new sulfonamide-carboxamide compounds

专利摘要:
The present invention relates to the compounds of the formula (I): Formula (I), where Q is selected from O or S; L is an optionally substituted optionally substituted saturated or unsaturated C1-C12 hydrocarbilene group including one or more N, O or S heteroatoms; R1 is? NR3R4,? OR5,? (C = NR6) R7,? (CO) R8,? CN,? N3, a quaternary ammonium group or an optionally substituted heterocycle; R3, R4, R5, R6, R7 and R8 are each, independently, hydrogen or an optionally substituted optionally substituted saturated or unsaturated hydrocarbyl group including one or more N, O or S heteroatoms; where optionally L and R3, or L and R4, or R3 and R4, or L and R5, or L and R6, or L and R7, or R6 and R7, or L and R8, together with the atom (s) ( s) to which they are attached, can form an optionally substituted 3 to 12 membered saturated or unsaturated cyclic group; and R2 is a cyclic group substituted at position a, where R2 can optionally be additionally substituted; provided that the L atom that is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of a heterocyclic or aromatic group. The present invention also relates to salts, solvates and prodrugs of these compounds, to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment and prevention of medical disorders and diseases, mainly by inhibiting NLRP3.
公开号:BR112020002906A2
申请号:R112020002906-8
申请日:2018-08-15
公开日:2020-08-04
发明作者:David Miller；Angus Macleod；Jimmy Van Wiltenburg；Stephen Thom；Stephen St-Gallay；Jonathan Shannon
申请人:Inflazome Limited；
IPC主号:

专利说明:

[0001] [0001] The present invention relates to sulfonylureas and sulfonylthioureas comprising a hydrocarbon group comprising at least one nitrogen or oxygen atom attached to the sulfon atom of the sulfonylurea group and an α-substituted cyclic group attached to the nitrogen atom of the urea group and associated salts, solvates, prodrugs and pharmaceutical compositions. The present invention also relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, mainly by inhibiting NLRP3. FUNDAMENTALS
[0002] [0002] The NOD-like receptor family (NLR), the inflammasome of protein 3 containing the pyrin domain (NLRP3) is a component of the inflammatory process, and its aberrant activity is pathogenic in hereditary diseases such as periodic syndromes associated with crypirin (CAPS ) and complex diseases like multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.
[0003] [0003] NLRP3 is an intracellular signaling molecule that detects many factors derived from pathogens, environmental and host derivatives. After activation, NLRP3 binds to the particle type protein associated with apoptosis, containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form a large aggregate known as an ASC particle. The polymerized ASC, in turn, interacts with the cysteine-protease caspase-1 to form a complex called inflammasome. This results in the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (called pro-IL-1 and pro-IL-18, respectively) to activate these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC particle can also recruit and activate caspase-8, which can process pro-IL-1 and pro-IL-18 and trigger apoptotic cell death.
[0004] [0004] Caspase-1 cleaves pro-IL-1 and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. By controlling the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmine molecules, such as IL-33 and box 1 protein in the high mobility group (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, resulting in its degradation and allowing the release of IL-1. In human cells, caspase-1 can also control the processing and secretion of IL-37. Several other substrates of caspase-1, such as components of the cytoskeleton and glycolysis, can contribute to caspase-1-dependent inflammation.
[0005] [0005] NLRP3-dependent ASC particles are released into the extracellular environment, where they can activate caspase-1, induce the processing of caspase-1 substrates and propagate inflammation.
[0006] [0006] Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1 signaling induces the secretion of pro-inflammatory cytokines IL-6 and TNF. IL-1 β and IL-18 synergize with IL-23 to induce the production of IL-17 by CD4 Th17 cells with memory and by γδ T cells in the absence of involvement with T cell receptors. IL-18 and IL-12 they also synergize to induce IFN-γ production from memory T cells and NK cells that drive a Th1 response.
[0007] [0007] Hereditary CAPS diseases, Muckle-Wells syndrome (MWS), familial autoinflammatory syndrome (FCAS) and neonatal onset multisystemic inflammatory disease (NOMID) are caused by NLRP3 function gain mutations, defining NLRP3 as a component critical of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of several complex diseases, including metabolic disorders, such as type 1 diabetes.
[0008] [0008] A role for NLRP3 in diseases of the central nervous system is emerging, and lung diseases have also been shown to be influenced by NLRP3. In addition, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using Nlrp3 - / - mice, but there were also intuitions about the specific activation of NLRP3 in these diseases. In type 2 diabetes mellitus (T2D), deposition of islet amylode polypeptide in the pancreas activates NLRP3 and IL-1β signaling, resulting in cell death and inflammation.
[0009] [0009] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits the production of IL-1β at micromolar concentrations in response to NLRP3 activation, but not NLRC4 or NLRP1. Other weak NLRP3 inhibitors previously characterized include parthenolide, 3,4-methylenedioxy-β-nitrostyrene and dimethyl sulfoxide (DMSO), although these agents have limited potency and are non-specific.
[0010] [0010] Current treatments for diseases related to NLRP3 include biological agents that target IL-1. These are the anakinra recombinant IL-1 receptor antagonist, the neutralizing IL-1β cannabinumab antibody and the soluble IL-1 receptor decoy rilonacept. These approaches have proven to be successful in the treatment of CAPS, and these biological agents have been used in clinical trials for other diseases associated with IL-1β.
[0011] [0011] Some compounds containing diaylsulfonylureas have been identified as cytokine release inhibiting drugs (CRIDs) (Perregaux et al .; J. Pharmacol. Exp. Ther. 299, 187-197, 2001). CRIDs are a class of compounds containing diarylsulfonylurea that inhibit post-translational processing of IL-1β. Post-translational processing of IL-1β is accompanied by activation of caspase-1 and cell death. CRIDs arrest activated monocytes so that caspase-1 remains inactive and plasma membrane latency is preserved.
[0012] [0012] Certain sulfonylurea-containing compounds are also disclosed as NLRP3 inhibitors (see, for example, 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, WO 2018/015445 A1 and WO 2018/136890 A1).
[0013] [0013] There is a need to provide compounds with better pharmacological and / or physiological and / or physicochemical properties and / or those that provide a useful alternative to known compounds. SUMMARY OF THE INVENTION
[0014] [0014] A first aspect of the invention provides a compound of formula (I):
[0015] [0015] A first aspect of the invention also provides a compound of formula (I):
[0016] [0016] In one embodiment, the compound is not: O O O O s N N N H H THE
[0017] [0017] In one embodiment, the compound is not: MeO MeO O O S O O S N Y N Y
[0018] [0018] In an embodiment of the first aspect of the invention, a compound of formula (I) is provided:
[0019] [0019] In one embodiment, the compound is not: O O O O s N N N H H
[0020] [0020] In another embodiment of the first aspect of the invention, a compound of formula (I) is provided:
[0021] [0021] In the context of this specification, a "hydrocarbyl" substituent group or a hydrocarbyl moiety in a substituent group includes only carbon and hydrogen atoms, but, unless otherwise stated, does not include hetero atoms, such as N, O or S, in its carbon structure. A hydrocarbyl group / fraction may be saturated or unsaturated (including aromatic) and may be straight or branched or be or include cyclic groups in which, unless otherwise indicated, the cyclic group does not include any heteroatom, such as N, O or S , in its carbon structure. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups and fractions and aryl groups / fractions and combinations of all these groups / fractions. Typically, a hydrocarbyl group is a C1-C12 hydrocarbyl group. More typically, a hydrocarbon group is a C1-C10 hydrocarbyl group. A group
[0022] [0022] An "alkyl" substituent group or an alkyl moiety in a substituent group can be straight or branched. Examples of alkyl groups / fractions include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n groups / fractions. Unless otherwise indicated, the term "alkyl" does not include "cycloalkyl". Typically, an alkyl group is a C1-C12 alkyl group. More typically, an alkyl group is a C1-C6 alkyl group. An "alkylene" group is similarly defined as a divalent alkyl group.
[0023] [0023] An "alkenyl" substituent group or an alkenyl fraction in a substituent group refers to an unsaturated alkyl group or fraction with one or more carbon-carbon double bonds. Examples of alkenyl groups / fractions include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl groups and moieties 4-hexadienyl. Unless otherwise specified, the term "alkenyl" does not include "cycloalkenyl". Typically, an alkenyl group is a C2-C12 alkenyl group. More typically, an alkenyl group is a C2-C6 alkenyl group. An "alkenylene" group is similarly defined as a divalent alkenyl group.
[0024] [0024] An "alkynyl" substituent group or an alkynyl fraction in a substituent group refers to an unsaturated alkyl group or fraction with one or more carbon-carbon triple bonds. Examples of alkynyl groups / fractions include ethynyl, propargyl, but-1-ynyl and but-2-ynyl. Typically, an alkynyl group is a C2-C12 alkynyl group. More typically, an alkynyl group is a C 2 -C 6 alkynyl group. An "alkynylene" group is similarly defined as a divalent alkynyl group.
[0025] [0025] A "cyclic" substituent group or a cyclic fraction in a substituent group refers to any hydrocarbyl ring, where the hydrocarbyl ring may be saturated or unsaturated (including aromatic) and may include one or more hetero atoms, for example, N, O or S, in its carbon structure. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups, as discussed below. A cyclic group can be monocyclic, bicyclic (for example, bridged, fused or spiro) or polycyclic. Typically, a cyclic group is a cyclic group with 3 to 12 members, which means that it contains 3 to 12 ring atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means that it contains 3 to 7 ring atoms.
[0026] [0026] A "heterocyclic" substituent group or a heterocyclic fraction in a substituent group refers to a cyclic group or fraction including one or more carbon atoms and one or more (such as one, two three or four) hetero atoms, for example , N, O or S, in the ring structure. Examples of heterocyclic groups include heteroaryl groups, as discussed below, and non-aromatic heterocyclic groups, such as azetinyl, oxetanil, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxatanil, tyridine, tylanilanil, pyridine, tylanilanil, pyridine, tylanilanil, pyridine, tylanilanil, pyridine, tylanilanil, pyridine, pyridine, pyridine. , piperazinyl, dioxanil, morpholinyl and thiomorpholinyl groups, typically as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinil, morpholinyl and thiomorphoryl groups.
[0027] [0027] A "cycloalkyl" substituent group or a "cycloalkyl" moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclo -hexil. Unless otherwise indicated, a cycloalkyl substituting group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
[0028] [0028] A "cycloalkenyl" substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring with 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 cyclohex-1,3-dien-1-yl. Unless otherwise indicated, a cycloalkenyl substituting group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
[0029] [0029] An "aryl" substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and fused ring polycyclic aromatic hydrocarbons, wherein all fused ring systems (excluding any ring systems that are part of or formed by optional substituents) are aromatic. Examples of aryl groups / fractions include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl".
[0030] [0030] A "heteroaryl" substituent group or a heteroaryl fraction in a substituent group refers to an aromatic heterocyclic group or fraction. The term "heteroaryl" includes monocyclic aromatic heterocycles and fused ring polycyclic aromatic heterocycles, wherein all fused ring systems (excluding any ring systems that are part of or formed by optional substituents) are aromatic. Examples of heteroaryl groups / fractions include the following: N N N N N N N N N N G G G G G G N N N N N N N N N N N G G N N N N
[0031] [0031] For the purposes of this specification, where a combination of fractions is referred to as a group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last fraction mentioned contains the atom by which the group is linked to the rest of the molecule. An example of an arylalkyl group is benzyl.
[0032] [0032] For the purposes of this specification, in a group or fraction optionally substituted: (i) each hydrogen atom can optionally be replaced by a group independently selected from the halo; -CN; -NO2; -N3; -Rβ; -OH; -Eβ; -Rα-halo; -Rα-CN; -Rα-NO2; -Rα-N3; -Rα-Rβ; -Rα-OH; -Rα-Eβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα- SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; - Si (Rβ) 3; -O-Si (Rβ) 3; -Rα-Si (Rβ) 3; -Rα-O-Si (Rβ) 3; -NH2; -NHRβ; -N (Rβ) 2; -N (O) (Rβ) 2; -N + (Rβ) 3; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -Rα-N (O) (Rβ) 2; -Rα-N + (Rβ) 3; -CHO; - CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα-COORβ; -Rα-OCORβ; -C (= NH) Rβ; -C (= NH) NH2; -C (= NH) NHRβ; -C (= NH) N (Rβ) 2; - C (= NRβ) Rβ; -C (= NRβ) NHRβ; -C (= NRβ) N (Rβ) 2; -C (= NOH) Rβ; -C (N2) Rβ; -Rα- C (= NH) Rβ; -Rα-C (= NH) NH2; -Rα-C (= NH) NHRβ; -Rα-C (= NH) N (Rβ) 2; -Rα- C (= NRβ) Rβ; -Rα-C (= NRβ) NHRβ; -Rα-C (= NRβ) N (Rβ) 2; -Rα-C (= NOH) Rβ; -Rα- C (N2) Rβ; -NH-CHO; -NRβ-CHO; -NH-CORβ; -NRβ-CORβ; -CONH2; -CONHRβ; - CON (Rβ) 2; -Rα-NH-CHO; -Rα-NRβ-CHO; -Rα-NH-CORβ; -Rα-NRβ-CORβ; -Rα- CONH2; -Rα-CONHRβ; -Rα-CON (Rβ) 2; -O-Rα-OH; -O-Rα-Eβ; -O-Rα-NH2; -O-Rα- NHRβ; -O-Rα-N (Rβ) 2; -O-Rα-N (O) (Rβ) 2; -O-Rα-N + (Rβ) 3; -NH-Rα-OH; -NH-Rα-Eβ; - NH-Rα-NH2; -NH-Rα-NHRβ; -NH-Rα-N (Rβ) 2; -NH-Rα-N (O) (Rβ) 2; -NH-Rα-N + (Rβ) 3; - NRβ-Rα-OH; -NRβ-Rα-Eβ; -NRβ-Rα-NH2; -NRβ-Rα-NHRβ; -NRβ-Rα-N (Rβ) 2; -NRβ- Rα-N (O) (Rβ) 2; -NRβ-Rα-N + (Rβ) 3; -N (O) Rβ-Rα-OH; -N (O) Rβ-Rα-Eβ; -N (O) Rβ-Rα-NH2; -N (O) Rβ-Rα-NHRβ; -N (O) Rβ-Rα-N (Rβ) 2; -N (O) Rβ-Rα-N (O) (Rβ) 2; -N (O) Rβ-Rα- N + (Rβ) 3; -N + (Rβ) 2-Rα-OH; -N + (Rβ) 2-Rα-Eβ; -N + (Rβ) 2-Rα-NH2; -N + (Rβ) 2-Rα-NHRβ; - N + (Rβ) 2-Rα-N (Rβ) 2; or -N + (Rβ) 2-Rα-N (O) (Rβ) 2; and / or (ii) any two hydrogen atoms attached to the same atom can optionally be replaced by a substituent connected to π independently selected from oxo (= O), = S, = NH e = NRβ; and / or (iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or fraction, can optionally be substituted by a bridged substituent independently selected from -O-, -S-, -NH -, -N = N-, -N (Rβ) -, -N (O) (Rβ) -, -N + (Rβ) 2- or - Rα-; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain the main alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, where one or more -CH2 groups in the main chain of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more -N (O) (Rβ) - or -N + (Rβ) 2-, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted with one or more halo and / or -Rβ groups; and where each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, or where two or three -Rβ linked to the same nitrogen atom may, together with the nitrogen atom to which they are attached, form a cyclic C2-C7 group, and where any –Rβ optionally, can be replaced by one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl groups, 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 heterocyclic group of 4 to 6 members.
[0033] [0033] Typically, the compounds of the present invention comprise at most one quaternary ammonium group such as -N + (Rβ) 3 or - N + (Rβ) 2-.
[0034] [0034] Where reference is made to a group-Rα-C (N2) Rβ, what is intended is:
[0035] [0035] Typically, in a fraction or optionally substituted group: (i) each hydrogen atom can optionally be substituted by a group independently selected from the halo; e / or-CN; -NO2; -N3; -Rβ; -OH; -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; - SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα- SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα- COORβ; -Rα-OCORβ; -NH-CHO; -NRβ-CHO; -NH-CORβ; -NRβ-CORβ; -CONH2; - CONHRβ; -CON (Rβ) 2; -Rα-NH-CHO; -Rα-NRβ-CHO; -Rα-NH-CORβ; -Rα-NRβ- CORβ; -Rα-CONH2; -Rα-CONHRβ; -Rα-CON (Rβ) 2; -O-Rα-OH; -O-Rα-ORβ; -O-Rα-NH2; -O-Rα-NHRβ; -O-Rα-N (Rβ) 2; -NH-Rα-OH; -NH-Rα-ORβ; -NH-Rα-NH2; -NH-Rα- NHRβ; -NH-Rα-N (Rβ) 2; -NRβ-Rα-OH; -NRβ-Rα-ORβ; -NRβ-Rα-NH2; -NRβ-Rα-NHRβ; and -NRβ-Rα-N (Rβ) 2; and / or (ii) any two hydrogen atoms attached to the same carbon atom can optionally be replaced by a substituent connected to π independently selected from oxo (= O), = S, = NH ou = NRβ; and / or (iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or fraction, can optionally be substituted by a bridged substituent independently selected from -O-, -S-, -NH -, -N (Rβ) - or -Rα-; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and wherein each -Rβ is independently selected from a C1- C6 alkyl, C2-C6alkenyl, C2-C6alkynyl or cyclic C2-C6 group, and where any -Rβ can optionally be replaced by one or more C1-C4alkyl, C1- C4haloalkyl, C3-C7 cycloalkyl, -O (C1-C4 alkyl), -O (C1-C4 haloalkyl), -O (C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -C≡CH or groups oxo (= O).
[0036] [0036] Typically, in a fraction or optionally substituted group: (i) each hydrogen atom can optionally be substituted by a group selected independently from halo; -CN; -NO2; -N3; -Rβ; -OH; -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; - CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα-COORβ; or -Rα-OCORβ; and / or (ii) any two hydrogen atoms attached to the same carbon atom can optionally be replaced by a substituent connected to π independently selected from oxo (= O), = S, = NH ou = NRβ; and / or (iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or fraction, can optionally be substituted by a bridged substituent independently selected from -O-, -S-, -NH -, -N (Rβ) - or -Rα-; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and wherein each -Rβ is independently selected from a C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl or C2-C6 cyclic group, and where any -Rβ can optionally be replaced by one or more C1-C4alkyl, C1- C4haloalkyl , C3-C7cycloalkyl, -O (C1-C4alkyl), -O (C1-C4haloalkyl), -O (C3-C7cycloalkyl), halo, -OH, -NH2, -CN, -C≡CH or oxo groups (= O ).
[0037] [0037] Typically, in a fraction or optionally substituted group: (i) each hydrogen atom can optionally be substituted by a group selected independently from halo; -CN; -NO2; -N3; -Rβ; -OH; -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; - CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα-COORβ; and -Rα-OCORβ; and / or (ii) any two hydrogen atoms attached to the same carbon atom can optionally be replaced by a substituent connected to π independently selected from oxo (= O), = S, = NH ou = NRβ; and / or (iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or fraction, can optionally be substituted by a bridged substituent independently selected from -O-, -S-, -NH -, -N (Rβ) - or -Rα-; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and wherein each -Rβ is independently selected from a C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and where any
[0038] [0038] Typically, a substituted group comprises 1, 2, 3 or 4 substituents, more typically 1, 2 or 3 substituents, more typically 1 or 2 substituents and more typically 1 substituent.
[0039] [0039] Unless otherwise specified, any divalent bridge substituent (for example, -O-, -S-, -NH-, -N (Rβ) -, -N (O) (Rβ) -, -N + (Rβ ) 2- or -Rα-) of an optionally substituted group or portion (for example, L) must be linked only to the specified group or fraction and cannot be linked to a second group or fraction (for example, R2), even if the second group or fraction can itself be optionally substituted.
[0040] [0040] The term "halo" includes fluorine, chlorine, bromine and iodine.
[0041] [0041] Unless otherwise specified, where a group is prefixed by the term "halo", such as a haloalkyl or halomethyl group, it should be understood that the group in question is replaced by one or more halo groups independently selected from fluorine, chlorine , bromine and iodine. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution in the corresponding group without the prefix halo. For example, a halomethyl group can contain one, two or three halo substituents. A haloethyl or halophenyl group can contain one, two, three, four or five halo substituents. Likewise, unless otherwise specified, where a group is prefixed by a specific halo group, it must be understood that the group in question is replaced by one or more specific halo groups. For example, the term "fluoromethyl" refers to a methyl group substituted by one, two or three fluoro groups.
[0042] [0042] Unless otherwise specified, where it is said that a group is "substituted with halo", it should be understood that the group in question is replaced by one or more halo groups selected independently from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution in the group said to be substituted by halo. For example, a halo-substituted methyl group may contain one, two or three halo substituents. A halo-substituted ethyl group or halo-substituted phenyl may contain one, two, three, four or five halo substituents.
[0043] [0043] Unless otherwise specified, any reference to an element should be considered a reference to all isotopes of that element. Thus, for example, unless otherwise stated, any reference to hydrogen is considered to encompass all isotopes of hydrogen, including deuterium and tritium.
[0044] [0044] Where reference is made to a hydrocarbon or other group, including one or more N, O or S heteroatoms in its carbon structure, or when reference is made to a carbon atom of a hydrocarbil or another group being replaced by a atom of N, O or S, what is intended is that: CH. N. . is replaced by. is replaced; –CH2 – is replaced by –NH–, –O– or –S–; –CH3 is replaced by –NH2, –OH or –SH; –CH = is replaced by –N =; CH2 = is replaced by NH =, O = Or S =; or CH≡ is replaced by N≡; provided that the resulting group comprises at least one carbon atom. For example, the methoxy, dimethylamino and aminoethyl groups are considered hydrocarbyl groups including one or more N, O or S heteroatoms in their carbon structure.
[0045] [0045] When reference is made to a CH2- group in the main chain of a hydrocarbon or another group being replaced by a -N (O) (Rβ) - or -N + (Rβ) 2- group, what is intended is that :
[0046] [0046] In the context of this specification, unless otherwise specified, a Cx-Cy group is defined as a group containing from x to y carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms. Optional substituents and fractions are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituents and / or containing the optional fractions. For the avoidance of doubt, substitution heteroatoms, for example, N, O or S, should not be counted as carbon atoms when calculating the number of carbon atoms in a Cx-Cy group. For example, a morpholinyl group should be considered a C6 heterocyclic group, not a C4 heterocyclic group.
[0047] [0047] For the purposes of this specification, in which it is stated that a first atom or group is "directly linked" to a second atom or group, it must be understood that the first atom or group is covalently connected to the second atom or group with no atom or intervening groups present. So, for example, for the group (C = ON (CH 3) 2, the carbon atom of each methyl group is directly linked to the nitrogen atom and the carbon atom of the carbonyl group is directly linked to the nitrogen atom, but the carbon atom of the carbonyl group is not directly linked to the carbon atom of the two methyl groups.
[0048] [0048] L is a saturated or unsaturated C1-C12 hydrocarbilene group, where the hydrocarbilene group can be straight or branched chain, or be or include cyclic groups, where the hydrocarbilene group can optionally be substituted, and in which the group hydrocarbilene can optionally include one or more (such as one, two or three) N, O or S heteroatoms in its carbon skeleton.
[0049] [0049] In one embodiment, L is a saturated or unsaturated C1-C10 hydrocarbilene group, in which the hydrocarbilene group can be straight or branched chain or be or include cyclic groups, where the hydrocarbilene group can optionally include an N heteroatom, O or S in its carbon skeleton, and where the hydrocarbilene group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, CN, -N (R9) 2, - OR9 or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0050] [0050] In one embodiment, L is a saturated or unsaturated C1-C8 hydrocarbilene group, in which the hydrocarbilene group can be straight or branched, or be or include cyclic groups, and in which the hydrocarbilene group can optionally be replaced by one or more substituents (such as one, two or three substituents) independently selected from the halo groups, - CN, -N (R9) 2, -OR9 or oxo (= O), where R9 is independently selected from an atom of hydrogen or a C1-C3 alkyl group.
[0051] [0051] In one embodiment, L is a saturated C1-C6 hydrocarbilene group, in which the hydrocarbilene group can be straight or branched, or be or include cyclic groups, and in which the hydrocarbilene group can optionally be replaced by one or more substituents (such as one, two or three substituents) independently selected from halo groups, -CN, -N (R9) 2, -OR9or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0052] [0052] In one embodiment, L is a saturated or unsaturated C1-C5 hydrocarbilene group, in which the hydrocarbilene group can be straight or branched chain, or be or include cyclic groups, and in which the hydrocarbilene group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from the halo groups, - CN, -N (R9) 2, -OR9 or oxo (= O), where R9 is independently selected from a hydrogen atom or one of C1-C3 alkyl group.
[0053] [0053] In one embodiment, L is a saturated or unsaturated C1-C10 hydrocarbilene group, in which the hydrocarbilene group can be straight or branched chain, or be or include cyclic groups, and in which the hydrocarbilene group does not include any heteroatom in your carbon skeleton.
[0054] [0054] In one embodiment, L is a C1-C10 alkylene group that can be straight or branched chain or be or include a cycloalkyl or cycloalkylene group. Typically, L is a C1-C8 alkylene group that can be straight or branched or be or include a cycloalkyl or cycloalkylene group. Typically, L is a C1-C6 alkylene group that can be straight or branched or be or include a cycloalkyl or cycloalkylene group. Typically, L is a C1-C6 alkylene group that can be straight or branched or includes a cycloalkyl or cycloalkylene group, wherein the L atom that is attached to the sulfur atom of the sulfonylurea group is not a ring atom of any cyclic group.
[0055] [0055] In one embodiment, L is a C1-C12 arylalkylene group in which R1 can be attached to the aryl or alkylene part of the arylalkylene group. Typically, L is a phenyl- (C1-C3 alkylene) group, where R1 can be attached to the phenyl or alkylene part of the phenyl- (C1-C3 alkylene) group.
[0056] [0056] In one embodiment, R1 is –NR3R4, and the compound has the formula (IA): R3 O O Q N S R2 4 R L N N H H (IA)
[0057] [0057] R3 and R4 are each saturated or unsaturated C1-C10 hydrocarbyl group or independent hydrogen, wherein the hydrocarbyl group may be straight or branched or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted and wherein the hydrocarbyl group may optionally include one or more N, O or S heteroatoms in its carbon backbone; and optionally L and R3, L and R4, or R3 and R4 together with the oxygen atom to which they are attached, can form a 3- to 12-membered saturated or unsaturated cyclic group, in which the cyclic group can be optionally substituted and in that the cyclic group can optionally include one or more other N, O or S heteroatoms in its carbon backbone.
[0058] [0058] In one embodiment, R3 and R4 are each independently hydrogen or a saturated or unsaturated C1-C8 hydrocarbyl group, wherein the hydrocarbyl group may be straight or branched or be or include cyclic groups, wherein the hydrocarbyl group can optionally include an N, O or S heteroatom in its carbon backbone and where the hydrocarbyl group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, -CN groups, -N (R9) 2, -OR9 or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0059] [0059] In one embodiment, R3 and R4 are each independently selected from a hydrogen atom or a C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O (C1-C6 alkyl), - CO (C1-C6 alkyl), - COO (C1-C6 alkyl), -CHO, C1-C6 cycloalkyl, phenyl or benzyl, each of which can be optionally substituted with one or more substituents (such as one, two or three substituents ) independently selected from halo, -CN, -N (R9) 2, -OR9 or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0060] [0060] In one embodiment, R3 and R4 are each independently hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl, phenyl or benzyl group, each of which can optionally be substituted by one or more substituents (such as one, two or three substituents) selected independently from the halo groups, -CN, -N (R9) 2, -OR9 oxo
[0061] [0061] In one embodiment, L and R3, or L and R4 or R3 and R4 together with the nitrogen atom to which they are attached, form a 3 to 7-membered saturated or unsaturated cyclic group, in which the cyclic group can optionally include one or two other N, O or S heteroatoms in their carbon skeleton and where the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, -CN, -N (R9) 2, -OR9, C1-C3 alkyl, C1-C3 alkylene or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0062] [0062] In one embodiment, L and R3, or L and R4, or R3 and R4 together with the nitrogen atom to which they are attached, form a saturated cyclic group of 4, 5 or 6 members, in which the cyclic group can optionally include another N, O or S heteroatom in its carbon skeleton, and in which the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, -CN, -N (R9) 2, -OR9, C1-C3 alkyl, C1-C3 alkylene or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0063] [0063] In one embodiment, R3 and R4 together with the nitrogen atom to which they are attached, form a saturated or unsaturated cyclic group of 4, 5 or 6 members, selected from azetidinyl, azetinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl , piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 6-oxa-2-azaspiro [3.4] octanyl group, each of which can optionally be substituted by one or two substituents selected independently from a halo, C1-C6 alkyl, C1-C6 haloalkyl , -CN, -N (R9) 2, -OR9 or a 4- to 6-membered saturated heterocyclic group, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0064] [0064] In one embodiment, R3 and R4 together with the nitrogen atom to which they are attached, form a saturated cyclic group of 4, 5 or 6 members, selected from an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group, each of which can optionally be substituted with one or two substituents independently selected from a halo, C 1 -C 6 alkyl, C1-C6 haloalkyl, -CN, -N (R9) 2, -OR9 or 4- to 6-membered saturated heterocyclic group, wherein R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0065] [0065] In one embodiment, R1 is –OR5, and the compound has the formula (IB):
[0066] [0066] R5 is hydrogen or a C1-C10 saturated or unsaturated hydrocarbyl group, where the hydrocarbyl group may be straight or branched or be or include cyclic groups, where the hydrocarbyl group may optionally be substituted and in which the group hydrocarbyl may optionally include one or more N, O or S heteroatoms in its carbon skeleton; and optionally L and R5 together with the oxygen atom to which they are attached, can form a 3- to 12-membered saturated or unsaturated cyclic group, in which the cyclic group can be optionally substituted and in which the cyclic group can optionally include one or plus other N, O or S heteroatoms in their carbon skeleton.
[0067] [0067] In one embodiment, R5 is a saturated or unsaturated C1-C8 hydrocarbilene group, in which the hydrocarbilene group can be straight or branched or be or include cyclic groups, where the hydrocarbilene group can optionally include an N heteroatom, O or S in its carbon skeleton, and where the hydrocarbilene group can optionally be substituted by one or more substituents (such as one, two or three substituents) selected independently from the halo, halo, -CN, -N (R9) 2, -OR9 or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0068] [0068] In one embodiment, R5 is hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl, phenyl or benzyl group, each of which can optionally be substituted by one or more substituents (as one, two or three substituents) independently selected from halo, -CN, -N (R9) 2, -OR9 or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0069] [0069] In one embodiment, R5 is hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl, phenyl or benzyl group. In one embodiment, R5 is hydrogen or a C1-C6 alkyl group. In one embodiment, R5 is a C1-C3 alkyl group.
[0070] [0070] In one embodiment, R5 is not -CH2CH2OCH2CH3.
[0071] [0071] In one embodiment, L and R5 together with the oxygen atom to which they are attached, form a saturated or unsaturated cyclic group of 3 to 7 members, in which the cyclic group can optionally include one or two other N, O heteroatoms or S in its carbon skeleton, and where the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) selected independently from halo, groups -CN, -N (R9) 2, -OR9, C1-C3 alkyl, C1-C3 alkylene or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0072] [0072] In one embodiment, L and R5, together with the oxygen atom to which they are attached, form a saturated cyclic group of 4, 5 or 6 members, in which the cyclic group can optionally include another N, O or heteroatom S in its skeleton carbon, and where the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, -CN, -
[0073] [0073] In one embodiment, R1 is - (C = NR6) R7, and the compound has the formula (IC): R6
[0074] [0074] R6 and R7 are each C1-C10 saturated or unsaturated hydrocarbyl group or independent hydrogen, wherein the hydrocarbyl group may be straight or branched or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted and wherein the hydrocarbyl group may optionally include one or more N, O or S heteroatoms in its carbon backbone; and optionally L and R6, L and R7, or R6 and R7 together with the group - (C = N) - to which they are attached, can form a 3 to 12-membered saturated or unsaturated cyclic group, where the cyclic group can be optionally substituted and wherein the cyclic group can optionally include one or more other N, O or S heteroatoms in its carbon backbone.
[0075] [0075] In one embodiment, R6 and R7 are each independently hydrogen or a saturated or unsaturated C1-C8 hydrocarbyl group, wherein the hydrocarbyl group may be straight or branched or be or include cyclic groups, wherein the hydrocarbyl group can optionally include an N, O or S heteroatom in its carbon backbone and where the hydrocarbyl group can optionally be substituted by one or more substituents (such as one, two or three substituents) selected independently from halo, -CN, -N groups (R9) 2, -OR9 or the oxo groups (= O), where R9 is selected independently of a hydrogen atom or a C1-C3 alkyl group.
[0076] [0076] In one embodiment, R6 and R7 are each independently hydrogen or a C1-C6 alkyl group, C2-C6 alkenyl, alkynyl
[0077] [0077] In one modality, L and R6, or L and R7 or R6 and R7 together with the group - (C = N) - to which they are attached, form a saturated or unsaturated cyclic group of 3 to 7 members, in which the cyclic group can optionally include one or two other N, O or S heteroatoms in its carbon backbone and where the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) selected independently from halo, -CN, -N (R9) 2, -OR9, C1-C3 alkyl, C1-C3 alkylene or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group .
[0078] [0078] In one modality, L and R6, or L and R7, or R6 and R7 together with the group - (C = N) - to which they are attached, form a saturated cyclic group of 4, 5 or 6 members, in that the cyclic group can optionally include another N, O or S heteroatom in its carbon backbone and where the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo , -CN, -N (R9) 2, -OR9, C1-C3 alkyl, C1-C3 alkylene or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a C1- alkyl group C3.
[0079] [0079] For example, L and R7 together with the group - (C = NR6) - to which they are linked, can form a group
[0080] [0080] R8 is hydrogen or a C1-C10 saturated or unsaturated hydrocarbyl group, where the hydrocarbyl group may be straight or branched or be or include cyclic groups, where the hydrocarbyl group may optionally be substituted and in which the group hydrocarbyl may optionally include one or more N, O or S heteroatoms in its carbon skeleton; and optionally L and R8 together with the group - (C = O) - to which they are attached, they can form a saturated or unsaturated cyclic group of 3 to 12 members, in which the cyclic group can be optionally substituted and in which the cyclic group it can optionally include one or more other N, O or S heteroatoms in its carbon skeleton.
[0081] [0081] In one embodiment, R8 is hydrogen or a saturated or unsaturated C1-C8 hydrocarbilene group, where the hydrocarbilene group can be straight or branched chain or be or include cyclic groups, where the hydrocarbilene group can optionally include a heteroatom N, O or S in its carbon skeleton, and in which the hydrocarbilene group can optionally be substituted by one or more substituents (such as one, two or three substituents) selected independently from halo, groups -CN, -N (R9) 2 , -OR9 or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0082] [0082] In one embodiment, R8 is hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl, phenyl or benzyl, each of which can optionally be substituted by one or more substituents (as one, two or three substituents) independently selected from halo groups, -CN, -N (R9) 2, -OR9 or oxo groups (= O), where R9 is independently selected from a hydrogen atom or a C 1- alkyl group
[0083] [0083] In one embodiment, R8 is hydrogen or a C1- C6 alkyl group, -N (R19) 2 or - -OR19, where R19 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0084] [0084] In one embodiment, L and R8 together with the group - (C = O) - to which they are attached, form a saturated or unsaturated cyclic group of 3 to 7 members, in which the cyclic group can optionally include one or two other N, O or S heteroatoms in their carbon skeleton and in which the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, groups -CN, -N (R9) 2, -OR9, C1-C3, C1-C3 alkylene or oxo (= O), where R9 is independently selected from a hydrogen atom or a C 1- C3 alkyl group.
[0085] [0085] In one embodiment, L and R8 together with the group - (C = O) - to which they are attached, form a saturated cyclic group of 4, 5 or 6 members, in which the cyclic group can optionally include another heteroatom N, O or S in its carbon skeleton and where the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, groups -CN, -N (R9) 2, -OR9, C1-C3 alkyl, C1-C3 alkylene or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 group.
[0086] [0086] For example, L and R8 together with the group - (C = O) - to which they are attached, can form an O or O group
[0087] [0087] In one embodiment, R1 is a group of quaternary ammonium and the compound has the formula (IE):
[0088] [0088] In one embodiment, R23, R24 and R25 are each independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl, phenyl or benzyl group. In one embodiment, R23, R24 and R25 are each independently a C1-C6 alkyl group. In one embodiment, R23, R24 and R25 are each methyl.
[0089] [0089] In one embodiment, R1 is an optionally substituted heterocycle. In one embodiment, R1 is an optionally substituted heterocycle comprising one, two or three N and / or O heteroatoms and no other hetero atoms in the ring structure. In one embodiment, R1 is an optionally substituted monocyclic heterocycle comprising one, two or three N and / or O hetero atoms and no other hetero atoms in the ring structure. In one embodiment, R1 is an optionally substituted heteroaryl group or an optionally substituted non-aromatic heterocyclic group.
[0090] [0090] In one embodiment, R1 is an optionally substituted heterocycle selected from a group diazirinil, azetidinyl, azetinil, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl hidrotiofenil, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxatiolanil, piperidinyl, tetrahydropyran, thianyl, piperazinyl,
[0091] [0091] In one embodiment, R1 is an optionally substituted heterocycle selected from a diazirinyl, azetidinyl, azetinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, dioxolanil, oxathiolanil, piperidinyl, tetra-hydroxyanil, tetra-hydroxy morpholinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl or 6-oxa-2-azaspiro [3.4] octanyl, each of which can optionally be substituted with one or two substitutes independently from a halo, C1-C 6 alkyl, -CN, -N (R9) 2, -OR9 or 4 to 6-membered saturated heterocyclic group, where R9 is independently selected from a hydrogen atom or a group C1-C3 alkyl.
[0092] [0092] In one embodiment, R1 is an optionally substituted heterocycle selected from a group of diazirinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrazolyl or 6-oxa-2-azaspiro [3.4] octanyl, each of which can optionally be substituted by one or two substituents independently selected from a halo, C1-C6 alkyl, -CN, -N (R9) 2, -OR9 or 4 to 6-membered saturated heterocyclic group, where R9 is independently selected from from a hydrogen atom or a C1-C3 alkyl group.
[0093] [0093] The L atom which is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of a heterocyclic or aromatic group. In one embodiment, the L atom that is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of a heterocyclic group, an aromatic group or a cyclic spiro group. In one embodiment, the L atom which is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of any cyclic group.
[0094] [0094] In one embodiment, L is attached to the sulfur atom of the sulfonylurea group by a -CH2- group. For the avoidance of doubt, note that this group - CH2- is part of L.
[0095] [0095] In one aspect of any of the above, -L– NR3R4, -L – OR5, -L– (C = NR6) R7 and -L– (CO) R8 contain 2 to 30 atoms other than hydrogen , more typically 3 to 25 non-hydrogen atoms, more typically 4 to 20 non-hydrogen atoms.
[0096] [0096] In one aspect of any of the above modalities, where R1 is a group of quaternary ammonium or an optionally substituted heterocycle, -L – R1 contains from 2 to 30 atoms other than hydrogen, more typically from 3 to 25 atoms that are not hydrogen, more typically 4 to 20 atoms other than hydrogen.
[0097] [0097] In one aspect of any of the previous modalities, -L – R1 contains from 2 to 30 atoms other than hydrogen. More typically, -L – R1 contains 2 to 25 atoms other than hydrogen. More typically, -L – R1 contains 2 to 20 atoms other than hydrogen.
[0098] [0098] R2 is a cyclic group substituted at the α position, where R2 can be optionally substituted. For the avoidance of doubt, note that it is a ring atom of the cyclic group of R2 that is directly linked to the nitrogen atom of the urea or thiourea group, and not any substituent.
[0099] [0099] As used in this document, the nomenclature α, β, α ', β' refers to the position of the atoms of a cyclic group, such as -R2, in relation to the point of attachment of the cyclic group to the rest of the molecule. For example, where - R2 is a 1,2,3,5,6,7-hexahydro-s-indacen-4-yl fraction, the positions α, β, α 'and β'
[0100] [0100] For the avoidance of doubt, when it is stated that a cyclic group, such as an aryl or heteroaryl group, is substituted in the α and / or α 'positions, it should be understood that one or more hydrogen atoms in the α and / or positions a 'respectively are replaced by one or more substituents, like any optional substituent as defined above. Unless otherwise indicated, the term "substituted" does not include the replacement of one or more ring carbon atoms with one or more ring hetero atoms.
[0101] [0101] In an embodiment of the first aspect of the invention, R 2 is an aryl or heteroaryl group, in which the aryl or heteroaryl group is substituted in the α position and in which R2 can optionally be additionally substituted. Typically, R2 is a phenyl or a 5- or 6-membered heteroaryl group, where the phenyl or heteroaryl group is substituted at the α position and where R2 can optionally be further substituted. Typically, R2 is an aryl or heteroaryl group, where the aryl or heteroaryl group is substituted at the α and α 'positions and where R2 can optionally be additionally substituted. Typically, R2 is a phenyl or a 5- or 6-membered heteroaryl group, where the phenyl or heteroaryl group is substituted at the α and α 'positions and where R2 can optionally be additionally substituted. For example, R2 can be a substituted phenyl group at positions 2 and 6 or a substituted phenyl group at positions 2, 4 and
[0102] [0102] In one embodiment, the parent phenyl or the 5- or 6-membered heteroaryl group of R2 can be selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,
[0103] [0103] In another embodiment, R2 is a cyclic group substituted at positions α and α ', where R2 can optionally be additionally substituted. For example, R2 may be a non-aromatic cycloalkyl, cycloalkenyl or heterocyclic group substituted at the α and α 'positions.
[0104] [0104] In any of the above modalities, typical substituents at the α and / or α 'positions of the precursor cyclic group of R2 comprise a carbon atom. For example, typical substituents at positions α and / or α 'of the precursor cyclic group of R2 can be selected independently from the groups –Rδ, -ORδ or –CORδ, where each Rδ is independently selected from a C1-C6 alkyl , C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group and wherein each Rδ is optionally further substituted with one or more halo groups. More typically, substituents at the α and / or α 'positions are independently selected from the alkyl and cycloalkyl groups, such as C3-C6 branched alkyl and C3-C6 cycloalkyl groups, for example, isopropyl, cyclopropyl, cyclohexyl or t- groups. butyl, where the alkyl and cycloalkyl groups are optionally further substituted by one or more fluoro and / or chloro groups.
[0105] [0105] In one aspect of any of the above modalities, each substituent at positions α and α 'comprises a carbon atom.
[0106] [0106] Other typical substituents at the α and / or α 'positions of the precursor cyclic group of R2 may include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings that are fused to the precursor cyclic group through the α, β and / or groups α ', β' positions respectively. Such fused cyclic groups are described in more detail below.
[0107] [0107] In one embodiment, R2 is a fused aryl or fused heteroaryl group, in which the aryl or heteroaryl group is fused to one or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings, where R2 can optionally still be substituted. Typically, a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group through the α, β positions. Typically, the aryl or heteroaryl group is also substituted at the α 'position, for example, with a substituent selected from -R43, -OR43 and -COR43, where each R43 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl , C2-C6 alkynyl or C2-C6 cyclic group and wherein each R43 is optionally further substituted with one or more halo groups. Typically, in such an embodiment, R2 is bicyclic or tricyclic.
[0108] [0108] More typically, R2 is a fused phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or 5- or 6-membered heteroaryl group is fused to one or more cycloalkyl, cycloalkenyl, non-aromatic, aryl or heterocyclic heteroaryl rings, where R2 can optionally be further substituted. Typically, a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 5- or 6-membered heteroaryl group at the α, β positions, to form a 4- to 6-membered fused ring structure. Typically, the phenyl or the 5- or 6-membered heteroaryl group is also substituted in the α 'position, for example, with a substituent selected from - R43, -OR43 and -COR43, where each R43 is selected independently from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group and wherein each R43 is optionally further substituted with one or more halo groups. Typically, in such an embodiment, R2 is bicyclic or tricyclic.
[0109] [0109] In another embodiment, R2 is a fused aryl or a fused heteroaryl group, in which the aryl or heteroaryl group is fused to two or more cycloalkyl, cycloalkenyl, heterocyclic, aryl, or non-aromatic heteroaryl rings independently selected, where R2 can optionally be further replaced. Typically, the two or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused to the aryl or heteroaryl group, that is, each cycloalkyl, cycloalkenyl, fused heterocyclic, aryl or heteroaryl ring has only two atoms and a connection in common with the aryl or heteroaryl group. Normally, R2 is tricyclic.
[0110] [0110] In yet another embodiment, R2 is a fused aryl or fused heteroaryl group, in which a first non-aromatic cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group at positions α, β and a second cycloalkyl , cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl is fused to the aryl or heteroaryl group through the α ', β' positions, where R2 can optionally be further substituted. Typically, in such an embodiment, R2 is tricyclic.
[0111] [0111] More typically, R2 is a fused phenyl or a 5- or 6-membered heteroaryl group, wherein a first non-aromatic cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 5- or 6-membered heteroaryl group in positions α, β, so as to form a first 4- to 6-membered fused ring structure, and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 5- or 6 heteroaryl group with members through positions α ', β' to form a second fused ring structure of 4 to 6 members, where R 2 can optionally be additionally substituted. Typically, in such an embodiment, R2 is tricyclic.
[0112] [0112] In one mode, -R2 has a formula selected from: Ra Rb A1 A1 Ra Rb Rc Rc Rc Rc
[0113] [0113] Normally, any ring containing A1 or A2 is a 5- or 6-membered ring. Typically, A1 and A2 are each independently selected from an optionally substituted straight chain alkylene group or an optionally substituted straight chain alkenylene group, where one or two carbon atoms in the backbone of the alkylene or alkenylene group can optionally be replaced by one or two heteroatoms selected independently of nitrogen and oxygen. More typically, A 1 and A2 are each independently selected from an optionally substituted straight chain alkylene group, wherein a carbon atom in the main chain of the alkylene group can optionally be replaced by an oxygen atom. Normally, no heteroatom at A1 or A2 is directly linked to another ring heteroatom. Normally, A 1 and A2 are unsubstituted or substituted by one or more substituents independently selected from halo, -OH, -CN, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, -O (C1-C4alkyl) or -O (C1-C4 haloalkyl). More typically, A1 and A2 are unsubstituted or replaced by one or more fluoro and / or chlorine groups. Where R2 contains both groups A1 and A2, A1 and A2 can be the same or different. Normally, A1 and A2 are the same.
[0114] [0114] Where Raa is a substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, usually the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group is replaced by one or more (for example , one or two) substituents independently selected from halo, -OH, -CN, -NO2, -O (C1-C4 alkyl) or -O (C1-C4 haloalkyl).
[0115] [0115] Where Raa is a 3- to 7-membered cyclic group substituted, normally the 3- to 7-membered cyclic group is replaced by one or more (eg one or two) substituents independently selected from halo, -OH, -NH2, -CN, -NO2, -B1, -OB1, -NHB1, -N (B1) 2, -CONH2, -CONHB1, - CON (B1) 2, -NHCOB1, -NB1COB1 or -B11-; wherein each B1 is independently selected from a C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl or phenyl group or a 4- to 6-membered heterocyclic group containing one or two hetero atoms in the N ring and / or O, or two B1 together with the nitrogen atom to which they are attached, can form a 4- to 6-membered heterocyclic group containing one or two N and / or O ring heteroatoms, where any B 1 can optionally be replaced by halo and / or substituted with one or two substituents independently selected from -OH, -NH2, -OB12, -NHB12 or - N (B12) 2; wherein each B11 is independently selected from a C1-C8 alkylene or C2-C8 alkenylene group, where one or two carbon atoms in the main chain of the alkylene or alkenylene group can optionally be replaced by one or two N and / or O heteroatoms , and wherein the alkylene or alkenylene group can optionally be substituted with halo and / or substituted with one or two substituents independently selected from -OH, -NH2, -OB12, -NHB12 or -N (B12) 2; and wherein each B12 is independently selected from a C1-C3 alkyl or C1-C3 haloalkyl group; typically, any divalent group -B11-
[0116] [0116] Normally, each Ra is -Raa. More typically, each Ra is independently selected from a C1-C6 alkyl group (in particular C3-C6 branched alkyl) or C3-C6 cycloalkyl, where each Ra is optionally further substituted with one or more halo groups. More typically, each R a is selected independently from a C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl group. Where a group Ra is present at positions α and α ', each Ra can be the same or different. Normally, each Ra is the same.
[0117] [0117] Normally, each Rb is selected independently from hydrogen or halo. More typically, each Rb is hydrogen.
[0118] [0118] Typically, each Rc is independently selected from hydrogen, halo, -OH, -NO2, -CN, -Rcc or -ORcc. More typically, each Rc is independently selected from hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclopropyl. More typically, each Rc is independently selected from hydrogen or halo.
[0119] [0119] Normally, each Rcc is independently selected from a C1-C4 alkyl or C3-C6 cycloalkyl group, or any two Rcc attached to the same nitrogen atom can, together with the nitrogen atom to which they are attached, form a heterocyclic group saturated 3 to 6 members, where each Rcc is optionally replaced. Where Rcc is substituted, normally Rcc is substituted by one or more halo, -OH, -CN, -NO2, -O (C1-C4 alkyl) groups or -O (C1-C4 haloalkyl) groups. More typically, each Rcc is independently selected from a C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl group.
[0120] [0120] In one mode, -R2 has a formula selected from:
[0121] [0121] where R10 and R11 are independently selected from C1- C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl and C3-C4 halocycloalkyl, and Rd is hydrogen, halo, -OH, -NO2, -CN, -Rdd , -ORdd, -CORdd, -COORdd, -CONH2, - CONHRdd or -CON (Rdd) 2, where each -Rdd is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl and C3-C4 halocycloalkyl. Typically, R10 and R11 are independently selected from C1-C4 alkyl and Rd is hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocycle-propyl. More typically, R10 and R11 are independently selected from C1-C4 alkyl, and Rd is hydrogen or halo.
[0122] [0122] Normally, -R2 has a formula selected from: Cl F, and.
[0123] [0123] In one mode, -R2 has a formula selected from: A1 A1 A1
[0124] [0124] In one embodiment, Re is hydrogen, halo, -OH, -NO2, -CN, - Ree, -ORee, -CORee, -COORee, -CONH2, -CONHRee or -CON (Ree) 2, where each -Ree is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl and C3-C4 halocycloalkyl. Typically, Re is hydrogen or a halo, hydroxyl, -CN, -NO2, -Ree and -ORee group, where Ree is a C1-C4 alkyl group that can optionally be substituted by halo. More typically, R e is hydrogen or halo.
[0125] [0125] Normally, any ring containing A1 or A2 is a 5- or 6-membered ring.
[0126] [0126] Typically, A1 and A2 are each independently selected from an optionally substituted straight chain alkylene group or an optionally substituted straight chain alkenylene group, where one or two carbon atoms in the main chain of the alkylene or alkenylene group can optionally be replaced by one or two heteroatoms selected independently from nitrogen and oxygen. More typically, A1 and A2 are each independently selected from an optionally substituted straight chain alkylene group, in which a carbon atom in the main chain of the alkylene group can optionally be replaced by an oxygen atom. Normally, no heteroatom at A1 or A2 is directly linked to another ring heteroatom. Typically, A 1 and A2 are unsubstituted or substituted by one or more halo, hydroxyl, - CN, -NO2, -B3 or -OB3 groups, where B3 is a C1-C4 alkyl group that can optionally be substituted by halo. More typically, A1 and A2 are unsubstituted or replaced by one or more fluoro and / or chlorine groups. Where R 2 contains both groups A1 and A2, A1 and A2 can be the same or different. Normally, A1 and A2 are the same.
[0127] [0127] In another mode, -R2 has a formula selected from:
[0128] [0128] where R11 is C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl, and Rf is hydrogen, halo, -OH, -NO2, -CN, -Rff, -ORff, - CORff, -COORff, -CONH2, -CONHRff or -CON (Rff) 2, where each -Rff is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl. Typically, R11 is C1-C4 alkyl and Rf is hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclopropyl. Typically, R11 is C1-C4 alkyl and Rf is hydrogen or halo.
[0129] [0129] Typically, -R2 has a formula selected from: N N N N,,,,,, N N N
[0130] [0130] More normally, -R2 has the formula:.
[0131] [0131] Still other typical substituents at the α position of the cyclic group of origin of R2 may include monovalent heterocyclic groups and monovalent aromatic groups, in which a ring atom of the heterocyclic or aromatic group is directly linked via a simple connection to the ring atom α of the parent cyclic group, where the heterocyclic or aromatic group can optionally be substituted and where the parent cyclic group can optionally be additionally substituted. These R 2 groups are described in more detail below.
[0132] [0132] In one embodiment, the parent cyclic group substituted with α from R2 is a 5- or 6-membered cyclic group, where the cyclic group can optionally be additionally substituted. In one embodiment, the parent cyclic group substituted with α from R2 is an aryl or heteroaryl group, all of which can optionally be additionally substituted. In one embodiment, the parent cyclic group substituted by α from R2 is a phenyl or a 5- or 6-membered heteroaryl group, all of which can optionally be additionally substituted. In one embodiment, the parent cyclic group substituted by α from R2 is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazoli group, all of which can be optional replaced later. In one embodiment, the parent cyclic group substituted by α from R2 is a phenyl or pyrazolyl group, both of which can optionally be additionally substituted. In one embodiment, the parent cyclic group substituted by α from R2 is a phenyl group, which can optionally be further substituted.
[0133] [0133] In one embodiment, the cyclic group of origin substituted by α from R2 is substituted in positions α and α 'and can optionally be further substituted. For example, the parent cyclic group substituted by α from R2 may be a phenyl group substituted at positions 2 and 6 or a phenyl group substituted at positions 2, 4 and 6.
[0134] [0134] In one embodiment, R2 is a cyclic group of origin substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group, in which the heterocyclic or aromatic group can be optionally substituted and in which the originating cyclic group can optionally still be replaced. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl or a 5- or 6-membered heterocyclic group, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group in the α position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolil, isoxazolil, thiazolol, isothiazolyl, triazolyl, isothiazolyl, triazolyl, triazole, azetidinyl, oxetanil, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanil, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, 1,4-piperazinil dioxatanil, thianyl, morpholinyl, thiomorpholinyl or 1-methyl-2-oxo-1,2-dihydropyridinyl, which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group in the α position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolil, isoxazolil, thiazolol, isothiazolyl, triazolyl, isothiazolyl, triazolyl, triazole, azetidinyl, oxetanil, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, tianyl, pianil, tianil, pianil, piperine 4-dioxatanil, morpholinyl or thiomorpholinyl, which can optionally be replaced. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolil, isoxazolil, thiazolil, pyridinyl or pyridinyl, or pyridinyl, or pyridinyl, or pyridinyl, pyridine or pyridine. all of which can optionally be replaced. In one embodiment, the monovalent heterocyclic or aromatic group in the α position is a phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl or tetrahydropyranyl or 1-methyl-2oxo-1,2-dihydrofiridinyl group, all of which can optionally be replaced. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl or tetrahydropyranyl group, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyrimidinyl, pyrazolyl group, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group in the α-position is an unsubstituted phenyl, pyridinyl, pyrimidinyl or pyrazolyl group. In one embodiment, the monovalent heterocyclic group at the α position is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic group at the α position is an unsubstituted pyridin-3-yl group or an optionally substituted pyridin-4-yl group.
[0135] [0135] For any of these monovalent heterocyclic or aromatic groups in the α position mentioned in the immediately preceding paragraph, the monovalent heterocyclic or aromatic group can optionally be substituted by one or two substituents independently selected from halo, -OH, -NH2, -CN, -NO2, -B4, -OB4, -NHB4, -N (B4) 2, -CONH2, -CONHB4, - CON (B4) 2, -NHCOB4, -NB4COB4, or -B44-; wherein each B4 is independently selected from a C1- C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl or phenyl group or a 4- to 6-membered heterocyclic group containing one or two heteroatoms in the N ring and / or O, or two B4 together with the nitrogen atom to which they are attached,
[0136] [0136] In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyrimidinyl or pyrazolyl group, all of which can optionally be substituted by one or two substituents selected independently from halo, -OH, - NH2, -CN, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, -OB4 or -N (B4) 2, where B4 is independently selected from C1-C4 alkyl which can optionally be replaced by halo. 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 can optionally be substituted by one or two substituents selected independently from halo, - OH, -NH2, -CN, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, -OB4 or -N (B4) 2, where B4 is independently selected from C1-C4 alkyl that can optionally be replaced by 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 by one or two substituents independently selected from halo, -OH, -NH2, - CN, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, -OB4 and -N (B4) 2, where B4 is independently selected from C1-C4 alkyl which can optionally be substituted by halo . Alternatively, any of these monovalent or heterocyclic phenyl groups in the α position can optionally be substituted by one or two substituents independently selected from halo, -OH, -NH2, -CN, -NO2, -B4, -OB4, -NHB4 or -N (B4) 2, wherein each B4 is independently selected from a group C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, which can optionally be substituted with halo.
[0137] [0137] In one embodiment, R2 is a cyclic group of origin substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group, in which the heterocyclic or aromatic group can be optionally substituted and in which the originating cyclic group can optionally still be replaced. In one embodiment, these additional substituents are at the α 'position of the parent cyclic group replaced by α from R2. These additional substituents can be selected independently from the halo groups -Rγ, -ORγ and -CORγ, where each Rγ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group and in which each Rγ is optionally substituted with one or more halo groups. Typically, these additional substituents on the parent cyclic group substituted by R2 are independently selected from halo, C1-C6 alkyl groups (in particular C3-C6 branched alkyl) or C3-C6 cycloalkyl groups, for example, fluorine, chlorine, isopropyl, cyclopropyl , cyclohexyl or t-butyl, wherein the alkyl and cycloalkyl groups are optionally further substituted by one or more fluoro and / or chloro groups.
[0138] [0138] In one mode, -R2 has a formula selected from:
[0139] [0139] Normally, -R2 has a formula selected from:
[0140] [0140] In one embodiment, R2 is a cyclic group of origin substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group, in which the heterocyclic or aromatic group can be optionally substituted and in which the originating cyclic group can optionally still be replaced. The other substituents on the parent cyclic group substituted with α from R2 also include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings that are fused to the parent cyclic group substituted with α from R2. Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused to the parent cyclic group substituted by α from R2, that is, each fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring has only two atoms and a common connection with the cyclic pair-substituted group of R2. Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused to the original cyclic group substituted by α from R2 through positions α ', β'.
[0141] [0141] In one mode, -R2 has a formula selected from: Rh N Rh Rh N Rh
[0142] [0142] In one mode, -R2 has a formula selected from: N N
[0143] [0143] Normally, -R2 has a formula selected from: N
[0144] [0144] In one embodiment, R2 is phenyl or a 5- or 6-membered heteroaryl group (such as phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl); where (i) the 5- or 6-membered phenyl or heteroaryl group is substituted in the α position by a substituent selected from -R43, -OR43 and-COR43, where R43 is selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group and where R43 is optionally substituted with one or more halo groups; and optionally, the 5- or 6-membered phenyl or heteroaryl group is further substituted in the α 'position by a substituent selected from -R44, -OR44 and - COR44, where R44 is selected from a C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group and where R44 is optionally substituted with one or more halo groups; and optionally, the 5- or 6-membered phenyl or heteroaryl group is further substituted (usually with one, two or three substituents independently selected from halo, -NO2, -CN, -COOR15, -CONH2, -CONHR15 or - CON ( R15) 2, wherein each -R15 is independently selected from a C1-C4 alkyl or C1-C4 haloalkyl group); or (ii) the 5- or 6-membered phenyl or heteroaryl group is replaced by a non-aromatic cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl ring that is fused to the parent phenyl or the 5- or 6-membered heteroaryl group through the α positions , β and which is optionally substituted by one or more halo groups; and optionally, the 5- or 6-membered phenyl or heteroaryl group is further substituted in the α 'position by a substituent selected from -R43, -OR43 and - COR43, where R43 is selected from a C1-C6 alkyl, C2-C6 alkenyl , C2-C6 alkynyl or C2-C6 cyclic group and wherein R43 is optionally substituted with one or more halo groups; and optionally, the 5- or 6-membered phenyl or heteroaryl group is further substituted (usually with one or two substituents independently selected from halo, -NO2, -CN, -COOR15, -CONH2, -CONHR15 and - CON (R15 ) 2, where each -R15 is independently selected from a C1-C4 alkyl or C1-C4 haloalkyl group); or (iii) the 5- or 6-membered phenyl or heteroaryl group is replaced by a first non-aromatic cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl ring that is fused to the parent phenyl or the 5- or 6-membered heteroaryl group through the α positions , β and which is optionally substituted by one or more halo groups; and the 5- or 6-membered phenyl or heteroaryl group is replaced by a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring that is fused to the parent phenyl or the 5- or 6-membered heteroaryl group through the positions α ', β 'and which is optionally substituted by one or more halo groups; and optionally, the phenyl group is further substituted (usually with a substituent selected from halo, -NO2, -CN, -COOR15, -CONH2, - CONHR15 and -CON (R15) 2, where each -R15 is selected independently from one C1-C4 alkyl or C1-C4 haloalkyl group); or (iv) the 5- or 6-membered phenyl or heteroaryl group is replaced in the α position by a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl,
[0145] [0145] In the modality directly above, where a group or fraction is optionally substituted by one or more halo groups, it can be replaced, for example, by one, two, three, four, five, five or six halo groups.
[0146] [0146] In one aspect of any of the above, R 2 contains 15 to 50 atoms. More typically, R2 contains 20 to 40 atoms. More typically, R2 contains 25 to 35 atoms.
[0147] [0147] In another aspect of any of the above modalities, R2 contains 10 to 50 atoms other than hydrogen. More typically, R2 contains 10 to 40 atoms other than hydrogen. More typically, R2 contains 10 to 35 atoms other than hydrogen. More typically, R2 contains 12 to 30 atoms other than hydrogen.
[0148] [0148] Q is selected from O or S. In an embodiment of the first aspect of the invention, Q is O.
[0149] [0149] In a specific embodiment, the invention provides a compound of formula (I), where: Q is O; L is - (CHR14) n-, where n is 1, 2, 3, 4 or 5, and R14 is independently selected from hydrogen, methyl or ethyl; R1 is a 3, 4, 5, 6 or 7 membered heterocycle comprising at least one atom of the nitrogen or oxygen ring, wherein the heterocycle can optionally be substituted by one, two or three substituents independently selected from halo, C1-C3 alkyl, C1-C3 haloalkyl, - CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O), where R15 is independently selected from hydrogen or C1-C3 alkyl; and R2 is a cyclic group substituted at the α position, where R2 can optionally be additionally substituted. In one embodiment, R2 is a cyclic group substituted at positions α and α '. In one embodiment, n is 1, 2 or 3. In one embodiment, the R1 heterocycle is a saturated heterocycle, such as azetidine, oxetane, tiethane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tiane, piperazine, dioxane, morpholine and thiomorpholine. In another embodiment, the R1 heterocycle is an aromatic heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole or triazole.
[0150] [0150] In another embodiment, the invention provides a compound of formula (I), in which: Q is O; L is a saturated or unsaturated C1-C8 hydrocarbilene group, where the hydrocarbilene group can be straight or branched or be or include cyclic groups, where the hydrocarbilene group can optionally be substituted by one, two or three substituents independently selected from from the halo, C1-C3 haloalkyl, -CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, - COOR15 or oxo (= O); R1 is –NR3R4; R3 and R4 are each independently selected from hydrogen, C1-C3 alkyl, phenyl or benzyl, where the C1-C3 alkyl group can be optionally substituted with one, two or three substituents independently selected from halo-CN, -N3, -NO2, -N (R15) 2, -OR15,
[0151] [0151] In another embodiment, the invention provides a compound of formula (I), in which: Q is O; L is - (CHR14) n-, where n is 1, 2, 3, 4 or 5, and R14 is independently selected from hydrogen, methyl or ethyl; R1 is –NR3R4; R3 and R4 are each independently selected from hydrogen, C1-C3 alkyl, phenyl or benzyl, where the C1-C3 alkyl group can be optionally substituted with one, two or three substituents independently selected from halo-CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O), where the phenyl or benzyl group can optionally be substituted with one, two or three independently selected substituents from halo, C1-C3 alkyl, C1-C3 haloalkyl, -CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O); R15 is independently selected from hydrogen or C 1 -C 3 alkyl; and R2 is a cyclic group substituted at the α position, where R2 can optionally be additionally substituted. In one embodiment, R2 is a cyclic group substituted at positions α and α '. In one embodiment, n is 1, 2 or 3.
[0152] [0152] In another embodiment, the invention provides a compound of formula (I), in which: Q is O; L is a saturated or unsaturated C1-C8 hydrocarbilene group, where the hydrocarbilene group can be straight or branched or be or include cyclic groups, where the hydrocarbilene group can optionally be substituted by one, two or three substituents independently selected from from the halo, C1-C3 haloalkyl, -CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, - COOR15 or oxo (= O); R1 is –OR5; R5 is selected from hydrogen, C1-C3 alkyl, phenyl or benzyl, where the C1-C3 alkyl group can optionally be substituted by one, two or three substituents independently selected from halo, -CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O), and where the phenyl or benzyl group can optionally be substituted by one, two or three substituents independently selected from halo, C1-C3 alkyl , C1-C3 haloalkyl, - CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O); R15 is independently selected from hydrogen or C1-C3 alkyl; and R2 is a cyclic group substituted at the α position, where R2 can optionally be additionally substituted; provided that the L atom which is attached to the sulfur atom of the sulfonylurea group is not an atom ring of an aromatic group. In one embodiment, R2 is a cyclic group substituted at positions α and α '. In one embodiment, the L atom which is attached to the sulfur atom of the sulfonylurea group is a ring atom of a heterocyclic or aromatic group. In one embodiment, the L atom which is attached to the sulfon atom of the sulfonylurea group is not a ring atom of any cyclic group.
[0153] [0153] In another embodiment, the invention provides a compound of formula (I), in which: Q is O; L is - (CHR14) n-, where n is 1, 2, 3, 4 or 5, and R14 is independently selected from hydrogen, methyl or ethyl; R1 is –OR5; R5 is selected from hydrogen, C1-C3 alkyl, phenyl or benzyl, where the C1-C3 alkyl group can optionally be substituted by one, two or three substituents independently selected from halo, -CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O), and where the phenyl or benzyl group can optionally be substituted by one, two or three substituents independently selected from halo, C1-C3 alkyl , C1-C3 haloalkyl, - CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O); R15 is independently selected from hydrogen or C1-C3 alkyl; and R2 is a cyclic group substituted at the α position, where R2 can optionally be additionally substituted. In one embodiment, R2 is a cyclic group substituted at positions α and α '. In one embodiment, n is 1, 2 or 3.
[0154] [0154] In another embodiment, the invention provides a compound of formula (I), in which: Q is O; -L-R1 is a C1-C12 saturated or unsaturated hydrocarbilene group substituted by oxo (= O), where the hydrocarbilene group can be straight or branched chain, or be or include cyclic groups, and where the hydrocarbilene group can be still optionally substituted by one, two or three substituents independently selected from halo, C1-C3 haloalkyl, - CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O) ;
[0155] [0155] In another embodiment, the invention provides a compound of formula (I), in which: Q is O; -L-R1 is - (CHR14) n-R16; n is 1, 2, 3, 4 or 5; R14 is independently selected from hydrogen, methyl or ethyl; R16 is a cyclic group of 5 or 6 members substituted by a substituent selected from -CN, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O), and optionally further substituted by one, two or three substituents independently selected from halo, C1-C3 alkyl, C1-C3 haloalkyl, - CN, -N3, -NO2, -N (R15) 2, -OR15, -COR15, -COOR15 or oxo (= O); R15 is independently selected from hydrogen or C1-C3 alkyl; and R2 is a cyclic group substituted at the α position, where R2 can optionally be additionally substituted. In one embodiment, R2 is a cyclic group substituted at positions α and α '. In one embodiment, n is 1, 2 or 3.
[0156] [0156] In another embodiment, the invention provides a compound of formula (I), in which: Q is O; -L-R1 is - (CHR14) n-R16; n is 1, 2 or 3; R14 is independently selected from hydrogen, methyl or ethyl; R16 is phenyl or a 5- or 6-membered heteroaryl group, where the phenyl or 5- or 6-membered heteroaryl group is replaced by a substituent selected from -CN, -N (R15) 2, -OR15, -COR15, - COOR15 oxo (= O), and optionally further substituted by one, two or three substituents independently selected from halo, C1-C3 alkyl, C1-C3 haloalkyl, -CN, -N3, -NO2, -N (R15) 2, - OR15, -COR15, -COOR15 and oxo (= O); R15 is independently selected from hydrogen or C1-C3 alkyl; and R2 is a cyclic group substituted at the α position, where R2 can optionally be additionally substituted. In one embodiment, R2 is a cyclic group substituted at positions α and α '.
[0157] [0157] In a specific embodiment, the invention provides a compound of formula (I):
[0158] [0158] The optionally substituted heterocycle selected from a group of diazirinil, azetidinyl, azetinil, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxatiolanil, piperidinyl, tetrahydropyranyl, piperazinyl, dioxanyl, morpholinyl, tiomorfolil, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl or 6-oxa-2-azaspiro [3.4] one of which can be substituted octanyl each or two substituents independently selected from a halo, C1-C6 alkyl, -CN, -N (R9) 2, -OR9 or a 4- to 6-membered saturated heterocyclic group, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group; R3 and R4 are each independently selected from a hydrogen atom or a C1-C6 alkyl group, C2-C6 alkenyl, C2-C6 alkynyl, -O (C1-C6 alkyl), -CO (C1-C6 alkyl) , -COO (C1-C6 alkyl), -CHO, C1-C6 cycloalkyl, phenyl or benzyl, each of which can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, - CN, -N (R9) 2, -OR9 or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group; or R3 and R4 together with the nitrogen atom to which they are attached, form a 4, 5 or 6 membered saturated or unsaturated cyclic group, selected from azetidinyl, azetinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl group, thiomorpholinyl or 6-oxa-2-azaspiro [3.4] octanyl, each of which can optionally be substituted by one or two substituents selected independently from a halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -N (R9) 2, -OR9 or a 4- to 6-membered saturated heterocyclic group, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group. R5 is hydrogen or a C1-C6 alkyl group; R6 and R7 are each independently a hydrogen group or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl, phenyl or benzyl group, each of which can optionally be substituted by one or more substituents (as one, two or three substituents) independently selected from halo, -CN, -N (R9) 2, -OR9 or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a group C1-C3 alkyl; or L and R6, or L and R7, or R6 and R7 together with the group - (C = N) - to which they are attached, form a saturated cyclic group of 4, 5 or 6 members, in which the cyclic group can optionally include another N, O or S heteroatom in its carbon skeleton and where the cyclic group can optionally be substituted by one or more substituents (such as one, two or three substituents) independently selected from halo, -CN, -N (R9 ) 2, -OR9, C1-C3 alkyl, C1-C3 alkylene or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[0159] [0159] In this specific modality directly above, the parent phenyl or the 5- or 6-membered heteroaryl group of R 2 can be selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.
[0160] [0160] In the specific modality directly above, where a group or fraction is optionally substituted by one or more halo groups, it can be replaced, for example, by one, two, three, four, five, five or six halo groups.
[0161] [0161] In one aspect of any of the above embodiments, the compound of formula (I) has a molecular weight of 200 to 2000 Da. Typically, the compound of formula (I) has a molecular weight of 235 to 1,400 Da. Typically , the compound of formula (I) has a molecular weight of 270 to 1000 Da. Typically, the compound of formula (I) has a molecular weight of 300 to 700 Da. More typically, the compound of formula (I) has a molecular weight molecular from 300 to 600 Da.
[0162] [0162] A second aspect of the invention provides a compound selected from the group consisting of: Me2N N O O O O O Y N Y N N N N H H H H THE HN THE O O O S HN THE N S N N H H O O O O O O O O S S N N N N N N H H H H H O O O O O O Y N Y N N N N N H H H H O O O O O O S S N N N N N N H H H H THE O O O O O O S S N N N N N N H H H H THE O O O O O O s N N N O S H H N N H H O O O O O O O N Y N Y N N N N H H H H O O O N O O O s Y N N N N N H H H H O O O O O O Y N Y N N N N N H H H H H O O O O O S S N N N N N H H H H N N O O O O O O S S N N N N H H H H N O O O O O O S S N N N N N H H H H O O O O O O s N Y N N N N N H H H H NC O O O O O O S S N N N N N H H H H
[0163] [0163] A third aspect of the invention provides a pharmaceutically acceptable salt, solvate or prodrug of any compound of the first or second aspect of the invention.
[0164] [0164] The compounds of the present invention can be used both in their free base form and in their acid addition salt form. For the purposes of this invention, a "salt" of a compound of the present invention includes an acid addition salt. Acid addition salts are preferably non-toxic pharmaceutically acceptable addition salts with suitable acids, including, but not limited to, inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids ( for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids, such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxylic, mucic or galactic, gluconic, gluconic , pantothenic or pamoic), organic sulfonic acids (e.g., methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic,
[0165] [0165] Where a compound of the invention includes a quaternary ammonium group, the compound is typically used in its salt form. The counterion for the quaternary ammonium group can be any non-toxic, pharmaceutically acceptable counterion. Examples of suitable counterions include the conjugated bases of protic acids discussed above in relation to acid addition salts.
[0166] [0166] The compounds of the present invention can also be used both in the form of free acid and in the form of salt. For the purposes of this invention, a "salt" of a compound of the present invention includes one formed between a protic acid functionality (such as a carboxylic acid group) of a compound of the present invention and a suitable cation. Suitable cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium and ammonium. The salt can be a mono, di, tri or multi salt. Preferably, the salt is a mono- or dilithium salt, sodium, potassium, magnesium, calcium or ammonium. More preferably, the salt is a mono- or disodium salt or a mono- or dipotassium salt.
[0167] [0167] Preferably any salt is a non-toxic, pharmaceutically acceptable salt. However, in addition to pharmaceutically acceptable salts, other salts are included in the present invention, since they have the potential to serve as intermediates in the purification or preparation of others, for example, pharmaceutically acceptable salts or are useful for identification, characterization or purification of the acid or free base.
[0168] [0168] The compounds and / or salts of the present invention can be anhydrous or in the form of a hydrate (for example, a hemihydrate, monohydrate, dihydrate or trihydrate) or other solvate. These solvates can be formed with common organic solvents, including, but not limited to, alcoholic solvents, for example, methanol, ethanol or isopropanol.
[0169] [0169] In some embodiments of the present invention, therapeutically inactive examples are provided. Examples are compounds that, when administered to a subject such as a human, are converted in whole or in part to a compound of the invention. In most embodiments, the examples are pharmacologically inert chemical derivatives that can be converted in vivo to molecules of the active drug to exert a therapeutic effect. Any of the compounds described in this document can be administered as a prodrug to increase the compound's stability, bioavailability or activity or otherwise change the properties of the compound. Typical examples of prodrugs include compounds that have biologically unstable protecting groups in a functional fraction of the active compound. The prodrugs, but are not limited to compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated and / or dephosphorylated to produce the active compound. The present invention also encompasses salts and solvates of such prodrugs, as described above.
[0170] [0170] The compounds, salts, solvates and prodrugs of the present invention can contain at least one chiral center. The compounds, salts, solvates and prodrugs can therefore exist in at least two isomeric forms. The present invention encompasses racemic mixtures of the compounds, salts, solvates and prodrugs of the present invention, as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of this invention, a "substantially enantiomerically pure" isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2% and more typically less than 0.5% by weight.
[0171] [0171] The compounds, salts, solvates and prodrugs of the present invention may contain any stable isotope, including, but not limited to 12C, 13C, 1H, 2H (D), 14N, 15N, 16O, 17O, 18O, 19F and 127I, and any radioisotope including, but not limited to, 11C, 14C, 3H (T), 13N, 15O, 18F, 123I, 124I, 125I and 131I.
[0172] [0172] The compounds, salts, solvates and prodrugs of the present invention can be in any polymorphic or amorphous form.
[0173] [0173] A fourth aspect of the invention provides a pharmaceutical composition comprising a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention and a pharmaceutically acceptable excipient.
[0174] [0174] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Aulton’s Pharmaceutics - The Design and Manufacture of Medicines", M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier, 4th Ed., 2013.
[0175] [0175] Pharmaceutically acceptable excipients, including adjuvants, diluents or vehicles that can be used in the pharmaceutical compositions of the present invention are those conventionally used in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen sulfate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, carboxymethyl cellulose sodium, polyacrylates, waxes, polyoxypropylene-polyethylene-, polyethylene-glycol block polymers and wool fat.
[0176] [0176] In one embodiment, the pharmaceutical composition of the fourth aspect of the invention further comprises one or more additional active agents.
[0177] [0177] In an additional embodiment, the pharmaceutical composition of the fourth aspect of the invention can 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 comprise a pharmaceutically acceptable excipient and one or more additional active agents.
[0178] [0178] A fifth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine and / or for use in the treatment or prevention of a disease, disorder or condition. Typically, the use comprises administering the compound, salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the use comprises the co-administration of one or more additional active agents.
[0179] [0179] The term "treatment", as used herein, also refers to curative and palliative or enhancing 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, symptom relief, symptom prevention, decrease in disease extent, stabilization (ie, do not worsen) of a condition, delay or slowing of progression / worsening of a condition / symptoms, improvement or palliation of the condition / symptoms and remission (partial or total), whether detectable or undetectable. The term "palliation" and its variations, as used here, means that the extent and / or undesirable manifestations of a physiological condition or symptom are decreased and / or the progression of the progression is slower or longer, compared to not administering a composition, salt, solvate, prodrug or pharmaceutical composition of the present invention. The term "prevention", as used herein in connection with a disease, disorder or condition, refers to prophylactic or preventive therapy, as well as therapy to reduce the risk of developing the disease, disorder or condition. The term "prevention" includes both preventing the occurrence of the disease, disorder or condition, and delaying the onset of the disease, disorder or condition. Any statistically significant prevention (p ≤ 0.05) of the occurrence, delay in onset or risk reduction, measured by a controlled clinical trial, can be considered a prevention of the disease, disorder or condition. Preventable subjects include those most at risk for a disease, disorder or condition identified by genetic or biochemical markers. Typically, genetic or biochemical markers are appropriate for the disease, disorder or condition under consideration and may include, for example, inflammatory biomarkers, such as C-reactive protein (CRP) and monocyte 1 chemoprotein protein 1 (MCP-1) in the case inflammation; total cholesterol, triglycerides, insulin resistance and C-peptide in the case of NAFLD and NASH; and more generally IL1β and IL18 in the case of a disease, disorder or condition responsive to NLRP3 inhibition.
[0180] [0180] A sixth aspect of the invention provides the use of a compound of the first or second aspect, or a pharmaceutically effective salt, solvate or prodrug of the third aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition. Typically, treatment or prevention comprises administering the compound, salt, solvate, prodrug or drug to a subject. In one embodiment, treatment or prevention comprises co-administering one or more additional active agents.
[0181] [0181] A seventh aspect of the invention provides a method of treating or preventing a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the first or second aspect, or a salt, solvate or protease. pharmaceutically acceptable drug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby treat or prevent the disease, disorder or condition. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, administration is for a subject in need.
[0182] [0182] An eighth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in the treatment or preventing an illness, disorder or condition in an individual, where the individual has a germline or a non-silent somatic mutation in NLRP3. The mutation can be, for example, a gain in function or another mutation resulting in increased NLRP3 activity. Typically, the use comprises administering the compound, salt, solvate, prodrug or pharmaceutical composition to an individual. In one embodiment, the use comprises the co-administration of one or more additional active agents. The use may also comprise the diagnosis of an individual with a non-silent somatic germline or somatic mutation in NLRP3, in which the compound, salt, solvate, prodrug or pharmaceutical composition is administered to an individual based on a positive diagnosis for the mutation . Typically, the identification of the mutation in the NLRP3 in the individual can be by any suitable genetic or biochemical means.
[0183] [0183] A ninth aspect of the invention provides the use of a compound of the first or second aspect, or a pharmaceutically effective salt, solvate or prodrug of the third aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition in an individual, where the individual has a germline or non-silent somatic mutation in NLRP3. The mutation can be, for example, a gain in function or another mutation resulting in increased NLRP3 activity. Typically, treatment or prevention comprises administering the compound, salt, solvate, prodrug or medication to an individual. In one embodiment, treatment or prevention comprises co-administering one or more additional active agents. Treatment or prevention may also comprise the diagnosis of an individual with a non-silent somatic germ or mutation in NLRP3, in which the compound, salt, solvate, prodrug or medication is administered to an individual based on a positive diagnosis for the mutation. Typically, the identification of the mutation in the NLRP3 in the individual can be by any suitable genetic or biochemical means.
[0184] [0184] A tenth aspect of the invention provides a method of treating or preventing a disease, disorder or condition, the method comprising the steps of diagnosing an individual with a germline or non-silent somatic mutation in NLRP3 and administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, for the positively diagnosed individual, to thereby treat or prevent the disease, disorder or condition. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, administration is for a subject in need.
[0185] [0185] In general modalities, the disease, disorder or condition can be a disease, disorder or condition of the immune system, the cardiovascular system, the endocrine system, the gastrointestinal tract, the renal system, the hepatic system, the metabolic system, the respiratory system, the central nervous system, may be cancer or other malignancy and / or may be caused or associated with a pathogen.
[0186] [0186] It will be appreciated that these general modalities defined according to broad categories of diseases, disorders and conditions are not mutually exclusive. In this regard, any particular disease, disorder or condition can be categorized according to more than one of the general modalities above. A non-limiting example is type I diabetes, which is an autoimmune disease and a disease of the endocrine system.
[0187] [0187] In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is responsive to the inhibition of NLRP3. As used herein, the term "inhibition of NLRP3" refers to the complete or partial reduction in the level of NLRP3 activity and includes, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.
[0188] [0188] There is evidence of a role for IL-1 and IL-18 induced by NLRP3 in inflammatory responses that occur in connection with or as a result of a multitude of different disorders (Menu et al., Clinical and Experimental Immunology, 166: 1 –15, 2011; Strowig et al., Nature, 481: 278-286, 2012).
[0189] [0189] NLRP3 has been implicated in several autoinflammatory diseases, including Familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), pyogenic arthritis, pyoderma gangrenous and acne (PAPA), Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO) and acne vulgaris (Cook et al., Eur. J. Immunol., 40: 595–653, 2010). In particular, it has been found that mutations in NLRP3 are responsible for a set of rare autoinflammatory diseases known as CAPS (Ozaki et al., J. Inflammation Research, 8: 15-27, 2015; Schroder et al., Cell, 140: 821-832, 2010; and Menu et al., Clinical and Experimental Immunology, 166: 1–15, 2011). CAPS are inherited diseases characterized by recurrent fever and inflammation and are composed of three autoinflammatory diseases that form a clinical continuum. These diseases, in ascending order of severity, are the familial auto-inflammatory syndrome associated with cold (FCAS), the Muckle-Wells syndrome (MWS) and the chronic infantile cutaneous neurological joint syndrome (CINCA; also called neonatal multisystemic inflammatory disease) , NOMID) and all have been shown to result from function gain mutations in the NLRP3 gene, which leads to increased secretion of IL-1β.
[0190] [0190] Various autoimmune diseases have been shown to involve NLRP3, 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. Nat. Rev. Drug Disc. 2004 3: 1-10; Inoue et al., Immunology 139: 11-18, Coll et al. Nat. Med. 2015 21 (3): 248-55 ; and Scott et al. Clin. Exp. Rheumatol 2016 34 (1): 88-93), systemic lupus erythematosus (Lu et al. J Immunol. 2017 198 (3): 1119-29), and systemic sclerosis (Artlett et al. Arthritis Rheum. 2011; 63 (11): 3563-74). NLRP3 has also been shown to play a role in several lung diseases, including chronic obstructive pulmonary disorder (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). It has also been suggested that NLRP3 plays a role in several conditions of the central nervous system, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury from 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. January 2, 2018). NRLP3 activity has also been shown to be involved in several metabolic diseases, including type 2 diabetes (T2D), atherosclerosis, obesity, gout, pseudo-gout, 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 steatohepatitis (Mridha et al.
[0191] [0191] The inflammasome, and NLRP3 specifically, has also been proposed as a target for modulation by several pathogens, including viruses such as DNA viruses (Amsleret al., Future Virol. (2013) 8 (4), 357–370).
[0192] [0192] 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 invasion, growth and metastasis, and inhibition of IL-1β with Canaquinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomized study, double-blind, placebo-controlled (Ridker et al. Lancet, S0140-6736 (17) 32247-X, 2017). Inhibition of NLRP3 or IL-1β inflammasome has also been shown to inhibit lung cancer cell proliferation and migration in vitro (Wang et al. Oncol Rep. 2016; 35 (4): 2053-64). A role for NLRP3 inflammasome has been suggested in myelodysplastic syndromes (Basiorka et al. Blood. December 22, 2016; 128 (25): 2960-2975) and also in the carcinogenesis of several other types of cancer, including glioma (Li et al Am J Cancer Res. 2015; 5 (1): 442-449), inflammation-induced tumors (Allen et al. J Exp Med. 2010; 207 (5): 1045-56 and Hu et al. PNAS. 2010; 107 (50): 21635-40), multiple myeloma (Li et al. Hematology 2016 21 (3): 144-51) and squamous cell carcinoma of the head and neck (Huang et al. J Exp Clin Câncer Res. 2017 2; 36 (1): 116). It has also been demonstrated that the activation of the NLRP3 inflammasome mediates the chemoresistance of tumor cells to 5-fluorouracil (Feng et al. J Exp Clin Cancer Res. 2017 21; 36 (1): 81) and the activation of the NLRP3 inflammasome in the peripheral nerve for neuropathic pain induced by chemotherapy (Jia et al. Mol Pain. 2017; 13: 1-11).
[0193] [0193] NLRP3 has also been shown to be necessary for the efficient control of infections by viral, bacterial, fungal and helminth pathogens (Strowig et al., Nature, 481: 278-286, 2012).
[0194] [0194] Therefore, examples of diseases, disorders or conditions that can respond 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 include: (i ) inflammation, including inflammation that occurs as a result of an inflammatory disorder, for example, an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs as a result of infection or inflammation secondary to trauma, injury or autoimmunity ; (ii) autoimmune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (PHC), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglutular insufficiency, autoimmune thyroiditis, autoimmune thyroiditis , Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, lupus erythematosus including systemic lupus erythematosus (SLE) , multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus syndrome (WHO), optic neuritis, Ord thyroiditis, pemphigus , pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis l or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjogren's syndrome, systemic sclerosis to a systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, hot autoimmune hemolytic anemia, Wegener's granulomatosis, universal alopecia, Behçet's disease , Chagas' disease, dysautonomia, endometriosis, suppurative hidradenitis (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo or vulvodynia;
[0195] [0195] In one modality, the disease, disorder or condition is selected from: (i) cancer; (ii) an infection; (iii) a disease of the central nervous system; (iv) cardiovascular disease; (v) a liver disease; (vi) eye diseases; or
[0196] [0196] More typically, the disease, disorder or condition is selected from: (i) cancer; (ii) an infection; (iii) a disease of the central nervous system; or (iv) cardiovascular disease.
[0197] [0197] In one modality, the disease, disorder or condition is selected from: (i) acne conglobata; (ii) atypical dermatitis; (iii) Alzheimer's disease; (iv) amyotrophic lateral sclerosis; (v) age-related macular degeneration (AMD); (vi) anaplastic thyroid cancer; (vii) cryopyrin-associated periodic syndromes (CAPS); (viii) contact dermatitis; (ix) cystic fibrosis; (x) congestive heart failure; (xi) chronic kidney disease; (xii) Crohn's disease; (xiii) cold-induced familial autoinflammatory syndrome (FCAS); (xiv) Huntington's disease; (xv) heart failure; (xvi) heart failure with preserved ejection fraction; (xvii) ischemic reperfusion injury; (xviii) juvenile idiopathic arthritis; (xix) myocardial infarction; (xx) macrophage activation syndrome;
[0198] [0198] In another typical 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 present invention include inflammatory responses that occur in connection with or as a result of: (i) a skin condition such as hypersensitivity on contact, bullous pemphigoid, sunburn, psoriasis, atypical dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, bullous epidermolysis, urticaria, erythema or alopecia; (ii) an articular condition such as osteoarthritis, systemic juvenile idiopathic arthritis, adult Still's disease, relapsing polychondritis, rheumatoid arthritis, chronic juvenile arthritis, gout or seronegative spondyloarthropathy (for example, ankylosing spondylitis, psoriatic arthritis or Reiter's disease); (iii) a muscle condition such as polymyositis or myasthenia gravis; (iv) a condition of the gastrointestinal tract, 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 allergy that may have remote effects the intestine (for example, migraine, rhinitis or eczema); (v) a condition of the respiratory system, such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or powder asthma, and particularly chronic or confirmed asthma, such as late asthma and airway hyperresponsiveness ), rhinitis bronchitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, pummel rhinitis, sicca rhinitis, drug rhinitis, membranous rhinitis, seasonal rhinitis, for example, 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; (vi) a vascular condition such as atherosclerosis, Behcet's disease, vasculitis or wegener's granulomatosis; (vii) an autoimmune condition, such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic purple thrombocytopenia or Graves' disease; (viii) an eye condition such as uveitis, allergic conjunctivitis or vernal conjunctivitis; (ix) a nervous condition such as multiple sclerosis or encephalomyelitis; (x) an infection or condition related to the infection, such as Acquired Immunodeficiency Syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis, mycobacterium avium intracellular, pneumocystis carinii pneumonia, orchitis / epididymitis, lyme disease, legionella, The epstein-barr virus,
[0199] [0199] In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is an autoinflammatory disease, such as periodic syndromes associated with crypirin (CAPS), Muckle-Wells syndrome ( MWS), cold-induced familial autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multisystemic inflammatory disease (NOMID), tumor necrosis factor (TNF), periodic receptor-associated syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis, gangrenous pyoderma and acne syndrome (PAPA), adult Still's disease (AOSD), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), antibody deficiency and PLCG2-associated immune dysregulation (PLAID), PLCG2-associated autoinflammatory, antibody deficiency and immune dysregulation (APLA ID) or sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD).
[0200] [0200] Examples of diseases, disorders or conditions that can respond 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 substantially or totally mediated by NLRP3 and IL-1β and / or IL-18 inflammasome activity. As a result, such diseases, disorders or conditions may be particularly responsive to inhibition of NLRP3 and may be particularly suitable for treatment or prevention in accordance with 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), cold familial autoinflammatory syndrome (FCAS), neonatal onset multisystemic inflammatory disease (NOMID), familial Mediterranean fever (FMF) ), pyogenic arthritis, gangrenous pyoderma and acne syndrome (PAPA), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic juvenile idiopathic arthritis, Still's disease adult (AOSD), relapsing polychondritis, Schnitzler's syndrome, Sweet's syndrome, Behcet's disease, anti-synthase syndrome, interleukin 1 receptor antagonist (DIRA) deficiency and A20 haploinsufficiency (HA20) insufficiency.
[0201] [0201] In addition, some of the diseases, disorders or conditions mentioned above arise due to mutations in NLRP3, in particular, resulting in increased activity of NLRP3. As a result, such diseases, disorders or conditions may be particularly responsive to inhibition of NLRP3 and may be particularly suitable for treatment or prevention in accordance with 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), cold-induced familial autoinflammatory syndrome (FCAS) and neonatal onset multisystemic inflammatory disease (NOMID).
[0202] [0202] In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is not an NFκB-mediated disease or disorder. In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is not rheumatoid arthritis, osteoarthritis, an autoimmune disease, psoriasis, asthma, a cardiovascular disease, a coronary syndrome acute, atherosclerosis, myocardial infarction, unstable angina, congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type II diabetes, metabolic syndrome X, inflammatory bowel disease, systemic lupus erythematosus, Grave's disease, myasthenia gravis, insulin resistance , autoimmune hemolytic anemia, scleroderma with anti-collagen antibodies, pernicious anemia or diabetes mellitus. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not an inflammatory bowel disease.
[0203] [0203] An eleventh aspect of the invention provides a method of inhibiting NLRP3, the method comprising the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to inhibit NLRP3.
[0204] [0204] In an eleventh aspect of the present invention, the method comprises the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention or a product pharmaceutical composition of the fourth aspect of the invention, in combination with one or more additional active agents.
[0205] [0205] In an embodiment of the eleventh aspect of the present invention, the method is performed ex vivo or in vitro, for example, in order to analyze the effect on cells of NLRP3 inhibition.
[0206] [0206] In another embodiment of the eleventh aspect of the present invention, the method is performed in vivo. For example, the method may comprise the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby inhibit NLRP3. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, administration is for a subject in need.
[0207] [0207] Alternatively, the eleventh aspect method of the invention may be a method of inhibiting NLRP3 in a non-human animal subject, the method comprising the steps of administering the compound, salt, solvate, prodrug or pharmaceutical composition to the subject non-human animal and optionally subsequently mutilating or sacrificing the non-human animal subject. Typically, this method further comprises the step of analyzing one or more tissue or fluid samples from the optionally mutilated or sacrificed non-human animal subject. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents.
[0208] [0208] A twelfth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in inhibition of NLRP3. Typically, the use comprises administering the compound, salt, solvate, prodrug or pharmaceutical composition to a subject.
[0209] [0209] A thirteenth aspect of the invention provides the use of a compound of the first or second aspect of the invention, or a pharmaceutically effective salt, solvate or prodrug of the third aspect of the invention, in the manufacture of a medicament for inhibiting 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.
[0210] [0210] In any embodiment of any of the fifth to thirteenth aspects of the present 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 active agents.
[0211] [0211] The one or more additional active agents can be used or administered before, simultaneously, sequentially to each other or subsequently to each other and / or to the compound of the first or second aspect of the invention, the pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or the pharmaceutical composition of the fourth aspect of the invention. Where 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, a pharmaceutical composition of the fourth aspect of the invention can be administered in that the pharmaceutical composition additionally comprises one or more additional active agents.
[0212] [0212] In an embodiment of any of the fifth to thirteenth aspects of the present invention comprising the use or co-administration of one or more additional active agents, one or more additional active agents are selected from: (i) chemotherapeutic agents ; (ii) antibodies; (iii) alkylating agents; (iv) anti-metabolites; (v) anti-angiogenic agents; (vi) vegetable alkaloids and / or terpenoids; (vii) topoisomerase inhibitors; (viii) mTOR inhibitors; (ix) stylbenoids; (x) STING agonists; (xi) cancer vaccines; (xii) immunomodulating agents; (xiii) antibiotics; (xiv) antifungal agents; (xv) anthelmintic agents; and / or (xvi) other active agents.
[0213] [0213] It will be appreciated that these general modalities defined according to broad categories of active agents are not mutually exclusive. In this regard, any specific active agent can be categorized according to more than one of the general modalities above. A non-limiting example is urelumab, which is an antibody that is an immunomodulatory agent for the treatment of cancer.
[0214] [0214] In some embodiments, one or more chemotherapeutic agents are selected from abiraterone acetate, altretamine, amsacrine, anhydrovinblastine, auristatin, azathioprine, adriamycin, bexarotene, bicalutamide, BMS 184476, bleomycin, N, N-dimethyl-L- valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, cisplatin, carboplatin, carboplatin cyclophosphamide, chlorambucil, cachectin, cemadotine, cyclophosphamide, carmustine, cryptophine, cytarabine, docetaxel, doxetaxel, doxorubicin, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine, dolastatin, etoposide, etoposide phosphate, enzalutamide (MDV3100), 5-fluorouracil, fludarabine, floamide, gencitabine, hydroxyamide, hydroxy, hydroxyurea RPR109881), meclorethamine, mercaptopurine, methotrexate, mitomycin C, mitoxantrone, melphalan, mivobulin, 3 ', 4'-didhydro-4'-deoxy-8'-norvin- kaleucoblastine, nilutamide, oxaliplatin, oxaliplatin, imusti na, procarbazine,
[0215] [0215] Alternatively or in addition, one or more chemotherapeutic agents can be selected from complement fragment CD59, fragment of fibronectin, gro-beta (CXCL2), heparinases, fragment of heparin hexasaccharide, human chorionic gonadotropin (hCG), interferon alpha, beta interferon, gamma interferon, interferon-inducible protein (IP-10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, inhibitor of placental activator plasminogen, platelet factor-4 (PF4), fragment of 16 kD prolactin, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), growth transformation beta factor (TGF - ), vasculostatin, vasostatin (fragment of calreticulin) and / or cytokines (including interleukins, such as interleukin-2 (IL-2) or IL-10).
[0216] [0216] In some embodiments, one or more antibodies may comprise one or more monoclonal antibodies. In some modalities, one or more antibodies are selected from abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximabe vedotina, canaquinumab, cetuximab, certolizumab pegol, daclizumabe, denosumabe, golumizbe, ecolizbebe infliximab, ipilimumab, muromonab CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumuabe, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab.
[0217] [0217] In some embodiments, one or more alkylating agents may comprise an agent capable of alkylating functional nucleophilic groups under conditions present in the cells, including, for example, cancer cells. In some embodiments, one or more alkylating agents are selected from cisplatin, carboplatin, mecloretamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin. In some embodiments, the alkylating agent may work by impairing cellular function, forming covalent connections with amino, carboxyl, sulfhydryl and / or phosphate groups in biologically important molecules. In some embodiments, the alkylating agent can work by modifying a cell's DNA.
[0218] [0218] In some embodiments, one or more anti-metabolites may comprise an agent capable of affecting or preventing the synthesis of RNA or DNA. In some embodiments, one or more anti-metabolites are selected from azathioprine and / or mercaptopurine.
[0219] [0219] In some embodiments, one or more antiangiogenic agents are selected from endostatin, angiogenin inhibitors, angiostatin, angioarrestin, angiostatin (plasminogen fragment), antiangiogenic factors derived from basement membrane collagen (tumstatin, canstatin or cravine), antiantithrombin III angiogenic and / or cartilage-derived inhibitor (ICD).
[0220] [0220] In some embodiments, one or more plant alkaloids and / or terpenoids may impair the function of the microtubule. In some embodiments, one or more plant alkaloids and / or terpenoids are selected from a vinca alkali, a podophyllotoxin and / or a taxane. In some embodiments, one or more vinca alkaloids can be derived from Madagascar's periwinkle, Catharanthus roseus (formerly known as Vinca rosea) and can be selected from vincristine, vinblastine, vinorelbine and / or vindesine. In some embodiments, one or more taxanes are selected from taxol, paclitaxel, docetaxel and / or orthataxel. In some embodiments, one or more podophyllotoxins are selected from an etoposide and / or teniposide.
[0221] [0221] In some embodiments, one or more topoisomerase inhibitors are selected from a type I topoisomerase inhibitor and / or a type II topoisomerase inhibitor and may interfere with DNA transcription and / or replication, interfering with supercoiling of the DNA. In some embodiments, one or more type I topoisomerase inhibitors may comprise a camptothecin, which can be selected from exactecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and / or ST 1481. In some embodiments, one or more type II topoisomerase inhibitors may comprise an epipodophyllotoxin, which can be selected from an amsacrine, etoposide, etoposide phosphate and / or teniposide.
[0222] [0222] In some embodiments, one or more inhibitors of mTOR (target of rapamycin in mammals, also known as mechanistic target of rapamycin) are selected from rapamycin, everolimus, temsirolimus and / or deforolimus.
[0223] [0223] In some embodiments, one or more stylbenoids are selected from resveratrol, piceatanol, pinsilvin, pterostilbene, alpha-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, epsilon-vinferin, flexuosol A, gnetin H, hemsleyanol D, hopeafenol D, transdiptoindonesin B, astringin, piceid and / or diptoindonesin A.
[0224] [0224] In some embodiments, one or more STING agonists (interferon gene stimulator, also known as transmembrane protein (TMEM) 173) may comprise cyclic dinucleotides, such as cAMP, cGMP and cGAMP and / or modified cyclic di-nucleotides that may include one or more of the following modification features: 2'-O / 3'- O bond, phosphorothioate bond, adenine and / or guanine analogue and / or 2'-OH modification (for example, 2'-OH protection with a methyl group or substitution of 2'-OH by -F or -N3).
[0225] [0225] In some modalities, one or more cancer vaccines are selected from an HPV vaccine, a vaccine against hepatitis B, Oncophage and / or Provenge.
[0226] [0226] In some embodiments, one or more immunomodulating agents may comprise an immune checkpoint inhibitor. The immune checkpoint inhibitor may target an immune checkpoint receptor or combination of receptors comprising, 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), MHC class I, MHC class II, 4-1BB, 4-1BBL, OX40, OX40L, GITR, GITRL, CD27, CD70 , TNFRSF25, TL1A, CD40, CD40L, HVEM, LIGHT, BTLA, CD160, CD80, CD244, CD48, ICOS, ICOSL, B7-H3, B7- H4, VISTA, TMIGD2, HHLA2, TMIGD2, butyrophylline (including BTNL2), one member of the Siglec family, TIGIT, PVR, a killer cell immunoglobulin type receptor, an ILT, a leukocyte immunoglobulin type receptor, NKG2D, NKG2A, MICA, MICB, CD28, CD86, SIRPA, CD47, VEGF, neuropiline, CD30, CD39, CD73, CXCR4 and / or CXCL12.
[0227] [0227] In some embodiments, the immune checkpoint inhibitor is selected from urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDDL3280A) (PDDL3280A) -L1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertibe, ulocuplumab, BKT140, bavituxima, and / or MNRP1685A.
[0228] [0228] In some embodiments, one or more antibiotics are selected from amikacin, gentamicin, kanamycin, neomycin, netilmycin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenatin, meripenem, imipenopenem, meripenem, , cefadroxil, cefazolin, cephalothin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren,
[0229] [0229] In some embodiments, one or more antibiotics may comprise one or more cytotoxic antibiotics. In some embodiments, one or more cytotoxic antibiotics are selected from actinomycin, anthracenedione, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose and / or clofazimine. In some embodiments, one or more actinomycins are selected from actinomycin D, bacitracin, colistin (polymyxin E) and / or polymyxin B. In some embodiments, one or more anthracenediones are selected from mitoxantrone and / or pixantrone. In some modalities, one or more anthracyclines are selected from bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin),
[0230] [0230] In some embodiments, one or more antifungal agents are selected from bifonazole, butoconazole, clotrimazole, econazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, flaconazole, ezaconazole, flaconazol, , itraconazole, posaconazole, propiconazole, ravusconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naphthphine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, cyclopyroxy, flucytosine, flucytosine, 5 / or balm from Peru.
[0231] [0231] In some embodiments, one or more anthelmintic agents are selected from benzimidazoles (including albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole and flubendazole), abamectin, diethylcarbamazine, ivermectin, suramine, pyrantelanamide, piramide, pyrantelanamide, piramide, pyrantelanide, piramide, pyrantelanide, piramide, pyrantelanamide, pyrantylamine, niclosamide and oxyclozanide) and / or nitazoxanide.
[0232] [0232] In some embodiments, other active agents are selected from growth-inhibiting agents, anti-inflammatory agents (including non-steroidal anti-inflammatory agents), anti-psoriatic agents (including anthralin and its derivatives), vitamins and derivatives of vitamins (including retinoids and VDR receptor ligands), corticosteroids, ion channel blockers (including potassium channel blockers), immune system regulators (including cyclosporine, FK 506 and glucocorticoids), lutenizing hormone that releases hormone agonists (like leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide) and / or hormones (including estrogen).
[0233] [0233] Unless otherwise indicated, in any of the fifth to thirteenth aspects of the invention, the subject can be any human or other animal. Usually, the subject is a mammal, more typically human or domesticated mammal, such as cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse etc. Usually, the subject is a human.
[0234] [0234] Any of the medications used in the present invention can be administered orally, parenterally (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), administration by air (aerosol), rectal, vaginal, ocular or topical (including transdermal, buccal, mucous, sublingual and topical oculat).
[0235] [0235] Usually, the mode of administration selected is the most appropriate for the disorder, disease or condition to be treated or prevented. When one or more additional active agents are administered, the mode of administration can be the same or different from the mode of administration of the compound, salt, solvate, prodrug or pharmaceutical composition of the invention.
[0236] [0236] For oral administration, the compounds, salts, solvates or prodrugs of the present invention will generally be supplied in the form of tablets, capsules, hard or soft gelatin capsules, capsules, sweetener or lozenges, as a powder or granules or as an aqueous solution, suspension or dispersion.
[0237] [0237] Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients, such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweeteners, flavoring agents, dyes and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose. Corn starch and alginic acid are suitable disintegrating agents. Binders can include starch and gelatin. The lubricating agent, if present, can be magnesium stearate, stearic acid or talc. If desired, tablets can be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. The tablets can also be effervescent and / or dissolved tablets.
[0238] [0238] 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. olive.
[0239] [0239] Powders or granules for oral use can be supplied in sachets or bathtubs. Aqueous solutions, suspensions or dispersions can be prepared by adding water to powders, granules or tablets.
[0240] [0240] Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavoring agents, colorings and / or preservatives.
[0241] [0241] Formulations for rectal administration can be presented as a suppository with a suitable base, which comprises, for example, cocoa butter or a salicylate.
[0242] [0242] 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, these carriers as are known in the art to be appropriate.
[0243] [0243] For parenteral use, the compounds, salts, solvates or prodrugs of the present invention will generally be supplied in a sterile aqueous solution or suspension, buffered at an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solutions and isotonic sodium chloride or glucose. The aqueous suspensions according to the invention can include suspending agents, such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth and a wetting agent, such as lecithin. Preservatives suitable for aqueous suspensions include ethyl p-hydroxybenzoate and n-propyl. The compounds of the invention can also be presented as liposome formulations.
[0244] [0244] For ocular administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in a form suitable for topical administration, for example, as eye drops. Suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels and eye inserts. Alternatively, the compounds, salts, solvates or prodrugs of the invention can be supplied in a form suitable for other types of ocular administration, for example, as intraocular preparations (including irrigation solutions, such as intraocular, intravitreal or just injection formulations) scleral or as intravitreal implants), as corneal packs or shields, as intracameral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations.
[0245] [0245] For transdermal and other topical administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in the form of ointments, poultices (malagma), pastes, powders, dressings, creams, plasters or adhesives.
[0246] [0246] Suitable suspensions and solutions can be used in inhalers for administration of airways (aerosol).
[0247] [0247] The dose of the compounds, salts, solvates or prodrugs of the present invention will vary, of course, with the disorder, disease or condition being treated or prevented. In general, an adequate dose will be in the range of 0.01 to 500 mg per kilogram of the recipient's body weight per day. The desired dose can be presented at an appropriate interval, such as once every two days, once a day, twice a day, three times a day or four times a day. The desired dose can be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.
[0248] [0248] To avoid doubts, as far as possible, any modality of a given aspect of the present invention can occur in combination with any other modality of the same aspect of the present invention. Furthermore, as far as possible, it should 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.
[0249] [0249] Examples - synthesis of compounds
[0250] [0250] All solvents, reagents and compounds were purchased and used without further purification, unless otherwise specified. Abbreviations 2-MeTHF - 2-methyltetrahydrofuran Acetic anhydride Ac2O AcOH - acetic acid aq - aqueous Boc - tert-butyloxycarbonyl br - broad Cbz - carboxybenzyl CDI - 1,1-carbonyl-di-imidazole conc - concentrate d - doublet DABCO - 1,4-diazabicyclo [2.2.2] octane DCE - 1,2-dichloroethane, also called ethylene dichloride DCM - dichloromethane DIPEA - N, N-diisopropylethylamine, also called Hünig DMA dimethylacetamide DMAP - 4-dimethylaminopyridine base, also called N, N-dimethylpyridin-4-amine DME - dimethoxyethane DMF - N, N-dimethylformamide DMSO - dimethyl sulfate eq or equivalent (ES +) - Electrospray ionization, positive mode Et - ethyl EtOAc - ethyl acetate EtOH - ethanol h - hour (s) HATU 1- [bis (dimethylamino) methylene] hexafluorphosphate 3-oxide -1H-1,2,3-triazole [4,5-b] pyridinium UPLC - high performance liquid chromatography LC - chromatography liquid m - multiplet m-CPBA - 3-chloroperoxybenzoic acid Me - methyl MeCN - acetonitrile MeOH - methanol (M + H) + - molecular ion protonated ular MHz - megahertz min - minute (s) MS - mass spectrometry Ms - mesyl, also called methanesulfonyl MsCl - mesyl chloride, also called methanesulfonyl chloride MTBE - methyl tert-butyl methyl, also called tert-butyl methyl ether m / z - mass to charge ratio NaOtBu - sodium tert-butoxide NBS - 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide NCS - 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide NMP - N -methylpyrrolidine
[0251] [0251] Experimental methods
[0252] [0252] Analytical Methods
[0253] [0253] NMR spectra were recorded at 300, 400 or 500 MHz (unless otherwise indicated) with chemical changes reported in parts per million. The spectra were measured at 298 K, unless otherwise stated, and were referenced for solvent resonance. The spectra were recorded using one of the following machines:
[0254] [0254] An Agilent VNMRS 300 instrument equipped with a magnet
[0255] [0255] An Agilent MercuryPlus 300 instrument equipped with a 7.05 Tesla magnet from Oxford Instruments, 4-core probe with automatic switching and Mercury plus console.
[0256] [0256] A 400 MHz Bruker spectrometer using ICON-NMR, under TopSpin program control.
[0257] [0257] A 400 MHz Bruker Avance III spectrometer equipped with a 5 mm BBO liquid probe.
[0258] [0258] A Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbeTM.
[0259] [0259] Alternatively, LC-MS has been registered using SHIMADZU UPLC-2020, Agilent 1200 LC / G1956A MSD and Agilent 1200 G6110A, Agilent 1200 LC & Agilent 6110 MSD. Mobile phase: A: 0.025% NH 3 · H2O in water (v / v); B: acetonitrile. Column: Kinetex EVO C18 2,1X30 mm, 5 µm.
[0260] [0260] Reverse-phase UPLC conditions for UPLC analytical methods:
[0261] [0261] Methods 1a and 1b: Waters Xselect CSH C18 XP column, 2.5 µm (4.6 x 30 mm) at 40 ° C; flow rate 2.5-4.5 mL min-1-1 eluted with a water-acetonitrile gradient containing 0.1% v / v formic acid (Method 1a) or 10 mM ammonium bicarbonate in water (Method 1b ) for 4 minutes, using UV detection at 254 nm. Gradient information: 0-3.00 min, increased from 95% in water - 5% in acetonitrile to 5% in water - 95% in acetonitrile; 3.00-3.01 min, maintained at 5% water and 95% acetonitrile, the flow rate increased to 4.5 mL min-1; 3.01-3.50 min, maintained at 5% water and 95% acetonitrile; 3.50-3.60 min, returned to 95% water-5% acetonitrile,
[0262] [0262] UPLC and LC-MS were registered in an Agilent 1290 series with UV detector and HP 6130 MSD mass detector. Mobile phase A: ammonium acetate (10 mM); water / MeOH / acetonitrile (900: 60:40); mobile phase B: ammonium acetate (10 mM); water / MeOH / acetonitrile (100: 540: 360); column, Waters XBridge BEH C18 XP (2.1 x 50 mm, 2.5 μm) Pump flow: 0.6 mL / min UV detection: 215, 238 nm Injection volume: 0.2 μL Execution time: 4 , 0 min Column temperature: 35 ° C Mass detection: API-ES + ve e -ive Pump program: Gradient time% A% B (min) 0.0 80 20 0.5 80 20
[0263] [0263] Reverse-phase UPLC conditions for UPLC analytical methods:
[0264] [0264] Methods 2a and 2b: BEH C18 waters (2.1 x 30 mm, 1.7 µm) at 40 ° C; flow rate 0.77 mL min-1 eluted with an H2O-MeCN gradient containing 0.1% v / v formic acid (Method 2a) or 10 mN NH4HCO3 in water (Method 2b) over 3 min using UV detection at 254 nm. Gradient information: 0-0.11 min, maintained at 95% water 5% acetonitrile, flow rate 0.77 mL min-1; 0.1-2.15 min, increased from 95% in water-5% in acetonitrile to 5% in water-95% in acetonitrile; 2.15-2.49 min, maintained at 5% water - 95% acetonitrile, flow rate 0.77 mL min -1; 2.49-2.56 min, returned to 95% water and 5% acetonitrile; 2.56-3.00 min, maintained at 95% water and 5% acetonitrile, flow rate reduced to 0.77 mL min-1.
[0265] [0265] Purification methods
[0266] [0266] Method 1 (acid preparation): Waters X-Select CSH C18 column, 5 µm (19 x 50 mm), flow rate of 28 mL / min eluting with a water-acetonitrile gradient containing 0.1% v / v of formic acid for 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 20% acetonitrile; 0.2-5.5 minutes, increased from 20% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, increased from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, maintained at 95% acetonitrile.
[0267] [0267] Method 2 (basic preparation): Waters X-Bridge Prep C18 column, 5 µm (19 x 50 mm), flow rate of 28 mL / min eluting with a 10 mM gradient of acetonitrile bicarbonate and 10 mM ammonium for 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 10% acetonitrile; 0.2-5.5 minutes, increased from 10% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, increased from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, maintained at 95% acetonitrile.
[0268] [0268] Method 3: Phenomenex Gemini column, 10 µm (150 x 25 mm), flow rate = 25 mL / min eluting with a water-acetonitrile gradient containing 0.04% NH3 at pH 10 for 9 minutes using UV detection at 220 and 254 nm. Gradient information: 0-9 minutes, increased from 8% to 35% acetonitrile; 9-9.2 minutes, increased from 35% to 100% acetonitrile; 9.2-15.2 minutes, maintained at 100% acetonitrile.
[0269] [0269] Method 4: Buchi Sepracore® X50 system powered by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and C-660 fraction collector. Revelis C18 12 g reverse phase cartridge Carbon charge 18% Surface area 568 m2 / g Pore diameter 65 Angstrom pH (5% paste) 5.1
[0270] [0270] The column was conditioned before use with MeOH (5 min) and then taken to H2O (in 5 min) and maintained for 5 min in H2O. Flow rate = 30 mL / min
[0271] [0271] Separation runs: Time (min) A: water (%) B: MeOH (%) 0 100 0 5 100 0 30 30 70
[0272] [0272] Synthesis of intermediaries
[0273] [0273] Intermediate A1: 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene
[0274] [0274] To a solution of phosgene (4.45 ml, 20% by weight of toluene, 8.4 mmol) in ethyl acetate (90 ml) was added dropwise a solution of 1,2,3,5, 6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in ethyl acetate (45 mL) at room temperature. The resulting reaction mixture was then heated to reflux for 3 hours and after cooling it was filtered and concentrated in vacuo to give the title compound as a brown oil (756 mg, 100% yield). The crude product was used directly in the next step without further purification.
[0275] [0275] 1H NMR (CDCl3): δ 6.8 (s, 1 H), 2.89 (m, 8 H) and 2.09 (m, 4 H).
[0276] [0276] Intermediate A2: 4- (7-Fluoro-4-isocyanato-2,3-dihydro-1H-
[0277] [0277] Step A: 7-Fluoro-4-nitro-2,3-dihydro-1H -inden-1-one
[0278] [0278] 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 drop a solution of HNO3 (5.37 mL, 82.25 mmol, 69 wt.% water, 1.3 eq) in concentrated H2SO4 (20 mL) at -15 ° C. Then, the reaction mixture was stirred at 0 ° C for 0.5 hour. 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 Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 10: 1 to 3: 1) to obtain the title compound (11.4 g, 92%) as a yellow solid.
[0279] [0279] 1H NMR (CDC3) δ 8.51 (dd, 1 H), 7.22 (t, 1 H), 3.69-3.65 (m, 2 H) and 2.88-2.82 (m, 2 H).
[0280] [0280] Step B: 7-Fluoro-4-nitro-2,3-dihydro-1-Hinden-1-ol
[0281] [0281] 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. Then, the mixture was poured into water (500 ml) and extracted with DCM (2 x 200 ml). The combined organic phases were washed with brine (200 ml), dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound (30 g, crude) as brown oil.
[0282] [0282] 1H NMR (CDCl3) δ 8.21 (dd, 1 H), 7.08 (t, 1 H), 5.59-5.56 (m,
[0283] [0283] Step C: 4-Fluoro-7-nitro-2,3-dihydro-1H-indene
[0284] [0284] 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) Et3SiH (7.96 g, 68.47 mmol, 3 eq) was added in one portion. The reaction mixture was stirred for 12 hours at 25 ° C. Then, the mixture was quenched with water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with saturated aqueous NaHCO3 solution (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain the title compound (5 g, crude) as brown oil.
[0285] [0285] 1H NMR (CDCl3) δ 8.06 (dd, 1 H), 7.01 (t, 1 H), 3.46 (t, 2 H),
[0286] [0286] Step D: 7-Fluoro-2,3-dihydro-1H -inden-4-amine
[0287] [0287] To a mixture of 4-fluoro-7-nitro-2,3-dihydro-1H-indene (5 g, 27.60 mmol, 1eq) in MeOH (50 mL) was added Pd / C (0 , 5 g, 10% weight loading on activated carbon) at 25 ° C under a nitrogen atmosphere. Then, the reaction mixture was stirred at 25 ° C for 12 hours under hydrogen (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 50: 1 to 10: 1) to obtain the title compound (1.8 g, 43%) as a brown solid.
[0288] [0288] 1H NMR (CDCl3) δ 6.69 (t, 1 H), 6.44 (dd, 1 H), 3.47 (br s, 2 H),
[0289] [0289] Step E: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine
[0290] [0290] To a solution of 7-fluoro-2,3-dihydro-1H-inden-4-amine (8.3 g, 54.90 mmol, 1 eq) in toluene (100 mL) was added NBS ( 10.26 g, 57.65 mmol, 1.05 eq) in a portion at 25 ° C. The reaction mixture was immediately dark brown and then the mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was quenched with saturated aqueous Na 2SO3 solution (200 ml) and extracted with EtOAc (2 x 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 column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 1: 0 to 20: 1) to obtain the title compound (8.51 g, 67%) as a brown solid.
[0291] [0291] 1H NMR (CDCl3) δ 6.99 (d, 1 H), 3.81 (br s, 2 H), 2.92 (t, 2 H),
[0292] [0292] Step F: 7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
[0293] [0293] 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- acid ilboronic (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 under a nitrogen atmosphere. The reaction mixture was 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 x 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 column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 10: 1 to 2: 1) to obtain the title compound (1.7 g, 45% yield, 90.98% UPLC purity) as a brown solid.
[0294] [0294] 1H NMR (CDCl3) δ 8.68 (dd, 2 H), 7.40 (dd, 2 H), 6.72 (d, 1 H),
[0295] [0295] Step G: 4- (7-Fluoro-4-Isocyanato-2,3-dihydro-1H-inden-5-yl) pyridine
[0296] [0296] 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, 2eq) in THF (30 ml) bis (trichloromethyl) carbonate (208 mg, 700.94 μmol, 0.4 eq) was added at 0 ° C. The reaction mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was filtered through a pad of silica gel and the filter cake was washed with THF (20 ml). The filtrate was concentrated in vacuo to reduce to 10 ml, which was used directly in the next step.
[0297] [0297] Intermediate A3: 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile
[0298] [0298] Step A: 4-Fluoro-2- (prop-1-en-2-yl) aniline
[0299] [0299] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K2CO3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H2O (40 mL) Pd (dppf) Cl2 (7.51 g, 10.26 mmol, 0.05 eq) was added under a nitrogen atmosphere. Then the reaction mixture was stirred at 80 ° C for 5 hours. The reaction mixture was quenched by adding H 2O (600 ml) and extracted with EtOAc (2 × 500 ml). The combined organic layers were washed with brine (2 × 600 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate 1: 0 to 100: 1) to obtain the title compound (27 g, 77% yield, 89% purity on UPLC) like a yellow oil.
[0300] [0300] 1H NMR (CDCl3) δ 6.81-6.76 (m, 2 H), 6.66-6.62 (m, 1 H), 5.38 (s, 1 H), 5.08 (s, 1 H), 3.69 (br s, 2 H) and 1.25 (s, 3 H).
[0301] [0301] LCMS: m / z 152.2 (M + H) + (ES +).
[0302] [0302] Step B: 4-Fluoro-2-isopropylaniline NH2 NH2 F F
[0303] [0303] To a solution of 4-fluoro-2- (prop-1-en-2-yl) aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd / C (2 , 1 g, 178.59 mmol, 10% by weight of activated carbon charge) 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 for 12 hours under hydrogen (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the title compound (20 g, crude) as a yellow oil.
[0304] [0304] 1H NMR (CDCl3) δ 6.86 (dd, 1 H), 6.75-6.72 (m, 1 H), 6.63-6.61 (m, 1 H), 3.50 (br s, 2 H), 2.95-2.84 ( m, 1 H) and 1.25 (d, 6 H).
[0305] [0305] LCMS: m / z 154.2 (M + H) + (ES +).
[0306] [0306] Step C: 2-Bromo-4-fluoro-6-isopropylaniline NH2 NH2 Br F F
[0307] [0307] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 ml) was added NBS (23.24 g, 130.55 mmol, 1 eq) to 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 x 250 ml). The combined organic phases were washed with brine (2 x 400 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, eluting only using petroleum ether) to obtain the title compound (30 g, 99%) as a black brown oil.
[0308] [0308] 1H NMR (CDCl3) δ 6.99 (dd, 1 H), 6.78 (dd, 1 H), 3.91 (br s, 2 H), 2.88-2.71 (m, 1 H) and 1.17 (d, 6 H ).
[0309] [0309] LCMS: m / z 232.1 (M + H) + (ES +).
[0310] [0310] Step D: 4- (2-Amino-5-fluoro-3-isopropylphenyl) picolinonitrile NH2 F Br O O + B H2N F NC N NC N
[0311] [0311] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (3.6 g, 15.51 mmol, 1 eq) and 4- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) picolinonitrile (3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 mL) and H2O (9 mL) were added
[0312] [0312] 1HNMR (CDCl3) δ 8.79 (d, 1 H), 7.86 (d, 1 H), 7.65 (dd, 1 H),
[0313] [0313] LCMS: m / z 256.2 (M + H) + (ES +).
[0314] [0314] Step E: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) picolinonitrile
[0315] [0315] To a solution of 4- (2-amino-5-fluoro-3-isopropylphenyl) picolinonitrile (1 g, 3.92 mmol, 1 eq) in THF (40 mL) was added TEA (793 mg, 7, 83 mmol, 2 eq). To the above mixture, triphosgene (465 mg, 1.57 mmol, 0.4 eq) was added in portions at 5 ° C. Then the mixture was stirred at 70 ° C for 1 hour. The mixture was diluted with EtOAc (200 ml) and then filtered through silica gel. The filtrate was concentrated in vacuo to obtain the title compound (1.2 g, crude) as a yellow solid, which was used directly in the next step.
[0316] [0316] Intermediate A4: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) -2-methoxypyridine
[0317] [0317] Step A: 4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) aniline
[0318] [0318] 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 acid (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. Then, Pd (dppf) Cl2 (3.78 g, 5.17 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The mixing result was heated to 80 ºC 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 × 800 ml), dried over filtered Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 70: 1 to 10: 1) and then triturated with hexane (100 mL) to obtain the title compound (10.05 g, 72% yield, 96% UPLC purity).
[0319] [0319] 1H NMR (CDCl3) δ 8.24 (d, 1 H), 6.97 (d, 1 H), 6.93 (d, 1 H),
[0320] [0320] LCMS: m / z 261.1 (M + H) + (ES +).
[0321] [0321] Step B: 4- (5-Fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine
[0322] [0322] To a solution of 4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-
[0323] [0323] Intermediate A5: 4- (4-isocyanate-2,3-dihydro-1H-5-yl) -2-methoxypyridine
[0324] [0324] Step A: 4-nitro-2,3-dihydro-1H-indene O2N
[0325] [0325] To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 62.50 mL, 1 eq) in concentrated H2SO4 (30 mL) was added a mixture of HNO3 (50 ml, 69% by weight in water) and concentrated H2SO4 (50 ml) dropwise at 0 ° C over a period of 3.5 hours. The reaction mixture was stirred at 0 ° C for 0.5 hour. Then, the reaction mixture was poured into ice water (600 ml) and extracted with ethyl acetate (2 × 400 ml). The combined organic layers were washed with water (500 ml), saturated aqueous NaHCO3 solution (500 ml) and brine (2 × 500 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel SiO2, petroleum ether: ethyl acetate, 1: 0 to 100: 1) to obtain the title compound (55 g, 66%) as a yellow oil.
[0326] [0326] 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.51 (d, 1 H), 7.30 (t, 1 H),
[0327] [0327] Step B: 2,3-Dihydro-1H-inden-4-amine O2N H2N
[0328] [0328] To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd / C (5 g, 10 µl charge % by weight of activated carbon) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (50 psi) at 20 ° C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 1: 0 to 100: 4) to obtain the title compound (19.82 g, 43% yield, 96.39% UPLC purity) as a brown oil.
[0329] [0329] 1H NMR (CDCl3): δ 7.01 (t, 1 H), 6.71 (d, 1 H), 6.51 (d, 1 H),
[0330] [0330] LCMS: m / z 134.2 (M + H) + (ES +).
[0331] [0331] Step C: N- (2,3-Dihydro-1H-inden-4-yl) acetamide
[0332] [0332] To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1 , 3 eq) in DCM (300 ml) Ac2O (17.45 g, 170.96 mmol, 1.15 eq) was added dropwise over 6 minutes at 0 ° C. Then, the reaction mixture was heated to 16 ° C and stirred for 1.4 hours. Then, the mixture was poured into water (500 ml) and extracted with DCM (2 x 300 ml). The combined organic phases were washed with brine (2 x 500 ml), dried over Na2SO4 in anhydrous, filtered and concentrated in vacuo to obtain the title compound (25.74 g, 96% yield, 96.69% purity in UPLC) as a white solid.
[0333] [0333] 1H NMR (CDCl3): δ 7.70 (d, 1 H), 7.15 (t, 1 H), 7.02 (d, 1 H),
[0334] [0334] LCMS: m / z 176.2 (M + H) + (ES +)
[0335] [0335] Step D: N- (5-Bromo-2,3-dihydro-1H-inden-4-yl) acetamide THE THE N
[0336] [0336] N- (2,3-dihydro-1H-inden-4-yl) acetamide (34.6 g, 197.46 mmol, 1 eq), p-toluenesulfonic acid (18.70 g, 108, 60 mmol, 0.55 eq) and Pd (OAc) 2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in toluene (400 mL) and stirred at 20 ° C for 0.5 hour under air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. The reaction mixture was stirred at 20 ° C for 2 hours. The reaction mixture was poured into ice water (500 ml) and extracted with ethyl acetate (2 × 500 ml). The combined organic phases were washed with brine (2 x 500 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 10: 1 to 2: 1) to obtain the title compound (13.9 g, 27% yield, 98.1% UPLC purity) as a brown solid.
[0337] [0337] 1H NMR (CDCl3): δ 7.33 (d, 1 H), 7.16 (s, 1 H), 6.98 (d, 1 H), 2.92-2.83 (m, 4 H), 2.21 (s, 3 H) and 2.10-2.02 (m, 2 H).
[0338] [0338] LCMS: m / z 254.1 (M + H) + (ES +).
[0339] [0339] Step E: 5-Bromo-2,3-dihydro-1H-inden-4-amine
[0340] [0340] A mixture of N- (5-bromo-2,3-dihydro-1H-inden-4-yl) acetamide (45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl (300 mL, 36 wt.% in water) was stirred at 80 ° C for 36 hours. The reaction mixture was cooled to 0 ° C in an ice bath and some solid precipitated. The suspension was filtered. The filter cake was washed with ice water (50 ml) and dried in vacuo to obtain the title compound (34.1 g, 72% yield,
[0341] [0341] 1H NMR (DMSO-d6): δ 7.67 (br s, 2 H), 7.24 (d, 1 H), 6.69 (d, 1 H), 2.85 (t, 2 H), 2.79 (t, 2 H) and 2.04-1.96 (m, 2 H).
[0342] [0342] LCMS: m / z 212.0 (M + H) + (ES +).
[0343] [0343] Step F: 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine HO OH
[0344] [0344] A solution of (2-methoxypyridin-4-yl) boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-indent 4-amine (34 g, 136.80 mmol, 1 eq, HCl salt) and K2CO3 (60.50 g, 437.74 mmol, 3.2 eq) in dioxane (500 mL) and H2O (100 mL) were degassed with nitrogen for 15 minutes before Pd (dppf) Cl2. CH2Cl2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80 ° C for 12 hours. The mixture was poured into ice water (500 ml) and extracted with ethyl acetate (2 × 500 ml). The combined organic phases were washed with brine (2 x 700 ml), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 1: 0 to 10: 1) to obtain the title compound (27.4 g, 79% yield, 95% purity UPLC) as a brown solid.
[0345] [0345] 1H NMR (CDCl3): δ 8.22 (d, 1H), 7.03-7.00 (m, 1 H), 6.99 (d, 1 H), 6.87 (s, 1 H), 6.77 (d, 1 H), 3.99 (s, 3 H), 3.77 (br s, 2 H), 2.97 (t, 2 H), 2.77 (t, 2 H) and 2.21 - 2.13 (m, 2 H).
[0346] [0346] LCMS: m / z 241.2 (M + H) + (ES +).
[0347] [0347] Step G: 4- (4-isocyanate-2,3-dihydro-H-5-yl) -2-methoxypyridine
[0348] [0348] To a solution of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1 H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA ( 5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL) was added in portions of bis (trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) at 0 ° Ç. Then the reaction mixture was stirred at 16 ° C for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to obtain the title compound (9.04 g, 74%) as a light yellow solid.
[0349] [0349] 1H NMR (CDCl3): δ 8.28 (d, 1 H), 7.20-7.16 (m, 3 H), 7.02 (s, 1 H), 4.16 (s, 3 H), 3.04-2.99 (m, 4 H) and 2.23-2.15 (m, 2 H).
[0350] [0350] Intermediate A6: 3- (5-Fluoro-2-isocyanato-3 isopropylphenyl) pyridine
[0351] [0351] Step A: 4-Fluoro-2-isopropyl-6- (pyridin-3-yl) aniline
[0352] [0352] 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 N 2 three times. Then, Pd (dppf) Cl2 (5.10 g, 6.97 mmol, 0.077 eq) was added under an atmosphere of N2. The resulting mixture was heated to 80 ° C and stirred for 2 hours. The reaction mixture was suppressed by adding H 2 O (800 ml) and extracted with EtOAc (2 × 600 ml). The combined organic layers were washed with brine (2 × 800 ml), dried over anhydrous Na 2SO4 filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 50: 1 to 1: 1) and then triturated with hexane (40 mL) to obtain the title compound (17 g, 82% ) as a solid gray.
[0353] [0353] 1H NMR (CDCl3 1HRMN (CDCl3): δ 8.70 (d, 1 H), 8.63 (dd, 1 H), 7.79 (dd, 1 H), 7.41-7.38 (m, 1 H), 6.94 (dd, 1 H), 6.71 (dd, 1 H), 3.57 (s, 2 H), 2.97-2.88 (m, 1 H) and 1.30 (d, 6 H).
[0354] [0354] LCMS: m / z 231.2 (M + H) + (ES +).
[0355] [0355] Step B :: 3- (5-Fluoro-2-isocyanato-3-isopropylphenyl) pyridine
[0356] [0356] To a solution of 4-fluoro-2-isopropyl-6- (pyridin-3-yl) aniline (0.5 g, 2.17 mmol, 1 eq) and TEA (439 mg, 4.34 mmol, 2 eq) in THF (10 mL) triphosgene (257 mg, 868.51 µmol, 0.4 eq) was added in portions at 5 ° C. Then the reaction mixture was 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 obtain the title compound (0.2 g, crude) as a yellow oil, which was used directly in the next step.
[0357] [0357] Intermediate A7: 4- (4-isocyanate-2,3-dihydro-1H-5-yl) -2-methoxypyridine
[0358] [0358] Step A: N- (5-Bromo-2,3-dihydro-1H-inden-4-yl) pivalamide
[0359] [0359] N- (2,3-Dihydro-1H-inden-4-yl) pivalamide (1 g, 4.60 mmol), p-toluenesulfonic 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 with EtOAc (20 ml) and then washed with aq. saturated. NaHCO3 (2 x 10 ml), water (2 x 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 chromatography on silica gel (40 g column, 0-30% EtOAc / isohexane) to provide the title compound (1.662 g, 100%) as a colorless crystalline solid that was contaminated with a small amount of by-products of the reaction.
[0360] [0360] UPLC m / z 296.3 / 298.3 (M + H) + (ES +).
[0361] [0361] Step B: 5-Bromo-2,3-dihydro-1H-inden-4-amine
[0362] [0362] N- (5-Bromo-2,3-dihydro-1H-inden-4-yl) pivalamide (0.632 g, 2.134 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H2SO4 (95% aq) (5 ml, 89 mmol) was added slowly to water (5 ml) and this mixture was then added to the reaction mixture. The paste was heated to 100 ° C (bath temperature), at which point the mixture became homogeneous and was stirred at this temperature throughout the week. The mixture was cooled to room temperature and then basified with 2M aq. NaOH. The mixture was extracted with dichloromethane (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 chromatography on silica gel (40 g column, 0-50% EtOAc / isohexane) to provide the title compound (0.138 g, 29%).
[0363] [0363] 1H NMR (CDCl3) δ 7.23 (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).
[0364] [0364] Step C: 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
[0365] [0365] 5-Bromo-2,3-dihydro-1H-inden-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 boronic acid (2-methoxypyridin-4-yl) (250 mg, 1.635 mmol) was added. The mixture was degassed with nitrogen for 15 minutes before Pd (dppf) Cl2. CH2Cl2 (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 ° C (bath temperature) for 2 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (30 ml) and water (20 ml). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to obtain a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc / isohexane) to provide the title compound (0.289 g, 87%) as a pale yellow crystalline solid.
[0366] [0366] 1H 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), NH2 not observed.
[0367] [0367] UPLC m / z 241.3 (M + H) + (ES +).
[0368] [0368] Step D: 4- (4-isocyanate-2,3-dihydro-H-5-yl) -2-methoxypyridine
[0369] [0369] 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (500 mg, 2.081 mmol) was dissolved in DCM (10 mL) and added NaHCO3 (5 ml). A solution of triphosgene (250 mg, 0.842 mmol) in DCM (5 mL) was added and the mixture was stirred at room temperature for 1 hour. The organic phase was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to provide the title compound (523 mg, 94%) as a pale yellow oil which was used without further purification.
[0370] [0370] 1H NMR (CDCl3) δ 8.25 (d, J = 5.2 Hz, 1H), 7.18 - 7.13 (m, 2H), 7.01 (dd, J = 5.3, 1.5 Hz, 1H), 6.86 (s, 1H), 4.03 (s, 3H), 3.04 (t, J = 7.5 Hz, 4H), 2.21 (p, J = 7.5 Hz, 2H).
[0371] [0371] Intermediate A8: 4- (4-isocyanate-2,3-dihydrobenzofuran-5-yl) - 2-methoxypyridine
[0372] [0372] Step A: N- (5-Bromo-2,3-dihydrobenzofuran-4-yl) acetamide
[0373] [0373] N- (2,3-dihydrobenzofuran-4-yl) acetamide (13.1 g, 73.9 mmol), 4-methylbenzenesulfonic acid hydrate (7.73 g, 40.7 mmol) and diacetoxipaladium (0.830 g, 3.70 mmol) were suspended in toluene (250 mL) and stirred for 20 minutes. NBS (14.47 g, 81 mmol) was added and the mixture was stirred for 30 minutes, diluted with EtOAc (150 ml) and washed with NaHCO 3 aq (100 ml) and Na2S2O3 aq (10% by weight, 100 ml) . The aqueous phases were further extracted with DCM (150 ml). The organic phases were combined, dried (MgSO 4), filtered and concentrated under reduced pressure to provide the title compound (22.27 g, quant., 85% Purity by UPLC) which was used crude in the next step.
[0374] [0374] LCMS; m / z 255.9, 257.9 (M + H) + (ES +).
[0375] [0375] Step B: 5-Bromo-2,3-dihydrobenzofuran-4-amine
[0376] [0376] A solution of N- (5-bromo-2,3-dihydrobenzofuran-4-yl) acetamide (22.27 g, 73.9 mmol) in MeOH (400 mL) and concentrated H2SO4 (40 mL) was stirred at reflux for 18 hours. The volatiles were removed under reduced pressure, the residue collected in DCM (300 ml) and basified with 1 M aq NaOH (100 ml). The organic phase was separated (Na 2SO4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-100% EtOAc / isohexane) to provide the title compound (9.17 g, 57%) as an off-white solid.
[0377] [0377] 1H NMR (CDCl3) δ 7.16 (dt, J = 8.4, 0.9 Hz, 1H), 6.17 (d, J = 8.4 Hz, 1H), 4.61 (t, J = 8 , 7 Hz, 2H), 3.99 (br. S, 2H), 3.05 (t, J = 8.7 Hz, 2H).
[0378] [0378] Step C: 5- (2-methoxypyridin-4-yl) -2,3-dihydrobenzofuran-4-amine
[0379] [0379] Prepared according to the general procedure of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A7, Step C) from 5- bromo-2,3-dihydrobenzofuran-4-amine and boronic acid (2-methoxypyridin-4-yl) to provide the title compound (2.25 g, 79%) as an off-white solid.
[0380] [0380] 1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 6.99 (dd, J =
[0381] [0381] LCMS; m / z 243.1 (M + H) + (ES +).
[0382] [0382] Step D: 4- (4-isocyanate-2,3-dihydrobenzofuran-5-yl) -2-methoxypyridine
[0383] [0383] Prepared according to the general procedure of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A7, Step D) of 5- (2 -methoxypyridin-4-yl) -2,3-dihydrobenzofuran-4-amine to provide the title compound (926 mg, 79%) as a pale yellow solid.
[0384] [0384] 1H NMR (CDCl3) δ 8.23 (d, J = 5.3 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.98 (dd, J = 5 , 3, 1.4 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 4.72 (t, J = 8.7 Hz, 2H ), 4.02 (s, 3H), 3.33 (t, J = 8.7 Hz, 2H).
[0385] [0385] Intermediate A9: 5-Chlorine-2-isocyanate-1,3-diisopropylbenzene
[0386] [0386] To a solution of 4-chloro-2,6-diisopropylaniline (0.105 g, 0.496 mmol) in toluene (1 mL) was added a solution of phosgene (0.65 mL, 20 wt% toluene, 1, 22 mmol) and the reaction mixture was refluxed for 1 hour. Upon cooling, the mixture was concentrated in vacuo to provide the title compound as an orange oil (0.111 g, 94%).
[0387] [0387] 1H NMR (CDCl3) δ 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H).
[0388] [0388] Intermediate A10: 5-Fluoro-2-isocyanate-1,3-diisopropylbenzene
[0389] [0389] 4-Fluoro-2,6-diisopropylaniline (1 g, 5.12 mmol) and triethylamine (0.785 mL, 5.63 mmol) were dissolved in THF (10 mL) and cooled to 0 ° C. Triphosgene (0.760 g, 2.56 mmol) was added to the mixture in portions and the reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated in vacuo. Isohexane (50 ml) was added and the suspension was filtered through silica (3 g). The filtrate was dried under reduced pressure to provide the title compound (900 mg, 75%) as a colorless oil.
[0390] [0390] 1H NMR (DMSO-d6) δ 6.80 (d, J = 9.4 Hz, 2H), 3.27-3.12 (m, 2H), 1.23 (d, J = 6, 8 Hz, 12H).
[0391] [0391] Intermediate P1: (1-ethylpiperidin-4-yl) methanesulfonamide
[0392] [0392] To a suspension of piperidin-4-ylmethanesulfonamide hydrochloric acid (200 mg, 0.93 mmol) and potassium carbonate (514 mg, 3.7 mmol, 4.0 equiv.) In acetonitrile (10 mL ) iodoethane (74 µL, 0.93 mmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature overnight, filtered. The residue was washed with methanol and the filtrates were combined and concentrated in vacuo. The crude was dissolved in methanol, coated in a hydro matrix and then subjected to normal phase flash chromatography on silica gel using dichloromethane and a mixture of 3.5 M ammonia in methanol to provide the title compound (176 mg, 91%).
[0393] [0393] 1H NMR (CD3OD) δ 3.34 (m, 2H), 3.09 (d, 2 H), 2.93 (q, 2 H), 2.64 (t, 2 H), 2, 19 (m, 3 H), 1.58 (q, 2 H) and 1.23 (t, 3 H).
[0394] [0394] Intermediate P2: 3- (4- (Dimethylamino) piperidin-1-yl) propane-1-sulfonamide
[0395] [0395] To a solution of 3-chloropropane-1-sulfonamide (213 mg, 1.35 mmol) in acetonitrile (10 mL) was added triethylamine (225 µL, 1.62 mmol, 1.2 equiv.), N, N-dimethylpiperidin-4-amine (208 mg, 1.62 mmol, 1.2 equiv.) And potassium iodide (45 mg, 0.27 mmol). The reaction mixture was irradiated in the microwave at 100 ° C for 90 minutes and heated for another 2 hours conventionally at 100 ° C. The mixture was allowed to cool to room temperature and was concentrated in vacuo to provide the crude title compound (> 100% yield); the material still contained salts and impurities, but was used without further purification.
[0396] [0396] 1H NMR (CD3OD) δ 3.3 (m, 2 H), 3.21 (m, 2 H), 3.03 (m, 2 H), 2.75 (m, 2 H), 2 , 5 (m, 1 H), 2.33 (s, 6 H), 1.95 (m, 2 H) and 1.72-1.42 (m, 4 H).
[0397] [0397] Intermediate P3: 3- (Diethylamino) propane-1-sulfonamide
[0398] [0398] To a solution of 3-chloropropane-1-sulfonamide (203 mg, 1.29 mmol) in acetonitrile (10 mL) was added triethylamine (214 µL, 1.55 mmol, 1.2 equiv.), N, N-diethylamine (159 µL, 1.55 mmol 1.2 equiv.) And potassium iodide (43 mg, 0.26 mmol) and the reaction mixture was irradiated in the microwave at 100 ° C for 90 minutes. Additional potassium iodide (150 mg) was added and the resulting mixture was heated conventionally for an additional 2 hours at 100 ° C. After cooling to room temperature, the mixture was concentrated in vacuo to provide the crude title compound (> 100 % of yield); the material still contained salts and impurities, but was used without further purification.
[0399] [0399] 1H NMR (CD3OD) δ 2.86 (m, 6 H), 2.47 (m, 2 H), 2.23 (m, 2 H) and 1.18 (t, 6 H).
[0400] [0400] LCMS: m / z 195.1 (M + H) + (ES +).
[0401] [0401] Intermediate P4: 3- (Dimethylamino) propane-1-sulfonamide
[0402] [0402] To a solution of 3-chloropropane-1-sulfonamide (203 mg, 1.29 mmol) in 2M dimethylamine in THF (7 mL) was added triethylamine (0.18 mL, 1.29 mmol) and potassium iodide (214 mg, 1.29 mmol). The mixture was heated in a microwave at 80 ° C for 90 minutes. The solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent, to provide the title compound as a white solid (51 mg, 24%).
[0403] [0403] 1H NMR (CD3OD) δ 3.20 (t, 2H), 2.44 (t, 2H), 2.24 (s, 6H), 2.04 (m, 2H).
[0404] [0404] Intermediate P5: 4-Morpholinobutane-1-sulfonamide
[0405] [0405] To a solution of 4-chlorobutane-1-sulfonamide (250 mg, 1.46 mmol) in acetonitrile (5 mL) was added potassium carbonate (200 mg, 1.46 mmol), potassium iodide (40 mg , 0.24 mmol) and morpholine (140 mg 1.6 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was purified by chromatography on silica gel using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent, providing the title compound as a white solid (56 mg, 17%).
[0406] [0406] 1H NMR (chloroform-d) δ 4.70 (s, 2H), 3.82-3.58 (m, 4H), 3.34- 3.04 (m, 2H), 2.64- 2.24 (m, 6H), 1.93 (m, 2H), 1.79 -1.52 (m, 2H).
[0407] [0407] Intermediate P6: 4- (Diethylamino) butane-1-sulfonamide
[0408] [0408] To a solution of 4-chlorobutane-1-sulfonamide (250 mg, 1.46 mmol) in acetonitrile (5 mL) was added potassium carbonate (200 mg, 1.46 mmol), potassium iodide (60 mg , 0.36 mmol) and diethylamine (0.3 mL 2.9 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was purified by chromatography on silica gel using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to provide the title compound (60 mg, 20%) as a colorless oil.
[0409] [0409] 1H NMR (Chloroform-d) δ 3.35-2.86 (m, 2H), 2.72-2.33 (m, 6H), 1.91 (m, 2H), 1.78- 1.48 (m, 2H), 1.03 (t, 6H).
[0410] [0410] Intermediate P7: 2- (Benzyl (ethyl) amino) ethane-1-sulfonamide
[0411] [0411] Ethylene sulfonamide (250 mg, 2.33 mmol) was dissolved in THF (12.5 mL) and N-ethylbenzylamine (0.36 mL, 331 mg, 2.45 mmol) was added and the solution was stirred for 15 minutes at room temperature. Triethylamine (0.98 mL, 0.71 g, 7.0 mmol) was added and the mixture was stirred for 24 hours at room temperature. The now slightly cloudy mixture was evaporated in vacuo. The residue was dissolved in a few mL of DCM / MeOH (1/1) and applied to automated column chromatography (40g SiO2, 5-30% MeOH / 3.5N ammonia in DCM). This provided the title compound (420 mg, 1.73 mmol, 74%) with 99.3% purity (ELSD-UPLC) after evaporating the selected fractions.
[0412] [0412] 1H NMR (CDCl3) δ 7.30 (m, 5 H), 3.64 (s, 2 H), 3.17 (dd, 2 H), 3.04 (dd, 2 H), 2 , 59 (q, 2 H), 1.10 (t, 3 H).
[0413] [0413] Intermediate P8: 2-Morpholinoethane-1-sulfonamide
[0414] [0414] Prepared according to 2- (benzyl (ethyl) amino) ethane-1-sulfonamide (Intermediate P7) using ethylene sulfonamide (375 mg, 3.5 mmol) and morpholine (0.35 mL, 351 mg, 4, 03 mmol) to produce the title compound (520 mg, 61%) after column chromatography.
[0415] [0415] UPLC-MS: 100% (ELSD), M 194 +1 (ACPI pos.)
[0416] [0416] 1H NMR (DMSO-d6) δ 6.75 (s, 2H), 3.56 (dd, J = 4.8, 4.4 Hz, 4H), 3.32 (s, 2H), 3.15 (dd, J = 8.7, 6.4 Hz, 2H), 2.69 (dd, J = 9.7, 8.0 Hz, 2H),
[0417] [0417] Intermediate P9: 4- (Benzyl (ethyl) amino) butane-1-sulfonamide
[0418] [0418] To a solution of 4-chlorobutane-1-sulfonamide (200 mg, 1.17 mmol) in acetonitrile (5 mL) was added and ethyl benzylamine (2 mL, 13.5 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was triturated with heptane. The resulting solids were filtered and dried to provide the title compound as a white solid (300 mg, 95%).
[0419] [0419] 1H NMR (Chloroform-d) δ 7.80-6.71 (m, 5H), 4.58 (s, 2H), 3.56 (s, 2H), 3.12 (t, 2H) , 2.47 (m, 4H), 1.97 (m, 2H), 1.60 (m, 2H), 1.11 (t, 3H).
[0420] [0420] Intermediate P10: 3-Morpholinopropane-1-sulfonamide
[0421] [0421] To a solution of 3-chloropropane-1-sulfonamide (200 mg,
[0422] [0422] 1H NMR (Chloroform-d) δ 3.71 (m, 4H), 3.24 (t, 2H), 2.62-2.40 (m, 6H), 2.08 (m, 2H) .
[0423] [0423] Intermediate P11: 3- (Piperidin-1-yl) propane-1-sulfonamide
[0424] [0424] To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.27 mmol) in acetonitrile (5 mL) was added pepiridine (0.44 g, 5 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was triturated with t-butyl methyl ether. The solids were filtered and ground in THF. The solids were filtered and the mother liquor was evaporated to provide the title compound as an oil which solidified on standing (100 mg, 38%).
[0425] [0425] 1H NMR (Chloroform-d) δ 3.23 (t, J = 6.6 Hz, 2H), 2.64-2.33 (m, 6H), 2.09 (m, 2H), 1 , 60 (m, 4H), 1.47 (dd, 2H).
[0426] [0426] Intermediate P12: 2- (Diethylamino) ethane-1-sulfonamide
[0427] [0427] Prepared according to 2-benzyl (ethyl) amino) ethane-1-sulfonamide (Intermediate P7) using ethylene sulfonamide (ca. 60% content, 500 mg, 2.8 mmol) and diethylamine (0.43 mL , 307 mg, 4.2 mmol) to produce the title compound (186 mg, 36%) after column chromatography.
[0428] [0428] UPLC-MS: 84% purity by ELSD, M 180 +1 (ACPI pos.)
[0429] [0429] 1H NMR (DMSO-d6) δ 6.74 (s, 2H), 3.13-3.01 (m, 2H), 2.88-
[0430] [0430] Intermediate P13: 2- (Ethylamino) ethane-1-sulfonamide
[0431] [0431] Prepared according to 2-benzyl (ethyl) amino) ethane-1-sulfonamide (Intermediate P7) using ethylene sulfonamide (ca. 60% content, 500 mg, 2.8 mmol) and ethylamine (2M in THF, 2.1 mL, 4.2 mmol) to produce the title compound (131 mg, 30%) after column chromatography.
[0432] [0432] UPLC-MS: 98% (ELSD), M 152 +1 (ACPI pos.)
[0433] [0433] 1H NMR (DMSO-d6) δ 6.74 (s, 2H), 3.09 (t, J = 7.0 Hz, 2H), 2.87 (t, J = 7.0 Hz, 2H ), 2.54 (m, 2H, overlap with d-DMSO), 0.96 (t, J = 7.2 Hz, 3H).
[0434] [0434] Intermediate P14: (1-ethylazetidin-3-yl) methanesulfonamide
[0435] [0435] To a solution of 7 M ammonia in methanol (2 mL, 14 mmol) was added azetidin-3-yl hydrochloride) methanesulfonyl fluoride (250 mg, 1.3 mmol). The reaction mixture was stirred for one hour and then concentrated in vacuo. The solid material was suspended in acetonitrile (10 ml) and then acetaldehyde (109 µL, 1.95 mmol) was added followed by sodium triacetoxyborohydride (413 mg, 1.95 mmol). The reaction mixture was then stirred at room temperature overnight. The solution was concentrated in vacuo. The crude material was dissolved in methanol, coated with Agilent hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and ammonia (3.5 M) in methanol to provide the title compound (17 mg, 7% yield) which was used without further purification.
[0436] [0436] 1H NMR (CD3OD) δ 3.90 (m, 2 H), 3.55 (m, 2 H), 3.38 (m, 2 H), 3.20 (m, 1 H), 2 , 88 (q, 2 H), 1.08 (t, 3 H).
[0437] [0437] Intermediate P15: (1-Methylpiperidin-4-yl) methanesulfonamide
[0438] [0438] To a suspension of piperidin-4-ylmethanesulfonamide hydrochloric acid (200 mg, 0.93 mmol, 1.0 equiv.), Triethylamine (0.16 mL, 1.16 mmol, 1.2 equiv. ), formaldehyde (37% in water, stabilized with methanol; 80 µL, 0.98 mmol, 1.05 equiv.) in acetonitrile (10 mL) and sodium triacetoxyborohydride (246 mg, 1.16 mmol, 1, 25 equiv.) Was added. The reaction mixture was stirred overnight and then concentrated in vacuo. The crude material was dissolved in methanol, coated with Agilent hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and ammonia (3.5 M) in methanol to provide the title compound (82 mg, 43% yield) which was used without further purification.
[0439] [0439] 1H NMR (DMSO-d6) δ 6.76 (s, 2 H), 2.88 (d, 2 H), 2.69 (m, 2 H), 2.10 (s, 3 H) , 1.78 (m, 5 H), 1.25 (m, 2 H).
[0440] [0440] Intermediate P16: (1-Methylpyrrolidin-3-yl) methanesulfonamide
[0441] [0441] Prepared as described for (1-methylpiperidin-4-yl) methanesulfonamide (Intermediate P15) from (pyrrolidin-3-yl) methanesulfonamide hydrochloride and formaldehyde. The title compound (95 mg, 53%) was used without further purification.
[0442] [0442] 1H NMR (DMSO-d6) δ 6.75 (s, 2 H), 3.00 (dd, 2 H), 2.67 (m, 1 H), 2.37 (m, 2 H) , 2.24 (m, 5 H), 2.00 (m, 1H), 1.49 (m, 1H).
[0443] [0443] Intermediate P17: (1-ethylpyrrolidin-3-yl) methanesulfonamide
[0444] [0444] Prepared as described for (1-methylpiperidin-4-yl) methanesulfonamide (Intermediate P15) from (pyrrolidin-3-yl) methanesulfonamide hydrochloride and acetaldehyde. The title compound (86 mg, 44%) was used without further purification.
[0445] [0445] 1H NMR (DMSO-d6) δ 6.76 (s, 2 H), 3.01 (m, 2 H), 2.71 (m, 1 H), 2.37 (m, 4 H) , 2.23 (m, 2 H), 1.99 (m, 1H), 1.48 (m, 1H), 0.98 (t, 3H).
[0446] [0446] Intermediate P18: (1-Isopropylpyrrolidin-3-yl) methanesulfonamide
[0447] [0447] Prepared as described for (1-methylpiperidin-4-yl) methanesulfonamide (Intermediate P15) from (pyrrolidin-3-yl) methanesulfonamide hydrochloride and acetone. The title compound (167 mg, 81%) was used without further purification.
[0448] [0448] 1H NMR (DMSO-d6) δ 6.75 (s, 2 H), 3.01 (m, 2 H), 2.79 (dd, 1 H), 2.55 (m, 1 H) , 2.41 (m, 1 H), 2.27 (m, 3 H), 1.97 (m, 1 H), 1.47 (m, 1 H), 0.98 (dd, 6 H) .
[0449] [0449] Intermediate P19: 1- (dimethylamino) propane-2-sulfonamide
[0450] [0450] Prepared as described for (1-methylpiperidin-4-yl) methanesulfonamide (Intermediate P15) from 1-aminopropane-2-sulfonamide hydrochloride, except that 2 equivalents of formaldehyde and sodium triacetoxyborohydride were used instead on one. The title compound
[0451] [0451] 1H NMR (CD3OD) δ 3.50 (m, 1 H), 3.21 (m, 1 H), 3.01 (dd, 1 H), 2.71 (s, 6 H), 1 , 40 (d, 3 H).
[0452] [0452] Intermediate P20: 2- (Piperidin-1-yl) ethane-1-sulfonamide
[0453] [0453] Prepared according to 2- (benzyl (ethyl) amino) ethane-1-sulfonamide (Intermediate P7) using ethylene sulfonamide (375 mg, 3.15 mmol) and piperidine (0.36 mL, 308 mg, 3, 62 mmol) to produce the title compound (206 mg, 34%) after column chromatography.
[0454] [0454] UPLC-MS: 100% (ELSD), M 192 +1 (ACPI pos.)
[0455] [0455] 1H NMR (Chloroform-d) δ 3.20 (dd, J = 7.4, 6.5 Hz, 2H), 2.87 (dd, J = 5.5, 4.6 Hz, 2H) , 2.48 (t, J = 5.2 Hz, 3H), 1.63-1.49 (m, 5H), 1.49-1.42 (m, 2H).
[0456] [0456] Intermediate P21: 2- (Azetidin-1-yl) ethane-1-sulfonamide
[0457] [0457] Prepared according to 2- (benzyl (ethyl) amino) ethane-1-sulfonamide (Intermediate P7) using ethylene sulfonamide (375 mg, 3.15 mmol) and azetidine hydrochloride (339 mg, 3.62 mmol) to produce the title compound (396 mg, 76%) after column chromatography.
[0458] [0458] UPLC-MS: 68% (ELSD), M 164 +1 (ACPI pos.)
[0459] [0459] 1H NMR (Chloroform-d) δ 3.96-3.76 (m, 2H), 3.37-3.16 (m, 2H), 2.43 (m, 4H), 1.18 ( dq, J = 9.4, 5.7, 4.5 Hz, 2H).
[0460] [0460] Intermediate P22: 3- (Ethyl (methyl) amino) propane-1-sulfonamide
[0461] [0461] To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.27 mmol) in acetonitrile (4 mL) was added N-methylethhanamine (300 mg, 5.08 mmol). The mixture was heated in a microwave at 80 ° C for 30 minutes. The solvents were evaporated and the residue was triturated in TBME. The resulting solids were isolated by decanting the solution and THF (5 mL) was added to the remaining solids, followed by 200 mg of triethylamine. After 3 hours, the mixture was filtered and the filtrate concentrated to provide the title compound as a white solid (70 mg, 31%).
[0462] [0462] 1H NMR (Chloroform-d) δ 3.18-3.04 (m, 2H), 2.64-2.41 (m, 4H), 2.29 (s, 3H), 2.12- 1.92 (m, 2H), 1.11 (t, 3H).
[0463] [0463] Intermediate P23: (4-Cyanophenyl) methanesulfonamide O O
[0464] [0464] To a solution of ammonia saturated in THF (3 ml) was added dropwise a solution of (4-cyanophenyl) methanesulfonyl chloride (100 mg, 646 µmol, 1 eq) in THF (1 ml). The mixture was stirred at 20 ° C for 1 hour and then concentrated under reduced pressure. The residue was diluted with water (3 ml) and then the mixture was extracted in ethyl acetate (2 x 3 ml). The combined organic layers were washed with brine (3 ml), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to obtain the title compound (110 mg,> 100%) as a white solid.
[0465] [0465] 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 2 H), 7.56 (d, 2 H), 6.93 (br s, 2 H) and 4.40 (s, 2 H).
[0466] [0466] Intermediate P24: 2-Ethyl-2-azaspiro [3.3] heptane-6-sulfonamide
[0467] [0467] Step A: tert-butyl 6 - ((Methylsulfonyl) oxy) -2-
[0468] [0468] 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 for 18 hours at room temperature and then washed with water and brine, dried (sodium sulfate), filtered and evaporated to provide the title compound (2.7 g, 100% yield) as a white solid.
[0469] [0469] 1H NMR (CDCl3): δ = 4.89 (m, 1 H), 3.94 (s, 4 H), 2.99 (s, 3 H), 2.70 (m, 2 H) , 2.48 (m, 2 H) and 1.44 (s, 9 H).
[0470] [0470] Step B: tert-Butyl 6- (Acetylthio) -2-azaspiro [3.3] heptane-2-carboxylate
[0471] [0471] 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) potassium thioacetate (1.57 g, 13.7 mmol) was added. The reaction was heated to reflux for 18 hours and, after cooling, was poured into water (200 ml) and ethyl acetate (100 ml). The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (4x) and brine, before being dried (sodium sulfate), filtered and evaporated in vacuo to provide the title compound (1 g, 100% yield) as a brown oil.
[0472] [0472] 1H NMR (CDCl3): δ = 3.96 (s, 2 H), 3.90 (m, 1 H), 3.86 (s, 2 H),
[0473] [0473] Step C: tert-Butyl 6-Sulfamoyl-2-azaspiro [3.3] heptane-2-carboxylate
[0474] [0474] 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) cooled in ice / water. N-chloro succinimide (960 mg, 7.8 mmol) was added in portions over a period of 10 minutes. Then, the reaction mixture was stirred at room temperature for 1 hour, before being poured into cold aqueous ammonium hydroxide (50 mL, 25%). The mixture was allowed to stir for 18 hours at room temperature, before the solvents were evaporated in vacuo and the residue was triturated in tetrahydrofuran and decanted. The combined tetrahydrofuran layers were evaporated and the residue was purified on silica, using dichloromethane / methanol (9: 1) as the eluent. The title compound was obtained as a white foam (240 mg, yield 36%).
[0475] [0475] 1H NMR (CDCl3): δ = 4.87 (br s, 2 H), 3.96 (s, 4 H), 3.72 (m, 1 H), 2.62 (m, 4 H ) and 1.44 (s, 9 H).
[0476] [0476] Step D: 2-azaspiro trifluoroacetic acid salt [3.3] heptane-6-sulfonamide
[0477] [0477] 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 solvents were evaporated. The residue was dissolved in methanol and purified on Amberlite 410 ion exchange resin, to provide the title compound (100 mg, 67% yield) as a pale yellow oil.
[0478] [0478] 1H NMR (CD3OD): δ = 3.93 (s, 4 H), 3.66 (m, 1 H) and 2.64 (m, 4 H).
[0479] [0479] Step E: 2-Ethyl-2-azaspiro [3.3] heptane-6-sulfonamide
[0480] [0480] To a salt mixture of 2-azaspiro trifluoroacetic acid [3.3] heptane-6-sulfonamide (75 mg, 0.43 mmol), triethylamine (160 mg, 1.6 mmol) and acetonitrile (5 mL) was added ethyl iodide (66 mg, 0.43 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. The crude material was purified by normal phase flash chromatography using ethyl acetate and methanol (9: 1) as the eluant to provide the product as a mixture with triethylamine salts. The crude product was dissolved in methanol and filtered over Amberlite 410. The solvent was evaporated to provide the title compound (8 mg, 15% yield).
[0481] [0481] 1H NMR (CD3 OD): δ = 3.67 (m, 1 H), 3.24 (d, 4 H), 2.50 (d, 4 H), 2.43 (q, 2 H ) and 0.95 (t, 3 H).
[0482] [0482] Intermediate P25: 2-Isopropyl-2-azaspiro [3.3] heptane-6-sulfonamide
[0483] [0483] To a solution of 2-azaspiro [3.3] heptane-6-sulfonamide (50 mg, 0.28 mmol) and acetone (25 mg, 0.43 mmol, 1.5 equiv.) In acetonitrile (5 mL) sodium triacetoxyborohydride (89 mg, 0.43 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 18 hours at room temperature 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 provide the title compound (40 mg, 65% yield) which was used as such.
[0484] [0484] 1H NMR (CD3OD): δ = 3.71 (m, 1H), 3.25 (m, 4H), 2.53 (m, 4H), 2.33 (m, 1H), 0.93 (d, 6H).
[0485] [0485] Intermediate P26: 2-Methyl-2-azaspiro [3.3] heptane-6-sulfonamide
[0486] [0486] To a solution of 2-azaspiro [3.3] heptane-6-sulfonamide (50 mg, 0.28 mmol) and formaldehyde (32 µL, 37% in water, 0.43 mmol, 1.5 equiv.) In acetonitrile (5 ml) was added sodium triacetoxyborohydride (90 mg, 0.43 mmol, 1.5 equiv.). The reaction mixture was stirred for 18 hours at room temperature 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 provide the title compound (40 mg, 74% yield) which was used as such.
[0487] [0487] 1H NMR (CD3OD): δ = 3.71 (m, 1H), 3.37 - 3.21 (m, 4H), 2.52 (m, 4H), 2.29 (s, 3H) .
[0488] [0488] Intermediate P27: 3- (Benzyl (ethyl) amino) propane-1-sulfonamide
[0489] [0489] Step A: 3- (benzyl (ethyl) amino) propane-1-sulfonic acid
[0490] [0490] To a solution of 2,2-dioxide 1,2-oxathiolane (1 g, 8.19 mmol, 719.42 µL, 1 eq) in DCM (5 mL) was added N-benzylethanamine (3.94 g, 29.15 mmol, 3.56 eq) at 0 ° C. Then, the resulting mixture was stirred at
[0491] [0491] 1H NMR (DMSO-d6): δ 7.37-7.23 (m, 5 H), 4.08 (s, 2 H), 2.91 (q, 2 H), 2.50- 2.40 (m, 4 H), 1.81 to 1.73 (m, 2 H) and 0.98 (t, 3 H).
[0492] [0492] LCMS: m / z 258.1 (M + H) + (ES +).
[0493] [0493] Step B: 3- (benzyl (ethyl) amino) propane-1-sulfonyl chloride O O O O
[0494] [0494] A solution of 3- (benzyl (ethyl) amino) propane-1-sulfonic acid (2.1 g, 8.16 mmol, 1 eq) in SOCl2 (17.22 g, 144.74 mmol, 17, 74 eq) was stirred at 80 ° C for 6 hours. The filtrate was concentrated in vacuo to obtain the title compound (2 g, crude) as a yellow oil, which was used directly in the next step.
[0495] [0495] Step C: 3- (Benzyl (ethyl) amino) propane-1-sulfonamide O O O O
[0496] [0496] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonyl chloride (2 g, crude) in THF (3 mL) was added to a saturated solution of NH3 in THF (100 mL) at 0 ° C. Then the mixture was stirred at 20 ° C for 14 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% NH 3.H2O) - MeCN) to obtain the title compound (1.15 g, 62% yield, 100% UPLC purity) as a white solid.
[0497] [0497] 1H NMR (CDCl3): δ 7.37-7.28 (m, 5 H), 4.98 (br s, 2 H), 3.57 (s, 2 H), 3.15 (t , 2 H), 2.61-2.52 (m, 4 H), 2.06-2.00 (m, 2H) and 1.07 (t, 3 H).
[0498] [0498] Intermediate P28: 3-Methoxypropane-1-sulfonamide
[0499] [0499] Step A: Sodium 3-methoxypropane-1-sulfonate THE
[0500] [0500] A mixture of 1-bromo-3-methoxypropane (2 g, 13.07 mmol, 1 eq) and Na2SO3 (1.65 g, 13.07 mmol, 1 eq) in H2O (20 ml) was heated to 100 ° C and stirred for 16 hours. Then the reaction mixture was cooled and lyophilized to obtain the title compound (2.25 g, 97%, Na salt) as a white solid.
[0501] [0501] 1H NMR (D2O): δ 3.56 (t, 2 H), 3.34 (s, 3 H), 2.95-2.92 (m, 2 H) and 2.02-1, 94 (m, 2 H).
[0502] [0502] LCMS: m / z 155.1 (M-Na + H) + (ES +).
[0503] [0503] Step B: 3-methoxypropane-1-sulfonyl chloride O O O O
[0504] [0504] A solution of sodium 3-methoxypropane-1-silphonate (0.7 g, 4.54 mmol, 1 eq) in POCl3 (8.25 g, 53.80 mmol, 11.85 eq) was stirred at 80 ° C for 5 hours. The mixture was stirred for 2 hours at 100 ° C. The mixture was diluted with DCM (80 ml) and filtered. The filtrate was concentrated in vacuo to obtain the title compound (600 mg, crude) as a yellow oil, which was used directly in the next step.
[0505] [0505] Step C: 3-methoxypropane-1-sulfonamide O O O O
[0506] [0506] NH3 (15 psi) was bubbled into THF (20 mL) at 0 ° C for 5 minutes. A solution of 3-methoxypropane-1-sulfonyl chloride (600 mg, crude) in THF (2 ml) was added to the NH3 / THF solution (20 ml). The mixture was stirred at 20 ° C for 14 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the title compound (300 g, crude) as a yellow oil.
[0507] [0507] 1H NMR (CDCl3): δ 4.94 (br s, 2 H), 3.53 (t, 2 H), 3.35 (s, 3 H), 3.25 (t, 2 H) and 2.17-2.10 (m, 2 H).
[0508] [0508] Intermediate P29: 3- (Dimethylamino) -2-methylpropane-1-sulfonamide
[0509] [0509] 3-Chloro-2-methylpropane-1-sulfonamide (50 mg, 0.3 mmol) was dissolved in dimethylamine (5 mL, 2 M in THF). The mixture was heated for 30 minutes at 180 ° C in the microwave. The solvents were evaporated. The residue was triturated in THF (20 ml) and triethylamine (100 mg, 1 mmol). The solids were removed by filtration and the solvent was evaporated to provide the title compound (14 mg, 11%) as a white solid.
[0510] [0510] 1H NMR (Methanol-d4) δ 3.30 (m, 2 H), 2.93 (m, 2H), 2.38 (s, 6 H), 1.40 (m, 1H), 1 , 16 (d, 3H).
[0511] [0511] Intermediate P30: 3-Azidopropane-1-sulfonamide
[0512] [0512] To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.3 mmol) in acetone (10 mL) was added sodium azide (200 mg, 3 mmol) in water (1 mL). The mixture was then refluxed for 36 hours. The solvents were evaporated. The residue was triturated in THF. The THF layer was filtered and evaporated to provide the title compound as a yellow oil (200 mg, 96%).
[0513] [0513] 1H NMR (CD3OD) δ 3.51 (t, 2 H), 3.17 (t, 2 H), 2.07 (m, 2H).
[0514] [0514] Intermediate P31: (1- (Oxetan-3-yl) pyrrolidin-3-yl) methanesulfonamide
[0515] [0515] To a suspension of (pyrrolidin-3- hydrochloride
[0516] [0516] 1H NMR (DMSO-d6) δ 6.77 (s, 2 H), 4.53 (td, 2 H), 4.40 (td, 2 H), 3.60 - 3.45 (m , 1 H), 3.03 (d, 2 H), 2.72 (dd, 1 H), 2.57 - 2.52 (m, 1 H), 2.44 - 2.32 (m, 2 H), 2.20 (dd, 1 H), 2.08 - 1.93 (m, 1 H), 1.58 - 1.43 (m, 1H).
[0517] [0517] Intermediate P32: N, N, N-trimethyl-3-sulfamoylpropan-1-amine
[0518] [0518] Trimethylamine (4.2 M in ethanol, 4 mL, 16.8 mmol) was added 3-chloropropane-1-sulfonamide (159 mg, 1 mol). The mixture was heated for 30 minutes at 100oC in a microwave. The solids were collected by filtration to provide the title compound (100 mg, 55%).
[0519] [0519] 1H NMR (dmso-D6) δ 3.45 (m, 2H), 3.10 (s, 9 H), 3.07 (m, 2 H), 2.17 (m, 2H).
[0520] [0520] Intermediate P33: 3- (Benzyl (methyl) amino) propane-1-sulfonamide
[0521] [0521] 3-Chloropropane sulfonamide (200 mg, 1.3 mmol) in acetonitrile (5 mL) was added N-methylbenzylamine (1 g, 5.1 mmol). The reaction was refluxed for 18 hours. The solvents were evaporated and the residue was triturated in TBME. The solids were removed by filtration and the solvent was evaporated. The residue was triturated in heptane. The solids were collected by filtration to provide the title compound (214 mg, 70%) as a white solid.
[0522] [0522] 1H NMR (CDCl3) δ 7.30 (m, 5 H), 3.54 (s, 2 H), 3.22 (t, 2 H), 2.53 (m, 2 H), 2 , 25 (s, 3 H), 2.09 (t, 2 H).
[0523] [0523] Intermediate P34: 2- (3-methyl-3H-diazirin-3-yl) ethane-1-sulfonamide
[0524] [0524] A solution of NH3 in water (25%, 5 ml) was cooled to 4 ° C. 2- (3-Methyl-3H-diazirin-3-yl) ethane-1-sulfonyl chloride (150 mg, 0.82 mmol) in THF (3 mL) was added. The mixture was stirred for 18 hours at room temperature. The organic layer was separated, dried (on sodium sulfate), filtered and evaporated to provide the title compound (75 mg, 50%) as a colorless oil, which solidified on standing.
[0525] [0525] 1H NMR (CD3OD) δ 3.15 (t, 2H), 1.78 (t, 2H), 1.05 (s, 3H).
[0526] [0526] Intermediate P35: 3- (Methoxy (methyl) amino) propane-1-sulfonamide
[0527] [0527] 3-chloropropane sulfonamide (200 mg, 1.3 mmol) in acetonitrile (5 mL) was added N, O-dimethylhydroxylamine (310 mg, 5 mmol) and triethylamine (1.4 g, 14 mmol) . The mixture was then refluxed for 18 hours. The solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to provide the title compound as a colorless oil (100 mg, 43%).
[0528] [0528] 1H NMR (CD3OD) δ 8.20 (m, 2 H), 7.62 (d, 1 H), 7.53 (d, 1 H),
[0529] [0529] Intermediate P36: ((1S, E) -2- (hydroxyimino) -7,7-dimethylbicyclo [2.2.1] heptan-1-yl) methanesulfonamide
[0530] [0530] To a suspension of (1S) -10-camphorsulfonamide (505 mg, 2.18 mmol) in ethanol (7 mL) and demineralized water (3.5 mL) was added sodium acetate (360 mg, 4.37 mmol), followed by hydroxylamine hydrochloride (303 mg 4.37 mmol). The mixture was stirred at reflux overnight and then concentrated in vacuo to remove ethanol. The residual aqueous phase was extracted with dichloromethane and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (448 mg, 83%) as a white solid.
[0531] [0531] 1H NMR (Chloroform-d) δ 6.95 (d, J = 25.2 Hz, 1H), 5.62 (s, 2H), 3.51 (d, J = 15.0 Hz, 1H ), 3.23 (d, J = 15.0 Hz, 1H), 2.62 (dt, J = 18.2, 4.0 Hz, 1H), 2.25 - 1.83 (m, 5H) , 1.36 (ddd, J = 12.8, 8.6, 4.7 Hz, 1H), 0.96 (s, 3H), 0.86 (s 3H).
[0532] [0532] Intermediate P37: 3- (Azetidin-1-yl) propane-1-sulfonamide
[0533] [0533] To a solution of azetidine HCl (267 mg, 2.8 mmol) in methanol (4 mL) was added a solution of sodium hydroxide (114 mg, 2.8 mmol) in water (1 mL) and 3- chloropropane-1-sulfonamide (200 mg 1.3 mmol). The mixture was heated for 30 minutes at 100 ° C in a microwave. The solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to provide the title compound as a colorless oil (10 mg, 4%).
[0534] [0534] 1H NMR (CD3OD) δ 4.19 (m, 4 H), 3.37 (m, 2 H), 3.19 (t, 2H), 2.52 (m, 2H), 2.17 (m, 2H).
[0535] [0535] Intermediate P38: 3- (Methyl (prop-2-in-1-yl) amino) propane-1-sulfonamide
[0536] [0536] 3-chloropropane sulfonamide (200 mg, 1.3 mmol) in acetonitrile (20 mL) was added 3-methylamino-1-propine (340 mg, 5.1 mmol) and potassium iodide (60 mg, 0 , 36 mmol). The reaction was refluxed for 18 hours. The solvents were evaporated and the residue was triturated in THF. The THF layer was decanted and evaporated to provide the title compound (175 mg, 73% yield) as a white solid.
[0537] [0537] 1H NMR (CDCl3) δ 3.37 (s, 2 H), 3.23 (t, 2 H), 2.63 (t, 2 H), 2.33 (s, 3 H), 2 , 26 (s, 1 H), 2.05 (m, 2 H).
[0538] [0538] Intermediate P39: (4-Methylmorpholin-2-yl) methanesulfonamide
[0539] [0539] To a suspension of morpholin-2-ylmethanesulfonamide hydrochloride (40 mg, 0.18 mmol), triethylamine (19 mg, 0.18 mmol, 1.0 equiv.) And formaldehyde (37% in water stabilized with methanol ; 18 mg, 0.22 mmol, 1.2 equiv.) In acetonitrile (5 mL) was added sodium triacetoxyborohydride (47 mg, 0.22 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature overnight. Methanol was added and the mixture was concentrated to provide the crude title compound (~ 0.1 g), which was used without further purification.
[0540] [0540] Intermediate P40: (4-ethylmorpholin-2-yl) methanesulfonamide
[0541] [0541] To a suspension of morpholin-2-ylmethanesulfonamide hydrochloride (32 mg, 0.15 mmol), triethylamine (15 mg, 0.15 mmol, 1.0 equiv.) And acetaldehyde (8 mg, 0.18 mmol) , 1.2 equiv.) In acetonitrile (5 ml) was added sodium triacetoxyborohydride (38 mg, 0.18 mmol, 1.2 equiv.). The reaction was stirred overnight. Methanol was added and the mixture was concentrated to provide the crude title compound (~ 90 mg), which was used without further purification.
[0542] [0542] Intermediate P41: (4-Isopropylmorpholin-2-yl) methanesulfonamide
[0543] [0543] To a suspension of morpholin-2-ylmethanesulfonamide hydrochloride (31 mg, 0.14 mmol), triethylamine (14 mg, 0.14 mmol, 1.0 equiv.) And acetone (10 mg, 0.17 mmol) , 1.2 equiv.) In acetonitrile (5 ml) was added sodium triacetoxyborohydride (36 mg, 0.17 mmol, 1.2 equiv.). The reaction was stirred overnight. Methanol was added and the mixture was concentrated to provide the crude title compound (~ 90 mg), which was used without further purification.
[0544] [0544] Intermediate P42: (2-isopropyl-6-oxa-2-azaspiro [3.4] octan-7-yl) methanesulfonamide
[0545] [0545] Prepared as described for (2-methyl-6-oxa-2-azaspiro [3.4] octan-7-yl) methanesulfonamide (Intermediate P45) from (6-
[0546] [0546] 1H NMR (CD3OD) δ 4.31 (m, 1 H), 3.99 (d, 1 H), 3.86 (d, 1 H), 3.28 (m, 6H), 2, 54 (m, 1 H), 2.44 (m, 1 H), 1.96 (m, 1H), 0.97 (d, 6H).
[0547] [0547] Intermediate P43: 3- (Dimethylamino) butane-1-sulfonamide
[0548] [0548] Step A: 3-Azidobutane-1-sulfonamide
[0549] [0549] To the 3-chlorobutane-1-sulfonamide chloride (50 mg, 0.3 mmol) in DMF (3 mL) was added NaN3 (25 mg, 0.4 mmol). The reaction was heated for 18 hours at 100 ° C. The solvents were evaporated and the residue was triturated in chloroform. The chloroform layer was filtered and evaporated to provide the title compound as a brown oil (25 mg, 47%).
[0550] [0550] 1H NMR (CDCl3) δ 3.15 (m, 2 H), 2.96 (d, 3 H), 2.01 (m, 2H), 1.36 (d, 3H).
[0551] [0551] Step B: 3-Aminobutane-1-sulfonamide
[0552] [0552] 3-Azidobutane-1-sulfonamide (130 mg, 0.73 mmol) in THF (5 mL) was added Pd-C (20 mg, 10% Pd). The mixture was stirred for 18 hours under a hydrogen atmosphere. The mixture was filtered over Celite ® and evaporated to provide the title compound as a brown oil (120 mg, 100%).
[0553] [0553] 1H NMR (CDCl3) δ 3.17 (m, 2 H), 3.12 (m, 2 H), 2.01 (m, 2H), 1.36 (d, 3H).
[0554] [0554] Step C: 3- (Dimethylamino) butane-1-sulfonamide
[0555] [0555] 3-Aminobutane-1-sulfonamide (110 mg, 0.72 mmol) in acetonitrile (5 mL) was added paraformaldehyde (86 mg, 3 mmol). Then, sodium triacetoxyborohydride (612 mg, 3 mmol) was added and the mixture was stirred for 18 hours at room temperature. Methanol (10 ml) was added and the solvents were evaporated (2x). The residue was triturated in THF (20 ml) containing triethylamine (0.7 g, 7 mmol). The solids were filtered and the solvent was evaporated. The residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent, to provide the title compound as a colorless oil (14 mg, 11%).
[0556] [0556] 1H NMR (CD3OD) δ 3.18 (t, 2 H), 2.63 (m, 1H), 2.60 (s, 6 H), 2.2 (m, 2H), 1.24 (d, 3H).
[0557] [0557] Intermediate P44: (2-ethyl-6-oxa-2-azaspiro [3.4] octan-7-yl) methanesulfonamide
[0558] [0558] Prepared as described for (2-methyl-6-oxa-2-azaspiro [3.4] octan-7-yl) methanesulfonamide (Intermediate P45) from (6-oxa-2-azaspiro [3.4] octan -7-yl) TFA salt of methanesulfonamide and acetone to provide the title compound as an oil (15 mg, 13%).
[0559] [0559] 1H NMR (CD3OD) δ 4.33 (m, 1 H), 4.02 (d, 1 H), 3.88 (d, 1 H), 3.35 (m, 6 H), 2 , 62 (q, 2 H), 2.45 (m, 1H) 2.03 (m, 1H), 1.00 (t, 3H).
[0560] [0560] Intermediate P45: (2-Methyl-6-oxa-2-azaspiro [3.4] octan-7-yl) methanesulfonamide
[0561] [0561] Step A: (6-Oxa-2-azaspiro [3.4] octan-7-yl) methanesulfonamide, TFA salt
[0562] [0562] To a solution of N-Boc- (6-oxa-2-azaspiro [3,4] octan-7-yl) methanesulfonamide (330 mg, 1 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (2 mL). After stirring for 18 hours at room temperature under nitrogen, the solvents were evaporated to provide the title compound as a pale yellow oil (330 mg, 100%).
[0563] [0563] 1H NMR (CD3OD) δ4.30 (m, 1 H), 4.10 (m, 5 H), 3.91 (m, 1 H), 3.35 (m, 2 H), 2, 59 (m, 1 H), 2.16 (m, 1 H).
[0564] [0564] Step B: (2-Methyl-6-oxa-2-azaspiro [3.4] octan-7-yl) methanesulfonamide
[0565] [0565] To the TFA salt of (6-oxa-2-azaspiro [3.4] octan-7-yl) methanesulfonamide (150 mg, 0.48 mmol) in acetonitrile (10 ml), triethylamine (100 mg, 0, 99 mmol), paraformaldehyde (30 mg, 0.97 mmol), followed by sodium triacetoxyborohydride (205 mg, 0.97 mmol). After 18 hours of stirring at room temperature under nitrogen, methanol (10 ml) was added and the mixture was evaporated (2x). The residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent, to provide the title compound as a colorless oil (17 mg, 17%).
[0566] [0566] 1H NMR (CD3OD) δ 4.33 (m, 1 H), 4.02 (d, 1 H), 3.88 (d, 1 H), 3.60 (m, 4H), 3, 32 (m, 2 H), 2.53 (s, 3 H), 2.45 (m, 1H) 2.03 (m, 1H).
[0567] [0567] Intermediate P46: 3- (Dimethylamino) -2,2-dimethylpropane-1-sulfonamide
[0568] [0568] Step A: 3-Azido-2,2-dimethylpropane-1-sulfonamide
[0569] [0569] To 3-chloro-2,2-dimethylpropane-1-sulfonamide (130 mg, 0.7 mmol) in DMF (3 mL) was added NaN3 (91 mg, 1.4 mmol). The reaction was heated for 48 hours at 120 ° C. The solvents were evaporated and the residue was triturated in THF. The solids were filtered and the THF was evaporated to provide the crude title compound (220 mg, 61%) as a brown oil.
[0570] [0570] 1H NMR (CDCl3) δ 2.95 (s, 2 H), 2.87 (s, 2 H), 1.27 (s, 6H).
[0571] [0571] Step B: 3-Amino-2,2-dimethylpropane-1-sulfonamide
[0572] [0572] To 3-azido-2,2-dimethylpropane-1-sulfonamide (130 mg, 0.67 mmol) in THF (5 mL) was added Pd-C (20 mg, 10% Pd). The mixture was stirred for 64 hours under a hydrogen atmosphere. The mixture was filtered over Celite ® and evaporated to provide the title compound (90 mg, 80%) as an oil.
[0573] [0573] 1H NMR (CDCl3) δ 2.95 (s, 2 H), 2.87 (s, 2 H), 1.27 (s, 6H).
[0574] [0574] Step C: 3- (dimethylamino) -2,2-dimethylpropane-1-sulfonic acid triethylamine salt
[0575] [0575] 3-Amino-2,2-dimethylpropane-1-sulfonamide (160 mg, 0.6 mmol) in water (1 mL) and formic acid (1 mL, 6.6 mmol) was added formaldehyde (1 mL , 37% aqueous solution, 2.5 mmol). The mixture was then refluxed for 6 hours. The solvents were evaporated. The residue was triturated in THF (10 ml) containing triethylamine (250 mg, 2.5 mmol). The solids were filtered to provide the title compound (80 mg, 45%) as a white solid.
[0576] [0576] 1H NMR (CD3OD) δ 3.06 (s, 2 H), 2.96 (s, 6H), 2.89 (s, 2 H), 1.27 (s, 6H).
[0577] [0577] Step D: 3- (Dimethylamino) -2,2-dimethylpropane-1-sulfonamide
[0578] [0578] To the triethylamine salt of 3- (dimethylamino) -2,2-dimethylpropane-1-sulfonic acid (70 mg, 0.24 mmol) in dichloromethane (10 mL) was added DMF (2 drops). The mixture was cooled to 0 ° C. Then thionyl chloride (0.1 ml, 1.4 mmol) was added. The reaction was stirred for 18 hours at room temperature. The solvents were evaporated. The residue was triturated in THF. The THF layer was separated and added dropwise to a solution of ammonia in methanol (7 N). The mixture was stirred for 18 hours. The solvents were evaporated. The residue was triturated in THF. The solids were filtered. THF was evaporated to provide the title compound (24 mg, 52%) as a white solid.
[0579] [0579] 1H NMR (CDCl3) δ 3.51 (s, 2 H), 3.29 (s, 2 H), 2.37 (s, 6 H), 1.19 (s, 6H).
[0580] [0580] Intermediate P47: 4- (Dimethylamino) butane-1-sulfonamide
[0581] [0581] 4-Chlorobutane-1-sulfonamide (200 mg, 1.2 mmol) in acetonitrile (4 mL) was added dimethylamine in THF (2.3 mL 2M, 4.6 mmol). The mixture was heated for 30 minutes at 100 ° C in a microwave. The solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to provide the title compound as a colorless oil (32 mg, 15%).
[0582] [0582] 1H NMR (CD3OD) δ 4.19 (m, 4H), 3.37 (m, 4H), 2.49 (m, 2H), 1.90 (m, 2H), 1.75 ( m, 2H).
[0583] [0583] Intermediate P48: (1-Methylpiperidin-3-yl) methanesulfonamide
[0584] [0584] To a suspension of piperidin-3-ylmethanesulfonamide (80 mg, 0.45 mmol) and formaldehyde (37% in water stabilized with methanol; 44 mg,
[0585] [0585] Intermediate P49: (1-ethylpiperidin-3-yl) methanesulfonamide
[0586] [0586] To a suspension of piperidin-3-ylmethanesulfonamide (70 mg, 0.39 mmol) and acetaldehyde (21 mg, 0.47 mmol, 1.2 equiv.) In acetonitrile (10 mL) was added triacetoxyborohydride sodium (100 mg, 0.47 mmol, 1.2 equiv.). The reaction was stirred overnight. Methanol was added and the mixture was concentrated to provide the crude title compound (~ 300 mg), which was used without further purification.
[0587] [0587] Intermediate P50: tert-butyl ((1S) -1 - ((N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) methyl) -7,7-dimethylbicyclo [2.2.1] heptan-2-yl) carbamate, potassium salt
[0588] [0588] Step A: ((1S) -2-Amino-7,7-dimethylbicyclo [2.2.1] heptan-1-yl) methanesulfonamide
[0589] [0589] A mixture of ((1S, E) -2- (hydroxyimino) -7,7-dimethylbicyclo [2.2.1] heptan-1-yl) methanesulfonamide (Intermediate P36) (365 mg, 1.48 mmol) and Raney-Ni (~ 50 mg) in ethanol (7 ml) and 25% ammonia (1 ml) were equipped with an H2 flask and stirred overnight at room temperature, followed by another 4 hours at 50 ° C.
[0590] [0590] The reaction mixture was allowed to cool to room temperature, filtered through Celite® and concentrated to provide the title compound (300 mg, 87%) as a white solid.
[0591] [0591] 1H NMR (Chloroform-d) δ 3.72 (q, J = 6.9 Hz, 1H), 3.46 (d, J = 19.5 Hz, 1H), 3.26 - 3.15 (m, 1H), 2.97 (d, J = 13.3 Hz, 1H), 2.86 - 2.64 (m, 1H), 2.41 - 1.10 (m, 9H), 1, 01 - 0.76 (m, 6H).
[0592] [0592] Step B: tert-butyl carbamate ((1S) -7,7-dimethyl-1- (sulfamoylmethyl) [2.2.1] heptan-2-yl) carbamate
[0593] [0593] A solution of ((1S) -2-amino-7,7-dimethylbicyclo [2.2.1] heptan-1-yl) methanesulfonamide (180 mg, 0.77 mmol) in THF (5 mL) treated with Et3N (0.11 mL, 0.77 mmol) and Boc2O (170 mg, 0.77 mmol) and stirred over the weekend. The mixture was concentrated and partitioned between DCM and water. The organic phase was separated and dried (Na2SO4), filtered and concentrated to provide the crude title compound (~ 300 mg), which was used as such in the next step.
[0594] [0594] 1H NMR (chloroform-d) δ 3.17 (d, J = 13.2 Hz, 1H), 2.96 (d, J = 13.3 Hz, 1H), 2.86 - 2.67 (m, 1H), 2.50 - 1.67 (m, 10H), 1.52 (s, 9H), 1.16 - 0.80 (m, 6H).
[0595] [0595] Step C: (((1S) -1 - ((N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) methyl) - 7,7-dimethylbicyclo [2.2.1] heptan-2-yl) tert-butyl carbamate, potassium salt BocHN
[0596] [0596] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-
[0597] [0597] LCMS: m / z 530 (M-H) - (ES-).
[0598] [0598] Intermediate P51: 4- (Azetidin-1-yl) butane-1-sulfonamide
[0599] [0599] Prepared as described for 3- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P37) using 4-chlorobutane-1-sulfonamide to provide the title compound as a colorless oil (6 mg, 3%) .
[0600] [0600] 1H NMR (CD3OD) δ 4.19 (m, 4H), 3.37 (m, 4H), 2.49 (m, 2H), 1.90 (m, 2H), 1.75 ( m, 2H).
[0601] [0601] Intermediate P52: 1- (Azetidin-1-ylmethyl) cyclopropane-1-sulfonamide
[0602] [0602] Step A: 1- (Azetidin-1-ylmethyl) -N- (tert-butyl) cyclopropane-1-sulfonamide
[0603] [0603] To a suspension of cyclobutylamine (68 mg, 0.73 mmol) in THF (5 mL) was added triethylamine (120 mg, 1.2 mmol) and N- (tert-butyl) -1- (2-oxoethyl ) cyclopropane-1-sulfonamide (100 mg, 0.49 mmol). Sodium cyanoborohydride (50 mg, 0.79 mmol) was added and the mixture was stirred for 18 hours at room temperature under nitrogen. Dichloromethane was added and the mixture was washed with water and brine. The organic layer was dried (over sodium sulfate), filtered and evaporated. The residue was purified on silica,
[0604] [0604] 1H NMR (CD3OD) δ 3.30 (m, 4H), 2.80 (s, 2 H), 2.10 (m, 2 H), 1.35 (s, 9 H), 1, 24 (m, 2 H), 0.89 (m, 2H).
[0605] [0605] Step B: 1- (Azetidin-1-ylmethyl) cyclopropane-1-sulfonamide
[0606] [0606] A solution of 1- (azetidin-1-ylmethyl) -N- (tert-butyl) cyclopropane-1-sulfonamide (50 mg, 0.2 mmol) in TFA (10 mL) was stirred for 64 hours at room temperature nitrogen environment. Then, the solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent, to provide the title compound as a white solid (20 mg, 51%).
[0607] [0607] 1H NMR (CD3OD) δ 3.36 (m, 4H), 2.87 (s, 2 H), 2.12 (m, 2 H), 1.26 (m, 2 H), 0, 89 (m, 2H).
[0608] [0608] Intermediate P53: 2- (Pyrrolidin-1-yl) ethane-1-sulfonamide
[0609] [0609] Step A: N, N-Bis (4-methoxybenzyl) -2- (pyrrolidin-1-yl) ethane-1-sulfonamide
[0610] [0610] Prepared as described for N, N-bis (4-methoxybenzyl) -2- (2-methylazetidin-1-yl) ethane-1-sulfonamide (Intermediate P54, Step A) from N, N-bis ( 4-methoxybenzyl) ethylene sulfonamide and pyrrolidine to provide the title compound as an oil (361 mg, 100%).
[0611] [0611] 1H NMR (CDCl3) δ 7.20 (d, 4H), 6.86 (d, 4 H), 4.25 (s, 4 H), 3.79 (s, 6 H), 3, 09 (m, 2H), 2.87 (m, 2H), 2.44 (m, 4H), 1.75 (m, 4H).
[0612] [0612] Step B: 2- (Pyrrolidin-1-yl) ethane-1-sulfonamide
[0613] [0613] Prepared as described for 2- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P56, Step B) from N, N-bis (4-methoxybenzyl) -2- (pyrrolidin-1-yl ) ethane-1-sulfonamide. The solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to provide the title compound as a white solid (110 mg, 74%).
[0614] [0614] 1H NMR (CDCl3) δ 3.32 (m, 2H), 2.96 (t, 2H), 2.61 (m, 4H), 1.84 (m, 4H).
[0615] [0615] Intermediate P54: 2- (2-Methylazetidin-1-yl) ethane-1-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -2- (2-methylazetidin-1-yl) ethane-1 - sulfonamide
[0616] [0616] Methyl azetidine HCl (55 mg, 0.52 mmol) in methanol (3 mL) was added N, N-bis (4-methoxybenzyl) prop-1-ene-1-sulfonamide (150 mg, 0, 43 mmol) and triethylamine (0.7 g, 7 mmol). The mixture was stirred for 18 hours at room temperature under nitrogen. The solvents were evaporated and the residue was triturated in THF. The mixture was filtered and the solvent was evaporated to provide the title compound (170 mg, 94%) as a colorless oil.
[0617] [0617] 1H NMR (CD3OD) δ 3.40 (m, 2H), 3.16 (m, 2H), 2.99 (m, 2 H), 2.82 (m, 1H), 2.15 ( m, 1 H), 1.83 (m, 1 H), 1.24 (d, 3H).
[0618] [0618] Step B: 2- (2-Methylazetidin-1-yl) ethane-1-sulfonamide
[0619] [0619] Prepared as described for 2- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P56, Step B) from N, N-bis (4-methoxybenzyl) -2- (2-methylazetidin-1 -yl) ethane-1-sulfonamide. The solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to provide the title compound as a colorless oil (41 mg, 54%).
[0620] [0620] 1H NMR (CD3OD) δ 3.40 (m, 2H), 3.16 (m, 2H), 2.99 (m, 2H), 2.82 (m, 1H), 2.15 ( m, 1 H), 1.83 (m, 1 H), 1.24 (d, 3H).
[0621] [0621] Intermediate P55: 2- (3-Fluoroazetidin-1-yl) ethane-1-sulfonamide
[0622] [0622] Step A: 2- (3-Fluoroazetidin-1-yl) -N, N-bis (4-methoxybenzyl) ethane-1-sulfonamide
[0623] [0623] 3-fluoroazetidine HCl (60 mg, 0.52 mmol) in methanol (3 mL) was added potassium hydroxide (29 mg, 0.42 mmol) and N, N-bis (4-methoxybenzyl) ethylene sulfonamide ( 150 mg, 0.43 mmol). The mixture was stirred for 30 minutes at 100 ° C in a microwave. The solvents were evaporated to provide the crude title compound (250 mg, 100%) as an oil.
[0624] [0624] 1H NMR (CDCl3) δ 7.23 (d, 4H), 6.91 (d, 4 H), 5.08 (m, 1 H), 4.27 (s, 4 H), 3, 83 (s, 6 H), 3.61 (m, 4H), 3.18 (m, 2H), 3.08 (m, 2H).
[0625] [0625] Step B: 2- (3-Fluoroazetidin-1-yl) ethane-1-sulfonamide
[0626] [0626] Prepared as described for 2- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P56, Step B) from 2- (3-fluoroazetidin-1-yl) -N, N-
[0627] [0627] 1H NMR (CD3OD) δ 5.14 (m, 1H), 3.75 (m, 4 H), 3.34 (m, 2 H), 3.14 (m, 2 H), 3, 04 (m, 2 H).
[0628] [0628] Intermediate P56: 2- (Azetidin-1-yl) propane-1-sulfonamide
[0629] [0629] Step A: 2- (Azetidin-1-yl) -N, N-bis (4-methoxybenzyl) propane-1-sulfonamide
[0630] [0630] Azetidine HCl (46 mg, 0.36 mmol) in methanol (3 mL) was added N, N-bis (4-methoxybenzyl) prop-1-ene-1-sulfonamide (150 mg, 0.41 mmol ) and triethylamine (200 mg, 1.98 mmol). The mixture was stirred for 30 minutes at 100 ° C in a microwave. The solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to provide the title compound as a colorless oil (100 mg, 58%).
[0631] [0631] 1H NMR (CD3OD) δ 7.23 (m, 4H), 6.88 (m, 4 H), 4.24 (s, 4 H), 3.80 (s, 6 H), 3, 13 (m, 4H), 2.76 (m, 2H), 2.53 (m, 1H), 2.00 (m, 2H), 1.16 (d, 3H).
[0632] [0632] Step B: 2- (Azetidin-1-yl) propane-1-sulfonamide
[0633] [0633] A solution of 2- (azetidin-1-yl) -N, N-bis (4-methoxybenzyl) propane-1-sulfonamide (100 mg, 0.58 mmol) in trifluoroacetic acid (3 mL) was stirred for 18 hours at 21 ° C. The solvents were evaporated and the residue was triturated in methanol and filtered over Celite®. The methanol layer was treated with strongly basic ion exchange resin
[0634] [0634] 1H NMR (CD3OD) δ 3.29 (m, 4H), 3.15 (m, 1 H), 2.84 (m, 2 H), 2.04 (m, 2 H), 1, 16 (d, 3H).
[0635] [0635] Intermediate P57: Methyl 3-sulfamylpropanoate
[0636] [0636] To 3-sulfamoylpropanoic acid (200 mg, 1.3 mmol) in methanol (20 mL) was added sulfuric acid (30 mg, 0.3 mmol). The reaction mixture was stirred for 18 hours at room temperature. The mixture was filtered through Celite® and the solvent was evaporated to provide the title compound (225 mg, 100%) as a colorless oil, which crystallized on standing.
[0637] [0637] 1H NMR (CD3OD) δ 3.70 (s, 3 H), 3.35 (m, 2 H), 2.84 (m, 2 H).
[0638] [0638] Intermediate P58: (1-Isopropylpiperidin-3-yl) methanesulfonamide
[0639] [0639] To a suspension of piperidin-3-ylmethanesulfonamide (70 mg, 0.39 mmol, 1.0 equiv.) And acetone (28 mg, 0.47 mmol, 1.2 equiv.) In acetonitrile (10 mL) sodium triacetoxyborohydride (100 mg, 0.47 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at room temperature overnight. Methanol was added and the mixture was concentrated to provide the crude title compound (~ 200 mg), which was used without further purification.
[0640] [0640] Intermediate P59: 3-Methoxy-N-methyl-N- (3-sulfamoylpropyl) propanamide
[0641] [0641] Prepared as described for methyl methyl (3-sulfamoylpropyl) carbamate (Intermediate P64) from 3- (methylamino) propane-1-sulfonamide and 3-methoxypropionyl chloride. The title compound was obtained as a colorless oil (54 mg, 69%).
[0642] [0642] 1H NMR (CD3OD) δ 3.66 (m, 2H), 3.54 (m, 2H), 3.30 (s, 3 H), 3.05 (m, 2H), 3.05 ( s, 3H), 2.51 (m, 2H), 2.05 (m, 2H).
[0643] [0643] Intermediate P60: N-Methyl-N- (3-sulfamoylpropyl) isobutyramide
[0644] [0644] Prepared as described for methyl methyl (3-sulfamoylpropyl) carbamate (Intermediate P64) from 3- (methylamino) propane-1-sulfonamide and isobutyryl chloride. The title compound was obtained as a colorless oil (64 mg, 88%).
[0645] [0645] 1H NMR (CD3OD) δ 3.50 (m, 2 H), 3.16 (m, 2 H), 3.05 (s, 3H), 2.40 (m, 1H), 2.16 (m, 2H), 0.92 (m, 6H).
[0646] [0646] Intermediate P61: N-Methyl-N- (3-sulfamoylpropyl) formamide
[0647] [0647] Prepared as described for methyl methyl (3-sulfamoylpropyl) carbamate (Intermediate P64) from 3- (methylamino) propane-1-sulfonamide and acetic formic anhydride. The title compound was obtained as a colorless oil (100 mg, 100%).
[0648] [0648] 1H NMR (CD3OD) δ 3.19 (m, 4H), 2.70 (s, 3H), 2.19 (m, 2 H).
[0649] [0649] Intermediate P62: N, N-Dimethyl-3-sulfamoylpropanamide
[0650] [0650] Methyl 3-sulfamoylpropanoate (160 mg, 0.96 mmol) was added to dimethylamine in methanol (2 M, 5 mL, 10 mmol). The mixture was stirred for 1 hour at 120 ° C in a microwave. The solvents were evaporated and the residue was purified on silica, using dichloromethane and methanol as the eluent, to provide the title compound as a white solid (28 mg, 16%).
[0651] [0651] 1H NMR (CD3OD) δ 3.35 (m, 2 H), 3.08 (s, 3 H), 2.96 (s, 3H), 2.90 (t, 2H).
[0652] [0652] Intermediate P63: 3- (Benzyl (isopropyl) amino) propane-1-sulfonamide
[0653] [0653] 3-chloropropane sulfonamide (250 mg, 1.6 mmol) in acetonitrile (5 mL) was added N-benzylpropan-2-amine (0.95 g, 6.34 mmol) and potassium iodide (50 mg , 0.3 mmol). The reaction was heated for 1 hour at 160 ° C. The solvents were evaporated and the residue was triturated in TBME. The organic layer was decanted and the residue was triturated in heptane. The organic layer was decanted to provide the title compound (190 mg, 44%) as a pale yellow oil.
[0654] [0654] 1H NMR (CDCl3) δ 7.31 (m, 5H), 3.50 (s, 2 H), 3.08 (m, 2 H), 2.98 (m, 1 H), 2, 57 (m, 2 H), 1.90 (m, 2H), 1.04 (d, 6H).
[0655] [0655] Intermediate P64: Methyl methyl (3-sulfamoylpropyl) carbamate
[0656] [0656] A 3- (methylamino) propane-1-sulfonamide (60 mg, 0.39 mmol)
[0657] [0657] 1H NMR (CD3OD) δ 3.70 (s, 3H), 3.69 (m, 2H), 3.55 (m, 2H), 3.07 (s, 3 H), 2.54 ( m, 3H).
[0658] [0658] Intermediate P65: 3- (Dimethylamino) propane-1-sulfonamide
[0659] [0659] To a solution of 3-chloropropane-1-sulfonamide (203 mg, 1.29 mmol) in 2M dimethylamine in THF (7 mL) was added triethylamine (0.18 mL, 1.29 mmol) and potassium iodide (214 mg, 1.29 mmol). The mixture was heated in a microwave at 80 ° C for 90 minutes. The solvents were evaporated and the residue was purified on silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent, to provide the title compound as a white solid (51 mg, 24%).
[0660] [0660] 1H NMR (CD3OD) δ 3.20 (t, 2H), 2.44 (t, 2H), 2.24 (s, 6H), 2.04 (m, 2H).
[0661] [0661] Intermediate P66: 2- (2,2-Dimethylazetidin-1-yl) ethane-1-sulfonamide, TFA salt
[0662] [0662] Step A: 2- (2,2-Dimethylazetidin-1-yl) -N, N-bis (4-methoxybenzyl) ethane-1-sulfonamide
[0663] [0663] Prepared as described for 2- (azetidin-1-yl) -N, N-bis (4-methoxybenzyl) propane-1-sulfonamide (Intermediate P56, Step A) from N, N-bis (4- methoxybenzyl) ethylene sulfonamide and 2,2-dimethylazetidine to provide the title compound as an oil (125 mg, 100%).
[0664] [0664] 1H NMR (CDCl3) δ 7.17 (d, 4 H), 6.87 (d, 4 H), 4.22 (s, 4 H), 3.77 (s, 6 H), 3 .00 (m, 2H), 2.84 (m, 2H), 2.73 (m, 2H), 1.82 (m, 2H), 1.10 (s, 6H).
[0665] [0665] Step B: 2- (2,2-Dimethylazetidin-1-yl) ethane-1-sulfonamide, TFA salt
[0666] [0666] Prepared as described for 2- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P56, Step B) from 2- (2,2-dimethylazetidin-1-yl) - N, N-bis (4-methoxybenzyl) ethane-1-sulfonamide to provide the title compound as a colorless oil (83 mg, 92%).
[0667] [0667] 1H NMR (CD3OD) δ 4.05 (m, 2 H), 3.47 (m, 6 H), 2.38 (m, 2H), 1.66 (d, 6H).
[0668] [0668] Intermediate P67: 2- (2,4-Dimethylazetidin-1-yl) ethane-1-sulfonamide, TFA salt
[0669] [0669] Step A: 2- (2,4-Dimethylazetidin-1-yl) -N, N-bis (4-methoxybenzyl) ethane-1-sulfonamide
[0670] [0670] Prepared as described for 2- (azetidin-1-yl) -N, N-bis (4-methoxybenzyl) propane-1-sulfonamide (Intermediate P56, Step A) from N, N-bis (4- methoxybenzyl) ethylene sulfonamide and 2,4-dimethylazetidine HCl salt to provide the title compound as a colorless oil (125 mg, 100%).
[0671] [0671] 1H NMR (CDCl3) δ 7.19 (d, 4 H), 6.84 (d, 4 H), 4.24 (s, 4 H), 3.78 (s, 6H), 3, 33 (m, 6H), 2.92 (m, 2H), 2.25 (m, 1H), 1.55 (d, 6H).
[0672] [0672] Step B: 2- (2,4-Dimethylazetidin-1-yl) ethane-1-sulfonamide, TFA salt
[0673] [0673] Prepared as described for 2- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P56, Step B) from 2- (2,4-dimethylazetidin-1-yl) - N, N-bis (4-methoxybenzyl) ethane-1-sulfonamide. The solvents were evaporated and the residue was triturated in water. The aqueous layer was filtered and lyophilized to provide the title compound as a white solid (120 mg, 133%) which was used as such.
[0674] [0674] 1H NMR (CD3OD) δ 3.50 (m, 6H), 2.74 (m, 1 H), 2.01 (m, 1H), 1.56 (d, 6H).
[0675] [0675] Intermediate P68: 2- (2-isopropylazetidin-1-yl) ethane-1-sulfonamide, TFA salt
[0676] [0676] Step A: 2- (2,2-Isopropylazetidin-1-yl) -N, N-bis (4-methoxybenzyl) ethane-1-sulfonamide
[0677] [0677] Prepared as described for 2- (azetidin-1-yl) -N, N-bis (4-methoxybenzyl) propane-1-sulfonamide (Intermediate P56, Step A) from N, N-bis (4- methoxybenzyl) ethylene sulfonamide and 2-isopropylazetidine HCl salt to provide the title compound as a colorless oil (129 mg, 100%).
[0678] [0678] 1H NMR (CDCl3) δ 7.19 (d, 4 H), 6.87 (d, 4 H), 4.25 (s, 4 H), 3.78 (s, 6 H), 3 , 76 (m, 2 H), 3.32 (m, 2H), 3.09 (m, 2H), 2.28 (m, 2H), 1.55 (m, 1H), 0.92 (d , 6H).
[0679] [0679] Step B: 2- (2-Isopropylazetidin-1-yl) ethane-1-sulfonamide, TFA salt
[0680] [0680] Prepared as described for 2- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P56, Step B) from 2- (2-isopropylazetidin-1-yl) - N, N-bis (4 -methoxybenzyl) ethane-1-sulfonamide to provide the title compound as a colorless oil (120 mg, 136%).
[0681] [0681] 1H NMR (CD3OD) δ 4.06 (m, 3 H), 3.67 (m, 2 H), 3.40 (m, 2H), 2.36 (m, 3H), 1.0 (d, 6H).
[0682] [0682] Intermediate P69: (1-Methylpyrrolidin-2-yl) methanesulfonamide
[0683] [0683] Prepared as described for 1- (oxetan-3-yl) pyrrolidin-3-yl) methanesulfonamide (Intermediate P31) from formaldehyde (37% in water stabilized with methanol) and pyrrolidin-2-ylmethanesulfonamide hydrochloride. The title compound (25 mg, 18%) was used without further purification.
[0684] [0684] 1H NMR (CD3OD) δ 3.49 (dd, 1 H), 3.25 - 3.16 (m, 1 H), 3.09 (dd, 1 H), 2.95 - 2.81 (m, 1 H), 2.52 - 2.38 (m, 4 H), 2.38 - 2.24 (m, 1 H), 1.98 - 1.75 (m, 3 H).
[0685] [0685] Intermediate P70: (1-Ethylpyrrolidin-2-yl) methanesulfonamide
[0686] [0686] Prepared as described for (1- (oxetan-3-yl) pyrrolidin-3-yl) methanesulfonamide (Intermediate P31) from acetaldehyde and pyrrolidin-2-ylmethanesulfonamide hydrochloride. The title compound (34 mg, 22%) was used without further purification.
[0687] [0687] 1H NMR (CD3OD) δ 3.54 - 3.40 (m, 1 H), 3.29 - 3.24 (m, 1 H), 3.23 - 2.99 (m, 2 H) , 2.60 - 2.41 (m, 2 H), 2.38 - 2.22 (m, 1 H), 1.96 - 1.77 (m,
[0688] [0688] Intermediate P71: (1-Isopropylpyrrolidin-2-yl) methanesulfonamide
[0689] [0689] Prepared as described for (1- (oxetan-3-yl) pyrrolidin-3-yl) methanesulfonamide (Intermediate P31) from acetaldehyde and pyrrolidin-2-ylmethanesulfonamide hydrochloride. The title compound (98 mg, 60%) was used without further purification.
[0690] [0690] 1H NMR (CD3OD) δ 3.53 - 3.32 (m, 2 H), 3.25 - 3.04 (m, 2 H), 2.99 (dt, 1 H), 2.79 - 2.66 (m, 1 H), 2.14 (dq, 1 H), 2.03 - 1.76 (m, 3 H), 1.21 (d, 3 H), 1.13 (d , 3 H).
[0691] [0691] Intermediate P72: (1-Isopropylpiperidin-2-yl) methanesulfonamide
[0692] [0692] Prepared as described for (1- (oxetan-3-yl) pyrrolidin-3-yl) methanesulfonamide (Intermediate P31) from acetaldehyde and piperidin-2-ylmethanesulfonamide hydrochloride. The title compound (33 mg, 19%) was used without further purification.
[0693] [0693] 1H NMR (CD3OD) δ 3.27 - 3.05 (m, 4 H), 2.82 - 2.67 (m, 2 H), 1.83 (d, 2 H), 1.74 - 1.56 (m, 1 H), 1.55 - 1.41 (m, 2 H), 1.41 - 1.25 (m, 1 H), 1.15 (dd, 6 H).
[0694] [0694] Intermediate P73: (1-Ethylpiperidin-2-yl) methanesulfonamide
[0695] [0695] Prepared as described for (1- (oxetan-3-yl) pyrrolidin-3-yl) methanesulfonamide (Intermediate P31) from acetaldehyde and piperidin-2-ylmethanesulfonamide hydrochloride. The title compound (9 mg, 5%) was used without further purification.
[0696] [0696] 1H NMR (CD3OD) δ 3.25 - 3.04 (m, 4 H), 2.73 (td, 1 H), 2.53 (dd, 2 H), 1.87 - 1.73 (m, 2 H), 1.74 - 1.58 (m, 1 H), 1.48 (m, 2 H), 1.39 - 1.24 (m, 1 H), 1.11 (t , 3 H).
[0697] [0697] Intermediate P74: (1-Isopropyl-1H-pyrazol-3-yl) methanesulfonamide
[0698] [0698] Step A: Methyl 1-isopropyl-1H-pyrazol-3-carboxylate and methyl 1-isopropyl-1H-pyrazol-5-carboxylate
[0699] [0699] A mixture of methyl 1H-pyrazol-3-carboxylate (2 g, 15.86 mmol), 2-iodopropane (1.8 mL, 18.03 mmol) and K2CO3 (4.38 g, 31.7 mmol) in DMF (20 mL) was stirred at 60 ° C for 3 days. The reaction was suppressed with water (30 ml) and extracted with EtOAc (3 x 60 ml). The combined organic extracts were washed with brine (50 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (40 g column, 0-100% EtOAc / isohexane) to provide methyl 1-isopropyl-1H-pyrazol-3-carboxylate (1.379 g, 51%) as a clear colorless oil and methyl 1-isopropyl-1H-pyrazol-5-carboxylate (951 mg, 35%) as a clear colorless oil.
[0700] [0700] Methyl 1-isopropyl-1H-pyrazol-3-carboxylate:
[0701] [0701] 1H NMR (DMSO-d6) δ 7.90 (d, J = 2.3 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 4.59 (sept, J = 6.7 Hz, 1H), 3.78 (s, 3H), 1.42 (d, J = 6.7 Hz, 6H).
[0702] [0702] LCMS; m / z 169.5 (M + H) + (ES +).
[0703] [0703] Methyl 1-isopropyl-1H-pyrazol-5-carboxylate:
[0704] [0704] 1H NMR (DMSO-d6) δ 7.57 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 5.41 (sept, J = 6.6 Hz, 1H), 3.82 (s, 3H), 1.40 (d, J = 6.6 Hz, 6H).
[0705] [0705] LCMS; m / z 169.2 (M + H) + (ES +).
[0706] [0706] Step B: (1-isopropyl-1H-pyrazol-3-yl) methanol
[0707] [0707] To a solution of methyl 1-isopropyl-1H-pyrazol-3-carboxylate (1.37 g, 7.98 mmol) in THF (20 mL) at 0 ° C was added slowly LiAlH4 (2 M in THF , 6 mL, 12.0 mmol). The resulting mixture was stirred at 0 ° C for 30 minutes and then at room temperature overnight. The reaction was suppressed sequentially with water (0.3 ml), 2 M NaOH (0.75 ml) and water (2 ml). Na2SO4 was added, the mixture was stirred for 30 minutes and then filtered over a Celite® buffer rinsing with EtOAc. The solvent was evaporated and the residue was purified by chromatography on silica gel (24 g column, 0-10% MeOH / DCM) to provide the title compound (779 mg, 70%) as a clear colorless oil.
[0708] [0708] 1H NMR (DMSO-d6) δ 7.63 (d, J = 2.2 Hz, 1H), 6.14 (d, J = 2.2 Hz, 1H), 4.92 (t, J = 5.8 Hz, 1H), 4.42 (sept, J = 6.7 Hz, 1H), 4.38 (d, J = 5.8 Hz, 2H), 1.38 (d, J = 6 , 7 Hz, 6H).
[0709] [0709] LCMS; m / z 141.1 (M + H) + (ES +).
[0710] [0710] Step C: 3- (Bromomethyl) -1-isopropyl-1H-pyrazole
[0711] [0711] To a solution of (1-isopropyl-1H-pyrazol-3-yl) methanol (779 mg, 5.56 mmol) in DCM (50 mL) at 0 ° C, tribromophosphine (0.55 mL) was added slowly , 5.85 mmol) in DCM (10 mL). The resulting mixture was warmed to room temperature and stirred overnight. The mixture was poured onto ice (~ 50 g) and stirred until all of the ice was dissolved. Aqueous saturated NaHCO3 (20 ml) was added. The layers were separated and the aqueous layer was extracted with DCM (2 x 50 ml). The combined organic extracts were passed through a phase separator and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (24 g column, 0-50% EtOAc / isohexane) to provide the title compound (865 mg, 73%) as a clear colorless oil.
[0712] [0712] 1H NMR (DMSO-d6) δ 7.71 (d, J = 2.3 Hz, 1H), 6.28 (d, J = 2.3 Hz, 1H), 4.60 (s, 2H ), 4.46 (sept, J = 6.7 Hz, 1H), 1.39 (d, J = 6.7 Hz, 6H).
[0713] [0713] LCMS; m / z 203.1 / 205.1 (M + H) + (ES +).
[0714] [0714] Step D: (1-Isopropyl-1H-pyrazol-3-yl) methanesulfonamide
[0715] [0715] A mixture of methyl 3- (chlorosulfonyl) propanoate (1.0 g, 5.36 mmol), sodium sulfite (1.4 g, 11.11 mmol) and sodium bicarbonate (0.94 g, 11.19 mmol) in water (6 mL) was stirred at 80 ° C overnight. The solvent was evaporated to obtain a white solid. Ethanol (30 ml) was added and the mixture was heated to 60 ° C for 1 hour and subsequently filtered while it was hot. The filtrate was evaporated to provide sodium 3-methoxy-3-oxopropane-1-sulfinate (588 mg, 50% purity by NMR) as a white solid that was used directly.
[0716] [0716] To a solution of sodium 3-methoxy-3-oxopropane-1-sulfinate (588 mg, 1.688 mmol) in DMSO (2.5 mL) was added 3- (bromomethyl) -1- isopropyl-1H-pyrazole (280 mg, 1.310 mmol) and the mixture was stirred at room temperature for 45 minutes. The mixture was diluted with water (5 ml) and extracted with EtOAc (4 x 30 ml). The combined organic extracts were washed with brine (25 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was dissolved in THF (5 ml) and MeOH (1.2 ml) and NaOMe (5.4 M in MeOH, 0.35 ml, 1.89 mmol) were added. The mixture was stirred at room temperature for 15 min. The solvent was removed in vacuo and the residue was dissolved in water (0.8 ml). (Aminooxy) sulfonic acid (1.2 g, 10.61 mmol) and sodium acetate (360 mg, 4.39 mmol) were added and the mixture was stirred at room temperature for 2 days. The mixture was diluted with saturated aqueous NaHCO3 (30 ml) and extracted with EtOAc (2 x 40 ml). The combined organic extracts were washed with brine (30 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (12 g column, 0-10% MeOH / DCM) and then purified by preparative UPLC (Teledyne EZ Prep, basic (0.1% ammonium bicarbonate), basic, Waters X-Bridge Prep-C18, 5 µm, 19x50 mm column, 5-10% MeCN in water) to provide the title compound (31 mg, 11%) as a white solid.
[0717] [0717] 1H NMR (DMSO-d6) δ 7.72 (d, J = 2.3 Hz, 1H), 6.79 (s, 2H), 6.26 (d, J = 2.3 Hz, 1H ), 4.46 (sept, J = 6.7 Hz, 1H), 4.23 (s, 2H), 1.40 (d, J = 6.7 Hz, 6H).
[0718] [0718] LCMS; m / z 204.5 (M + H) + (ES +).
[0719] [0719] Intermediate P75: N-Methyl-N- (3-sulfamoylpropyl) acetamide
[0720] [0720] Prepared as described for methyl methyl (3-sulfamoylpropyl) carbamate (Intermediate P64) from 3- (methylamino) propane-1-sulfonamide and acetic formic anhydride. The solvents were evaporated and the residue was triturated in THF. THF was filtered (over Celite®) and evaporated to provide the title compound as a colorless oil (100 mg, quant.) Which was used without further purification.
[0721] [0721] 1H NMR (Methanol-d4) δ 3.54 (t, 2 H), 3.16 (t, 2 H), 3.05 (s, 3H),
[0722] [0722] Preparation of Examples
[0723] [0723] Example 1: 1- (1-Ethylpiperidin-4-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) metasulfonamide, potassium salt
[0724] [0724] To a cooled (0 ° C) solution of (1-ethylpiperidin-4-yl) methanesulfonamide (Intermediate P1; 76 mg, 0.37 mmol) in THF (2.5 mL) was added potassium tert-butoxide (41 mg, 0.37 mmol). The ice bath was removed and the reaction mixture was stirred while allowing to warm to room temperature for 40 minutes. A solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1; 73 mg, 0.37 mmol) in THF (1 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and DMSO (1 ml) was added. The suspension was filtered over cotton and subsequently subjected to purification by reverse phase column chromatography (see "Experimental Methods") to provide the title compound (28 mg, 19%) as a white solid.
[0725] [0725] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.18 (m, 2 H), 3.07 (m, 2 H), 2.82 (m, 8 H), 2 , 57 (m, 2 H), 2.24 (m, 2 H), 2.04 (m, 7 H), 1.44 (m, 2 H) and 1.16 (t, 3 H).
[0726] [0726] LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[0727] [0727] Example 2: 3- (4- (Dimethylamino) piperidin-1-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl ) propane-1-sulfonamide, potassium salt
[0728] [0728] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (4- (dimethylamino) piperidin-1-yl ) propane-1-sulfonamide (Intermediate P2) to provide the title compound (13%) as a light yellow solid.
[0729] [0729] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.23 (m, 1 H), 3.08 (m, 4 H), 2.82 (m, 8 H), 2 , 46 (m, 2 H), 2.34 (s, 6 H), 2.02 (m, 10 H) and 1.58 (m, 2 H).
[0730] [0730] LCMS: m / z 449 (M + H) + (ES +); 447 (M-H) - (ES-).
[0731] [0731] Example 3: 3- (diethylamino) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1-sulfonamide, salt potassium
[0732] [0732] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (dimethylamino) propane-1-sulfonamide (Intermediate P3 ) to provide the title compound (11%) as a light yellow solid.
[0733] [0733] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.28 (m, 4 H), 2.95 (m, 2 H), 2.82 (m, 10 H), 2 , 02 (m, 6 H) and 1.18 (t, 6 H).
[0734] [0734] LCMS: m / z 394 (M + H) + (ES +).
[0735] [0735] Example 4: 1 - ((1S) -7,7-Dimethyl-2-oxobicyclo [2.2.1] heptan-1-yl) - N - ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, potassium salt THE
[0736] [0736] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1S) -10-camphorsulfonamide to provide the title compound ( 63%) as a light yellow solid.
[0737] [0737] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.63 (d, 1 H), 3.23 (d, 1 H), 2.82 (m, 8 H), 2 , 62 (m, 1 H), 2.37 (m, 1 H), 2.02 (m, 6 H), 1.88 (d, 1 H), 1.7 (m, 1 H), 1 , 42 (m, 1 H), 1.1 (s, 3 H) and 0.85 (s, 3 H).
[0738] [0738] LCMS: m / z 431 (M + H) + (ES +); 429 (M-H) - (ES-).
[0739] [0739] Example 5: 2- (Dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ethane-1-sulfonamide, salt of potassium
[0740] [0740] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (dimethylamino) ethane-1-sulfonamide to provide the title compound (52%) as a white solid.
[0741] [0741] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.42 (m, 2 H), 2.88 (m, 2 H), 2.82 (m, 8 H), 2 , 33 (s, 6 H) and 2.02 (m, 4 H).
[0742] [0742] LCMS: m / z 352 (M + H) + (ES +); 350 (MH) - (ES-).
[0743] [0743] Example 6: N- (2- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) ethyl) acetamide, salt of potassium
[0744] [0744] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N- (2-sulfamethyl) acetamide to provide the title compound (67%) as a white solid.
[0745] [0745] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.61 (m, 2 H), 3.37 (m, 2 H), 2.82 (m, 8 H), 2 , 02 (m, 4 H) and 1.93 (s, 3 H).
[0746] [0746] LCMS: m / z 366 (M + H) + (ES +); 364 (M-H) - (ES-).
[0747] [0747] Example 7: 1- (1- (Dimethylamino) cyclopropyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, salt potassium
[0748] [0748] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1- (dimethylamino) cyclopropyl) methanesulfonamide to provide the compound holder (57%) as a white solid.
[0749] [0749] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.58 (s, 2 H), 2.82 (m, 8 H), 2.38 (s, 6 H), 2 , 02 (m, 4 H), 1.17 (m, 2 H) and 1.66 (m, 2 H).
[0750] [0750] LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[0751] [0751] Example 8: 3- (Dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-
[0752] [0752] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (dimethylamino) propane-1-sulfonamide (Intermediate P4 ) to provide the title compound (52%) as a white solid.
[0753] [0753] 1H NMR (CD3OD) δ 6.87 (s, 1H), 3.24 (dd, 2H), 2.83 (m, 10H), 2.59 (t, 2H), 2.35 (s , 6H), 2.02 (m, 4H).
[0754] [0754] LCMS: m / z 366 (M + H) + (ES +); 364 (M-H) - (ES-).
[0755] [0755] Example 9: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-isobutyryl piperidine-4-sulfonamide, potassium salt
[0756] [0756] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4-morpholinobutane-1-sulfonamide (Intermediate P5) to provide the title compound (55%) as a white solid.
[0757] [0757] 1H NMR (CD3OD) δ 6.87 (s, 1H), 3.73-3.62 (m, 4H), 3.28-3.18 (m, 2H), 2.82 (m, 8H), 2.46 (t, 4H), 2.44-2.32 (m, 2H), 2.03 (m, 4H), 1.93-1.74 (m, 2H), 1.66 (t, 2H).
[0758] [0758] LCMS: m / z 422 (M + H) + (ES +); 420 (M-H) - (ES-).
[0759] [0759] Example 10: 4- (Diethylamino) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1-sulfonamide, salt potassium
[0760] [0760] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4- (diethylamino) butane-1-sulfonamide (Intermediate P6 ) to provide the title compound (61%) as a white solid.
[0761] [0761] 1H NMR (CD3OD) δ 6.88 (s, 1H), 3.26 (dd, 2H), 3.04 (m, 6H), 2.83 (m, 9H), 2.13-1 , 92 (m, 4H), 1.91-1.73 (m, 3H), 1.22 (t, 6H).
[0762] [0762] LCMS: m / z 408 (M + H) + (ES +); 406 (M-H) - (ES-).
[0763] [0763] Example 11: 2- (Benzyl (ethyl) amino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ethane-1- sulfonamide, potassium salt
[0764] [0764] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (benzyl (ethyl) amino) ethane-1- sulfonamide (Intermediate P7) to provide the title compound (24%) as a white solid.
[0765] [0765] 1H NMR (CD3OD) δ 7.42-7.11 (m, 5H), 6.86 (s, 1H), 3.63 (s, 2H), 3.51-3.40 (m, 2H), 3.11 - 2.95 (m, 2H), 2.81 (m, 8H), 2.55 (q, 2H), 2.02 (m,
[0766] [0766] LCMS: m / z 442 (M + H) + (ES +); 440 (M-H) - (ES-).
[0767] [0767] Example 12: N - ((1,2,3,5,6,7-Hexa-hydro-s-indacen-4-yl) carbamoyl) -2-morpholinoethane-1 - sulfonamide, potassium salt
[0768] [0768] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-morpholinoethane-1-sulfonamide (Intermediate P8) to provide the title compound (87%) as a white solid.
[0769] [0769] 1H NMR (CD3OD) δ 6.87 (s, 1H), 3.68 (m, 4H), 3.53-3.38 (m, 2H), 2.96-2.74 (m, 10H), 2.51 (dd, 4H), 2.02 (m, 4H).
[0770] [0770] LCMS: m / z 394 (M + H) + (ES +); 392 (M-H) - (ES-).
[0771] [0771] Example 13: 4- (Benzyl (ethyl) amino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) butane-1- sulfonamide, potassium salt
[0772] [0772] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene
[0773] [0773] 1H NMR (CD3OD) δ 7.52-7.20 (m, 5H), 6.87 (s, 1H), 3.86 (s, 2H), 3.24 (t, 2H), 2 , 90-2.62 (m, 12H), 2.16-1.89 (m, 8H), 1.23-1.06 (m, 3H).
[0774] [0774] LCMS: m / z 470 (M + H) + (ES +); 468 (M-H) - (ES-).
[0775] [0775] Example 14: N - (((1,2,3,5,6,7-Hexa-hydro-s-indacen-4-yl) carbamoyl) -3-methoxypropane-1-sulfonamide, potassium salt
[0776] [0776] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-methoxypropane-1-sulfonamide to provide the title compound ( 51%) as a white solid.
[0777] [0777] 1H NMR (CD3OD) δ 6.87 (s, 1H), 3.50 (t, 2H), 3.33 (s, 3H), 3.30-3.16 (m, 2H), 2 , 82 (m, 8H), 2.17-1.91 (m, 6H).
[0778] [0778] LCMS: m / z 353 (M + H) + (ES +); 351 (M-H) - (ES-).
[0779] [0779] Example 15: N - (((1,2,3,5,6,7-Hexa-hydro-s-indacen-4-yl) carbamoyl) -3-morpholinopropane-1-sulfonamide, potassium salt
[0780] [0780] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-morpholinopropane-1-sulfonamide (Intermediate P10) to provide the title compound (62%) as a white solid.
[0781] [0781] 1H NMR (CD3OD) δ 6.87 (s, 1H), 3.79-3.59 (m, 4H), 3.28-3.18 (m, 2H), 2.82 (m, 8H), 2.58-2.41 (m, 6H), 2.02 (m, 6H).
[0782] [0782] LCMS: m / z 408 (M + H) + (ES +); 406 (M-H) - (ES-).
[0783] [0783] Example 16: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -3- (piperidin-1-yl) propane-1- sulfonamide, potassium salt
[0784] [0784] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (piperidin-1-yl) propane-1- sulfonamide (Intermediate P11) to provide the title compound (28%) as a white solid.
[0785] [0785] 1H NMR (CD3OD) δ 6.88 (s, 1H), 3.26 (t, 2H), 2.83 (m, 10H), 2.50 (t, 2H), 2.12 (q , 2H), 2.02 (m, 6H), 1.68 (q, 3H), 1.64-1.38 (m, 3H).
[0786] [0786] LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[0787] [0787] Example 17: 1- (1-Ethylazetidin-3-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, potassium salt
[0788] [0788] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylazetidin-3-yl) methanesulfonamide (Intermediate P14 )
[0789] [0789] 1H NMR (CD3OD) δ 6.89 (s, 1H), 4.05 (t, 1H), 3.87 (t, 2H), 3.59 (m, 1H), 3.55-3 , 39 (m, 3H), 3.24-3.05 (m, 1H), 2.95-2.70 (m, 9H), 2.04 (m, 4H), 1.05 (t, 3H ).
[0790] [0790] LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[0791] [0791] Example 18: 2- (Diethylamino) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ethane-1-sulfonamide, salt of potassium
[0792] [0792] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (diethylamino) ethane-1-sulfonamide (Intermediate P12 ) to provide the title compound (33%) as a white solid.
[0793] [0793] 1H NMR (CD3OD) δ 6.88 (s, 1H), 3.48 (t, 2H), 2.83 (m, 14H), 2.02 (m, 4H), 1.19 (t , 6H).
[0794] [0794] LCMS: m / z 380 (M + H) + (ES +); 378 (M-H) - (ES-).
[0795] [0795] Example 19: 2- (Ethylamino) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ethane-1-sulfonamide, salt potassium
[0796] [0796] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N-
[0797] [0797] 1H NMR (CD3OD) δ 6.90 (s, 1H), 3.45 (t, 2H), 3.22 (t, 2H), 2.86 (t, 10H), 2.81 (s, 1H ), 2.04 (m, 4H), 1.21 (t, 3H).
[0798] [0798] LCMS: m / z 352 (M + H) + (ES +); 350 (M-H) - (ES-).
[0799] [0799] Example 20: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (pyridin-3-yl) methanesulfonamide, salt potassium
[0800] [0800] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and pyridin-3-ylmethanesulfonamide to provide the title compound (66% ) as a white solid.
[0801] [0801] 1H NMR (CD3OD) δ 8.61 (d, 1H), 8.46 (dd, 1H), 7.94 (d, 1H), 7.42 (dd, 1H), 6.90 (s , 1H), 4.54 (s, 2H), 2.85 (m, 8H), 2.06 (m, 4H).
[0802] [0802] LCMS: m / z 372 (M + H) + (ES +); 370 (M-H) - (ES-).
[0803] [0803] Example 21: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (pyridin-2-yl) methanesulfonamide, salt potassium
[0804] [0804] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and pyridin-2-ylmethanesulfonamide to provide the title compound (67% ) as a white solid.
[0805] [0805] 1H NMR (CD3OD) δ 8.54-8.42 (m, 1H), 7.79 (td, 1H), 7.61 (d, 1H), 7.33 (ddd, 1H), 6 , 88 (s, 1H), 4.66 (s, 2H), 2.84 (m, 8H), 2.04 (m, 4H).
[0806] [0806] LCMS: m / z 372 (M + H) + (ES +); 370 (M-H) - (ES-).
[0807] [0807] Example 22: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-methylpiperidin-2-yl) methanesulfonamide, potassium salt
[0808] [0808] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-methylpiperidin-4-yl) methanesulfonamide (Intermediate P15 ) to provide the title compound (27%) as a white solid.
[0809] [0809] 1H NMR (CD3OD) δ 7.01 (s, 1H), 3.42 (m, 2H), 3.17 (m, 2H), 2.93 (m, 2H), 2.77-2 , 67 (m, 11H), 2.13-1.95 (m, 9H).
[0810] [0810] LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[0811] [0811] Example 23: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-methylpyrrolidin-3-yl) methanesulfonamide, potassium salt
[0812] [0812] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate
[0813] [0813] 1H NMR (CD3OD) δ 6.92 (s, 1H), 3.53-3.39 (m, 2H), 3.05 (dt, 2H), 2.86 (m, 10H), 2 , 70 (d, 4H), 2.30 (m, 1H), 2.06 (m, 4H), 1.95-1.74 (m, 1H).
[0814] [0814] LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[0815] [0815] Example 24: 1- (1-Ethylpyrrolidin-3-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, potassium salt
[0816] [0816] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylpyrrolidin-3-yl) methanesulfonamide (Intermediate P17 ) to provide the title compound (53%) as a white solid.
[0817] [0817] 1H NMR (CD3OD) δ 6.90 (s, 1H), 3.54 (dd, 1H), 3.46-3.34 (m, 1H), 3.24-3.09 (m, 3H), 3.04 (q, 2H), 2.83 (m, 10H), 2.39-2.19 (m, 1H), 2.03 (m, 4H), 1.92-1.72 (m, 1H), 1.24 (t, 3H).
[0818] [0818] LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[0819] [0819] Example 25: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-isopropylpyrrolidin-3-yl) methanesulfonamide, potassium salt
[0820] [0820] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene
[0821] [0821] 1H NMR (CD3OD) δ 6.89 (s, 1H), 3.57 (dd, 1H), 3.49-3.34 (m, 1H), 3.26-3.12 (m, 3H), 3.06 (dd, 1H), 2.83 (m, 10H), 2.40-2.21 (m, 1H), 2.03 (m, 4H), 1.81 (dq, 1H ), 1.28 (dd, 6H).
[0822] [0822] Example 26: 1- (Dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-2-sulfonamide, salt potassium
[0823] [0823] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (dimethylamino) ethane-1-sulfonamide (Intermediate P19 ) to provide the title compound (17%) as a white solid.
[0824] [0824] 1H NMR (CD3OD) δ 6.88 (s, 1H), 3.71 (d, 1H), 2.94 (s, 1H), 2.83 (m, 8H), 2.69 (d , 1H), 2.39 (s, 6H), 2.03 (m, 4H), 1.38 (d, 3H).
[0825] [0825] LCMS: m / z 366 (M + H) + (ES +); 364 (M-H) - (ES-).
[0826] [0826] Example 27: 3- (Ethyl (methyl) amino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1- sulfonamide, potassium salt
[0827] [0827] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (ethyl (methyl) amino) propane-1- sulfonamide (Intermediate
[0828] [0828] 1H NMR (CD3OD) δ 6.88 (s, 1H), 3.26 (t, 2H), 3.00-2.89 (m, 2H), 2.89-2.73 (m, 10H), 2.53 (s, 3H), 2.06 (m, 6H), 1.19 (t, 3H).
[0829] [0829] LCMS: m / z 380 (M + H) + (ES +); 378 (M-H) - (ES-).
[0830] [0830] Example 28: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -2- (piperidin-1-yl) ethane-1- sulfonamide, potassium salt THE THE
[0831] [0831] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (piperidin-1-yl) ethane-1- sulfonamide (Intermediate P20) to provide the title compound (37%) as a white solid.
[0832] [0832] 1H NMR (CD3OD) δ 6.87 (s, 1H), 3.55-3.40 (m, 2H), 3.03-2.92 (m, 2H), 2.83 (m, 8H), 2.60 (d, 4H), 2.02 (m, 4H), 1.64 (dq, 4H), 1.50 (t, 2H).
[0833] [0833] LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[0834] [0834] Example 29: 2- (Azetidin-1-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ethane-1- sulfonamide, potassium salt THE THE
[0835] [0835] Prepared as described for 1- (1-ethylpiperidin-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide , potassium salt (Example 1) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (azetidin-1-yl) ethane-1- sulfonamide (Intermediate P21) to provide the title compound (1%) as a white solid.
[0836] [0836] LCMS: m / z 364 (M + H) + (ES +); 362 (M-H) - (ES-).
[0837] [0837] Example 30: 1- (4-Cyanophenyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, sodium salt NCO THE
[0838] [0838] To a solution of (4-cyanophenyl) methanesulfonamide (Intermediate P23) (110 mg, 560.58 µmol, 1 eq) in THF (5 ml) was added sodium methoxide (30.28 mg, 560.58 µmol , 1 eq) at 20 ° C. After stirring for 15 minutes, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (111.69 mg, 560.58 µmol, 1 eq) was added to the mixture. The mixture was stirred at 20 ° C for 15 hours and then filtered. The collected solid was triturated with ethyl acetate (3 x 5 ml) and the combined layers were concentrated in vacuo to obtain the title compound (99 mg, 40%) as a white solid.
[0839] [0839] 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, 2 H), 7.47 (d, 2 H), 7.24 (br s, 1 H), 6.78 (s , 1 H), 4.34 (s, 2 H), 2.77-2.69 (m, 8 H) and 1.95-1.91 (m, 4 H).
[0840] [0840] LCMS: m / z 396 (M + H) + (ES +).
[0841] [0841] Example 31: 4 - ((N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) methyl) methyl benzoate, salt of sodium
[0842] [0842] Prepared as described for 1- (4-cyanophenyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, sodium salt (Example 30) to provide the title compound (125 mg, 72%) as a white solid.
[0843] [0843] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, 2 H), 7.44 (d, 2 H),
[0844] [0844] LCMS: m / z 429 (M + H) + (ES +).
[0845] [0845] Example 32: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (3-methoxyphenyl) methanesulfonamide, sodium salt
[0846] [0846] Prepared as described for 1- (4-cyanophenyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, sodium salt (Example 30) to provide the title compound (172 mg, 31%) as a white solid.
[0847] [0847] 1H NMR (400 MHz, DMSO-d6) δ 7.30-7.29 (m, 4 H), 7.25 (br s, 1 H), 6.78 (s, 1 H), 4 , 21 (s, 2 H), 3.33 (s, 3 H), 2.77-2.72 (m, 8 H) and 1.95-1.91 (m, 4 H).
[0848] [0848] LCMS: m / z 401 (M + H) + (ES +).
[0849] [0849] Example 33: 2 - ((N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) methyl) methyl benzoate, salt of sodium
[0850] [0850] To a solution of methyl 2- (sulfamoylmethyl) benzoate (100 mg, 436.20 µmol) in THF (4 ml) was added sodium methoxide (23.56 mg, 436.20 µmol). The mixture was stirred at 20 ° C for 30 minutes before adding 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (104.29 mg, 523, 44 µmol, 1.2 eq). The reaction mixture was stirred at 20 ° C for 16 hours and then concentrated in vacuo. The crude product was purified by preparative UPLC (column: Phenomenex Gemini 150 mm * 25 mm * 10µm; mobile phase: [water
[0851] [0851] 1H NMR (400 MHz, DMSO-d6) δ 10.17 (br s, 1 H), 7.88-7.86 (m, 2 H), 7.63-7.61 (m, 1 H), 7.57-7.55 (m, 1 H), 7.42-7.40 (m, 1 H), 6.98 (s, 1 H), 5.19 (s, 2 H) , 3.79 (s, 3 H), 2.85-2.81 (m, 4 H), 2.74-2.72 (m, 4 H) and 2.05-1.99 (m, 4 H).
[0852] [0852] LCMS: m / z 451 (M + Na) + (ES +).
[0853] [0853] Example 34: 3-Azido-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1-sulfonamide, potassium salt
[0854] [0854] To a solution of 3-azidopropane-1-sulfonamide (Intermediate P30) (200 mg, 2.1 mmol) in THF (15 mL) was added potassium tert-butoxide (236 mg, 2.1 mmol). The mixture was stirred at room temperature for 45 minutes. 4-Isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (419 mg, 2.1 mmol) was added and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was concentrated in vacuo and part of the mixture was dissolved in DMSO (1 ml) and subjected to purification by reverse phase column chromatography (see "Experimental methods", "Purification methods") to provide an initial amount of title compound (55 mg) as a white solid. The rest of the batch was stored.
[0855] [0855] LCMS: m / z 364 (M + H) + (ES +); 362 (M-H) - (ES-).
[0856] [0856] Example 35: N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-methyl-1H-pyrazol-4- il) methanesulfonamide
[0857] [0857] NaOtBu (2 M in THF, 0.17 mL, 0.34 mmol) was added to a solution of (1-methyl-1H-pyrazol-4-yl) methanesulfonamide (60 mg, 0.325 mmol) in a mixture THF (3.5 mL) and DMF (0.5 mL) at room temperature. The mixture was stirred for 1 hour, before 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (71 mg, 0.358 mmol) was added in a single portion and the reaction mixture is stirred for 21 hours at room temperature. EtOAc (10 ml) was added, followed by 2 M aq NaOH (~ 0.2 ml) and water (3 ml). The phases were separated and the organic phase was washed with water (3 ml). The combined aqueous phases were filtered and purified by RP Flash C18 chromatography (12 g column, 5-100% MeCN / 10 mM ammonium bicarbonate) to obtain the title compound (0.10 g, 81%) as a solid White.
[0858] [0858] 1H NMR (DMSO-d6) δ 7.58 (s, 1H), 7.53 (br s, 1H), 7.30 (s, 1H), 6.86 (s, 1H), 4, 31 - 4.23 (m, 2H), 3.80 (s, 3H), 2.79 (t, J = 7.4 Hz, 4H), 2.72 (t, J = 7.3 Hz, 4H ), 1.96 (p, J = 7.5 Hz, 4H). NH not observed.
[0859] [0859] LCMS; m / z 397.3 (M + Na) + (ES +).
[0860] [0860] Example 36: 3- (Dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2-methylpropane-1-sulfonamide , potassium salt
[0861] [0861] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene
[0862] [0862] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.29 - 3.06 (m, 2H), 2.83 (m, 9H), 2.77 - 2.59 ( m, 1H), 2.46 (s, 6H), 2.45 (m, 1H), 2.02 (m, 4H), 1.15 (d, 3H).
[0863] [0863] LCMS: m / z 380 (M + H) + (ES +); 378 (M-H) - (ES-).
[0864] [0864] Example 37: 3- (Diethylamino) -N - (((4-fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) propane-1-sulfonamide F OCN
[0865] [0865] To a solution of 3- (diethylamino) propane-1-sulfonamide (Intermediate P3) (200 mg, 1.03 mmol, 1 eq) in THF (5 mL) was added NaOMe (56 mg, 1.03 mmol , 1 eq) and 3- (5-fluoro-2-isocyanate-3-isopropylphenyl) iridine (Intermediate A6) (263.80 mg, 1.03 mmol, 1 eq). The reaction mixture was stirred at 70 ° C for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative UPLC (column: Phenomenex Gemini, 250mm * 25mm * 5μm; mobile phase: [A: water (0.04% v / v ammonium hydroxide); B: MeCN]; B%: 18% -39%, 10 min) to obtain the title compound (58.2 mg, 11% yield, 100% UPLC purity) as a brown solid.
[0866] [0866] 1H NMR (DMSO-d6): δ 8.59 (br s, 1 H), 8.50 (dd, 1 H), 7.83- 7.81 (m, 1 H), 7.38 (dd 2 H), 7.12 (dd, 1 H), 6.97 (d, 1 H), 3.29-3.25 (m, 1 H), 2.75-2.73 (m, 2 H), 2.49-2.43 (m, 6 H), 1.64-1.60 (m, 2 H), 1.16 (d, 6 H) and 0.97 (t,
[0867] [0867] LCMS: m / z 451.2 (M + H) + (ES +).
[0868] [0868] Example 38: 2-Ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2-azaspiro [3.3] heptane-6 -sulfonamide, potassium salt
[0869] [0869] To a cooled (0C) solution of 2-ethyl-2-azaspiro [3.3] heptane-6-sulfonamide (Intermediate P24) (10 mg, 0.05 mmol) in THF (3 mL) was added tert - potassium butoxide (6 mg, 0.05 mmol). The ice bath was removed and the reaction mixture was stirred while allowing to warm to room temperature for 40 minutes. A solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (10 mg, 0.05 mmol) in THF (1 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and DMSO (1 ml) was added. The suspension was filtered over cotton and subsequently subjected to purification by reverse phase column chromatography (see "Experimental Methods") to provide the title compound (7 mg, 35%) as a white solid.
[0870] [0870] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.05 (m, 1 H), 3.61 (m, 4 H), 2.82 (m, 8 H), 2 , 73 (m, 2 H), 2.64 (m, 2 H), 2.53 (m, 2 H), 2.02 (m, 4 H) and 1.03 (t, 3 H).
[0871] [0871] LCMS: m / z 404 (M + H) + (ES +); 402 (M-H) - (ES-).
[0872] [0872] Example 39: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2-isopropyl-2-azaspiro [3.3] heptane-6 -sulfonamide, potassium salt
[0873] [0873] Prepared as described for 2-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2-azaspiro [3.3] heptane- 6-sulfonamide, potassium salt (Example 38) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-isopropyl-2-azaspiro [3.3] heptane-6-sulfonamide (Intermediate P25) to provide the title compound (41%) as a white solid.
[0874] [0874] 1H NMR (CD3OD) δ 6.89 (s, 1H), 4.28-3.80 (m, 5H), 3.26-3.12 (m, 1H), 2.81 (dt, 8H), 2.73-2.55 (m, 4H), 2.04 (q, 4H), 1.14 (d, 6H).
[0875] [0875] LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[0876] [0876] Example 40: N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2-methyl-2-azaspiro [3.3] heptane-6 -sulfonamide, potassium salt
[0877] [0877] Prepared as described for 2-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2-azaspiro [3.3] heptane- 6-sulfonamide, potassium salt (Example 38) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-isopropyl-2-azaspiro [3.3] heptane-6-sulfonamide (Intermediate P26) to provide the title compound (14%) as a white solid.
[0878] [0878] 1H NMR (CD3OD) δ 6.88 (s, 1H), 4.04 (m, 5H), 2.96-2.72 (m, 11H), 2.72-2.55 (m, 4H), 2.02 (m, 4H).
[0879] [0879] LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[0880] [0880] Example 41: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -3- (diethylamino) propane-1-sulfonamide F F
[0881] [0881] To a solution of 3- (diethylamino) propane-1-sulfonamide (Intermediate P3) (80 mg, 411.75 μmol, 1 eq) in THF (1 ml) was added t-BuONa (40 mg, 411, 75 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A3) (116 mg, 411.75 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150mm * 25mm * 5μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B%: 12 % -42%, 11.5 min) to obtain the title compound (105.29 mg, 55% yield, 100% UPLC purity) as a white solid.
[0882] [0882] 1H NMR (DMSO-d6): δ 8.75 (d, 1 H), 8.08 (s, 1 H), 7.79-7.73 (m, 2 H), 7.23 ( d, 1 H), 7.13 (d, 1 H), 3.09-3.06 (m, 1 H), 3.03-2.88 (m, 8 H), 1.75-1, 72 (m, 2 H), 1.16 (d, 6 H) and 1.09 (t, 6 H).
[0883] [0883] LCMS: m / z 476.3 (M + H) + (ES +).
[0884] [0884] Example 42: 3- (Diethylamino) -N - (((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) propane-1-sulfonamide
[0885] [0885] To a solution of 3- (diethylamino) propane-1-sulfonamide (Intermediate P3) (80 mg, 411.75 μmol, 1 eq) in THF (1 ml) was added t-BuONa (40 mg, 411, 75 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A4) (118 mg, 411.75 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 18% -48%, 11.5 min) to obtain the title compound (59.65 mg, 30% yield, 100% UPLC purity) as a white solid.
[0886] [0886] 1H NMR (DMSO-d6): δ 8.15 (d, 1 H), 7.64 (s, 1 H), 7.19 (d, 1 H), 7.09-6.95 ( m, 2 H), 6.85 (s, 1 H), 3.87 (s, 3 H), 3.23-3.20 (m, 1 H), 3.04-2.75 (m, 8 H), 1.77-1.72 (m, 2 H), 1.16 (d, 6 H) and 1.09-1.04 (m, 6 H).
[0887] [0887] LCMS: m / z 481.3 (M + H) + (ES +).
[0888] [0888] Example 43: 3- (Diethylamino) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) propane-1- sulfonamide
[0889] [0889] To a solution of 3- (diethylamino) propane-1-sulfonamide (Intermediate P3) (80 mg, 411.75 μmol, 1 eq) in THF (1 ml) was added t-BuONa (40 mg, 411, 75 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A5) (171 mg, 411.75 μmol, purity: 64% in UPLC, 1 eq ) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 15% -45%, 11.5 min) to obtain the title compound (53.15 mg, 28% yield, 100% UPLC purity) as a pink solid.
[0890] [0890] 1H NMR (DMSO-d6): δ 8.13 (d, 1 H), 7.64 (br s, 1 H), 7.15 (d, 1 H), 7.09 (d, 1 H), 6.97 (dd, 1 H), 6.78 (s, 1 H), 3.86 (s, 3 H), 3.08 (t, 2 H), 2.91
[0891] [0891] LCMS: m / z 461.3 (M + H) + (ES +).
[0892] [0892] Example 44: 3- (Diethylamino) -N - ((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) propane- 1-sulfonamide O O O
[0893] [0893] A mixture of 3- (diethylamino) propane-1-sulfonamide (Intermediate P3) (60 mg, 308.81 μmol, 1 eq) and t-BuONa (30 mg, 308.81 μmol, 1 eq) in THF (2 mL) was stirred at 25 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A2) (78 mg, 308.81 μmol, 1 eq) was added. The resulting mixture was stirred at 25 ° C for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 10% -40%, 10 min) to obtain the title compound (18.1 mg, 13% yield, 100% UPLC purity) as a white solid.
[0894] [0894] 1H NMR (DMSO-d6): δ 8.58-8.56 (m, 2 H), 7.61 (br s, 1 H), 7.41 (d, 2 H), 6.99 (d, 1 H), 3.03 (t, 2 H), 2.96 (t, 2 H), 2.90-2.78 (m, 8 H), 2.11-2.04 (m , 2 H), 1.82– 1.75 (m, 2 H) and 1.07 (t, 6 H).
[0895] [0895] LCMS: m / z 449.2 (M + H) + (ES +).
[0896] [0896] Example 45: 3- (Benzyl (ethyl) amino) -N - ((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) propane-1-sulfonamide
[0897] [0897] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonamide
[0898] [0898] 1H NMR (DMSO-d6): δ 8.13 (d, 1 H), 7.72 (s, 1 H), 7.32-7.20 (m, 6 H), 7.06- 7.01 (m, 2 H), 6.83 (s, 1 H), 3.85 (s, 3 H), 3.53 (s, 2 H), 3.19-3.15 (m, 1 H), 3.04-3.01 (m, 2 H), 2.44-2.40 (m, 4 H), 1.68-1.64 (m, 2 H), 1.15 ( d, 6 H) and 0.96 (t, 3 H).
[0899] [0899] LCMS: m / z 543.4 (M + H) + (ES +).
[0900] [0900] Example 46: 3- (Benzyl (ethyl) amino) -N - ((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) propane-1-sulfonamide
[0901] [0901] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonamide (Intermediate P27) (100 mg, 390.07 μmol, 1 eq) in THF (1 ml) was added t-BuONa (37 mg, 390.07 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A3) (110 mg, 390.07 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 28% -58%, 11.5 min) to obtain the title compound (37.69 mg, 18%
[0902] [0902] 1H NMR (DMSO-d6): δ 10.49 (br s, 1 H), 8.76 (d, 1 H), 8.14 (s, 1 H), 8.09 (s, 1 H), 7.76 (dd, 1 H), 7.34-7.20 (m, 7 H), 3.74 (s, 2 H), 3.18-3.09 (m, 3 H) , 2.47-2.42 (m, 4 H), 1.65-1.62 (m, 2 H), 1.17 (d, 6 H) and 0.96 (t, 3 H).
[0903] [0903] LCMS: m / z 538.4 (M + H) + (ES +).
[0904] [0904] Example 47: 3- (Benzyl (ethyl) amino) -N - ((5- (2-methoxypyridin-4-yl) - 2,3-dihydro-1H-inden-4-yl) carbamoyl) propane-1-sulfonamide
[0905] [0905] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonamide (Intermediate P27) (100 mg, 390.07 μmol, 1 eq) in THF (1 ml) was added t-BuONa (37 mg, 390.07 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A5) (146 mg, 390.07 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 18% -48%, 11.5 min) to obtain the title compound (35.98 mg, 17% yield, 98% UPLC purity) as a white solid.
[0906] [0906] 1H NMR (DMSO-d6): δ 10.31 (br s, 1 H), 8.16 (d, 1 H), 8.00 (s, 1H), 7.32-7.26 ( m, 4 H), 7.24 (d, 2 H), 7.14 (d, 1 H), 6.93 (d, 1 H), 6.75 (s, 1 H), 3.86 ( s, 3 H), 3.56 (s, 2 H), 3.26-3.22 (m, 2 H), 2.93 (t, 2 H), 2.79 (t, 2 H), 2.47-2.40 (m, 4 H), 2.02-1.97 (m, 2 H), 1.81-1.76 (m, 2 H) and 0.96 (t, 3 H ).
[0907] [0907] LCMS: m / z 523.3 (M + H) + (ES +).
[0908] [0908] Example 48: 3- (Benzyl (ethyl) amino) -N - ((7-fluoro-5- (pyridin-4-yl) - 2,3-dihydro-1H-inden-4-yl) carbamoyl) propane-1-sulfonamide
[0909] [0909] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonamide (Intermediate P27) (101 mg, 393.30 μmol, 1 eq) in THF (1 mL) was added t-BuONa (38 mg, 393.30 μmol, 1 eq). The reaction mixture was stirred at 15 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A2) (100 mg, 393.30 μmol, 1 eq) was added. The resulting mixture was stirred at 15 ° C for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (67.23 mg, 33% yield, 100% UPLC purity) as a pink solid.
[0910] [0910] 1H NMR (DMSO-d6): δ 8.57 (d, 2 H), 7.86 (br s, 1 H), 7.38 (d, 2 H), 7.31 (d, 4 H), 7.26-7.23 (m, 1 H), 7.03 (d, 1 H), 3.56 (s, 2 H), 3.18-3.15 (m, 2 H) , 2.96 (t, 2 H), 2.85 (t, 2 H), 2.47-2.42 (m, 4 H), 2.10-2.03 (m, 2 H), 1 , 76-1.70 (m, 2 H) and 0.96 (t, 3 H).
[0911] [0911] LCMS: m / z 511.3 (M + H) + (ES +).
[0912] [0912] Example 49: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -3-methoxypropane-1-sulfonamide THE THE F O S O The HN
[0913] [0913] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P28) (65 mg, 426.62 μmol, 1.2 eq) in THF (1 ml) was added t-BuONa (34 mg, 355.51 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A3) (100 mg, 355.51 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 11.5 min) to obtain the title compound (113.93 mg, 74% yield, 100% UPLC purity) as a white solid.
[0914] [0914] 1HNMR (DMSO-d6): δ 8.71 (d, 1 H), 8.06 (s, 1 H), 7.77 (s, 1 H), 7.58 (s, 1 H) , 7.23-7.18 (m, 1 H), 7.10 (d, 1 H), 3.29-3.24 (m, 3 H), 3.21 (s, 3 H), 2 , 76-2.73 (m, 2 H), 1.60-1.57 (m, 2 H) and 1.16 (d, 6 H).
[0915] [0915] LCMS: m / z 435.2 (M + H) + (ES +).
[0916] [0916] Example 50: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -3-methoxypropane-1-sulfonamide
[0917] [0917] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P28) (64 mg, 419.14 μmol, 1.2 eq) in THF (1 ml) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A4) (100 mg, 349.28 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% -38%, 11.5 min) to obtain the title compound (130.95 mg, 85%
[0918] [0918] 1H NMR (DMSO-d6): δ 8.11 (d, 1 H), 7.51 (s, 1 H), 7.16 (d, 1 H), 7.02-6.95 ( m, 2 H), 6.84 (s, 1 H), 3.86 (s, 3 H), 3.34-3.27 (m, 3 H), 3.21 (s, 3 H), 2.90-2.86 (m, 2 H), 1.72-1.61 (m, 2 H) and 1.15 (d, 6 H).
[0919] [0919] LCMS: m / z 440.2 (M + H) + (ES +).
[0920] [0920] Example 51: 3-Methoxy-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) propane-1-sulfonamide
[0921] [0921] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P28) (72 mg, 469.98 μmol, 1.2 eq) in THF (1 ml) was added t-BuONa (38 mg, 391.65 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A5) (163 mg, 391.65 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 11.5 min) to obtain the title compound (15.13 mg, 9% yield, 100% UPLC purity) as a white solid.
[0922] [0922] 1H NMR (DMSO-d6): δ 10.34 (br s, 1 H), 8.17 (d, 1 H), 7.97 (br s, 1 H), 7.24 (d, 1 H), 7.14 (d, 1 H), 6.94 (d, 1 H), 6.76 (s, 1 H), 3.88 (s, 3 H), 3.37 (t, 2 H), 3.26-3.20 (m, 5 H), 2.95 (t, 2 H), 2.81 (t, 2 H), 2.06-2.02 (m, 2 H ) and 1.84 - 1.78 (m, 2 H).
[0923] [0923] LCMS: m / z 420.2 (M + H) + (ES +).
[0924] [0924] Example 52: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -3-methoxypropane-1-sulfonamide
[0925] [0925] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P28) (60 mg, 393.30 μmol, 1 eq) in THF (1 ml) was added t-BuONa (38 mg, 393.30 μmol, 1 eq). The reaction mixture was stirred at 15 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A2) (100 mg, 393.30 μmol, 1 eq) was added. The resulting mixture was stirred at 15 ° C for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative UPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 0% -30%, 10 min) to obtain the title compound (62.33 mg, 38% yield, 100% UPLC purity) as a pink solid.
[0926] [0926] 1H NMR (DMSO-d6): δ 8.57 (d, 2 H), 7.63 (br s, 1 H), 7.40 (d, 2 H), 7.00 (d, 1 H), 3.37-3.34 (m, 2 H), 3.23 (s, 3 H), 3.07-3.04 (m, 2 H), 2.97 (t, H), 2.87 (t, 2 H), 2.11-2.05 (m, 2 H) and 1.79-1.72 (m, 2 H).
[0927] [0927] LCMS: m / z 408.2 (M + H) + (ES +).
[0928] [0928] Example 53: N- (3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) propyl) -N-methylacetamide , potassium salt
[0929] [0929] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-methyl-N- (3- sulfamoylpropyl) acetamide (Intermediate P75) to provide the title compound (60 mg, 37%) as a white solid.
[0930] [0930] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.51 (q, 2H), 3.22 (m, 2H), 3.06 (s, 3H), 2.92 (s, 3H), 2.82 (m, 8H), 2.12 - 1.92 (m, 6H).
[0931] [0931] LCMS: m / z 394 (M + H) + (ES +); 392 (M-H) - (ES-).
[0932] [0932] Example 54: N - ((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1- (pyridin-3-yl) methanesulfonamide N F O N S O
[0933] [0933] To a solution of pyridin-3-ylmethanesulfonamide (60 mg, 348.42 μmol, 1 eq) in THF (5 ml) was added t-BuONa (33 mg, 348.42 μmol, 1 eq) and 4- (5-fluoro-2-isocyanato-3-isopropylphenyl) -2-methoxypyridine (Intermediate A4) (100 mg, 348.42 µmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative UPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 8% - 38%, 11.5 min) to obtain the title compound (70 mg, 44% yield, 100% UPLC purity) as a white solid.
[0934] [0934] 1H NMR (DMSO-d6): δ 8.50 (d, 1 H), 8.41 (s, 1 H), 8.16 (d, 1 H), 7.61 (br s, 1 H), 7.50 (d, 1 H), 7.33-7.30 (m, 1 H), 7.21 (d, 1 H), 7.06-7.00 (m, 2 H) , 6.87 (s, 1 H), 4.33 (s, 2 H), 3.85 (s, 3 H), 3.22-3.17 (t, 1 H) and 1.20-1 , 04 (m, 6 H).
[0935] [0935] LCMS: m / z 459.3 (M + H) + (ES +).
[0936] [0936] Example 55: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden- 4-yl) carbamoyl) -1- (pyridin-3-yl) methanesulfonamide N THE N S O
[0937] [0937] To a solution of pyridin-3-ylmethanesulfonamide (70 mg, 406.49 μmol, 1 eq) in THF (5 ml) was added t-BuONa (39 mg, 406.49 μmol, 1 eq) and 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A5) (108 mg, 406.49 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative UPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 5% - 35%, 11.5 min) to obtain the title compound (65 mg, 36% yield, 100% UPLC purity) as a white solid.
[0938] [0938] 1H NMR (DMSO-d6): δ 8.52 (d, 1 H), 8.46 (d, 1 H), 8.16 (d, 1 H), 7.61 (d, 1 H ), 7.37-7.34 (m, 1 H), 7.17 (d, 1 H), 7.10 (d, 1 H), 6.97-6.95 (m, 1 H), 6.78 (s, 1 H), 4.45 (s, 2 H), 3.86 (s, 3 H), 2.93 (t, 2 H), 2.83 (t, 2 H) and 2.07 - 1.98 (m, 2 H).
[0939] [0939] LCMS: m / z 439.3 (M + H) + (ES +).
[0940] [0940] Example 56: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (pyridin-3- il) methanesulfonamide N F N F THE
[0941] [0941] To a solution of pyridin-3-ylmethanesulfonamide (68 mg, 393.30 μmol, 1 eq) in THF (2 ml) was added t-BuONa (38 mg, 393.30 μmol, 1 eq). The reaction mixture was stirred at 25 ° C for 10 minutes. A solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A2) (100 mg, 393.30 μmol, 1 eq) in THF ( 2.5 mL) was added. The reaction mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative UPLC (column: Xtimate C18, 250 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B% : 1% -31%, 10 min) to obtain the title compound (22.34 mg, 13%) as a white solid.
[0942] [0942] 1H NMR (DMSO-d6): δ 8.57 (d, 2 H), 8.49- 8.45 (m, 2 H), 7.59 (d, 1 H), 7.39 ( d, 2 H), 7.34-7.30 (m, 1 H), 6.96 (d, 1 H), 4.34 (s, 2 H), 2.95 (t, 2 H), 2.87 (t, 2 H) and 210-2.05 (m, 2 H).
[0943] [0943] LCMS: m / z 427.2 (M + H) + (ES +).
[0944] [0944] Example 57: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1- (1-methylpyrrolidin-3-yl) methanesulfonamide F F O O O O O
[0945] [0945] A solution of (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate P16) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) at 25 ° C for 10 minutes. So, 4- (5-fluoro-2-isocyanate-3-
[0946] [0946] 1H NMR (DMSO-d6 + D2O): δ 8.70 (d, 1H), 8.00 (s, 1 H), 7.74 (s, 1 H), 7.17 (dd, 1 H), 7.06 (dd, 1 H), 3.26-3.15 (m, 2 H), 3.10-3.01 (m, 2 H), 2.95-2.80 (m , 2 H), 2.77-2.72 (m, 1 H), 2.67 (s, 3 H), 2.45-2.40 (m, 1 H), 2.10 - 1.98 (m, 1 H), 1.62-1.51 (m, 1 H) and 1.13 (d, 6 H).
[0947] [0947] LCMS: m / z 460.2 (M + H) + (ES +).
[0948] [0948] Example 58: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1- (1-methylpyrrolidin-3-yl) methanesulfonamide F F O O O O O
[0949] [0949] A solution of (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate P16) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 ml) at 25 ° C for 10 minutes. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A4) (58 mg, 201.96 µmol, 0.2 eq) was added. The resulting mixture was stirred at 25 ° C for 30 minutes and then concentrated in vacuo. The residue was purified by preparative UPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 12% -42%, 10.0 min) to obtain the title compound (4.92 mg, 1% yield, 100% UPLC purity) as a white solid.
[0950] [0950] 1H NMR (DMSO-d6 + D2O): δ 8.12 (d, 1H), 7.14-7.11 (m, 1 H),
[0951] [0951] LCMS: m / z 465.2 (M + H) + (ES +).
[0952] [0952] Example 59: N - ((5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden- 4-yl) carbamoyl) -1- (1-methylpyrrolidin-3- il) methanesulfonamide NH2 OO O O
[0953] [0953] A solution of (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate P16) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) at 25 ° C for 10 minutes. Then 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A5) (54 mg, 201.96 µmol, 0.2 eq) was added . The resulting mixture was stirred at 25 ° C for 30 minutes and then concentrated in vacuo. The residue was purified by preparative UPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 10% -40%, 10.0 min) to obtain the title compound (5.47 mg, 1% yield, 100% UPLC purity) as a white solid.
[0954] [0954] 1H NMR (DMSO-d6 + D2O): δ 8.09 (d, 1 H), 7.11 (d, 1 H), 7.04 (d, 1 H), 6.98 (d, 1 H), 6.78 (s, 1 H), 3.84 (s, 3 H), 3.28-3.21 (m, 1 H), 3.15-3.01 (m, 3 H) , 2.95-2.90 (m, 1 H), 2.89-2.86 (m, 3 H), 2.84 -2.78 (m, 2 H), 2.64 (s, 3 H), 2.61-2.55 (m, 1 H), 2.11-1.96 (m, 3 H) and 1.66-1.55 (m, 1 H).
[0955] [0955] LCMS: m / z 445.2 (M + H) + (ES +).
[0956] [0956] Example 60: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (1-methylpyrrolidin- 3-yl) methanesulfonamide F F O O O O
[0957] [0957] To a solution of (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate P16) (180 mg, 1.01 mmol, 5 eq) in THF (2 mL) was added t-BuONa (97 mg, 1, 01 mmol, 5 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A2) (51 mg, 201.96 μmol, 1 eq) in THF (1, 5 mL) was added. The reaction mixture was stirred at 25 ° C for 30 minutes. Most of the solvent was evaporated under reduced pressure. The residue was purified by preparative UPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 8% -38%, 10 min) to obtain the title compound (5.52 mg, 6% yield, 100% UPLC purity) as a white solid.
[0958] [0958] 1H NMR (DMSO-d6): δ 8.55 (d, 2 H), 7.41 (d, 2 H), 7.40 (br s, 1 H), 6.95 (d, 1 H), 3.12-3.08 (m, 2 H), 2.97-2.85 (m, 7 H), 2.75-2.71 (m, 1 H), 2.58 (s , 3 H), 2.53-2.50 (m, 1 H), 2.09-2.00 (m, 3 H) and 1.59-1.57 (m, 1 H).
[0959] [0959] LCMS: m / z 433.2 (M + H) + (ES +).
[0960] [0960] Example 61: 2-isopropoxy-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) ethanesulfonamide, sodium salt
[0961] [0961] The 2-isopropoxyethanesulfonamide (50 mg, 0.299 mmol) was dissolved in dry THF (2 ml). Sodium tert-butoxide (2M in THF) (160 µL, 0.320 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A solution of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) - 2-methoxypyridine (Intermediate A7) (80 mg, 0.299 mmol) in THF (1 mL) was added and the mixture was stirred for 2 hours at room temperature. THF was removed in vacuo. The residue was dissolved in DMSO (2 mL) and then purified by basic preparative UPLC to provide 2-isopropoxy-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden -4-yl) carbamoyl) ethanesulfonamide as a colorless solid. The solid was dissolved in aq NaOH (0.1 M, 0.74 ml, 1 eq) and the solution was lyophilized overnight to provide the title compound (30 mg, 22%) as a colorless solid.
[0962] [0962] 1H NMR (DMSO-d6) δ 8.10 (d, J = 5.3 Hz, 1H), 7.13 - 7.02 (m, 3H), 7.00 (d, J = 5, 3 Hz, 1H), 6.81 (s, 1H), 3.86 (s, 3H), 3.57 - 3.48 (m, 3H), 3.14 - 3.06 (m, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 1.99 (p, J = 7.5 Hz, 2H), 1, 07 (d, J = 6.1 Hz, 6H).
[0963] [0963] LCMS; m / z 434.2 (M + H) + (ES +); 432.1 (M-H) - (ES-).
[0964] [0964] Example 62: 2-isopropoxy-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-benzofuran-4-yl) carbamoyl) ethanesulfonamide, sodium salt
[0965] [0965] Prepared according to the general procedure of 2-isopropoxy-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) ethanesulfonamide , Sodium (Example 61) from 2-isopropoxyethanesulfonamide and 4- (4-isocyanate-2,3-dihydrobenzofuran-5-yl) -2-methoxypyridine (Intermediate A8) and 2-isopropoxyethanesulfonamide to provide the title compound ( 22 mg, 16%) as a white solid.
[0966] [0966] 1H NMR (DMSO-d6) δ 8.09 (d, J = 5.3 Hz, 1H), 7.20 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H ), 6.96 (dd, J = 5.3, 1.4 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 6.62 (d, J = 8.2 Hz , 1H), 4.54 (t, J = 8.7 Hz, 2H), 3.86 (s, 3H), 3.65 - 3.47 (m, 3H),
[0967] [0967] LCMS; m / z 436.1 (M + H) + (ES +); 434.4 (M-H) - (ES-).
[0968] [0968] Example 63: N-Ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cyclo- hexyl) acetamide, potassium salt
[0969] [0969] To a solution of N-ethyl-N- (4-sulfamoylcyclohexyl) acetamide (50 mg, 0.2 mmol) in THF (5 mL) was added potassium tert-butoxide (23 mg, 0.2 mmol). The mixture was stirred at room temperature for 45 minutes. 4-Isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (40 mg, 0.2 mmol) was added and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was concentrated in vacuo and DMSO (0.5-1 ml) was added. The mixture (filtered over cotton when solids were present) was subjected to purification by reverse phase column chromatography (see "Experimental Methods", "Purification Method",) to obtain the title compound (5 mg, 6%) as a white solid.
[0970] [0970] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 4.22 (m, 1H), 3.65 (m, 1H), 2.82 (m, 10H), 2.29 (m, 2H), 2.12 (d, 2H), 2.12 - 1.88 (m, 6H), 1.72 (m, 5H), 1.20 (t, 3H).
[0971] [0971] LCMS: m / z 448 (M + H) + (ES +); 446 (M-H) - (ES-).
[0972] [0972] Example 64: N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (1- (oxetan-3-yl) pyrrolidin -3-yl) methanesulfonamide, potassium salt
[0973] [0973] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1- (oxetan-3-yl ) pyrrolidin-3-yl) methanesulfonamide (Intermediate P31) to provide the title compound (25 mg, 36%) as a white solid.
[0974] [0974] 1H NMR (Deuterium Oxide) δ 6.95 (s, 1H), 4.73 - 4.58 (m, 2H), 4.56 - 4.37 (m, 2H), 3.80 - 3.57 (m, 1H), 3.21 (d, 2H), 3.01 - 2.82 (m, 1H), 2.68 (m, 9H), 2.46 (ddt, 2H), 2 , 16 (t, 1H), 2.07 (dd, 1H), 1.90 (m, 4H), 1.50 (dt, 1H).
[0975] [0975] LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[0976] [0976] Example 65: 3-Amino-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1-sulfonamide, potassium salt
[0977] [0977] For 3-azido-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1-sulfonamide, potassium salt (Example 34 ) (50 mg, 0.14 mmol) in methanol (5 ml) Pd-C (10%, 20 mg) in water (0.5 ml) was added. The mixture was stirred for 18 hours under a hydrogen atmosphere. Then the mixture was filtered through Celite® and evaporated. DMSO (0.5 - 1 ml) was added and the mixture was subjected to purification by reverse phase column chromatography (see "Experimental methods", "Purification method") to provide the title compound (50 mg, 100%) like a white solid.
[0978] [0978] 1H NMR (Methanol-d4) δ 6.96 (s, 1H), 3.19 (t, 2H), 2.86 (t, 2H),
[0979] [0979] LCMS: m / z 338 (M + H) + (ES +); 336 (M-H) - (ES-).
[0980] [0980] Example 66: 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N, N, N-trimethylpropan- 1-amine, potassium salt
[0981] [0981] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N, N, N-trimethyl-3 -sulfamoylpropan-1-amine (Intermediate P32) to provide the title compound (6 mg, 5%) as a white solid.
[0982] [0982] 1H NMR (Deuterium Oxide) δ 7.01 (s, 1H), 3.50 - 3.35 (m, 2H), 3.24 (t, 2H), 3.06 (s, 9H) , 2.79 - 2.58 (m, 8H), 2.17 (p, 2H), 1.95 (p, 4H).
[0983] [0983] LCMS: m / z 380 (M + H) + (ES +).
[0984] [0984] Example 67: 3- (Benzyl (methyl) amino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1- sulfonamide, potassium salt
[0985] [0985] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (benzyl (methyl) amino) propane-1-sulfonamide (Intermediate P33) to provide the title compound (39 mg, 31%) as a white solid.
[0986] [0986] 1H NMR (Methanol-d4) δ 7.48 - 7.23 (m, 5H), 6.88 (s, 1H), 3.80 (s, 2H), 3.34 (m, 2H) , 2.82 (m, 10H), 2.37 (s, 3H), 2.13 (p, 2H), 2.01 (p, 4H).
[0987] [0987] LCMS: m / z 442 (M + H) + (ES +); 440 (M-H) - (ES-).
[0988] [0988] Example 68: N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2- (3-methyl-3H-diazirin-3- il) ethane-1-sulfonamide, potassium salt
[0989] [0989] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (3-methyl-3H- diazirin-3-yl) ethane-1-sulfonamide (Intermediate P34) to provide the title compound (134 mg, 81%) as a white solid.
[0990] [0990] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.22 - 3.02 (m, 2H), 2.82 (dt, 8H), 2.03 (p, 4H) , 1.85 - 1.61 (m, 2H), 1.04 (s, 3H).
[0991] [0991] LCMS: m / z 363 (M + H) + (ES +); 361 (M-H) - (ES-).
[0992] [0992] Example 69: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -3- (methylamino) propane-1-sulfonamide, salt potassium
[0993] [0993] 3- (Benzyl (methyl) amino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -propane-1-sulfonamide, potassium salt (Example 67) (32 mg, 0.072 mmol) was stirred in water (1 ml). 10% Pd / C (5 mg) was added and a hydrogen flask was applied. The mixture was stirred overnight, filtered through Celite® and lyophilized to provide the title compound (5 mg, 20%) as a white solid.
[0994] [0994] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 2.83 (m, 12H), 2.47 (s, 3H), 2.04 (m, 6H).
[0995] [0995] LCMS: m / z 352 (M + H) + (ES +); 350 (MH) - (ES-).
[0996] [0996] Example 70: N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-
[0997] [0997] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (methoxy (methyl) amino) propane-1-sulfonamide (Intermediate P35) to provide the title compound (14 mg, 52%) as a white solid.
[0998] [0998] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.49 (s, 3H), 2.83 (m, 10H), 2.80 - 2.67 (m, 2H) , 2.54 (s, 3H), 2.03 (m, 6H).
[0999] [0999] LCMS: m / z 382 (M + H) + (ES +); 380 (M-H) - (ES-).
[1000] [1000] Example 71: N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((1S, E) -2- (hydroxyimino ) -7,7-dimethylbicyclo [2.2.1] heptan-1-yl) methanesulfonamide, potassium salt THE
[1001] [1001] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), ((1S, E) -2- (hydroxyimino) -7,7-dimethylbicyclo [2.2.1] heptan-1-yl) methanesulfonamide (Intermediate P36) and KOtBu (2 equiv.) to provide the title compound (35 mg, 23%) as a white solid.
[1002] [1002] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.80 (d, 1H), 3.39 (d, 1H), 2.83 (m, 8H), 2.71 - 2.40 (m, 3H), 2.03 (p, 4H), 1.95 - 1.83 (m, 2H), 1.74 (m, 1H),
[1003] [1003] LCMS: m / z 446 (M + H) + (ES +); 444 (M-H) - (ES-).
[1004] [1004] Example 72: 3- (Azetidin-1-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1- sulfonamide, potassium salt
[1005] [1005] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P37) to provide the title compound (2 mg, 10%) as a white solid.
[1006] [1006] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 3.55 (t, 4H), 3.25 (t, 2H), 2.84 (m, 10H), 2.30 - 2.13 (m, 2H), 2.04 (p, 4H), 1.99-1.82 (m, 2H).
[1007] [1007] LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1008] [1008] Example 73: N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -3- (methyl (prop-2-in-1- il) amino) propane-1-sulfonamide, potassium salt
[1009] [1009] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (methyl (prop-2- in-1-yl) amino) propane-1-sulfonamide (Intermediate P38) to provide the title compound (60 mg, 41%) as a white solid.
[1010] [1010] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.43 - 3.29 (m, 3H), 3.29
[1011] [1011] LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[1012] [1012] Example 74: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (4-methylmorpholin-2-yl) methanesulfonamide, potassium salt
[1013] [1013] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (4-methylmorpholin-2-yl) methanesulfonamide (Intermediate P39) to provide the title compound (9 mg, 13%) as a white solid.
[1014] [1014] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 4.05 (q, 1H), 3.94 - 3.77 (m, 1H), 3.65 (td, 1H) , 3.40 (dd, 2H), 3.25 - 3.19 (m, 1H), 3.13 (d, 1H), 2.93 - 2.74 (m, 8H), 2.74 - 2 , 55 (m, 1H), 2.28 (d, 3H), 2.23 - 1.79 (m, 5H).
[1015] [1015] LCMS: m / z 394 (M + H) + (ES +); 392 (M-H) - (ES-).
[1016] [1016] Example 75: 1- (4-Ethmormorpholin-2-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, potassium salt
[1017] [1017] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (4-ethylmorpholin-2-yl) methanesulfonamide (Intermediate P40) to provide the title compound (7 mg, 11%) as a white solid.
[1018] [1018] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 4.06 (s, 1H), 3.92 - 3.79 (m, 1H), 3.74 - 3.62 ( m, 1H), 3.42 (dd, 2H), 3.22 (d, 2H), 2.83 (q, 9H), 2.46 (q,
[1019] [1019] LCMS: m / z 408 (M + H) + (ES +); 406 (M-H) - (ES-).
[1020] [1020] Example 76: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (4-isopropylmorpholin-2-yl) methanesulfonamide, potassium salt
[1021] [1021] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (4-isopropylmorpholin-2-yl) methanesulfonamide (Intermediate P41) to provide the title compound (6 mg, 10%) as a white solid.
[1022] [1022] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 4.06 (s, 1H), 3.89 (d, 1H), 3.79 - 3.59 (m, 1H) , 3.44 (dd, 2H), 3.21 (d, 1H), 2.83 (m, 10H), 2.38 (m, 1H), 2.28 - 2.12 (m, 1H), 2.03 (p, 4H), 1.22 - 1.00 (m, 6H).
[1023] [1023] LCMS: m / z 422 (M + H) + (ES +); 420 (M-H) - (ES-).
[1024] [1024] Example 77: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2-isopropyl-6-oxa-2- azaspiro [3,4] octan-7-yl) methanesulfonamide, potassium salt
[1025] [1025] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (2-isopropyl-6-oxa- 2-azaspiro [3,4] octan-7-
[1026] [1026] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 4.47 - 4.22 (m, 1H), 3.98 (d, 1H), 3.89 - 3.67 ( m, 5H), 3.55 (dd, 1H), 3.49 - 3.37 (m, 1H), 2.95 (m, 1H), 2.83 (m, 8H), 2.46 (td , 1H), 2.15 (dd, 1H), 2.10 - 1.85 (m, 4H), 1.08 - 0.99 (m, 6H).
[1027] [1027] LCMS: m / z 448 (M + H) + (ES +); 446 (M-H) - (ES-).
[1028] [1028] Example 78: 3- (Dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) butane-1-sulfonamide, salt potassium
[1029] [1029] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (dimethylamino) butane-1- sulfonamide (Intermediate P43) to provide the title compound (3 mg, 10%) as a white solid.
[1030] [1030] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 3.35 (m, 2H), 2.83 (m, 9H), 2.65 (s, 6H), 2.36 - 2.13 (m, 1H), 2.13 - 1.82 (m, 5H), 1.34 - 1.17 (m, 3H).
[1031] [1031] LCMS: m / z 380 (M + H) + (ES +); 378 (M-H) - (ES-).
[1032] [1032] Example 79: 1- (2-Ethyl-6-oxa-2-azaspiro [3.4] octan-7-yl) -N- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl) methanesulfonamide, potassium salt
[1033] [1033] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-
[1034] [1034] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 4.36 (dd, 1H), 3.98 (d, 1H), 3.84 (dd, 1H), 3.69 (s, 3H), 3.53 (dd, 1H), 3.37 (d, 1H), 2.83 (m, 10H), 2.74 - 2.58 (m, 1H), 2.49 ( dd, 1H), 2.23 - 2.12 (m, 1H), 2.04 (m, 4H), 1.03 (m, 3H).
[1035] [1035] LCMS: m / z 434 (M + H) + (ES +); 432 (M-H) - (ES-).
[1036] [1036] Example 80: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2-methyl-6-oxa-2- azaspiro [3,4] octan-7-yl) methanesulfonamide, potassium salt
[1037] [1037] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (2-methyl-6-oxa- 2-azaspiro [3,4] octan-7-yl) methanesulfonamide (Intermediate P45) to provide the title compound (8 mg, 25%) as a white solid.
[1038] [1038] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 4.32 (p, 1H), 3.96 (d, 1H), 3.82 (d, 1H), 3.67 - 3.44 (m, 5H), 3.37 (m, 1H), 2.83 (m, 8H), 2.52 - 2.34 (m, 1H), 2.45 (s, 3H), 2.16 - 1.91 (m, 5H).
[1039] [1039] LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1040] [1040] Example 81: 3- (Dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2,2-dimethylpropane-1 -sulfonamide, potassium salt
[1041] [1041] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (dimethylamino) -2.2 -dimethylpropane-1-sulfonamide (Intermediate P46) to provide the title compound (7 mg, 15%) as a white solid.
[1042] [1042] 1H NMR (Methanol-d4) δ 6.92 (s, 1H), 3.44 (s, 2H), 3.32 (m, 6H), 3.21 (s, 2H), 2.84 (m, 8H), 2.05 (m, 4H), 1.29 (s, 6H).
[1043] [1043] LCMS: m / z 394 (M + H) + (ES +); 392 (M-H) - (ES-).
[1044] [1044] Example 82: 4- (Dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) butane-1-sulfonamide, salt potassium
[1045] [1045] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4- (dimethylamino) butane-1- sulfonamide (Intermediate P47) to provide the title compound (18 mg, 27%) as a white solid.
[1046] [1046] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 3.28 (m, 2H), 2.94 (t, 2H), 2.83 (m, 8H), 2.66 (s, 6H), 2.03 (m, 4H), 1.85 (m, 4H).
[1047] [1047] LCMS: m / z 380 (M + H) + (ES +); 378 (M-H) - (ES-).
[1048] [1048] Example 83: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-methylpiperidin-3-yl) methanesulfonamide, potassium salt
[1049] [1049] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-methylpiperidin-3-yl) methanesulfonamide (Intermediate P48) to provide the title compound (19 mg, 11%) as a white solid.
[1050] [1050] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.29 - 3.06 (m, 2H), 3.01 (d, 2H), 2.83 (m, 9H) , 2.55 - 2.29 (m, 1H), 2.30 (s, 3H), 2.16 - 1.82 (m, 5H), 1.82 - 1.57 (m, 2H), 1 , 31 - 1.13, 2H).
[1051] [1051] LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1052] [1052] Example 84: 1- (1-Ethylpiperidin-3-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, potassium salt
[1053] [1053] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylpiperidin-3-yl) methanesulfonamide (Intermediate P49) to provide the title compound (45 mg, 28%) as a white solid.
[1054] [1054] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.26 - 3.11 (m, 2H), 3.00 (m, 3H), 2.83 (m, 9H) , 2.74 - 2.29 (m, 2H), 2.04 (m, 4H), 1.97 - 1.55 (m, 3H), 1.34 (m, 1H), 1.28 (t , 3H), 1.13 (m, 1H).
[1055] [1055] LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1056] [1056] Example 85: 1 - ((1S) -2-amino-7,7-dimethylbicyclo [2.2.1] heptan-
[1057] [1057] ((1S) -1 - ((N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) methyl) -7.7 -dimethylbicyclo [2.2.1] heptan-2-yl) tert-butyl carbamate, potassium salt (Intermediate P50) (100 mg, 0.19 mmol) was stirred in DCM (0.3 mL) and TFA (0, 3 mL) for 2.5 hours. Then, the reaction mixture was concentrated and subjected to purification by reverse phase column chromatography (see "Experimental methods", "Purification method") to provide the title compound (1 mg, 1%) as a white solid .
[1058] [1058] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 3.67 - 3.44 (m, 2H), 2.82 (m, 8H), 2.41 (m, 1H) , 2.03 (m, 4H), 1.94 - 1.53 (m, 4H), 1.49 - 1.06 (m, 3H), 0.97 (m, 6H).
[1059] [1059] LCMS: m / z 432 (M + H) + (ES +); 430 (M-H) - (ES-).
[1060] [1060] Example 86: 4- (Azetidin-1-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) butane-1- sulfonamide, potassium salt
[1061] [1061] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4- (azetidin-1-yl) butane-1-sulfonamide (Intermediate P51) to provide the title compound (1 mg, 3%) as a white solid.
[1062] [1062] LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1063] [1063] Example 87: 1- (Azetidin-1-ylmethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) cyclopropane-1- sulfonamide, potassium salt
[1064] [1064] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (azetidin-1-ylmethyl) cyclopropane-1-sulfonamide (Intermediate P52) to provide the title compound (15 mg, 37%) as a white solid.
[1065] [1065] 1H NMR (Methanol-d4) δ 6.93 (s, 1H), 4.09 (m, 4H), 2.84 (m, 8H), 2.65 (s, 2H), 2.40 (m, 2H), 2.05 (m, 4H), 1.40 (s, 2H), 0.97 (s, 2H).
[1066] [1066] LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[1067] [1067] Example 88: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -2- (pyrrolidin-1-yl) ethane-1- sulfonamide, potassium salt
[1068] [1068] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (pyrrolidin-1-yl) ethane-1-sulfonamide (Intermediate P53) to provide the title compound (25 mg, 20%) as a white solid.
[1069] [1069] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.46 (s, 2H), 3.09 (s, 2H), 2.81 (m, 12H), 2.03 (m, 4H), 1.86 (m, 4H).
[1070] [1070] LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1071] [1071] Example 89: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-
[1072] [1072] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (2-methylazetidin-1- il) ethane-1-sulfonamide (Intermediate P54) to provide the title compound (35 mg, 42%) as a white solid.
[1073] [1073] 1H NMR (Methanol-d4) δ 6.91 (s, 1H), 4.21 (q, 1H), 3.90 (td, 1H), 3.84 - 3.63 (m, 2H) , 3.56 - 3.33 (m, 3H), 2.84 (m, 8H), 2.52 - 2.30 (m, 1H), 2.18 - 1.95 (m, 5H), 1 , 45 (d, 3H).
[1074] [1074] LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1075] [1075] Example 90: 2- (3-Fluoroazetidin-1-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ethane- 1-sulfonamide, potassium salt
[1076] [1076] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (3-fluoroazetidin-1- il) ethane-1-sulfonamide (Intermediate P55) to provide the title compound (6 mg, 5%) as a white solid.
[1077] [1077] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.81 - 3.53 (m, 2H), 3.31 (m, 1H), 3.19 - 3.04 ( m, 1H), 3.04 - 2.91 (m, 2H), 2.83 (s, 11H), 2.02 (m, 4H).
[1078] [1078] LCMS: m / z 382 (M + H) + (ES +); 380 (M-H) - (ES-).
[1079] [1079] Example 91: 2- (Azetidin-1-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1- sulfonamide, potassium salt
[1080] [1080] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (azetidin-1-yl) propane-1-sulfonamide (Intermediate P56) to provide the title compound (21 mg, 20%) as a white solid.
[1081] [1081] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.58 - 3.38 (m, 4H), 3.07 - 2.93 (m, 2H), 2.83 ( m, 9H), 2.05 (m, 6H), 1.22 (d 3H).
[1082] [1082] LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1083] [1083] Example 92: methyl 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) propanoate, potassium salt
[1084] [1084] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl 3-sulfamoylpropanoate (Intermediate P57) to provide the title compound (60 mg, 44%) as a white solid.
[1085] [1085] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.68 (s, 3H), 3.48 (t, 2H), 2.95 - 2.68 (m, 10H) , 2.04 (m, 4H).
[1086] [1086] LCMS: m / z 367 (M + H) + (ES +); 365 (M-H) - (ES-).
[1087] [1087] Example 93: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-isopropylpiperidin-3-yl) methanesulfonamide, potassium salt
[1088] [1088] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-isopropylpiperidin-3-yl) methanesulfonamide (Intermediate P58) to provide the title compound (34 mg, 34%) as a white solid.
[1089] [1089] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.58 (d, 1H), 3.25 - 3.06 (m, 2H), 2.83 (m, 10H) , 2.77 - 2.50 (m, 2H), 2.39 (m, 1H), 2.02 (m, 5H), 1.94 - 1.59 (m, 2H), 1.33 (m , 1H), 1.25 (d, 6H).
[1090] [1090] LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1091] [1091] Example 94: N- (3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) propyl) -3-methoxy -N-methylpropanamide, potassium salt
[1092] [1092] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-methoxy-N-methyl-N - (3-sulfamoylpropyl) propanamide (Intermediate P59) to provide the title compound (7 mg, 9%) as a white solid.
[1093] [1093] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.64 (m, 2H), 3.61 - 3.47 (m, 2H), 3.21 (m, 2H) , 3.07 (s, 3H), 2.94 (s, 3H), 2.82 (m, 8H), 2.65 (m, 2H), 2.03 (m, 6H).
[1094] [1094] LCMS: m / z 438 (M + H) + (ES +); 436 (M-H) - (ES-).
[1095] [1095] Example 95: N- (3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) propyl) -N-methylisobutyramide , potassium salt
[1096] [1096] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-methyl-N- (3- sulfamoylpropyl) isobutyramide (Intermediate P60) to provide the title compound (22 mg, 17%) as a white solid.
[1097] [1097] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.52 (q, 2H), 3.20 (dd, 1H), 3.09, 2.95 (d, 3H) , 2.82 (m, 8H), 2.37 (dt, 2H), 2.02 (m, 7H), 1.62 (qd, 2H), 1.06 - 0.77 (m, 3H).
[1098] [1098] LCMS: m / z 422 (M + H) + (ES +); 420 (M-H) - (ES-).
[1099] [1099] Example 96: N- (3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) propyl) -N-methylformamide , potassium salt
[1100] [1100] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-methyl-N- (3- sulfamoylpropyl) formamide (Intermediate P61) to provide the title compound (29 mg, 13%) as a white solid.
[1101] [1101] 1H NMR (Methanol-d4) δ 8.04 (d, 1H), 6.87 (s, 1H), 3.48 (td, 2H), 3.25 - 3.09 (m, 2H) , 3.00, 2.95 (d, 3H), 2.95 - 2.70 (m, 8H), 2.03 (m, 6H).
[1102] [1102] LCMS: m / z 380 (M + H) + (ES +); 378 (M-H) - (ES-).
[1103] [1103] Example 97: 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-
[1104] [1104] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N, N-dimethyl-3-sulfamoylpropanamide (Intermediate P62) to provide the title compound (19 mg, 41%) as a white solid.
[1105] [1105] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.58 - 3.38 (m, 2H), 3.09 (s, 3H), 2.93 (s, 3H) , 2.83 (m, 10H), 2.02 (p, 4H)
[1106] [1106] LCMS: m / z 380 (M + H) + (ES +); 378 (M-H) - (ES-).
[1107] [1107] Example 98: 3- (Benzyl (methyl) amino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane-1- sulfonamide, potassium salt
[1108] [1108] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3- (benzyl (isopropyl) amino) propane-1-sulfonamide (Intermediate P63) to provide the title compound (82 mg, 24%) as a white solid.
[1109] [1109] 1H NMR (Methanol-d4) δ 7.55 - 7.16 (m, 5H), 6.89 (s, 1H), 3.59 (s, 2H), 3.28 - 3.17 ( m, 1H), 3.12 - 3.00 (m, 2H), 2.81 (dt, 8H), 2.58 (t, 2H), 2.01 (m, 6H), 1.05 (d , 6H).
[1110] [1110] LCMS: m / z 470 (M + H) + (ES +); 468 (M-H) - (ES-).
[1111] [1111] Example 99: Methyl (3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) propyl) methyl) carbamate, potassium salt
[1112] [1112] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using methyl 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl (3-sulfamoylpropyl) carbamate (Intermediate P64) to provide the title compound (4 mg, 13%) as a white solid.
[1113] [1113] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.66 (s, 3H), 3.40 (t, 2H), 3.24 - 3.14 (m, 2H) , 2.92 (s, 3H), 2.82 (m, 8H), 2.02 (p, 6H).
[1114] [1114] LCMS: m / z 410 (M + H) + (ES +); 408 (M-H) - (ES-).
[1115] [1115] Example 100: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -3- (isopropylamino) propane-1-sulfonamide, salt potassium
[1116] [1116] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -3- (methylamino) propane-1-sulfonamide, salt potassium (Example 69), using 3- (benzyl (isopropyl) amino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) propane- 1-sulfonamide, potassium salt (Example 98) to provide the title compound (59 mg, 87%) as a white solid.
[1117] [1117] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.26 - 3.19 (m, 1H), 3.08 (m, 2H), 2.83 (m, 10H) , 2.02 (td, 6H), 1.12 (d, 6H)
[1118] [1118] LCMS: m / z 380 (M + H) + (ES +); 378 (M-H) - (ES-).
[1119] [1119] Example 101: 3- (Dimethylamino) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) propane-1-sulfonamide, potassium salt
[1120] [1120] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A10) and 3- (dimethylamino) propane-1-sulfonamide (Intermediate P65) to provide the title compound (10 mg, 24%) as a white solid.
[1121] [1121] 1H NMR (Methanol-d4) δ 6.83 (d, 2H), 3.26 (m, 2H), 3.02 (t, 2H), 2.67 (s, 6H), 2.14 (m, 2H), 1.29 (m, 2H), 1.19 (d, 12 H).
[1122] [1122] LCMS: m / z 388 (M + H) + (ES +); 386 (M-H) - (ES-).
[1123] [1123] Example 102: 2- (2,2-Dimethylazetidin-1-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ethane-1-sulfonamide, potassium salt
[1124] [1124] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (2,2-dimethylazetidin- 1-yl) ethane-1-sulfonamide, TFA salt (Intermediate P66) to provide the title compound (66 mg, 56%) as a white solid.
[1125] [1125] 1H NMR (Methanol-d4) δ 6.88 (s, 1H), 3.46 (t, 2H), 3.09 (dd, 2H), 2.83 (m, 10H), 2.03 (m, 6H), 1.38 (d, 6H).
[1126] [1126] LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1127] [1127] Example 103: 2- (2,4-Dimethylazetidin-1-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ethane-1-sulfonamide, potassium salt
[1128] [1128] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (2,4-dimethylazetidin- 1-yl) ethane-1-sulfonamide, TFA salt (Intermediate P67) to provide the title compound (33 mg, 20%) as a white solid.
[1129] [1129] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 3.51 (m, 2H), 3.12 (m, 4H), 2.84 (m, 8H), 2.06 (dt, 6H), 1.26 (t, 6H).
[1130] [1130] LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1131] [1131] Example 104: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -2- (2-isopropylazetidin-1-yl) ethane- 1-sulfonamide, potassium salt
[1132] [1132] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2- (2-isopropylazetidin-1- il) ethane-1-sulfonamide, TFA salt (Intermediate P68) to provide the title compound (17 mg, 11%) as a white solid.
[1133] [1133] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.45 (m, 1H), 3.26 (m, 1H), 3.03 (q, 2H), 2.83 (m, 11H), 2.15 (m, 1H), 2.03 (m, 4H), 1.95 - 1.68 (m, 2H), 0.95 (d, 3H), 0.82 ( d, 3H).
[1134] [1134] LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1135] [1135] Example 105: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-
[1136] [1136] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-methylpyrrolidin-2-yl) methanesulfonamide (Intermediate P69) to provide the title compound (38 mg, 45%) as a white solid.
[1137] [1137] 1H NMR (Methanol-d4) δ 6.87 (s, 1H), 3.71 (dd, 1H), 3.21 - 3.00 (m, 3H), 2.83 (m, 10H) , 2.42 (d, 3H), 2.31 (m, 1H), 2.13 - 1.94 (m, 4H), 1.81 (m, 2H).
[1138] [1138] LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1139] [1139] Example 106: 1- (1-Ethylpyrrolidin-2-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, potassium salt
[1140] [1140] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylpyrrolidin-2-yl) methanesulfonamide (Intermediate P70) to provide the title compound (36 mg, 37%) as a white solid.
[1141] [1141] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 3.78 - 3.56 (m, 1H), 3.26 - 3.14 (m, 3H), 2.94 - 2.75 (m, 10H), 2.60 (dt, 2H), 2.34 (m, 1H), 2.03 (m, 4H), 1.97-1.82 (m, 2H), 1 , 21 (td, 3H).
[1142] [1142] LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1143] [1143] Example 107: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-
[1144] [1144] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-isopropylpyrrolidin-2-yl) methanesulfonamide (Intermediate P71) to provide the title compound (101 mg, 40%) as a white solid.
[1145] [1145] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 3.79 - 3.54 (m, 2H), 3.44 (q, 1H), 3.08 (dt, 1H) , 2.94 (dd, 1H), 2.82 (m, 10H), 2.22 (ddt, 1H), 2.13 - 1.97 (m, 4H), 1.89 (m, 2H), 1.21 (ddd, 6H).
[1146] [1146] LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1147] [1147] Example 108: 3- (Dimethylamino) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) propane-1-sulfonamide, potassium salt
[1148] [1148] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 5-chloro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A9) and 3- (dimethylamino) propane-1-sulfonamide (Intermediate P65) to provide the title compound (15 mg, 34%) as a white solid.
[1149] [1149] 1H NMR (Methanol-d4) δ 7.09 (d, 2H), 3.26 (m, 2H), 2.86 (t, 2H), 2.54 (s, 6H), 2.10 (m, 2H), 1.19 (d, 14 H).
[1150] [1150] LCMS: m / z 404 (M + H) + (ES +); 402 (M-H) - (ES-).
[1151] [1151] Example 109: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-isopropylpiperidin-2-yl) methanesulfonamide, potassium salt
[1152] [1152] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-isopropylpiperidin-2-yl) methanesulfonamide (Intermediate P72) to provide the title compound (11 mg, 8%) as a white solid.
[1153] [1153] 1H NMR (Methanol-d4) δ 6.90 (s, 1H), 4.05 (m, 1H), 3.88 - 3.67 (m, 2H), 3.58 (dd, 1H) , 3.04 (t, 1H), 2.83 (m, 9H), 2.23 (m, 1H), 2.03 (m, 5H), 1.81 (d, 3H), 1.62 ( m, 1H), 1.33 (dd, 6H).
[1154] [1154] LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1155] [1155] Example 110: 1- (1-Ethylpiperidin-2-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) methanesulfonamide, potassium salt
[1156] [1156] Prepared as described for N-ethyl-N- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) cycle -hexyl) acetamide, potassium salt (Example 63) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylpiperidin-2-yl) methanesulfonamide (Intermediate P73) to provide the title compound (2 mg, 1%) as a white solid.
[1157] [1157] 1H NMR (Methanol-d4) δ 6.89 (s, 1H), 4.07 (m, 1H), 3.79 - 3.48 (m, 2H), 3.21 - 2.99 ( m, 3H), 2.83 (m, 9H), 2.03 (m, 6H), 1.74 (m, 3H), 1.59 (s, 1H), 1.26 (t, 3H).
[1158] [1158] LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1159] [1159] Example 111: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-isopropyl-1H-pyrazol-3- il) methanesulfonamide
[1160] [1160] Prepared according to the general procedure of N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-methyl-1H -pyrazol-4-yl) methanesulfonamide (Example 35) from (1-isopropyl-1H-pyrazol-3-yl) methanesulfonamide (Intermediate P74) and 4-isocyanate-1,2,3,5,6,7- hexahydro-s-indacene (Intermediate A1) to provide the title compound (14 mg, 24%) as a white solid.
[1161] [1161] 1H NMR (DMSO-d6) δ 10.11 (s, 1H), 7.89 (s, 1H), 7.78 (d, J = 2.3 Hz, 1H), 6.96 (s , 1H), 6.26 (d, J = 2.3 Hz, 1H), 4.65 (s, 2H), 4.47 (sept, J = 6.7 Hz, 1H), 2.82 (t , J = 7.4 Hz, 4H), 2.74 (t, J = 7.4 Hz, 4H), 1.99 (p, J = 7.4 Hz, 4H), 1.40 (d, J = 6.7 Hz, 6H).
[1162] [1162] LCMS; m / z 403.4 (M + H) + (ES +).
[1163] [1163] Example 112: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1- (pyridin-3-yl) methanesulfonamide N F O N S O
[1164] [1164] To a solution of pyridin-3-ylmethanesulfonamide (70 mg, 406.49 μmol, 1 eq) in THF (5 ml) was added t-BuONa (39 mg, 406.49 μmol, 1 eq) and 4- (5-fluoro-2-isocyanato-3-isopropylphenyl) picolinonitrile (Intermediate A3) (114 mg, 406.49 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative UPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 5% - 35%, 11.5 min) to obtain the title compound (68 mg, 37% yield, 100% UPLC purity) as a white solid.
[1165] [1165] 1H NMR (DMSO-d6): δ 8.77 (d, 1 H), 8.50 (d, 1 H), 8.37 (s, 1 H), 8.10 (s, 1 H ), 7.86 (br s, 1 H), 7.79 (d, 1 H), 7.61-7.45 (m, 1 H), 7.33-7.27 (m, 2 H) , 7.19-7.02 (m, 1 H), 4.31 (s, 2 H), 3.24-3.18 (m, 1H) and 1.20-1.06 (m, 6H) .
[1166] [1166] LCMS: m / z 454.3 (M + H) + (ES +).
[1167] [1167] Examples - biological studies
[1168] [1168] NLRP3 and Pyroptosis It is well established that the activation of NLRP3 leads to cell pyroptosis and this characteristic plays an important role in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8 (2) , e2579; Alexander Wree et al., Hepatology, 2014, 59 (3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59 (5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1 (2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57 (24) , 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that NLRP3 inhibitors block pyroptosis, as well as the release of pro-inflammatory cytokines (eg, IL-1β) from the cell.
[1169] [1169] THP-1 Cells: Culture and Preparation
[1170] [1170] THP-1 cells (ATCC # TIB-202) were cultured in RPMI containing L-glutamine (Gibco # 11835) supplemented with 1 mM sodium pyruvate (Sigma # S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma # P4333) in 10% Bovine Fetal Serum (FBS) (Sigma # F0804). The cells were routinely passed and cultured until confluence (~ 106 cells / ml). On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted and the viability (> 90%) was checked for trypan blue (Sigma # T8154).
[1171] [1171] Pyroptosis Assay with THP-1 Cells
[1172] [1172] The following step-by-step assay method was followed for screening compounds.
[1173] [1173] 96 Well Plate Map 1 2 3 4 5 6 7 8 9 10 11 12 Co Co Co Co Co Co Co Co Co Co Bai Alt A mp mp mp mp mp mp mp mp mp mp xa a 1 2 3 4 5 6 7 8 9 10 Co Co Co Co Co Co Co Bai Alt B mp mp mp mp mp mp mp mp mp mp xa a 1 2 3 4 5 6 7 8 9 10 Co Co Co Co Co Co Co Co Co Co Bai Alt C mp mp mp mp mp mp mp mp mp mp xa a 1 2 3 4 5 6 7 8 9 10 Co Co Co Co Co Co Co Co Co Co Co Bai Alt D mp mp mp mp mp mp mp xa a 1 2 3 4 5 6 7 8 9 10 Co Co Co Co Co Co Co Co Co Bai Alt E mp mp mp mp mp mp mp mp mp mp xa a 1 2 3 4 5 6 7 8 9 10 Co Co Co Co Co Co Co Co Co Co Bai Alt F mp mp mp mp mp mp mp mp mp mp xa a 1 2 3 4 5 6 7 8 9 10 Co Co Co Co Co Co Co Co Co Co Co Co Bai Alt G mp mp mp mp mp mp mp mp mp xa a 1 2 3 4 5 6 7 8 9 10 Co Co Co Co Co Co Co Co Co Co Bai Alt H mp mp mp mp mp mp mp mp mp mp xa a 1 2 3 4 5 6 7 8 9 10
[1174] [1174] The results of the pyroptosis assay performed are summarized in Table 1 below as THP IC50.
[1175] [1175] Human Blood IL1β Release Assay
[1176] [1176] For systemic delivery, the ability to inhibit NLRP3 when compounds are present in the bloodstream is of great importance. For this reason, the NLRP3 inhibitory activity of various compounds in human whole blood has been investigated according to the following protocol.
[1177] [1177] Human whole blood in Li-heparin tubes was obtained from healthy donors from a panel of voluntary donors.
[1178] [1178] The results of the human whole blood assay are summarized in Table 1 below as HWB IC50. Example THP IC50 HWB IC50 Example THP IC50 HWB IC50 1 +++ ●●●● 57 + ND 2 + ND 58 +++++ ●●●● 3 +++++ ●●●● 59 +++++ ●●●● 4 +++++ NA 60 + NA 5 +++ NA 61 +++++ ●●●● 6 + NA 62 +++++ ●●●● 7 +++ NA 63 + NA 8 +++++ ●●●● 64 + NA 9 + NA 65 + NA 10 ++++ NA 66 + NA 11 +++++ ●● 67 +++++ ● 12 +++++ NA 68 ++++ ND 13 +++++ ●●● 69 ++++ ND 14 +++++ ●●● 70 +++++ ●●● 15 ++ ND 71 +++++ ● 16 ++ NA 72 +++ ●●●● 17 +++ NA 73 +++++ ●●● 18 + NA 74 +++++ ●●● 19 +++ NA 75 +++++ NA 20 +++++ ●●● 76 +++ NA 21 ++++ NA 77 + ●● 22 + NA 78 +++++ ●●●● 23 +++++ ●●●● 79 ++ + NA 24 ++++ NA 80 +++++ ●●● 25 + NA 81 ++++ ●●● 26 + NA 82 ++ ●●● 27 +++++ ●●●● 83 ++ ++ ●●●● 28 +++++ ●●●● 84 +++++ ●●●● 29 +++++ ●●●● 85 + ND
[1179] [1179] PK Protocol
[1180] [1180] Pharmacokinetic parameters were determined in rats
[1181] [1181] For intravenous administration, the compounds were formulated as a solution in water or DMSO: PBS [10:90] in a dosage volume of 2 ml / kg and administered through the tail vein. For oral administration, the compounds were formulated as a solution in DMSO: water [10:90] in a dosage volume of 5 ml / kg and administered orally.
[1182] [1182] Blood samples were collected in series (about 120- 300 μL) from each animal in each of the 8 moments after the dose (0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h) or at each of the 12 post-dose moments (0.03, 0.1, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h) or pre -dose and at each of the 9 post-dose moments (0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h). The samples were kept on ice for no more than 30 minutes before centrifugation (10,000 rpm (8,385g) for 3 minutes; or 5,696 rpm (3,000g) for 15 minutes) for plasma generation. The plasma was frozen on dry ice before bioanalysis. PK parameters were generated from LC-MS / MS data using Dotmatics or Phoenix WinNonlin 6.3 software. Example Dose AUC T½ Vdss Cl No. (mg / kg) (ng · hr / mL) (h) (L / kg) (mL / min / kg) 3 1 1181.1 1.5 0.79 14.2 8 1 2346.4 1.1 0.49 7.1 29 1 2776.5 1.3 0.53 6.0 37 1 591.0 0.9 0.55 28.2
[1183] [1183] Table 2: PK data (intravenous administration) Exem Dose Cmax. AUC Tmax T½ Cl / F Bioavailability plo (mg / k (ng / mL (ng · (h) (h) (mL / min / No. g)) hr / mL) kg) 3 3 819.0 2271.3 0, 42 1, 22.6 64.1 8
[1184] [1184] Table 3: PK data (oral administration)
[1185] [1185] As is evident from the results shown in Table 1, surprisingly, despite the structural differences from the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and, in particular, in the assay of human whole blood.
[1186] [1186] As is evident from the results presented in Tables 2 and 3, the compounds of the invention show advantageous pharmacokinetic properties, for example, T½ half-life, area under the AUC curve, Cl clearance and / or bioavailability, compared to the prior art compounds.
[1187] [1187] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and modalities can be made without departing from the scope and spirit of the invention, which is defined only by the following claims.

权利要求:
Claims (22)
[1]
1. Compound of formula (I):
O O Q R1 S R2
L N N
H H Formula (I) characterized by the fact that: Q is selected from O or S; L is a saturated or unsaturated C1-C12 hydrocarbilene group, where the hydrocarbilene group can be straight or branched chain, or be or include cyclic groups, where the hydrocarbilene group can optionally be substituted, and where the hydrocarbilene group can optionally include one or more N, O or S heteroatoms in your carbon skeleton; R1 is –NR3R4, –OR5, - (C = NR6) R7, - (CO) R8, –CN, –N3, a quaternary ammonium group or an optionally substituted heterocycle; R3, R4, R5, R6, R7 and R8 are each independently hydrogen or a saturated or unsaturated C1-C10 hydrocarbyl group, where the hydrocarbyl group may be straight or branched, or be or include cyclic groups, where the hydrocarbyl group can optionally be substituted, and wherein the hydrocarbyl group can optionally include one or more N, O or S heteroatoms in its carbon backbone; where optionally L and R3, or L and R4, or R3 and R4, together with the nitrogen atom to which they are attached, can form a 3- to 12-membered saturated or unsaturated cyclic group, where the cyclic group can optionally be replaced; wherein optionally L and R5, together with the oxygen atom to which they are attached, can form a 3- to 12-membered saturated or unsaturated cyclic group, where the cyclic group can optionally be substituted; where optionally L and R6, or L and R7, or R6 and R7, together with the group - (C = N) - to which they are attached, can form a saturated or unsaturated cyclic group of 3 to 12 members, where the cyclic group can optionally be substituted; where optionally L and R8, together with the group - (C = O) - to which they are attached, can form a 3 to 12-membered saturated or unsaturated cyclic group, where the cyclic group can optionally be substituted; R2 is a cyclic group substituted at the α position, where R2 can optionally be additionally substituted; provided that the L atom that is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of a heterocyclic or aromatic group.
[2]
2. A compound according to claim 1, characterized by the fact that L is a saturated or unsaturated C1-C8 hydrocarbilene group, in which the hydrocarbilene group may be straight or branched, or be or include cyclic groups, and in that the hydrocarbilene group can optionally be substituted by one or more substituents independently selected from halo, -CN, -N (R9) 2, -OR9 or oxo (= O) groups, where R9 is independently selected from a hydrogen atom, or a C1-C3 alkyl group.
[3]
A compound according to claim 1 or 2, characterized by the fact that the L atom that is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of any cyclic group.
[4]
A compound according to any one of claims 1 to 3, characterized in that R1 is –NR3R4, and R3 and R4 are each, independently, hydrogen or a C 1-C6 alkyl group,
C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl, phenyl or benzyl, each of which can optionally be substituted by one or more substituents independently selected from halo groups, -CN, -N (R9) 2, -OR9 or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[5]
Compound according to any one of claims 1 to 3, characterized in that R1 is -OR5, and R5 is hydrogen or a C1-C6 alkyl group, C2-C6 alkenyl, C2-C6 alkynyl, C1- cycloalkyl C6, phenyl or benzyl, each of which can optionally be substituted by one or more substituents independently selected from halo, -CN, -N (R9) 2, -OR9 or oxo (= O) groups, where R9 is independently selected between a hydrogen atom or a C1-C3 alkyl group.
[6]
A compound according to any one of claims 1 to 3, characterized by the fact that R1 is - (C = NR6) R7, and R6 and R7 are each, independently, hydrogen or a C1-C6 alkyl group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl, phenyl or benzyl, each of which can optionally be substituted by one or more substituents independently selected from halo groups, -CN, -N (R9) 2, -OR9 or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[7]
A compound according to any one of claims 1 to 3, characterized in that R1 is - (CO) R8, and R8 is hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C1-C6 cycloalkyl, phenyl or benzyl, each of which can optionally be substituted by one or more substituents independently selected from halo, -CN, -N (R9) 2, -OR9 or oxo (= O) groups, where R9 is independently selected from a hydrogen atom or a C1-C3 alkyl group.
[8]
8. Compound according to any one of claims 1 to 3, characterized by the fact that R1 is - (CO) R8 and L and R8, together with the group - (C = O) - to which they are attached, form a 4, 5 or 6-membered saturated cyclic group, in which the cyclic group can optionally include an additional N, O or S heteroatom in its carbon backbone, and in which the cyclic group can optionally be substituted by one or more substituents independently selected from halo groups, - CN, -N (R9) 2, -OR9, C1-C3 alkyl, C1-C3 alkylene or oxo (= O), where R9 is independently selected from a hydrogen atom or a C1 alkyl group -C3.
[9]
Compound according to any one of claims 1 to 8, characterized in that R2 is an aryl or heteroaryl group, in which the aryl or heteroaryl group is substituted in the α position, and in which R2 can optionally be additionally substituted .
[10]
Compound according to claim 9, 2 characterized by the fact that R is an aryl or heteroaryl group, in which the aryl or heteroaryl group is substituted in the α and α 'positions, and in which R 2 can optionally be additionally substituted.
[11]
A compound according to claim 10, characterized by the fact that R2 is a fused aryl or fused heteroaryl group, in which a first non-aromatic cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group through of the α, β positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group through the α ', β' positions, where R2 can optionally be additionally substituted.
[12]
A compound according to any one of claims 1 to 8, characterized in that R2 is a cyclic group substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the heterocyclic group or The aromatic is directly attached to the ring atom α of the cyclic group, where the heterocyclic or aromatic group can optionally be substituted, and where the cyclic group can optionally be substituted.
[13]
13. A compound according to any one of claims 1 to 8, characterized in that R2 is a cyclic group substituted at positions α and α ', in which R2 can optionally be additionally substituted.
[14]
Compound according to any one of claims 1 to 13, characterized by the fact that Q is O.
[15]
15. Compound characterized by the fact that it is selected from the group consisting of: Me2N
N O O O O O
Y N Y
N N N N
H H H H
THE
HN
THE
O O O S HN
THE
N S
N N
H H O
O O O O O O O
S S
N N N N N N
H H H H H
O O O O O O
Y N Y
N N N N N
H H H H
O O O O O O
S S
N N N N N N
H H H H
THE
O O O O O O
S S
N N N N N N
H H H H
THE
O O O
O O O
s
N N N O S
H H N N
H H
O O O O O O O
N Y N Y
N N N N
H H H H
O O O
N O O O
s
Y N N N
N N H H
H H
O O O O O O
Y N Y
N N N N N
H H H H H
O O O O O
S S
N N N N N
H H H H
N N
O O O O O O
S S
N N N N
H H H H
N
O O O O O O
S S
N N N N N
H H H H
O O O
O O O
s
N Y N N N
N N H H
H H
NC
O O O O O O
S S
N N N N N
H H H H
O MeO O O O O O
Y Y N N MeO N N
H H H H
O O O
Y O O N N N3 Y
H H N N O OMe H H
O O O O O
THE
N Y N Y
N N N N
N H H H H
F
O O O
N S
N N
H H
N
O O O
S O O O
N N
H H S
N N
N H H
N
The N
F
O O
THE
S O H H
N N N N Et2N S
H H O O Et2N
F
NC N
THE
Et2N S O O O O
HN S F HN Et2N N
H N
H
THE
N N
THE
THE
F N S O
O O HN
Y N HN F
N N
H H O
NC
The N N
THE
O O
O N S O
N S O
HN
HN
HN HN F
THE
N N
THE
O O
O O O
O S O S O S O
HN O HN
HN
HN F HN F HN
NC O O
N N N
N
THE
O O
The N
O S O S O
HN O O
S O HN
HN F O HN F
HN
HN
THE
N N
N
The N
S O F F
O O
HN O O O
S O
HN S
N N N N
The H H
N H H
THE
N N NC N
F
O O O
O O
The S
Y N N
N N H H
N H H N
O N O N
F
O O O
THE
S OO
N N Y N N
N H H H
H
THE
THE
N N
THE
N
THE
O O
OO O
S O
Y N N HN
H HN
H
THE
THE
N
AT THE
S O
THE
The HN
HN O O H2N S
N N
The H H
O O O O
N Y N Y
N N O N N
O H H H
N N
O O O O
Y N Y
N N H N N
O H H O H H
THE
HN
THE
S HN
THE
O O
THE
N S
N N N
O H H HO
O O O O
N Y N Y
N N N N
O H H O H H
O O O O
N Y N Y
N N N N
O O H H O O H H
O O O O
N Y N Y
N N N N
O O H H O O H H
O O H H
N N
O O N S
N S O O
N N
The H H
O O O O
N Y N Y
N N N N
O O H H O H H
O O O O
N
Y N Y
N N N N
O H H O H H
THE
HN
THE
S HN
O O O
N S
N N O H H NH2
O O O O
N N
S S
N N N N
O H H O H H
O O O O
N N
S S
N N N N
O H H O H H
F
O O O O
N N
S S
N N N N
O H H O H H
O O
O O O
O Y N Y
N N O N N
O H H H H
O O
O O O O
O N Y N Y
N N N N
O H H O H H
THE
O O O O
O N Y N Y
N N N N
O H H O H H
The H H
N N O
N S O O
O O O N S
N N
The H H
F
O O O O
N Y N Y
H N N N N
O H H O H H
O O O O
N N
S S
N N N N
O H H O H H
The H H
N N
O O S
N N
S O O
N N
The H H
The H H
N N
S O O
N N
O O S
N N
The H H
The H H
N N
N S O O
O O N
Y Cl N N
The H H
O O
s
O O N N
N N N O H H
s
N N
The H H
N
THE
S O
THE
HN
HN F
NC and N.
[16]
16. Pharmaceutically acceptable salt, solvate or prodrug characterized by the fact that it is of a compound as defined in any one of claims 1 to 15.
[17]
Pharmaceutical composition characterized by the fact that it comprises a compound as defined in any one of claims 1 to 15, or a salt, solvate or prodrug as defined in claim 16, and a pharmaceutically acceptable excipient.
[18]
A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or prodrug according to claim 16, or a pharmaceutical composition according to claim 17, characterized in that which is for medical use.
[19]
19. A compound, salt, solvate, pharmaceutically acceptable prodrug or pharmaceutical composition according to claim 18, characterized by the fact that it is for use in the treatment or prevention of a disease, disorder or condition, characterized by the fact that the disease, disorder or condition is responsive to NLRP3 inhibition.
[20]
20. Compound, salt, solvate, pharmaceutically acceptable prodrug or pharmaceutical composition according to claim 18 or 19, characterized by the fact that it is for use in the treatment or prevention of a disease, disorder or condition, in which the disease , disorder or condition is selected from: (i) inflammation; (ii) an autoimmune disease; (iii) cancer; (iv) an infection; (v) a disease of the central nervous system; (vi) a metabolic disease; (vii) a cardiovascular disease; (viii) a respiratory disease; (ix) a liver disease; (x) a kidney disease; (xi) an eye disease; (xii) a skin disease; (xiii) a lymphatic condition; (xiv) a psychological disorder; (xv) graft versus host disease; and (xvi) allodynia; and (xvii) any disease in which an individual has been determined to have a somatic or germline non-silent mutation in NLRP3.
[21]
21. A compound, salt, solvate, pharmaceutically acceptable prodrug or pharmaceutical composition according to claim 18 or 19, characterized by the fact that it is for use in the treatment or prevention of a disease, disorder or condition, in which the disease , disorder or condition is selected from: (i) cryopyrin-associated periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii) familial cold-induced autoinflammatory syndrome (FCAS); (iv) neonatal onset multisystemic inflammatory disease (NOMID); (v) familial Mediterranean fever (FMF); (vi) pyogenic arthritis, gangrenous pyoderma and acne syndrome (PAPA); (vii) hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); (viii) Periodic Syndrome Associated with the Tumor Necrosis Factor (TNF) Receptor (TRAPS); (ix) Systemic Juvenile Idiopathic Arthritis; (x) Adult onset Still's disease (AOSD); (xi) Recurrent Polyondritis; (xii) Schnitzler syndrome; (xiii) Sweet's syndrome; (xiv) Behçet's disease; (xv) Antisynthetase Syndrome; (xvi) Deficiency of the Interleukin 1 Receptor Antagonist (DIRA); and (xvii) Haploinsufficiency of A20 (HA20).
[22]
22. NLRP3 inhibition method, the method being characterized by the fact that it comprises the use of a compound, according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or prodrug, according to claim 16, or a pharmaceutical composition according to claim 17, to inhibit NLRP3.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

JP3196404B2|1993-03-16|2001-08-06|王子製紙株式会社|Thermal recording medium|

---

WO2016131098A1|2015-02-16|2016-08-25|The University Of Queensland|Sulfonylureas and related compounds and use of same|

---

ME03733B|2015-05-20|2021-01-20|Amgen Inc|Triazole agonists of the apj receptor|

---

US10906890B2|2016-11-16|2021-02-02|Amgen Inc.|Triazole phenyl compounds as agonists of the APJ receptor|PE20191615A1|2017-01-23|2019-11-05|Genentech Inc|CHEMICAL COMPOUNDS AS INHIBITORS OF INTERLEUQUIN-1 ACTIVITY|

---

PE20200758A1|2017-08-15|2020-07-27|Inflazome Ltd|SULFONYLUREAS AND SULFONYLTIOUREAS AS INHIBITORS OF NLRP3|

---

WO2019166619A1|2018-03-02|2019-09-06|Inflazome Limited|Novel compounds|

---

WO2019211463A1|2018-05-04|2019-11-07|Inflazome Limited|Novel compounds|

---

CN112584899A|2018-07-03|2021-03-30|诺华股份有限公司|NLRP modulators|

---

EP3836917A1|2018-08-15|2021-06-23|Inflazome Limited|Novel sulfonamideurea compounds|

---

CN113056451A|2018-10-24|2021-06-29|诺华股份有限公司|Compounds and compositions for treating conditions associated with NLRP activity|

---

GB201819083D0|2018-11-23|2019-01-09|Inflazome Ltd|Novel compounds|

---

GB201902327D0|2019-02-20|2019-04-03|Inflazome Ltd|Novel compounds|

---

GB201905265D0|2019-04-12|2019-05-29|Inflazome Ltd|Inflammasome inhibition|

---

WO2020254697A1|2019-06-21|2020-12-24|Ac Immune Sa|Fused 1,2 thiazoles and 1,2 thiazines which act as nl3p3 modulators|

---

WO2021032591A1|2019-08-16|2021-02-25|Inflazome Limited|Macrocyclic sulfonylurea derivatives useful as nlrp3 inhibitors|

---

WO2021043966A1|2019-09-06|2021-03-11|Inflazome Limited|Nlrp3 inhibitors|

---

WO2021111351A1|2019-12-03|2021-06-10|Cadila Healthcare Limited|Novel substituted sulfonylurea and sulfoximineurea derivatives|

---

WO2021165245A1|2020-02-18|2021-08-26|Inflazome Limited|Compounds|

---

WO2021255279A1|2020-06-19|2021-12-23|Ac Immune Sa|D i h yd rooxazo le and thiourea derivatives modulating the nlrp3 inflammasome pathway|

法律状态:
2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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GBGB1713083.2A|GB201713083D0|2017-08-15|2017-08-15|Novel compounds|

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GB1713082.4|2017-08-15|

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GB1713079.0|2017-08-15|

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GB1713083.2|2017-08-15|

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GBGB1713079.0A|GB201713079D0|2017-08-15|2017-08-15|Novel Compounds|

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GBGB1713082.4A|GB201713082D0|2017-08-15|2017-08-15|Novel compounds|

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GB1718563.8|2017-11-09|

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GBGB1718563.8A|GB201718563D0|2017-11-09|2017-11-09|Novel compounds|

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GB1718564.6|2017-11-09|

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GB1718561.2|2017-11-09|

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GBGB1718561.2A|GB201718561D0|2017-11-09|2017-11-09|Novel compounds|

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GBGB1718564.6A|GB201718564D0|2017-11-09|2017-11-09|Novel compounds|

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GB1721726.6|2017-12-22|

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GBGB1721726.6A|GB201721726D0|2017-12-22|2017-12-22|Novel compounds|

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GBGB1810983.5A|GB201810983D0|2018-07-04|2018-07-04|Novel compounds|

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GB1810983.5|2018-07-04|

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GBGB1812225.9A|GB201812225D0|2018-07-26|2018-07-26|Novel compounds|

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GB1812225.9|2018-07-26|

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PCT/EP2018/072133|WO2019034696A1|2017-08-15|2018-08-15|Novel sulfonamide carboxamide compounds|

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