383] (xii) Crohn's disease;

[0384] (xiii) familial cold autoinflammatory syndrome (FCAS);

[0385] (xiv) Huntington's disease;

[0386] (xv) heart failure;

[0387] (xvi) heart failure with preserved ejection fraction;

[0388] (xvii) ischemia-reperfusion injury;

[0389] (xviii) juvenile idiopathic arthritis;

[0390] (xix) myocardial infarction;

[0391] (xx) macrophage activation syndrome;

[0392] (xxi) myelodysplastic syndrome;

[0393] (xxii) multiple myeloma;

[0394] (xxiii) motor neuron disease;

[0395] (xxiv) multiple sclerosis;

[0396] (xxv) Muckle-Wells syndrome;

[0397] (xxvi) nonalcoholic liver fibrosis (NASH);

[0398] (xxvii) neonatal onset multisystem inflammatory disease (NOMID);

[0399] (xxviii) Parkinson's disease;

[0400] (xxix) systemic juvenile idiopathic arthritis;

[0401] (xxx) systemic lupus erythematosus;

[0402] (xxxi) traumatic brain injury;

[0403] (xxxii) transient ischemic attack; and

[0404] (xxxiii) ulcerative colitis.

[0405] In another exemplary embodiment of the application, the disease, disorder or condition is inflammation. Examples of inflammation that can be treated or prevented in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspects of the application include inflammatory responses associated with or arising from:

[0406] (i) a skin condition such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema or alopecia;

[0407] (ii) a joint condition such as osteoarthritis, systemic-onset juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout or a seronegative spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter's disease);

[0408] (iii) a muscle condition such as polymyositis or myasthenia gravis;

[0409] (iv) a gastrointestinal condition such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulceration, coeliac disease, proctitis, pancreatitis, eosinopilic gastro-enteritis, mastocytosis, anti-phospholipid syndrome or food-related allergies that can have effects away from the gut (e.g. migraine, rhinitis or eczema);

[0410] (v) a respiratory condition such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or dust asthma, and in particular chronic or inveterate asthma such as late asthma and airways hyper-responsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis (rhinitis pumlenta), dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestos, adult respiratory distress syndrome, hypersensitivity pneumonitis or idiopathic interstitial pneumonia;

[0411] (vi) a vascular condition such as atherosclerosis, Behcet's disease, vasculitis or Wegener's granulomatosis;

[0412] (vii) an autoimmune condition such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease;

[0413] (viii) an ocular condition such as uveitis, allergic conjunctivitis, or vernal conjunctivitis;

[0414] (ix) a neurological condition such as multiple sclerosis or encephalomyelitis;

[0415] (x) an infection or condition associated with an infection such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, tuberculous bacillus, mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis / epididymitis, legionella, Lyme disease, influenza type A, epstein-barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease;

[0416] (xi) a renal condition such as mesengioproliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or the renal syndrome;

[0417] (xii) a lymphatic condition such as Castleman's disease;

[0418] (xiii) a condition of or involving the immune system such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease;

[0419] (xiv) a liver condition such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), or primary biliary cirrhosis;

[0420] (xv) a cancer including those listed above;

[0421] (xvi) burns, wounds, trauma, bleeding, or stroke;

[0422] (xvii) radiation exposure; and / or

[0423] (xviii) obesity; and / or

[0424] (xix) pain, such as inflammatory hyperalgesia.

[0425] In one embodiment of the fifth, sixth, seventh, eighth, ninth, or tenth aspect of the application, 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), tumor 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 anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD).

[0426] Examples of diseases, disorders or conditions responsive to NLRP3 inhibition and treatable or preventable in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspects of the application are listed above. Some of these diseases, disorders or conditions are substantially or entirely mediated by NLRP3 inflammasome activity and IL-1 β and / or IL-18 induction by NLRP3. Accordingly, such diseases, disorders or conditions can be particularly responsive to NLRP3 inhibition and are particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspects of the application. 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), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic juvenile idiopathic arthritis, adult onset Still's disease (AOSD), relapsing polychondritis, Schnitzler's syndrome, Sjogren's syndrome, Behcet's disease, anti-synthetase syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), and haploinsufficiency of A20 (HA20).

[0427] In addition, some of the diseases, disorders or conditions mentioned above are elevated due to mutations in NLRP3, in particular, leading to increased NLRP3 activity. Accordingly, such diseases, disorders or conditions can be particularly responsive to NLRP3 inhibition and are particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspects of the application. 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).

[0428] In one embodiment of the fifth, sixth, seventh, eighth, ninth, or tenth aspect of the application, the disease, disorder, or condition is not an ocular inflammatory disease or a symptom of an ocular inflammatory disease. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a skin disease. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a disease involving a chemokine receptor. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a skin disease. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not dermatitis. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a disease involving increased eosinophils. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not an allergic disease. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a disease susceptible to treatment with a chymase inhibitor. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a fibrosis or a disorder of extracellular matrix metabolism. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a disease accompanied by abnormal vascular function. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a rheumatic disease. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a heart or circulatory system disease. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not an inflammatory bowel disease. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not an HCV infection. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a cancer. In one embodiment of the fifth, sixth, or seventh aspect of the application, the disease, disorder, or condition is not a disease susceptible to treatment with a hypoglycemic agent.

[0429] The eleventh aspect of the application provides a method of inhibiting NLRP3, comprising using a compound of the first or second aspect of the application, or a pharmaceutically acceptable salt, solvate, or prodrug of the third aspect of the application, or a pharmaceutical composition of the fourth aspect of the application, to inhibit NLRP3.

[0430] In one embodiment of the eleventh aspect of the application, the method comprises using a compound of the first or second aspect of the application, or a pharmaceutically acceptable salt, solvate, or prodrug of the third aspect of the application, or a pharmaceutical composition of the fourth aspect of the application, and one or more additional active agents.

[0431] In one embodiment of the eleventh aspect of the application, the method is performed ex vivo or in vitro, for example to analyze the effect of the cells on NLRP3 inhibition.

[0432] In another embodiment of the eleventh aspect of the application, the method is performed in vivo. For example, the method can 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, thereby inhibiting NLRP3. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, the administration is to a subject in need thereof.

[0433] Alternatively, the method of the eleventh aspect of the application can be a method of inhibiting NLRP3 in a non-human animal subject, the method comprising the step of administering the compound, salt, solvate, prodrug, or pharmaceutical composition to the non-human animal subject, and optionally subsequently sacrificing or killing the non-human animal subject. Typically, the method further comprises the step of analyzing one or more tissue or fluid samples of the optionally sacrificed or killed non-human animal subject. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents.

[0434] The twelfth aspect of the application provides a compound of the first or second aspect of the application, or a pharmaceutically acceptable salt, solvate, or prodrug of the third aspect of the application, or a pharmaceutical composition of the fourth aspect of the application, for use in the inhibition of NLRP3. Typically, the use comprises administering the compound, salt, solvate, prodrug, or pharmaceutical composition to a subject. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents.

[0435] The thirteenth aspect of the application provides the use of a compound of the first or second aspect of the application, or a pharmaceutically acceptable salt, solvate, or prodrug of the third aspect of the application, in the manufacture of a medicament for the inhibition of NLRP3. Typically, the inhibition comprises administering 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 additional active agents.

[0436] In any embodiment of any of the fifth through thirteenth aspects of the application that includes the use of or co-administration of one or more additional active agents, the one or more additional active agents can include, for example, one, two, or three different additional active agents.

[0437] The one or more additional active agents can be administered before, at the same time as, sequentially with, and / or after the compound of the first or second aspect of the application, the pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the application, or the pharmaceutical composition of the fourth aspect of the application. Where the one or more additional active agents are administered at the same time as the compound of the first or second aspect of the application, or the pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the application, the pharmaceutical composition of the fourth aspect of the application can be administered, wherein the pharmaceutical composition additionally comprises the one or more additional active agents.

[0438] In one embodiment of any one of the fifth to thirteenth aspects of the application comprising the use of, or co-administration with, one or more additional active agents, the one or more additional active agents are selected from:

[0439] (i) a chemotherapeutic agent;

[0440] (ii) an antibody;

[0441] (iii) an alkylating agent;

[0442] (iv) an antimetabolite;

[0443] (v) an anti-angiogenic agent;

[0444] (vi) a plant alkaloid and / or a terpenoid;

[0445] (vii) a topoisomerase inhibitor;

[0446] (viii) an mTOR inhibitor;

[0447] (ix) a stilbenoid;

[0448] (x) a STING agonist;

[0449] (xi) a cancer vaccine;

[0450] (xii) an immunomodulatory agent;

[0451] (xiii) an antibiotic;

[0452] (xiv) an antifungal agent;

[0453] (xv) an anti-intestinal worm agent; and / or

[0454] (xvi) another active agent.

[0455] It will be appreciated that these general embodiments defined according to broad classes of active agents are not mutually exclusive of one another. In this regard, any particular active agent can be classified 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.

[0456] In some embodiments, the one or more chemotherapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, amsacrine, anhydrovinblastine, auristatin, azathioprine, adriamycin, bexarotene, bicalutamide, BMS 184476, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-L-proly-L-proline- t-butylamide, cisplatin, carboplatin, carmustin, chlorambucil, cachectin, cemadotin, cyclophosphamide, carmustine, cryptophycin, cytarabine, docetaxel, docetaxel, doxorubicin, dacarbazine (DTIC), dactinomycin, duazomycin, decitabine, dolastatin, etoposide, etoposide phosphate, enzalutamide (MDV3100), 5-fluorouracil, fludarabine, flutamide, gemcitabine, hydroxyurea and hydroxyurea taxoids, idarubicin, ifosfamide, irinotecan, leucovorin, lonidamine, lomustine (CCNU), larotaxel (RPR109881), mechlorethamine, mercaptopurine, methotrexate, mitomycin C, mitoxantrone, melphalan, mivobulin, 3',4'-didehydro-4'-deoxy-8'-dehomovincaleukoblastine, nilutamide, oxaliplatin, onapristone, prednimustine, procarbazine, paclitaxel, platinum containing anti-cancer agents, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, prednimustine, procarbazine, sertenef, streptozocin, stramustine phosphate, tacrolimus, tasonermin, taxol, topotecan, tamoxifen, teniposide, taxoids, tegafur / uracil, vincristine, vinblastine, vinorelbine, vindesine, vindesine sulfate, and / or vinflunine.

[0457] Alternatively or in addition, the one or more chemotherapeutic agents can be selected from CD59-complementary fragments, fibronectin fragments, gro-β (CXCL2), heparanase, heparin hexasaccharide fragments, human chorionic gonadotropin (hCG), interferon alpha, interferon beta, interferon gamma, interferon-inducible protein (IP-10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16kD fragment, prolactin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-beta (TGF-beta), vasculostatin, vasostatin (calreticulin fragment), and / or cytokines (including interleukins such as interleukin-2 (IL-2) or IL-10).

[0458] In some embodiments, the one or more antibodies can include one or more monoclonal antibodies. In some embodiments, the one or more monoclonal antibodies are selected from abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, ceertolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumuab, ranibizumab, rituximab, tocilizumab, tositumomab, and / or trastuzumab.

[0459] In some embodiments, the one or more alkylating agents can include an agent capable of alkylating a nucleophilic functional group in the presence of a cell, including, for example, a cancer cell. In some embodiments, the one or more alkylating agents are selected from cisplatin, carboplatin, dichloromethyldiacetic acid, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin. In some embodiments, alkylating agents can act by forming covalent bonds with amino, carboxyl, sulfhydryl, and / or phosphate groups in biologically important molecules to affect cellular function. In some embodiments, alkylating agents can act by modifying the DNA of a cell.

[0460] In some embodiments, the one or more antimetabolites can include an agent capable of affecting or preventing RNA or DNA synthesis. In some embodiments, the one or more antimetabolites are selected from azathioprine and / or mercaptopurine.

[0461] In some embodiments, the one or more anti-angiogenic agents are selected from endostatin, angiopoietin inhibitors, angiostatin, angioarrestin, angiostatic proteins (tumstatin, canstatin or arrestin) derived from basement membrane collagen, anti-angiogenic anti-thrombin III and / or cartilage-derived inhibitor (CDI).

[0462] In some embodiments, the one or more plant alkaloids and / or terpenoids can provide microtubule function. In some embodiments, the one or more plant alkaloids and / or terpenoids are selected from vinca alkaloids, podophyllotoxins and / or taxanes. In some embodiments, the one or more vinca alkaloids can be derived from Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea), and can be selected from vincristine, vinblastine, vinorelbine and / or vindesine. In some embodiments, the one or more taxanes are selected from paclitaxel, pacilitaxel, docetaxel and / or ortataxel. In some embodiments, the one or more podophyllotoxins are selected from etoposide and / or teniposide.

[0463] In some embodiments, the one or more topoisomerase inhibitors are selected from type I topoisomerase inhibitors and / or type II topoisomerase inhibitors, and can interfere with the reverse transcription and / or replication of DNA by interfering with DNA supercoiling. In some embodiments, the one or more type I topoisomerase inhibitors can include camptothecins, which can 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 can include epipodophyllotoxins, which can be selected from amascrine, etoposide, etoposide phosphate and / or teniposide.

[0464] In some embodiments, the one or more mTOR (mammalian target of rapamycin, also known as mechanistic target of rapamycin) inhibitors are selected from rapamycin, everolimus, temsirolimus, and / or deforolimus.

[0465] In some embodiments, the one or more stilbenoids are selected from resveratrol, piceatannol, pinosylvin, pterostilbene, a-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, epsilon-viniferin, flexuosol A, gnetin H, hemsleyanol D, hopeaphenol, trans-diptoindonesin B, astringin, piceid, and / or diptoindonesin A.

[0466] In some embodiments, the one or more STING (stimulator of interferon genes, also known as transmembrane protein (TMEM) 173) agonists can include cyclic di-nucleotides, such as cAMP, cGMP, and cGAMP, and / or modified cyclic di-nucleotides, which can include one or more of the following modification features: 2'-O / 3'-O linkage, phosphorothioate linkage, adenine and / or guanine analog, and / or 2'-OH modification (e.g., 2'-OH protected with a methyl group or replaced by -F or -N3).

[0467] In some embodiments, the one or more cancer vaccines are selected from HPV vaccine, hepatitis B vaccine, Oncophage, and / or Provenge.

[0468] In some embodiments, the one or more immunomodulatory agents can include an immune checkpoint inhibitor. The immune checkpoint inhibitor can target an immune checkpoint receptor, or a combination of receptors including, for example, CTLA-4, PD-1, PD-L1, PD-L2, T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9, phospholipid serine, lymphocyte-activation gene 3 protein (LAG3), MHC class I, MHC class II, 4-1BB, 4-1BBL, OX40, OX40L, GITR, GITRL, CD27, CD70, TNFRSF25, TL1A, CD40, CD40L, HVEM, LIGHT, BTLA, CD160, CD80, CD244, CD48, ICOS, ICOSL, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2, TMIGD2, butyrophilin (including BTNL2), Siglec family members, TIGIT, PVR, killer cell immunoglobulin-like receptors, ILTs, leukocyte immunoglobulin-like receptors, NKG2D, NKG2A, MICA, MICB, CD28, CD86, SIRPA, CD47, VEGF, neuropilin, CD30, CD39, CD73, CXCR4, and / or CXCL12.

[0469] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PD-L1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, ulocuplumab, BKT140, bavituximab, CC-90002, bevacizumab, and / or MNRP1685A.

[0470] In some embodiments, the one or more antibiotics are selected from amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin, oritavancin, clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin,spiramycin, aztreonam, furazolidone, nitrofurantoin, linezolid, posizolid, radezolid, torezolid, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, ticarcillin, calvulanate, ampicillin, subbactam, tazobactam, ticarcillin, calvulanate, suberanile, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, acetyl sulfisomidine, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfisoxazole, sulfanamide, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole, sulfonamideochrysoidine, demeclocycline, minocycline,Oytetracycline, tetracycline, clofazimine, dapsone, dapreomycin, cycloserine, ethambutol, ethionicotinamide, isonicotinic acid tincture, pyrazinecarboxamide, rifampicin, rifabutin, rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin, dalopristin, thiamphenicol, tigecycline, tinidazole, trimethoprim, and / or teixobactin. 、

[0471] 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 actinomycin, anthraquinone, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxygluconic acid and / or clofazimine. In some embodiments, the one or more actinomycins are selected from actinomycin D, subtilisin, colistin (polymyxin E) and / or polymyxin B. In some embodiments, the one or more anthraquinones are selected from mitoxantrone and / or pixantrone. In some embodiments, the one or more anthracyclines are selected from bleomycin, doxorubicin (adriamycin), daunomycin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and / or valrubicin.

[0472] In some embodiments, the one or more antifungal agents are selected from bifonazole, butoconazole, clotrimazole, econazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoziconazole, fluconazole, isavuconazole, itraconazo le, posaconazole, propiconazole, ravusconazole, terconazole, voriconazole, abafungin, amorolfin, butenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, 5-fluorocytosine, griseofulvin, haloprogin, tolnaflate, undecylenic acid, and / or balsam of Peru.

[0473] In some embodiments, the one or more anthelmintics are selected from benzimidazoles (including albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, and flubendazole), abamectin, diethylcarbamazine, ivermectin, suramin, pyrantel pamoate, levamisole, salicylanilides (including niclosamide and oxyclozanide), and / or nitazoxanide.

[0474] In some embodiments, the additional active agent is selected from growth inhibitory agents, anti-inflammatory agents (including non-steroidal anti-inflammatory agents), anti-psoriatic agents (including onionol and its derivatives), vitamins and vitamin derivatives (including retinoids and VDR receptor ligands), corticosteroids, ion channel blockers (including potassium channel blockers), immune system modulators (including cyclosporine, FK 506 and glucocorticoids), luteinizing hormone-releasing hormone agonists (such as leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide) and / or hormones (including estrogens).

[0475] Unless otherwise indicated, in any of the fifth to thirteenth aspects of the present invention, the subject may be any human or another 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. More typically, the subject is a human.

[0476] Any pharmaceutical product used in the present invention may be administered orally, parenterally (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), by the airway (aerosol), rectal, vaginally or topically (including transdermal, buccal, mucosal and sublingual).

[0477] Generally, the mode of administration chosen will be that which is most suitable for the condition, disease, or disorder to be treated or prevented. When one or more additional active agents are administered, the mode of administration can be the same or different from the mode of administration of the compounds, salts, solvates, prodrugs, or pharmaceutical compositions of the application.

[0478] For oral administration, the compounds, salts, solvates, or prodrugs of the application will generally be provided in the form of tablets, capsules, hard or soft gelatin capsules, cachets, lozenges or rhombus-shaped tablets, as a powder or granules, or as an aqueous solution, suspension or dispersion.

[0479] Tablets for oral use can include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring 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 can include starch and gelatin. The lubricating agent, when used, can be magnesium stearate, stearic acid or talc. If desired, tablets can be coated with material such as sugar or shellac. Capsules can include active ingredient mixed with solid or liquid diluents, including cocoa butter and milk sugar.

[0480] Capsules for oral use include hard gelatin capsules having mixed in them active ingredient and a solid diluent such as lactose, starch, or calcium phosphate; and soft gelatin capsules having mixed in them active ingredient and either water or oil such as peanut oil, liquid paraffin, or olive oil.

[0481] Powders or granules for oral use can be provided in sachets or in bottles. Aqueous solutions, suspensions or dispersions can be prepared from the powders, granules or tablets by addition of water.

[0482] Any form suitable for oral administration can optionally include a sweetening agent such as sugar, a flavoring agent, a coloring agent and / or a preservative.

[0483] Formulations suitable for rectal administration can be provided as suppositories by mixing the active ingredient with suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum to release the active ingredient.

[0484] Formulations suitable for vaginal administration can be provided in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0485] For parenteral use, the compounds, salts, solvates or prodrugs of the present application will generally be provided in a sterile aqueous solution or suspension, buffered to the appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution, and isotonic sodium chloride or dextrose. The aqueous solutions of the present application can include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, and gum tragacanth, and wetting agents such as lecithin. Suitable preservatives for aqueous suspensions include methyl and propyl parabens. The compounds of the present application can also be provided as liposome formulations.

[0486] For transdermal and other local administration, the compounds, salts, solvates or prodrugs of the present application will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches.

[0487] Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.

[0488] The dosage of the compounds, salts, solvates or prodrugs of the present application will, of course, vary depending on the condition, 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 can be provided in a single dose or in multiple doses, such as once every other day, once a day, twice a day, three times a day or four times a day. The desired dose can be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.

[0489] To avoid doubt, any embodiment of a given aspect of the present application can be combined with any other embodiment of the same aspect of the present application, provided it is practicable. Furthermore, to avoid doubt, it is to be understood that any preferred, typical or optional embodiment of any aspect of the present application is also to be considered a preferred, typical or optional embodiment of any other aspect of the present application, provided it is practicable.

[0490] Example - Compound Synthesis

[0491] Unless otherwise stated, all solvents, reagents and compounds are purchased and used without further purification.

[0492] Abbreviations

[0493] 2-MeTHF 2-methyltetrahydrofuran

[0494] AcOH acetic acid

[0495] aq aqueous

[0496] Boc tert-butyloxycarbonyl

[0497] br broad

[0498] Cbz carboxybenzyl

[0499] CDI 1,1-carbonyl-diimidazole

[0500] conc concentrated

[0501] d doublet

[0502] DABCO 1,4-diazabicyclo[2.2.2]octane

[0503] DCE 1,2-dichloroethane, also known as ethylene dichloride

[0504] DCM dichloromethane

[0505] DIPEA N,N-diisopropylethylamine, also known as Hunig's base

[0506] DMAP 4-dimethylaminopyridine, also known as N,N-dimethylpyridin-4-amine

[0507] DME dimethoxyethanamine

[0508] DMF N,N-dimethylformamide

[0509] DMSO dimethyl sulfoxide

[0510] (ES+) electrospray ionization, positive mode

[0511] Et ethyl

[0512] EtOAc ethyl acetate

[0513] EtOH ethanol

[0514] h hour(s)

[0515] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0516] HPLC high performance liquid chromatography

[0517] LC liquid chromatography

[0518] m multiplet

[0519] m-CPBA 3-chloroperbenzoic acid

[0520] Me methyl

[0521] MeCN acetonitrile

[0522] MeOH methanol

[0523] (M+H)+ protonated molecular ion

[0524] MHz megahertz

[0525] min minute

[0526] MS mass spectrometry

[0527] Ms methylsulfonyl, also called methanesulfonyl

[0528] MsCl methanesulfonyl chloride, also called methane sulfonyl chloride

[0529] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether

[0530] m / z mass-to-charge ratio

[0531] NaO t Bu sodium tert-butoxide

[0532] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide

[0533] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide

[0534] NMP N-methylpyrrolidine

[0535] NMR nuclear magnetic resonance (spectroscopy)

[0536] Pd(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0537] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0538] PE petroleum ether

[0539] Ph phenyl

[0540] PMB p-methoxybenzyl

[0541] preparative HPLC preparative high-performance liquid chromatography

[0542] preparative TLC preparative thin-layer chromatography

[0543] PTSA p-toluenesulfonic acid

[0544] q quartet

[0545] RP reversed phase

[0546] RT room temperature

[0547] s singlet

[0548] Sept septet

[0549] sat saturated

[0550] SCX solid supported cation exchange (resin)

[0551] t triplet

[0552] TBME tert-butyl methyl ether, also known as methyl tert-butyl ether

[0553] TEA triethylamine

[0554] TFA 2,2,2-trifluoroacetic acid

[0555] THF tetrahydrofuran

[0556] TLC thin layer chromatography

[0557] wt% weight percent (or percent by weight)

[0558] Experimental methods

[0559] Analytical method

[0560] NMR spectra were recorded at 300 MHz or 400 MHz with chemical shifts recorded in parts per million. Spectra were collected using one of the following three machines:

[0561] - Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, an indirect detection probe and a direct drive control console including a PFG module.

[0562] - Agilent Mercury Plus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, a 4 nucleus auto-switchable probe and a Mercury plus control console.

[0563] - Bruker 400 MHz spectrometer using ICON-NMR under TopSpin program control.

[0564] HPLC and LC-MS were recorded on an Agilent 1290 series with a UV detector and HP 6130 MSD mass detector. Mobile phase A: ammonium acetate (10 mM); water / MeOH / acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water / MeOH / acetonitrile (100:540:360); column, Waters XBridge BEH C18 XP (2.1 x 50 mm, 2.5 μm)

[0565] Pump flow rate: 0.6 mL / min UV detection: 215, 238 nm

[0566] Injection volume: 0.2 μL Run time: 4.0 min

[0567] Column temperature: 35℃ Quality test: API-ES+ve and -ive

[0568] Pump Program:

[0569] Gradient time (min) A％ B％ 0.0 80 20 0.5 80 20 2.0 0 100

[0570] Alternatively, LC-MS was recorded using a SHIMADZU LCMS-2020, an Agilent 1200LC / G1956A MSD, and an Agilent 1200 / G6110A, an Agilent 1200LC, and an Agilent 6110MSD. Mobile phases: A: 0.025% NH₃·H₂O in water (v / v); B: acetonitrile. Column: Kinetex EVO C18 2.1×30 mm, 5 μm.

[0571] Purification method 1

[0572] Using Buchi Automated reverse phase column chromatography was performed on an X50 system driven by a C-605 pump module, a C-620 Sepracore control package, a C-640 UV photometer detection unit and a C-660 fraction collector.

[0573] Revelis C18 Reversed Phase 12g Cartridge

[0574]

[0575] The column was conditioned and then loaded with MeOH (5 min), then H2O (over 5 min), and held for 5 min with H2O. Flow rate = 30 mL / min.

[0576] Separate operation:

[0577] Time (min) A: Water (%) B: MeOH (%) 0 100 0 5 100 0 30 30 70 30.1 0 100 35 0 100

[0578] Detection wavelengths: 215, 235, 254 and 280 nm. Before each new run, clean the cartridge using the conditioning method.

[0579] Purification method 2

[0580] Alternatively, automated reverse phase column chromatography was performed using a Gilson GX-281 system consisting of a Gilson-322 pump module, Gilson-156 UV spectrometer detection unit and Gilson-281 fraction collector drive.

[0581] Phenomenex Gemini 150mm x 25mm x 10μm

[0582] pH (water (0.05% ammonium hydroxide v / v) - acetonitrile) = 10

[0583] Average particle size = 10μm

[0584] The column was conditioned followed by a run using 100% acetonitrile (2 min) then 5% acetonitrile (over 1.5 min). Flow rate = 25 mL / min.

[0585] Separation run:

[0586] Time (min) A: Water (0.05% ammonium hydroxide v / v) B: Acetonitrile (%) 0 99 1 12 85 15 12.2 0 100 14.2 0 100 14.5 95 5 16.0 95 5

[0587] Detection wavelength: 220 and 254 nm. The cartridge was cleaned using the conditioning method prior to each new run.

[0588] Synthesis of intermediates

[0589] Intermediate A1: 4-isocyano-1,2,3,5,6,7-hexahydro-s-indacene

[0590]

[0591] To a solution of phosgene (4.45 mL, 20 wt% 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 after cooling was filtered and concentrated in vacuo to give the title compound as a brown oil (756 mg, 100% yield). The crude product was used directly in the next step without further purification.

[0592] 1 H NMR (CDCI3): δ 6.8 (s, 1 H), 2.89 (m, 8H) and 2.09 (m, 4H).

[0593] Intermediate A2: 2-isocyano-1,3-diisopropylbenzene

[0594]

[0595] To a suspension of 2,6-diisopropylaniline hydrochloride (1 g, 4.7 mmol) in toluene (50 mL) was added 1 drop of pyridine and the resulting mixture was heated to near reflux while a solution of phosgene (7.3 mL, 20 wt% in toluene, 13.8 mmol) was added dropwise over a period of 10 minutes. The mixture was stirred at 105 °C for an additional 45 minutes, then allowed to cool partially before being concentrated in vacuo to give the title compound as a yellow flowing oil (1.5 g, >100% yield). The crude product was used directly in the next step without further purification.

[0596] 1 H NMR (CDCI3): δ 7.2 (m, 3H), 3.12 (m, 2H) and 1.25 (d, 12H).

[0597] Intermediate A3: 5-Fluoro-2-isocyanato-l,3-diisopropylbenzene

[0598]

[0599] To a solution of 4-fluoro-2,6-diisopropylaniline (0.103 g, 0.527 mmol) in toluene (1.4 mL) was added a solution of phosgene (0.69 mL, 20 wt% in toluene, 1.3 mmol) and the reaction mixture was refluxed for 1 hour. After cooling, the mixture was concentrated in vacuo to give the title compound as a brown oil (0.110 g, yield 100%). The crude product was used directly in the next step without further purification.

[0600] 1 H NMR (CDCI3): δ 7.2 (m, 3H), 3.12 (m, 2H) and 1.25 (d, 12H).

[0601] Intermediate A4: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-amine Step A: N-(5-Bromo-2,3-dihydro-lH-inden-4-yl)trimethylacetamide (pivalamide)

[0602]

[0603] N-(2,3-dihydro-lH-inden-4-yl)trimethylacetamide (1 g, 4.60 mmol), p-toluenesulfonic acid monohydrate (0.45 g, 2.366 mmol), Pd(OAc)2(0.05 g, 0.223 mmol) and NBS (0.9 g, 5.06 mmol) were suspended in toluene (20 mL) and stirred for 16 h. The dark green mixture was diluted in EtOAc (20 mL) and then washed with saturated aqueous NaHC03(2 x 10 mL), water (2 x 10 mL) and brine (10 mL). The organic phase was dried (Na2S04), filtered and concentrated in vacuo to give a dark green amorphous solid. The crude product was purified by silica gel chromatography (40 g column, 0-30% EtOAc / isohexane) to give the title compound as a colourless crystalline solid (1.662 g, 100%) contaminated with a small amount of reaction by-product.

[0604] LCMS: m / z 296.3 / 298.3 (M+H) + (ES + ).

[0605] Step B: 5-bromo-2,3-dihydro-lH-inden-4-amine

[0606]

[0607] N-(5-bromo-2,3-dihydro-lH-inden-4-yl)trimethylacetamide (0.632 g, 2.134 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H2S04(95% aqueous solution) (5 mL, 89 mmol) was slowly added to water (5 mL) and this mixture was then added to the reaction mixture. The slurry was heated to 100 °C (bath temperature) at which point the mixture became homogeneous and it was stirred at this temperature over the weekend. The mixture was cooled to room temperature and then basified with 2M aqueous NaOH. The mixture was extracted with DCM (3 x 20 mL). The organic phase was dried by passing through a hydrophobic glass frit and then concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-50% EtOAc / isohexane) to give the title compound (0.14 g, 29%).

[0608] 1 H NMR (CDCI3) δ 7.23 (d, J = 7.9 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 3.92 (s, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.15 (p, J = 7.5 Hz, 2H).

[0609] Step C: 5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-amine

[0610]

[0611] Step C: 5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-amine

[0612] 1 H NMR (CDCI3) d 8.26 (d, J = 5.4 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.97 (s, 1H), 6.80 (d, J = 7.6 Hz, 1H), 4.06 (s, 3H), 2.98 (t, J = 7.6 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.19 (p, J = 7.5 Hz, 2H). Two exchangeable protons were not observed.

[0613] LCMS: m / z 241.3 (M+H) + (ES + ).

[0614] Intermediate A5: 4-(4-amino-2,3-dihydro-lH-inden-5-yl)-2-cyanopyridine

[0615]

[0616] 5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-amine (Intermediate A4, Step C) was prepared according to the general procedure from 5-bromo-2,3-dihydro-lH-inden-4-amine (Intermediate A4, Step B) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-cyanopyridine to afford the title compound (215 mg, 61%) as a light yellow solid.

[0617] 1 H (DMSO-d6) δ 8.72 (dd, J = 5.1, 0.8 Hz, 1H), 8.03 (dd, J = 1.8, 0.8 Hz, 1H), 7.74 (dd, J = 5.1, 1.8 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 4.94 (s, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H).

[0618] LCMS: m / z 236.3 (M+H) + (ES + ).

[0619] Intermediate A6: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)2-cyanopyridine

[0620] Step A: 4-Fluoro-2-(prop-1-en-2-yl)aniline

[0621]

[0622] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K2CO3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H2O (40 mL) was added Pd(dppf)Cl2 (7.51 g, 10.26 mmol, 0.05 eq) under nitrogen atmosphere. The reaction mixture was then stirred at 80 °C for 5 h. The reaction mixture was quenched by the addition of H2O (600 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (2 x 600 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate 1:0 to 100:1) to afford the title compound (27 g, 77% yield, 89% LCMS purity) as a yellow oil.

[0623] 1 H NMR (CDCI3) δ 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

[0624] LCMS: m / z 152.2 (M+H) + (ES + ).

[0625] Step B: 4-Fluoro-2-isopropylaniline

[0626]

[0627] To a solution of 4-fluoro-2-(prop-l-en-2-yl)aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd / C (2.1 g, 178.59 mmol, 10 wt% on activated carbon) under nitrogen atmosphere. The reaction mixture was degassed in vacuum and purged with hydrogen gas for several times. The reaction mixture was stirred at 25 °C under hydrogen gas (50 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to afford the title compound as yellow oil (20 g, crude).

[0628] 1 H NMR (CDCI3) d 6.86 (dd, 1H), 6.75-6.72 (m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and 1.25 (d, 6H).

[0629] LCMS: m / z 154.2 (M+H) + (ES + ).

[0630] Step C: 2-Bromo-4-fluoro-6-isopropylaniline

[0631]

[0632] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130.55 mmol, 1 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. The reaction mixture was poured into H2O (300 mL) and extracted with EtOAc (2 x 250 mL). The combined organic phase was washed with brine (2 x 400 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (Si02, eluted with only petroleum ether) to afford the title compound as brownish black oil (30 g, 99%).

[0633] 1H NMR (CDCI3) δ 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

[0634] LCMS: m / z 232.1 (M+H) + (ES + ).

[0635] Step D: 4-(2-amino-5-fluoro-3-isopropylphenyl)2-cyanopyridine

[0636]

[0637] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (3.6 g, 15.51 mmol, 1 eq) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)2-cyanopyridine (3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 mL) and H20 (9 mL) was added Na2C03(4.11 g, 38.78 mmol, 2.5 eq). Then Pd(dppf)C12(1.13 g, 1.55 mmol, 0.1 eq) was added to the mixture under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen. Then the mixture was concentrated in vacuum. The residue was purified by silica gel column chromatography (Si02, petroleum ether: ethyl acetate 20: 1 to 5: 1) and then triturated with petroleum ether (10 mL) to give the title compound as a yellow solid (2.65 g, 65% yield, 97% LCMS purity).

[0638] 1 H NMR (CDCI3) δ 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

[0639] LCMS: m / z 256.2 (M+H) + (ES + ).

[0640] Step E: 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)2-cyanopyridine

[0641]

[0642] To a solution of 4-(2-amino-5-fluoro-3-isopropylphenyl)2-cyanopyridine (1 g, 3.92 mmol, 1 eq) in THF (40 mL) was added TEA (793 mg, 7.83 mmol, 2 eq). To the above mixture was added portionwise, at 5 °C, trphosgene (465 mg, 1.57 mmol, 0.4 eq). The mixture was then stirred at 70 °C for 1 h. The mixture was diluted with EtOAc (200 mL) and then filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.2 g, crude) as a yellow solid which was used directly in the next step.

[0643] Intermediate A7: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine Step A: 4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline

[0644]

[0645] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (12 g, 51.70 mmol, 1 eq) in dioxane (240 mL) and H2O (48 mL) was added (2-methoxypyridin-4-yl)boronic acid (9.49 g, 62.04 mmol, 1.2 eq) and Na2CO3(13.70 g, 129.26 mmol, 2.5 eq). The reaction mixture was purged with nitrogen three times. Pd(dppf)Cl2(3.78 g, 5.17 mmol, 0.1 eq) was then added to the mixture under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched with H2O (800 mL) and extracted with EtOAc (2 x 600 mL). The combined organic layers were washed with brine (2 x 800 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate 70:1 to 10:1) and then triturated with hexane (100 mL) to give the title compound (10.05 g, 72% yield, 96% LCMS purity).

[0646] 1 H NMR (CDCI3) d 8.24 (d, 1H), 6.97 (d, 1H), 6.93 (d, 1H), 6.83 (s, 1H), 6.73-6.70 (m, 1H), 3.99 (s, 3H), 3.66 (br s, 2H), 2.97-2.89 (m, 1H) and 1.29 (dd, 6H).

[0647] LCMS: m / z 261.1 (M+H) + (ES+ ).

[0648] Step B: 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

[0649]

[0650] To a solution of 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (1 g, 3.84 mmol, 1 eq) in THF (40 mL) was added TEA (777 mg, 7.68 mmol, 2 eq). Then triphosgene (456 mg, 1.54 mmol, 0.4 eq) was added portionwise at 5 °C. The mixture was stirred at 70 °C for 1 h. The mixture was diluted with EtOAc (200 mL) and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.1 g, crude) as a yellow oil, which was used directly in the next step.

[0651] Intermediate A8: 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2- methoxypyridine

[0652]

[0653] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A4) (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL) was added bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) portionwise at 0 °C. The reaction mixture was then stirred at 16 °C for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74%) as a light yellow solid.

[0654] 1 H NMR (CDCI3) δ 8.28 (d, 1H), 7.20-7.16 (m, 3H), 7.02 (s, 1H), 4.16 (s, 3H), 3.04-2.99 (m, 4H) and 2.23-2.15 (m, 2H).

[0655] Intermediate A9: 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

[0656] Step A: 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one

[0657]

[0658] To a mixture of 7-fluoro-2,3-dihydro-lH-inden-l-one (9.5 g, 63.27 mmol, 1 eq) in cone. H2SO4(100 mL) was added a solution of HNO3(5.37 mL, 82.25 mmol, 69 wt% in water, 1.3 eq) in cone. H2SO4(20 mL) dropwise at -15 °C. The reaction mixture was then stirred at 0 °C for 0.5 h. The mixture was quenched with water (500 mL) at 0 °C, then extracted with EtOAc (3 x 300 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate, 10: 1 to 3: 1) to give the title compound (11.4 g, 92%) as a yellow solid.

[0659] 1 H NMR (CDCI3) δ 8.51 (dd, 1H), 7.22 (t, 1H), 3.69-3.65 (m, 2H) and 2.88-2.82 (m, 2H).

[0660] Step B: 7-Fluoro-4-nitro-2,3-dihydro-lH-inden-l-ol

[0661]

[0662] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-lH-inden-l-one (30 g, 153.73 mmol, 1 eq) in EtOH (450 mL) was added NaBH4(11.63 g, 307.46 mmol, 2 eq) portionwise. The reaction mixture was stirred at 15 °C for 1 h. The mixture was then poured into water (500 mL) and extracted with DCM (2 x 200 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (30 g, crude) as a brown oil.

[0663] 1 H NMR (CDCI3) δ 8.21 (dd, 1H), 7.08 (t, 1H), 5.59-5.56 (m, 1H), 3.66-3.59 (m, 1H), 3.44-3.39 (m, 1H), 2.56-2.51 (m, 1H) and 2.22-2.17 (m, 2H).

[0664] Step C: 4-Fluoro-7-nitro-2,3-dihydro-lH-indene

[0665]

[0666] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol (4.5 g, 22.82 mmol, 1 eq) in TFA (20 mL) was added Et3SiH (7.96 g, 68.47 mmol, 3 eq) in one portion. The reaction mixture was stirred at 25 ° C for 12 hours. The mixture was then quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (5 g, crude product) as a brown oil.

[0667] 1 H NMR (CDCl3) δ 8.06 (dd, 1H), 7.01 (t, 1H), 3.46 (t, 2H), 3.04 (t, 2H) and 2.25-2.20 (m, 2H).

[0668] Step D: 7-Fluoro-2,3-dihydro-1H-inden-4-amine

[0669]

[0670] To a mixture of 4-fluoro-7-nitro-2,3-dihydro-1H-indene (5 g, 27.60 mmol, 1 equivalent) in MeOH (50 mL) was added Pd / C (0.5 g, 10% by weight on activated carbon) at 25 ° C. under a nitrogen atmosphere. The reaction mixture was then stirred at 25 ° C. under hydrogen (15 psi) for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO 2 , petroleum ether: ethyl acetate, 50: 1 to 10: 1) to give the title compound (1.8 g, 43%) as a brown solid.

[0671] 1 H NMR(CDCl3) δ6.69(t,1H), 6.44(dd,1H), 3.47(br s,2H), 2.95(t,2H), 2.75(t,2H) and 2.19-2.11(m,2H).

[0672] Step E: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine

[0673]

[0674] To a solution of 7-fluoro-2,3-dihydro-lH-inden-4-amine (8.3 g, 54.90 mmol, 1 eq) in toluene (100 mL) was added NBS (10.26 g, 57.65 mmol, 1.05 eq) in one portion at 25 °C. The reaction mixture turned dark brown immediately, then the mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched with saturated aqueous Na2S03solution (200 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (S1O2, petroleum ether: ethyl acetate, 1 :0 to 20: 1) to give the title compound (8.51 g, 67%) as a brown solid.

[0675] 1 H NMR (CDC13) δ 6.99 (d, 1H), 3.81 (br s, 2H), 2.92 (t, 2H), 2.78 (t, 2H) and 2.21-2.13 (m, 2H).

[0676] Step F: 7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-lH-inden-4-amine

[0677]

[0678] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-lH-inden-4-amine (3.5 g, 15.21 mmol, 1 eq) and pyridin-4-ylboronic acid (1.96 g, 15.97 mmol, 1.05 eq) in dioxane (50 mL) and H20 (5 mL) was added K2C03(6.31 g, 45.64 mmol, 3 eq) and Pd(dppf)Cl2(1.11 g, 1.52 mmol, 0.1 eq) in one portion under nitrogen atmosphere. The reaction mixture was then heated to 80 °C for 12 h. The reaction mixture was filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (S1O2, petroleum ether: ethyl acetate 10: 1 to 2: 1) to give the title compound (1.7 g, 45% yield, 90.98% HPLC purity) as a brown solid.

[0679] 1H NMR (CDC13) δ 8.68 (dd, 2H), 7.40 (dd, 2H), 6.72 (d, 1H), 3.76 (br s, 2H), 3.01 (t, 2H), 2.80 (t, 2H) and 2.26-2.18 (m, 2H).

[0680] Step G: 4-(7-Fluoro-4-isocyano-2,3-dihydro-lH-inden-5-yl)pyridine

[0681]

[0682] To a solution of 7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-lH-inden-4-amine (400 mg, 1.75 mmol, 1 equiv) and TEA (355 mg, 3.50 mmol, 2 equiv) in THF (30 mL) was added bis(trichloromethyl)carbonate (208 mg, 700.94 μmol, 0.4 equiv) at 0 °C. The reaction mixture was stirred at 70 °C for 30 min. Then the reaction mixture was filtered through a pad of silica gel and the filter cake was washed with THF (20 mL). The filtrate was concentrated in vacuo to reduce to 10 mL, which was used directly in the next step.

[0683] Intermediate A10: 3-(5-Fluoro-2-isocyano-3-isopropylphenyl)pyridine

[0684] Step A: 4-Fluoro-2-isopropyl-6-(pyridin-3-yl)aniline

[0685]

[0686] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (21 g, 90.48 mmol, 1 eq) in dioxane (450 mL) and H2O (90 mL) was added 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (22.26 g, 108.58 mmol, 1.2 eq) and Na2CO3(23.98 g, 226.20 mmol, 2.5 eq). The reaction mixture was purged with nitrogen three times. Then under nitrogen atmosphere, Pd(dppf)Cl2(5.10 g, 6.97 mmol, 0.077 eq) was added. The resulting mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was quenched by the addition of H2O (800 mL) and extracted with EtOAc (2 x 600 mL). The combined organic layers were washed with brine (2 x 800 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate 50:1 to 1:1) then triturated with hexane (40 mL) to afford the title compound (17 g, 82%) as a grey solid.

[0687] 1 H NMR (CDCI3) δ 8.70 (d, 1H), 8.63 (dd, 1H), 7.79 (dd, 1H), 7.41-7.38 (m, 1H), 6.94 (dd, 1H), 6.71 (dd, 1H), 3.57 (s, 2H), 2.97-2.88 (m, 1H) and 1.30 (d, 6H).

[0688] LCMS: m / z 231.2 (M+H) + (ES + ).

[0689] Step B: 3-(5-Fluoro-2-isocyanato-3-isopropylphenyl)pyridine

[0690]

[0691] To a solution of 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (0.5 g, 2.17 mmol, 1 eq) and TEA (439 mg, 4.34 mmol, 2 eq) in THF (10 mL) was added portionwise, at 5 °C, trphosgene (257 mg, 868.51 μmol, 0.4 eq). The reaction mixture was then heated to 70 °C and stirred for 1 h. The reaction mixture was concentrated in vacuo. The residue was treated with EtOAc (100 mL) and filtered. The filtrate was concentrated in vacuo to afford the title compound (0.2 g, crude) as a yellow oil which was used directly in the next step.

[0692] Intermediate A11: 4-(7-Fluoro-4-isocy anoxy-2,3-dihydro-1 H-inden-5-yl)-2-methoxy pyridine

[0693] Step A: 7-Fluoro-5-(2-methoxy pyridin-4-yl)-2,3-dihydro-1 H-inden-4-amine

[0694]

[0695] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1 H-inden-4-amine (Intermediate A9, Step E) (8.5 g, 36.94 mmol, 1 equiv) and (2-methoxypyridin-4-yl)boronic acid (5.93 g, 38.79 mmol, 1.05 equiv) in dioxane (150 mL) and water (15 mL) was added K2CO3(15.32 g, 110.83 mmol, 3 equiv) and Pd(dppf)Cl2(2.70 g, 3.69 mmol, 0.1 equiv) in one portion under nitrogen. The reaction mixture was then heated to 80 °C and stirred for 12 h. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:EtOAc, 1 :0 to 10:1), then purified by trituration with a mixture of TBME and n-hexane (50 mL, 1 :20) to give the title compound as an off-white solid (5.06 g, 52% yield, 97.44% LCMS purity).

[0696] 1 H NMR (CDCI3) d 8.23 (d, 1H), 6.99 (dd, 1H), 6.86 (s, 1H), 6.71 (d, 1H), 3.99 (s, 3H), 3.67 (br s, 2H), 3.00 (t, 2H), 2.79 (t, 2H) and 2.25-2.17 (m, 2H).

[0697] Step B: 4-(7-Fluoro-4-isocy anoxy-2,3-dihydro-1 H-inden-5-yl)-2-methoxy pyridine

[0698]

[0699] To a solution of 4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A5) (300 mg, 1.3 mmol) in toluene (20 mL) at ambient temperature was added phosgene (1.7 mL, 20 wt% in toluene, 3.2 mmol) dropwise. The resulting reaction mixture was then heated to reflux for 70 minutes and concentrated in vacuo after cooling to afford the title compound as a brown oil (333 mg, 100%). The crude product was used directly in the next step without further purification.

[0700] 1 H NMR (CDCI3) δ 8.24 (d, 1H), 6.95 (dd, 1H), 6.88 (s, 1H), 6.85-6.75 (m, 1H), 4.00 (s, 3H), 3.15-2.95 (m, 4H), 2.32-2.12 (m, 2H).

[0701] Intermediate A12: 4-(4-Isocyano-2,3-dihydro-1H-inden-5-yl)pyridine

[0702]

[0703] To a solution of 4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A5) (300 mg, 1.3 mmol) in toluene (20 mL) at ambient temperature was added phosgene (1.7 mL, 20 wt% in toluene, 3.2 mmol) dropwise. The resulting reaction mixture was then heated to reflux for 70 minutes and concentrated in vacuo after cooling to afford the title compound as a brown oil (333 mg, 100%). The crude product was used directly in the next step without further purification.

[0704] 1 H NMR (CDCI3) δ 8.24 (d, 1H), 6.95 (dd, 1H), 6.88 (s, 1H), 6.85-6.75 (m, 1H), 4.00 (s, 3H), 3.15-2.95 (m, 4H), 2.32-2.12 (m, 2H).

[0705] Intermediate A13: 4-(4-Isocyano-2,3-dihydro-1H-inden-5-yl)pyridine

[0706] Step A: 5-(Pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0707]

[0708] Dissolve 5-bromo-2,3-dihydro-lH-inden-4-amine (1.2 g, 5.7 mmol) in dioxane (25 mL). Add a solution of potassium carbonate (3.1 g, 23 mmol) in water (6 mL) and pyridin-4-ylboronic acid (0.83 g, 6.8 mmol). Degass the mixture with nitrogen for 20 minutes before adding Pd(dppf)Cl2.DCM (0.74 g, 0.91 mmol). Heat the reaction mixture to 77 °C for 2 hours. Then cool the mixture to room temperature and filter through celite with DCM (100 mL) and water (25 mL). Dry the organic phase (Na2S04), filter and concentrate in vacuo to give a brown oil (3.3 g). Purify the crude product by silica gel chromatography (80 g column, 0-100% EtOAc / heptane) to give the title compound as a light yellow crystalline solid (0.75 g, 63%).

[0709] 1 H NMR (CDC13) δ 8.72-8.54 (m, 2H), 7.50-7.37 (m, 2H), 6.97 (d, 1H), 6.78 (d, 1H), 3.72 (s, 2H), 2.96 (t, 2H), 2.77 (t, 2H), 2.18 (m, 2H).

[0710] Step B: 4-(4-isocyano-2,3-dihydro-lH-inden-5-yl)pyridine

[0711]

[0712] To a solution of phosgene (1.1 mL, 20 wt% in toluene, 2.06 mmol) in toluene (40 mL) at ambient temperature, add a solution of 5-(pyridin-4-yl)-2,3-dihydro-lH-inden-4-amine (175 mg, 0.83 mmol) in toluene (20 mL) dropwise. Then heat the resulting mixture to reflux for 70 minutes and after cooling to room temperature, a yellow precipitate forms. Filter the solid and dry in vacuo to give the title compound as a yellow solid (145 mg, 74%). The crude product is used directly in the next step without further purification.

[0713] 1 H NMR (CDC13) δ 8.76 (d, 2H), 8.04 (d, 2H), 7.26-7.08 (m, 2H), 3.08 (t, 4H), 2.26 (m, 2H).

[0714] Intermediate A14: 8-isocyano-l,2,3,5-tetrahydro-s-indacene

[0715]

[0716] To a solution of phosgene (1.4 mL, 20 wt% in toluene, 2.6 mmol) in toluene (40 mL) was added dropwise a solution of 1,2,3,7-tetrahydro-s-indacen-4-amine (180 mg, 1.05 mmol) in toluene (20 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, concentrated in vacuo to give the title compound as a brown oil (207 mg, 100%). The crude product was used directly in the next step without further purification.

[0717] 1 H NMR (CDC13) δ 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H).

[0718] Intermediate A15: 5-Chloro-2-isocyanato-l,3-diisopropylbenzene

[0719]

[0720] To a solution of 4-chloro-2,6-diisopropylaniline (0.105 g, 0.496 mmol) in toluene (1 mL) was added a solution of phosgene (0.65 mL, 20 wt% in toluene, 1.22 mmol) and the reaction mixture was refluxed for 1 hour. After cooling, the mixture was concentrated in vacuo to give the title compound as an orange oil (0.111 g, 94%).

[0721] 1 H NMR (CDC13) δ 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H).

[0722] Intermediate P3: 1-(Prop-2-yn-1-yl)piperidine-4-sulfonamide

[0723]

[0724] To a mixture of piperidine-4-sulfonamide hydrochloride (200 mg, 1.0 mmol, 1.0 equiv), potassium carbonate (4.0 equiv, 4.0 mmol, 552 mg) and acetonitrile (10 mL) was added 3-bromopropynyl (0.1 mL, 1.0 mmol, 1.0 equiv). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo and the crude material was suspended in methanol, coated on Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (115 mg, 56%).

[0725] 1 H NMR (CDC13): δ 4.42 (br s, 1H), 3.38 (s, 2H), 3.05 (d, 2H), 2.95 (m, 1H), 2.12 (m, 4H) and 1.95 (m, 2H).

[0726] Intermediate P4: 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide

[0727]

[0728] To a suspension of piperidine-4-sulfonamide hydrochloride (200 mg, 1.0 mmol, 1.0 equiv) and triethylamine (0.35 mL, 2.5 mmol, 2.5 equiv) in acetonitrile (10 mL) was added trifluoroacetic anhydride (0.14 mL, 1.0 mmol, 1.0 equiv). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and subjected to normal phase flash chromatography using a mixture of dichloromethane and trimethylamine-methanol (ratio 1 : 1) to give the title compound (61 mg, yield 23%).

[0729] 1 H NMR (CDC13): δ 4.73 (d, 1H), 4.52 (s, 2H), 4.20 (d, 1H), 3.21 (t, 2H), 2.91 (t, 1H), 2.37 (d, 2H) and 1.95 (m, 2H).

[0730] Intermediate P5: N-isopropyl-4-sulfamoyl piperidine-1-carboxamide

[0731]

[0732] To a suspension of piperidin-4-sulfonamide hydrochloride (200 mg, 1.0 mmol, 1.0 equiv), 4-dimethylaminopyrimidine (12 mg, 0.1 mmol, 0.1 equiv) and triethylamine (0.34 mL, 2.5 mmol, 2.5 equiv) was added isopropyl isocyanate (0.1 mL, 1.0 mmol, 1.0 equiv). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and then purified by normal phase flash chromatography using a mixture of dichloromethane and trimethylamine-methanol (ratio 1 :1) as eluent to give the title compound (55 mg, yield 22%).

[0733] 1 H NMR (CDCI3): δ 4.45 (br s, 1 H), 4.22 (m, 1 H), 4.10 (d, 2H), 3.98 (m, 1 H), 3.10 (m, 1 H), 2.81 (t, 2H), 2.20 (d, 2H), 1.80 (m, 2H) and 1.19 (d, 6H).

[0734] Intermediate P6: 1 -acetylpiperidin-4-sulfonamide

[0735]

[0736] Prepared as described for 1 -(prop-2-yn-1 -yl)piperidin-4-sulfonamide (Intermediate P3) using ethyl iodide instead of 3-bromopropyne. The crude product was coated on Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and normal phase flash chromatography was performed using a mixture of dichloromethane and trimethylamine-methanol (ratio 1 :1) as eluent to give the title compound (50 mg, yield 26%) contaminated with triethylamine hydrochloride. The crude product was used as such in the preparation of examples.

[0737] 1 H NMR (CDCI3): δ 5.05 (br s, 2H), 3.10 (m, 2H), 2.95 (m, 1 H), 2.45 (m, 2H), 2.20 (d, 2H), 1.95 (m, 4H) and 1.08 (t, 3H).

[0738] Intermediate P7: 1 -acetylpiperidin-4-sulfonamide

[0739]

[0740] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4), except that the suspension was cooled to 0°C and acetic anhydride was added instead of trifluoroacetic anhydride. The reaction mixture was allowed to warm to room temperature overnight. The crude product was coated on an Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5M) in methanol as eluent to give the title compound (139 mg, 67% yield) as a mixture with triethylamine hydrochloride. The crude product was used in the preparation of the examples.

[0741] 1 H NMR (CDCl3): δ4.90(m,3H), 3.99(d,1H), 3.10(m,2H), 2.60(t,1H), 2.10(t,2H), 2.05(s,3H) and 1.75(m,2H).

[0742] Intermediate P8: 1-(Cyclopropanecarbonyl)piperidine-4-sulfonamide

[0743]

[0744] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4), except using cyclopropanecarbonyl chloride (1.0 equiv) instead of trifluoroacetic anhydride. The crude product was applied to an Agilent hydromatrix and subjected to normal phase flash chromatography using a mixture of dichloromethane and trimethylamine-methanol (ratio 1:1) as eluent to give the title compound (84 mg, 36% yield).

[0745] 1 H NMR(CDCl3): δ4.80(br s,1H), 4.58(s,2H), 4.40(br s,1H), 3.18(m,2H), 2.64(br s,1H), 2.25(br s,2H), 1.78(m,3H), 1.00(m,2H) and 0.79(m,2H).

[0746] Intermediate P9: 1-(Cyanomethyl)piperidine-4-sulfonamide

[0747]

[0748] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) using bromoacetonitrile instead of 3-bromopropyne to give the title compound as a solid (40%).

[0749] 1 H NMR (DMSO-d6): δ = 6.71 (s, 2H), 3.73 (s, 2H), 2.89 (d, 2H), 2.79 (m, 1H), 2.19 (t, 2H), 1.99 (d, 2H) and 1.60 (m, 2H).

[0750] Intermediate P10: 1 -isobutyryl piperidine-4-sulfonamide

[0751]

[0752] Prepared as described for 1 -(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using propionic anhydride instead of trifluoroacetic anhydride to give the title compound as a solid (71 %).

[0753] 1 H NMR (CD3OD): δ = 4.67 (d, 1H), 4.05 (d, 1H), 3.17 (m, 2H), 2.65 (t, 1H), 2.42 (q, 2H), 2.18 (t, 2H), 1.65 (m, 2H) and 1.10 (t, 3H).

[0754] Intermediate P11: 1 -isobutyryl piperidine-4-sulfonamide

[0755]

[0756] Prepared as described for 1 -(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using isobutyric anhydride instead of trifluoroacetic anhydride to give the title compound contaminated with triethylamine hydrochloride (64%).

[0757] 1 H NMR (CDCI3): δ = 4.83 (d, 1H), 4.63 (s, 2H), 4.10 (d, 1H), 3.10 (m, 2H), 2.79 (m, 1H) 2,60 (t, 1H), 2.14 (m, 2H), 2.76 (m, 2H) and 1.16 (d, 6H).

[0758] Intermediate P12: 1 -(2-methoxyacetyl)piperidine-4-sulfonamide

[0759]

[0760] Prepared as described for 1 -(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using 2-methoxyacetyl chloride instead of cyclopropanecarbonyl chloride to give the title compound contaminated with triethylamine hydrochloride (55%).

[0761] 1 H NMR (CDC13): δ = 5.37 (bs, 2H), 4.72 (d, 1H), 4.10 (m, 3H), 3.41 (s, 3H), 3.16 (m, 2H), 2.64 (t, 1H), 2.23 (d, 2H) and 1.79 (m, 2H).

[0762] Intermediate P13: 4-aminosulfonylpiperidine-1-carboxylic acid methyl ester

[0763]

[0764] Prepared as described for 1 -(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using methyl chloroformate instead of cyclopropanecarbonyl chloride to give the title compound as a solid (10%).

[0765] 1 H NMR (CDC13): δ = 4.49 (s, 2H), 4.33 (bs, 2H), 3.72 (s, 3H), 3.07 (m, 1H), 2.80 (t, 2H), 2.19 (d, 2H) and 1.77 (m, 2H).

[0766] Intermediate P14: 1-cyclobutylpiperidine-4-sulfonamide

[0767]

[0768] To a suspension of piperidine-4-sulfonamide hydrochloride (157 mg, 0.79 mmol, 1.0 equiv) and triethylamine (0.12 mL, 0.86 mmol, 1.1 equiv) in acetonitrile (10 mL) was added cyclobutanone (61 μL, 0.82 mmol, 1.05 equiv) followed by sodium triethoxyborohydride (207 mg, 0.98 mmol, 1.25 equiv). After stirring overnight, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, spotted on hydromatrix and then purified by normal phase flash chromatography using a mixture of dichloromethane and trimethylamine-methanol (1 :1) as eluent to give the title compound contaminated with trimethylamine hydrochloride (110 mg of product, 64% yield).

[0769] 1 H NMR (CDC13): δ = 4.76 (bs, 2H), 2.98 (m, 3H), 2.78 (m, 1H), 2.19 (d, 2H), 2.00 (m, 2H), 1.88 (m, 6H) and 1.65 (m, 2H).

[0770] Intermediate P15: 1 -Ethylpiperidine-3-sulfonamide

[0771]

[0772] Piperidine-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) was suspended in acetonitrile (10 mL) and potassium carbonate (1.75 g, 12.6 mmol) was added before the mixture was stirred for 30 minutes. To the resulting slurry was added ethyl bromide (0.24 mL, 0.34 g, 3.2 mmol) and the mixture was stirred at ambient temperature for 60 hours. The reaction was concentrated in vacuo and then purified by column chromatography (40 g Silicycle FLH-R10030B-ISO40 cartridge, 5-25% methanol in DCM) to give the title compound (0.11 g, 0.57 mmol, 18% yield).

[0773] 1 H NMR (1 :1 CD3OD:CDCl3): d 3.36 (m, 2H), 3.10 (m, 1 H), 2.92 (bd, 1 H), 2.56 (q, 2H), 2.22 (bd, 1 H), 2.11 (t, 1 H), 1.88 (m, 2H), 1.58 (m, 2H) and 1.10 (t, 3H).

[0774] Intermediate P16: 1 -Propylpiperidine-4-sulfonamide

[0775]

[0776] Prepared from 1-bromopropane and piperidine-4-sulfonamide hydrochloride as described for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3). This gave the title compound (44 mg, 40% yield) which was used without purification.

[0777] 1 H NMR (CDCI3): d = 3.10 (m, 3H), 2.38 (m, 2H), 2.20 (m, 2H), 2.00 (m, 4H), 1.25 (m, 2H) and 0.95 (t, 3H).

[0778] Intermediate P17: 1 -(Oxetan-3-yl)piperidine-4-sulfonamide

[0779]

[0780] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 3-oxetanone and piperidine-4-sulfonamide hydrochloride (130 mg, 59% yield).

[0781] 1 H NMR (DMSO-d6): δ = 6.75 (s, 2H), 4.49 (t, 2H), 4.38 (t, 2H), 3.38 (m, 2H), 2.79 (m, 2H), 1.98 (d, 2H), 1.79 (t, 2H) and 1.59 (m, 2H).

[0782] Intermediate P18: 2-(4-sulfamoylpiperidin-1-yl)acetic acid methyl ester

[0783]

[0784] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) using methyl bromoacetate instead of 3-bromopropyne (91 mg, 39% yield).

[0785] 1 H NMR (DMSO-d6): δ = 6.70 (s, 2H), 3.60 (s, 3H), 3.19 (s, 2H), 2.93 (d, 2H), 2.76 (m, 1H), 2.18 (t, 2H), 1.93 (d, 2H) and 1.59 (m, 2H).

[0786] Intermediate P19: 1-cyclopropylpiperidine-4-sulfonamide

[0787]

[0788] Prepared as described for 1-cyclopropylpyrrolidine-3-sulfonamide (Intermediate P30) from piperidine-4-sulfonamide hydrochloride and adding triethylamine (1.1 eq) to the suspension. This gave the title compound (150 mg, 73% yield) which was used without further purification.

[0789] 1 H NMR (DMSO-d6): δ = 6.67 (s, 2H), 2.98 (m, 2H), 2.77 (m, 1H), 2.15 (t, 2H), 1.92 (m, 2H), 1.52 (m, 3H), 0.23 (m, 2H) and 0.39 (m, 2H).

[0790] Intermediate P20: 1-(1-ethylazetidin-3-yl)piperidine-4-sulfonamide

[0791]

[0792] A suspension of 1-(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride (145 mg, 0.45 mmol) in acetonitrile (5.8 mL) was stirred with triethylamine (0.13 mL, 95 mg, 0.94 mmol) for 30 minutes. To this was added acetaldehyde (0.03 mL, 25 mg, 0.6 mmol) and sodium triethoxyborohydride (122 mg, 0.56 mmol). Stirring was continued for 20 hours, then the mixture was concentrated in vacuo. The residue was dissolved in methanol / dichloromethane (1 :1) and purified by chromatography (40 g Silicycle Si02cartridge, filtered through a syringe filter, and eluted with 5-30% 3.5 N ammonia in methanol / dichloromethane) to give the title compound (73 mg, 0.28 mmol, 63% yield).

[0793] 1 H NMR (CDC13): δ = 4.81 (d, 1H), 4.58 (s, 2H), 3.84 (d, 1H), 3.24 (m, 1H), 3.18 (m, 1H), 3.01 (t, 1H), 2.60 (t, 1H), 2.37 (m, 2H), 2.20 (m, 4H), 1.99 (m, 1H), 1.89 (m, 1H), and 1.72 (m, 2H).

[0794] Intermediate P21: 1-(Cyclobutanecarbonyl)piperidine-4-sulfonamide

[0795]

[0796] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using cyclobutanecarbonyl chloride instead of trifluoroacetic anhydride to give the title compound (158 mg, 64% yield).

[0797] 1 H NMR (CDC13): δ = 4.81 (d, 1H), 4.58 (s, 2H), 3.84 (d, 1H), 3.24 (m, 1H), 3.18 (m, 1H), 3.01 (t, 1H), 2.60 (t, 1H), 2.37 (m, 2H), 2.20 (m, 4H), 1.99 (m, 1H), 1.89 (m, 1H), and 1.72 (m, 2H).

[0798] Intermediate P22: N-Ethyl-4-sulfamoylpipehdine-1-carboxamide

[0799]

[0800] To a suspension of piperidin-4-sulfonamide hydrochloride (200 mg, 1.0 mmol, 1.0 equiv) and triethylamine (0.34 mL, 2.5 mmol, 2.5 equiv) in acetonitrile (10 mL) was added ethyl isocyanate (79 μL, 1.0 mmol, 1.0 equiv). The reaction mixture was stirred overnight, then concentrated in vacuo. The crude product was applied to Agilent Hydromatrix, then normal phase flash silica gel chromatography using a mixture of dichloromethane and methanol and triethylamine (ratio 1 :1) to give the title compound (141 mg, yield 60%) which was used without any further purification.

[0801] 1 H NMR (CDCI3): δ = 4.18 (d, 2H), 3.18 (m, 1H), 2.78 (m, 5H), 2.20 (m, 2H) and 1.75 (m, 2H).

[0802] Intermediate P23: N-methyl-4-sulfamoylpiperidine-1 -carboxamide

[0803]

[0804] Prepared as described for N-isopropyl-4-sulfamoylpiperidine-1 -carboxamide (Intermediate P5) from piperidin-4-sulfonamide hydrochloride and N-methyl-1 H-imidazole-1 - carboxamide, but without the need for 4-dimethylaminopyrimidine. The title compound (12 mg, yield 5%) was used without purification.

[0805] 1 H NMR (CDCI3): δ = 4.18 (d, 2H), 3.18 (m, 1H), 2.78 (m, 5H), 2.20 (m, 2H) and 1.75 (m, 2H).

[0806] Intermediate P24: 1 -(methylsulfonyl)piperidine-4-sulfonamide

[0807]

[0808] Prepared as described for 1 -(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) from piperidin-4-sulfonamide hydrochloride and methane sulfonic anhydride. The title compound (18 mg, yield 7%) was used without purification.

[0809] 1H NMR (CD3OD): δ = 3.90 (m, 2H), 3.08 (m, 2H), 2.82 (m, 4H), 2.23 (d, 2H) and 1.83 (m, 2H).

[0810] Intermediate P25: N-ethyl-3-sulfamoylpyrrolidine-1 -carboxamide

[0811]

[0812] Prepared from ethyl isocyanate and pyrrolidine-3-sulfonamide as described for N- isopropyl-4-sulfamoylpiperidine-1 -carboxamide (Intermediate P5), but without the need for 4-dimethylaminopyrimidine or triethylamine. The title compound (13 mg, 5% yield) was used as a crude without purification.

[0813] 1 H NMR (CD3OD): δ = 3.81 (m, 1H), 3.57 (m, 1H), 3.39 (m, 1H), 3.19 (m, 4H), 2.38 (m, 2H) and 1.10 (t, 3H).

[0814] Intermediate P26: N-ethyl-3-sulfamoylpyrrolidine-1 -carboxamide

[0815]

[0816] Prepared from isopropyl isocyanate and piperidine-3-sulfonamide hydrochloride as described for N-isopropyl-4-sulfamoylpiperidine-1 -carboxamide (Intermediate P5) to give the title compound (0.11 g, 0.44 mmol, 41% yield).

[0817] 1 H NMR (CD3OD): δ = 3.85 (m, 2H), 2.98 (m, 2H), 2.77 (br t, 1H), 2.25 (br d, 1H), 2.00 (s, 2H), 1.65-1.90 (m, 2H) and 1.13 (d, 6H).

[0818] Intermediate P27: 1 -methylpyrrolidine-3-sulfonamide

[0819]

[0820] To a suspension of pyrrolidine-3-sulfonamide (150 mg, 1.0 mmol, 1.0 equiv) and formaldehyde (37% in water stabilized with methanol; 78 μL, 1.05 mmol, 1.05 equiv) in acetonitrile (10 mL) was added sodium triethoxyborohydride (265 mg, 1.25 mmol, 1.25 equiv). The reaction mixture was stirred at room temperature for 5 days and then concentrated in vacuo. The crude material was dissolved in methanol, applied to a hydromatrix, and subjected to normal phase flash chromatography using a mixture of dichloromethane and triethylamine:methanol (ratio 1:1) as eluents to afford the impure title compound (80 mg, 49% yield), which was used as such in further reactions.

[0821] 1 H NMR (CD3OD): δ = 3.78 (m, 1H), 3.18 (m, 3H), 2.86 (m, 2H), 2.70 (m, 1H) and 2.43 (s, 3H).

[0822] Intermediate P28: 1-Ethylpyrrolidine-3-sulfonamide

[0823]

[0824] Prepared from pyrrolidine-3-sulfonamide and ethyl iodide as described for 1-ethylpiperidine-4-sulfonamide (Intermediate P6).The title compound (75 mg, 42% yield) was used without further purification.

[0825] 1 H NMR (CD3OD): δ=3.77(m,1H), 3.10(t,1H), 2.79(m,2H), 2.57(m,3H), 2.19(m,2H) and 1.16(t,3H).

[0826] Intermediate P29: 1-Acetylpyrrolidine-3-sulfonamide

[0827]

[0828] Prepared from acetic anhydride (1.0 equiv) and pyrrolidine-3-sulfonamide as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4).The title compound (75 mg, 39% yield) was used without purification.

[0829] 1 H NMR (CD3OD): δ = 3.89 (m, 2H), 3.78 (m, 2H), 3.62 (m, 1H), 2.41 (m, 2H) and 2.08 (s, 3H).

[0830] Intermediate P30: 1 -cyclopropylpyrrolidine-3-sulfonamide

[0831]

[0832] To a suspension of pyrrolidine-3-sulfonamide (150 mg, 1.00 mmol) and 1- (ethoxycyclopropoxy)trimethylsilane (0.4 mL, 2.0 mmol, 2.0 equiv) in tetrahydrofuran (5 mL) and methanol (5 mL) was added acetic acid (0.12 mL, 2.2 mmol, 2.2 equiv) followed by sodium cyanoborohydride (94 mg, 1.5 mmol, 1.5 equiv). The reaction mixture was stirred overnight, then concentrated in vacuo. The crude material was dissolved in methanol, coated onto hydromatrix, then subjected to normal phase flash chromatography using a mixture of dichloromethane and triethylamine:methanol (ratio 1 :1) as eluent to give the title compound (75 mg, yield 39%).

[0833] 1 H NMR (DMSO-d6): δ = 6.79 (s, 2H), 3.57 (m, 1H), 2.98 (t, 1H), 2.80 (t, 1H), 2.71 (m, 1H), 2.58 (q, 1H), 2.01 (q, 2H), 1.64 (m, 1H), 0.28 (m, 2H) and 0.38 (m, 2H).

[0834] Intermediate P31: N,N-dimethyl-3-sulfamoylpyrrolidine-1 -carboxamide

[0835]

[0836] To a solution of carbonyl diimidazole (269 mg, 1.66 mmol) in acetonitrile (10 mL) was added dimethylamine hydrochloride (122 mg, 1.55 mmol, 0.9 equiv). The resulting solution was allowed to stir at room temperature for 1.5 h before the addition of triethylamine (0.3 mL, 2.0 mmol, 1.2 equiv) and pyrrolidine-3-sulfonamide (250 mg, 1.66 mmol). The reaction mixture was stirred for 3 h before additional triethylamine (0.3 mL, 2.0 mmol, 1.2 equiv) was added to the suspension. After stirring overnight, more carbonyl diimidazole (269 mg, 1.66 mmol, 1.0 equiv) and dimethylamine 2M in tetrahydrofuran (0.83 mL, 1.66 mmol, 1.0 equiv) were added. The reaction mixture was heated to 50 °C overnight, then more dimethylamine (2M in tetrahydrofuran; 0.83 mL, 1.66 mmol, 1.0 equiv) was added. After heating overnight, more dimethylamine (2M in tetrahydrofuran; 4.2 mL, 8.3 mmol, 5.0 equiv) was added. The reaction mixture was again heated overnight. After cooling, the reaction mixture was concentrated in vacuo. The crude material was dissolved in methanol, coated on hydromatrix, and subjected to normal phase silica gel flash chromatography using a mixture of dichloromethane and 3.5 M ammonia in methanol as eluent to give the title compound (35 mg, 15% yield) still not completely pure. The product was used as such.

[0837] 1 H NMR (DMSO-d6): δ = 7.19 (s, 2H), 3.84 (m, 2H), 3.79 (m, 1H), 3.58 (m, 2H), 2.73 (s, 6H) and 2.02 (m, 2H).

[0838] Intermediate P32: 1 -isopropylpyrrolidine-3-sulfonamide

[0839]

[0840] Prepared from pyrrolidine-3-sulfonamide and acetone as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14), but without the need for triethylamine. The title compound (130 mg, 67% yield) was used without purification.

[0841] 1 H NMR (CD3OD): δ = 3.76 (m, 1H), 3.23 (t, 1H), 2.92 (m, 1H), 2.90 (m, 1H), 2.62 (m, 1H), 2.52 (m, 1H), 2.21 (m, 2H) and 1.17 (m, 6H).

[0842] Intermediate P33: azetidine-3-sulfonamide

[0843] Step A: 3-sulfamoylazetidine-1 -carboxylic acid benzyl ester

[0844]

[0845] A solution of ammonium hydroxide (25% in water; 22 mL, 73 mmol, 10.0 equiv) was added to 3-(chlorosulfonyl)azetidine-1 -carboxylic acid benzyl ester (2.1 g, 7.3 mmol, 1.0 equiv). The suspension was stirred at room temperature for 20 min to give a clear solution, then the resulting mixture was acidified to pH 8-9 using hydrochloric acid (2 M, aqueous) and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, then concentrated in vacuo to give the title compound (1.52 g, 5.62 mmol, 77% yield) which was used without further purification.

[0846] 1 H NMR (CDCI3): δ = 7.38 (m, 5H), 5.18 (s, 4H), 4.40 (m, 4H) and 4.00 (m, 1 H).

[0847] Step B: azetidine-3-sulfonamide

[0848]

[0849] A suspension of 3-sulfamoylazetidine-1 -carboxylic acid benzyl ester (1.52 g, 5.62 mmol, 1.0 equiv) in ethyl acetate (30 mL) was flushed with a stream of nitrogen before Pd / C (10 wt% loading, 595 mg, 0.56 mmol, 0.1 equiv) was added, then the flask was flushed with hydrogen. The reaction mixture was heated to reflux under a hydrogen atmosphere (balloon) for 20 h. After cooling, the suspension was filtered through Celite, and the Celite was thoroughly washed with methanol. The filtrate was combined and concentrated in vacuo to give the title compound (541 mg, 3.97 mmol, 70% yield) which was used without further purification. 545545

[0850] 1 H NMR (DMSO-d6): δ = 6.91 (br s, 2H), 4.08 (m, 1 H), 3.74 (t, 2H) and 3.63 (t, 2H).

[0851] Intermediate P34: quinuclidine-3-sulfonamide

[0852] Step A: (quinuclidin-3-yl)thioacetate

[0853]

[0854] To a solution of triphenylphosphine (4.12 g, 15.7 mmol, 2.0 eq) in tetrahydrofuran (64 mL) cooled in an ice bath was added diisopropyl azodicarboxylate (3.1 mL, 15.7 mmol, 2.0 eq). The clear yellow solution was stirred for 10 minutes during which time a precipitate appeared. 3-Quinuclidinol (1.0 g, 7.86 mmol, 1.0 eq) was added followed by thioacetic acid (1.2 mL, 15.7 mmol, 2.0 eq) and the ice bath was removed and the green solution was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by normal phase flash chromatography using dichloromethane and methanol as eluents to give the title compound (581 mg, yield 40%).

[0855] 1 H NMR (CDCI3): δ = 3.71 (m, 1H), 2.97 (m, 5H), 2.77 (dd, 1H), 2.33 (s, 3H) 1.92 (m, 1H), 1.81 (m, 3H) and 1.57 (m, 1H).

[0856] Step B: Quinuclidin-3-sulfonamide

[0857]

[0858] To a suspension of N-chlorosuccinimide (1.7 g, 12.5 mmol, 4.0 eq) in acetonitrile (7.0 mL) was added hydrochloric acid (aqueous, 2M, 1.2 mL, 2.50 mmol, 0.8 eq). The solution was cooled in an ice bath before a solution of S-(quinuclidin-3-yl) thioacetate (581 mg, 3.14 mmol, 1.0 eq) in acetonitrile (3.0 mL) was added and the ice bath was removed. The reaction mixture was stirred for 45 minutes before being added dropwise to a solution of ammonium hydroxide (25 wt% in water; 25 mL, 160 mmol, 51 eq). The mixture was stirred for 10 minutes before being concentrated in vacuo. The resulting solid was suspended in methanol, filtered and the filtrate concentrated in vacuo. The crude material was purified by reverse phase flash chromatography using water and methanol as eluents (see 'Experimental Methods', 'Purification Method 1') to give the title compound (43 mg, 0.22 mmol, 7% yield) which was impure.

[0859] 1H NMR (DMSO-d6): δ = 3.74 (m, 1H), 3.55 (m, 4H), 3.01 (m, 1H), 2.65 (m, 1H), 2.38 (m, 2H), 2.23 (m, 2H) and 2.01 (m, 1H).

[0860] Intermediate P35: 1 -(1 -Ethylpiperidin-4-yl)pyrrolidine-3-sulfonamide

[0861]

[0862] Prepared from pyrrolidine-3-sulfonamide and 1 -ethyl-4-piperidinone as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14)) but without the need for triethylamine. The crude compound was purified by normal phase flash chromatography using a mixture of dichloromethane and 3.5 M ammonia in methanol as eluent to give the title compound (217 mg, yield 83%).

[0863] 1 H NMR (DMSO-d6): δ = 6.81 (s, 2H), 3.58 (m, 1H), 3.00 (m, 3H), 2.65 (m, 4H), 2.44 (m, 3H), 2.08 (br s, 1H), 2.03 (m, 2H), 1.82 (m, 2H), 1.49 (br s, 2H) and 1.07 (t, 3H).

[0864] Intermediate P36: (1R*,3R*,5S*)-8-Isopropyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[0865] Step A: (1R*,3S*,5S*)-3-((Methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester

[0866]

[0867] To a mixture of 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.0 g, 13.2 mmol, 1.0 equiv) and N,N-diisopropylethylamine (3.0 mL, 17.2 mmol, 1.3 equiv) in dichloromethane (66 mL) was added methanesulfonyl chloride (1.1 mL, 14.5 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 2.5 hours, then the solution was washed twice with water, once with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (4.08 g, 13.2 mmol, quantitative yield).

[0868] 1 H NMR (CDC13): δ = 5.08 (m, 1H), 4.28 (br s, 2H), 3.00 (s, 3H), 2.10 (br d, 4H), 1.82 (br s, 2H), 1.63 (d, 2H) and 1.44 (s, 9H).

[0869] Step B: (1R*,3R*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0870]

[0871] To a solution of (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (4.08 g, 13.2 mmol, 1.0 equiv) in dimethylformamide (50 mL) and acetonitrile (13 mL) was added potassium thioacetate (4.52 g, 39.6 mmol, 3.0 equiv). The reaction mixture was heated to reflux for 1 h, then allowed to cool to room temperature. Brine and ethyl acetate were added to the solution, and after thorough mixing, the organic layer was separated, washed twice with brine, dried (via sodium sulfate), filtered, and concentrated in vacuo. The crude material was purified by normal phase flash chromatography using ethyl acetate and heptane as eluents to give the title compound (2.95 g, 78% yield).

[0872] 1 H NMR (CDC13): δ = 5.08 (m, 1H), 4.28 (br s, 2H), 3.00 (s, 3H), 2.10 (br d, 4H), 1.82 (br s, 2H), 1.63 (d, 2H) and 1.44 (s, 9H).

[0873] Step C: (1R*,3R*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0874]

[0875] To a solution of (1R*,3R*,5S*)-3-(acetylsulfanyl)-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (2.95 g, 10.3 mmol, 1.0 equiv) in water (10.3 mL) and acetic acid (103 mL) was added N-chlorosuccinimide (4.1 g, 30.9 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 1 h, then concentrated to about 20-30 mL, after which the resulting solution was added dropwise to a solution of ammonium hydroxide (25 wt% in water; 400 mL) and then stirred at room temperature for 10 min. The solution was then acidified to pH 7-8 with hydrochloric acid (aqueous, 1 M) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the impure title compound (387 mg, 12% yield) which was used without further purification.

[0876] 1 H NMR (CDCI3): δ = 4.33 (br s, 2H), 3.11 (m, 1H), 2.00 (m, 4H), 1.82 (m, 2H), 1.64 (m, 2H), and 1.44 (s, 9H).

[0877] Step D: (1R*,3R*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride

[0878]

[0879] To a solution of (1R*,3R*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (387 mg, 1.33 mmol, 1.0 equiv) in dichloromethane (10 mL) was added hydrochloric acid (4 M in dioxane, 3.3 mL, 13.3 mmol, 10.0 equiv). The solution was stirred at room temperature for 1.5 h. The solvent was then decanted and dichloromethane was added, then decanted again. This gave the impure title compound (200 mg, 66% yield) which was used without purification.

[0880] 1 H NMR (DMSO-d6): δ = 9.40 (br s, 1H), 9.20 (br s, 1H), 6.93 (br s, 2H), 4.01 (m, 2H), 3.32 (m, 1H), 2.18 (m, 1H), 1.98 (m, 6H), and 1.79 (m, 1H).

[0881] Step E: (1R*,3R*,5S*)-8-isopropyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[0882]

[0883] Prepared from (1R*,3R*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride and acetone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The crude compound was purified by normal phase flash chromatography using a mixture of dichloromethane and 3.5 M ammonia in methanol as eluent to give the title compound (22 mg, 21% yield) in a heterogeneous state which was used without further purification.

[0884] 1 H NMR (DMSO-d6): δ = 6.61 (s, 2H), 3.50 (s, 2H), 3.12 (m, 2H), 1.82 (m, 4H), 1.50 (m, 4H) and 0.97 (d, 6H).

[0885] Intermediate P37: 1 -isopropylazetidine-3-sulfonamide

[0886]

[0887] Prepared from azetidine-3-sulfonamide (Intermediate P33) and acetone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) but without triethylamine. The title compound (12 mg, 6% yield) was used without purification.

[0888] 1 H NMR (DMSO-d6): δ = 6.87 (br s, 2H), 3.82 (m, 1H), 3.39 (m, 2H), 3.23 (t, 2H), 2.32 (m, 1H) and 0.81 (d, 6H).

[0889] Intermediate P38: 1 '-ethyl-[1,4'-bipiperidine]-4-sulfonamide

[0890]

[0891] A suspension of 4-piperidinesulfonamide hydrochloride (0.35 g, 1.6 mmol) in acetonitrile (14 mL) was stirred with triethylamine (0.17 g, 0.24 mL, 1.7 mmol) for 30 minutes. To this was added 1-ethyl-4-piperidinone (0.21 g, 0.23 mL, 1.6 mmol) and sodium triethoxyborohydride (0.43 g, 2.0 mmol). Stirring was continued for 20 hours, then the solution was concentrated in vacuo. The crude material was suspended in a few mL of dichloromethane / methanol / 7 N ammonia in methanol (1 : 1 : 1) and purified by chromatography (40 g Silicycle Si02cartridge, filtered through a syringe filter, eluted with 5-30% 3.5 N ammonia in dichloromethane / methanol) to give the title compound (290 mg, 90% yield).

[0892] 1 H NMR (CD3OD): δ = 3.09 (m, 4H), 2.88 (m, 1H), 2.52 (q, 2H), 2.40 (m, 1H), 2.27 (m, 2H), 2.15 (m, 4H), 1.84 (m, 4H), 1.64 (m, 2H) and 1.13 (t, 3H).

[0893] Intermediate P39: 1 -Methylazetidine-3-sulfonamide

[0894]

[0895] Prepared from azetidine-3-sulfonamide (Intermediate P33) and formaldehyde as described for 1 -methylpyrrolidine-3-sulfonamide (Intermediate P27). The crude compound was purified by normal phase silica gel flash chromatography using a mixture of dichloromethane and 3.5 M ammonia in methanol as eluent to give the title compound (24 mg, 16% yield).

[0896] 1 H NMR (CD3OD): δ = 4.08 (m, 1H), 3.91 (t, 2H), 3.87 (t, 2H) and 2.54 (s, 3H).

[0897] Intermediate P40: 2-Ethyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0898] Step A: 6-((Methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0899]

[0900] To a solution of 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2 g, 9.4 mmol) in dichloromethane (25 mL) was added triethylamine (2.6 mL, 18.8 mmol). The solution was cooled to 0 °C and a solution of methanesulfonyl chloride (0.8 mL, 10.3 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was stirred at room temperature for 18 h, then washed with water and brine, dried (sodium sulfate), filtered and evaporated to give the title compound as a white solid (2.7 g, yield 100%).

[0901] 1 H NMR (CDC13): δ = 4.89 (m, 1H), 3.94 (s, 4H), 2.99 (s, 3H), 2.70 (m, 2H), 2.48 (m, 2H) and 1.44 (s, 9H).

[0902] Step B: 6-(acetylthio)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0903]

[0904] To a solution of 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1 g, 3.4 mmol) in acetonitrile (10 mL) and dimethylformamide (40 mL) was added potassium thioacetate (1.57 g, 13.7 mmol). The reaction was heated to reflux for 18 h and, after cooling, was poured into water (200 mL) and ethyl acetate (100 mL). The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (4x) and brine, then dried (sodium sulfate), filtered and evaporated in vacuo to give the title compound as a brown oil (1 g, yield 100%).

[0905] 1 H NMR (CDC13): δ = 4.89 (m, 1H), 3.94 (s, 4H), 2.99 (s, 3H), 2.70 (m, 2H), 2.48 (m, 2H) and 1.44 (s, 9H).

[0906] Step C: 6-sulfamoyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0907]

[0908] A mixture of 6-(acetylthio)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (650 mg, 2.4 mmol), acetic acid (5 mL) and water (1 mL) was cooled in ice / water. N-Chlorosuccinimide (960 mg, 7.8 mmol) was added portionwise over a 10 minute period. The reaction mixture was then stirred at room temperature for 1 hour, after which it was poured into cold aqueous ammonium hydroxide solution (50 mL, 25%). The mixture was stirred at room temperature for 18 hours, after which the solvent was evaporated in vacuo and the residue was triturated in tetrahydrofuran and decanted. The combined tetrahydrofuran layers were evaporated and the residue was purified via silica using dichloromethane / methanol (9:1) as eluent. The title compound was obtained as a white foam (240 mg, yield 36%).

[0909] 1 H NMR (CDCI3): δ = 4.87 (br s, 2H), 3.96 (s, 4H), 3.72 (m, 1H), 2.62 (m, 4H) and 1.44 (s, 9H).

[0910] Step D: 2-Azaspiro[3.3]heptane-6-sulfonamide

[0911]

[0912] To a solution of 6-sulfamoyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (240 mg, 0.87 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.26 mL, 3.5 mmol). The reaction was stirred for 48 hours and the solvent evaporated. The residue was dissolved in methanol and purified via Amberlite 410 ion exchange resin to give the title compound as a pale yellow oil (100 mg, yield 67%).

[0913] 1 H NMR (CDCI3): δ = 4.87 (br s, 2H), 3.96 (s, 4H), 3.72 (m, 1H), 2.62 (m, 4H) and 1.44 (s, 9H).

[0914] Step E: 2-Ethyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0915]

[0916] Following the procedure as described for 1 -(prop-2-yn-1 -yl)piperidine-4- sulfonamide (Intermediate P3), prepared from ethyl iodide and 2-azaspiro[3.3]heptane-6- sulfonamide. The crude material was purified by normal phase flash chromatography using ethyl acetate and methanol (9:1) as eluent to give the product as a mixture with triethylamine salt. The crude product was dissolved in methanol and filtered through Amberlite 410. The solvent was evaporated to give the title compound (8 mg, yield 15%).

[0917] 1 H NMR (CD3OD): δ = 3.67 (m, 1 H), 3.24 (d, 4H), 2.50 (d, 4H), 2.43 (q, 2H) and 0.95 (t, 3H).

[0918] Intermediate P41: 1 -(1 -isopropylazetidin-3-yl)pyrrolidine-3-sulfonamide

[0919] Step A: 1 -(azetidin-3-yl)pyrrolidine-3-sulfonamide dihydrochloride

[0920]

[0921] To a solution of tert-butyl 3-(3-sulfamidopyrrolidin-1 -yl)azetidine-1 -carboxylate (726 mg, 2.38 mmol, 1.0 equiv) in dichloromethane (24 mL) was added hydrochloric acid in dioxane (4 M, 6.0 mL, 23.8 mmol, 10.0 equiv). The reaction mixture was stirred for 1.5 h, then concentrated in vacuo to give the title compound as dihydrochloride salt (774 mg, 2.38 mmol, yield 100%) which was used without purification.

[0922] 1 H NMR (DMSO-d6): δ = 9.60 (br s, 1 H), 9.17 (br s, 1 H), 7.24 (s, 2H), 4.34 (m, 4H), 4.11 (m, 3H), 3.91 (m, 2H) and 2.23 (m, 4H).

[0923] Step B: 1 -(1 -isopropylazetidin-3-yl)pyrrolidine-3-sulfonamide

[0924]

[0925] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 1-(azetidin-3-yl)pyrrolidine-3-sulfonamide dihydrochloride and acetone, but requiring 2.5 equivalents of triethylamine. The crude compound was purified by normal phase flash chromatography using a mixture of dichloromethane and 3.5M ammonia in methanol as eluent to give the title compound (94 mg, 38% yield).

[0926] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.58 (m, 1H), 3.24 (t, 2H), 2.98 (m, 1H), 2.90 (m, 3H), 2.52 (m, 2H), 2.38 (q, 1H), 2.21 (m, 1H), 2.01 (m, 2H) and 0.81 (d, 6H).

[0927] Intermediate P42: (1R*,3R*,5S*)-8-ethyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[0928]

[0929] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from iodoethane and (1R,3R,5S)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride. The title compound (36 mg, 41% yield) was used without further purification.

[0930] 1 H NMR (DMSO-d6): δ = 6.63 (br s, 2H), 3.97 (br s, 2H), 3.10 (q, 2H), 2.98 (br s, 1H), 2.58 (m, 2H), 2.30 (m, 2H), 2.11 (m, 4H) and 1.11 (m, 3H).

[0931] Intermediate P43: 1-ethylazetidine-3-sulfonamide

[0932]

[0933] Prepared as described for 1-ethylpiperidine-4-sulfonamide (Intermediate P6) from azetidine-3-sulfonamide (Intermediate P33) and ethyl iodide. This gave the title compound (15 mg, 9% yield) which was used without further purification.

[0934] 1H NMR (CDCI3): δ = 4.11 (m, 1 H), 3.81 (t, 2H), 3.62 (t, 2H), 2.74 (q, 2H) and 1.02 (t, 3H).

[0935] Intermediate P44: 1 -(2,2,2-trifluoroacetyl)piperidin-4-sulfonamide

[0936]

[0937] Prepared from piperidin-4-sulfonamide and bis-trifluoroacetic anhydride as described for 1 -(2,2,2-trifluoroacetyl)piperidin-4-sulfonamide (Intermediate P4). This gave the title compound (72 mg, 36% yield) which was used without purification.

[0938] 1 H NMR (CDCI3): δ = 4.11 (m, 1 H), 3.81 (t, 2H), 3.62 (t, 2H), 2.74 (q, 2H) and 1.02 (t, 3H).

[0939] Intermediate P45: 1 -(2,2,2-trifluoroacetyl)piperidin-4-sulfonamide

[0940]

[0941] Prepared as described for 1 -ethylpiperidin-3-sulfonamide (Intermediate P15) using piperidin-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) and iodo-methyl-cyclopropane (0.29 mL, 0.58 g, 3.2 mmol) to give the title compound (0.28 g, 1.26 mmol, 40% yield) after column purification.

[0942] 1 H NMR (CDCI3): δ = 4.11 (m, 1 H), 3.81 (t, 2H), 3.62 (t, 2H), 2.74 (q, 2H) and 1.02 (t, 3H).

[0943] Intermediate P46: 1 -(2,2,2-trifluoroacetyl)piperidin-4-sulfonamide

[0944]

[0945] Prepared as described for 1 -ethylpiperidine-3-sulfonamide (Intermediate P15) using piperidine-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) and methyl iodide (0.20 mL, 0.45 g, 3.2 mmol) to give the title compound (0.24 g, 1.35 mmol, 43% yield) which was used without further purification.

[0946] 1 H NMR (CD3OD): δ = 3.2-3.4 (m, 3H), 2.97 (br d, 1 H), 2.45 (s, 3H), 2.38 (br t, 1 H), 2.20 (m, 1 H), 1.90 (br d, 1 H) and 1.5-1.8 (m, 2H).

[0947] Intermediate P47: 3-aminosulfonylazetidine-1 -carboxylic acid benzyl ester

[0948]

[0949] To a stirred solution of 3-(chlorosulfonyl)azetidine-1 -carboxylic acid benzyl ester (2.0 g, 6.9 mmol) in dichloromethane (30 mL) at 0 °C was added ammonia (7 N in methanol, 30 mL). The resulting mixture was stirred overnight, slowly warmed to room temperature, then concentrated to a white solid, triturated with THF, and the resulting title compound was isolated by filtration as a white solid (95% yield) which was used without further purification.

[0950] 1 H NMR (CD3OD): δ = 7.3 (m, 5H), 5.05 (d, 2H), 4.25 (m, 2H), 4.13 (m, 2H) and 2.47 (m, 1 H).

[0951] Intermediate P48: N,N-dimethyl-4-aminosulfonylpiperidine-1 -carboxamide

[0952]

[0953] To a solution of carbonyl diimidazole (162 mg, 1.0 mmol) in acetonitrile (10 mL) was added dimethylamine hydrochloride (81 mg, 1.0 mmol) and the solution was stirred at room temperature overnight. Triethylamine (0.42 mL, 3.0 mmol, 3.0 equiv) and piperidin-4-sulfonamide hydrochloride (200 mg, 1.0 mmol) were added to the suspension. The reaction mixture was stirred overnight and an additional portion of carbonyl diimidazole (162 mg, 1.0 mmol), triethylamine (0.42 mL, 3.0 mmol, 3.0 equiv) and 2M dimethylamine in tetrahydrofuran (0.5 mL, 1.0 mmol) was added. After stirring overnight, an additional 2M dimethylamine in tetrahydrofuran (2 mL, 4.0 mmol, 4.0 equiv) was added. The reaction mixture was then stirred at room temperature for 3 days after which it was transferred to a microwave vial and an additional 2M dimethylamine in tetrahydrofuran (2.0 mL, 4.0 mmol, 4.0 equiv) was added. The vial was heated to 50 °C overnight and then concentrated in vacuo. The crude material was dissolved in methanol, coated onto hydromatrix and purified by normal phase flash chromatography using a mixture of dichloromethane and triethylamine with methanol (ratio 1 :1) as eluent to give the title compound (73 mg, yield 31%).

[0954] 1 H NMR (DMSO-d6): δ = 6.72 (s, 2H), 3.60 (d, 2H), 2.98 (m, 1H), 2.72 (m, 8H), 1.94 (d, 2H), 1.52 (m, 2H).

[0955] Intermediate P49: 1-(1-Isopropyl-azetidin-3-yl)piperidine-4-sulfonamide

[0956] Step A: 3-(4-Sulfamidopiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester

[0957]

[0958] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from piperidine-4-sulfonamide hydrochloride (0.35 g, 1.6 mmol) and 1-Boc-azetidinone (0.28 g, 1.6 mmol) using 2 equiv of triethylamine. The crude compound was purified by normal phase flash chromatography using a mixture of dichloromethane and 3.5M ammonia in methanol as eluent to give the title compound as a white waxy solid (236 mg, yield 47%).

[0959] HPLC-MS: 100% (ELSD), M 319 + 1 (ACPI pos.)

[0960] 1 H NMR (Methanol-d4): δ = 4.37 (s, 2H), 3.94 (dd, J = 8.8, 7.2 Hz, 2H), 3.77 (dd, J = 9.0, 5.3 Hz, 2H), 3.09 (tt, J = 7.1, 5.3 Hz, 1 H), 3.00-2.81 (m, 3H), 2.22-2.08 (m, 2H), 1.98-1.70 (m, 4H), 1.41 (s, 9H).

[0961] Step B: 1 -(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride

[0962]

[0963] Step A: tert-butyl 3-(4-sulfamidopiperidin-1 -yl)azetidine-1 -carboxylate Step A: tert-butyl 3-(4-sulfamidopiperidin-1 -yl)azetidine-1 -carboxylate

[0964] HPLC-MS: 97% (ELSD), M 291 + 1 (ACPI pos.)

[0965] 1 H NMR (Methanol-d4): δ = 4.72-4.57 (m, 2H), 4.44-4.28 (m, 3H), 3.61 (d, J = 1 1.7 Hz, 2H), 3.26 (dd, J = 1 1.1, 4.2 Hz, 2H), 3.01 (s, 1 H), 2.44 (dd, J = 14.3, 3.1 Hz, 2H), 2.24 (t, 1 H), 1.61 (s, 1 H).

[0966] Step C: 1 -(1 -isopropyl-azetidin-3-yl)piperidine-4-sulfonamide

[0967]

[0968] Prepared following the procedure as described for 1 -cyclobutylpiperidine-4- sulfonamide (Intermediate P14) from Step B: 1 -(azetidin-3-yl)piperidine-4- sulfonamide dihydrochloride (100 mg, 0.31 mmol) and acetone (0.03 mL, 22 mg, 0.39 mmol) to yield the title compound (70 mg, yield 87%) as a white solid after column chromatography.

[0969] HPLC-MS: 59+40% (ELSD) showed two peaks with M 262+1 (ACPI pos.)

[0970] 1 H NMR (methanol-d4): δ = 3.55 (t, J = 6.5 Hz, 2H), 3.02-2.82 (m, 6H), 2.49 (h, J = 6.2 Hz, 1H), 2.13 (ddd, J = 12.0, 4.2, 2.2 Hz, 2H), 1.88 (dd, J = 11.3, 2.1 Hz, 2H), 1.77 (qd, J = 12.1, 3.5 Hz, 2H), 0.97 (d, J = 6.3 Hz, 6H).

[0971] Intermediate P50: 2-Isopropyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0972]

[0973] To a solution of 2-azaspiro[3.3]heptane-6-sulfonamide (50 mg, 0.28 mmol) and acetone (25 mg, 0.43 mmol, 1.5 equiv) in acetonitrile (5 mL) was added sodium triethoxyborohydride (89 mg, 0.43 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The crude material was dissolved in methanol and treated with Amberlite 410 ion exchange resin. The mixture was filtered and the methanol evaporated. The residue was triturated in THF. The mixture was filtered and the THF evaporated to give the title compound (40 mg, yield 65%) which was used as such.

[0974] 1 H NMR (CD3OD): δ = 3.71 (m, 1H), 3.25 (m, 4H), 2.53 (m, 4H), 2.33 (m, 1H), 0.93 (d, 6H).

[0975] Intermediate P51: 2-Methyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0976]

[0977] To a solution of 2-azaspiro[3.3]heptane-6-sulfonamide (50 mg, 0.28 mmol) and formaldehyde (32 μL, 37% in water, 0.43 mmol, 1.5 equiv) in acetonitrile (5 mL) was added sodium triethoxyborohydride (90 mg, 0.43 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The crude material was dissolved in methanol and treated with Amberlite 410 ion exchange resin. The mixture was filtered and the methanol evaporated. The residue was triturated in THF. The mixture was filtered and the THF evaporated to give the title compound (40 mg, 74% yield) which was used as such.

[0978] 1 H NMR (CD3OD): δ = 3.71 (m, 1H), 3.37-3.21 (m, 4H), 2.52 (m, 4H), 2.29 (s, 3H).

[0979] Intermediate P52: 1 -(Pentan-3-yl)azetidine-3-sulfonamide

[0980]

[0981] Prepared from azetidine-3-sulfonamide hydrochloride and 3-pentanone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (20 mg, 12% yield) was used without further purification.

[0982] 1 H NMR (DMSO-d6): δ = 6.86 (s, 2H), 3.82 (m, 1H), 3.42 (t, 2H), 3.21 (t, 2H), 2.03 (m, 1H), 1.24 (m, 4H), 0.74 (m, 6H).

[0983] Intermediate P53: 1 -Ethyl- 1,2,3,4-tetrahydroquinoline-3 -sulfonamide

[0984]

[0985] Prepared from 1,2,3,4-tetrahydroquinoline-3 -sulfonamide, acetone and acetic acid as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14), but without the need for triethylamine. The title compound (27 mg, 11 % yield) was used without further purification. The expected isopropyl analogue was not isolated.

[0986] 1H NMR (CDCl3): δ = 7.09 (m, 2H), 6.70 (m, 2H), 4.52 (br s, 2H), 3.60 (m, 3H), 3.44 (m, 2H), 3.26 (m, 2H), 1.17 (t, 3H).

[0987] Intermediate P54: 1-(2,2,2-Trifluoroethyl)piperidine-4-sulfonamide

[0988] Step A: 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide

[0989]

[0990] Piperidine-4-sulfonamide hydrochloride (600 mg, 2.7 mmol) was stirred with triethylamine (0.75 mL, 0.54 g, 5.4 mmol) in acetonitrile (12 mL) for 30 minutes. Trifluoroacetic anhydride (0.38 mL, 0.57 g, 2.7 mmol) was added to this slurry and stirring was continued for 20 hours. The mixture was concentrated in vacuo and the residue was dissolved in methanol, then applied to a silica column (40 g) and eluted with 0-30% methanol in DCM to give 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (182 mg, 26% yield), which was contaminated with bis-trifluoroacetylated byproducts. This was used as such in the next step.

[0991] HPLC-MS: 76% (ELSD), M 260+1 (ACPI pos.).

[0992] HPLC-MS: 23% (ELSD), M 356+1 (ACPI pos.) for the bis-trifluoroacetylated by-product.

[0993] 1 H NMR (methanol-d4): δ = 7.39 (s, 1H), 4.64-4.47 (m, 1H), 4.10 (d, J = 13.1Hz, 1H), 3.51 (tt, J = 11.4, 4.0Hz, 1H), 3.22 (dt, J = 12.6, 3 .5Hz,2H),2.87(td,J=13.0,2.9Hz,1H),2.21(ddt,J=20.3,13.9,3.2Hz,2H),1.78(ddtt,J=24.0,16.4,7.6,4.4Hz,2H).

[0994] Step B: 1-(2,2,2-trifluoroethyl)piperidine-4-sulfonamide

[0995]

[0996] Step A: (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester

[0997] HPLC-MS: 100% (ELSD), M 246 + 1 (ACPI pos.)

[0998] 1 H NMR (methanol-d4): d = 3.16 - 3.00 (m, 4H), 2.88 (tt, J = 12.2, 3.8 Hz, 1H), 2.42 (td, J = 12.0, 2.5 Hz, 2H), 2.08 (dt, J = 13.1, 2.9 Hz, 2H), 1.80 (qd, J = 12.4, 4.1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 1H), 1.00 - 0.81 (m, 1H).

[0999] Intermediate P55: (1R*,3S*,5S*)-8-Isopropyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[1000] Step A: (1R*,3R*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester

[1001]

[1002] Prepared as for (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (Intermediate P36, Step A) from 3-endo-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester to give the title compound (3.3 g, 81% yield).

[1003] 1H NMR (CDCl3): δ = 5.02 (t, 1H), 4.21 (br s, 2H), 3.00 (s, 3H), 2.03 (m, 8H), 1.45 (s, 9H).

[1004] Step B: tert-Butyl (1R*,3S*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate

[1005]

[1006] Prepared as for tert-butyl (1R*,3R*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate P36 Step B) from tert-butyl (1R*,3R*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate to give the title compound (1.65 g, 53% yield).

[1007] 1 H NMR (CDCl3): δ = 4.19 (br s, 2H), 3.87 (m, 1H), 2.28 (s, 3H), 1.98 (m, 2H), 1.79 (d, 6H), 1.45 (s, 9H).

[1008] Step C: tert-Butyl (1R*,3S*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate

[1009]

[1010] Prepared as for tert-butyl (1R*,3R*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate P36, Step C) from tert-butyl (1R*,3S*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate, except that the crude title compound was purified by normal phase flash chromatography using heptane and ethyl acetate to give the title compound (235 mg, 14% yield).

[1011] 1 H NMR (CDCl3): δ = 4.50 (m, 2H), 3.11 (m, 1H), 2.03 (m, 4H), 1.68 (m, 4H), 1.46 (s, 9H).

[1012] Step D: (1R*,3S*,5S*)-8-Azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride

[1013]

[1014] Prepared as for (1R*,3R*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride (Intermediate P36, step D) from (1R*,3S*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester to give the title compound (203 mg, quantitative yield) used without further purification.

[1015] 1 H NMR (DMSO-d6): δ = 9.28 (s, 1H), 9.11 (s, 1H), 6.90 (s, 2H), 4.04 (m, 2H), 3.95 (s, 1H), 2.07 (m, 1H), 1.96 (m, 6H), 1.82 (d, 1H).

[1016] Step E: (1R*,3S*,5S*)-8-isopropyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[1017]

[1018] Prepared as for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R*,3S*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride except that the crude compound was purified by normal phase flash chromatography using dichloromethane and a mixture of 7M ammonia in methanol to give the title compound (15 mg, yield 16%) which was used without further purification.

[1019] 1 H NMR (CD3OD): δ = 4.24 (m, 1H), 4.14 (m, 1H), 3.53 (m, 2H), 2.49 (m, 1H), 2.20 (m, 5H), 2.00 (m, 2H), 1.37 (d, 6H).

[1020] Intermediate P56: (1R*,3S*,5S*)-8-ethyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[1021]

[1022] Prepared as for 1-ethylpiperidine-4-sulfonamide (Intermediate P6) from (1R*,3S*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride to give the title compound (30 mg, yield 34%) which was used without further purification.

[1023] 1H NMR (DMSO-d6): δ = 7.24 (m, 5H), 6.93 (s, 2H), 3.92 (m, 1H), 3.58 (s, 2H), 3.46 (t, 2H), 3.35 (m, 2H).

[1024] Intermediate P57: 1 -Benzylazetidine-3 -sulfonamide

[1025]

[1026] Prepared as described for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and benzyl bromide. The title compound (57 mg, yield 25%) was used without further purification.

[1027] 1 H NMR (DMSO-d6): δ = 7.24 (m, 5H), 6.93 (s, 2H), 3.92 (m, 1H), 3.58 (s, 2H), 3.46 (t, 2H), 3.35 (m, 2H).

[1028] Intermediate P58: 1 -(1 -Ethylpiperidin-4-yl)azetidine-3-sulfonamide

[1029]

[1030] Prepared as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1 -ethyl-4-piperidinone. The title compound (111 mg, yield 44%) was used without further purification.

[1031] 1 H NMR (DMSO-d6): δ = 7.24 (m, 5H), 6.93 (s, 2H), 3.92 (m, 1H), 3.58 (s, 2H), 3.46 (t, 2H), 3.35 (m, 2H).

[1032] Intermediate P59: 1 -Acetylazetidine-3-sulfonamide

[1033]

[1034] Prepared from azetidine-3-sulfonamide hydrochloride as described for 1- acetylpiperidine-4-sulfonamide (Intermediate P7). The title compound (31 mg, yield 20%) was used without further purification.

[1035] 1 H NMR (CD3OD): δ = 4.57 (m, 1 H), 4.50 (m, 2H), 4.36 (m, 2H), 1.98 (s, 3H).

[1036] Intermediate P60: 1 -(Tetrahydro-2H-pyran-4-yl)azetidine-3-sulfonamide

[1037]

[1038] Prepared from azetidine-3-sulfonamide hydrochloride and tetrahydro-4H- pyran-4-one as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (112 mg, yield 50%) was used without further purification.

[1039] 1 H NMR (DMSO-d6): δ = 6.89 (s, 2H), 3.86 (m, 1 H), 3.77 (dt, 2H), 3.44 (t, 2H), 3.24 (m, 3H), 2.98 (q, 1 H), 2.26 (tq, 1 H), 1.55 (dd, 2H), 1.11 (m, 2H).

[1040] Intermediate P61: 1 -Propylazetidine-3-sulfonamide

[1041]

[1042] Prepared from azetidine-3-sulfonamide hydrochloride and 1-bromopropane as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3). The title compound (15 mg, yield 8%) was used without further purification.

[1043] 1 H NMR (DMSO-d6): δ = 6.88 (s, 2H), 3.87 (m, 1 H), 3.44 (t, 2H), 3.22 (t, 2H), 2.32 (t, 2H), 1.24 (m, 2H), 0.80 (t, 3H).

[1044] Intermediate P62: 3-Sulfamoylazetidine-1 -carboxylic acid tert-butyl ester

[1045] Step A: tert-Butyl 3-(acetylthio)azetidine-1-carboxylate

[1046]

[1047] To a solution of tert-butyl 3-iodoazetidine-1-carboxylate (17.2 g, 60.8 mmol, 1.0 equiv) and thioacetic acid (8.7 mL, 121.6 mmol, 2.0 equiv) in dimethylformamide (83 mL) was added portionwise cesium carbonate (39.6 g, 121.6 mmol, 2.0 equiv). The reaction was exothermic during this addition. The reaction mixture was then heated to 70 ° C for 1 hour to obtain complete conversion. The mixture was diluted with water (600 mL) and then extracted with diethyl ether (600 mL). The organic layer was washed twice with water (600 mL) and once with brine (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was subjected to normal phase silica gel flash chromatography using heptane and ethyl acetate as eluents to obtain the title compound (8.76 g, 62% yield).

[1048] 1 H NMR (CDCl3): δ = 4.35 (t, 2H), 4.10 (m, 1H), 3.78 (dd, 2H), 2.28 (s, 3H), 1.39 (s, 9H).

[1049] Step B: tert-Butyl 3-(chlorosulfonyl)azetidine-1-carboxylate

[1050]

[1051] To a solution of tert-butyl 3-(acetylthio)azetidine-1-carboxylate (8.76 g, 37.9 mmol, 1.0 equiv) in water (38 mL) and acetic acid (380 mL) was added N-chlorosuccinimide (15.2 g, 113.7 mmol, 3.0 equiv). The suspension was stirred at room temperature for 20 minutes to obtain a clear solution and complete conversion. The reaction mixture was diluted with water (600 mL) and then extracted with dichloromethane (600 mL). The organic layer was washed twice with water (600 mL) and once with brine (300 mL), dried over Na2SO4, filtered, and then used in the following reaction without further concentration of the organic layer.

[1052] 1 H NMR (CDCl3): δ = 4.57 (m, 1H), 4.38 (m, 4H), 1.42 (s, 9H).

[1053] Step C: tert-Butyl 3-sulfamoylazetidine-1-carboxylate

[1054]

[1055] To a solution of tert-butyl 3-(chlorosulfonyl)azetidine-1 -carboxylate (max 37.9 mmol) in dichloromethane (600 mL) was added 7 M ammonia in methanol (55 mL, 379 mmol, 10 eq). The clear solution was stirred at room temperature for half an hour. The suspension was concentrated in vacuo. The crude material was dissolved in methanol, coated onto hydromatrix and then subjected to normal phase flash chromatography eluting with a mixture of dichloromethane and ammonia (3.5 M) in methanol as eluent to give the title compound (2.67 g, 11.3 mmol, 30% yield over two steps).

[1056] 1 H NMR (DMSO-d6): δ = 7.18 (s, 2H), 4.10 (m, 2H), 3.98 (m, 3H), 1.39 (s, 9H).

[1057] Intermediate P63: 2-(3-aminosulfonylazetidin-1-yl)methyl acetate

[1058]

[1059] Prepared as for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and methyl bromoacetate. The title compound (43 mg, 21% yield) was used without further purification.

[1060] 1 H NMR (DMSO-d6): δ = 6.92 (s, 2H), 3.92 (m, 1 H), 3.58 (m, 5H), 3.41 (dd, 2H), 3.29 (s, 2H).

[1061] Intermediate P64: 1 -isopropyl-2-oxopyrrolidine-3-sulfonamide

[1062] Step A: 2-bromo-4-chlorobutyryl chloride

[1063]

[1064] To a solution of 4-chlorobutyryl chloride (25 g, 177.31 mmol, 1 eq) in DCM (45 mL) was added NBS (47.34 g, 265.97 mmol, 1.5 eq) and SOCl2 (1.05 g, 8.87 mmol, 643.13 μL, 0.05 eq) at 25 °C, followed by HBr (1.33 g, 6.58 mmol, 892.86 μL, 40% purity, 0.037 eq). The mixture was stirred at 50 °C for 1.5 hours. The reaction mixture was diluted with hexanes (300 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (35 g, crude product), which was used in the next step without further purification.

[1065] 1 H NMR (CDCl3): δ = 4.87-4.80 (m, 1H), 3.76-3.74 (m, 2H) and 2.59-2.44 (m, 2H).

[1066] Step B: 2-Bromo-4-chloro-N-isopropylbutanamide

[1067]

[1068] To a solution of 2-bromo-4-chlorobutyryl chloride (20 g, 90.95 mmol, 1 eq) in DCM (50 mL) at 0°C was added propan-2-amine (6.45 g, 109.14 mmol, 9.38 mL, 1.2 eq). The mixture was warmed to 25°C and stirred at 25°C for an additional hour. The reaction mixture was diluted with DCM (200 mL) and washed with water (100 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to afford the title compound (19.1 g, 78.75 mmol, 87% yield).

[1069] Step C: 3-Bromo-1-isopropylpyrrolidin-2-one

[1070]

[1071] To a solution of 3-bromo-l-isopropylpyrrolidin-2-one (1 g, 4.85 mmol, 1 eq) in DMSO (10 mL) was added sodium 3-methoxy-3-oxo-propane-l-sulfinate (845 mg, 4.85 mmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with brine (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (60 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si02, petroleum ether: ethyl acetate, 10: 1 to 1: 1) to give the title compound (1.1 g, 3.97 mmol, 82% yield).

[1072] 1 H NMR (CDC13): δ = 4.41-4.31 (m, 2H), 3.46-3.43 (m, 1H), 3.32-3.29 (m, 1H), 2.55-2.49 (m, 1H), 2.32-2.30 (m, 1H) and 1.16-1.14 (m, 6H).

[1073] Step D: 3-((l-isopropyl-2-oxopyrrolidin-3-yl)sulfonyl)methyl methanesulfonate

[1074]

[1075] To a solution of 3-bromo-l-isopropylpyrrolidin-2-one (1 g, 4.85 mmol, 1 eq) in DMSO (10 mL) was added sodium 3-methoxy-3-oxo-propane-l-sulfinate (845 mg, 4.85 mmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with brine (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (60 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si02, petroleum ether: ethyl acetate, 10: 1 to 1: 1) to give the title compound (1.1 g, 3.97 mmol, 82% yield).

[1076] 1 H NMR (CDC13): δ = 4.41-4.31 (m, 2H), 3.46-3.43 (m, 1H), 3.32-3.29 (m, 1H), 2.55-2.49 (m, 1H), 2.32-2.30 (m, 1H) and 1.16-1.14 (m, 6H).

[1077] LCMS: m / z 277.9 (M+H) + (ES + ).

[1078] Step E: Sodium l-isopropyl-2-oxopyrrolidin-3-sulfmate

[1079]

[1080] To a solution of methyl 3-((l-isopropyl-2-oxopyrrolidin-3-yl)sulfonyl)propanoate (0.6 g, 2.16 mmol, 1 eq) in a mixture of MeOH (4.8 mL) and THF (4.8 mL) was added NaOMe in MeOH (6.2 M, 1.05 mL, 3 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was then concentrated in vacuum to give the title compound (461.3 mg, crude) as a brown solid, which was used in the next step without further purification.

[1081] 1 H NMR (CD3OD): δ = 4.34-4.27 (m, 1H), 3.53-3.41 (m, 1H), 3.19-3.15 (m, 2H), 2.54-2.51 (m, 1H), 2.17-2.12 (m, 1H) and 1.19-1.14 (m, 6H).

[1082] LCMS: m / z 192.0 (M+H) + (ES + ).

[1083] Step F: l-isopropyl-2-oxopyrrolidin-3-sulfamate

[1084]

[1085] To a solution of sodium l-isopropyl-2-oxopyrrolidin-3-sulfmate (461 mg, 2.16 mmol, 1 eq) in DMSO (6 mL) was added (aminooxy)sulfonic acid (1.22 g, 10.82 mmol, 5 eq) and AcONa (709 mg, 8.65 mmol, 4 eq) in H2O (2 mL) at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (see “Experimental methods”, “Purification method 2”) to give the title compound (219.8 mg, 1.07 mmol, 49% yield, 100% purity) as a white solid.

[1086] LCMS: m / z 277.9 (M+H) + (ES + ).

[1078] Step E: Sodium l-isopropyl-2-oxopyrrolidin-3-sulfmate

[1079]

[1080] To a solution of methyl 3-((l-isopropyl-2-oxopyrrolidin-3-yl)sulfonyl)propanoate (0.6 g, 2.16 mmol, 1 eq) in a mixture of MeOH (4.8 mL) and THF (4.8 mL) was added NaOMe in MeOH (6.2 M, 1.05 mL, 3 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was then concentrated in vacuum to give the title compound (461.3 mg, crude) as a brown solid, which was used in the next step without further purification.

[1081] 1 H NMR (CD3OD): δ = 4.34-4.27 (m, 1H), 3.53-3.41 (m, 1H), 3.19-3.15 (m, 2H), 2.54-2.51 (m, 1H), 2.17-2.12 (m, 1H) and 1.19-1.14 (m, 6H).

[1082] LCMS: m / z 192.0 (M+H) + (ES + ).

[1083] Step F: l-isopropyl-2-oxopyrrolidin-3-sulfamate

[1084]

[1085] To a solution of sodium l-isopropyl-2-oxopyrrolidin-3-sulfmate (461 mg, 2.16 mmol, 1 eq) in DMSO (6 mL) was added (aminooxy)sulfonic acid (1.22 g, 10.82 mmol, 5 eq) and AcONa (709 mg, 8.65 mmol, 4 eq) in H2O (2 mL) at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (see “Experimental methods”, “Purification method 2”) to give the title compound (219.8 mg, 1.07 mmol, 49% yield, 100% purity) as a white solid.

[1086] 1 H NMR (DMSO-d6): δ = 6.92 (br s, 2H), 4.18-4.15 (m, 1H), 3.91-3.88 (m, 1H), 3.33-3.27 (m, 2H), 2.38-2.30 (m, 2H) and 1.10-1.03 (m, 6H).

[1087] LCMS: m / z 206.9 (M+H) + (ES + ).

[1088] Intermediate P65: 1-(1- Acetylazetidin-3-yl)piperidine-4-sulfonamide

[1089]

[1090] A suspension of 1-(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride (95%, 250 mg, 0.81 mmol) and triethylamine (0.23 mL, 164 mg, 1.63 mmol) in acetonitrile (10 mL) was stirred for 30 minutes. Acetic anhydride (0.08 mL, 87 mg, 0.85 mmol) was added to this slurry and stirring was continued for 20 hours. The mixture was concentrated in vacuo and the residue was dissolved in methanol and applied to a silica column (40 g) and eluted with 0-30% methanol in DCM to give the title compound (93 mg, yield 43%).

[1091] HPLC-MS: 100% (ELSD), M 261 + 1 (ACPI pos.)

[1092] 1 H NMR (DMSO-d6): δ = 6.72 (s, 2H), 4.08 (t, J = 7.8 Hz, 1H), 3.91 (dd, J = 8.6, 5.1 Hz, 1H), 3.81 (dd, J = 9.7, 7.2 Hz, 1H), 3.61 (dd, J = 9.8, 5.1 Hz, 1H), 3.13-2.98 (m, 1H), 2.94-2.72 (m, 3H), 2.04-1.92 (m, 2H), 1.90-1.73 (m, 5H), 1.59 (qt, J = 12.9, 3.5 Hz, 2H).

[1093] Intermediate P66: 1-(1- Acetylazetidin-3-yl)piperidine-4-sulfonamide

[1094]

[1095] A suspension of 1-(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride (95%, 200 mg, 0.65 mmol) and triethylamine (0.19 mL, 138 mg, 1.36 mmol) in acetonitrile (8 mL) was stirred for 30 minutes. Formalin solution (37% w / w, 15% methanol, 0.09 mL, 0.81 mmol) and sodium triethoxyborohydride (1.25 equivalents, 178 mg, 0.81 mmol) were added portionwise to the resulting slurry. Stirring was continued at ambient temperature for 20 hours, then the mixture was concentrated in vacuo. The residue was dissolved in 3.5 N ammonia in methanol and applied to a cartridge of silica (40 g, silicycle). The title compound (65 mg, 38% yield) was isolated by elution with a gradient of 0-30% 3.5 N (ammonia / methanol) in DCM.

[1096] HPLC-MS: 100% (ELSD), M 233 + 1 (ACPI pos.)

[1097] 1 H NMR (DMSO-d6): δ = 6.70 (s, 2H), 3.44 (s, 2H), 2.89-2.66 (m, 6H), 2.25 (s, 2H), 1.95 (dd, J = 13.0, 3.5 Hz, 2H), 1.81-1.67 (m, 3H), 1.56 (qd, J = 12.2, 3.9 Hz, 2H).

[1098] Intermediate P67: 1-(Pent-3-yl)pyrrolidine-3-sulfonamide

[1099]

[1100] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-sulfonamide and 3-pentanone, but without the need for triethylamine. The title compound (143 mg, 64% yield) was used without further purification.

[1101] 1 H NMR (DMSO-d6): δ = 6.80 (s, 2H), 3.53 (m, 1H), 2.90 (dd, 1H), 2.65 (m, 2H), 2.48 (m, 1H), 2.01 (m, 3H), 1.40 (m, 4H), 0.79 (m, 6H).

[1102] Intermediate P68: 1-(sec-Butyl)pyrrolidine-3-sulfonamide

[1103]

[1104] Prepared from pyrrolidine-3-sulfonamide and 2-butanone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14), but without triethylamine. The title compound (143 mg, yield 64%) was used without further purification.

[1105] 1 H NMR (CD3OD): δ = 3.78 (m, 1H), 3.33 (m, 1H), 2.99 (m, 2H), 2.78 (m, 1H), 2.51 (m, 1H), 2.25 (q, 2H), 1.74 (m, 1H), 1.40 (m, 1H), 1.15 (dd, 3H), 0.93 (t, 3H).

[1106] Intermediate P69: 1 -Butylazetidine-3-sulfonamide

[1107]

[1108] Prepared from azetidine-3-sulfonamide hydrochloride and butyraldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (82 mg, yield 42%) was used without further purification.

[1109] 1 H NMR (DMSO-d6): δ = 6.88 (s, 2H), 3.85 (m, 1H), 3.43 (t, 2H), 3.22 (m, 2H), 2.34 (t, 2H), 1.22 (m, 4H), 0.83 (t, 3H).

[1110] Intermediate P70: 1 -(2-Hydroxy-2-methylpropyl)azetidine-3-sulfonamide

[1111]

[1112] To a solution of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol, 1.0 equiv) and potassium carbonate (691 mg, 5.0 mmol, 5.0 equiv) in water (5 mL) and ethanol (5 mL) in a microwave vial (20 mL) was added 1,2-epoxy-2-methylpropane (88 μL, 1.0 mmol, 1.0 equiv). The reaction mixture was heated at 110 °C in the microwave for 30 min and then concentrated in vacuo. The crude material was suspended in methanol and filtered. The filtrate was applied to Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (38 mg, 18% yield) which was used without further purification.

[1113] 1 H NMR (DMSO-d6): δ = 6.86 (s, 2H), 4.03 (s, 1H), 3.88 (m, 1H), 3.54 (t, 2H), 3.36 (m, 2H), 2.31 (s, 2H), 1.00 (s, 6H).

[1114] Intermediate P71: 1-cyclopropylazetidine-3-sulfonamide

[1115]

[1116] Prepared from azetidine-3-sulfonamide hydrochloride as described for 1- cyclopropylpyrrolidine-3-sulfonamide (Intermediate P30) except that the reaction was stirred at room temperature for 3 days and at 50 °C for an additional 8 h. The title compound (47 mg, 26% yield) was used without further purification.

[1117] 1 H NMR (DMSO-d6): δ = 6.92 (s, 2H), 3.84 (m, 1H), 3.50 (t, 2H), 3.40 (t, 2H), 1.94 (m, 1H), 0.32 (m, 2H), 0.19 (m, 2H).

[1118] Intermediate P72: 1-(1,3-difluoroprop-2-yl)azetidine-3-sulfonamide

[1119]

[1120] Prepared from azetidine-3-sulfonamide hydrochloride and 1,3-difluoroacetone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (87 mg, 40% yield) was used without further purification.

[1121] 1 H NMR (DMSO-d6): δ = 6.93 (s, 2H), 4.47 (m, 2H), 4.32 (m, 2H), 3.94 (m, 1H), 3.59 (t, 2H), 3.48 (t, 2H), 2.80 (m, 1H).

[1122] Intermediate P73: 1 -(Cyanomethyl)azetidine-3-sulfonamide

[1123]

[1124] Prepared as for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and bromoacetonitrile. The title compound (47 mg, yield 26%) was used without further purification.

[1125] 1 H NMR (DMSO-d6): δ = 6.98 (s, 2H), 3.91 (m, 1H), 3.62 (s, 2H), 3.53 (m, 4H).

[1126] Intermediate P74: 1 -(2-Methoxyethyl)azetidine-3-sulfonamide

[1127]

[1128] Prepared as for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 2-bromoethyl methyl ether. The title compound (38 mg, yield 20%) was used without further purification.

[1129] 1 H NMR (DMSO-d6): δ = 6.89 (s, 2H), 3.87 (m, 1H), 3.47 (t, 2H), 3.32 (m, 2H), 3.25 (m, 2H), 3.18 (s, 3H), 2.54 (m, 2H).

[1130] Intermediate P75: 1 -(Cyclohexylmethyl)azetidine-3-sulfonamide

[1131]

[1132] Prepared from azetidine-3-sulfonamide hydrochloride and cyclohexanecarboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (202 mg, 86% yield) was used without further purification.

[1133] 1 H NMR (DMSO-d6): δ = 6.87 (s, 2H), 3.86 (m, 1H), 3.44 (t, 2H), 3.22 (t, 2H), 2.21 (d, 2H), 1.63 (m, 5H), 1.14 (m, 4H), 0.81 (m, 2H).

[1134] Intermediate P76: 1-(Pyridin-3-ylmethyl)azetidine-3-sulfonamide

[1135]

[1136] Prepared from azetidine-3-sulfonamide hydrochloride and pyridine-3-carboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (131 mg, 58% yield) was used without further purification.

[1137] 1 H NMR (DMSO-d6): δ = 8.44 (m, 2H), 7.65 (dt, 1H), 7.32 (dd, 1H), 6.95 (s, 2H), 3.92 (m, 1H), 3.61 (s, 2H), 3.48 (t, 2H), 3.37 (m, 2H).

[1138] Intermediate P77: N,N-Dimethyl-2-(3-sulfamidazetidin-1-yl)acetamide

[1139]

[1140] Prepared from azetidine-3-sulfonamide hydrochloride and 2-chloro-N,N- dimethylacetamide as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3), except that potassium iodide (0.5 eq) was added to the reaction mixture. The title compound (40 mg, 18% yield) was used without further purification.

[1141] 1 H NMR (DMSO-d6): δ = 7.17 (s, 2H), 4.07 (m, 3H), 3.90 (m, 4H), 2.88 (s, 3H), 2.80 (s, 3H).

[1142] Intermediate P78:1 -(2-chloroethyl)azetidine-3-sulfonamide

[1143]

[1144] Prepared from azetidine-3-sulfonamide hydrochloride and chloroacetaldehyde (ca. 50% w / w in H2O) as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (100 mg, 50% yield) was used without further purification.

[1145] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.86 (m, 1 H), 3.39 (t, 2H), 3.30 (m, 2H), 3.09 (q, 1 H), 1.87 (m, 2H), 1.67 (m, 4H).

[1146] Intermediate P79: 1 -cyclobutylazetidine-3-sulfonamide

[1147]

[1148] Prepared from azetidine-3-sulfonamide hydrochloride and cyclobutanone as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (127 mg, 66% yield) was used without further purification.

[1149] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.86 (m, 1 H), 3.39 (t, 2H), 3.30 (m, 2H), 3.09 (q, 1 H), 1.87 (m, 2H), 1.67 (m, 4H).

[1150] Intermediate P80: 1 -isopropyl-N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide Step A: 2-(dimethylcarbamoyl)-4-sulfamoylpyrrolidine-1 -carboxylic acid 4-nitrobenzyl ester

[1151]

[1152] A suspension of 2-(dimethylcarbamoyl)-4-mercaptopyrrolidine-1 -carboxylic acid 4- nitrobenzyl ester (1 g, 2.83 mmol) in acetic acid (5 mL) / water (1 mL) was cooled in an ice bath at 0 °C. N-Chlorosuccinimide (1.13 g, 8.49 mmol, 3.0 eq) was added in portions over a 5 min period. The mixture was allowed to stir for an additional hour at room temperature. The reaction was then poured into ammonia (50 mL, 25% aqueous solution). The resulting solution was stirred at room temperature for 18 h. The solvent was evaporated and the residue was triturated with ethanol (50 mL). Sodium sulfate (15 g) was added and the mixture was filtered and evaporated. The residue was dissolved in methanol (50 mL) and Amberlite 400 (OH - ) (20 g) was added. After stirring for 18 h, the mixture was filtered and evaporated to give the title compound (610 mg, yield 54%) as an oil which crystallized upon standing.

[1153] 1 H NMR (CD3OD): δ = 8.20 (m, 2H), 7.62 (d, 1 H), 7.53 (d, 1 H), 5.26 (d, 2H), 4.08-3.66 (m, 4H), 3.00 (m, 6H), 2.12 (m, 2H).

[1154] Step B: N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide

[1155]

[1156] Step B: N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide

[1157] 1 H NMR (CD3OD): δ = 8.20 (m, 2H), 7.62 (d, 1 H), 7.53 (d, 1 H), 5.26 (d, 2H), 4.08-3.66 (m, 4H), 3.00 (m, 6H), 2.12 (m, 2H).

[1158] Step C: 1 -isopropyl-N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide

[1159]

[1160] N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide (84 mg, 0.38 mmol) was dissolved in acetonitrile (10 mL). Acetone (90 mg, 1.5 mmol) was added followed by sodium triethoxyborohydride. After stirring at room temperature for 18 hours, the solvent was evaporated and the residue was purified via silica to give the title compound as an oil (10 mg, yield 10%).

[1161] 1 H NMR (CD3OD): δ = 3.92 (t, 1H), 3.73 (m, 1H), 3.46 (dd, 1H), 3.18 (s, 3H), 3.05 (m, 1H), 2.95 (s, 3H), 2.88 (m, 1H), 2.57 (m, 1H), 2.14 (m, 1H), 1.08 (d, 3H), 1.03 (d, 3H).

[1162] Intermediate P81: 1-ethyl-5-oxopyrrolidine-3-sulfonamide

[1163]

[1164] 1-ethyl-5-oxopyrrolidine-3-sulfonamide (150 mg, 0.71 mmol) was dissolved in THF (3 mL) and added dropwise to ammonia (25% aqueous solution, 5 mL) at 4°C. After stirring at room temperature for 18 hours, the solvent was evaporated. The residue was triturated in THF. The THF layer was decanted and evaporated to give the title compound as a brown oil (30 mg, yield 22%).

[1165] 1 H NMR (CD3OD): δ = 3.80 (m, 2H), 3.34 (m, 3H), 2.78 (m, 2H), 1.13 (t, 3H).

[1166] Intermediate P82: 1-(tert-butyl)azetidine-3-sulfonamide

[1167] Step A: methanesulfonic acid 1-(tert-butyl)azetidin-3-yl ester

[1168]

[1169] To a suspension of N-tert-butyl-3-hydroxyazetidine hydrochloride (1.0 g, 6.0 mmol) in dichloromethane (30 mL) was added N,N-diisopropylethylamine (2.4 mL, 13.8 mmol, 2.5 equiv). After stirring at room temperature for 20 min, the clear solution was cooled to 0 °C and methanesulfonyl chloride (0.5 mL, 6.6 mmol, 1.1 equiv) was added dropwise. The reaction mixture was stirred for 1 h while allowing it to warm to room temperature. The solvent was then removed by evaporation in vacuo. The crude product was dissolved in methanol, coated onto Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (456 mg, 37% yield).

[1170] 1 H NMR (CDCI3): δ = 5.10 (m, 1 H), 3.74 (m, 2H), 3.47 (m, 2H), 3.02 (s, 3H), 1.04 (s, 9H).

[1171] Step B: S-(l-(tert-butyl)azetidin-3-yl)thioacetate

[1172]

[1173] To a solution of methanesulfonic acid 1-(tert-butyl)azetidin-3-yl ester (269 mg, 1.3 mmol) in acetonitrile (20 mL) was added potassium thioacetate (447 mg, 3.9 mmol, 3 equiv). The reaction mixture was stirred at room temperature overnight and then at 50 °C for a further 7 h. The solvent was removed by evaporation in vacuo. The crude product was dissolved in methanol, coated onto Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (90 mg, 37% yield).

[1174] 1 H NMR (CDCI3): δ = 4.15 (m, 1 H), 3.80 (m, 2H), 3.30 (m, 2H), 2.31 (s, 3H), 1.03 (s, 9H).

[1175] Step C: 1-(tert-butyl)azetidine-3-sulfonamide

[1176]

[1177] To a suspension of N-chlorosuccinimide (200 mg, 1.5 mmol, 3 equiv) in acetonitrile (2.0 mL) was added hydrochloric acid (aqueous solution, 2 M, 0.2 mL, 0.38 mmol, 0.8 equiv). The solution was cooled in an ice bath before adding a solution of S-(1-(tert-butyl)azetidin-3-yl)thioacetate (90 mg, 0.48 mmol, 1.0 equiv) in acetonitrile (1.0 mL) and removing the ice bath. The reaction mixture was stirred for 1 hour before being added dropwise to a solution of ammonia in methanol (7 M, 50 mL, 350 mmol, 729 equiv). The mixture was stirred for 30 minutes before being concentrated in vacuo. The crude product was dissolved in methanol, applied to Agilent hydromatrix (high purity, inert diatomaceous earth sorbent), and subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (11 mg, 10% yield).

[1178] 1 H NMR (CD3OD): δ = 3.97 (m, 1H), 3.68 (m, 2H), 3.51 (m, 2H), 1.02 (s, 9H).

[1179] Intermediate P83: 1-(Cyclopropylmethyl)azetidine-3-sulfonamide

[1180]

[1181] Prepared from azetidine-3-sulfonamide hydrochloride and cyclopropanecarboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The crude product was dissolved in methanol, applied to an Agilent hydromatrix (high purity, inert diatomaceous earth sorbent), and subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (180 mg, 94% yield), which was used without further purification.

[1182] 1 H NMR (DMSO-d6): δ = 6.90 (s, 2H), 3.90 (m, 1H), 3.49 (t, 2H), 3.30 (t, 2H), 2.26 (d, 2H), 0.69 (m, 1H), 0.37 (m, 2H), 0.07 (m, 2H).

[1183] Intermediate P84: 1-Isobutylazetidine-3-sulfonamide

[1184]

[1185] Prepared from azetidine-3-sulfonamide hydrochloride and isobutyraldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (138 mg, yield 71%) was used without further purification.

[1186] 1 H NMR (DMSO-d6): δ = 6.88 (s, 2H), 3.88 (m, 1H), 3.46 (t, 2H), 3.23 (m, 2H), 2.18 (d, 2H), 1.47 (m, 1H), 0.80 (d, 6H).

[1187] Intermediate P85: 1-(2,2,2-trifluoroethyl)azetidine-3-sulfonamide

[1188]

[1189] To a solution of 1-(2-chloroethyl)azetidine-3-sulfonamide (45 mg, 0.22 mmol, 1.0 equiv) in acetonitrile (5 mL) was added sodium azide (14 mg, 0.22 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature over the weekend. Additional sodium azide (56 mg, 0.88 mmol, 4.0 equiv) was added and the reaction mixture was heated to 50 °C. After stirring overnight, water (0.4 mL) was added and the reaction mixture was stirred for an additional 2 days. The solution was concentrated in vacuo. The residue was suspended in methanol, filtered, and the filtrate was concentrated in vacuo to give the crude title compound (45 mg, 0.22 mmol, quantitative yield). The crude title compound was used without further purification.

[1190] 1 H NMR (DMSO-d6): δ = 6.93 (s, 2H), 3.92 (m, 1H), 3.53 (t, 2H), 3.34 (m, 2H), 3.21 (dd, 2H), 2.59 (dd, 2H).

[1191] Intermediate P86: 1-(2,2,2-trifluoroethyl)azetidine-3-sulfonamide

[1192]

[1193] To a suspension of azetidine-3-sulfonamide hydrochloride (333 mg, 1.92 mmol) and triethylamine (0.67 mL, 4.8 mmol, 2.5 equiv) in acetonitrile (20 mL) was added trifluoroacetic anhydride (0.24 mL, 1.73 mmol, 0.9 equiv). After stirring at room temperature for 4 hours, the reaction mixture was concentrated in vacuo. The crude intermediate 1-(2,2,2-trifluoroacetyl)azetidine-3-sulfonamide was dissolved in methanol, applied to an Agilent hydromatrix (high-purity, inert diatomaceous earth sorbent), and subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol. The impure intermediate (maximum 1.92 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0°C. To this solution was added borane dimethyl sulfide (0.85 mL, 9.0 mmol, 4.5 equiv) dropwise. The reaction mixture was refluxed overnight and then cooled to room temperature. Methanol was added to the reaction mixture until no further gas evolution was observed, and the reaction mixture was then concentrated in vacuo. The crude product was dissolved in methanol, applied to an Agilent hydromatrix (high purity, inert diatomaceous earth sorbent), and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to afford the title compound (20 mg, 5% yield). The title compound was used without further purification.

[1194] 1 H NMR (DMSO-d6): δ = 7.07 (s, 2H), 4.24-4.08 (m, 1H), 3.65 (t, 2H), 3.52 (dd, 2H), 3.31-3.16 (m, 2H).

[1195] Intermediate P87: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)azetidine-3-sulfonamide

[1196]

[1197] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and (2-bromoethoxy)-tert-butyldimethylsilane. The title compound (44 mg, 16% yield) was used without further purification.

[1198] 1 H NMR (DMSO-d6): δ = 6.89 (s, 2H), 3.88 (q, 1H), 3.50 (m, 4H), 3.31 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H).

[1199] Intermediate P88: 1 -cyclohexylazetidine-3-sulfonamide

[1200]

[1201] Prepared from azetidine-3-sulfonamide hydrochloride and cyclopentanone as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (204 mg, equivalent yield) was used without further purification.

[1202] 1 H NMR (DMSO-d6): δ = 6.86 (s, 2H), 3.83 (p, 1 H), 3.41 (t, 2H), 3.21 (dd, 2H), 2.00 (m, 1 H), 1.59 (m, 6H), 1.15 (q, 2H), 0.93 (m, 2H).

[1203] Intermediate P89: 1 -cyclopentylazetidine-3-sulfonamide

[1204]

[1205] Prepared from azetidine-3-sulfonamide hydrochloride and cyclopentanone as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (204 mg, equivalent yield) was used without further purification.

[1206] 1 H NMR (DMSO-d6): δ = 6.86 (s, 2H), 3.82 (m, 1 H), 3.41 (t, 2H), 3.18 (m, 2H), 2.72 (m, 1 H), 1.49 (m, 6H), 1.24 (m, 2H).

[1207] Intermediate P90: 1 -(1 -iminoethyl)azetidine-3-sulfonamide

[1208]

[1209] To a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol, 1.0 equiv) and triethylamine (0.49 mL, 3.5 mmol, 3.5 equiv) in acetonitrile (10 mL) was added imine ethyl acetate hydrochloride (123 mg, 1.0 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo. The crude compound (approximately 300 mg) was dissolved in water / methanol (ratio 1 :1) (3 mL). 1 mL of this solution was purified by reverse phase flash chromatography to give the title compound (30 mg, yield 9%).

[1210] 1 H NMR (DMSO-d6): δ = 10.25 (s, 1H), 7.41 (s, 2H), 4.61 (dd, 1H), 4.44 (m, 2H), 4.21 (m, 2H), 2.08 (s, 3H).

[1211] Intermediate P91: 1 -(Oxetan-3-ylmethyl)azetidine-3-sulfonamide

[1212]

[1213] Prepared from azetidine-3-sulfonamide hydrochloride and 3-oxetanemethanol as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (156 mg, yield 75%) was used without further purification.

[1214] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 4.57 (dd, 2H), 4.22 (t, 2H), 3.90 (m, 1H), 3.47 (t, 2H), 3.28 (m, 2H), 2.90 (m, 1H), 2.68 (d, 2H).

[1215] Intermediate P92: 1 -(2-(Dimethylamino)ethyl)azetidine-3-sulfonamide

[1216]

[1217] To a solution of 1-(cyanomethyl)azetidine-3-sulfonamide (220 mg, 1.25 mmol) in tetrahydrofuran (15 mL) cooled to 0 °C was added borane dimethylsulfide (0.16 mL, 1.63 mmol, 1.3 eq). The reaction mixture was refluxed overnight, then quenched with methanol. The solution was concentrated in vacuo. The crude intermediate was suspended in acetonitrile (20 mL) and formaldehyde (37% in water stabilized with methanol, 186 μL, 2.5 mmol, 2.1 eq), followed by sodium triethoxyborohydride (688 mg, 3.25 mmol, 2.6 eq). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo. The crude product was dissolved in methanol, coated on Agilent hydromatrix (high purity, inert celite sorbent), then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (28 mg, yield 14%).

[1218] 1 H NMR (CD3OD): δ = 4.02 (m, 1H), 3.67 (m, 2H), 3.55 (m, 2H), 2.74 (dt, 4H), 2.56 (s, 6H).

[1219] Intermediate P93: 1-(Pyridin-4-ylmethyl)azetidine-3-sulfonamide

[1220]

[1221] Prepared from azetidine-3-sulfonamide hydrochloride and 4-pyridinecarboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (130 mg, yield 57%) was used without further purification.

[1222] 1 H NMR (DMSO-d6): δ = 8.47 (d, 2H), 7.26 (d, 2H), 6.97 (s, 2H), 3.94 (m, 1H), 3.64 (s, 2H), 3.52 (t, 2H), 3.39 (t, 2H).

[1223] Intermediate P94: 1-(Pyridin-2-ylmethyl)azetidine-3-sulfonamide

[1224]

[1225] Prepared from azetidine-3-sulfonamide hydrochloride and 2-pyridinecarboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (196 mg, yield 86%) was used without further purification.

[1226] 1 H NMR (DMSO-d6): δ = 8.46 (dd, 1 H), 7.73 (td, 1 H), 7.32 (d, 1 H), 7.24 (m, 1 H), 6.95 (s, 2H), 3.94 (tt, 1 H), 3.70 (s, 2H), 3.55 (t, 2H), 3.44 (t, 2H).

[1227] Intermediate P95: 1-((2-bromopyridin-3-yl)methyl)azetidine-3-sulfonamide

[1228]

[1229] Prepared from azetidine-3-sulfonamide hydrochloride and 2-bromo-3-pyridinecarboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (137 mg, yield 45%) was used without further purification.

[1230] 1 H NMR (DMSO-d6): δ = 8.27 (dd, 1 H), 7.79 (dd, 1 H), 7.44 (dd, 1 H), 7.02 (s, 2H), 3.97 (m, 1 H), 3.67 (s, 2H), 3.61 (t, 2H), 3.49 (dd, 2H).

[1231] Intermediate P96: 3-sulfamoyl-[1,3'-biazetidinyl]-1 '-tert-butyl carboxylate

[1232]

[1233] Prepared from azetidine-3-sulfonamide hydrochloride and tert-butyl-3-oxoazetidine-1 - carboxylate as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (350 mg, yield 24%) was used without further purification.

[1234] 1 H NMR (DMSO-d6): δ = 6.95 (s, 2H), 3.92 (m, 1 H), 3.80 (t, 2H), 3.57 (d, 2H), 3.48 (t, 2H), 3.36 (m, 3H), 1.35 (s, 9H).

[1235] Intermediate P97: 1 '-methyl-[1,3'-aziridinium]-3-sulfonamide

[1236] Step A: [1,3'-aziridinium]-3-sulfonamide dihydrochloride

[1237]

[1238] To a solution of 3-sulfamoyl-[1,3'-aziridinium]-1 '-tert-butyl carbonate (Intermediate P96; 315 mg, 1.08 mmol) in dichloromethane (10 mL) was added 4 M hydrochloric acid in dioxane (2.7 mL, 10.8 mmol). After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo to give the title compound (285 mg, quantitative yield) which was used without further purification.

[1239] 1 H NMR (DMSO-d6): δ = 9.50 (bs, 1 H), 9.18 (bs, 1 H), 7.42 (s, 2H), 4.57-4.31 (m, 3H), 4.31 -4.00 (m, 8H).

[1240] Step B: 1 '-methyl-[1,3'-aziridinium]-3-sulfonamide

[1241]

[1242] Prepared from [1,3'-aziridinium]-3-sulfonamide dihydrochloride as described for 1 - methylazetidine-3-sulfonamide (Intermediate P39). The title compound (63 mg, yield 61 %) was used without further purification.

[1243] 1 H NMR (CD3OD): δ = 4.10-3.94 (m, 1 H), 3.75-3.60 (m, 4H), 3.59-3.51 (m, 2H), 3.51 -3.44 (m, 1 H), 3.41 -3.32 (m, 2H), 2.55 (s, 3H).

[1244] Intermediate P98: 1 -(2-(methylthio)ethyl)azetidine-3-sulfonamide

[1245]

[1246] To 0.5 M hydrochloric acid in water (6.0 mL, 3.0 mmol) was added (methylthio)acetaldehyde dimethylformaldehyde (0.4 mL, 3.0 mmol). After heating the reaction at 50 °C for 1 h, the reaction mixture was cooled to room temperature and then extracted with dichloromethane (10 mL). The organic layer was added to a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol) and triethylamine (0.17 mL, 1.2 mmol) in acetonitrile. After this, sodium triethoxyborohydride (265 mg, 1.25 mmol) was added. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The crude product was dissolved in methanol, coated onto Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (89 mg, yield 42%).

[1247] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 4.44 (t, 1H), 4.29 (t, 1H), 3.90 (q, 1H), 3.53 (t, 2H), 3.36 (t, 2H), 2.79-2.69 (m, 1H), 2.64 (t, 1H).

[1248] Intermediate P99: 1 -(2-Fluoroethyl)azetidine-3-sulfonamide

[1249]

[1250] Prepared as for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 1 -bromo-2-fluoroethane. The title compound (yield 10%) was used without further purification.

[1251] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 4.44 (t, 1H), 4.29 (t, 1H), 3.90 (q, 1H), 3.53 (t, 2H), 3.36 (t, 2H), 2.79-2.69 (m, 1H), 2.64 (t, 1H).

[1252] Intermediate P100: 1 -(2-Fluoroethyl)azetidine-3-sulfonamide

[1253]

[1254] Prepared from azetidine-3-sulfonamide hydrochloride and thietan-3-one as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (54 mg, 26% yield) was used without further purification.

[1255] 1 H NMR (DMSO-d6): δ = 6.95 (s, 2H), 3.98-3.83 (m, 2H), 3.43 (p, 4H), 3.19 (t, 2H), 2.97 (t, 2H).

[1256] Intermediate P101: 1-(2-(3-(But-3-yn-1-yl)-3H-diaziridin-3-yl)ethyl)azetidine-3-sulfonamide

[1257]

[1258] Prepared from azetidine-3-sulfonamide hydrochloride and (3-(but-3-yn-1-yl)-3-(2- iodoethyl)-3H-diaziridine (0.8 eq) as described for 1-(prop-2-yn-1-yl)piperidine-4- sulfonamide (Intermediate P3), except that a more dilute solution (0.02 M solution) was used. The title compound (10% yield) was used without further purification.

[1259] 1 H NMR (CD3OD): δ = 4.09-3.92 (m, 1H), 3.61 (td, 2H), 3.47-3.35 (m, 2H), 2.37 (dd, 2H), 2.27 (t, 1H), 2.02 (td, 2H), 1.60 (t, 2H), 1.51-1.39 (m, 2H).

[1260] Intermediate P102: (Z)-(((tert-butoxycarbonyl)amino)(3-sulfamidazetidin-1-yl)methylene)carbamic acid tert-butyl ester

[1261]

[1262] To a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol), triethylamine (0.49 mmol, 3.5 mmol) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-sulfanylazetidine (290 mg, 1.0 mmol) in acetonitrile (10 mL) was added mercury dichloride (271 mg, 1.0 mmol). After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated onto Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (216 mg, yield 57%).

[1263] 1 H NMR (DMSO-d6): δ = 10.24 (s, 1H), 7.16 (s, 2H), 4.41-3.94 (m, 5H), 1.41 (s, 9H), 1.35 (s, 9H).

[1264] Intermediate P103: 1-(3,3-dimethylcyclobutyl)azetidine-3-sulfonamide

[1265]

[1266] Prepared from azetidine-3-sulfonamide hydrochloride and 3-methylcyclobutan-1-one as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (79 mg, yield 39%) was used without further purification.

[1267] 1 H NMR (DMSO-d6): δ = 6.88 (s, 2H), 3.84 (td, 1H), 3.44-3.18 (m, 4H), 2.92 (m, 1H), 2.10-1.96 (m, 1H), 1.91-1.78 (m, 2H), 1.59-1.45 (m, 1H), 1.39-1.24 (m, 1H), 1.00 (s, 3H).

[1268] Intermediate P104: 1-(3,3-dimethylcyclobutyl)azetidine-3-sulfonamide

[1269]

[1270] Prepared from azetidine-3-sulfonamide hydrochloride and 3,3-dimethylcyclobutan-1-one as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (96 mg, yield 44%) was used without further purification.

[1271] 1 H NMR (DMSO-d6): δ = 6.88 (s, 2H), 3.84 (m, 1H), 3.34 (t, 2H), 3.29-3.19 (m, 2H), 3.08 (dq, 1H), 1.77-1.62 (m, 2H), 1.58-1.43 (m, 2H), 1.03 (td, 6H).

[1272] Intermediate P105: 1 -(Pyrimidin-5-ylmethyl)azetidine-3-sulfonamide

[1273]

[1274] Prepared from azetidine-3-sulfonamide hydrochloride and pyrimidine-5- carboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (98 mg, 43% yield) was used without further purification.

[1275] 1 H NMR (DMSO-d6): δ = 9.07 (s, 1H), 8.69 (s, 2H), 6.96 (s, 2H), 3.93 (m, 1H), 3.64 (s, 2H), 3.52 (t, 2H), 3.40 (t, 2H).

[1276] Intermediate P106: 1 -(Tetrahydrofuran-3-yl)azetidine-3-sulfonamide

[1277]

[1278] Prepared from azetidine-3-sulfonamide hydrochloride and tetrahydrofuran-3- one as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (31 mg, 15% yield) was used without further purification.

[1279] 1 H NMR (DMSO-d6): δ = 6.90 (s, 2H), 3.86 (m, 1H), 3.70-3.54 (m, 2H), 3.54-3.34 (m, 4H), 3.29-3.19 (m, 2H), 3.08-2.98 (m, 1H), 1.83-1.67 (m, 1H), 1.62-1.49 (m, 1H).

[1280] Intermediate P107: 1 -(sec-Butyl)azetidine-3-sulfonamide

[1281]

[1282] Prepared from azetidine-3-sulfonamide hydrochloride and 2-butanone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (191 mg, 85% yield) was used without further purification.

[1283] 1 H NMR (DMSO-d6): δ = 6.87 (s, 2H), 3.81 (m, 1H), 3.41 (td, 2H), 3.21 (t, 2H), 2.45-2.34 (m, 1H), 2.18-2.03 (m, 1H), 1.42-1.25 (m, 1H), 1.01 (t, 3H), 0.78 (d, 3H).

[1284] Intermediate P108: 1-((1-Methyl-1H-imidazol-2-yl)methyl)azetidine-3-sulfonamide

[1285]

[1286] Prepared from azetidine-3-sulfonamide hydrochloride and 1-methylimidazole-2- carboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (144 mg, 63% yield) was used without further purification.

[1287] 1 H NMR (DMSO-d6): δ = 7.03 (d, 1H), 6.91 (s, 2H), 6.71 (d, 1H), 3.96-3.80 (m, 1H), 3.61 (s, 2H), 3.57 (s, 3H), 3.45 (t, 2H), 3.37 (dd, 2H).

[1288] Intermediate P109: 1-(2,2-Dimethylcyclobutyl)azetidine-3-sulfonamide

[1289]

[1290] Prepared from azetidine-3-sulfonamide hydrochloride and 2-butanone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (191 mg, 85% yield) was used without further purification.

[1291] 1H NMR (DMSO-d6): δ = 6.87 (s, 2H), 3.90 (p, 1H), 3.40 (dd, 2H), 3.20 (dt, 2H), 2.57 (d, 1H), 1.86-1.72 (m, 1H), 1.56-1.33 (m, 3H), 1.00 (s, 3H), 0.92 (s, 3H).

[1292] Intermediate P110: (E)-(((tert-butoxycarbonyl)imino)(3-sulfamidazetidin-l-yl)methyl)(methyl)carbamic acid tert-butyl ester

[1293] Step A: l-methyl-l,3-bis(tert-butoxycarbonyl)-2-methyl-2-sulfanyl pseudourea

[1294]

[1295] In a cooling bath, a solution of l,3-bis(tert-butoxycarbonyl)-2-methyl-2-sulfanyl pseudourea (435 mg, 1.5 mmol) in dimethylformamide (5 mL) was cooled to 0 °C, then sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol) was added. The cooling bath was removed. After stirring at room temperature for 1 h, methyl iodide (0.19 mL, 3.0 mmol) was added. After stirring overnight, the reaction mixture was poured into water, then extracted once with dichloromethane and once with ethyl acetate. The organic layers were combined, washed twice with water, once with brine, dried over sodium sulfate, filtered, then concentrated in vacuo to give the title compound (230 mg, 50% yield) which was used without further purification.

[1296] 1 H NMR (CDC13): δ = 3.12 (s, 3H), 2.39 (s, 3H), 1.51 (s, 9H), 1.48 (s, 9H).

[1297] Step B: (E)-(((tert-butoxycarbonyl)imino)(3-sulfamidazetidin-l-yl)methyl)(methyl)carbamic acid tert-butyl ester

[1298]

[1299] Prepared from 1-methyl-1,3-bis(tert-butoxycarbonyl)-2-methyl-2-sulfanyl pseudourea as described for tert-butyl (Z)-(((tert-butoxycarbonyl)amino)(3- sulfamoylazetidin-1-yl)methylene)carbamate (Intermediate P102), except that after stirring overnight, water was added to the reaction mixture. The mixture was extracted three times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered, and then concentrated in vacuo. The crude product was suspended in methanol, applied to Agilent hydromatrix (high purity, inert diatomaceous earth sorbent), and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (48 mg, 16% yield).

[1300] 1 H NMR (DMSO-d6): δ = 7.23 (s, 2H), 4.20 (bs, 1H), 4.09 (p, 4H), 2.84 (s, 3H), 1.41 (s, 9H), 1.36 (s, 9H).

[1301] Intermediate P111: 1-(Cyclobutylmethyl)azetidine-3-sulfonamide

[1302]

[1303] Prepared from azetidine-3-sulfonamide hydrochloride and cyclobutanecarboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (145 mg, 11% yield) was used without further purification.

[1304] 1 H NMR (DMSO-d6): δ = 6.88 (s, 2H), 3.87 (m, 1H), 3.43 (t, 2H), 3.29-3.18 (m, 2H), 2.39 (d, 2H), 2.22 (dt, 1H), 1.98-1.85 (m, 2H), 1.77 (m, 2H), 1.67-1.49 (m, 2H).

[1305] Intermediate P112: 1-(2-(hydroxyimino)propyl)azetidine-3-sulfonamide

[1306] Step A: 1-(2-oxopropyl)azetidine-3-sulfonamide

[1307]

[1308] Prepared from azetidine-3-sulfonamide hydrochloride and chloroacetone as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) to give the title compound (125 mg, yield 21%).

[1309] 1 H NMR (CD3OD): δ = 4.06 (m, 1H), 3.75 (td, 2H), 3.60-3.49 (m, 4H), 2.07 (s, 3H).

[1310] Step B: 1-(2-(hydroxyimino)propyl)azetidine-3-sulfonamide

[1311]

[1312] Step B: 1-(2-(hydroxyimino)propyl)azetidine-3-sulfonamide

[1313] 1 H NMR (CD3OD): δ = 4.06 (m, 1H), 3.75 (td, 2H), 3.60-3.49 (m, 4H), 2.07 (s, 3H).

[1314] Intermediate P113: 1-(1-hydroxypropan-2-yl)azetidine-3-sulfonamide

[1315]

[1316] Prepared from azetidine-3-sulfonamide hydrochloride and hydroxyacetone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (36 mg, yield 18%) was used without further purification.

[1317] 1 H NMR (DMSO-d6): δ = 6.85 (s, 2H), 4.41 (t, 1H), 3.83 (t, 1H), 3.45 (dt, 2H), 3.27-3.17 (m, 3H), 3.05 (dd, 2H), 0.78 (d, 3H).

[1318] Intermediate P114: 1 -(1,1 -difluoroprop-2-yl)azetidine-3-sulfonamide

[1319]

[1320] Prepared from azetidine-3-sulfonamide hydrochloride and 1,1 -difluoropropanone as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (81 mg, 38% yield) was used without further purification.

[1321] 1 H NMR (DMSO-d6): δ = 6.93 (s, 2H), 5.73 (td, 1H), 3.90 (m, 1H), 3.55 (q, 2H), 3.44 (dd, 2H), 2.68-2.57 (m, 1H), 0.90 (d, 3H).

[1322] Intermediate P115: 1 -allylazetidine-3-sulfonamide

[1323]

[1324] Prepared from azetidine-3-sulfonamide hydrochloride and allyl bromide as described for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3) to give the title compound (56 mg, 32% yield).

[1325] 1 H NMR (DMSO-d6): δ = 6.90 (s, 2H), 5.77-5.57 (m, 1H), 5.22-4.96 (m, 2H), 3.96-3.82 (m, 1H), 3.44 (t, 2H), 3.31-3.22 (m, 2H), 3.01 (dt, 2H).

[1326] Intermediate P116: 1 -(prop-2-yn-1 -yl)azetidine-3-sulfonamide

[1327]

[1328] Prepared from azetidine-3-sulfonamide hydrochloride and 3-bromoprop-1- yne (80 wt% in toluene) as described for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3) to give the title compound (21 mg, 15% yield).

[1329] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.86 (m, 1 H), 3.43 (dt, 4H), 3.20 (d, 2H), 3.16-3.12 (m, 1 H).

[1330] Intermediate P117: 1 -(3-hydroxypropyl)azetidine-3-sulfonamide

[1331]

[1332] Prepared from azetidine-3-sulfonamide hydrochloride and 3-bromo-1 -propanol as described for 1 -(prop-2-yn-1 -yl)piperidine-4-sulfonamide (Intermediate P3) to give the title compound (60 mg, 38% yield).

[1333] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.89 (m, 1 H), 3.49 (t, 2H), 3.37 (t, 2H), 3.32-3.24 (m, 2H), 2.47-2.41 (m, 2H), 1.39 (p, 2H).

[1334] Intermediate P118: 1 -neopentylazetidine-3-sulfonamide

[1335]

[1336] Prepared from azetidine-3-sulfonamide hydrochloride and trimethylacetaldehyde as described for 1 -cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (71 mg, 35% yield) was used without further purification.

[1337] 1 H NMR (DMSO-d6): δ = 6.90 (s, 2H), 3.92 (m, 1 H), 3.57 (t, 2H), 3.39-3.29 (m, 2H), 2.20 (s, 2H), 0.80 (s, 9H).

[1338] Intermediate P119: 1 -((trimethylsilyl)methyl)azetidine-3-sulfonamide

[1339]

[1340] Prepared from azetidine-3-sulfonamide hydrochloride and (iodomethyl)trimethylsilane as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) to give the title compound (60 mg, yield 33%).

[1341] 1 H NMR (DMSO-d6): δ = 6.92 (s, 2H), 3.89 (t, 1H), 3.61 (bs, 2H), 3.31 (bs, 2H), 2.07 (s, 2H), -0.01 (s, 9H).

[1342] Intermediate P120: 1-(2-hydroxypropyl)azetidine-3-sulfonamide

[1343]

[1344] To a solution of 1-(2-oxopropyl)azetidine-3-sulfonamide (Intermediate P112, step A, 125 mg, 0.65 mmol) in methanol (10 mL) was added sodium borohydride (29 mg, 0.78 mmol). After stirring at room temperature for 4 hours, more sodium borohydride (7.4 mg, 0.2 mmol) was added. After stirring overnight, the reaction mixture was quenched with water (1.0 mL) and then concentrated in vacuo. The crude product was suspended in methanol, coated onto Agilent hydromatrix (high purity, inert diatomaceous earth sorbent) and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (11 mg, yield 8%).

[1345] 1 H NMR (CD3OD): δ = 4.09-3.96 (m, 1H), 3.77-3.64 (m, 3H), 3.61-3.48 (m, 2H), 2.55-2.44 (m, 2H), 1.12 (d, 3H).

[1346] Intermediate P121: 1-(4-hydroxybutyl)azetidine-3-sulfonamide

[1347]

[1348] Prepared from azetidine-3-sulfonamide hydrochloride and 4-bromo-1-butanol as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) to give the title compound (41 mg, yield 20%).

[1349] 1H NMR (DMSO-d6): δ = 6.98 (s, 2H), 3.93 (m, 1H), 3.57 (t, 2H), 3.36 (t, 4H), 3.16 (d, 1H), 2.50-2.42 (m, 2H), 1.47-1.21 (m, 4H).

[1350] Intermediate P122: 1 -(2-(3-methyl-3H-diaziridin-3-yl)ethyl)azetidine-3-sulfonamide

[1351] Step A: 2-(3-methyl-3H-diaziridin-3-yl)ethan-1 -ol

[1352]

[1353] To cooled liquid ammonia (-78 °C, 30 mL) was added 4-hydroxy-2-butanone (5.3 mL, 60.5 mmol). The solution was stirred at -40 °C for 4 h, then cooled back to -78 °C. To the cooled mixture was added dropwise a solution of hydroxylamine-O-sulfonic acid (7.6 g, 67 mmol) in methanol (60 mL). The cooling bath was removed, and at room temperature, the reaction mixture was stirred overnight. The suspension was filtered, and the residue was washed thoroughly with methanol. The filtrates were combined and concentrated in vacuo to ca. 100 mL, then degassed by passing nitrogen through the filtrate for 20 min. The solution was cooled in an ice bath, then added triethylamine (7.5 mL, 53.8 mmol), followed by iodine (5.0 g, 19.7 mmol). After stirring for 1 h, another batch of iodine (4.0 g, 15.8 mmol) was added. After 5 min, the reaction mixture was concentrated in vacuo to ca. 100 mL, then added brine. The aqueous solution was extracted with diethyl ether three times. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated in vacuo. Vacuum distillation (90 °C, 10 -2 mbar) gave the title compound as a yellow oil (226 mg, yield 3%).

[1354] 1 H NMR (CDCI3): δ = 3.53 (t, 2H), 1.73 (s, 1H), 1.64 (t, 2H), 1.07 (s, 3H).

[1355] Step B: Methanesulfonic acid 2-(3-methyl-3H-diaziridin-3-yl)ethyl ester

[1356]

[1357] A solution of 2-(3-methyl-3H-diazirine-3-yl)ethan-1-ol (100 mg, 1.0 mmol) and triethylamine (160 μL, 1.15 mmol) in dichloromethane (5 mL) was cooled in an ice bath. To the cooled solution was added methanesulfonyl chloride (93 μL, 1.2 mmol). The reaction mixture was stirred in the ice bath for 1.5 hours, then saturated ammonium chloride was added, and the organic layer was separated. The aqueous layer was extracted once with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated in vacuo to give the title compound (178 mg, quantitative yield) which was used without further purification.

[1358] 1 H NMR (CDCI3): δ = 4.13 (t, 2H), 3.05 (s, 3H), 1.79 (t, 2H), 1.09 (s, 3H).

[1359] Step C: 1 -(2-(3-methyl-3H-diazirine-3-yl)ethyl)azetidine-3-sulfonamide

[1360]

[1361] To a solution of methanesulfonic acid 2-(3-methyl-3H-diazirine-3-yl)ethyl ester (178 mg, 1.0 mmol) in acetonitrile (20 mL) was added azetidine-3-sulfonamide hydrochloride (344 mg, 2.0 mmol), then potassium carbonate (1.1 g, 8.0 mmol). The reaction mixture was stirred at 55 °C overnight, then potassium iodide (158 mg, 1.0 mmol) and N,N-dimethylformamide (2 mL) were added. The reaction mixture was stirred at 60 °C for 6 hours, then filtered through a glass filter. The residue was washed with methanol. The filtrates were combined and concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (high purity, inert diatomaceous earth sorbent), then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (16 mg, 7% yield).

[1362] 1 H NMR (DMSO-d6): δ = 6.90 (s, 2H), 3.92-3.82 (m, 1H), 3.44 (t, 2H), 3.21 (t, 2H), 2.27 (t, 2H), 1.25 (t, 2H), 0.97 (s, 3H).

[1363] Intermediate P123: 1 -((1 -Methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)azetidine-3-sulfonamide

[1364]

[1365] Prepared from azetidine-3-sulfonamide hydrochloride and 1-methyl-6-oxo-1,6- dihydropyridine-3-carboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (116 mg, yield 62%) was used without further purification.

[1366] 1 H NMR (DMSO-d6): δ = 7.54 (s, 1H), 7.29 (d, 1H), 6.93 (s, 2H), 6.32 (d, 1H), 3.97-3.79 (m, 1H), 3.43 (t, 2H), 3.37 (s, 3H), 3.31-3.24 (m, 4H).

[1367] Intermediate P124: 1-((1-Methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)azetidine-3-sulfonamide

[1368]

[1369] Prepared from azetidine-3-sulfonamide hydrochloride and 1-methyl-2-oxo-1,2- dihydropyridine-4-carboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (51 mg, yield 27%) was used without further purification.

[1370] 1 H NMR (DMSO-d6): δ = 7.57 (d, 1H), 6.98 (s, 2H), 6.23 (s, 1H), 6.07 (d, 1H), 4.00-3.79 (m, 1H), 3.49 (t, 2H), 3.42 (s, 3H), 3.40-3.33 (m, 4H).

[1371] Intermediate P125: 1-(2-(Tetrahydrofuran-3-yl)ethyl)azetidine-3-sulfonamide

[1372]

[1373] Prepared from azetidine-3-sulfonamide hydrochloride and 2-(oxolan-3-yl)acetaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (90 mg, yield 27%) was used without further purification.

[1374] 1H NMR (DMSO-d6): δ = 6.93 (s, 2H), 3.90 (m, 1H), 3.75 (t, 1H), 3.68 (dt, 1H), 3.59 (q, 1H), 3.47 (t, 2H), 3.26 (t, 3H), 2.45-2.33 (m, 2H), 2.09 (m, 1H), 2.00-1.86 (m, 1H), 1.42 (dt, 1H), 1.30 (q, 2H).

[1375] Intermediate P126: 1 -((tetrahydrofuran-3-yl)methyl)azetidine-3-sulfonamide

[1376]

[1377] Prepared from azetidine-3-sulfonamide hydrochloride and tetrahydrofuran-3- carboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (85 mg, 39% yield) was used without further purification.

[1378] 1 H NMR (CD3OD): δ = 4.06 (t, 1H), 3.88-3.66 (m, 5H), 3.59 (t, 2H), 3.43 (dd, 1H), 2.66 (d, 2H), 2.35-2.22 (m, 1H), 2.12-1.97 (m, 1H), 1.65-1.52 (m, 1H).

[1379] Intermediate P127: 1 -((tetrahydrofuran-2-yl)methyl)azetidine-3-sulfonamide

[1380]

[1381] To a solution of (tetrahydrofuran-2-yl)methanol (291 μL, 3.00 mmol) in dichloromethane (30 mL) was added Dess-Martin periodinane (1.40 g, 3.30 mmol). The reaction mixture was stirred at room temperature. After stirring for 1 h, the solution was washed once with saturated sodium bicarbonate. To the organic solution was added acetonitrile (10 mL), azetidine-3-sulfonamide hydrochloride (172 mg, 1.00 mmol), triethylamine (0.17 mL, 1.20 mmol), followed by sodium triethoxyborohydride (265 mg, 1.25 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo. The crude product was suspended in methanol, coated onto Agilent hydromatrix (high purity, inert diatomaceous earth sorbent), then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol to give the title compound (77 mg, 35% yield).

[1382] 1 H NMR (DMSO-d6): δ = 6.90 (s, 2H), 3.90 (m, 1H), 3.69 (q, 2H), 3.60-3.46 (m, 3H), 3.43-3.33 (m, 2H), 2.44 (d, 2H), 1.89-1.68 (m, 3H), 1.47 (q, 1H).

[1383] Intermediate P128: (1R,3R,5S)-8-(1-methylazetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide

[1384] Step A: tert-butyl 3-((1R,3R,5S)-3-sulfamoyl-8-azabicyclo[3.2.1]oct-8-yl)azetidine-1-carboxylate

[1385]

[1386] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R*,3R*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride and 1-Boc-3-azetidinone. The title compound (286 mg, 41% yield) was used without further purification.

[1387] 1H NMR (DMSO-d6): δ = 6.62 (s, 2H), 3.82 (s, 2H), 3.49 (s, 2H), 3.20-3.04 (m, 4H), 2.36-2.18 (m, 2H), 1.85-1.74 (m, 2H), 1.72-1.64 (m, 2H), 1.58 (dd, 2H), 1.35 (s, 9H).

[1388] Step B: (1R,3R,5S)-8-(azetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide dihydrochloride

[1389]

[1390] To a solution of tert-butyl 3-((1R,3R,5S)-3-sulfamoyl-8-azabicyclo[3.2.1]octan-8- yl)azetidine-1-carboxylate (286 mg, 0.83 mmol) in dichloromethane (10 mL) was added hydrochloric acid (4 M in dioxane, 2.1 mL, 8.3 mmol). After stirring for 2 h, the reaction mixture was concentrated in vacuo to give the title compound (237 mg, 89% yield) which was used without further purification.

[1391] 1 H NMR (DMSO-d6): δ = 9.86 (bs, 1H), 9.01 (bs, 1H), 6.95 (d, J = 6.1 Hz, 2H), 4.46 (bs, 2H), 4.21-3.84 (m, 6H), 3.42-3.25 (m, 1H), 2.83 (bs, 2H), 2.30 (t, 2H), 2.20-1.97 (m, 4H).

[1392] Step C: (1R,3R,5S)-8-(1-methylazetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide

[1393]

[1394] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R,3R,5S)-8-(azetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide dihydrochloride and formaldehyde (37 wt% in water). The title compound (37 mg, 35% yield) was used without further purification.

[1395] 1H NMR (CDCI3): δ = 4.15 (bs, 3H), 3.92 (bs, 3H), 2.93 (s, 3H), 2.61-2.39 (m, 2H), 2.03-1.89 (m, 4H), 1.89-1.63 (m, 4H).

[1396] Intermediate P129: 4-methoxy-1 -methylpyrrolidine-3-sulfonamide

[1397] Step A: 3-methoxy-4-sulfamoylpyrrolidine-1 -carboxylic acid benzyl ester

[1398]

[1399] To an ammonia in methanol solution (7 M, 42 mL) was added dropwise a solution of 3-(chlorosulfonyl)-4-methoxypyrrolidine-1 -carboxylic acid benzyl ester (500 mg, 1.49 mmol) in dichloromethane (10 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (236 mg, yield 50%).

[1400] 1 H NMR (CDCI3): δ = 4.15 (bs, 3H), 3.92 (bs, 3H), 2.93 (s, 3H), 2.61-2.39 (m, 2H), 2.03-1.89 (m, 4H), 1.89-1.63 (m, 4H).

[1401] Step B: 4-methoxypyrrolidine-3-sulfonamide

[1402]

[1403] Prepared from 3-methoxy-4-sulfamoylpyrrolidine-1 -carboxylic acid benzyl ester as described for azetidine-3-sulfonamide (Intermediate P33) to give the title compound (91 mg, yield 67%) which was used without further purification.

[1404] 1 H NMR (CDCI3): δ = 4.15 (bs, 3H), 3.92 (bs, 3H), 2.93 (s, 3H), 2.61-2.39 (m, 2H), 2.03-1.89 (m, 4H), 1.89-1.63 (m, 4H).

[1405] Step C: 4-methoxy-1 -methylpyrrolidine-3-sulfonamide

[1406]

[1407] Prepared from 4-methoxypyrrolidine-3-sulfonamide and formaldehyde (37% w / w in water) as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (mixture of diastereoisomers, 17 mg, 35% yield) was used without further purification.

[1408] Major diastereoisomer of 1 H NMR (CD3OD): δ = 4.21-4.11 (m, 1H), 3.65 (td, 1H), 3.40-3.35 (m, 2H), 3.27-3.18 (m, 1H), 2.90 (d, 1H), 2.81 (dd, 1H), 2.70-2.52 (m, 2H), 2.35 (s, 3H).

[1409] Intermediate P130: 1 -ethyl-4-methoxypyrrolidine-3-sulfonamide

[1410]

[1411] Prepared from 4-methoxypyrrolidine-3-sulfonamide and acetaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14). The title compound (mixture of diastereoisomers, 12 mg, 23% yield) was used without further purification.

[1412] Major diastereoisomer of 1 H NMR (CD3OD): δ = 4.18 (d, 1H), 3.75-3.56 (m, 1H), 3.38 (s, 3H), 3.13-2.94 (m, 2H), 2.72 (dd, 2H), 2.66-2.50 (m, 2H), 1.14 (dd, 3H).

[1413] Intermediate P131: 1 -(oxetan-3-yl)azetidine-3-sulfonamide

[1414]

[1415] To a solution of azetidine-3-sulfonamide (22 mg, 0.16 mmol) in methanol (5 mL) was added oxetan-3-one (23 mg, 0.32 mmol) and 2 drops of acetic acid. Next, sodium cyanoborohydride (20 mg, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The solvent was then evaporated to give the crude title compound (80 mg) as an oil which was used without further purification.

[1416] NMR data of the crude product was very complex. LCMS showed the desired mass.

[1417] LCMS: m / z 193 (M+H) + (ES + ); 191 (M-H) - (ES - ).

[1418] Intermediate P132: 1 -isopropyl-6-oxo- 1,6-dihydropyridine-3-sulfonamide

[1419] Step A: 6-chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1420]

[1421] To a solution of bis(4-methoxybenzyl)amine (3.71 g, 14.4 mmol) in DCM (50 mL) at 0 °C was added 2-chloropyridine-5-sulfonyl chloride (3.00 g, 13.7 mmol) and triethylamine (2.49 mL, 17.8 mmol). The reaction was stirred at 0 °C for 15 minutes, then allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then diluted with DCM (150 mL), washed with saturated aqueous NH4C1 (3 x 40 mL) and water (40 mL), dried over MgS04, filtered and concentrated in vacuo to give the crude product as a cream coloured solid. The crude product was triturated with TBME (70 mL), filtered and rinsed with TBME (2 x 40 mL) to give the title compound as an off-white solid (4.97 g, 83%).

[1422] 1 H NMR (DMSO-d6) δ 8.76 (dd, J = 2.6, 0.7 Hz, 1H), 8.19 (dd, J = 8.4, 2.6 Hz, 1H), 7.69 (dd, J = 8.4, 0.7 Hz, 1H), 7.08 - 7.02 (m, 4H), 6.83 - 6.76 (m, 4H), 4.29 (s, 4H), 3.71 (s, 6H).

[1423] LCMS: m / z 433.3 (M+H) + (ES + )。

[1424] Step B: 6-Hydroxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1425]

[1426] A suspension of 6-chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.508 g, 1.17 mmol) in ethane-1,2-diol (10 mL) was treated with 2M KOH (aq) (2.4 mL, 4.80 mmol). The resulting suspension was stirred at 140 °C for 18 h. Then, the reaction mixture was treated with additional 2M KOH (aq) (0.6 mL, 1.2 mmol, 1 equiv) and heated at 140 °C for an additional 6 h, and treated with additional 2M KOH (aq) (0.6 mL, 1.2 mmol, 1 equiv) and heated at 140 °C for an additional 18 h. The reaction mixture was then diluted with water (40 mL) and DCM (30 mL). Brine (5 mL) was added and the organic layer was collected. The aqueous phase was extracted with DCM (5 x 30 mL). The combined organic extracts were washed with water (10 mL), dried over MgS04, filtered and concentrated in vacuo. The residue was dried at 50 °C under reduced pressure overnight to give the title compound (542 mg, 100%).

[1427] 1 H NMR (DMSO-d6) δ 12.17 (s, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.63 (dd, J = 9.6, 2.9 Hz, 1H), 7.11 - 7.02 (m, 4H), 6.87 - 6.79 (m, 4H), 6.37 (d, J = 9.6 Hz, 1H), 4.21 (s, 4H), 3.72 (s, 6H).

[1428] LCMS: m / z 415.4 (M+H) + (ES + ), 413.4 (M-H) - (ES - )。

[1429] Step C: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3- sulfonamide and 6-Isopropoxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1430]

[1431] At 0 ° C, sodium hydride (60% by weight dispersion in mineral oil) (36 mg, 0.91 mmol) was added to a mixture of 6-hydroxy-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide (0.40 g, 0.869 mmol) and lithium bromide (0.154 g, 1.737 mmol) in DME:DMF (5 mL, 4: 1). The mixture was stirred at 0 ° C for 10 minutes and then stirred at room temperature for another 10 minutes. 2-iodopropane (0.10 mL, 1.04 mmol) was then added and the mixture was stirred at room temperature for 46 hours. The reaction mixture was heated to 65 ° C for 17 hours, cooled to room temperature, and quenched with saturated NH4Cl aqueous solution (5 mL) and diluted with EtOAc (100 mL). The organic layer was washed with water (15 mL) and brine (3×15 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to give 1-isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.28 g, 70%) and 6-isopropoxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.11 g, 27%) as white solids.

[1432] 1-Isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide:

[1433] 1 H NMR(CDCl3)δ7.91(d,J=2.7Hz,1H),7.41(dd,J=9.6,2.6Hz,1H),7.09-7.04(m,4H),6.84-6.79(m,4H), 6.54 (dd, J=9.6, 0.5Hz, 1H), 5.17 (sept, J=6.8Hz, 1H), 4.26 (s, 4H), 3.79 (s, 6H), 1.34 (d, J=6.8Hz, 6H).

[1434] LCMS: m / z 457.4 (M+H) + (ES + ).

[1435] 6-Isopropoxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide:

[1436] 1H NMR (CDCI3) δ 8.60-8.55 (m, 1H), 7.84-7.79 (m, 1H), 7.06-6.99 (m, 4H), 6.81-6.75 (m, 4H), 6.72-6.67 (m, 1H), 5.43-5.33 (m, 1H), 4.26 (s, 4H), 3.78 (s, 6H), 1.37 (d, J = 6.2 Hz, 6H).

[1437] LCMS: m / z 457.4 (M+H) + (ES + ).

[1438] Step D: 1 -isopropyl-6-oxo- 1,6-dihydropyridine-3-sulfonamide

[1439]

[1440] TFA (0.43 ml, 5.64 mmol) was added to a solution of l-isopropyl-N,N-bis(4- methoxybenzyl)-6-oxo-l,6-dihydropyridine-3-sulfonamide (0.26 g, 0.564 mmol) in DCM (3 mL) at room temperature and the mixture was stirred for 66 h. The reaction was then concentrated in vacuo and the residue was re-dissolved in DCM (5 mL). The product was purified by silica gel chromatography (12 g column, 0-10% MeOH / DCM) to give the title compound as a white solid (60 mg, 49%).

[1441] LCMS: m / z 217.3 (M+H) + (ES + ).

[1442] Intermediate P133: 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1443] Step A: 2-(benzylthio)-5-chloropyrazine

[1444]

[1445] To a solution of NaH (0.755 g, 18.88 mmol) in THF (55 mL) was added benzyl mercaptan (1.5 mL, 12.68 mmol) at 0 °C. The reaction mixture was diluted with THF (20 mL) and stirred at 0 °C for 10 min. Then a solution of 2,5-dichloropyrazine (1.370 mL, 13.42 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C, MeOH (1 mL) was added cautiously and stirred for 5 min. Water (20 mL) was added, then DCM (150 mL) and the biphasic mixture was passed through a phase separator. The organic phase was concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-3% EtOAc / isohexane) to give the title compound as a clear yellow oil (2.373 g, 72%).

[1446] 1 H NMR (DMSO-d6) δ 8.68 (d, J = 1.5 Hz, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.43-7.39 (m, 2H), 7.34-7.29 (m, 2H), 7.28-7.23 (m, 1H), 4.46 (s, 2H).

[1447] Step B: 5-Chloro-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide

[1448]

[1449] A solution of 2-(benzylsulfanyl)-5-chloropyrazine (0.916 g, 3.87 mmol) in DCM (15 mL, 233 mmol) was treated with water (1.5 mL) and the resulting suspension was cooled to between -5 and 0 °C. Sulfuryl chloride (2.2 mL, 26.2 mmol) was added and the reaction mixture was stirred for 2 h, maintaining the temperature between -5 and 0 °C. A slurry of ice / water (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (2 x 10 mL) and the combined organic extracts were dried (MgS04) and concentrated in vacuo to give the crude intermediate 5-chloropyrazine-2-sulfonyl chloride as a pale yellow liquid (1.198 g).

[1450] A suspension of bis(4-methoxybenzyl)amine hydrochloride (1.198 g, 4.08 mmol) and TEA (1.2 mL, 8.61 mmol) in DCM (15 mL) at 0 °C was treated dropwise with a solution of 5-chloropyrazine-2-sulfonyl chloride (0.824 g, 3.87 mmol) in DCM (5 mL). The resulting solution was stirred at 0 °C for 15 min, then allowed to warm to room temperature for 16 h. Saturated aqueous NH4Cl (10 mL) was added, and the organic phase was collected. The aqueous phase was extracted with DCM (2 x 10 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-30% EtOAc / isohexane) to give the title compound as a white solid (1.312 g, 77%).

[1451] 1 H NMR (CDCI3) δ 8.78 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.11-7.07 (m, 4H), 6.79-6.75 (m, 4H), 4.43 (s, 4H), 3.79 (s, 6H).

[1452] Step C: N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1453]

[1454] A suspension of 5-chloro-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide (1.31 g, 2.99 mmol) in ethylene glycol (15 mL) was treated with 2M KOH (aq) (7.5 mL, 15 mmol). The resulting suspension was stirred at 140 °C for 18 h. The reaction mixture was then allowed to cool to room temperature, diluted with water (100 mL), and neutralized with saturated aqueous NH4Cl (30 mL). The white precipitate was collected by filtration, washed with water, and dried at 60 °C under vacuum to give the title compound as a light yellow solid (1.094 g, 79%).

[1455] 1 H NMR (DMSO-d6) δ 7.94 (d, J = 1.2 Hz, 1H), 7.89 (br s, 1H), 7.10-7.06 (m, 4H), 6.84-6.79 (m, 4H), 4.28 (s, 4H), 3.71 (s, 6H). One exchangeable proton was not observed.

[1456] LCMS: m / z 438.2 (M + Na) + (ES +) ; 414.2 (M-H) - (ES - ).

[1457] Step D: 4-isopropyl-N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2- sulfonamide

[1458]

[1459] A suspension of N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2- sulfonamide (0.503 g, 1.090 mmol) and lithium bromide (0.192 g, 2.167 mmol) in DME:DMF (6 mL, 4:1) at 0 °C was treated with NaH (0.053 g, 1.325 mmol). The resulting suspension was stirred at 0 °C for 10 min, treated with 2-iodopropane (0.218 ml, 2.136 mmol), and then stirred at 65 °C for 64 h. Saturated aqueous NH4Cl (6 mL) and EtOAc (10 mL) were added, and the organic layer was collected. The aqueous layer was extracted with EtOAc (2 x 10 mL), and the combined organic extracts were washed with water (10 mL) and brine (2 x 10 mL), dried (MgSO4), and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a clear yellow oil (0.293 g, 53%).

[1460] 1 H NMR (DMSO-d6) δ 8.07 (d, J = 1.0 Hz, 1H), 7.96 (d, J = 0.9 Hz, 1H), 7.13-7.09 (m, 4H), 6.83-6.79 (m, 4H), 4.78 (sept, J = 6.5 Hz, 1H), 4.33 (s, 4H), 3.71 (s, 6H), 1.34 (d, J = 6.8 Hz, 6H).

[1461] LCMS: m / z 480.3 (100, [M+Na] + ), 458.5 (9, [M+H] + (ES + ).

[1462] Step E: 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1463]

[1464] A solution of 4-isopropyl-N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2- sulfonamide (0.287 g, 0.565 mmol) in DCM (1 mL) was treated with TFA (1 mL, 12.98 mmol) at room temperature. The resulting solution was stirred for 28 h. The reaction mixture was then concentrated in vacuo and the crude product was purified by silica gel chromatography (4 g column, 0-10% MeOH / DCM) to give the title compound as a white solid (0.116 g, 94%).

[1465] 1 H NMR (DMSO-d6) δ 8.14 (d, J = 1.0 Hz, 1H), 8.08 (d, J = 1.0 Hz, 1H), 7.40 (s, 2H), 4.88 (sept, J = 6.7 Hz, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[1466] LCMS: 216.1 (M-H) - (ES - ).

[1467] Intermediate P134: 1 -isopropylazetidine-3-sulfonamide

[1468] Step A: 3-hydroxyazetidine-1 -carboxylic acid tert-butyl ester

[1469]

[1470] To a solution of azetidin-3-ol hydrochloride (45 g, 410.75 mmol, 1 eq) in MeOH (1.2 L) was added TEA (83.13 g, 821.51 mmol, 2 eq) and di-tert-butyl dicarbonate (89.65 g, 410.75 mmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was then concentrated in vacuo. The residue was re-dissolved in EtOAc (1 L). The mixture was washed with H2O (3 x 500 mL) and brine (3 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound as a yellow oil (65 g, 91%)...

Claims

1. A pharmaceutical composition comprising a compound of formula (I): in: Q is selected from O or S; R 1 is a non-aromatic heterocyclic group containing at least one ring nitrogen atom, wherein R 1 is connected to the sulfur atom of the sulfonylurea group via a ring carbon atom, and wherein R 1 is optionally substituted; and R 2 is a cyclic group substituted at the α position, wherein R 2 which may be optionally further substituted, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1, wherein R 1 is a monocyclic or bicyclic non-aromatic heterocyclic group, wherein R 1 Optionally substituted.

3. The pharmaceutical composition of claim 2, wherein R 1 is a 4-, 5-, 6- or 7-membered monocyclic non-aromatic heterocyclic group or a 7-, 8-, 9- or 10-membered bicyclic non-aromatic heterocyclic group, wherein R 1 Optionally substituted.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the non-aromatic heterocyclic group R 1 is fully saturated.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein R 1 Contains one, two or three ring nitrogen, oxygen or sulfur atoms.

6. The pharmaceutical composition of claim 5, wherein R 1 Contains one or two ring nitrogen or oxygen atoms.

7. The pharmaceutical composition of claim 6, wherein R 1 Contains one or two ring nitrogen atoms.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein R 1 Selected from: where R 1 is connected to the sulfur atom of the sulfonylurea group through a non-aromatic ring carbon atom, and wherein R 1 may be optionally substituted or further substituted.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein R 1 Substituted by one or more substituents independently selected from the group consisting of: halo; -CN; -NO2; -N3; ​​-R β ;-OH;-OR β ;-SH;-SR β ;-SOR β ;-SO2H;-SO2R β ;-SO2NH2;-SO2NHR β ;-SO2N(R β )2;-R α -SH; -R α -SR β ;-R α -SOR β ;-R α -SO2H; -R α -SO2R β ;-R α -SO2NH2;-R α -SO2NHR β ;-R α -SO2N(R β )2;-NH2;-NHR β ;-N(R β )2;-R α -NH2; -R α -NHR β ;-R α -N(R β )2;-CHO;-COR β ;-COOH;-COOR β ;-OCOR β ;-R α -CHO; -R α -COR β ;-R α -COOH; -R α -COOR β ;-R α -OCOR β ;-NH-CHO;-NR β -CHO; -NH-COR β ;-NR β -COR β ;-CONH2;-CONHR β ;-CON(R β )2;-R α -NH-CHO; -R α -NR β -CHO; -R α -NH-COR β ;-R α -NR β -COR β ;-R α -CONH2;-R α -CONHR β ;-R α -CON(R β )2;-OR α -OH; -OR α -OR β ;-OR α -NH2; -OR α -NHR β ;-OR α -N(R β )2;-NH-R α -OH;-NH-R α -OR β ;-NH-R α -NH2; -NH-R α -NHR β ;-NH-R α -N(R β )2;-NR β -R α -OH; -NR β -R α -OR β ;-NR β -R α -NH2; -NR β -R α -NHR β ;-NR β -R α -N(R β )2; a C3-C7 cycloalkyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a C3-C7 cycloalkenyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a 3- to 7-membered non-aromatic heterocyclic group optionally substituted by one or more C1-C6 alkyl or C1-C3 haloalkyl groups; an oxo group (=O); or a C1-C4 alkylene bridge; Each of these -R α - is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains 1 to 6 atoms in its main chain, wherein one or more carbon atoms in the main chain of the alkylene, alkenylene or alkynylene group may be optionally replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may be optionally replaced by one or more halo groups and / or -R β group substitution; and Each of these -R β are independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic groups, and any -R β It may be optionally substituted with one or more C1-C3 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, -O(C1-C3 alkyl), halo, -CN, -C≡CH or oxo (=O) groups.

10. The pharmaceutical composition of claim 9, wherein R 1 Substituted on one or more ring nitrogen atoms by substituents independently selected from the group consisting of: halo; -CN; -NO2; -N3; ​​-R β ;-OH;-OR β ;-SH;-SR β ;-SOR β ;-SO2H;-SO2R β ;-SO2NH2;-SO2NHR β ;-SO2N(R β )2;-R α -SH; -R α -SR β ;-R α -SOR β ;-R α -SO2H; -R α -SO2R β ;-R α -SO2NH2;-R α -SO2NHR β ;-R α -SO2N(R β )2;-NH2;-NHR β ;-N(R β )2;-R α -NH2; -R α -NHR β ;-R α -N(R β )2;-CHO;-COR β ;-COOH;-COOR β ;-OCOR β ;-R α -CHO; -R α -COR β ;-R α -COOH; -R α -COOR β ;-R α -OCOR β ;-NH-CHO;-NR β -CHO; -NH-COR β ;-NR β -COR β ;-CONH2;-CONHR β ;-CON(R β )2;-R α -NH-CHO; -R α -NR β -CHO; -R α -NH-COR β ;-R α -NR β -COR β ;-R α -CONH2;-R α -CONHR β ;-R α -CON(R β ) 2; a C3-C7 cycloalkyl group optionally substituted with one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a C3-C7 cycloalkenyl group optionally substituted with one or more C1-C3 alkyl or C1-C3 haloalkyl groups; Oxo (=O); or a C1-C4 alkylene bridge; Each of these -R α - is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains 1 to 6 atoms in its main chain, and wherein the alkylene, alkenylene or alkynylene group may be optionally substituted with one or more halo groups and / or -R β group substitution; Each of these -R β are independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic groups, and any -R β may be optionally substituted with one or more C1-C3 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, -O(C1-C3 alkyl), halo, -CN, -C≡CH or oxo (=O) groups; Each of these -R δ Independently selected from C1-C6 alkyl or C1-C3 haloalkyl groups; wherein each m is independently selected from 1, 2 or 3; and wherein each n is independently selected from 1, 2 or 3.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein R 2 is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is substituted in the α position, and wherein R 2 May be optionally further substituted.

12. The pharmaceutical composition of claim 11, wherein R 2 is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is substituted in the α and α' positions, and wherein R 2 May be optionally further substituted.

13. The pharmaceutical composition of claim 12, wherein R 2 is a fused aryl or fused heteroaryl group, wherein the first cycloalkyl ring, cycloalkenyl ring, non-aromatic heterocyclic ring, aryl ring or heteroaryl ring is fused to the aryl or heteroaryl group at the α,β positions and the second cycloalkyl ring, cycloalkenyl ring, non-aromatic heterocyclic ring, aryl ring or heteroaryl ring is fused to the aryl or heteroaryl group at the α',β' positions, and wherein R 2 May be optionally further substituted.

14. The pharmaceutical composition according to any one of claims 1 to 10, wherein R 2 is a cyclic group substituted at the α and α' positions, wherein R 2 May be optionally further substituted.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein Q is O.

16. A pharmaceutical composition comprising a compound selected from the group consisting of: or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

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