Novel sulfonamide carboxamide compounds

Abstract

The present invention relates to compounds of formula (I): # imgabs0 # 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 the patent application with application number 201880044712.X, application date July 4, 2018, and name “Novel Sulfonamide Carboxamide Compounds”. Technical Field

[0002] The present invention relates to sulfonylureas and sulfonylthioureas comprising a non-aromatic heterocyclic group containing at least one ring nitrogen atom and further comprising a second cyclic group substituted at the alpha position, and to related salts, solvates, prodrugs, and pharmaceutical compositions. The present invention also relates to the use of such compounds in therapeutic agents for preventing medical conditions and diseases, most particularly for treating and preventing medical conditions and diseases by inhibiting NLRP3. Background Art

[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 syndrome (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. The polymerized ASC then interacts with the cysteine ​​protease caspase-1 to form a complex known as the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (respectively, pro-IL-1β and pro-IL-18), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. ASC specks can also recruit and activate caspase-8, which processes pro-IL-1β and pro-IL-18 and triggers 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. Although it controls the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, causing 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 components of the cellular backbone and glycolytic pathways, can lead to caspase-1-dependent inflammation.

[0006] NLRP3-dependent ASC specks are released into the extracellular milieu, where they 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 immune responses to infection and injury. For example, IL-1β signaling induces the secretion of proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 collaborate with IL-23 to induce IL-17 production by memory CD4 Th17 cells and by γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also collaborate to induce IFN-γ production by memory T cells and NK cells that drive Th1 responses.

[0008] The inherited CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, defining NLRP3 as a key component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of many complex diseases, including, in particular, 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 disease, kidney disease and aging. Many of these associations are linked using NLRP3. - / - Although the role of NLRP3 in type 2 diabetes (T2D) is well defined in mice, there is also an understanding of the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), deposition of amylin in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

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

[0011] Current treatments for NLRP3-related diseases include biologics targeting IL-1. These include the recombinant IL-1 receptor antagonist anakinra, the IL-1β-neutralizing antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologics have been used in clinical trials for other IL-1β-related diseases.

[0012] Some compounds containing diarylsulfonylureas 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 compounds containing diarylsulfonylureas that inhibit the post-translational processing of IL-1β. Post-translational processing of IL-1β is accompanied by activation of caspase-1 and cell death. CRIDs block activated monocytes, rendering caspase-1 inactive and preserving plasma membrane latency.

[0013] Certain sulfonylurea-containing compounds have also been disclosed as inhibitors of NLRP3 (see, e.g., Baldwin et al., J. Med. Chem., 59(5), 1691-1710, 2016; and WO 2016 / 131098 A1, WO 2017 / 129897 A1, WO 2017 / 140778 A1, WO 2017 / 184604 A1, WO 2017 / 184623 A1, WO 2017 / 184624 A1, and WO 2018 / 015445 A1).

[0014] There is a need to provide compounds having improved pharmacological and / or physiological and / or physiochemical properties and / or compounds which provide useful alternatives to known compounds. Summary of the Invention

[0015] The first aspect of the present invention provides a compound of formula (I):

[0016]

[0017] in:

[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 connected to the sulfur atom of the sulfonylurea group via a ring carbon atom, and wherein R 1 is optionally substituted; and

[0020] R 2 is a cyclic group substituted at the α position, wherein R 2 May be optionally further substituted.

[0021] In the context of this specification, a "hydrocarbyl" substituent group or the hydrocarbyl portion of 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. The hydrocarbyl group / moiety may be saturated or unsaturated (including aromatic) and may be linear or branched, or be or include a cyclic group, wherein the cyclic group does not include any heteroatoms such as N, O or S in its carbon backbone unless otherwise specified. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups / moieties and combinations of all of these groups / moieties. Typically, a hydrocarbyl group is C1-C 20 More typically, the hydrocarbyl group is C1-C 15 More typically, the hydrocarbyl group is C1-C 10 A "hydrocarbyl" 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-) to form a bridged, fused or spiro substituent. However, unless otherwise indicated, the substituted monocyclic group may be substituted by one or more monovalent cyclic groups. Similarly, when a group is described as bicyclic, it is understood that the cyclic group (including any bridged, fused or spiro divalent bridged substituents connecting the cyclic group, but excluding any monovalent cyclic substituents) is bicyclic.

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

[0028] A "cycloalkyl" substituent group or cycloalkyl moiety in a substituent group refers to a saturated hydrocarbon ring containing, for example, 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a cycloalkyl substituent group or moiety may include a monocyclic, bicyclic, or polycyclic hydrocarbon ring.

[0029] A "cycloalkenyl" substituent group or the cycloalkenyl moiety of a substituent group refers to a non-aromatic, unsaturated hydrocarbon ring having one or more carbon-carbon double bonds and containing, for example, 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohexa-1,3-dien-1-yl. Unless otherwise specified, a cycloalkenyl substituent group or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbon rings.

[0030] The aryl moiety in an "aryl" substituent group or a substituent group refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic condensed ring aromatic hydrocarbons, wherein all condensed ring systems (excluding any ring system that is a part of an optional substituent or formed by an optional substituent) are aromatic. Examples of aryl groups / parts include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl".

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

[0032]

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

[0034] Unless otherwise stated, when explaining that cyclic group or part are non-aromatic such as cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group, it should be understood that the group or part (not including any ring system that is a part for optional substituent or formed by optional substituent) is non-aromatic.Similarly, when explaining that cyclic group or part are aromatic such as aryl or heteroaryl group, it should be understood that the group or part (not including any ring system that is a part for optional substituent or formed by optional substituent) is aromatic.Usually, when cyclic group or part do not have any tautomer that is aromatic, it is regarded as non-aromatic.Usually, when cyclic group or part have tautomer that is aromatic, it is regarded as aromatic, even if it has tautomer that is not aromatic.

[0035] For the purposes of this specification, when a combination of moieties is referred to as a group such as arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned moiety contains the atom to which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl.

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

[0037] (i) Each hydrogen atom may be optionally replaced by a group independently selected from the group consisting of: 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 )3;-N + (R β )2-R α -OH; -N + (R β )2-R α -OR β ;-N + (R β )2-R α -NH2; -N + (R β )2-R α -NHR β ;-N + (R β )2-R α -N(R β )2; or -N + (R β )2-R α -N(O)(R β )2; and / or

[0038] (ii) Any two hydrogen atoms attached to the same atom may optionally be replaced by a π-bonded substituent independently selected from the group consisting of oxo (=O), =S, =NH, or =NR β and / or

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

[0040] 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 -Rβ group substitution; and

[0041] 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.

[0042] Typically, the compounds of the present invention contain at least one quaternary ammonium group, such as -N + (R β )3 or -N + (R β )2-.

[0043] When mentioning -R α -C(N2)R β When a group is used, it is intended to be:

[0044]

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

[0046] (i) Each hydrogen atom may be optionally replaced by a group 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 -SO2Rβ ;-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 -COLOR β ;-R α -COOH;-R α -COOR β ;-R α -OCOR β ;-NH-CHO;-NR β -CHO;-NH-COR β ;-NR β -COLOR 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 -COLOR 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-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-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; or a 3- to 7-membered non-aromatic heterocyclic group optionally substituted by one or more C1-C6 alkyl or C1-C3 haloalkyl groups; and / or

[0047] (ii) Any two hydrogen atoms attached to the same carbon atom may be optionally replaced by a π-bonded substituent independently selected from the group consisting of oxo (=O), =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) may be optionally replaced by a bridging substituent independently selected from: -O-, -S-, -NH-, -N(R β )-or-R α -;

[0049] 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

[0050] Each of these -R βare 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.

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

[0052] (i) Each hydrogen atom may be optionally replaced by a group 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;

[0053] and / or

[0054] (ii) Any two hydrogen atoms attached to the same carbon atom may optionally be replaced by a π-bonded substituent independently selected from the group consisting of: (oxo)=O, =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) may be optionally replaced by a bridging substituent independently selected from: -O-, -S-, -NH-, -N(R β )-or-R α -;

[0056] 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;

[0057] 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 βmay 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;

[0058] Each of these -R δ Independently selected from C1-C6 alkyl or C1-C3 haloalkyl groups;

[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 contains 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 stated, an optionally substituted group or moiety (e.g., R 1 ) any divalent bridging substituent (e.g., -O-, -S-, -NH-, -N(R β )-、-N(O)(R β )-、-N + (R β )2-or-R α -) must only be attached to a specific group or moiety and may not be attached to a second group or moiety (e.g., R 2 ), even though the second group or moiety may itself be optionally substituted.

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

[0064] Unless otherwise stated, any reference to an element should be taken to include all isotopes of that element. Thus, for example, any reference to hydrogen should be taken to include all isotopes of hydrogen, including deuterium and tritium, unless otherwise stated.

[0065] When referring to a hydrocarbyl group or other group including 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 replaced by an N, O or S atom, it is intended that:

[0066] Depend on replacement;

[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] The proviso is 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 hydrocarbon group or other group consisting of -N(O)(R β )-or-N + (R β )2- group in the main chain of the group replaced by the -CH2- group, it is intended that:

[0074] -CH2- by replacement; or

[0075] -CH2- by Replacement.

[0076] In the context of this specification, unless otherwise stated, C x -C y A radical is defined as a radical containing from x to y carbon atoms. For example, a C1-C4 alkyl radical is defined as an alkyl radical containing from 1 to 4 carbon atoms. When calculating the total number of carbon atoms in a parent radical substituted with optional substituents and / or containing optional moieties, the optional substituents and moieties are not taken into account. For the avoidance of doubt, when calculating C x -C y When counting the number of carbon atoms in a group, replacing heteroatoms such as N, O or S are not considered as carbon atoms. For example, a morpholinyl group is considered a C4 heterocyclic group, not a C6 heterocyclic group.

[0077] For the purposes of this specification, when a first atom or group is stated to be "directly bonded to" a second atom or group, it is understood that the first atom or group is covalently bonded to the second atom or group in the absence of one or more intervening atoms or groups. Thus, for example, for the group (C=O)N(CH3)2, the carbon atom of each methyl group is directly bonded to the nitrogen atom, and the carbon atom of the carbonyl group is directly bonded to the nitrogen atom, but the carbon atom of the carbonyl group is not directly bonded to the carbon atom of either methyl group.

[0078] R 1 For the avoidance of doubt, it should be noted that it is R that is directly attached to the sulfur atom of the sulfonylurea group (not any optional substituents). 1 A ring atom of a non-aromatic heterocyclic group.

[0079] R 1is a non-aromatic heterocyclic group which may be monocyclic, bicyclic (including bridged, fused and spiro), tricyclic or polycyclic. The bicyclic, tricyclic and polycyclic ring structures may be partially aromatic. For the avoidance of doubt, it should be noted that when R 1 When the sulfonylurea group is a partially aromatic bicyclic, tricyclic or polycyclic group, the R 1 For the avoidance of doubt, it should also be noted that when R 1 When it is a bicyclic, tricyclic or polycyclic group, R 1 The at least one ring nitrogen atom is in a non-aromatic ring, but not necessarily in the direct connection to the sulfur atom of the sulfonylurea group R 1 In one embodiment, when R 1 When it is a bicyclic, tricyclic or polycyclic group, R 1 The at least one ring nitrogen atom of R is directly connected to the sulfur atom of the sulfonylurea group 1 in the non-aromatic rings.

[0080] Usually, R 1 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 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 Optionally substituted.

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

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

[0083]

[0084]

[0085] R1 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 due to 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 In one embodiment, R 1 The at least one ring nitrogen atom of R is directly connected to the sulfur atom of the sulfonylurea group 1 in the non-aromatic rings.

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

[0099] where R 1 This 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.

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

[0101] 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.

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

[0103] where R 1 This non-aromatic heterocyclic R 1 The group is attached to the sulfur atom of the sulfonylurea group via any suitable ring carbon atom.

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

[0105]

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

[0119] R 1 is a non-aromatic heterocyclic group containing at least one ring nitrogen atom. 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 It may be optionally substituted with one or more substituents such as those defined above.

[0121] In one embodiment, R 1 Substituted by 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 ;-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;-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 )3;-N + (R β )2-R α -OH;-N + (R β )2-R α -OR β ;-N + (R β )2-R α -NH2;-N + (R β )2-R α -NHR β ;-N + (Rβ )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; 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;

[0126] 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

[0127] 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.

[0128] Usually, R 1 One or more ring nitrogen atoms are substituted by such a substituent.

[0129] In another embodiment, R 1 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; 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;

[0130] Oxo (=O); or a C1-C4 alkylene bridge;

[0131] 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 carbon 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;

[0132] 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 βmay 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;

[0133] Each of these -R δ Independently selected from C1-C6 alkyl or C1-C3 haloalkyl groups;

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

[0137] In another embodiment, R 1 Substituted by one or more (such as one, two or three) substituents independently selected from the group consisting of: 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 (=O);

[0139] Each of these -R α - independently selected from C1-C3 alkylene groups;

[0140] Each of these -R β are independently selected from C1-C6 alkyl or C3-C6 cycloalkyl groups, and any -R β may be optionally substituted with one or more C3-C6 cycloalkyl, -O(C1-C3 alkyl), halo, -CN or -C≡CH groups;

[0141] Each of these -R δ independently selected from C1-C6 alkyl groups;

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

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

[0144] Usually, R 1 One or more ring nitrogen atoms are substituted by such a substituent.

[0145] In one embodiment, R 1 is substituted by one or more (such as one, two or three) substituents independently selected from the group consisting of: halo; C1-C6 alkyl; C1-C6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; -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 (=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

[0147] R 5 independently selected from a bond or a C1-C5 alkylene group;

[0148] 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;

[0149] 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;

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

[0155] In one embodiment, R 1 is substituted on one or more (such as one, two or three) ring nitrogen atoms by substituents independently selected from the group consisting of: halo; C1-C6 alkyl; C1-C6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; -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 (=O); -CH2CH2-; -CH2CH2CH2-; -CH2CH2CH2CH2-; 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

[0157] R 5 independently selected from a bond or a C1-C5 alkylene group;

[0158] 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;

[0159] 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;

[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 is substituted on one or more (such as one, two or three) ring nitrogen atoms by substituents independently selected from the group consisting of: halo; C1-C6 alkyl; C1-C6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; -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 -pyridinyl; -R 5 -(C3-C6 cycloalkyl);

[0165] Oxo (=O); -CH2CH2CH2-; or -CH2CH2CH2CH2-; wherein

[0166] R 5 independently selected from a bond or a C1-C5 alkylene group;

[0167] R6 Independently selected from hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 cycloalkyl, -CO-(C1-C3 alkyl) or benzyl;

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

[0169] n is 1, 2 or 3.

[0170] In one embodiment, R 1 Substituted on one or more (such as one, two or three) ring carbon atoms by substituents independently selected from the group consisting of: oxo (=O); -CH2CH2-; -CH2CH2CH2-; -CH2CH2CH2CH2-; -CH=CH-CH=CH2-; -OR 7 or-CON(R 7 )2; where R 7 Independently selected from hydrogen or C1-C3 alkyl.

[0171] In one embodiment, R 1 Substituted on one or more (such as one, two or three) ring carbon atoms by substituents independently selected from the group consisting of oxo (=O); -CH2CH2CH2-; -CH2CH2CH2CH2-; or -CH=CH-CH=CH2-.

[0172] In one aspect of any one 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 substituted at the α position, wherein R 2 For the avoidance of doubt, it is indicated that it is the R that is directly attached to the nitrogen atom of the urea or thiourea group (not any substituents). 2 A ring atom of a cyclic group.

[0174] In one embodiment of the first aspect of the present invention, R 2 is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is α-substituted, and wherein R 2 Optionally further substituted. Typically, R 2 is phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is α-substituted, and wherein R 2 Optionally further substituted. Typically, R 2is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is substituted in the α and α' positions, and wherein R 2 Optionally further substituted. Typically, R 2 is phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is substituted in the α and α' positions, and wherein R 2 Can be optionally further substituted. For example, R 2 It 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 nomenclature α, β, α′, β′ refers to a cyclic group (such as -R 2 ) relative to the point of attachment of the cyclic group to the rest of the molecule. 2 In the case of a 1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl moiety, the α, β, α' and β' positions are as follows:

[0176]

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

[0178] In any of the above embodiments, in R 2 Typical substituents at the α and / or α' positions of the parent cyclic group comprise carbon atoms. For example, in R 2 Typical substituents at the α and / or α′ positions of the parent cyclic group may be independently selected from -R 4 、-OR 4 and-COR 4 group, where each R 4 are independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic groups, and wherein each R 4 Optionally further substituted by one or more halo groups. More typically, the substituents at α and / or α' 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 fluorine and / or chlorine groups.

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

[0180] In one embodiment, -R 2 Having a formula selected from the following:

[0181]

[0182] where R 8 and R 9 are independently selected from C1-C4 alkyl, and X is hydrogen or halo.

[0183] Typically, -R 2 Having a formula selected from the following:

[0184]

[0185] In R 2 Other typical substituents at the α and / or α' positions of the parent cyclic group may include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings fused to the parent cyclic group at the α, β and / or α', β' 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 be optionally 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 Optionally further substituted. Typically, the two or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are each ortho-fused to an aryl or heteroaryl group, i.e., each fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring has only two atoms and one bond in common with the aryl or heteroaryl group. Typically, R 2 It is three-ring shaped.

[0188] In another embodiment, 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, wherein R 2 May be optionally further substituted.

[0189] In one embodiment, -R2 Having a formula selected from the following:

[0190]

[0191] Among them A 1 and A 2 are each independently selected from optionally substituted alkylene or alkenylene groups, wherein one or more carbon atoms in the backbone of the alkylene or alkenylene group may be optionally replaced by one or more heteroatoms N, O or S, and wherein B 1 is hydrogen or any optional substituent. 1 or A 2 B 1 and any optional substituents may be taken together with the atoms to which they are attached to form a further fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring, which may itself be optionally substituted. Similarly, the attachment of A 1 Any optional substituent and connecting A 2 Any optional substituents of may also be taken together with the atoms to which they are attached to form a further fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring, which may itself be optionally substituted.

[0192] Usually, B 1 is hydrogen or halogen, hydroxyl, -CN, -NO2, -B 2 or -OB 2 Group, where B 2 is a C1-C4 alkyl group which may be optionally substituted with a halo group.

[0193] Generally, any 1 or A 2 The ring is a 5- or 6-membered ring. 1 and A 2 is unsubstituted or substituted with one or more halogenated groups, hydroxyl groups, -CN, -NO2, -B 3 or -OB 3 Group substitution, where B 3 is a C1-C4 alkyl group which may be optionally substituted with a halo group.

[0194] In another embodiment, -R 2 Having a formula selected from the following:

[0195]

[0196] Typically, -R 2 Has the following formula:

[0197]

[0198] In R 2Other typical substituents at the α position of the parent cyclic group may include monovalent heterocyclic groups and monovalent aromatic groups, wherein the ring atoms of the heterocyclic or aromatic group are directly connected to the α ring atoms of the parent cyclic group via a single bond, wherein the heterocyclic or aromatic group may be optionally substituted, and wherein the parent cyclic group may be optionally further substituted. Such R is described in more detail below. 2 group.

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

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

[0201] In one embodiment, R 2is a parent cyclic group substituted at the α position with a monovalent heterocyclic group or a monovalent aromatic group, wherein the heterocyclic or aromatic group is optionally substituted, and wherein the parent cyclic group is optionally further substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl group or a 5- or 6-membered heterocyclic group, all of which are 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 may be optionally substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, piperidinyl or tetrahydropyranyl group, all of which may be optionally substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl or tetrahydropyranyl group, all of which may be optionally substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridyl, pyrimidinyl or pyrazolyl group, all of which may be optionally substituted with one or two substituents independently selected from the group consisting of halo, -OH, -NH2, -CN, -NO2, -B 4 、-OB 4 、-NHB 4 or -N(B 4 )2, where B 4 are independently selected from C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl groups, all of which may be optionally substituted with halo. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is an unsubstituted phenyl, pyridyl, pyrimidinyl or pyrazolyl group. In one embodiment, the monovalent heterocyclic group at the α position is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, all of which may be optionally substituted with one or two substituents independently selected from the group consisting of halo, -OH, -NH2, -CN, -NO2, -B 4 、-OB 4 、-NHB 4 or -N(B 4 )2, where B 4are independently selected from C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl groups, all of which may be optionally substituted with halo. In one embodiment, the monovalent heterocyclic group at the α position is an unsubstituted pyridin-3-yl group or a pyridin-4-yl group optionally substituted with one or two substituents independently selected from the group consisting of halo, -OH, -NH2, -CN, -NO2, -B 4 、-OB 4 、-NHB 4 or -N(B 4 )2, where B 4 Independently selected from C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl groups, all of which may be optionally substituted with a halo group. Alternatively, any of these monovalent heterocyclic groups in the α position may be optionally substituted with one or two substituents independently selected from the following: 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.

[0202] In one embodiment, R 2 is 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. In one embodiment, such further substituents are present in R 2 Such further substituents may be independently selected from: halo, -R δ 、-OR δ or-COR δ group, where each R δ are independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic groups, and wherein each R δ Optionally further substituted with one or more halo groups. 2 Such further substituents on the α-substituted parent cyclic group are independently selected from halo, C1-C6 alkyl (especially C3-C6 branched alkyl) or C3-C6 cycloalkyl groups, such as fluoro, chloro, 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.

[0203] In one embodiment, -R 2 Having a formula selected from the following:

[0204]

[0205] where R 10 is a C1-C4 alkyl group, R 11 is a 5- or 6-membered optionally substituted heterocyclic or aromatic group, and X is hydrogen or a halo group. In one embodiment, the optional substituents on the heterocyclic or aromatic group are selected from halo, -OH, -NH 2 , -CN, -NO 2 , -B 5 、-OB 5 、-NHB 5 or -N(B 5 )2, where B 5 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.

[0206] Typically, -R 2 Having a formula selected from the following:

[0207]

[0208] 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 6 、-OB 6 、-NHB 6 or -N(B 6 )2, where B 6 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.

[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 , 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

[0215] 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

[0216] 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

[0217] (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

[0218] 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

[0219] 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 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 with one or more halo groups, it may, for example, be substituted with 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 commonly, R 2 Contains 25 to 35 atoms.

[0231] In another aspect of any 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 commonly, 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 present invention, Q is O.

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

[0234] Q is O;

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

[0236]

[0237] where R 1 is connected to the sulfur atom of the sulfonylurea group through a non-aromatic ring carbon atom, and wherein R 1 is optionally substituted; and

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

[0239] (i) phenyl or a 5- or 6-membered heteroaryl group is 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

[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 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

[0247] 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

[0248] (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

[0249] 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

[0250] 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

[0251] (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

[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 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

[0253] 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);

[0254] The restriction condition is that when R 1 The non-aromatic heterocyclic group is selected from:

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

[0256] In this particular embodiment immediately above, when a group or moiety is optionally substituted with one or more halo groups, it may, for example, be 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 may be selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0258] In this particular embodiment just above, R 1 It may be optionally substituted by one or more (such as one, two or three) substituents independently selected from the group consisting of: halo; C1-C6 alkyl; C1-C6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; -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] The third aspect of the present invention provides a pharmaceutically acceptable salt, solvate or prodrug of any compound of the first or second aspect of the present invention.

[0310] The compounds of the present invention can be used in their free base form and in their acid addition salt form.For the purposes of the present invention, "salts" of the compounds of the present invention include acid addition salts. Acid addition salts are preferably pharmaceutically acceptable non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalic acids (e.g., hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (e.g., nitric, perchloric, sulfuric 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 pamoic acid), organic sulfonic acids (e.g., methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene-2-sulfonic or camphorsulfonic) or amino acids (e.g., ornithine, glutamic or aspartic acid). The acid addition salt may be a monoacid addition salt, a diacid addition salt, a triacid addition salt or a polyacid addition salt. Preferred salts are hydrohalic acid, sulfonic acid, phosphoric acid or organic acid addition salts. Preferred salts are hydrochloric acid addition salts.

[0311] When the compound of the present invention includes a quaternary ammonium group, the compound is typically used in its salt form. The counterion of the quaternary ammonium group can be any pharmaceutically acceptable non-toxic counterion. Examples of suitable counterions include the conjugate bases of the protonic acids discussed above for acid addition salts.

[0312] The compounds of the present invention can also be used in their free acid form and their acid salt form. For the purposes of the present invention, the "salt" of the compounds of the present invention includes a salt formed between the protonic acid functionality (such as a carboxylic acid group) of the compounds of the present invention and a suitable cation. Suitable cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium, and ammonium. The salt can be a monosalt, a disalt, a trisalt, or a 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 disodium 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 are included in the present invention because they may serve as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable salts, or may be used in the identification, characterization or purification of free acids or bases.

[0314] The compounds and / or salts of the present invention may be anhydrous or in the form of hydrates (e.g., hemihydrates, monohydrates, dihydrates, or trihydrates) or other solvates. Such solvates may 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 invention, therapeutically inactive prodrugs are provided. Prodrugs are compounds that are completely or partially converted into compounds of the present invention when administered to a subject, such as a human. In most embodiments, prodrugs are pharmacologically inert chemical derivatives that can be converted into active drug molecules in vivo to exert therapeutic effects. 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 to otherwise change the properties of the compound. Typical examples of prodrugs include compounds with biologically unstable protective groups on the functional portion of the active compound. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and / or dephosphorylated to produce active compounds. The present invention also encompasses salts and solvates of such prodrugs, as described above.

[0316] The compounds, salts, solvates and prodrugs of the present invention may contain at least one chiral center. Compounds, salts, solvates and prodrugs may therefore exist in at least two isomeric forms. The present invention encompasses racemic mixtures of compounds, salts, solvates and prodrugs of the present invention and enantiomerically enriched and substantially enantiomerically pure isomers. For purposes of the present invention, a "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 isomers of the same compound.

[0317] The compounds, salts, solvates and prodrugs of the present invention may 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 radioisotope, 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 present invention may be in any polymorphic or amorphous form.

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

[0320] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in “Aulton's Pharmaceutics—The Design and Manufacture of Medicines”, ME Aulton and KMG Taylor, Churchill Livingstone Elsevier, 4th edition, 2013.

[0321] Pharmaceutically acceptable excipients (including adjuvants, diluents or carriers) that can be used in the pharmaceutical composition of the present invention are excipients conventionally used in the field of pharmaceutical preparations and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, aluminum oxide, aluminum 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 sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, 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 present invention provides the use of the compound of the first or second aspect or the 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. Typically, the treatment or prevention comprises administering the compound, salt, solvate, prodrug or medicament to the subject. In one embodiment, the treatment or prevention comprises co-administering one or more additional active agents.

[0327] A seventh aspect of the present invention provides a method for treating or preventing a disease, disorder or condition, the method comprising the steps of administering an effective amount of the 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, administration is performed on a subject in need.

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

[0329] The ninth aspect of the present invention provides the use of a compound of the first or second aspect, or a pharmaceutically effective salt, solvate or prodrug of the third aspect, in the manufacture of a medicament for 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 may be, for example, a gain-of-function mutation or other mutation that results in increased NLRP3 activity. Typically, the treatment or prevention comprises administering the compound, salt, solvate, prodrug or medicament to the individual. In one embodiment, the treatment or prevention comprises co-administering one or more additional active agents. The treatment or prevention may also include diagnosing an individual with a germline or somatic non-silent mutation of NLRP3, wherein the compound, salt, solvate, prodrug or medicament 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.

[0330] The tenth aspect of the present invention provides a method for treating or preventing a disease, disorder or condition, comprising the steps of diagnosing an individual with a germline or somatic non-silent mutation of NLRP3, and administering to the individual diagnosed positive 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, administration is performed on a subject in need thereof.

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

[0332] It should be understood that these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive. In this regard, any specific disease, disorder or condition may be classified according to more than one of the general embodiments above. Non-limiting examples are type I diabetes, autoimmune diseases and diseases of the endocrine system.

[0333] In one embodiment of the fifth, sixth, seventh, eighth, ninth or tenth aspects of the invention, the disease, disorder or condition is responsive to NLRP3 inhibition. As used herein, the term "NLRP3 inhibition" refers to a complete or partial decrease 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 the inflammatory response associated with or resulting from a number of different conditions (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0335] NLRP3 has been implicated in many autoinflammatory diseases, including familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), septic arthritis, pyoderma gangrenosum, and acne (PAPA), Schweder's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al., Eur. J. Immunol., 40:595-653, 2010). In particular, NLRP3 mutations have been found to cause a group of rare autoinflammatory diseases called 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 is a heritable disease characterized by recurrent fever and inflammation and includes 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 neurocutaneous arthritis 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 result in increased IL-1β secretion.

[0336] NLRP3 has been implicated in a number of autoimmune diseases, including multiple sclerosis, type 1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler 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; and Schnitzler 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 lung 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 suggested 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 non-alcoholic 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. Vasc. Biol. 2017 37(4):694-706), and other cardiovascular events (Ridker et al., NEngl J Med., doi:10.1056 / NEJMoa1707914, 2017) via IL-1β.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 damage (Puyang et al., Sci Rep. 2016 Feb 19;6:20998); liver diseases, including nonalcoholic liver fibrosis (NASH) (Henao-Meija et al., Nature, 482:179-185, 2012); inflammatory responses in the lungs and skin (Primiano et al., J Ophthalmol. 2016;149(4):847-59); Immunol. 2016 197(6):2421-33), including contact allergies (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 in joints (Braddock et al., Nat. Rev. Drug 2015 191:A5816); 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 disease, 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).The NLRP3 inflammasome has been found to be activated in response to oxidative stress and UVB irradiation (Schroder et al., Science, 327:296-300, 2010). NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al., Inflammation, 40:366-386, 2017).

[0337] The inflammasome, and NLRP3 in particular, has also been proposed to be a target of regulation by various pathogens, including viruses such as DNA viruses (Amsler et al., Future Virol. (2013) 8(4), 357-370).

[0338] NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al., Clinical and Experimental Immunology 166: 1-15, 2011; and Masters Clin. Immunol. 2013). For example, several previous studies have suggested a role for IL-1β in cancer invasiveness, growth, and metastasis, and inhibition of IL-1β with canakinumab 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 the NLRP3 inflammasome or IL-1β has also been shown to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al. Oncol Rep. 2016; 35(4): 2053-64). A role for the NLRP3 inflammasome has been suggested in myelodysplastic syndrome (Basiorka et al. Blood. 2016 Dec 22;128(25):2960-2975); and also in the carcinogenesis of various other cancers, including gliomas (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). It has also been shown that activation of the NLRP3 inflammasome mediates chemoresistance of tumor cells to 5-fluorouracil (Feng et al. J Exp Clin Cancer Res. 2017 21;36(1):81), and activation of the NLRP3 inflammasome in peripheral nerves leads to chemotherapy-induced neuropathic pain (Jia et al. Mol Pain. 2017;13:1-11).

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

[0340] Thus, examples of diseases, disorders or conditions that are responsive to NLRP3 inhibition and that can be treated or prevented according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the invention include:

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

[0342] (ii) autoimmune diseases such as acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Guillain-Barré syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki 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)), severe Myasthenia gravis, opsoclonus-myoclonus syndrome (OMS), optic neuritis, Odd's thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, nonresponsive gouty arthritis, Reiter's syndrome, Sjögren's syndrome, systemic sclerosis, systemic connective tissue disease, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia areata, Behçet's disease, Chagas disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler 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) infection, including viral infection (e.g., from influenza virus, human immunodeficiency virus (HIV), alphavirus (such as chikungunya virus and rhesus virus), flavivirus (such as dengue virus and Zika virus), herpes virus (such as Ehrlich virus, cytomegalovirus, varicella-zoster virus and KSHV), pox virus (such as varicella virus (modified vaccinia virus Ankara) and myxovirus), 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, 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, Borrelia burgdorferi burgdorferi or Yersinia pestis); fungal infections (e.g., from Candida species or Aspergillus species); protozoan infections (e.g., from Plasmodium, Pirozoa, Giardia lamblia, Entamoeba, Leishmania, or Trypanosoma);Helminth 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 neurone disease, Huntington's disease, cerebral malaria, brain damage due to 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, ischemia, reperfusion injury (including ischemic reperfusion injury after MI), stroke (including ischemic stroke), transient ischemic attack, myocardial infarction (including recurrent myocardial infarction), heart failure (including congestive heart failure and heart failure with preserved ejection fraction), embolism, aneurysm (including abdominal aortic aneurysm) and pericarditis (including Troisler'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 advanced fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH);

[0350] (x) renal diseases, including chronic kidney disease, oxalate nephropathy, renal calcitonin deposition disease, glomerulonephritis, and diabetic nephropathy;

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

[0352] (xii) skin diseases, including dermatitis (such as contact dermatitis and atopic dermatitis), contact allergies, sunburn, skin lesions, hidradenitis suppurativa (HS), other cystic skin diseases, and acne conglobata;

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

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

[0355] (xv) graft-versus-host disease;

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

[0357] (xvii) Any disease in which the individual has been identified as carrying 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 diseases;

[0362] (iv) cardiovascular disease;

[0363] (v) liver disease;

[0364] (vi) eye disease; or

[0365] (vii) Skin diseases.

[0366] More typically, 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 conglobata;

[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 syndrome (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) ischemic 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 neurone disease;

[0395] (xxiv) Multiple sclerosis;

[0396] (xxv) Muckle-Wells syndrome;

[0397] (xxvi) non-alcoholic 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 invention, the disease, disorder or condition is inflammation. Examples of inflammation that can be treated or prevented according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the invention include inflammatory responses that occur in conjunction with or as a result of:

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

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

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

[0409] (iv) gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, proctitis, pancreatitis, eosinopilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects distal to the intestine (e.g., migraine, rhinitis, or eczema);

[0410] (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, exogenous or dust asthma, and in particular chronic or intractable asthma, such as late-stage asthma and airway hyperreactivity), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis (rhinitis pumlenta), dry rhinitis, medicamentous rhinitis, membranous rhinitis, seasonal rhinitis such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis or idiopathic interstitial pneumonia;

[0411] (vi) vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wagner's granulomatosis;

[0412] (vii) autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type 1 diabetes mellitus, idiopathic thrombocytopenic purpura, or Graves' disease;

[0413] (viii) eye conditions such as uveitis, allergic conjunctivitis or vernal conjunctivitis;

[0414] (ix) neurological conditions, such as multiple sclerosis or encephalomyelitis;

[0415] (x) infection or infection-related conditions 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 (type A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, tuberculosis, mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis / epididymitis, legionella, Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease;

[0416] (xi) renal conditions such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or renal syndrome;

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

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

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

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

[0421] (xvi) burns, wounds, trauma, hemorrhage 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 invention, the disease, disorder or condition is an autoinflammatory disease such as cryopyrin-associated periodic syndrome (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 and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (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 immunity deficiency, periodic fever and delayed development (SIFD).

[0426] Examples of diseases, disorders, or conditions that are responsive to NLRP3 inhibition and that can be treated or prevented according to the fifth, sixth, seventh, eighth, ninth, or tenth aspects of the present invention are listed above. Some of these diseases, disorders, or conditions are mediated substantially or entirely by NLRP3 inflammasome activity and NLRP3-induced IL-1β and / or IL-18. Therefore, such diseases, disorders, or conditions may be particularly responsive to NLRP3 inhibition and are particularly suitable for treatment or prevention according to the fifth, sixth, seventh, eighth, ninth, or tenth aspects of the present invention. Examples of such diseases, disorders, or conditions include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), suppurative arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), hyperimmunoglobulinemia 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, Schweizer syndrome, Behçet's disease, antisynthetase syndrome, interleukin-1 receptor antagonist deficiency (DIRA), and haploinsufficiency of A20 (HA20).

[0427] In addition, some of the above-mentioned diseases, disorders or conditions are elevated due to mutations in NLRP3, in particular, resulting in increased NLRP3 activity. Therefore, such diseases, disorders or conditions may be particularly responsive to NLRP3 inhibition and are particularly suitable for treatment or prevention according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention. Examples of such diseases, disorders or conditions include cryopyrin-associated periodic syndrome (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 present invention, the disease, disorder or condition is not an inflammatory disease of the eye or a symptom of an inflammatory disease of the eye. In one embodiment of the fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a skin disease. In one embodiment of the fifth, sixth or seventh aspect of the present invention, 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 present invention, the disease, disorder or condition is not a skin disease. In one embodiment of the fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not dermatitis. In one embodiment of the fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a disease involving an increase in eosinophils. In one embodiment of the fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not an allergic disease. In one embodiment of the fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a disease susceptible to treatment with a chymosin inhibitor. In one embodiment of the fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not fibrosis or an extracellular matrix metabolism disorder. In one embodiment of the fifth, sixth or seventh aspects of the present invention, the disease, disorder or condition is not a disease associated with abnormal vascular function. In one embodiment of the fifth, sixth or seventh aspects of the present invention, the disease, disorder or condition is not a rheumatic disease. In one embodiment of the fifth, sixth or seventh aspects of the present invention, the disease, disorder or condition is not a heart or circulatory system disease. In one embodiment of the fifth, sixth or seventh aspects of the present invention, the disease, disorder or condition is not inflammatory bowel disease. In one embodiment of the fifth, sixth or seventh aspects of the present invention, the disease, disorder or condition is not HCV infection. In one embodiment of the fifth, sixth or seventh aspects of the present invention, the disease, disorder or condition is not cancer. In one embodiment of the fifth, sixth or seventh aspects of the present invention, the disease, disorder or condition is not a disease susceptible to treatment with a hypoglycemic agent.

[0429] The eleventh aspect of the present invention provides a method for inhibiting NLRP3, comprising using 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 to inhibit NLRP3.

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

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

[0432] In another embodiment of the eleventh aspect of the present invention, the method is performed in vivo. For example, the method may comprise the steps 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, administration is performed to a subject in need thereof.

[0433] Alternatively, the method of the eleventh aspect of the present invention may be a method of inhibiting NLRP3 in a non-human animal subject, comprising the steps of administering the compound, salt, solvate, prodrug, or pharmaceutical composition to the non-human animal subject, and optionally subsequently amputating or killing the non-human animal subject. Typically, such a method further comprises the steps of analyzing one or more tissue or fluid samples from the optionally amputated 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 present invention provides a compound of the first or second aspect of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the present invention, or a pharmaceutical composition of the fourth aspect of the present invention, for 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 present invention provides a compound of the first or second aspect of the present invention, or a pharmaceutically effective salt, solvate or prodrug of the third aspect of the present invention, for use in the manufacture of a drug for the inhibition of NLRP3. Typically, the inhibition comprises administering the compound, salt, solvate, prodrug or drug to a subject. In one embodiment, the compound, salt, solvate, prodrug or drug is co-administered with one or more additional active agents.

[0436] In any embodiment of any one of the fifth to thirteenth aspects of the invention comprising the use or co-administration of one or more additional active agents, the one or more additional active agents may comprise, for example, one, two or three different additional active agents.

[0437] The one or more additional active agents may be administered before, simultaneously with, sequentially with, or after each other and / or the compound of the first or second aspect of the invention, the pharmaceutically acceptable salt, solvate, or prodrug of the third aspect of the invention, or the pharmaceutical composition of the fourth aspect of the invention. When the one or more additional active agents are administered simultaneously with the compound of the first or second aspect of the invention, or the pharmaceutically acceptable salt, solvate, or prodrug of the third aspect of the invention, the pharmaceutical composition of the fourth aspect of the invention may be administered, wherein the pharmaceutical composition further comprises the one or more additional active agents.

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

[0439] (i) chemotherapeutic agents;

[0440] (ii) antibodies;

[0441] (iii) alkylating agents;

[0442] (iv) antimetabolites;

[0443] (v) anti-angiogenic agents;

[0444] (vi) alkaloids and / or terpenoids;

[0445] (vii) topoisomerase inhibitors;

[0446] (viii) mTOR inhibitors;

[0447] (ix) diphenylethylenes;

[0448] (x) STING agonists;

[0449] (xi) cancer vaccines;

[0450] (xii) immunomodulators;

[0451] (xiii) antibiotics;

[0452] (xiv) antifungal agents;

[0453] (xv) anthelmintics; and / or

[0454] (xvi) Other active agents.

[0455] It should be understood that these general embodiments defined according to broad classes of active agents are not mutually exclusive. In this regard, any specific active agent may be classified according to more than one of the above general embodiments. A non-limiting example is urelumab, 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 abiraterone acetate, altretamine, amsacrine, anhydrovinblastine, auristatin, azathioprine, adriamycin, bexarotene, bicalutamide, BMS184476, bleomycin bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-tert-butylamide, cisplatin, carboplatin, carboplatin cyclophosphamide, chlorambucil, cachectin, cemadotin, cyclophosphamide, carmustine, cryptophycin, cytarabine, docetaxel, European Paclitaxel, doxorubicin, dacarbazine (DTIC), actinomycin, dactinomycin, decitabine, dolastatin, etoposide, etoposide phosphate, enzalutamide (MDV3100), 5-fluorouracil, fludarabine, flutamide, gemcitabine, hydroxyurea and hydroxyurea taxanes, idarubicin, ifosfamide , irinotecan, leucovorin, lonidamine, lomustine (CCNU), larotaxel (RPR109881), mechlorethamine, mercaptopurine, methotrexate, mitomycin C, mitoxantrone, melphalan, mivobulin, 3',4'-Didehydro-4'-deoxy-8'-norvin-caleukoblastine, nilutamide, oxaliplatin, onapristone, prednimustine, procarbazine, paclitaxel, platinum-containing anticancer agents, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, prednimustine, benzylbenzylamine, sertenef, streptozocin, stramustine phosphate phosphate), retinoic acid, tasonermin, taxol, topotecan, tamoxifen, teniposide, taxanes, tegafur / uracil, vincristine, vinblastine, vinorelbine, vindesine, vindesine sulfate, and / or vinflunine.

[0457] Alternatively or in addition, the one or more chemotherapeutic agents may be selected from CD59 complementary fragments, fibronectin fragments, gro-β (CXCL2), heparinase, heparin hexasaccharide fragments, human chorionic gonadotropin (hCG), interferon α, interferon β, interferon γ, interferon-inducible protein (IP-10), interleukin-12, kringle 5 (plasminogen fragment), inhibitors of metalloproteinases (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitors, plasminogen activator inhibitors, platelet factor-4 (PF4), prolactin 16kD fragment, prolactin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-β (TGF-β), 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 may 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 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 may include agents that are capable of alkylating nucleophilic functional groups under conditions present in cells, including, for example, cancer cells. In some embodiments, the one or more alkylating agents are selected from cisplatin, carboplatin, dichloromethane diacetic 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 cells.

[0460] In some embodiments, the one or more antimetabolites may include agents 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, angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factors (tumstatin, canstatin or arrestin), anti-angiogenic antithrombin III and / or cartilage-derived inhibitor (CDI).

[0462] In some embodiments, the one or more alkaloids and / or terpenoids can provide microtubule function. In some embodiments, the one or more 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, paclitaxel, paclitaxel, 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 reverse transcription and / or replication of DNA by interfering with DNA supercoiling. In some embodiments, the one or more type I topoisomerase inhibitors may include camptothecin, which may be selected from exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and / or ST 1481. In some embodiments, the one or more class II topoisomerase inhibitors may include epipodophyllotoxin, which may be selected from amsacrine, 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 stilbenes are selected from resveratrol, piceatannol, pinosylvin, pterostilbene, α-glucose, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, epsilon-glucose, 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 may include cyclic dinucleotides, such as cAMP, cGMP, and cGAMP, and / or modified cyclic dinucleotides, which may include one or more of the following modification features: 2'-O / 3'-O linkages, phosphorothioate linkages, adenine and / or guanine analogs, and / or 2'-OH modifications (e.g., protection of the 2'-OH with a methyl group or replacement of the 2'-OH with -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 immunomodulators may include immune checkpoint inhibitors. Immune checkpoint inhibitors can target immune checkpoint receptors, 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, phosphatidylserine, lymphocyte activation gene 3 protein (LAG3), class I MHC, class II MHC, 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 receptor, ILT, leukocyte immunoglobulin receptor, 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 usurelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PD-L1), MEDI4736 (PD-L1), avelumab (a velumab) (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, polymycin, daptomy ... doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, and cefdiroxime cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftarolinefosamil, 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 cillin), oxacillin, penicillin G, penicillin V, piperacillin, temocillin, ticarcillin, calvulanate, ampicillin, subbactam, tazobactam, ticarcillin, clavulanate, subtilisin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid acid), norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethoxazole, 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] Typically, the mode of administration selected is that which is most suitable for the disorder, disease or condition to be treated or prevented.When one or more additional active agents are administered, the mode of administration may be the same or different from that of the compound, salt, solvate, prodrug or pharmaceutical composition of the invention.

[0478] For oral administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in the form of tablets, capsules, hard or soft gelatin capsules, caplets, lozenges or lozenges, as powders or granules, or as aqueous solutions, suspensions or dispersions.

[0479] Tablets for oral use may include active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrants, binding agents, lubricants, sweeteners, flavorings, coloring agents, and preservatives. Suitable inert diluents include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, and lactose. Corn starch and alginic acid are suitable disintegrants. Binding agents may include starch and gelatin. Lubricants (when present) may be magnesium stearate, stearic acid, or talc. When necessary, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and / or dissolving tablets.

[0480] Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent and soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0481] Powders or granules for oral use are provided in sachets or tubs. Aqueous solutions, suspensions or dispersions can be prepared by adding powders, granules or tablets.

[0482] Any form suitable for oral administration may optionally contain sweetening agents such as sugar, flavoring agents, coloring agents and / or preservatives.

[0483] Formulations for rectal administration may be presented as a suppository with a suitable base containing for example cocoa butter or a salicylate.

[0484] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0485] For parenteral use, the compounds, salts, solvates or prodrugs of the present invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride or dextrose. Aqueous solutions according to the present invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl pyrrolidone and tragacanth gum, as well as wetting agents such as lecithin. Suitable preservatives for aqueous suspensions include ethyl p-hydroxybenzyl ester and n-propyl p-hydroxybenzyl ester. The compounds of the present invention may also be provided as liposomal formulations.

[0486] For transdermal and other topical administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in the form of an ointment, poultice (catharsis), paste, powder, dressing, cream, plaster or patch.

[0487] Suitable suspensions and solutions may be used in an inhaler for administration to the airways (aerosol).

[0488] The dosage of the compounds, salts, solvates or prodrugs of the present invention will of course vary with the disorder, disease or condition to be treated or prevented. In general, a suitable dosage will be in the range of 0.01 to 500 mg per kilogram of recipient body weight per day. The desired dosage can be provided at appropriate intervals, such as once every other day, once a day, twice a day, three times a day or four times a day. The desired dosage can be administered in a unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.

[0489] For the avoidance of doubt, any embodiment of a given aspect of the present invention may be combined with any other embodiment of the same aspect of the present invention, as long as it is practicable. In addition, it will be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention, as long as it is practicable.

[0490] Example - Compound Synthesis

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

[0492] abbreviation

[0493] 2-MeTHF 2-Methyltetrahydrofuran

[0494] AcOH acetic acid

[0495] aq water-based

[0496] Boc tert-Butoxycarbonyl

[0497] br broad peak

[0498] Cbz carboxybenzyl

[0499] CDI 1,1-Carbonyl-diimidazole

[0500] conc

[0501] d Twin Peaks

[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 dimethoxyethylamine

[0508] DMF N,N-dimethylformamide

[0509] DMSO dimethyl sulfoxide

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

[0511] Et ethyl

[0512] EtOAc

[0513] EtOH

[0514] h hour

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

[0516] HPLC high-performance liquid chromatography

[0517] LC liquid chromatography

[0518] m multiplet

[0519] m-CPBA 3-Chloroperoxybenzoic acid

[0520] Me methyl

[0521] MeCN Acetonitrile

[0522] MeOH methanol

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

[0524] MHz Megahertz

[0525] min

[0526] MS

[0527] Ms methylsulfonyl, also known as methanesulfonyl

[0528] MsCl Methanesulfonyl chloride, also known as methanesulfonyl chloride

[0529] MTBE Methyl tert-butyl ether, also known as 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 known as N-bromosuccinimide

[0533] NCS 1-chloropyrrolidine-2,5-dione, also known as 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 Inverter

[0546] RT Room temperature

[0547] s single peak

[0548] Sept

[0549] sat saturation

[0550] SCX solid supported cation exchange resin

[0551] t Triplet

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

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

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

[0562] - Agilent MercuryPlus 300 instrument, equipped with a 7.05 Tesla magnet from Oxford instruments, a 4-core auto-switching probe and a Mercury Plus 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 an HP 6130MSD 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 (2.1×50 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 / G1956AMSD, an Agilent 1200G6110A, 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 driven by a Gilson-322 pump module, a Gilson-156 UV photometer detection unit and a Gilson-281 fraction collector.

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

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

[0583] Average particle size = 10 μm

[0584] The column was conditioned and then used with 100% acetonitrile (2 min) and then 5% acetonitrile (over 1.5 min). Flow rate = 25 mL / min.

[0585] Separate operation:

[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 wavelengths: 220 and 254 nm. Before each new run, clean the cartridge using the conditioning method.

[0588] Synthesis of intermediates

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

[0590]

[0591] At ambient temperature, to a solution of phosgene (4.45 mL, 20% by weight in toluene, 8.4 mmol) in EtOAc (90 mL) was added dropwise a solution of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienolphenyl-4-amine (589 mg, 3.4 mmol) in EtOAc (45 mL). The resulting reaction mixture was then heated to reflux for 3 hours, and after cooling, filtered and concentrated in vacuo to give the title compound (756 mg, 100% yield) as a brown oil. The crude product was used directly in the next step without further purification.

[0592] 1 H NMR (CDCl3): δ 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

[0593] Intermediate A2: 2-Isocyanoxy-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% by weight 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 partially cooled before being concentrated in vacuo to afford the title compound (1.5 g, >100% yield) as a mobile yellow oil. The crude product was used directly in the next step without further purification.

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

[0597] Intermediate A3: 5-Fluoro-2-isocyanato-1,3-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 phosgene solution (0.69 mL, 20% by weight 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 (0.110 g, 100% yield) as a brown oil. The crude product was used directly in the next step without further purification.

[0600] 1 H NMR (CDCl3): δ = 6.80 (d, 2H), 3.20 (m, 2H), 1.24 (d, 12H).

[0601] Intermediate A4: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine Step A: N-(5-bromo-2,3-dihydro-1H-inden-4-yl)trimethylacetamide (pivalamide)

[0602]

[0603] N-(2,3-Dihydro-1H-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 hours. The dark green mixture was diluted in EtOAc (20 mL) and then washed with saturated aqueous NaHCO3 solution (2×10 mL), water (2×10 mL) and brine (10 mL). The organic phase was dried (Na2SO4), 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 (1.662 g, 100%) as a colorless crystalline solid, which was contaminated with a small amount of reaction by-products.

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

[0605] Step B: 5-Bromo-2,3-dihydro-1H-inden-4-amine

[0606]

[0607] N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)trimethylacetamide (0.632 g, 2.134 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H2SO4 (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 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 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 (CDCl3) δ7.23 (d, J = 7.9 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 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-1H-inden-4-amine

[0610]

[0611] 5-Bromo-2,3-dihydro-1H-indene-4-amine (280 mg, 1.320 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (600 mg, 4.34 mmol) in water (1 mL) and (2-methoxypyridin-4-yl)boronic acid (250 mg, 1.635 mmol) were added. The mixture was degassed with nitrogen for 15 minutes, after which Pd(dppf)Cl2.DCM (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80°C (bath temperature) for 2 hours. The mixture was then cooled to room temperature and partitioned between DCM (30 mL) and water (20 mL). The organic phase was dried by passing through a hydrophobic glass frit and concentrated in vacuo to give a brown oil. The crude product was purified by silica gel chromatography (12 g column, 0-50% EtOAc / isohexane) to give the title compound (0.29 g, 87%) as a pale yellow crystalline solid.

[0612] 1 H NMR (CDCl3) δ 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-1H-inden-5-yl)2-cyanopyridine

[0615]

[0616] 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A4, Step C) was prepared from 5-bromo-2,3-dihydro-1H-inden-4-amine (Intermediate A4, Step B) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)2-cyanopyridine according to the general procedure to give the title compound (215 mg, 61%) as a light yellow solid.

[0617] 1 H(DMSO-d6)δ8.72(dd,J=5.1,0.8Hz,1H),8.03(dd,J=1.8,0.8Hz,1H),7.74(dd,J=5.1,1.8Hz,1H),6.91(d,J=7. 7Hz, 1H), 6.61 (d, J = 7.7Hz, 1H), 4.94 (s, 2H), 2.83 (t, J = 7.4Hz, 2H), 2.71 (t, J = 7.4Hz, 2H), 2.03 (p, J = 7.4Hz, 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] Under nitrogen atmosphere, 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 KCO (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H0 (40 mL) was added Pd(dppf)Cl (7.51 g, 10.26 mmol, 0.05 eq). The reaction mixture was then stirred at 80° C. for 5 h. The reaction mixture was quenched by the addition of H0 (600 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×600 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate 1:0 to 100:1) to give the title compound (27 g, 77% yield, 89% LCMS purity) as a yellow oil.

[0623] 1 H NMR(CDCl3) δ6.81-6.76(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-1-en-2-yl)aniline (21 g, 138.91 mmol, 1 equivalent) in MeOH (300 mL) was added Pd / C (2.1 g, 178.59 mmol, 10% by weight on activated carbon) under a nitrogen atmosphere. The reaction mixture was degassed in vacuo and purged with hydrogen several times. The reaction mixture was stirred at 25° C. under hydrogen (50 psi) for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (20 g, crude product) as a yellow oil.

[0628] 1 H NMR(CDCl3) δ6.86(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 equivalent) in toluene (250 mL) was added NBS (23.24 g, 130.55 mmol, 1 equivalent) at 25 ° C. The reaction mixture was stirred at 25 ° C for 10 minutes. The reaction mixture was poured into H2O (300 mL) and extracted with EtOAc (2 × 250 mL). The combined organic phases were washed with brine (2 × 400 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on a silica gel column (SiO2, eluted only with petroleum ether) to give the title compound (30 g, 99%) as a brown-black oil.

[0633] 1H NMR(CDCl3) δ6.99(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 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 2-cyanocyanide (3.60 g, 15.67 mmol, 1.01 equiv) in dioxane (90 mL) and H₂O (9 mL) was added Na₂CO₃ (4.11 g, 38.78 mmol, 2.5 equiv). Pd(dppf)Cl₂ (1.13 g, 1.55 mmol, 0.1 equiv) was then added to the mixture under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under nitrogen for 2 hours. The mixture was then concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate 20:1 to 5:1) 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 HNMR(CDCl3)δ8.79(d,1H),7.86(d,1H),7.65(dd,1H),6.99(dd,1H),6.70(dd,1H),3.63(br s,2H),2.98-2.87(m,1H) and 1.30(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 THF (40 mL) solution of 4-(2-amino-5-fluoro-3-isopropylphenyl)2-cyanopyridine (1 g, 3.92 mmol, 1 equivalent) was added TEA (793 mg, 7.83 mmol, 2 equivalents). Triphosgene (465 mg, 1.57 mmol, 0.4 equivalents) was added to the above mixture in batches at 5 ° C. The mixture was then stirred for 1 hour at 70 ° C. 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 product) 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 a nitrogen atmosphere. The reaction mixture was stirred at 80°C for 2 hours. 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 (SiO 2 , petroleum ether:ethyl acetate 70:1 to 10:1) and then triturated with hexanes (100 mL) to give the title compound (10.05 g, 72% yield, 96% LCMS purity).

[0646] 1 H NMR(CDCl3)δ8.24(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 THF (40 mL) solution of 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (1 g, 3.84 mmol, 1 equiv) was added TEA (777 mg, 7.68 mmol, 2 equiv). Triphosgene (456 mg, 1.54 mmol, 0.4 equiv) was then added in portions at 5 ° C. The mixture was stirred for 1 hour at 70 ° C. 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 product) 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) in portions at 0 ° C. The reaction mixture was then stirred at 16 ° C for 0.5 hours. 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 (CDCl3) 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-1H-inden-1-one (9.5 g, 63.27 mmol, 1 eq) in concentrated H2SO4 (100 mL) was added dropwise a solution of HNO3 (5.37 mL, 82.25 mmol, 69 wt% in water, 1.3 eq) in concentrated H2SO4 (20 mL) 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 and then extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (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 (CDCl 3 ) 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-1H-inden-1-ol

[0661]

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

[0663] 1 H NMR (CDCl3) 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-1H-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] At 25 ° C, to a solution of 7-fluoro-2,3-dihydro-1H-indene-4-amine (8.3 g, 54.90 mmol, 1 equivalent) in toluene (100 mL) was added NBS (10.26 g, 57.65 mmol, 1.05 equivalents) in one portion. The reaction mixture immediately turned dark brown, and then the mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was quenched with saturated aqueous Na2SO3 solution (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2, 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(CDCl3) δ6.99(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-1H-inden-4-amine

[0677]

[0678] Under a nitrogen atmosphere, to a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-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 H2O (5 mL) was added K2CO3 (6.31 g, 45.64 mmol, 3 eq) and Pd(dppf)Cl2 (1.11 g, 1.52 mmol, 0.1 eq) in one portion. The reaction mixture was then heated to 80 ° C for 12 hours. The reaction mixture was filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO 2 , 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 (CDCl3) 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-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

[0681]

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

[0683] Intermediate A10: 3-(5-Fluoro-2-isocyanato-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-1,3,2-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. Pd(dppf)Cl₂ (5.10 g, 6.97 mmol, 0.077 eq) was then added under a nitrogen atmosphere. 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 (2×800 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate 50:1 to 1:1) and then triturated with hexanes (40 mL) to give the title compound (17 g, 82%) as a grey solid.

[0687] 1 H NMR(CDCl3) δ8.70(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] At 5 ° C, triphosgene (257 mg, 868.51 μmol, 0.4 equivalent) was added in batches to a THF (10 mL) solution of 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (0.5 g, 2.17 mmol, 1 equivalent) and TEA (439 mg, 4.34 mmol, 2 equivalents). The reaction mixture was then heated to 70 ° C and stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was treated with EtOAc (100 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (0.2 g, crude product) as a yellow oil, which was used directly in the next step.

[0692] Intermediate A11: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

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

[0694]

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

[0696] 1 H NMR(CDCl3) δ8.23(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-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

[0698]

[0699] At ambient temperature, a toluene (20 mL) solution of 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (300 mg, 1.16 mmol) was added dropwise to a toluene (20 mL) solution of phosgene (1.5 mL, 20% by weight in toluene, 2.9 mmol) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, concentrated in vacuo to give the title compound (325 mg, 98%) as a brown oil. The crude product was used directly in the next step without further purification.

[0700] 1 H NMR(CDCl3)δ8.24(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-Isocyanoxy-2,3-dihydro-1H-inden-5-yl)2-cyanopyridine

[0702]

[0703] At ambient temperature, a solution of phosgene (1.7 mL, 20% by weight in toluene, 3.2 mmol) in toluene (40 mL) was added dropwise to a solution of 4-(4-amino-2,3-dihydro-1H-inden-5-yl)-2-cyanopyridine (Intermediate A5) (300 mg, 1.3 mmol) in toluene (20 mL). The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, concentrated in vacuo to give the title compound (333 mg, 100%) as a brown oil. The crude product was used directly in the next step without further purification.

[0704] 1 H NMR(CDCl3)δ8.75(dd,1H),7.81(dd,1H),7.63(dd,1H),7.22-7.08(m,2H),3.04(m,4H),2.23(m,2H).

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

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

[0707]

[0708] 5-Bromo-2,3-dihydro-1H-indene-4-amine (1.2 g, 5.7 mmol) was dissolved in dioxane (25 mL). 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) was added. The mixture was degassed with nitrogen for 20 minutes, after which Pd(dppf)Cl2.DCM (0.74 g, 0.91 mmol) was added. The reaction mixture was heated to 77 ° C for 2 hours. The mixture was then cooled to room temperature and filtered through celite with DCM (100 mL) and water (25 mL). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give a brown oil (3.3 g). The crude product was purified by silica gel chromatography (80 g column, 0-100% EtOAc / heptane) to give the title compound (0.75 g, 63%) as a light yellow crystalline solid.

[0709] 1 H NMR(CDCl3)δ8.72-8.54(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-Isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

[0711]

[0712] At ambient temperature, a toluene (20 mL) solution of 5-(pyridin-4-yl)-2,3-dihydro-1H-indene-4-amine (175 mg, 0.83 mmol) was added dropwise to a toluene (40 mL) solution of phosgene (1.1 mL, 20% by weight in toluene, 2.06 mmol). The resulting mixture was then heated to reflux for 70 minutes, and after cooling to room temperature, a yellow precipitate was formed. The solid was filtered and dried in vacuo to give the title compound (145 mg, 74%) as a yellow solid. The crude product was used directly in the next step without further purification.

[0713] 1 H NMR(CDCl3)δ8.76(d,2H),8.04(d,2H),7.26-7.08(m,2H),3.08(t,4H),2.26(m,2H).

[0714] Intermediate A14: 8-Isocyanoxy-1,2,3,5-tetrahydro-s-dicyclopentadienyl acene

[0715]

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

[0717] 1 H NMR (CDCl3) (mixture of isomers) δ 7.18, 7.12 (m, 1H), 6.94, 6.80 (m, 1H), 6.52, 6.50 (s, 1H), 3.38, 3.34 (m, 2H), 2.95 (m, 4H), 2.16 (m, 2H).

[0718] Intermediate A15: 5-Chloro-2-isocyanato-1,3-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 phosgene solution (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 (0.111 g, 94%) as an orange oil.

[0721] 1 H NMR(CDCl3)δ7.07(d,2H),3.17(h,2H),1.24(d,12H).

[0722] Intermediate P3: 1-(Propan-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-bromopropyne (0.1 mL, 1.0 mmol, 1.0 equiv). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and the crude material was suspended 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 (115 mg, 56%).

[0725] 1 H NMR (CDCl3): δ4.42(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 overnight at room temperature, the reaction mixture was concentrated in vacuo. The crude product was suspended 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 trimethylamine-methanol (ratio 1:1) to afford the title compound (61 mg, 23% yield).

[0729] 1 H NMR (CDCl3): δ4.73(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-sulfamoylpiperidine-1-carboxamide

[0731]

[0732] To a suspension of piperidine-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 overnight at room temperature, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, applied to an 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 the eluent to give the title compound (55 mg, 22% yield).

[0733] 1 H NMR (CDCl3): δ4.45(br s,1H), 4.22(m,1H), 4.10(d,2H), 3.98(m,1H), 3.10(m,1H), 2.81(t,2H), 2.20(d,2H), 1.80(m,2H) and 1.19(d,6H).

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

[0735]

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

[0737] 1 H NMR (CDCl3): δ5.05(br s,2H), 3.10(m,2H), 2.95(m,1H), 2.45(m,2H), 2.20(d,2H), 1.95(m,4H) and 1.08(t,3H).

[0738] Intermediate P7: 1-Acetylpiperidine-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-Propionylpiperidine-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-Isobutyrylpiperidine-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 (CDCl3): 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 (CDCl3): 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: Methyl 4-sulfamoylpiperidine-1-carboxylate

[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 (CDCl3): 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, applied to a hydromatrix, and then purified by normal phase flash chromatography using a mixture of dichloromethane and trimethylamine-methanol (1:1) as the eluent to afford the title compound (110 mg of product, 64% yield), contaminated with trimethylamine hydrochloride.

[0769] 1 H NMR (CDCl3): 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, after which 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 (1:1CD3OD:CDCl3): δ3.36(m,2H), 3.10(m,1H), 2.92(bd,1H), 2.56(q,2H), 2.22(bd,1H), 2.11(t,1H), 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 afforded the impure title compound (44 mg, 40% yield) which was used without purification.

[0777] 1 H NMR (CDCl3): δ = 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-(Oxetane-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: Methyl 2-(4-sulfamoylpiperidin-1-yl)acetate

[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 from piperidine-4-sulfonamide hydrochloride as described for 1-cyclopropylpyrrolidine-3-sulfonamide (Intermediate P30), and triethylamine (1.1 eq) was added to the suspension. This gave the title compound (150 mg, 73% yield), which was used as is 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. Acetaldehyde (0.03 mL, 25 mg, 0.6 mmol) and sodium triethoxyborohydride (122 mg, 0.56 mmol) were added thereto. Stirring was continued for 20 hours, and the mixture was then concentrated in vacuo. The residue was dissolved in methanol / dichloromethane (1: 1) and purified by chromatography (40 g Silicycle SiO2 cartridge, passed through a syringe filter, and eluted with 5-30% 3.5N ammonia in methanol / dichloromethane) to give the title compound (73 mg, 0.28 mmol, 63% yield).

[0793] 1 H NMR (DMSO-d6): δ = 6.71 (br s, 2H), 3.49 (m, 4H), 2.89 (m, 3H), 2.77 (m, 3H), 1.95 (br d, 2H), 1.77 (m, 2H), 1.57 (dq, 2H) and 0.89 (t, 3H).

[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(CDCl3): 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-sulfamoylpiperidine-1-carboxamide

[0799]

[0800] To a suspension of piperidine-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 and then concentrated in vacuo. The crude product was applied to an Agilent Hydromatrix and subjected to normal phase flash silica gel chromatography using a mixture of dichloromethane, methanol, and triethylamine (ratio 1:1) to afford the title compound (141 mg, 60% yield), which was used without further purification.

[0801] 1 H NMR (DMSO-d6): δ = 6.78 (br s, 2H), 4.04 (d, 2H), 2.98 (m, 3H), 2.64 (t, 2H), 1.91 (d, 2H), 1.39 (m, 2H) and 0.98 (t, 3H).

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

[0803]

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

[0805] 1 H NMR (CDCl3): 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 piperidine-4-sulfonamide hydrochloride and methanesulfonic anhydride. The title compound (18 mg, 7% yield) 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 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-Isopropyl-3-sulfamoylpiperidine-1-carboxamide

[0815]

[0816] Prepared as described for N-isopropyl-4-sulfamoylpiperidine-1-carboxamide (Intermediate P5) from isopropyl isocyanate and piperidine-3-sulfonamide hydrochloride 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-(ethoxycyclopropyloxy)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 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 eluent to afford the title compound (75 mg, 39% yield).

[0833] 1 H NMR(DMSO-d6): δ=6.79(s,2H),3.57(m,1H),2.98(t,1H),2.80(t,1H),2.7 1(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 carbonyldiimidazole (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 stirred at room temperature for 1.5 hours 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 hours before additional triethylamine (0.3 mL, 2.0 mmol, 1.2 equiv) was added to the suspension. After stirring overnight, more carbonyldiimidazole (269 mg, 1.66 mmol, 1.0 equiv) and 2M dimethylamine in tetrahydrofuran (0.83 mL, 1.66 mmol, 1.0 equiv) were added. The reaction mixture was heated to 50 ° C overnight, and 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 heated again overnight. After cooling, the reaction mixture was concentrated in vacuo. The crude material was dissolved in methanol, applied to a hydromatrix, and then 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 still not completely pure title compound (35 mg, 15% yield). The product was used in this way.

[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 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: Benzyl 3-sulfamoylazetidine-1-carboxylate

[0844]

[0845] A solution of ammonium hydroxide (25% in water; 22 mL, 73 mmol, 10.0 equiv) was added to benzyl 3-(chlorosulfonyl)azetidine-1-carboxylate (2.1 g, 7.3 mmol, 1.0 equiv). The suspension was stirred at room temperature for 20 minutes to give a clear solution, and the resulting mixture was then acidified to pH 8-9 using hydrochloric acid (2 M, aqueous solution) and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and 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 (CDCl3): δ = 7.38 (m, 5H), 5.18 (s, 4H), 4.40 (m, 4H) and 4.00 (m, 1H).

[0847] Step B: Azetidine-3-sulfonamide

[0848]

[0849] A suspension of benzyl 3-sulfamoylazetidine-1-carboxylate (1.52 g, 5.62 mmol, 1.0 eq) in ethyl acetate (30 mL) was flushed with a stream of nitrogen, followed by the addition of Pd / C (10 wt% loading, 595 mg, 0.56 mmol, 0.1 eq) and 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 passed through 545 was filtered and the celite was washed thoroughly with methanol. The filtrates were combined and concentrated in vacuo to give the title compound (541 mg, 3.97 mmol, 70% yield), which was used without further purification.

[0850] 1 H NMR (DMSO-d6): δ = 6.91 (br s, 2H), 4.08 (m, 1H), 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 equiv) in tetrahydrofuran (64 mL) cooled in an ice bath was added diisopropyl azodicarboxylate (3.1 mL, 15.7 mmol, 2.0 equiv). 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 equiv) was added, followed by thioacetic acid (1.2 mL, 15.7 mmol, 2.0 equiv), the ice bath was then 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, 40% yield).

[0855] 1 H NMR (CDCl3): 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: Quinuclidine-3-sulfonamide

[0857]

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

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

[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: tert-Butyl (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0866]

[0867] To a mixture of tert-butyl 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (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 and 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 (CDCl3): 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: tert-Butyl (1R*,3R*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0870]

[0871] To a solution of tert-butyl (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (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 hour and 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 (over 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 (CDCl3): δ = 4.20 (br s, 2H), 3.98 (t, 1H), 2.42 (br s, 2H), 2.28 (s, 3H), 1.98 (m, 4H), 1.64 (m, 2H) and 1.44 (s, 9H).

[0873] Step C: tert-Butyl (1R*,3R*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate

[0874]

[0875] To a solution of tert-butyl (1R*,3R*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate (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 hour and then concentrated to approximately 20-30 mL. The resulting solution was then added dropwise to ammonium hydroxide solution (25 wt% in water; 400 mL) and stirred at room temperature for 10 minutes. The solution was then acidified to pH 7-8 with hydrochloric acid (aqueous solution, 1 M) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the impure title compound (387 mg, 12% yield), which was used without further purification.

[0876] 1 H NMR (CDCl3): 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 tert-butyl (1R*,3R*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate (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 hours. The solvent was then decanted, and dichloromethane was added, followed by further decanting. This afforded 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 eluents to give the title compound as a heterogeneous product (22 mg, 21% yield) 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'-bipiperidinyl]-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. 1-Ethyl-4-piperidone (0.21 g, 0.23 mL, 1.6 mmol) and sodium triethoxyborohydride (0.43 g, 2.0 mmol) were added. Stirring was continued for 20 hours, after which the solution was concentrated in vacuo. The crude material was suspended in a few mL of dichloromethane / methanol / 7N ammonia in methanol (1:1:1) and purified by chromatography (40 g Silicycle SiO2 cartridge, syringe filter, eluting with 5-30% 3.5N ammonia in dichloromethane / methanol) to afford 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 flash chromatography on normal phase silica gel 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: tert-Butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0899]

[0900] To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (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 hours, then washed with water and brine, dried (sodium sulfate), filtered, and evaporated to give the title compound as a white solid (2.7 g, 100% yield).

[0901] 1 H NMR (CDCl3): 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: tert-Butyl 6-(acetylthio)-2-azaspiro[3.3]heptane-2-carboxylate

[0903]

[0904] To a solution of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (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 hours and poured into water (200 mL) and ethyl acetate (100 mL) after cooling. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (4×) and brine, then dried (sodium sulfate), filtered and evaporated in vacuo to give the title compound (1 g, 100% yield) as a brown oil.

[0905] 1 H NMR (CDCl3): δ = 3.96 (s, 2H), 3.90 (m, 1H), 3.86 (s, 2H), 2.65 (m, 2H), 2.27 (s, 3H), 2.18 (m, 2H) and 1.42 (s, 9H).

[0906] Step C: tert-Butyl 6-sulfamoyl-2-azaspiro[3.3]heptane-2-carboxylate

[0907]

[0908] A mixture of tert-butyl 6-(acetylthio)-2-azaspiro[3.3]heptane-2-carboxylate (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 in portions over a 10-minute period. The reaction mixture was then stirred at room temperature for 1 hour before being poured into a 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 ground in tetrahydrofuran and decanted. The combined tetrahydrofuran layer was evaporated, and the residue was purified via silica using dichloromethane / methanol (9: 1) as eluent. The title compound (240 mg, 36% yield) was obtained as a white foam.

[0909] 1 H NMR (CDCl3): 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 tert-butyl 6-sulfamoyl-2-azaspiro[3.3]heptane-2-carboxylate (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 was evaporated. The residue was dissolved in methanol and purified over Amberlite 410 ion exchange resin to give the title compound (100 mg, 67% yield) as a pale yellow oil.

[0913] 1 H NMR (CD3OD): δ = 3.93 (s, 4H), 3.66 (m, 1H) and 2.64 (m, 4H).

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

[0915]

[0916] Following the procedure described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (intermediate P3), it was 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 obtain the product in 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, 15% yield).

[0917] 1 H NMR (CD3 OD): δ = 3.67 (m, 1H), 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-sulfamoylpyrrolidin-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 hours and then concentrated in vacuo to afford the title compound as a dihydrochloride salt (774 mg, 2.38 mmol, 100% yield), which was used without purification.

[0922] 1 H NMR (DMSO-d6): δ = 9.60 (br s, 1H), 9.17 (br s, 1H), 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 from 1-(azetidin-3-yl)pyrrolidine-3-sulfonamide dihydrochloride and acetone as described for 1-cyclobutylpiperidine-4-sulfonamide (intermediate P14), but requiring 2.5 equivalents of 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 (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),2.9 0(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 from azetidine-3-sulfonamide (Intermediate P33) and ethyl iodide as described for 1-ethylpiperidine-4-sulfonamide (Intermediate P6). This afforded the impure title compound (15 mg, 9% yield) which was used without further purification.

[0934] 1H NMR (CD3OD): δ = 4.11 (m, 1H), 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)pyrrolidine-3-sulfonamide

[0936]

[0937] Prepared from pyrrolidine-3-sulfonamide and bis-trifluoroacetic anhydride as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4). This afforded the title compound (72 mg, 36% yield) which was used without purification.

[0938] 1 H NMR (CD3OD): δ = 4.08 (m, 1H), 3.91 (m, 3H), 3.63 (m, 1H), 2.45 (m, 1H) and 2.38 (m, 1H).

[0939] Intermediate P45: 1-(Cyclopropylmethyl)piperidine-3-sulfonamide

[0940]

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

[0942] 1 H NMR (CDCl3): δ=3.41(br d,1H),3.31(m,1H),2.96(br d,1H), 2.44(t,1H), 2.36(d,2H), 2.20(m,2H), 1.91(m,1H), 1.71(m,2H), 0.90(m,1H), 0.57(m,2H) and 0.15(m,2H).

[0943] Intermediate P46: 1-Methylpiperidine-3-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). The crude product was used without further purification.

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

[0947] Intermediate P47: Benzyl 3-sulfamoylazetidine-1-carboxylate

[0948]

[0949] To a stirred solution of benzyl 3-(chlorosulfonyl)azetidine-1-carboxylate (2.0 g, 6.9 mmol) in dichloromethane (30 mL) at 0° C. was added ammonia (7N 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) and 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, 1H).

[0951] Intermediate P48: N,N-Dimethyl-4-sulfamoylpiperidine-1-carboxamide

[0952]

[0953] To a solution of carbonyldiimidazole (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 piperidine-4-sulfonamide hydrochloride (200 mg, 1.0 mmol) were added to the suspension. The reaction mixture was stirred overnight, and additional portions of carbonyldiimidazole (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) were added. After stirring overnight, 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 before being transferred to a microwave vial and 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, applied to a hydromatrix, and then purified by normal phase flash chromatography using a mixture of dichloromethane and triethylamine to methanol (ratio 1:1) as eluents to give the title compound (73 mg, 31% yield).

[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: tert-Butyl 3-(4-sulfamoylpiperidin-1-yl)azetidine-1-carboxylate

[0957]

[0958] 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), 2 equivalents of triethylamine were used to prepare the crude compound. 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 (236 mg, 47% yield) as a white waxy solid.

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

[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, 1H), 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] Tert-butyl 3-(4-sulfamoylpiperidin-1-yl)azetidine-1-carboxylate (0.23 g, 0.7 mmol) from step A was suspended in HCl (4N, 9 mL, 36 mmol) in dioxane and stirred at ambient temperature for 20 hours. The solvent was evaporated in vacuo, and the residue was stripped once with dioxane (25 mL) to give the crude product (250 mg, equivalent yield), which was used in the next step.

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

[0965] 1 H NMR (methanol-d4): δ = 4.72-4.57 (m, 2H), 4.44-4.28 (m, 3H), 3.61 (d, J = 11.7 Hz, 2H), 3.26 (dd, J = 11.1, 4.2 Hz, 2H), 3.01 (s, 1H), 2.44 (dd, J = 14.3, 3.1 Hz, 2H), 2.24 (t, 1H), 1.61 (s, 1H).

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

[0967]

[0968] Prepared from 1-(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride of step B (100 mg, 0.31 mmol) and acetone (0.03 mL, 22 mg, 0.39 mmol) following the procedure as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) to give the title compound as a white solid (70 mg, 87% yield) 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=6.5Hz, 2H), 3.02-2.82 (m, 6H), 2.49 (h, J=6.2Hz, 1H), 2.13 (ddd, J=12.0, 4.2, 2.2Hz, 2H), 1.88 (dd, J=11.3, 2.1Hz, 2H), 1.77 (qd, J=12.1, 3.5Hz, 2H), 0.97 (d, J=6.3Hz, 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 eq) in acetonitrile (5 mL) was added sodium triethoxyborohydride (89 mg, 0.43 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 18 hours and 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 was evaporated. The residue was triturated in THF. The mixture was filtered and the THF was evaporated to give the title compound (40 mg, 65% yield), 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 eq) in acetonitrile (5 mL) was added sodium triethoxyborohydride (90 mg, 0.43 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 18 hours and 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 was evaporated. The residue was triturated in THF. The mixture was filtered and the THF was 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-(Pent-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 as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 1,2,3,4-tetrahydroquinoline-3-sulfonamide, acetone, and acetic acid, but without triethylamine. The title compound (27 mg, 11% yield) was used without further purification. The expected isopropyl analog 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] 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (65 mg, 0.22 mmol) of step A was dissolved in THF (3.25 mL) and cooled to 0 ° C. Borane-DMS-adduct (94%, 9.9 M, 0.10 mL, 1.01 mmol) was added dropwise to this solution at 0 ° C. The mixture was then heated to reflux for 4 hours and then allowed to cool to room temperature over the weekend. This mixture was quenched with MeOH until no more gas evolution was apparent, then evaporated in vacuo and stripped twice with methanol. Drying in vacuo gave the crude product as a clear oil (with a slight DMS odor), which was purified by ISCO 5-30% MeOH (3.5 N NH 3) in DCM to give the title compound (31 mg, 56% yield).

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

[0998] 1 H NMR (methanol-d4): δ = 3.16-3.00 (m, 4H), 2.88 (tt, J = 12.2, 3.8Hz, 1H), 2.42 (td, J = 12.0, 2.5Hz, 2H), 2.0 8(dt,J=13.1,2.9Hz,2H),1.80(qd,J=12.4,4.1Hz,2H),1.17(t,J=7.1Hz,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: tert-Butyl (1R*,3R*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

[1001]

[1002] Prepared as for tert-butyl (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate P36 Step A) from tert-butyl 3-endo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate 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 tert-butyl (1R*,3S*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate to give the title compound (203 mg, quantitative yield).

[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 a mixture of dichloromethane and 7M ammonia in methanol to give the title compound (15 mg, 16% yield), 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, 34% yield) which was used without further purification.

[1023] 1H NMR (CD3OD): δ = 4.10 (m, 1H), 4.00 (m, 1H), 3.53 (m, 1H), 3.08 (m, 2H), 2.58 (m, 1H), 2.24 (m, 5H), 2.02 (m, 2H), 1.34 (m, 3H).

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

[1025]

[1026] Prepared as 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, 25% yield) 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 from azetidine-3-sulfonamide hydrochloride and 1-ethyl-4-piperidone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14).The title compound (111 mg, 44% yield) was used without further purification.

[1031] 1 H NMR(DMSO-d6): δ=6.88(s,2H),3.85(m,1H),3.42(t,2H),3.22(t,2H),2.71(m,2H ),2.27(q,2H),2.02(m,1H),1.87(m,2H),1.57(dd,2H),1.09(m,2H),0.95(t,3H).

[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, 20% yield) was used without further purification.

[1035] 1 H NMR (CD3OD): δ = 4.57 (m, 1H), 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, 50% yield) was used without further purification.

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

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

[1041]

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

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

[1044] Intermediate P62: tert-Butyl 3-sulfamoylazetidine-1-carboxylate

[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 (maximum 37.9 mmol) in dichloromethane (600 mL) was added 7 M ammonia in methanol (55 mL, 379 mmol, 10 equivalents). 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, applied to a hydromatrix, and subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5 M) in methanol as eluents to afford 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: Methyl 2-(3-sulfamoylazetidin-1-yl)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, 1H), 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 2-bromo-4-chloro-N-isopropylbutanamide (19 g, 78.34 mmol, 1 eq) in THF (200 mL) at 0°C was added NaH (6.27 g, 156.67 mmol, 60% purity, 2 eq). The mixture was stirred at 25°C for 1 hour. The reaction mixture was then quenched with H₂O (200 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate, 20:1 to 1:1) to give the title compound (11.5 g, 55.80 mmol, 71% yield).

[1072] 1 H NMR (CDCl3): 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: Methyl 3-((1-isopropyl-2-oxopyrrolidin-3-yl)sulfonyl)propanoate

[1074]

[1075] To a solution of 3-bromo-1-isopropylpyrrolidin-2-one (1 g, 4.85 mmol, 1 eq) in DMSO (10 mL) was added sodium 3-methoxy-3-oxo-propane-1-sulfinate (845 mg, 4.85 mmol, 1 eq). The mixture was stirred at 25°C for 16 hours. 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 Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 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 (CDCl3): δ=4.37-4.33(m,1H),3.97-3.93(m,1H),3.82-3.72(m,5H),3.58-3.51(m,1H), 3.39-3.38(m,1H),2.94-2.90(m,2H),2.77-2.73(m,1H),2.44-2.34(m,1H)and1.18(d,6H).

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

[1078] Step E: Sodium 1-isopropyl-2-oxopyrrolidine-3-sulfinate

[1079]

[1080] To a solution of methyl 3-((1-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 a solution of NaOMe in MeOH (6.2 M, 1.05 mL, 3 eq) at 25° C. The mixture was stirred at 25° C. for 3 hours. The reaction mixture was then concentrated in vacuo 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: 1-Isopropyl-2-oxopyrrolidine-3-sulfonamide

[1084]

[1085] At 0 ° C, to a solution of sodium 1-isopropyl-2-oxopyrrolidine-3-sulfinate (461 mg, 2.16 mmol, 1 equivalent) in DMSO (6 mL) was added (aminooxy)sulfonic acid (1.22 g, 10.82 mmol, 5 equivalents) and AcONa (709 mg, 8.65 mmol, 4 equivalents) in H2O (2 mL). The mixture was warmed to 25 ° C and stirred at 25 ° C for 16 hours. The reaction mixture was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated in vacuo. The residue was purified by preparative 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, then applied to a silica column (40 g) and eluted with 0-30% methanol in DCM to give the title compound (93 mg, 43% yield).

[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=7.8Hz,1H),3.91(dd,J=8.6,5.1Hz,1H),3.81(dd,J=9.7,7.2Hz,1H),3.61(dd,J= 9.8,5.1Hz,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=12.9,3.5Hz,2H).

[1093] Intermediate P66: 1-(1-Methylazetidin-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 for 20 hours at ambient temperature, and the mixture was then concentrated in vacuo. The residue was dissolved in 3.5 N ammonia in methanol and applied to a silica cartridge (40 g, silicycle). The title compound (65 mg, 38% yield) was separated by elution with a 0-30% gradient of 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=13.0,3.5Hz,2H),1.81-1.67(m,3H),1.56(qd,J=12.2,3.9Hz,2H).

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

[1099]

[1100] Prepared from pyrrolidine-3-sulfonamide and 3-pentanone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14), but without 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, 64% yield) 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, 42% yield) 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 in a microwave at 110 ° C for 30 minutes and then concentrated in vacuo. The crude material was suspended in methanol and filtered. The filtrate was 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 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 hours. 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-Difluoropropan-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, 26% yield) 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, 20% yield) 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-aldehyde 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-sulfamoylazetidin-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 equiv) 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 as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and chloroacetaldehyde (approximately 50 wt% in H 2 O). The title compound (100 mg, 50% yield) was used without further purification.

[1145] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.92 (m, 1H), 3.53 (m, 4H), 3.36 (t, 2H), 2.73 (t, 2H).

[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, 1H), 3.39 (t, 2H), 3.30 (m, 2H), 3.09 (q, 1H), 1.87 (m, 2H), 1.67 (m, 4H).

[1150] Intermediate P80: 1-Isopropyl-N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide Step A: 4-Nitrobenzyl 2-(dimethylcarbamoyl)-4-sulfamoylpyrrolidine-1-carboxylate

[1151]

[1152] A suspension of 4-nitrobenzyl 2-(dimethylcarbamoyl)-4-mercaptopyrrolidine-1-carboxylate (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 equiv) was added portionwise over a 5 minute period. The mixture was stirred for another hour at room temperature. The reactants were then poured into ammonia (50 mL, 25% aqueous solution). The resulting solution was stirred for 18 hours at room temperature. 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) was added. - ) (20 g). After stirring for 18 hours, the mixture was filtered and evaporated to give the title compound (610 mg, 54% yield) as an oil which crystallized upon standing.

[1153] 1 H NMR (CD3OD): δ = 8.20 (m, 2H), 7.62 (d, 1H), 7.53 (d, 1H), 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] 4-Nitrobenzyl 2-(dimethylcarbamoyl)-4-sulfamoylpyrrolidine-1-carboxylate (610 mg, 1.53 mmol) was dissolved in methanol (10 mL). Palladium (47 mg, 10% on charcoal) was added, and the mixture was stirred under a hydrogen atmosphere (balloon) for 18 hours. The mixture was filtered through celite and evaporated. The residue was purified by reverse phase silica to give a white solid (0.5 g), which was triturated with THF. The THF layer was decanted and evaporated to give the title compound as a white solid (350 mg, 100% yield).

[1157] 1 H NMR (CD3OD): δ = 3.79-3.55 (m, 4H), 3.00 (m, 6H), 1.90 (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 over silica to give the title compound as an oil (10 mg, 10% yield).

[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-sulfonyl chloride (150 mg, 0.71 mmol) was dissolved in THF (3 mL) at 4°C and added dropwise to ammonia (25% aqueous solution, 5 mL). 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 (30 mg, 22% yield) as a brown oil.

[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: 1-(tert-Butyl)azetidin-3-yl methanesulfonate

[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 minutes, 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 hour while warming to room temperature. The solvent was then removed by evaporation in vacuo. The crude product was dissolved in methanol, coated on 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 give the title compound (456 mg, 37% yield).

[1170] 1 H NMR (CDCl3): δ = 5.10 (m, 1H), 3.74 (m, 2H), 3.47 (m, 2H), 3.02 (s, 3H), 1.04 (s, 9H).

[1171] Step B: S-(1-(tert-butyl)azetidin-3-yl)thioacetate

[1172]

[1173] To a solution of 1-(tert-butyl)azetidin-3-yl methanesulfonate (269 mg, 1.3 mmol) in acetonitrile (20 mL) was added potassium thioacetate (447 mg, 3.9 mmol, 3 equivalents). The reaction mixture was stirred at room temperature overnight and then stirred at 50 ° C for another 7 hours. The solvent was removed by evaporation in vacuo. The crude product was dissolved in methanol, coated on 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 give the title compound (90 mg, 37% yield).

[1174] 1 H NMR (CDCl3): δ = 4.15 (m, 1H), 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, 71% yield) 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-Azidoethyl)azetidine-3-sulfonamide

[1188]

[1189] To a solution of 1-(2-chloroethyl)azetidine-3-sulfonamide (45mg, 0.22mmol, 1.0 equivalent) in acetonitrile (5mL) was added sodium azide (14mg, 0.22mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature over the weekend. Additional sodium azide (56mg, 0.88mmol, 4.0 equivalent) was added, and the reaction mixture was heated to 50°C. After stirring overnight, water (0.4mL) was added, and the reaction mixture was stirred for another 2 days. The solution was concentrated in vacuo. The residue was suspended in methanol, filtered, and the filtrate was concentrated in vacuo to obtain the crude title compound (45mg, 0.22mmol, 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 cyclohexanone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14).The title compound (218 mg, equivalent yield) was used without further purification.

[1202] 1 H NMR (DMSO-d6): δ = 6.86 (s, 2H), 3.83 (p, 1H), 3.41 (t, 2H), 3.21 (dd, 2H), 2.00 (m, 1H), 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, 1H), 3.41 (t, 2H), 3.18 (m, 2H), 2.72 (m, 1H), 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 ethyl imide hydrochloride (123 mg, 1.0 mmol, 1.0 equiv). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude compound (approximately 300 mg) was dissolved in water / methanol (1:1 ratio) (3 mL). 1 mL of this solution was purified by reverse phase flash chromatography to give the title compound (30 mg, 9% yield).

[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-(Oxetane-3-ylmethyl)azetidine-3-sulfonamide

[1212]

[1213] Prepared from azetidine-3-sulfonamide hydrochloride and 3-oxetanecarboxaldehyde as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14).The title compound (156 mg, 75% yield) 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 dimethyl sulfide (0.16 mL, 1.63 mmol, 1.3 equiv). The reaction mixture was refluxed overnight and 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 equiv), followed by the addition of sodium triethoxyborohydride (688 mg, 3.25 mmol, 2.6 equiv). The reaction mixture was stirred at room temperature overnight and then 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 (28 mg, 14% yield).

[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, 57% yield) 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, 86% yield) was used without further purification.

[1226] 1 H NMR (DMSO-d6): δ=8.46(dd,1H),7.73(td,1H),7.32(d,1H),7.24(m,1H),6.95(s,2H),3.94(tt,1H),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, 45% yield) was used without further purification.

[1230] 1 H NMR (DMSO-d6): δ=8.27(dd,1H),7.79(dd,1H),7.44(dd,1H),7.02(s,2H),3.97(m,1H),3.67(s,2H),3.61(t,2H),3.49(dd,2H).

[1231] Intermediate P96: tert-Butyl 3-sulfamoyl-[1,3'-diazetidine]-1'-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, 24% yield) was used without further purification.

[1234] 1 H NMR (DMSO-d6): δ = 6.95 (s, 2H), 3.92 (m, 1H), 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'-azetidine]-3-sulfonamide

[1236] Step A: [1,3'-Azetidine]-3-sulfonamide dihydrochloride

[1237]

[1238] To a solution of tert-butyl 3-sulfamoyl-[1,3'-diazetidine]-1'-carboxylate (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 hours, 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, 1H), 9.18 (bs, 1H), 7.42 (s, 2H), 4.57-4.31 (m, 3H), 4.31-4.00 (m, 8H).

[1240] Step B: 1'-Methyl-[1,3'-azidetidine]-3-sulfonamide

[1241]

[1242] Prepared from [1,3'-azide]-3-sulfonamide dihydrochloride as described for 1-methylazetidine-3-sulfonamide (Intermediate P39).The title compound (63 mg, 61% yield) was used without further purification.

[1243] 1 H NMR (CD3OD): δ=4.10-3.94(m,1H), 3.75-3.60(m,4H), 3.59-3.51(m,2H), 3.51-3.44(m,1H), 3.41-3.32(m,2H), 2.55(s,3H).

[1244] Intermediate P98: 1-(2-(Methylthio)ethyl)azetidine-3-sulfonamide

[1245]

[1246] To 0.5M hydrochloric acid in water (6.0mL, 3.0mmol) was added (methylthio)acetaldehyde dimethylformaldehyde (0.4mL, 3.0mmol). After heating the reactants at 50°C for 1 hour, the reaction mixture was cooled to room temperature and then extracted with dichloromethane (10mL). The organic layer was added to a suspension of azetidine-3-sulfonamide hydrochloride (172mg, 1.0mmol) and triethylamine (0.17mL, 1.2mmol) in acetonitrile. Thereafter, sodium triethoxyborohydride (265mg, 1.25mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude product was dissolved in methanol, coated on an Agilent hydromatrix (high purity, inert diatomaceous earth sorbent), and then subjected to normal phase flash chromatography using a mixture of dichloromethane and ammonia (3.5M) in methanol to obtain the title compound (89mg, 42% yield).

[1247] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.89 (p, 1H), 3.49 (t, 2H), 3.33-3.25 (m, 2H), 2.59 (dd, 2H), 2.37 (dd, 2H), 2.03 (s, 3H).

[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-(Thietan-3-yl)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-diazirin-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-diazirine (0.8 equiv) as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3), except using a more dilute solution (0.02 M solution). 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: tert-Butyl (Z)-(((tert-Butoxycarbonyl)amino)(3-sulfamoylazetidin-1-yl)methylene)carbamate

[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-thiopseudurea (290 mg, 1.0 mmol) in acetonitrile (10 mL) was added mercuric 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, 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 afford the title compound (216 mg, 57% yield).

[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-Methylcyclobutyl)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, 39% yield) 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, 44% yield) 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-carbaldehyde 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,4 H),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-carbaldehyde 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 2,2-dimethylcyclobutanone as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14).The title compound (24 mg, 11% 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: tert-Butyl (E)-(((tert-Butoxycarbonyl)imino)(3-sulfamoylazetidin-1-yl)methyl)(methyl)carbamate

[1293] Step A: 1-Methyl-1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea

[1294]

[1295] A solution of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (435 mg, 1.5 mmol) in dimethylformamide (5 mL) was cooled to 0°C in a cooling bath, followed by the addition of sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol). The cooling bath was removed. After stirring at room temperature for 1 hour, methyl iodide (0.19 mL, 3.0 mmol) was added. After stirring overnight, the reaction mixture was poured into water and extracted once with dichloromethane and once with ethyl acetate. The organic layers were combined, washed twice with water and once with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo to afford the title compound (230 mg, 50% yield), which was used without further purification.

[1296] 1 H NMR (CDCl3): δ = 3.12 (s, 3H), 2.39 (s, 3H), 1.51 (s, 9H), 1.48 (s, 9H).

[1297] Step B: tert-Butyl (E)-(((tert-Butoxycarbonyl)imino)(3-sulfamoylazetidin-1-yl)methyl)(methyl)carbamate

[1298]

[1299] Prepared from tert-butyl (Z)-(((tert-butoxycarbonyl)amino)(3-sulfamoylazetidin-1-yl)methylene)carbamate (Intermediate P102) from 1-methyl-1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea, except that water was added to the reaction mixture after stirring over the weekend. 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 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 (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 cyclobutanecarbaldehyde 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 as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and chloroacetone to give the title compound (125 mg, 21% yield).

[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] 1- (2- oxopropyl) azetidine -3- sulfonamide (138 mg, 0.72 mmol) and 7M ammonia in methanol (4.1 mL, 28.7 mmol) were cooled to 0 ° C, and hydroxylamine -O- sulfonic acid (81 mg, 0.72 mmol) was added. After stirring for 3 hours, the reaction mixture was filtered through cotton, and the residue was thoroughly washed with methanol. The filtrates were combined and then concentrated in vacuo. The residue was dissolved in methanol (10 mL), and triethylamine (0.1 mL, 0.72 mmol) was added. The mixture was cooled in an ice bath, and iodine (183 mg, 0.72 mmol) was added in small batches. After stirring for 5 minutes, the mixture was concentrated in vacuo. The crude product was suspended 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 (18 mg, 12% yield).

[1313] 1 H NMR (CD3OD): δ = 4.16-4.01 (m, 1H), 3.82-3.72 (m, 2H), 3.60 (dd, 2H), 3.33 (p, 2H), 1.85 (s, 3H).

[1314] Intermediate P113: 1-(1-Hydroxyprop-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, 18% yield) 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-difluoropropan-2-yl)azetidine-3-sulfonamide

[1319]

[1320] Prepared from azetidine-3-sulfonamide hydrochloride and 1,1-difluoroacetone 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, J 2H), 2.68-2.57 (m, 1H), 0.90 (d, 3H).

[1322] Intermediate P115: 1-Allylazetidine-3-sulfonamide

[1323]

[1324] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and allyl bromide 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-(Propan-2-yn-1-yl)azetidine-3-sulfonamide

[1327]

[1328] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 3-bromopropyne (80 wt% in toluene) to give the title compound (21 mg, 15% yield).

[1329] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.86 (m, 1H), 3.43 (dt, 4H), 3.20 (d, 2H), 3.16-3.12 (m, 1H).

[1330] Intermediate P117: 1-(3-Hydroxypropyl)azetidine-3-sulfonamide

[1331]

[1332] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 3-bromo-1-propanol to give the title compound (60 mg, 38% yield).

[1333] 1 H NMR (DMSO-d6): δ = 6.91 (s, 2H), 3.89 (m, 1H), 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, 1H), 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 as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and (iodomethyl)trimethylsilane to give the title compound (60 mg, 33% yield).

[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 on 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 give the title compound (11 mg, 8% yield).

[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 as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 4-bromo-1-butanol to give the title compound (41 mg, 20% yield).

[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-diazirin-3-yl)ethyl)azetidine-3-sulfonamide

[1351] Step A: 2-(3-Methyl-3H-diazirin-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 hours and 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 the reaction mixture was stirred overnight at room temperature. The suspension was filtered and the residue was washed thoroughly with methanol. The filtrates were combined and concentrated in vacuo to approximately 100 mL, then degassed by passing nitrogen through the filtrate for 20 minutes. The solution was cooled in an ice bath, and triethylamine (7.5 mL, 53.8 mmol) was added, followed by iodine (5.0 g, 19.7 mmol). After stirring for 1 hour, another portion of iodine (4.0 g, 15.8 mmol) was added. After 5 minutes, the reaction mixture was concentrated in vacuo to approximately 100 mL, and then brine was added. The aqueous solution was extracted three times with diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered, and then concentrated in vacuo. Vacuum distillation (90°C, 10 -2 mbar) to afford the title compound (226 mg, 3% yield) as a yellow oil.

[1354] 1 H NMR (CDCl3): δ = 3.53 (t, 2H), 1.73 (s, 1H), 1.64 (t, 2H), 1.07 (s, 3H).

[1355] Step B: 2-(3-methyl-3H-diazirin-3-yl)ethyl methanesulfonate

[1356]

[1357] A solution of 2-(3-methyl-3H-diazirin-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. Methanesulfonyl chloride (93 μL, 1.2 mmol) was added to the cooled solution. The reaction mixture was stirred in an 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, and then concentrated in vacuo to give the title compound (178 mg, quantitative yield), which was used without further purification.

[1358] 1 H NMR (CDCl3): 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-diazirin-3-yl)ethyl)azetidine-3-sulfonamide

[1360]

[1361] To a solution of 2-(3-methyl-3H-diazirin-3-yl)ethyl methanesulfonate (178 mg, 1.0 mmol) in acetonitrile (20 mL) was added azetidine-3-sulfonamide hydrochloride (344 mg, 2.0 mmol), followed by potassium carbonate (1.1 g, 8.0 mmol). The reaction mixture was stirred at 55 ° C overnight, followed by the addition of potassium iodide (158 mg, 1.0 mmol) and N, N-dimethylformamide (2 mL). The reaction mixture was stirred at 60 ° C for 6 hours and 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 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 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 as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde. The title compound (116 mg, 62% yield) 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 as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-methyl-2-oxo-1,2-dihydropyridine-4-carbaldehyde. The title compound (51 mg, 27% yield) 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, 27% yield) 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,2 H),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-carbaldehyde 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 hour, the solution was washed once with saturated sodium bicarbonate. Acetonitrile (10 mL), azetidine-3-sulfonamide hydrochloride (172 mg, 1.00 mmol), triethylamine (0.17 mL, 1.20 mmol) were added to the organic solution, followed by sodium triethoxyborohydride (265 mg, 1.25 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude product was suspended in methanol, coated on 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 obtain 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]octan-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),2.3 6-2.18(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 hours, 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 = 6.1Hz, 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 (CD3OD): 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: Benzyl 3-methoxy-4-sulfamoylpyrrolidine-1-carboxylate

[1398]

[1399] To a solution of ammonia in methanol (7 M, 42 mL) was added dropwise a solution of benzyl 3-(chlorosulfonyl)-4-methoxypyrrolidine-1-carboxylate (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 then washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and then concentrated in vacuo to give the title compound (236 mg, 50% yield).

[1400] 1 H NMR (DMSO-d6): δ=7.43-7.28(m,5H),7.21(s,2H),5.08(s,2H),4.24(bs,1H),3.82-3.64(m,3H),3.66-3.55(m,1H),3.46(d,1H),3.29(s,3H).

[1401] Step B: 4-Methoxypyrrolidine-3-sulfonamide

[1402]

[1403] Prepared from benzyl 3-methoxy-4-sulfamoylpyrrolidine-1-carboxylate as described for azetidine-3-sulfonamide (Intermediate P33) to give the title compound (91 mg, 67% yield) which was used without further purification.

[1404] 1 H NMR (DMSO-d6): δ = 6.98 (s, 2H), 4.08 (dt, 1H), 3.76-3.62 (m, 1H), 3.56-3.33 (m, 3H), 3.30-3.15 (m, 3H), 2.99 (dd, 1H), 2.83 (t, 1H).

[1405] Step C: 4-Methoxy-1-methylpyrrolidine-3-sulfonamide

[1406]

[1407] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 4-methoxypyrrolidine-3-sulfonamide and formaldehyde (37 wt% in water). The title compound (mixture of diastereomers, 17 mg, 35% yield) was used without further purification.

[1408] The main diastereomer 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 diastereomers, 12 mg, 23% yield) was used without further purification.

[1412] The main diastereomer 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-(Oxetane-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 oxetane-3-one (23 mg, 0.32 mmol) and 2 drops of acetic acid. Then, 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 obtain the crude title compound (80 mg) in an oily form, which was used without further purification.

[1416] The NMR data of the crude product was very complex. LCMS showed the desired mass.

[1417] LCMS: m / z 193 (M+H) + (ES + ); 191(MH) - (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] At 0 ° C, bis (4-methoxybenzyl) amine (3.71 g, 14.4 mmol) was added to a solution of 2-chloropyridine-5-sulfonyl chloride (3.00 g, 13.7 mmol) and triethylamine (2.49 mL, 17.8 mmol) in DCM (50 mL). 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 NH4Cl solution (3 × 40 mL) and water (40 mL), dried over MgSO4, filtered and concentrated in vacuo to give the crude product as a milky white solid. The crude product was triturated with TBME (70 mL), filtered and rinsed with TBME (2 × 40 mL) to give the title compound (4.97 g, 83%) as an off-white solid.

[1422] 1 H NMR(DMSO-d6)δ8.76(dd,J=2.6,0.7Hz,1H),8.19(dd,J=8.4,2.6Hz,1H),7.69(dd, J=8.4,0.7Hz,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 (aqueous solution) (2.4 mL, 4.80 mmol). The resulting suspension was stirred at 140 ° C for 18 hours. The reaction mixture was then treated with another 2M KOH (aqueous solution) (0.6 mL, 1.2 mmol, 1 equivalent) and heated at 140 ° C for another 6 hours, and treated with another 2M KOH (aqueous solution) (0.6 mL, 1.2 mmol, 1 equivalent) and heated at 140 ° C for another 18 hours. 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 × 30 mL). The combined organic extracts were washed with water (10 mL), dried over MgSO4, 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)δ12.17(s,1H),7.86(d,J=2.8Hz,1H),7.63(dd,J=9.6,2.9Hz,1H),7. 11-7.02(m,4H),6.87-6.79(m,4H),6.37(d,J=9.6Hz,1H),4.21(s,4H),3.72(s,6H).

[1428] LCMS: m / z 415.4 (M+H) + (ES + ),413.4(MH) - (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(CDCl3)δ8.60-8.55(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=6.2Hz,6H).

[1437] LCMS: m / z 457.4 (M+H) + (ES + ).

[1438] Step D: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1439]

[1440] At room temperature, TFA (0.43 ml, 5.64 mmol) was added to a solution of 1-isopropyl-N, N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.26 g, 0.564 mmol) in DCM (3 mL), and the mixture was stirred for 66 hours. The reactants were then concentrated in vacuo, and the residue was redissolved in DCM (5 mL). The product was purified by silica gel chromatography (12 g column, 0-10% MeOH / DCM) to give the title compound (60 mg, 49%) as a white solid.

[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] At 0 ° C, benzyl mercaptan (1.5 mL, 12.68 mmol) was added to a THF (55 mL) solution of NaH (0.755 g, 18.88 mmol). The reaction mixture was diluted with THF (20 mL) and stirred at 0 ° C for 10 minutes. Then a THF (10 mL) solution of 2,5-dichloropyrazine (1.370 mL, 13.42 mmol) was added dropwise. At 0 ° C, the reaction mixture was stirred for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0 ° C, MeOH (1 mL) was carefully added and stirred for 5 minutes. Water (20 mL) was added, followed by DCM (150 mL), and the two-phase 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 obtain the title compound (2.373 g, 72%) as a clear yellow oil.

[1446] 1 H NMR (DMSO-d6) δ8.68 (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-(benzylthio)-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. Sulfonyl chloride (2.2 mL, 26.2 mmol) was added, and the reaction mixture was stirred for 2 hours, 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 (MgSO4) and concentrated in vacuo to give the crude intermediate 5-chloropyrazine-2-sulfonyl chloride (1.198 g) as a pale yellow liquid.

[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 with a solution of 5-chloropyrazine-2-sulfonyl chloride (0.824 g, 3.87 mmol) in DCM (5 mL) dropwise. The resulting solution was stirred at 0 ° C for 15 minutes and then allowed to warm to room temperature for 16 hours. Saturated NH4Cl aqueous solution (10 mL) was added, and the organic phase was collected. The aqueous phase was extracted with DCM (2 × 10 mL) and ...

Claims

1. 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 May be optionally further substituted.

2. The compound of claim 1, wherein R 1 is a monocyclic or bicyclic non-aromatic heterocyclic group, wherein R 1 Optionally substituted.

3. The compound 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 compound according to any one of claims 1 to 3, wherein the non-aromatic heterocyclic group R 1 is fully saturated.

5. The compound of any one of claims 1 to 4, wherein R 1 Contains one, two or three ring nitrogen, oxygen or sulfur atoms.

6. The compound of claim 5, wherein R 1 Contains one or two ring nitrogen or oxygen atoms.

7. The compound of claim 6, wherein R 1 Contains one or two ring nitrogen atoms.

8. The compound of 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 compound of 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 compound 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 compound of 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 compound 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 compound 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 compound of 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 compound of any one of claims 1 to 14, wherein Q is O.

16. A compound selected from the group consisting of:

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