new sulfonamide-carboxamide compounds

专利摘要:
The present invention relates to the compounds of the formula (I): Formula (I) in which Q is selected from O or S; R1 is a non-aromatic heterocyclic group comprising at least one nitrogen atom in the ring, where R1 is attached to the sulfonyl sulfur group by a carbon atom in the ring, and where R1 can optionally be substituted; and R2 is a cyclic group substituted at position a, where R2 can optionally be additionally substituted. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment and prevention of medical disorders and diseases, mainly by inhibiting NLRP3.
公开号:BR112020000259A2
申请号:R112020000259-3
申请日:2018-07-04
公开日:2020-07-14
发明作者:Matthew Cooper；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 non-aromatic heterocyclic group comprising at least one nitrogen atom of the ring and further comprising a second cyclic group substituted in the α position and salts, solvates, prodrugs and pharmaceutical compositions associated companies. 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. Foundations
[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 like 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 its 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 and IL-18 synergize with IL-23 to induce 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 2 diabetes, atherosclerosis, obesity and gout.
[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 activation of NLRP3, 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 and WO 2018/015445 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] In the context of the present 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 heteroatoms, 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 and aryl groups / fractions and combinations of all these groups / fractions. Typically, a hydrocarbon group is a C1-C20 hydrocarbyl group. More typically, a hydrocarbon group is a C1-C15 hydrocarbyl group. More typically, a hydrocarbon group is a C1-C10 hydrocarbyl group. A "hydrocarbilene" group is defined in the same way as a divalent hydrocarbil group.
[0016] [0016] In the context of this specification, unless otherwise specified, an "alkyl" substituent group or an "alkyl" moiety in a substituent group may be linear 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.
[0017] [0017] An "alkenyl" substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl moiety or moiety with one or more carbon-carbon double bonds. Examples of alkenyl groups / fractions include ethylene, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl groups and fractions 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.
[0018] [0018] 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 C2-C6 alkynyl group. An "alkynylene" group is similarly defined as a divalent alkynyl group.
[0019] [0019] 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, meaning that it contains 3 to 7 ring atoms.
[0020] [0020] As used herein, where it is claimed that a cyclic group is monocyclic, it should be understood that the cyclic group is not replaced by a divalent bridge substituent (for example, -O-, -S-, -NH-, - N (Rβ) - or -Rα-) in order to form a bridged, fused or spiro substituent. However, unless otherwise indicated, a substituted monocyclic group may be substituted for one or more monovalent cyclic groups. Likewise, when a group is claimed to be bicyclic, it must be understood that the cyclic group including any divalent bridged, fused or spiro substituents attached to the cyclic group, but excluding any monovalent cyclic substituents, is bicyclic.
[0021] [0021] 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 hetero atoms, for example, N, O or S, in the structure of the ring. Examples of heterocyclic groups include heteroaryl groups, as discussed below, and non-aromatic heterocyclic groups, such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinethyl, oxyaminyl, tinhydrone, tinnanyl, oxymethyl, tetanyl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydryl, tetrahydrol. pyrazolidinyl, imidazolidinyl, dioxolanil, oxathiolanil, thianyl and dioxanil.
[0022] [0022] 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 substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
[0023] [0023] 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 substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
[0024] [0024] 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".
[0025] [0025] 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
[0026] [0026] Unless otherwise specified, when a cyclic group or fraction is declared non-aromatic, such as a non-aromatic cycloalkyl, cycloalkenyl or heterocyclic group, it should be understood that the group or fraction, excluding any ring systems that are part of or formed by optional substituents, it is not aromatic. Likewise, when a cyclic group or fraction is declared aromatic, such as an aryl or heteroaryl group, it must be understood that the group or fraction, excluding any ring systems that are part of or formed by optional substituents, is aromatic. Usually, a cyclic group or fraction is considered non-aromatic, when it does not have aromatic tautomers. Typically, when a group or cyclic moiety has a tautomer that is aromatic, it is considered aromatic, even if it has tautomers that are not aromatic.
[0027] [0027] For the purposes of the present invention, where a combination of fractions is referred to as a group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned fraction contains the atom by which the group is linked to rest of the molecule. An example of an arylalkyl group is benzyl.
[0028] [0028] For the purposes of this specification, in an optionally substituted group or fraction:
[0029] [0029] Typically, the compounds of the present invention comprise at most one quaternary ammonium group such as -N + (Rβ) 3 or - N + (Rβ) 2-.
[0030] [0030] Where reference is made to a group-Rα-C (N2) Rβ, what is intended is:
[0031] [0031] Normally, in an optionally substituted group or fraction: (i) each hydrogen atom can be optionally substituted by a group independently selected 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; -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; -NRβ-Rα-N (Rβ) 2; a C3-C7 cycloalkyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a C3-C7 cycloalkenyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; or a 3- to 7-membered non-aromatic heterocyclic group optionally substituted by one or more C1-C6 alkyl or C1-C3 haloalkyl groups; and / or (ii) any two hydrogen atoms attached to the same carbon atom can optionally be replaced by a substituent attached to π independently selected from oxo (= O), = S, = NH or = NRβ; and / or (iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or 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 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 where each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and where any -Rβ optionally can be replaced by one or more C1- groups C3 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, -O (C1-C3 alkyl), halo, -CN, -C≡CH or oxo (= O).
[0032] [0032] Normally, in an optionally substituted group or fraction: (i) each hydrogen atom can be optionally substituted by a group independently selected 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; -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; a C3-C7 cycloalkyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a C3-C7 cycloalkenyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; (CH2) m (CH2) m 
[0033] [0033] 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.
[0034] [0034] 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, R1) must be attached only to the specified group or fraction and cannot be attached to a second group or fraction (for example, R2), even if the second group or fraction can be optionally substituted.
[0035] [0035] The term "halo" includes fluorine, chlorine, bromine and iodine.
[0036] [0036] 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.
[0037] [0037] Where reference is made to a hydrocarbyl 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 hydrocarbyl 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 by; –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.
[0038] [0038] 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 : OR
[0039] [0039] 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 moieties are not taken into account when calculating the total number of carbon atoms in the precursor 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 C4 heterocyclic group, not a C6 heterocyclic group.
[0040] [0040] For the purposes of this specification, where 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 linked to the second atom or group with no atom or intervening groups present. So, for example, for the (C = O) N (CH3) 2 group, the carbon atom of each methyl group is directly attached to the nitrogen atom and the carbon atom of the carbonyl group is directly attached to the nitrogen atom, but the carbon atom of the carbonyl group is not directly linked to the carbon atom of the two methyl groups.
[0041] [0041] R1 is a non-aromatic heterocyclic group that can optionally be substituted. For the avoidance of doubt, note that it is a ring atom of the non-aromatic heterocyclic group of R1 that is directly linked to the sulfon atom of the sulfonylurea group, and not any optional substituent.
[0042] [0042] R1 is a non-aromatic heterocyclic group that can be monocyclic, bicyclic (including bridge, fused and spiro), tricyclic or polycyclic. The structures of the bicyclic, tricyclic and polycyclic ring can be partially aromatic. For the avoidance of doubt, note that when R1 is a partially aromatic bicyclic, tricyclic or polycyclic group, the ring of R1 that is directly attached to the sulfon atom of the sulfonylurea group is not aromatic. For the avoidance of doubt, it is also observed that when R1 is a bicyclic, tricyclic or polycyclic group, at least one nitrogen atom in the R1 ring is in a non-aromatic ring, but not necessarily in the non-aromatic ring of R1 that is directly linked to the sulfur atom of the sulfonylurea group. In one embodiment, when R1 is a bicyclic, tricyclic or polycyclic group, the at least one nitrogen atom in the R1 ring is in the non-aromatic ring of R1 that is directly linked to the sulfon atom of the sulfonylurea group.
[0043] [0043] Typically R1 is monocyclic or bicyclic. In one embodiment, R1 is a 4, 5, 6 or 7 membered monocyclic ring or a 7, 8, 9 or 10 membered bicyclic ring, where R1 can optionally be substituted. In one embodiment, R1 is a 4, 5 or 6 membered monocyclic ring or a 7, 8, 9 or 10 membered bicyclic ring, where R1 can optionally be substituted.
[0044] [0044] The non-aromatic heterocyclic group of R1 can be fully saturated or partially unsaturated. In one embodiment, the non-aromatic heterocyclic group of R1 is fully saturated.
[0045] [0045] In one embodiment, the non-aromatic heterocyclic group of R1 is monocyclic. Where the non-aromatic heterocyclic group of R1 is monocyclic, it can optionally be substituted by any monovalent substituent or any π-linked divalent substituent, as defined above, but it cannot be substituted by a divalent bridged substituent (for example, -O -, -S-, -NH-, -N (Rβ) - or -Rα-) in order to form a bridged, fused or spiro substituent. Examples of monocyclic non-aromatic heterocyclic groups include: H H H N N N HN HN HN N H H H H N N N HN HN NH NH O AT THE H H H N O N HN HN O O HN S THE H H N N S HN HN S S HN S S H H H H N N N N HN H N HN HN HN HN HN H H H N N N HN HN NH NH NH N N H H H H H H H N N N N N HN HN NH O O H H N N HN HN HN O S S S HN NH HN HN H NH N HN HN
[0046] The non-aromatic heterocyclic group of R1 may comprise one or more double bonds in the heterocyclic ring, provided that the heterocyclic ring is non-aromatic. The non-aromatic heterocyclic group of R1 does not have tautomers that are aromatic.
[0047] [0047] The following groups are considered aromatic heterocyclics because they have an aromatic tautomer: NH N The OH NH N N O N OH NH N O N O HO N OH
[0048] [0048] For the avoidance of doubt, the term "non-aromatic heterocyclic group" does not exclude heterocyclic groups or portions that may have an aromatic character only due to the separation of the mesomeric charge. For example, the following is considered a non-aromatic heterocyclic group, because it does not have an aromatic tautomer: N N N HO HO HO HO
[0049] [0049] In one embodiment, the non-aromatic heterocyclic group of R1 is monocyclic and is selected from: O O THE THE NH NH NH NH NH NH NH NH O O O O O O O NH HN NH HN NH HN NH HN NH N NH NH N
[0050] [0050] In another embodiment, the non-aromatic heterocyclic group of R1 can be replaced by one or more cycloalkyl rings,
[0051] [0051] In one embodiment, the non-aromatic heterocyclic group of R1 is a fused bicyclic ring. For example, the non-aromatic heterocyclic group of R1 can be:
[0052] [0052] In another embodiment, the non-aromatic heterocyclic group of R is a bridged bicyclic ring. For example, the non-aromatic heterocyclic group of R1 can be:
[0053] [0053] In one embodiment, the non-aromatic heterocyclic group of R1 is selected from: O O NH NH NH NH HN NH NH THE O O N NH NH HN N HN N N
[0054] [0054] In one embodiment, the non-aromatic heterocyclic group of R1 is selected from: O O O NH NH NH NH NH N NH NH
[0055] [0055] In one embodiment, the non-aromatic heterocyclic group of R1 is selected from: O O NH NH HN NH NH NH THE HN N HN
[0056] [0056] In one embodiment, the non-aromatic heterocyclic group of R1 is selected from: NH NH
[0057] [0057] R1 is a non-aromatic heterocyclic group that comprises at least one nitrogen atom in the ring. In one embodiment, R1 comprises one, two or three nitrogen, oxygen or sulfur atoms in the ring. In another embodiment, R1 comprises one or two nitrogen or oxygen atoms in the ring. In another embodiment, R1 comprises one or two nitrogen atoms in the ring. In yet another embodiment, R1 comprises a nitrogen atom in the ring.
[0058] [0058] R1 can optionally be substituted with one or more substituents, as defined above.
[0059] [0059] In one embodiment, R1 is replaced by one or more (such as one, two or three) substituents independently selected from halo; -CN; -NO2; -N3; -Rβ; -OH; -ORβ; -Rα-halo; -Rα-CN; -Rα-NO2; -Rα-N3; -Rα-Rβ; -Rα-OH; -Rα-ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; - SO2NHRβ; -SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα- SO2NH2; -Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; -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-
[0060] [0060] Typically, R1 is substituted on one or more nitrogen atoms in the ring by such a substituent.
[0061] [0061] In another embodiment, R1 is substituted by one or more (such as one, two or three) substituents selected independently from halo; -CN group; -NO2; -N3; -Rβ; -OH; -ORβ; -SH; -SRβ; -SO2Rβ; -NH2; - NHRβ; -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; -NRβ-Rα-N (Rβ) 2; C3-C7 cycloalkyl optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a C3-C7 cycloalkenyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a 3- to 7-membered non-aromatic heterocyclic group optionally substituted by one or more C1-C6 alkyl or C1- C3 haloalkyl groups; oxo (= O); or a C1-C4 alkylene bridge; 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 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 where each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and where any -Rβ optionally can be replaced by one or more C1- groups C3 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, -O (C1-C3 alkyl), halo, -CN, -C≡CH or oxo (= O).
[0062] [0062] Typically, R1 is substituted on one or more nitrogen atoms in the ring by such a substituent.
[0063] [0063] In another embodiment, R1 is substituted by one or more (such as one, two or three) substituents selected independently from halo; -CN; -NO2; -N3; -Rβ; -OH; -ORβ; -SH; -SRβ; -SO2Rβ; -NH2; -NHRβ; -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; a C3-C7 cycloalkyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a C3-C7 cycloalkenyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; (CH2) m (CH2) m 
[0064] [0064] In another embodiment, R1 is substituted by one or more (such as one, two or three) substituents selected independently from halo; -CN; -N3; -Rβ; -SO2Rβ; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; -CORβ; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COORβ; -Rα-OCORβ; -NH-CHO; -NRβ-CHO; -NH-CORβ; -NRβ-CORβ; -CONH2; - CONHRβ; -CON (Rβ) 2; (CH2) m (CH2) m 
[0065] [0065] Typically, R1 is substituted on one or more nitrogen atoms in the ring by such a substituent.
[0066] [0066] In one embodiment, R1 is replaced by one or more (such as one, two or three) substituents selected independently from halo; C1-C6 alkyl; C1-C6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; -R5-CN; -R5-N3; -R5-NO2; -R5-N (R6) 2; -R5-OR6; -R5-
[0067] [0067] Typically, R1 is substituted on one or more nitrogen atoms in the ring by such a substituent.
[0068] [0068] In one embodiment, R1 is substituted on one or more (as one, two or three) nitrogen atoms of the ring by a substituent selected independently from halo; C1-C6 alkyl; C1-C6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; -R5-CN; -
[0069] [0069] In one embodiment, R1 is substituted on one or more (such as one, two or three) nitrogen atoms in the ring by a substituent selected independently from halo; C1-C6 alkyl; C1-C6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; -R5-CN; - R5-N3; -R5-NO2; -R5-N (R6) 2; -R5-OR6; -R5-COR6; -R5-COOR6; -R5-CO-R5-OR6; - R5-CON (R6) 2; -R5-CO-R5-N (R6) 2; -R5-SO2R6; -R5-phenyl; -R5-pyridinyl; -R5- (C3-C6 cycloalkyl); (CH2) m (CH2) m O N R6 (CH2) n; (CH2) n; oxo (= O); -CH2CH2CH2-; or - CH2CH2CH2CH2-; wherein R5 is selected independently of a bond or C1-C5alkylene; R6 is independently selected from hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 cycloalkyl, -CO- (C1-C3 alkyl) or benzyl; m is 1, 2 or 3; and n is 1, 2 or 3.
[0070] [0070] In one embodiment, R1 is substituted on one or more (as one, two or three) carbon atoms in the ring by a substituent selected independently from oxo (= O); -CH2CH2-; -CH2CH2CH2-; -CH2CH2CH2CH2-; -CH = CH-CH = CH2-; -OR7 or -CON (R7) 2; where R7 is selected independently of hydrogen or C1-C3 alkyl.
[0071] [0071] In one embodiment, R1 is substituted on one or more (as one, two or three) carbon atoms in the ring by a substituent selected independently from oxo (= O); -CH2CH2CH2-; - CH2CH2CH2CH2-; or -CH = CH-CH = CH2-.
[0072] [0072] In one aspect of any of the previous modalities 1, R contains 4 to 25 atoms other than hydrogen. More typically, R1 contains 4 to 20 non-hydrogen atoms. More typically, R1 contains 4 to 17 atoms other than hydrogen.
[0073] [0073] R2 is a cyclic group substituted in the α position, where R2 can optionally be additionally 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.
[0074] [0074] In an embodiment of the first aspect of the invention, 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 further 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 further 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 phenyl group substituted at positions 2 and 6 or a phenyl group substituted at positions 2, 4 and 6.
[0075] [0075] As used herein, 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' are as follows:    ''
[0076] [0076] In another embodiment, R2 is a cyclic group substituted in 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.
[0077] [0077] In any of the above modalities, typical substituents at the α and / or α 'positions of the parent cyclic group of R2 comprise a carbon atom. For example, typical substituents at the α and / or α 'positions of the parent cyclic group of R2 can be selected independently from -R4, -OR4 and -COR4 groups, where each R4 is selected independently from a C1-C6 alkyl, C2 group -C6 alkenyl, C2-C6 alkynyl or cyclic C2-C6 and wherein each R4 is optionally further substituted with one or more halo groups. More typically, substituents at the α and / or α 'positions are independently selected from alkyl and cycloalkyl groups, such as C3-C6 branched alkyl and C3-C6 cycloalkyl groups, for example, isopropyl, cyclopropyl, cyclohexyl or t groups -butyl, in which the alkyl and cycloalkyl groups are optionally further substituted by one or more fluoro and / or chloro groups.
[0078] [0078] In one aspect of any of the above modalities, each substituent at positions α and α 'comprises a carbon atom.
[0079] [0079] In one mode, -R2 has a formula selected from: R8
[0080] [0080] Normally, -R2 has a formula selected from: Cl F, or.
[0081] [0081] Other typical substituents at the α and / or α 'positions of the parent cyclic group of R2 may include cycloalkyl, cycloalkenyl,
[0082] [0082] 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 may optionally still be substituted.
[0083] [0083] 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 heteroaryl non-aromatic rings independently selected, where R2 can optionally be further replaced. Normally, 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 bond in common with the aryl or heteroaryl group. Normally, R2 is tricyclic.
[0084] [0084] 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.
[0085] [0085] In one mode, -R2 has a formula selected from: A1 A1 B1
[0086] [0086] Typically, B1 is hydrogen or a halo, hydroxyl, -CN, -NO2, -B2 or -OB2 group, wherein B2 is a C1-C4 alkyl group that can optionally be substituted by halo.
[0087] [0087] Normally, any ring containing A1 or A2 is a 5- or 6-membered ring. Typically, A1 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 can optionally be substituted by halo.
[0088] [0088] In another modality, -R2 has a formula selected from: N N N,,,, N,, N N
[0089] [0089] Normally, -R2 has the formula:.
[0090] [0090] Still other typical substituents at the α position of the cyclic precursor group of R2 may include monovalent heterocyclic groups and monovalent aromatic groups, wherein a ring atom of the heterocyclic or aromatic group is directly linked via a single bond to the ring atom of the α the cyclic precursor group, in which the heterocyclic or aromatic group can optionally be substituted and in which the cyclic precursor group can optionally be substituted. These R2 groups are described in more detail below.
[0091] [0091] In one embodiment, the cyclic precursor group substituted with α from R2 is a cyclic group of 5 or 6 members, in which the cyclic group can optionally be additionally substituted. In one embodiment, the cyclic precursor group substituted with α from R2 is an aryl or heteroaryl group, all of which can optionally be additionally substituted. In one embodiment, the α-substituted cyclic precursor group of R2 is a phenyl or a 5- or 6-membered heteroaryl group, all of which can optionally be additionally substituted. In one embodiment, the α-substituted cyclic precursor group of R2 is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or optionally triazolyl or triazolyl optionally, triazolyl or triazolyl optionally, or triazolyl or triazolyl. replaced later. In one embodiment, the cyclic precursor group substituted by α from R2 is a phenyl group, which can optionally be further substituted.
[0092] [0092] In one embodiment, the precursor cyclic group substituted by α from R2 is substituted in positions α and α 'and can optionally be further substituted. For example, the cyclic precursor group substituted by α from R2 can be a phenyl group substituted at positions 2 and 6 or a phenyl group substituted at positions 2, 4 and 6.
[0093] [0093] In one embodiment, R2 is a precursor cyclic group 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 precursor cyclic group can optionally still be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is 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, tietanil, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, tianyl, pianil, pyridine, pyridine, 4-dioxatanil,
[0094] [0094] In one embodiment, R2 is a precursor cyclic group 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 precursor cyclic group can optionally still be substituted. In one embodiment, these additional substituents are at the α 'position of the cyclic precursor group replaced by α from R2. These additional substituents can be selected independently from the halo, -Rδ, -ORδ or -CORδ groups, where each Rδ is selected independently from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 group and where each Rδ is optionally substituted with one or more halo groups. Typically, these additional substituents on the cyclic precursor group substituted by R2 are independently selected from halo, C1-C6 alkyl (particularly C3-C6 branched alkyl) or C3-C6 cycloalkyl groups, for example, fluorine, chlorine, isopropyl, cyclopropyl , cyclohexyl or t-butyl groups, wherein the alkyl and cycloalkyl groups are optionally further substituted by one or more fluoro and / or chloro groups.
[0095] [0095] In one mode, -R2 has a formula selected from: R10
[0096] [0096] Normally, -R2 has a formula selected from:
[0097] [0097] In one embodiment, R2 is a precursor cyclic group 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 precursor cyclic group can optionally still be substituted. The other substituents on the α-substituted cyclic precursor group of R2 also include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings that are fused to the α-substituted parent cyclic group of R2. Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused to the parent cyclic group substituted by α of R2, that is, each fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring has only two atoms and one common bond with the R2 pair-substituted cyclic group. Typically, cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused to the cyclic precursor group substituted by α from R2 through positions α ', β'.
[0098] [0098] In one mode, -R2 has a formula selected from: N
[0099] [0099] 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 -R4, -OR4 and -COR4, where R4 is selected from the C1-C6 alkyl, C2-C6 alkenyl group , C2-C6 alkynyl or C2-C6 cyclic and wherein R4 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 - -R14, -OR14 and -COR14, where R14 is selected from a C1-C6 alkyl, C2-C6 group alkenyl, C2-C6 alkynyl or cyclic C2-C6 and wherein R14 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, 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 - R4, -OR4 and -COR4, where R4 is selected from a C1-C6 alkyl, C2-C6 group alkenyl, C2-C6 alkynyl or cyclic C2-C6 and wherein R4 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 or -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 or -CON (R15) 2, where each -R15 is selected independently from a group C1-C4 alkyl or C1-C4 haloalkyl); 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, triazolyl or tetrahydropyranyl, where the monovalent heterocyclic or aromatic group can optionally be substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1- C3 haloalkyl, -R12-OR13, -R12-N (R13) 2, -R12-CN or -R12-C≡CR13, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the ring atom α of the 5- or 6-membered phenyl precursor or heteroaryl group; wherein R12 is independently selected from a bond or a C1-C3 alkylene group; and R13 is independently selected from hydrogen or a C1-C3 alkyl or C1-C3 haloalkyl group; and optionally, the 5- or 6-membered phenyl or heteroaryl group is further substituted in the α 'position by a substituent selected from - R4, -OR4 and -COR4, where R4 is selected from a C1-C6 alkyl, C2-C6 group alkenyl, C2-C6 alkynyl or cyclic C2-C6 and wherein R4 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 (v) 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, triazolyl or tetrahydropyranyl, where the monovalent heterocyclic or aromatic group can optionally be substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1- C3 haloalkyl, -R12-OR13, -R12-N (R13) 2, -R12-CN or -R12-C≡CR13, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the ring atom α of the 5- or 6-membered phenyl precursor or heteroaryl group; wherein R12 is independently selected from a bond or a C1-C3 alkylene group; and R13 is independently selected from hydrogen or a C1-C3 alkyl or C1-C3 haloalkyl group; and optionally the 5- or 6-membered phenyl or heteroaryl group is further replaced by a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which 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 (usually with one or two substituents independently selected from halo, -NO2, -CN, -COOR15, - CONH2, -CONHR15 or -CON (R15 ) 2, where each -R15 is selected independently from a C1-C4 alkyl or C1-C4 haloalkyl group).
[0100] [0100] 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.
[0101] [0101] In one aspect of any of the above, R2 contains 15 to 50 atoms. More typically, R2 contains 20 to 40 atoms. More typically, R2 contains 25 to 35 atoms.
[0102] [0102] In another aspect of any of the above 2 modalities, R 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.
[0103] [0103] Q is selected from O or S. In an embodiment of the first aspect of the invention, Q is O.
[0104] [0104] In a specific embodiment, the invention provides a compound of formula (I), where: Q is O; R1 is a non-aromatic heterocyclic group selected from: O O NH NH NH NH HN NH NH THE O O N NH NH HN N HN
[0105] [0105] 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.
[0106] [0106] In this specific modality directly above, the precursor phenyl or the 5- or 6-membered heteroaryl group of R2 can be selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.
[0107] [0107] In this specific modality directly above, R1 can optionally be substituted by one or more (such as one, two or three) substituents independently selected from halo; C1-C6 alkyl; C1- C6 haloalkyl; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkynyl; C2-C6 haloalkynyl; -R5-CN; -R5-N3; -R5-NO2; -R5-N (R6) 2; -R5-OR6; -R5-SR6; -R5-Si (R6) 3;
[0108] [0108] Typically, R1 is substituted on one or more (like one, two or three) nitrogen atoms in the ring by this substituent.
[0109] [0109] In one aspect of any of the above embodiments, the compound of formula (I) has a molecular weight of 250 to 2000 Da. Typically, the compound of formula (I) has a molecular weight of 280 to 900 Da. More typically, the compound of formula (I) has a molecular weight of 310 to 550 Da.
[0110] [0110] A second aspect of the invention provides a compound selected from the group consisting of: O O O s N N H H N O O O s N N H H N O O O s N N H H N THE O O O s N N H H HN O O O s N N H H H N N THE O O O s N N H H
[0111] [0111] 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.
[0112] [0112] 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 (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-sulfonic acid, naphthalene-2-sulfonic or camphor sulfonic) or amino acids (for example, ornithinic, glutamic acid, glutamic or aspartic). The acid addition salt can be a mono, di, tri or multi-acid addition salt. A preferred salt is a hydrohalogenic, sulfuric, phosphoric or organic addition salt. A preferred salt is a hydrochloric acid addition salt.
[0113] [0113] 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.
[0114] [0114] 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 di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably, the salt is a mono- or di-sodium salt or a mono- or di-potassium salt.
[0115] [0115] 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.
[0116] [0116] 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.
[0117] [0117] 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. 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.
[0118] [0118] The compounds, salts, solvates and prodrugs of the present invention may contain any stable isotope, including, but not limited to C, C, 1H, 2H (D), 14 N, 15 N, 16 O, 17 O, 18 O, 19 F and 127 I, and any 11 14 3 13 15 18 123 radioisotope including, but not limited to C, C, H (T), N, O, F, I, 124 I, 125I and 131I.
[0119] [0119] The compounds, salts, solvates and prodrugs of the present invention can be in any polymorphic or amorphous form.
[0120] [0120] 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.
[0121] [0121] 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”,
[0122] [0122] 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.
[0123] [0123] In one embodiment, the pharmaceutical composition of the fourth aspect of the invention further comprises one or more additional active agents.
[0124] [0124] 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.
[0125] [0125] 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 co-administration of one or more additional active agents.
[0126] [0126] 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,
[0127] [0127] 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-administration of one or more additional active agents.
[0128] [0128] 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 pro- 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.
[0129] [0129] 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 activity of
[0130] [0130] 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-administration of 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 drug 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.
[0131] [0131] 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.
[0132] [0132] In general terms, 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.
[0133] [0133] 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.
[0134] [0134] In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is responsive to 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.
[0135] [0135] 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).
[0136] [0136] 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.
[0137] [0137] 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 erythematosis (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.
[0138] [0138] The inflammasome, and NLRP3 specifically, has also been proposed as a target for modulation by various pathogens, including viruses such as DNA viruses (Amsler et al., Future Virol. (2013) 8 (4), 357–370).
[0139] [0139] 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. blind, placebo-controlled study (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 Cancer 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).
[0140] [0140] 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).
[0141] [0141] Therefore, examples of diseases, disorders or conditions that can respond to inhibition of NLRP3 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), anti-synthase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune insufficiency, autoimmune thyroiditis Celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, erythematous lupus 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, myoclonus opsoclonus 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, hot autoimmune granulomatosis, Wegener granulomatosis, universal alopecia , Behçet's disease, Behçet's disease, Begas disease, endometriosis, suppurative hydradenitis (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo or vulvodynia; (iii) cancer, including lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal cell and squamous skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, tumors of the Ewing family, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer , laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumor, lymphoma, including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, skin cancer of Merkel cells, multiple myeloma, nasal cavity and paranasal sinuses cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penis cancer, pituitary tumors , prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer , including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia and Wilms' tumor; (iv) infections including viral infections (for example, influenza virus, human immunodeficiency virus (HIV), alphavirus (such as Chikungunya and Ross River virus), flavivirus (such as dengue virus and Zika virus), herpes (such as Epstein Barr virus, cytomegalovirus, Varicella zoster virus and KSHV), poxvirus (such as vaccinia virus (modified vaccinia virus Ankara) and Myxoma virus), adenovirus (such as Adenovirus 5) or papillomavirus), bacterial infections (for example, Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, pertussis Bordatella, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, L. monocytogenes, Hemophilobacteria Mycoplasma Hemophilobacteria Mycoplasma, Pasteurella tuberculosis, Pasteurella Neisseria meningitidis gonorrhoeae, Neisseria, Rickettsia rickettsii, Legionella pneumophila, Klebs iella pneumoniae, Pseudomonas aeruginosa, Propionibacterium ac nes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or Yersinia pestis); fungal infections (for example, Candida or Aspergillus species), protozoan infections (for example, Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth infections (for example, schistosoma, roundworms, tapeworms or worms ) and prion infections; (v) diseases of the central nervous system, such as Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury and amyotrophic lateral sclerosis; (vi) metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout and pseudo-gout; (vii) cardiovascular diseases such as hypertension, ischemia, reperfusion injury, including ischemic reperfusion injury after MI, stroke, including ischemic stroke, transient ischemic attack, myocardial infarction, including recurrent myocardial infarction, heart failure, including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysms including abdominal aortic aneurysm and pericarditis including Dressler's syndrome; (viii) respiratory diseases including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis and idiopathic pulmonary fibrosis; (ix) liver disease, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including advanced stages of fibrosis F3 and F4, alcoholic fatty liver disease (AFLD) and alcoholic steatohepatitis (ASH); (x) kidney disease including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis and diabetic nephropathy; (xi) eye diseases, including those of the eye epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye and glaucoma; (xii) skin diseases, including dermatitis such as contact dermatitis and atopic dermatitis, hypersensitivity to contact, sunburn, skin lesions, hidradenitis suppurativa (HS), other skin diseases that cause cysts and acne conglobata;
[0142] [0142] 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 (vii) a skin disease.
[0143] [0143] 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.
[0144] [0144] In one modality, the disease, disorder or condition is selected from: (i) acne conglobata; (ii) atopic dermatitis; (iii) Alzheimer's disease; (iv) amyotrophic lateral sclerosis;
[0145] [0145] 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, atopic 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
[0146] [0146] 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 cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome ( MWS), cold-induced familial autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multisystem 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 (APL AID) or sideroblastic anemia with B cell immunodeficiency, periodic fevers and developmental delay (SIFD).
[0147] [0147] Examples of diseases, disorders or conditions that can respond to inhibition of NLRP3 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-induced auto-inflammatory 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, disease Adult Still (AOSD), relapsing polychondritis, Schnitzler syndrome, Sweet syndrome, Behcet's disease, anti-synthase syndrome, interleukin 1 receptor antagonist deficiency (DIRA) and A20 haploinsufficiency (HA20) insufficiency.
[0148] [0148] In addition, some of the diseases, disorders or conditions mentioned above arise due to mutations in NLRP3, in particular, resulting in increased NLRP3 activity. As a result, such diseases, disorders or conditions may be particularly responsive to 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).
[0149] [0149] In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is not an inflammatory eye disease or a symptom of an inflammatory eye disease. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a skin disease. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a disease involving a chemokine receptor. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a skin disease. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not dermatitis. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a disease that involves an increase in eosinophils. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not an allergic disease. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a disease susceptible to treatment with a chymase inhibitor. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not fibrosis or dysbolism of the extracellular matrix. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a disease accompanied by abnormal vascular function. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a rheumatic disease. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a heart or circulatory system disease. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not an inflammatory bowel disease. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not HCV infection. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not cancer. In a fifth, sixth or seventh aspect of the present invention, the disease, disorder or condition is not a disease susceptible to treatment with a hypoglycemic agent.
[0150] [0150] 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.
[0151] [0151] 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.
[0152] [0152] In an embodiment of the eleventh aspect of the present invention, the method is carried out ex vivo or in vitro, for example, in order to analyze the effect on cells of NLRP3 inhibition.
[0153] [0153] 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.
[0154] [0154] 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.
[0155] [0155] 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. In one embodiment, the compound, salt, solvate, prodrug or pharmaceutical composition is co-administered with one or more additional active agents.
[0156] [0156] 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.
[0157] [0157] 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.
[0158] [0158] 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.
[0159] [0159] In an embodiment of any one 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;
[0160] [0160] 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.
[0161] [0161] 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, hydroxy, hydroxy, hydroxy, hydroxy CCNU) lomustine (RPR109881), meclorethamine, mercaptopurine, methotrexate, mitomycin C, mitoxantrone, melphalan, mivobulin, 3 ', 4'-dideshydro-4'-deoxy-8'- norvin-kaleucoblastine, nilutamide, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, oxaliplatin, liplatin, imustine, procarbazine, paclitaxel, platinum-containing anticancer agents, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzene sulfonamide, prednimustine, procarbazine, rhizoxin, sertenef, streptozocine, phosphate of estramustine, tretinoin, tasonermin, taxol, topotecan, tamoxifen, teniposide, taxane, tegafur / uracil, vincristine, vinblastine, vinorelbine, vindesine, vindesine sulfate and / or vinflunine.
[0162] [0162] 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 hexassaccharide, human chorionic gonadotrophin (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 transforming beta factor (TGF -β), vasculostatin, vasostatin (fragment of calreticulin) and / or cytokines (including interleukins, such as interleukin-2 (IL-2) or IL-10).
[0163] [0163] 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.
[0164] [0164] 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 bonds 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.
[0165] [0165] 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.
[0166] [0166] In some embodiments, one or more antiangiogenic agents are selected from endostatin, angiogenin, angiostatin, angioarrestin, angiostatin (plasminogen fragment), antiangiogenic factors derived from the basement membrane collagen (tumstatin, canstatin or carnation), angiogenic antiantithrombin III and / or cartilage-derived inhibitor (ICD).
[0167] [0167] 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.
[0168] [0168] 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.
[0169] [0169] 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.
[0170] [0170] 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, trans-diptoindonesin B, astringin, piceid and / or diptoindonesin A.
[0171] [0171] In some embodiments, one or more agonists of STING (Stimulator of interferon genes, also known as transmembrane protein (TMEM) 173) may comprise cyclic di-nucleotides, such as cAMP, cGMP and cGAMP and / or cyclic di-nucleotides modified which 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 (eg 2 'protection -OH with a methyl group or replacement of 2'-OH by -F or -N3).
[0172] [0172] In some modalities, one or more vaccines against cancer are selected from an HPV vaccine, a vaccine against hepatitis B, Oncophage and / or Provenge.
[0173] [0173] 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,
[0174] [0174] 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) (PD -L1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertibe, ulocuplumab, BKT140, bavituxima, and / or MNRP1685A.
[0175] [0175] In some modalities, one or more antibiotics are selected from amikacin, gentamycin, kanamycin, neomycin, netilmycin, tobramycin, paromomycin, streptomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, imipenem, imipemem, imipemem, imipemem, imipememem, imipemem, imipemem, imipemem, imipemememememememememememememememememememememememememipem. imipenemil, cefazoline, cephalothin, cephalothin, cephalexin, cefaclor, cefamandol, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditorene, cefoperazone, cefotaxime, cefpodximate, ceftaxine, ceftaxine, ceftaxine, ceftaxine, ceftaxine , telavancin, dalbavancin, oritavancin, clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spiramycin aztreonam, furazolidone, nitrofurantoin, amphotericin, amziline, linezolide, zazolide, zazidine cloxacillin, dicloxacillin, flucl oxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, ticarcillin, clavulanate, ampicillin, subbactam, tazobactam, tiracycline,
[0176] [0176] 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 embodiments, one or more anthracyclines are selected from bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and / or valrubicin.
[0177] [0177] 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, flaconazole, ezaconazole, flaconazole, , itraconazole, posaconazole, propiconazole, ravusconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naphthifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid,
[0178] [0178] In some embodiments, one or more anthelmintic agents are selected from benzimidazois (including albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole and flubendazole), abamectin, diethylcarbamazine, ivermectin, suramine, piramide, pirantelanamide, piramide, pyrantelanamide, piramide, pyrantelanamide, pyrantelanamide, piramide, pyrantyl, piramide, pyrantyl, piramide. niclosamide and oxyclozanide) and / or nitazoxanide.
[0179] [0179] In some embodiments, other active agents are selected from growth inhibitory 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).
[0180] [0180] 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 human.
[0181] [0181] 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), air (aerosol), rectal, vaginal or topical (including transdermal, buccal, mucous and sublingual).
[0182] [0182] 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.
[0183] [0183] 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.
[0184] [0184] 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.
[0185] [0185] 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.
[0186] [0186] 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.
[0187] [0187] Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavoring agents, dyes and / or preservatives.
[0188] [0188] Formulations for rectal administration can be presented as a suppository with a suitable base, which comprises, for example, cocoa butter or a salicylate.
[0189] [0189] 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.
[0190] [0190] 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 solution 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.
[0191] [0191] 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.
[0192] [0192] Suitable suspensions and solutions can be used in inhalers for administration of airways (aerosol).
[0193] [0193] The dose of the compounds, salts, solvates or prodrugs of the present invention will, of course, vary with the disorder, disease or condition to be treated or prevented. In general, 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.
[0194] [0194] For the avoidance of doubt, as far as possible, any modality of a particular 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.
[0195] [0195] Examples - synthesis of compounds
[0196] [0196] All solvents, reagents and compounds were purchased and used without further purification, unless otherwise specified. Abbreviations 2-MeTHF 2-methyltetrahydrofuran AcOH aqueous acetic acid Boc tert-butyloxycarbonyl broad Cbz carboxybenzyl CDI 1,1-carbonyl-diimidazole conc concentrate doublet DABCO 1,4-diazabicyclo [2.2.2] octane DCE 1 , 2-dichloroethane, also called ethylene dichloride DCM dichloromethane
[0197] [0197] Experimental methods
[0198] [0198] Analytical Methods
[0199] [0199] NMR spectra were recorded at 300 MHz or 400 MHz with chemical changes reported in parts per million. The spectra were collected using one of the three machines below: - - An Agilent VNMRS 300 instrument equipped with an Oxford Instruments 7.05 Tesla magnet, indirect detection probe and direct drive console, including the PFG module. - 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. - A Bruker 400 MHz spectrometer using ICON-NMR, controlled by TopSpin program.
[0200] [0200] HPLC 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 and -ive
[0201] [0201] Pump program:
[0202] [0202] Alternatively, LC-MS has been registered using SHIMADZU LCMS-2020, Agilent 1200 LC / G1956A MSD and Agilent 1200 G6110A, Agilent 1200 LC & Agilent 6110 MSD. Mobile phase: A: 0.025% NH3 · H2O in water (v / v); B: acetonitrile. Column: Kinetex EVO C18 2.1 x 30 mm, 5 µm. Purification Method 1
[0203] [0203] Automated reverse phase column chromatography was performed using a Buchi Sepracore® X50 system powered by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and collector of fractions C-660. Revelis C18 12 g reverse phase cartridge Carbon charge 18% Surface area 568 m2 / g Pore diameter 65 Angstrom pH (5% yield paste) 5.1 Average particle size 40 µm
[0204] [0204] 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
[0205] [0205] Separation runs: Time (min) A: water (% B: MeOH (% yield) yield) 0 100 0 5 100 0 30 30 70
[0206] [0206] Detection wavelength: 215, 235, 254 and 280 nm. Before each new run, the cartridge was cleaned using the conditioning method. Purification Method 2
[0207] [0207] Alternatively, automated reverse phase column chromatography was performed using a Gilson GX-281 system powered by a Gilson-322 pump module, Gilson-156 UV photometer detection unit and Gilson-281 fraction collector. Phenomenex Gemini 150mm x 25mm x 10µm pH (water (0.05% v / v ammonium hydroxide) - acetonitrile) = 10 Average particle size = 10 µm
[0208] [0208] The column was conditioned before use with 100% acetonitrile (2 min) and then it was brought to 5% acetonitrile (in 1.5 min). Flow rate = 25 mL / min.
[0209] [0209] Separation runs: Time (min) A: water (B hydroxide: Acetonitrile (% 0.05% v / v ammonium) yield) 0 99 1 12 85 15 12.2 0 100 14.2 0 100 14.5 95 5 16.0 95 5
[0210] [0210] Detection wavelength: 220 and 254 nm.
[0211] [0211] Intermediate A1: 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene
[0212] [0212] To a solution of phosgene (4.45 ml, 20 wt% toluene, 8.4 mmol) in EtOAc (90 ml) was added dropwise a solution of 1,2,3,5,6, 7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in EtOAc (45 mL) at 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.
[0213] [0213] 1H NMR (CDCl3): δ 6.8 (s, 1 H), 2.89 (m, 8 H) and 2.09 (m, 4 H).
[0214] [0214] Intermediate A2: 2-Isocyanate-1,3-diisopropylbenzene
[0215] [0215] To a suspension of 2,6-diisopropylaniline hydrochloride (1 g, 4.7 mmol) in toluene (50 mL) was added 1 drop of pyridine and the resulting mixture was heated to almost reflux as a solution phosgene (7.3 ml, 20 wt% in toluene, 13.8 mmol) was added dropwise over a period of 10 minutes. The mixture was stirred for an additional 45 minutes at 105 ° C and then allowed to cool partially before being concentrated in vacuo to provide the title compound as a mobile yellow oil (1.5 g,> 100% yield). The crude product was used directly in the next step without further purification.
[0216] [0216] 1H NMR (CDCl3): δ 7.2 (m, 3 H), 3.12 (m, 2 H) and 1.25 (d, 12 H).
[0217] [0217] Intermediate A3: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene
[0218] [0218] To a solution of 4-fluoro-2,6-diisopropylaniline (0.103 g, 0.527 mmol) in toluene (1.4 mL) was added a solution of phosgene (0.69 mL, 20% by weight of toluene, 1.3 mmol) and the reaction mixture was refluxed for 1 hour. After cooling, the mixture was concentrated in vacuo to give the title compound as a brown oil (0.110 g, 100% yield). The crude product was used directly in the next step without further purification.
[0219] [0219] 1H NMR (CDCl3): δ = 6.80 (d, 2H), 3.20 (m, 2H), 1.24 (d, 12H).
[0220] [0220] Intermediate A4: 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
[0221] [0221] Step A: N- (5-Bromo-2,3-dihydro-1H-inden-4-yl) pivalamide
[0222] [0222] N- (2,3-Dihydro-1H-inden-4-yl) pivalamide (1 g, 4.60 mmol), dep-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 saturated aqueous 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 silica gel chromatography (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 by-products of the reaction. LCMS: m / z 296.3 / 298.3 (M + H) + (ES +).
[0223] [0223] Step B: 5-Bromo-2,3-dihydro-1H-inden-4-amine
[0224] [0224] 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% aqueous) (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 over the weekend. The mixture was cooled to room temperature and then basified with 2M aqueous NaOH. The mixture was extracted with DCM (3 x 20 ml). The organic phase was dried by passing through a hydrophobic frit and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc / isohexane) to give the title compound (0.14 g, 29%).
[0225] [0225] 1H NMR (CDCl3) δ 7.23 (d, J = 7.9 Hz, 1H), 6.57 (d,
[0226] [0226] Step C: 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
[0227] [0227] 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. DCM (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 ° C (bath temperature) for 2 hours. Then the mixture was cooled to room temperature and partitioned between DCM (30 ml) and water (20 ml). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to give 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 (0.29 g, 87%) as a pale yellow crystalline solid.
[0228] [0228] 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). Two exchangeable protons were not observed. LCMS: m / z 241.3 (M + H) + (ES +).
[0229] [0229] Intermediate A5: 4- (4-Amino-2,3-dihydro-1H-inden-5-yl) picolinonitrile
[0230] [0230] Prepared according to the general procedure of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A4, Step C) from 5- bromo-2,3-dihydro-1H-inden-4-amine (Intermediate A4, Step B) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) picolinonitrile to provide the title compound (215 mg, 61%) as a pale yellow solid.
[0231] [0231] 1H (DMSO-d6) δ 8.72 (dd, J = 5.1, 0.8 Hz, 1H), 8.03 (dd, J = 1.8, 0.8 Hz, 1H), 7.74 (dd, J = 5.1, 1.8 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H ), 4.94 (s, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H). LCMS: m / z 236.3 (M + H) + (ES +).
[0232] [0232] Intermediate A6: 4- (5-Fluoro-2-isocyanato-3 isopropylphenyl) picolinonitrile
[0233] [0233] Step A: 4-Fluoro-2- (prop-1-en-2-yl) aniline NH2 NH2 Br
[0234] [0234] 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 H2O (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 over silica gel (SiO2, petroleum ether: ethyl acetate 1: 0 to 100: 1) to give the title compound (27 g, 77% yield, 89% purity in LCMS ) as a yellow oil.
[0235] [0235] 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). LCMS: m / z 152.2 (M + H) + (ES +).
[0236] [0236] Step B: 4-Fluoro-2-isopropylaniline NH2 NH2 F F
[0237] [0237] 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 give the title compound (20 g, crude) as a yellow oil.
[0238] [0238] 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). LCMS: m / z 154.2 (M + H) + (ES +).
[0239] [0239] Step C: 2-Bromo-4-fluoro-6-isopropylaniline NH2 NH2 Br F F
[0240] [0240] To a solution of 4-fluoro-2-isopropylaniline (20 g,
[0241] [0241] 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). LCMS: m / z 232.1 (M + H) + (ES +).
[0242] [0242] Step D: 4- (2-Amino-5-fluoro-3-isopropylphenyl) picolinonitrile NH2 F Br O O + B H2N F NC N NC N
[0243] [0243] 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) Na2CO3 (4.11 g, 38.78) were added mmol, 2.5 eq). Then, Pd (dppf) Cl2 (1.13 g, 1.55 mmol, 0.1 eq) was added to the mixture under an atmosphere of nitrogen. The resulting mixture was stirred at 80 ° C for 2 hours under nitrogen. Then the mixture was concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2 petroleum ether: ethyl acetate, 20: 1 to 5: 1) and then triturated with petroleum ether (10 mL) to give the title compound (2.65 g, 65% yield, 97% purity in LCMS) as a yellow solid.
[0244] [0244] 1HNMR (CDCl3) δ 8.79 (d, 1 H), 7.86 (d, 1 H), 7.65
[0245] [0245] Step E: 4- (5-Fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile
[0246] [0246] 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 give the title compound (1.2 g, crude) as a yellow solid, which was used directly in the next step.
[0247] [0247] Intermediate A7: 4- (5-Fluoro-2-isocyanato-3 isopropylphenyl) -2-methoxypyridine
[0248] [0248] Step A: 4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) aniline NH2 F
[0249] [0249] 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 (9.49 g, 62.04 mmol, 1.2 eq)
[0250] [0250] 1H NMR (CDCl3) δ 8.24 (d, 1 H), 6.97 (d, 1 H), 6.93 (d, 1 H), 6.83 (s, 1 H), 6 , 73-6.70 (m, 1 H), 3.99 (s, 3 H), 3.66 (br s, 2 H), 2.97 - 2.89 (m, 1 H) and 1, 29 (dd, 6 H). LCMS: m / z 261.1 (M + H) + (ES +).
[0251] [0251] Step B: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) - 2-methoxypyridine
[0252] [0252] To a solution of 4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) aniline (1 g, 3.84 mmol, 1 eq) in THF (40 mL) was added TEA (777 mg, 7.68 mmol, 2 eq). Then, triphosgene (456 mg, 1.54 mmol, 0.4 eq) was added in portions at 5 ° C. The mixture was stirred at 70 ° C for 1 hour. The mixture was diluted with EtOAc (200 ml) and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.1 g, crude) as a yellow oil, which was used directly in the next step.
[0253] [0253] Intermediate A8: 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine
[0254] [0254] To a solution of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A4) (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL) was added in portions of bis (trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) at 0 ° C. Then the reaction mixture was stirred at 16 ° C for 0.5 hour. The reaction mixture was filtered and the filter residue was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74%) as a light yellow solid.
[0255] [0255] 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).
[0256] [0256] Intermediate A9: 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine
[0257] [0257] Step A: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-one
[0258] [0258] 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 provide the title compound (11.4 g, 92%) as a yellow solid.
[0259] [0259] 1H NMR (CDCl3) 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).
[0260] [0260] Step B: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol
[0261] [0261] 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 give the title compound (30 g, crude) as brown oil.
[0262] [0262] 1H NMR (CDCl3) δ 8.21 (dd, 1 H), 7.08 (t, 1 H), 5.59-5.56 (m, 1 H), 3.66-3.59 (m, 1 H), 3.44-3.39 (m, 1 H), 2.56-2.51 (m, 1 H) and 2.22-2.17 (m, 2 H).
[0263] [0263] Step C: 4-Fluoro-7-nitro-2,3-dihydro-1H-indene
[0264] [0264] 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
[0265] [0265] 1H NMR (CDCl3) δ 8.06 (dd, 1 H), 7.01 (t, 1 H), 3.46 (t, 2 H), 3.04 (t, 2 H) and 2 , 25-2.20 (m, 2 H).
[0266] [0266] Step D: 7-Fluoro-2,3-dihydro-1H-inden-4-amine
[0267] [0267] 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 give the title compound (1.8 g, 43%) as a brown solid.
[0268] [0268] 1H NMR (CDCl3) δ 6.69 (t, 1 H), 6.44 (dd, 1 H), 3.47 (br s, 2 H), 2.95 (t, 2 H), 2.75 (t, 2 H) and 2.19-2.11 (m, 2 H).
[0269] [0269] Step E: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine
[0270] [0270] 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 Na2SO3 solution
[0271] [0271] 1H NMR (CDCl3) δ 6.99 (d, 1 H), 3.81 (br s, 2 H), 2.92 (t, 2 H), 2.78 (t, 2 H) and 2.21 - 2.13 (m, 2 H).
[0272] [0272] Step F: 7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
[0273] [0273] 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 give the title compound (1.7 g, 45% yield, 90.98 % HPLC purity) as a brown solid.
[0274] [0274] 1H NMR (CDCl3) δ 8.68 (dd, 2 H), 7.40 (dd, 2 H), 6.72 (d, 1 H), 3.76 (br s, 2 H), 3.01 (t, 2 H), 2.80 (t, 2 H) and 2.26-2.18 (m, 2 H).
[0275] [0275] Step G: 4- (7-Fluoro-4-Isocyanato-2,3-dihydro-1H-inden-5-yl) pyridine
[0276] [0276] For 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.
[0277] [0277] Intermediate A10: 3- (5-Fluoro-2-isocyanato-3 isopropylphenyl) pyridine
[0278] [0278] Step A: 4-Fluoro-2-isopropyl-6- (pyridin-3-yl) aniline NH2 F Br O O + B H2N F N N
[0279] [0279] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (21 g, 90.48 mmol, 1 eq) in dioxane (450 ml) and H2O (90 ml) was added 3- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (22.26 g, 108.58 mmol, 1.2 eq) and Na2CO3 (23.98 g, 226.20 mmol, 2 , 5 eq). The reaction mixture was purged with nitrogen three times. Then, Pd (dppf) Cl2 (5.10 g, 6.97 mmol, 0.077 eq) was added under an atmosphere of nitrogen. The resulting mixture was heated to 80 ° C and stirred for 2 hours. The reaction mixture was quenched by adding H2O (800 ml) and extracted with EtOAc (2 × 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, 50: 1 to 1: 1) and then triturated with hexane (40 mL) to give the title compound (17 g, 82 %) as a solid gray.
[0280] [0280] 1H NMR (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). LCMS: m / z 231.2 (M + H) + (ES +).
[0281] [0281] Step B: 3- (5-Fluoro-2-isocyanate-3-isopropylphenyl) pyridine
[0282] [0282] For 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 give the title compound (0.2 g, crude) as a yellow oil, which was used directly in the next step.
[0283] [0283] Intermediate A11: 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine
[0284] [0284] Step A: 7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine HO OH F
[0285] [0285] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (Intermediate A9, Step E) (8.5 g, 36.94 mmol, 1 eq ) and (2-methoxypyridin-4-yl) boronic acid (5.93 g, 38.79 mmol, 1.05 eq) in dioxane (150 ml) and water (15 ml) were added K2CO3 (15.32 g, 110.83 mmol, 3 eq) and Pd (dppf) Cl2 (2.70 g, 3.69 mmol, 0.1 eq) in one portion under nitrogen. The reaction mixture was heated to 80 ° C and stirred for 12 hours. The reaction mixture was quenched with water (300 ml) and extracted with EtOAc (3 x 300 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 chromatography on silica gel (petroleum ether: EtOAc, 1: 0 to 10: 1) and then purified by trituration with a mixture of TBME and n-hexane (50 ml, 1:20) to give the compound of the title (5.06 g, 52% yield, 97.44% purity in LCMS) as an off-white solid.
[0286] [0286] 1H NMR (CDCl3) δ 8.23 (d, 1 H), 6.99 (dd, 1 H), 6.86 (s, 1 H), 6.71 (d, 1 H), 3 , 99 (s, 3 H), 3.67 (br s, 2 H), 3.00 (t, 2 H), 2.79 (t, 2 H) and 2.25-2.17 (m, 2 H).
[0287] [0287] Intermediate B: 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine
[0288] [0288] To a solution of phosgene (1.5 ml, 20 wt% toluene, 2.9 mmol) in toluene (40 ml) was added dropwise a solution of 7-fluoro-5- (2-methoxypyridine) -4-yl) -2,3-dihydro-1H-inden-4-amine (300 mg, 1.16 mmol) in toluene (20 mL) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, was concentrated in vacuo to provide the title compound as a brown oil (325 mg, 98%). The crude product was used directly in the next step without further purification.
[0289] [0289] 1H NMR (CDCl3) δ 8.24 (d, 1H), 6.95 (dd, 1H), 6.88 (s, 1H), 6.85 - 6.75 (m, 1H), 4 .00 (s, 3H), 3.15 - 2.95 (m, 4H), 2.32 - 2.12 (m, 2H).
[0290] [0290] Intermediate A12: 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) picolinonitrile
[0291] [0291] To a solution of phosgene (1.7 mL, 20 wt% toluene, 3.2 mmol) in toluene (40 mL) was added dropwise a solution of 4- (4-amino-2,3 -dihydro-1H-inden-5-yl) picolinonitrile (Intermediate A5) (300 mg, 1.3 mmol) in toluene (20 mL) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, was concentrated in vacuo to provide the title compound as a brown oil (333 mg, 100%). The crude product was used directly in the next step without further purification.
[0292] [0292] 1H NMR (CDCl3) δ 8.75 (dd, 1H), 7.81 (dd, 1H), 7.63 (dd, 1H), 7.22 - 7.08 (m, 2H), 3 , 04 (m, 4H), 2.23 (m, 2H),
[0293] [0293] Intermediate A13: 4- (4-Isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine
[0294] [0294] Step A: 5- (Pyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
[0295] [0295] The 5-bromo-2,3-dihydro-1H-inden-4-amine (1.2 g, 5.7 mmol) was dissolved in dioxane (25 ml). A solution of potassium carbonate (3.1 g, 23 mmol) in water (6 mL) and pyridin-4-ylboronic acid (0.83 g, 6.8 mmol) was added. The mixture was degassed with nitrogen for 20 minutes before Pd (dppf) Cl2. DCM (0.74 g, 0.91 mmol) was added. The reaction mixture was heated to 77 ° C for 2 hours. Then, the mixture was cooled to room temperature and filtered over Celite with DCM (100 ml) and water (25 ml). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to provide a brown oil (3.3g). The crude product was purified by chromatography on silica gel (80 g column, 0-100% EtOAc / heptane) to provide the title compound (0.75 g, 63% yield) as a pale yellow crystalline solid.
[0296] [0296] 1H NMR (CDCl3) δ 8.72 - 8.54 (m, 2H), 7.50 - 7.37 (m, 2H), 6.97 (d, 1H), 6.78 (d, 1H), 3.72 (s, 2H), 2.96 (t, 2H), 2.77 (t, 2H), 2.18 (m, 2H).
[0297] [0297] Step B: 4- (4-Isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine
[0298] [0298] To a solution of phosgene (1.1 mL, 20 wt% toluene, 2.06 mmol) in toluene (40 mL) was added dropwise a solution of 5- (pyridin-4-yl) - 2,3-dihydro-1H-inden-4-amine (175 mg, 0.83 mmol) in toluene (20 mL) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling to room temperature, a yellow precipitate formed. The solid was filtered and dried in vacuo to provide the title compound as a yellow solid (145 mg, 74% yield). The crude product was used directly in the next step without further purification.
[0299] [0299] 1H NMR (CDCl3) δ 8.76 (d, 2H), 8.04 (d, 2H), 7.26 - 7.08 (m, 2H), 3.08 (t, 4H), 2 , 26 (m, 2H).
[0300] [0300] Intermediate A14: 8-Isocyanate-1,2,3,5-tetrahydro-s-indacene
[0301] [0301] To a solution of phosgene (1.4 ml, 20% by weight of toluene, 2.6 mmol) in toluene (40 ml) was added dropwise a solution of 1,2,3,7-tetra- hydro-s-indacen-4-amine (180 mg 1.05 mmol) in toluene (20 ml) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, was concentrated in vacuo to provide the title compound as a brown oil (207 mg, 100% yield). The crude product was used directly in the next step without further purification.
[0302] [0302] 1H NMR (CDCl3) (mixture of isomers) δ 7.18, 7.12 (m, 1H), 6.94, 6.80 (m, 1H), 6.52, 6.50 (s, 1H), 3.38, 3.34 (m, 2H), 2.95 (m, 4H), 2.16 (m, 2H).
[0303] [0303] Intermediate A15: 5-Chlorine-2-isocyanate-1,3-diisopropylbenzene
[0304] [0304] 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. After cooling, the mixture was concentrated in vacuo to provide the title compound as an orange oil (0.111 g, 94% yield).
[0305] [0305] 1H NMR (CDCl3) δ 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H). Intermediate P3: 1- (Prop-2-in-1-yl) piperidine-4-sulfonamide
[0306] [0306] To a mixture of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.), Potassium carbonate (4.0 equiv., 4.0 mmol, 552 mg) and acetonitrile (10 ml) propargyl bromide (0.1 ml, 1.0 mmol, 1.0 equiv.) was added. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and the crude material was suspended in methanol, coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to phase flash chromatography. normal using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (115 mg, 56% yield).
[0307] [0307] 1H NMR (CDCl3): δ 4.42 (br s, 1 H), 3.38 (s, 2 H), 3.05 (d, 2 H), 2.95 (m, 1 H) , 2.12 (m, 4 H) and 1.95 (m, 2 H).
[0308] [0308] Intermediate P4: 1- (2,2,2-Trifluoroacetyl) piperidine-4-sulfonamide
[0309] [0309] To a suspension of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.) And triethylamine (0.35 mL, 2.5 mmol, 2.5 equiv.) In acetonitrile (10 ml) was added trifluoroacetic anhydride (0.14 ml, 1.0 mmol, 1.0 equiv.). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and subjected to normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (ratio 1: 1) to provide the title compound (61 mg, 23% yield).
[0310] [0310] 1H NMR (CDCl3): δ 4.73 (d, 1 H), 4.52 (s, 2 H), 4.20 (d, 1 H), 3.21 (t, 2 H), 2.91 (t ,, 1 H), 2.37 (d, 2 H) and 1.95 (m, 2 H).
[0311] [0311] Intermediate P5: N-iso-Propyl-4-sulfamoylpiperidine-1-carboxamide
[0312] [0312] To a suspension of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.), 4-dimethylaminopyrimidine (12 mg, 0.1 mmol, 0.1 equiv.) And triethylamine (0.34 ml, 2.5 mmol, 2.5 equiv.) isopropyl isocyanate (0.1 ml, 1.0 mmol, 1.0 equiv) was added. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated in Agilent's Hydromatrix (a high-purity inert diatomite sorbent) and purified by normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (ratio 1: 1) to provide the title compound (55 mg, 22% yield).
[0313] [0313] 1H NMR (CDCl3): δ 4.45 (br s, 1 H), 4.22 (m, 1 H), 4.10 (d, 2 H), 3.98 (m, 1 H) , 3.10 (m, 1 H), 2.81 (t, 2 H), 2.20 (d, 2 H), 1.80 (m, 2 H) and 1.19 (d, 6 H) .
[0314] [0314] Intermediate P6: 1-Ethylpiperidine-4-sulfonamide
[0315] [0315] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) using ethyl iodide instead of propargyl bromide. The crude product was coated on Agilent's Hydromatrix (a high purity inert diatomite sorbent) and subjected to normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (1: 1 ratio) as the eluent to provide the compound holder contaminated with triethylamine hydrochloride (50 mg, 26% yield). The crude product was used as such in the preparation of examples.
[0316] [0316] 1H NMR (CDCl3): δ 5.05 (br s, 2 H), 3.10 (m, 2 H), 2.95 (m, 1 H), 2.45 (m, 2 H) , 2.20 (d, 2 H), 1.95 (m, 4 H) and 1.08 (t, 3 H).
[0317] [0317] Intermediate P7: 1-Acetylpiperidine-4-sulfonamide
[0318] [0318] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4), except that the suspension was cooled to 0 ° C and then acetic anhydride was added instead trifluoroacetic anhydride. The reaction mixture was warmed to room temperature overnight. The crude product was coated on Agilent's Hydromatrix (a high purity inert diatomite sorbent) and subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol as the eluent to provide the compound titrator as a mixture with triethylamine hydrochloride salt (139 mg, 67% yield). The crude product was used as such in the preparation of examples.
[0319] [0319] 1H NMR (CDCl3): δ 4.90 (m, 3 H), 3.99 (d, 1 H), 3.10 (m, 2 H), 2.60 (t, 1 H), 2.10 (t, 2 H), 2.05 (s, 3 H) and 1.75 (m, 2 H).
[0320] [0320] Intermediate P8: 1- (Cyclopropanecarbonyl) piperidine-4-sulfonamide
[0321] [0321] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4), except that cyclopropanecarbonyl chloride (1.0 equiv.) Was used instead of trifluoroacetic anhydride. The crude product was coated on Agilent's Hydromatrix and subjected to normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (1: 1 ratio) as eluant to provide the title compound (84 mg, 36% yield) .
[0322] [0322] 1H NMR (CDCl3): δ 4.80 (br s, 1 H), 4.58 (s, 2 H), 4.40 (br s, 1 H), 3.18 (m, 2 H ), 2.64 (br s, 1 H), 2.25 (br s, 2 H), 1.78 (m, 3 H), 1.00 (m, 2 H) and 0.79 (m, 2 H).
[0323] [0323] Intermediate P9: 1- (Cyanomethyl) piperidine-4-sulfonamide
[0324] [0324] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) using acetonitrile bromine instead of propargyl bromide to provide the title compound as a solid (40% Yield).
[0325] [0325] 1H NMR (DMSO-d6): δ = 6.71 (s, 2 H), 3.73 (s, 2 H), 2.89 (d, 2 H), 2.79 (m, 1 H), 2.19 (t, 2 H), 1.99 (d, 2 H) and 1.60 (m, 2 H).
[0326] [0326] Intermediate P10: 1-Propionylpiperidine-4-sulfonamide
[0327] [0327] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4) using propionic anhydride instead of trifluoroacetic anhydride to provide the title compound as a solid (71%).
[0328] [0328] 1H NMR (CD3OD): δ = 4.67 (d, 1 H), 4.05 (d, 1 H), 3.17 (m, 2 H), 2.65 (t, 1 H) , 2.42 (q, 2 H), 2.18 (t, 2 H), 1.65 (m, 2 H) and 1.10 (t, 3 H).
[0329] [0329] Intermediate P11: 1-iso-Butyrylpiperidine-4-sulfonamide
[0330] [0330] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4) using isobutyric anhydride instead of trifluoroacetic anhydride to provide the title compound contaminated with triethylamine hydrochloride (64% yield ).
[0331] [0331] 1H NMR (CDCl3): δ = 4.83 (d, 1 H), 4.63 (s, 2 H), 4.10 (d, 1 H), 3.10 (m, 2 H) , 2.79 (m, 1 H) 2.60 (t, 1 H), 2.14 (m, 2 H), 2.76 (m, 2 H) and 1.16 (d, 6 H).
[0332] [0332] Intermediate P12: 1- (2-Methoxyacetyl) piperidine-4-sulfonamide
[0333] [0333] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4) using 2-methoxyacetyl chloride instead of cyclopropanecarbonyl chloride to provide the title compound contaminated with triethylamine hydrochloride ( 55% yield).
[0334] [0334] 1H NMR (CDCl3): δ = 5.37 (bs, 2 H), 4.72 (d, 1 H), 4.10 (m, 3 H), 3.41 (s, 3 H) , 3.16 (m, 2 H), 2.64 (t, 1 H), 2.23 (d, 2 H) and 1.79 (m, 2 H).
[0335] [0335] Intermediate P13: Methyl 4-sulfamylpiperidine-1-carboxylate
[0336] [0336] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4) using methyl chloroformate instead of cyclopropanecarbonyl chloride to provide the title compound as a solid (10% yield ).
[0337] [0337] 1H NMR (CDCl3): δ = 4.49 (s, 2 H), 4.33 (bs, 2 H), 3.72 (s, 3 H), 3.07 (m, 1 H) , 2.80 (t, 2 H), 2.19 (d, 2 H) and 1.77 (m, 2 H).
[0338] [0338] Intermediate P14: 1-Cyclobutylpiperidine-4-sulfonamide
[0339] [0339] To a suspension of piperidine-4-sulfonamide hydrochloric acid (157 mg, 0.79 mmol, 1.0 equiv.) And triethylamine (0.12 mL, 0.86 mmol, 1.1 equiv.) In acetonitrile (10 mL) was added cyclobutanone (61 µL, 0.82 mmol 1.05 equiv.) followed by sodium triacetoxyborohydride (207 mg, 0.98 mmol, 1.25 equiv.). After allowing to stir overnight, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated in hydromatrix and then purified by normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (1: 1) as eluant to provide the title compound contaminated with trimethylamine hydrochloride (110 mg product, 64% yield).
[0340] [0340] 1H NMR (CDCl3): δ = 4.76 (bs, 2 H), 2.98 (m, 3 H), 2.78 (m, 1 H), 2.19 (d, 2 H) , 2.00 (m, 2 H), 1.88 (m, 6 H) and 1.65 (m, 2 H).
[0341] [0341] Intermediate P15: 1-Ethylpiperidine-3-sulfonamide
[0342] [0342] Piperidine-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) was suspended in acetonitrile (10 mL) and potassium carbonate (1.75 g, 12.6 mmol) was added before mixing be stirred for 30 minutes. To the resulting slurry was added ethyl bromide (0.24 ml, 0.34 g, 3.2 mmol) and the mixture was stirred for 60 hours at room temperature. The reaction was concentrated in vacuo and then purified by column chromatography (40 g Silicycle FLH-R10030B-ISO40 cartridge, 5-25% methanol in DCM) to provide the title compound (0.11 g, 0.57 mmol, 18% yield).
[0343] [0343] 1H NMR (1: 1 CD3OD: CDCl3): δ 3.36 (m, 2 H), 3.10 (m, 1 H), 2.92 (bd, 1 H), 2.56 (q , 2 H), 2.22 (bd, 1 H), 2.11 (t, 1 H), 1.88 (m, 2 H), 1.58 (m, 2 H) and 1.10 (t , 3 H). Intermediate P16: 1-Propylpiperidine-4-sulfonamide
[0344] [0344] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from 1-bromopropane and piperidine-4-sulfonamide hydrochloric acid. This provided the crude title compound (44 mg, 40% yield) which was used without purification.
[0345] [0345] 1H NMR (CDCl3): δ = 3.10 (m, 3 H), 2.38 (m, 2 H), 2.20 (m, 2 H), 2.00 (m, 4 H) , 1.25 (m, 2 H) and 0.95 (t, 3 H).
[0346] [0346] Intermediate P17: 1- (Oxetan-3-yl) piperidine-4-sulfonamide
[0347] [0347] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 3-oxetanone and piperidine-4-sulfonamide hydrochloric acid (130 mg, 59% yield).
[0348] [0348] 1H NMR (DMSO-d6): δ = 6.75 (s, 2 H), 4.49 (t, 2 H), 4.38 (t, 2 H), 3.38 (m, 2 H), 2.79 (m, 2 H), 1.98 (d, 2 H), 1.79 (t, 2 H) and 1.59 (m, 2 H).
[0349] [0349] Intermediate P18: 2- (4-Sulfamoylpiperidin-1-yl) methyl acetate
[0350] [0350] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) using methyl bromoacetate instead of propargyl bromide (91 mg, 39% yield).
[0351] [0351] 1H NMR (DMSO-d6): δ = 6.70 (s, 2 H), 3.60 (s, 3 H), 3.19 (s, 2 H), 2.93 (d, 2 H), 2.76 (m, 1 H), 2.18 (t, 2 H), 1.93 (d, 2 H) and 1.59 (m, 2 H).
[0352] [0352] Intermediate P19: 1-Cyclopropylpiperidine-4-sulfonamide
[0353] [0353] Prepared as described for 1-cyclopropylpyrrolidine-3-sulfonamide (Intermediate P30) from piperidine-4-sulfonamide hydrochloric acid and triethylamine (1.1 equiv.) Was added to the suspension. This provides the title compound (150 mg, 73% yield) which was used as such without further purification.
[0354] [0354] 1H NMR (DMSO-d6): δ = 6.67 (s, 2 H), 2.98 (m, 2 H), 2.77 (m, 1 H), 2.15 (t, 2 H), 1.92 (m, 2 H), 1.52 (m, 3 H), 0.23 (m, 2 H) and 0.39 (m, 2 H).
[0355] [0355] Intermediate P20: 1- (1-Ethylazetidin-3-yl) piperidine-4-sulfonamide
[0356] [0356] A suspension of 1- (azetidin-3-yl) piperidine-4-sulfonamide dihydrochloride (145 mg, 0.45 mmol) in acetonitrile (5.8 mL) was stirred with triethylamine (0.13 mL, 95 mg, 0.94 mmol) for 30 minutes. To this was added acetaldehyde (0.03 ml, 25 mg, 0.6 mmol) and sodium triacetoxyborohydride (122 mg, 0.56 mmol). Stirring was continued for 20 hours and then the mixture concentrated in vacuo. The residue was dissolved in methanol / dichloromethane (1: 1) and purified by chromatography (40 g Silicycle SiO2 cartridge through a syringe filter and eluted with 5-30% 3.5 N ammonia in methanol / dichloromethane) to provide the title compound (73 mg 0.28 mmol, 63% yield).
[0357] [0357] 1H NMR (DMSO-d6): δ = 6.71 (br s, 2 H), 3.49 (m, 4 H), 2.89 (m, 3 H), 2.77 (m, 3 H), 1.95 (br d, 2 H), 1.77 (m, 2 H), 1.57 (dq, 2 H) and 0.89 (t, 3 H).
[0358] [0358] Intermediate P21: 1- (Clobutanocarbonyl) piperidine-4-sulfonamide
[0359] [0359] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4) using cyclobutanocarbonyl chloride instead of trifluoroacetic anhydride to provide the title compound (158 mg, 64% yield) .
[0360] [0360] 1H NMR (CDCl3): δ = 4.81 (d, 1 H), 4.58 (s, 2 H), 3.84 (d, 1 H), 3.24 (m, 1 H) , 3.18 (m, 1 H), 3.01 (t, 1 H), 2.60 (t, 1 H), 2.37 (m, 2 H), 2.20 (m, 4 H) , 1.99 (m, 1 H), 1.89 (m, 1 H) and 1.72 (m, 2 H). Intermediate P22: N-Ethyl-4-sulfamoylpiperidine-1-carboxamide
[0361] [0361] To a suspension of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.) And triethylamine (0.34 mL, 2.5 mmol, 2.5 equiv.) In acetonitrile (10 mL) was added ethyl isocyanate (79 µL, 1.0 mmol, 1.0 equiv.). The reaction mixture was stirred overnight and then concentrated in vacuo. The crude product was coated with Agilent's Hydromatrix and then subjected to normal phase flash chromatography on silica gel using dichloromethane and a mixture of methanol and triethylamine (1: 1 ratio) to provide the title compound (141 mg, 60% yield) that was used without further purification.
[0362] [0362] 1H NMR (DMSO-d6): δ = 6.78 (br s, 2 H), 4.04 (d, 2 H), 2.98 (m, 3 H), 2.64 (t, 2 H), 1.91 (d, 2 H), 1.39 (m, 2 H) and 0.98 (t, 3 H). Intermediate P23: N-Methyl-4-sulfamoylpiperidine-1-carboxamide
[0363] [0363] Prepared as described for N-isopropyl-4-sulfamoyl-piperidine-1-carboxamide (Intermediate P5) from piperidine-4-sulfonamide hydrochloric acid and N-methyl-1H-imidazole-1-carboxamide, but it was not necessary 4-dimethylaminopyrimidine. The title compound (12 mg, 5% yield) was used without purification.
[0364] [0364] 1H NMR (CDCl3): δ = 4.18 (d, 2 H), 3.18 (m, 1 H), 2.78 (m, 5 H), 2.20 (m, 2 H) and 1.75 (m, 2 H). Intermediate P24: 1- (Methylsulfonyl) piperidine-4-sulfonamide
[0365] [0365] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4) from piperidine-4-sulfonamide hydrochloric acid and methanesulfonic anhydride. The title compound (18 mg, 7% yield) was used without purification.
[0366] [0366] 1H NMR (CD3OD): δ = 3.90 (m, 2 H), 3.08 (m, 2 H), 2.82 (m, 4 H), 2.23 (d, 2 H) and 1.83 (m, 2 H).
[0367] [0367] Prepared as described for N-isopropyl-4-sulfamoyl-piperidine-1-carboxamide (Intermediate P5) from ethyl isocyanate and pyrrolidine-3-sulfonamide, but 4-dimethylaminopyrimidine or triethylamine was not required. The title compound (13 mg, 5% yield) was used crude without purification.
[0368] [0368] 1H NMR (CD3OD): δ = 3.81 (m, 1 H), 3.57 (m, 1 H), 3.39 (m, 1 H), 3.19 (m, 4 H) , 2.38 (m, 2 H) and 1.10 (t, 3 H).
[0369] [0369] Intermediate P26: N-iso-Propyl-3-sulfamoylpiperidine-1-carboxamide
[0370] [0370] Prepared as described for N-isopropyl-4-sulfamoyl-piperidine-1-carboxamide (Intermediate P5) from isopropyl isocyanate and piperidine-3-sulfonamide hydrochloride to provide the title compound (0.11 g, 0.44 mmol, 41% yield).
[0371] [0371] 1H NMR (CD3OD): δ = 3.85 (m, 2 H), 2.98 (m, 2 H), 2.77 (br t, 1 H), 2.25 (br d, 1 H), 2.00 (s, 2 H), 1.65-1.90 (m, 2 H) and 1.13 (d, 6 H). Intermediate P27: 1-Methylpyrrolidine-3-sulfonamide
[0372] [0372] To a suspension of pyrrolidine-3-sulfonamide (150 mg, 1.0 mmol, 1.0 equiv.) And formaldehyde (37% in water stabilized with methanol; 78 µl, 1.05 mmol, 1.05 equiv. .) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (265 mg, 1.25 mmol, 1.25 equiv.). The reaction mixture was stirred for 5 days at room temperature and then concentrated in vacuo. The crude material was dissolved in methanol, coated in hydromatrix and then subjected to normal phase flash chromatography using dichloromethane and a mixture of triethylamine: methanol (ratio 1: 1) as the eluent to provide the impure title compound (80 mg , 49% yield) that was used as such in additional reactions.
[0373] [0373] 1H NMR (CD3OD): δ = 3.78 (m, 1 H), 3.18 (m, 3 H), 2.86 (m, 2 H), 2.70 (m, 1 H) and 2.43 (s, 3 H). Intermediate P28: 1-Ethylpyrrolidine-3-sulfonamide
[0374] [0374] Prepared as described for 1-ethylpiperidine-4-sulfonamide (Intermediate P6) from pyrrolidine-3-sulfonamide and ethyl iodide. The title compound (75 mg, 42% yield) was used without further purification.
[0375] [0375] 1H NMR (CD3OD): δ = 3.77 (m, 1 H), 3.10 (t, 1 H), 2.79 (m, 2 H), 2.57 (m, 3 H) , 2.19 (m, 2 H) and 1.16 (t, 3 H). Intermediate P29: 1-Acetylpyrrolidine-3-sulfonamide
[0376] [0376] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4) from acetic anhydride (1.0 equiv.) And pyrrolidine-3-sulfonamide. The title compound (75 mg, 39% yield) was used without purification.
[0377] [0377] 1H NMR (CD3OD): δ = 3.89 (m, 2 H), 3.78 (m, 2 H), 3.62 (m, 1 H), 2.41 (m, 2 H) and 2.08 (s, 3 H). Intermediate P30: 1-Cyclopropylpyrrolidine-3-sulfonamide
[0378] [0378] To a suspension of pyrrolidine-3-sulfonamide (150 mg, 1.00 mmol) and 1- (ethoxycyclopropoxy) trimethylsilane (0.4 mL, 2.0 mmol, 2.0 equiv.) In tetrahydrofuran (5 mL ) and methanol (5 ml) were added acetic acid (0.12 ml, 2.2 mmol, 2.2 equiv.) followed by sodium cyanoborohydride (94 mg, 1.5 mmol, 1.5 equiv.) . The reaction mixture was stirred overnight and then concentrated in vacuo. The crude was dissolved in methanol, coated in hydromatrix and then subjected to normal phase flash chromatography using dichloromethane and a mixture of triethylamine: methanol (1: 1 ratio) as the eluent to provide the title compound (75 mg, 39 % of yield).
[0379] [0379] 1H NMR (DMSO-d6): δ = 6.79 (s, 2 H), 3.57 (m, 1 H), 2.98 (t, 1 H), 2.80 (t, 1 H), 2.71 (m, 1 H), 2.58 (q, 1 H), 2.01 (q, 2 H), 1.64 (m, 1 H), 0.28 (m, 2 H) and 0.38 (m, 2 H). Intermediate P31: N, N-Dimethyl-3-sulfamoylpyrrolidine-1-carboxamide
[0380] [0380] To a solution of carbonyldiimidazole (269 mg, 1.66 mmol) in acetonitrile (10 mL) was added dimethylamine hydrochloride (122 mg, 1.55 mmol, 0.9 equiv.). The resulting solution was allowed to stir for 1.5 hours at room temperature, after which triethylamine (0.3 ml, 2.0 mmol, 1.2 equiv.) And pyrrolidine-3-sulfonamide (250 mg, 1 ml) were added. , 66 mmol). The reaction mixture was stirred for 3 hours before adding extra triethylamine (0.3 mL, 2.0 mmol, 1.2 equiv.) To the suspension. After stirring overnight, more carbonyldiimidazole (269 mg, 1.66 mmol, 1.0 equiv.) And 2 M dimethylamine in tetrahydrofuran (0.83 mL, 1.66 mmol, 1.0 equiv) were added. The reaction mixture was heated to 50 ° C overnight and then more dimethylamine (2 M in tetrahydrofuran; 0.83 ml, 1.66 mmol, 1.0 equiv) was added. After heating overnight, more dimethylamine (2M in tetrahydrofuran; 4.2 ml, 8.3 mmol, 5.0 equiv.) Was added. The reaction mixture was again heated overnight. After cooling, the reaction mixture was concentrated in vacuo. The crude was dissolved in methanol, coated in hydromatrix and then subjected to normal phase flash chromatography on silica gel using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to provide the title compound, not yet completely pure (35 mg, 15% yield). The product was used as such.
[0381] [0381] 1H NMR (DMSO-d6): δ = 7.19 (s, 2 H), 3.84 (m, 2 H), 3.79 (m, 1 H), 3.58 (m, 2 H), 2.73 (s, 6 H) and 2.02 (m, 2 H). Intermediate P32: 1-iso-propylpyrrolidine-3-sulfonamide
[0382] [0382] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-sulfonamide and acetone, but no triethylamine was required. The title compound (130 mg, 67% yield) was used without purification.
[0383] [0383] 1H NMR (CD3OD): δ = 3.76 (m, 1 H), 3.23 (t, 1 H), 2.92 (m, 1 H), 2.90 (m, 1 H) , 2.62 (m, 1 H), 2.52 (m, 1 H), 2.21 (m, 2 H) and 1.17 (m, 6 H).
[0384] [0384] Intermediate P33: Azetidine-3-sulfonamide
[0385] [0385] Step A: Benzyl 3-Sulfamoylazetidine-1-carboxylate
[0386] [0386] A solution of ammonium hydroxide (25% in water; 22 mL, 73 mmol, 10.0 equiv.) Was added to benzyl 3- (chlorosulfonyl) azetidine-1-carboxylate (2.1 g, 7, 3 mmol, 1.0 equiv.). The suspension was stirred at room temperature for 20 minutes to provide a clear solution and the reaction mixture was then acidified to pH 8-9, using hydrochloric acid (2M, aqueous) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound (1.52 g, 5.62 mmol, 77% yield) which was used without further purification.
[0387] [0387] 1H NMR (CDCl3): δ = 7.38 (m, 5 H), 5.18 (s, 4 H), 4.40 (m, 4 H) and 4.00 (m, 1 H) .
[0388] [0388] Step B: Azetidine-3-sulfonamide
[0389] [0389] A suspension of benzyl 3-sulfamoylazetidine-1-carboxylate (1.52 g, 5.62 mmol, 1.0 equiv.) In ethyl acetate (30 mL) was washed with a stream of nitrogen before Pd / C (10% by weight loading, 595 mg, 0.56 mmol, 0.1 equiv.) Was added and the flask was then washed with hydrogen. The reaction mixture was heated to reflux for 20 hours under a hydrogen atmosphere (flask). After cooling, the suspension was filtered over Celite® 545 and Celite was washed extensively with methanol. The filtrates were combined and concentrated in vacuo to provide the title compound (541 mg, 3.97 mmol, 70% yield) which was used without further purification.
[0390] [0390] 1H NMR (DMSO-d6): δ = 6.91 (br s, 2 H), 4.08 (m, 1 H), 3.74 (t, 2 H) and 3.63 (t, 2 H).
[0391] [0391] Intermediate P34: Quinuclidine-3-sulfonamide
[0392] [0392] Step A: (Quinuclidin-3-yl) ethanothioate
[0393] [0393] To a solution of triphenylphosphine (4.12 g, 15.7 mmol, 2.0 equiv.) In tetrahydrofuran (64 mL) cooled in an ice bath was added diisopropyl azodicarboxylate (3.1 mL, 15.7 mmol, 2.0 equiv.). The light yellow solution was stirred for 10 minutes, during which time a precipitate appeared. 3-quinuclidinol (1.0 g, 7.86 mmol, 1.0 equiv.) Was added, followed by thioacetic acid (1.2 ml, 15.7 mmol, 2.0 equiv.) And then the ice bath was removed and the green solution was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by normal phase flash chromatography using dichloromethane and methanol as the eluent to provide the title compound (581 mg, 40% yield).
[0394] [0394] 1H NMR (CDCl3): δ = 3.71 (m, 1 H), 2.97 (m, 5 H), 2.77 (dd, 1 H), 2.33 (s, 3 H) 1.92 (m, 1 H), 1.81 (m, 3 H) and 1.57 (m, 1 H).
[0395] [0395] Step B: Quinuclidine-3-sulfonamide
[0396] [0396] To a suspension of N-chlorosuccinimide (1.7 g, 12.5 mmol, 4.0 equiv.) In acetonitrile (7.0 mL) was added hydrochloric acid (aqueous, 2 M, 1.2 mL, 2.50 mmol, 0.8 equiv.). The solution was cooled in an ice bath, after which a solution of S- (quinuclidin-3-
[0397] [0397] 1H NMR (DMSO-d6): δ = 3.74 (m, 1 H), 3.55 (m, 4 H), 3.01 (m, 1 H), 2.65 (m, 1 H), 2.38 (m, 2 H), 2.23 (m, 2 H) and 2.01 (m, 1 H). Intermediate P35: 1- (1-Ethylpiperidin-4-yl) pyrrolidine-3-sulfonamide
[0398] [0398] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-sulfonamide and 1-ethyl-4-piperidone, but triethylamine was not required. The crude product was purified by flash flash chromatography using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluant to provide the title compound (217 mg, 83% yield).
[0399] [0399] 1H NMR (DMSO-d6): δ = 6.81 (s, 2 H), 3.58 (m, 1 H), 3.00 (m, 3 H), 2.65 (m, 4 H), 2.44 (m, 3 H), 2.08 (br s, 1 H), 2.03 (m, 2 H), 1.82 (m, 2 H), 1.49 (br s , 2 H) and 1.07 (t, 3 H).
[0400] [0400] Intermediate P36: (1R *, 3R *, 5S *) - 8-iso-Propyl-8-azabicyclo [3.2.1] octane-3-sulfonamide
[0401] [0401] Step A: (1R *, 3S *, 5S *) - 3 - ((Methylsulfonyl) oxy) -8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate
[0402] [0402] To a mixture of tert-butyl 3-exohydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate (3.0 g, 13.2 mmol, 1.0 equiv.) And N, N-diisopropylethylamine (3.0 mL, 17.2 mmol, 1.3 equiv.) In dichloromethane (66 mL) was added methanesulfonyl chloride (1.1 mL, 14.5 mmol, 1.1 equiv.). The reaction mixture was stirred for 2.5 hours at room temperature and then the solution was washed twice with water, once with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound. (4.08 g, 13.2 mmol, quantitative yield).
[0403] [0403] 1H NMR (CDCl3): δ = 5.08 (m, 1 H), 4.28 (br s, 2 H), 3.00 (s, 3 H), 2.10 (br d, 4 H), 1.82 (br s, 2 H), 1.63 (d, 2 H) and 1.44 (s, 9 H).
[0404] [0404] Step B: (1R *, 3R *, 5S *) - 3- (Acetylthio) -8- azabicyclo [3.2.1] tert-butyl octane-8-carboxylate
[0405] [0405] To a solution of tert-butyl (1R *, 3S *, 5S *) - 3- ((methylsulfonyl) oxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (4.08 g, 13.2 mmol, 1.0 equiv.) In dimethylformamide (50 ml) and acetonitrile (13 ml) potassium thioacetate (4.52 g, 39.6 mmol, 3.0 equiv) was added. The reaction mixture was heated to reflux for 1 hour and then allowed to cool to room temperature. Brine and ethyl acetate were added to the solution and, after complete mixing, the organic layer was separated, washed twice with brine, dried (over sodium sulfate), filtered and concentrated in vacuo. The crude material was purified by normal phase flash chromatography using ethyl acetate and heptane as the eluant to provide the title compound (2.95 g, 78% yield).
[0406] [0406] 1H NMR (CDCl3): δ = 4.20 (br s, 2 H), 3.98 (t, 1 H), 2.42 (br s, 2 H), 2.28 (s, 3 H), 1.98 (m, 4 H), 1.64 (m, 2 H) and 1.44 (s, 9 H).
[0407] [0407] Step C: (1R *, 3R *, 5S *) - 3-Sulfamoyl-8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate
[0408] [0408] To a solution of tert-butyl (1R *, 3R *, 5S *) - 3- (acetylthio) -8-azabicyclo [3.2.1] octane-8-carboxylate (2.95 g, 10.3 mmol, 1.0 equiv.) in water (10.3 ml) and acetic acid (103 ml) N-chlorosuccinimide (4.1 g, 30.9 mmol, 3.0 equiv) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated to about 20-30 ml before the resulting solution was added dropwise to an ammonium hydroxide solution (25% by weight of water; 400 ml) and then stirred for 10 minutes at room temperature. The solution was then acidified with hydrochloric acid (aqueous, 1 M) to pH 7-8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo to provide the impure title compound (387 mg, 12% yield) which was used without further purification.
[0409] [0409] 1H NMR (CDCl3): δ = 4.33 (br s, 2 H), 3.11 (m, 1 H), 2.00 (m, 4 H), 1.82 (m, 2 H ), 1.64 (m, 2 H) and 1.44 (s, 9 H).
[0410] [0410] Step D: (1R *, 3R *, 5S *) - 8-azabicyclo [3.2.1] octane-3-sulfonamide hydrochloride
[0411] [0411] To a solution of tert-butyl (1R *, 3R *, 5S *) - 3-sulfamoyl-8-azabicyclo [3.2.1] octane-8-carboxylate (387 mg, 1.33 mmol, 1, 0 equiv.) In dichloromethane (10 ml) hydrochloric acid (4 M in dioxane, 3.3 ml, 13.3 mmol, 10.0 equiv) was added. The solution was stirred at room temperature for 1.5 hours. Then the solvent was decanted and dichloromethane was added and then decanted again. This provided the impure title compound (200 mg, 66% yield) which was used without purification.
[0412] [0412] 1H NMR (DMSO-d6): δ = 9.40 (br s, 1 H), 9.20 (br s, 1 H), 6.93 (br s, 2 H), 4.01 ( m, 2 H), 3.32 (m, 1 H), 2.18 (m, 1 H), 1.98 (m, 6 H) and 1.79 (m, 1 H).
[0413] [0413] Step E: (1R *, 3R *, 5S *) - 8-iso-Propyl-8-azabicyclo [3.2.1] octane-3-sulfonamide
[0414] [0414] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R *, 3R *, 5S *) - 8-azabicyclo [3.2.1] octane-3-sulfonamide and acetone hydrochloride . The crude compound was purified by normal phase flash chromatography using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to provide the title compound (22 mg, 21% yield) in an inhomogeneous state, which was used without further purification.
[0415] [0415] 1H NMR (DMSO-d6): δ = 6.61 (s, 2 H), 3.50 (s, 2 H), 3.12 (m, 2 H), 1.82 (m, 4 H), 1.50 (m, 4 H) and 0.97 (d, 6 H).
[0416] [0416] Intermediate P37: 1-iso-propylazetidine-3-sulfonamide
[0417] [0417] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide (Intermediate P33) and acetone, but triethylamine was not required. The title compound (12 mg, 6% yield) was used without purification.
[0418] [0418] 1H NMR (DMSO-d6): δ = 6.87 (br s, 2 H), 3.82 (m, 1 H), 3.39 (m, 2 H), 3.23 (t, 2 H), 2.32 (m, 1 H) and 0.81 (d, 6 H).
[0419] [0419] Intermediate P38: 1'-Ethyl- [1,4'-bipiperidine] -4-sulfonamide
[0420] [0420] A suspension of 4-piperidine sulfonamide hydrochloric acid (0.35 g, 1.6 mmol) in acetonitrile (14 mL) was stirred with triethylamine (0.17 g, 0.24 mL, 1.7 mmol ) for 30 minutes. To this was added 1-ethyl-4-piperidone (0.21 g, 0.23 ml, 1.6 mmol) and sodium triacetoxyborohydride (0.43 g, 2.0 mmol). Stirring was allowed to continue for 20 hours and then the solution was concentrated in vacuo. The crude material was suspended in a few ml of dichloromethane / methanol / 7 N ammonia in methanol (1: 1: 1) and purified by chromatography (40 g Silicycle SiO2 cartridge through a syringe filter eluting with 5-30% ammonia 3.5 N / methanol in dichloromethane) to provide the title compound (290 mg, 90% yield).
[0421] [0421] 1H NMR (CD3OD): δ = 3.09 (m, 4 H), 2.88 (m, 1 H), 2.52 (q, 2 H), 2.40 (m, 1 H) , 2.27 (m, 2 H), 2.15 (m, 4 H), 1.84 (m, 4 H), 1.64 (m, 2 H) and 1.13 (t, 3 H) .
[0422] [0422] Intermediate P39: 1-Methylazetidine-3-sulfonamide
[0423] [0423] Prepared as described for 1-methylpyrrolidine-3-sulfonamide (Intermediate P27) from azetidine-3-sulfonamide (Intermediate P33) and formaldehyde. The crude product was purified by normal phase flash chromatography on silica gel using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to provide the title compound (24 mg, 16% yield).
[0424] [0424] 1H NMR (CD3OD): δ = 4.08 (m, 1 H), 3.91 (t, 2 H), 3.87 (t, 2 H) and 2.54 (s, 3 H) .
[0425] [0425] Intermediate P40: 2-Ethyl-2-azaspiro [3.3] heptane-6-sulfonamide
[0426] [0426] Step A: 6 - ((Methylsulfonyl) oxy) -2-azaspiro [3.3] tert-butyl heptane-2-carboxylate
[0427] [0427] 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.
[0428] [0428] 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).
[0429] [0429] Step B: 6- (Acetylthio) -2-azaspiro [3.3] tert-butyl heptane-2-carboxylate
[0430] [0430] 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.
[0431] [0431] 1H NMR (CDCl3): δ = 3.96 (s, 2 H), 3.90 (m, 1 H), 3.86 (s, 2 H), 2.65 (m, 2 H) , 2.27 (s, 3 H), 2.18 (m, 2 H) and 1.42 (s, 9 H).
[0432] [0432] Step C: 6-Sulfamoyl-2-azaspiro [3.3] tert-butyl heptane-2-carboxylate
[0433] [0433] A mixture of 6- (acetylthio) -2-azaspiro [3.3] tert-butyl 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% yield). 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, 36% yield).
[0434] [0434] 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).
[0435] [0435] Step D: 2-Azaspiro [3.3] heptane-6-sulfonamide
[0436] [0436] 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.
[0437] [0437] 1H NMR (CD3OD): δ = 3.93 (s, 4 H), 3.66 (m, 1 H) and 2.64 (m, 4 H).
[0438] [0438] Step E: 2-Ethyl-2-azaspiro [3.3] heptane-6-sulfonamide
[0439] [0439] Prepared according to the procedure described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from ethyl iodide and 2-azaspiro [3.3] heptane-6- sulfonamide. The crude material was purified by normal phase flash chromatography using ethyl acetate and methanol (9: 1) as 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).
[0440] [0440] 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).
[0441] [0441] Intermediate P41: 1- (1-iso-propylazetidin-3-yl) pyrrolidine-3-sulfonamide
[0442] [0442] Step A: 1- (azetidin-3-yl) pyrrolidine-3-sulfonamide dihydrochloride
[0443] [0443] To a solution of tert-butyl 3- (3-sulfamoylpyrrolidin-1-yl) azetidine-1-carboxylate (726 mg, 2.38 mmol, 1.0 equiv.) In dichloromethane (24 mL) hydrochloric acid in dioxane (4 M, 6.0 mL, 23.8 mmol, 10.0 equiv.). The reaction mixture was stirred for 1.5 hours and then concentrated in vacuo to provide the title compound as a dihydrochloride salt (774 mg, 2.38 mmol, 100% yield) which was used without purification.
[0444] [0444] 1H NMR (DMSO-d6): δ = 9.60 (br s, 1 H), 9.17 (br s, 1 H), 7.24 (s, 2 H), 4.34 (m , 4 H), 4.11 (m, 3 H), 3.91 (m, 2 H) and 2.23 (m, 4 H).
[0445] [0445] Step B: 1- (1-iso-Propylazetidin-3-yl) pyrrolidine-3-sulfonamide
[0446] [0446] Prepared as described for 1- cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 1- (azetidin-3-yl) pyrrolidine-3-sulfonamide dihydrochloride and acetone, but 2.5 equivalents of triethylamine was required. The crude compound was purified by flash flash chromatography using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluant to provide the title compound (94 mg, 38% yield).
[0447] [0447] 1H NMR (DMSO-d6): δ = 6.91 (s, 2 H), 3.58 (m, 1 H), 3.24 (t, 2 H), 2.98 (m, 1 H), 2.90 (m, 3 H), 2.52 (m, 2 H), 2.38 (q, 1 H), 2.21 (m, 1 H), 2.01 (m, 2 H) and 0.81 (d, 6 H).
[0448] [0448] Intermediate P42: (1R *, 3R *, 5S *) - 8-Ethyl-8-azabicyclo [3.2.1] octane-3-sulfonamide
[0449] [0449] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from iodoethane and (1R, 3R, 5S) -8-azabicycles [3.2.1] octane-3-sulfonamide hydrochloride. The title compound (36 mg, 41% yield) was used without further purification.
[0450] [0450] 1H NMR (DMSO-d6): δ = 6.63 (br s, 2 H), 3.97 (br s, 2 H), 3.10 (q, 2 H), 2.98 (br s, 1 H), 2.58 (m, 2 H), 2.30 (m, 2 H), 2.11 (m, 4 H) and 1.11 (m, 3 H).
[0451] [0451] Intermediate P43: 1-Ethylazetidine-3-sulfonamide
[0452] [0452] Prepared as described for 1-ethylpiperidine-4-sulfonamide (Intermediate P6) from azetidine-3-sulfonamide (Intermediate P33) and ethyl iodide. This provided the impure title compound (15 mg, 9% yield) which was used without further purification.
[0453] [0453] 1H NMR (CD3OD): δ = 4.11 (m, 1 H), 3.81 (t, 2 H), 3.62 (t, 2 H), 2.74 (q, 2 H) and 1.02 (t, 3 H).
[0454] [0454] Intermediate P44: 1- (2,2,2- Trifluoroacetyl) pyrrolidine-3-sulfonamide
[0455] [0455] Prepared as described for 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide (Intermediate P4) from pyrrolidine-3-sulfonamide and bis-trifluoroacetic anhydride. This provided the title compound (72 mg, 36% yield) which was used without purification.
[0456] [0456] 1H NMR (CD3OD): δ = 4.08 (m, 1 H), 3.91 (m, 3 H), 3.63 (m, 1 H), 2.45 (m, 1 H) and 2.38 (m, 1 H).
[0457] [0457] Intermediate P45: 1- (Cyclopropylmethyl) piperidine-3-sulfonamide
[0458] [0458] Prepared as described for 1-ethylpiperidine-3-sulfonamide (Intermediate P15) using piperidine-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) and iodomethyl-cyclopropane (0.29 mL, 0.58 g, 3.2 mmol) to provide the title compound (0.28 g, 1.26 mmol, 40% yield) after column purification.
[0459] [0459] 1H NMR (CDCl3): δ = 3.41 (br d, 1 H), 3.31 (m, 1 H), 2.96 (br d, 1 H), 2.44 (t, 1 H), 2.36 (d, 2 H), 2.20 (m, 2 H), 1.91 (m, 1 H), 1.71 (m, 2 H), 0.90 (m, 1 H), 0.57 (m, 2 H) and 0.15 (m, 2 H).
[0460] [0460] Intermediate P46: 1-Methylpiperidine-3-sulfonamide
[0461] [0461] Prepared as described for 1-ethylpiperidine-3-sulfonamide (Intermediate P15) using piperidine-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) and methyl iodide (0.20 mL, 0.45 g, 3.2 mmol) to provide the title compound (0.24 g 1.35 mmol, 43% yield). The crude product was used without further purification.
[0462] [0462] 1H NMR (CD3OD): δ = 3.2-3.4 (m, 3 H), 2.97 (br d, 1 H), 2.45 (s, 3 H), 2.38 ( br t, 1 H), 2.20 (m, 1 H), 1.90 (br d, 1 H) and 1.5-1.8 (m, 2 H).
[0463] [0463] Intermediate P47: benzyl 3-sulfamylazetidine-1-carboxylate
[0464] [0464] To a stirred solution of benzyl 3- (chlorosulfonyl) azetidine-1-carboxylate (2.0 g, 6.9 mmol) in dichloromethane (30 mL) at 0 ° C was added ammonia (7 N in methanol, 30 mL). The resulting mixture was stirred overnight, slowly warming to room temperature and then concentrated to a white solid, ground with THF and the resulting title compound isolated as a white solid by filtration (95% yield) and used without further purification.
[0465] [0465] 1H NMR (CD3OD): δ = 7.3 (m, 5 H), 5.05 (d, 2 H), 4.25 (m, 2 H), 4.13 (m, 2 H) and 2.47 (m, 1 H).
[0466] [0466] Intermediate P48: N, N-Dimethyl-4-sulfamoylpiperidine-1-carboxamide
[0467] [0467] To a solution of carbonyldiimidazole (162 mg, 1.0 mmol) in acetonitrile (10 mL) was added dimethylamine hydrochloride (81 mg, 1.0 mmol) and the solution was stirred overnight at room temperature. Triethylamine (0.42 ml, 3.0 mmol, 3.0 equiv.) And piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol) were added to the suspension. The reaction mixture was stirred overnight and additional portions of carbonyldiimidazole (162 mg, 1.0 mmol), triethylamine (0.42 mL, 3.0 mmol, 3.0 equiv.) And 2 M dimethylamine in tetrahydrofuran (0 , 5 mL, 1.0 mmol) were added. After stirring overnight, extra 2 M dimethylamine in tetrahydrofuran (2 ml, 4.0 mmol, 4.0 equiv.) Was added. The reaction mixture was then stirred at room temperature for 3 days, before being transferred to a microwave flask and an additional 2 M dimethylamine in tetrahydrofuran (2.0 mL, 4.0 mmol, 4.0 equiv.) Was added. The flask was heated to 50 ° C overnight and then concentrated in vacuo. The crude product was dissolved in methanol, coated in hydromatrix and then purified by normal phase flash chromatography using dichloromethane and a mixture of triethylamine and methanol (1: 1 ratio) as the eluant to provide the title compound (73 mg, 31% yield).
[0468] [0468] 1H NMR (DMSO-d6): δ = 6.72 (s, 2 H), 3.60 (d, 2 H), 2.98 (m, 1 H), 2.72 (m, 8 H), 1.94 (d, 2 H), 1.52 (m, 2 H).
[0469] [0469] Intermediate P49: 1- (1-Isopropyl-azetidin-3-yl) piperidine-4-sulfonamide
[0470] [0470] Step A: tert-butyl 3- (4-Sulfamoylpiperidin-1-yl) azetidine-1-carboxylate
[0471] [0471] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from piperidine-4-sulfonamide hydrochloride salt (0.35 g, 1.6 mmol) and 1-Boc-azetidinone
[0472] [0472] HPLC-MS: 100% (ELSD), M 319 +1 (ACPI pos.)
[0473] [0473] 1H NMR (Methanol-d4): δ = 4.37 (s, 2H), 3.94 (dd, J = 8.8, 7.2 Hz, 2H), 3.77 (dd, J = 9.0, 5.3 Hz, 2H), 3.09 (tt, J = 7.1, 5.3 Hz, 1H), 3.00 - 2.81 (m, 3H), 2.22 - 2 .08 (m, 2H), 1.98 - 1.70 (m, 4H), 1.41 (s, 9H).
[0474] [0474] Step B: 1- (azetidin-3-yl) piperidine-4-sulfonamide dihydrochloride
[0475] [0475] The tert-butyl 3- (4-sulfamoylpiperidin-1-yl) azetidine-1-carboxylate (0.23 g, 0.7 mmol) from step A was suspended in HCl in dioxane (4N, 9 mL, 36 mmol) and stirred for 20 hours at room temperature. The solvents were evaporated in vacuo and the residue was removed once with dioxane (25 ml) to provide the crude product (250 mg, quant.), Which was used as shown in the next step.
[0476] [0476] HPLC-MS: 97% (ELSD), M 291 +1 (ACPI pos.)
[0477] [0477] 1H NMR (Methanol-d4): δ = 4.72 - 4.57 (m, 2H), 4.44 - 4.28 (m, 3H), 3.61 (d, J = 11.7 Hz, 2H), 3.26 (dd, J = 11.1, 4.2 Hz, 2H), 3.01 (s, 1H), 2.44 (dd, J = 14.3, 3.1 Hz , 2H), 2.24 (t, 1H), 1.61 (s, 1H).
[0478] [0478] Step C: 1- (1-Isopropyl-azetidin-3-yl) piperidine-4-sulfonamide
[0479] [0479] Prepared according to the procedure described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 1- (azetidin-3-yl) piperidine-4-sulfonamide dihydrochloride (100 mg, 0.31 mmol) from step B and acetone (0.03 ml, 22 mg, 0.39 mmol) to provide the title compound as a white solid (70 mg, 87% yield) after column chromatography.
[0480] [0480] HPLC-MS: 59 + 40% (ELSD) showed two peaks both with M 262 + 1 (ACPI pos.)
[0481] [0481] 1H NMR (Methanol-d4): δ = 3.55 (t, J = 6.5 Hz, 2H), 3.02 - 2.82 (m, 6H), 2.49 (h, J = 6.2 Hz, 1H), 2.13 (ddd, J = 12.0, 4.2, 2.2 Hz, 2H), 1.88 (dd, J = 11.3, 2.1 Hz, 2H ), 1.77 (qd, J = 12.1, 3.5 Hz, 2H), 0.97 (d, J = 6.3 Hz, 6H).
[0482] [0482] Intermediate P50: 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 P51: 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 ion exchange resin
[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 P52: 1- (Pentan-3-yl) azetidine-3-sulfonamide
[0489] [0489] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 3-pentanone. The title compound (20 mg, 12% yield) was used without further purification.
[0490] [0490] 1H NMR (DMSO-d6): δ = 6.86 (s, 2 H), 3.82 (m, 1 H), 3.42 (t, 2 H), 3.21 (t, 2 H), 2.03 (m, 1 H), 1.24 (m, 4 H), 0.74 (m, 6 H).
[0491] [0491] Intermediate P53: 1-Ethyl-1,2,3,4-tetrahydroquinoline-3-sulfonamide
[0492] [0492] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 1,2,3,4-tetrahydroquinoline-3-sulfonamide, acetone and acetic acid, but triethylamine was not required. The title compound (27 mg, 11% yield) was used without further purification. The expected iso-propyl analog was not isolated.
[0493] [0493] 1H NMR (CDCl3): δ = 7.09 (m, 2H), 6.70 (m, 2H), 4.52 (br s, 2H), 3.60 (m, 3H), 3, 44 (m, 2H), 3.26 (m, 2H), 1.17 (t, 3H).
[0494] [0494] Intermediate P54: 1- (2,2,2-Trifluoroethyl) piperidine-4-sulfonamide
[0495] [0495] Step A: 1- (2,2,2-Trifluoroacetyl) piperidine-4-sulfonamide
[0496] [0496] A suspension of piperidine-4-sulfonamide hydrochloride salt (600 mg, 2.7 mmol) was stirred with triethylamine (0.75 mL, 0.54 g, 5.4 mmol) in acetonitrile (12 mL) for 30 minutes. To this paste was added trifluoroacetic anhydride (0.38 mL, 0.57 g, 2.7 mmol) and stirring was continued for 20 hours. The mixture was concentrated in vacuo and the residue dissolved in methanol, then applied to a silica column (40 g) and eluted with 0-30% methanol in DCM to provide 1- (2,2,2-trifluoroacetyl) piperidine- 4- sulfonamide (182 mg, 26% yield), contaminated with a bistrifluoroacetylated by-product. This was used for the next step as such.
[0497] [0497] HPLC-MS: 76% (ELSD), M 260 +1 (ACPI pos.).
[0498] [0498] HPLC-MS: 23% (ELSD), M 356 +1 (ACPI pos.) For the bistrifluoroacetylated by-product.
[0499] [0499] 1H NMR (Methanol-d4): δ = 7.39 (s, 1H), 4.64 - 4.47 (m, 1H), 4.10 (d, J = 13.1 Hz, 1H) , 3.51 (tt, J = 11.4, 4.0 Hz, 1H), 3.22 (dt, J = 12.6, 3.5 Hz, 2H), 2.87 (td, J = 13 , 0, 2.9 Hz, 1H), 2.21 (ddt, J = 20.3, 13.9, 3.2 Hz, 2H), 1.78 (ddtt, J = 24.0, 16.4 , 7.6, 4.4 Hz, 2H).
[0500] [0500] Step B: 1- (2,2,2-Trifluoroethyl) piperidine-4-sulfonamide
[0501] [0501] The 1- (2,2,2-trifluoroacetyl) piperidine-4-sulfonamide from step A (65 mg, 0.22 mmol) was dissolved in THF (3.25 mL) and cooled to 0 ° C. Borane-DMS adduct (94%, 9.9M, 0.10 mL, 1.01 mmol) was added dropwise to this solution at 0 ° C and then the mixture was heated to reflux for 4 hours and subsequently allowed to cool to room temperature over the weekend. The mixture was quenched with MeOH until there was no further evolution of the visible gas and then evaporated in vacuo and removed twice with methanol. Drying in vacuo provided the crude product as a clear oil (with a slight smell of DMS), which was purified by ISCO 5-30% MeOH (3.5N NH3) in DCM to provide the title compound (31 mg, 56 % of yield).
[0502] [0502] HPLC-MS: 100% (ELSD), M 246 +1 (ACPI pos.)
[0503] [0503] 1H NMR (Methanol-d4): δ = 3.16 - 3.00 (m, 4H), 2.88 (tt, J = 12.2, 3.8 Hz, 1H), 2.42 ( td, J = 12.0, 2.5 Hz, 2H), 2.08 (dt, J = 13.1, 2.9 Hz, 2H), 1.80 (qd, J = 12.4, 4, 1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 1H), 1.00 - 0.81 (m, 1H).
[0504] [0504] Intermediate P55: (1R *, 3S *, 5S *) - 8-iso-Propyl-8-azabicyclo [3.2.1] octane-3-sulfonamide
[0505] [0505] Step A: (1R *, 3R *, 5S *) - 3 - ((Methylsulfonyl) oxy) -8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate
[0506] [0506] Prepared as described for (1R *, 3S *, 5S *) - 3- ((methylsulfonyl) oxy) -8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate (intermediate P36 step A) from tert-butyl 3-endohydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate to provide the title compound (3.3 g, 81% yield).
[0507] [0507] 1H NMR (CDCl3): δ = 5.02 (t, 1H), 4.21 (br s, 2H), 3.00 (s, 3H), 2.03 (m, 8H), 1, 45 (s, 9H).
[0508] [0508] Step B: (1R *, 3S *, 5S *) - 3- (Acetylthio) -8- azabicyclo [3.2.1] tert-butyl octane-8-carboxylate
[0509] [0509] Prepared as described for tert-butyl (1R *, 3R *, 5S *) - 3- (acetylthio) -8-azabicyclo [3.2.1] octane-8-carboxylate (intermediate P36, step B) tert-butyl (1R *, 3R *, 5S *) - 3 - ((methylsulfonyl) oxy) -8-azabicyclo [3.2.1] octane-8-carboxylate to provide the title compound (1.65 g, 53% income).
[0510] [0510] 1H NMR (CDCl3): δ = 4.19 (br s, 2H), 3.87 (m, 1H), 2.28 (s, 3H), 1.98 (m, 2H), 1, 79 (d, 6H), 1.45 (s, 9H).
[0511] [0511] Step C: (1R *, 3S *, 5S *) - 3-Sulfamoyl-8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate
[0512] [0512] Prepared as described for (1R *, 3R *, 5S *) - tert-butyl 3-sulfamoyl-8-azabicyclo [3.2.1] octane-8-carboxylate (intermediate P36, step C) from ( 1R *, 3S *, 5S *) - 3- (acetylthio) -8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate, except that the crude title compound was purified by normal phase flash chromatography using heptane and ethyl acetate to provide the title compound (235 mg, 14% yield).
[0513] [0513] 1H NMR (CDCl3): δ = 4.50 (m, 2H), 3.11 (m, 1H), 2.03 (m, 4H), 1.68 (m, 4H), 1.46 (s, 9H).
[0514] [0514] Step D: (1R *, 3S *, 5S *) - 8-azabicyclo [3.2.1] octane-3-sulfonamide hydrochloride
[0515] [0515] Prepared as described for (1R *, 3R *, 5S *) - 8-azabicyclo [3.2.1] octane-3-sulfonamide hydrochloride (intermediate P36, step D) from (1R *, 3S * , 5S *) - tert-butyl 3-sulfamoyl-8-azabicyclo [3.2.1] octane-8-carboxylate to provide the title compound (203 mg, quantitative yield).
[0516] [0516] 1H NMR (DMSO-d6): δ = 9.28 (s, 1H), 9.11 (s, 1H), 6.90 (s, 2H), 4.04 (m, 2H), 3 , 95 (s, 1H), 2.07 (m, 1H), 1.96 (m, 6H), 1.82 (d, 1H).
[0517] [0517] Step E: (1R *, 3S *, 5S *) - 8-iso-Propyl-8-azabicyclo [3.2.1] octane-3-sulfonamide
[0518] [0518] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R *, 3S *, 5S *) - 8-azabicyclo [3.2.1] octane-3-sulfonamide chloridate, except that the crude compound was purified by normal phase flash chromatography using dichloromethane and a mixture of 7M ammonia in methanol to provide the title compound (15 mg, 16% yield), which was used without further purification.
[0519] [0519] 1H NMR (CD3OD): δ = 4.24 (m, 1H), 4.14 (m, 1H), 3.53 (m, 2H), 2.49 (m, 1H), 2.20 (m, 5H), 2.00 (m, 2H), 1.37 (d, 6H).
[0520] [0520] Intermediate P56: (1R *, 3S *, 5S *) - 8-Ethyl-8-azabicyclo [3.2.1] octane-3-sulfonamide
[0521] [0521] Prepared as described for 1-ethylpiperidine-4-sulfonamide (intermediate P6) from (1R *, 3S *, 5S *) - 8-azabicyclo [3.2.1] octane-3-sulfonamide chloridate to provide the title compound (30 mg, 34% yield), which was used without further purification.
[0522] [0522] 1H NMR (CD3OD): δ = 4.10 (m, 1H), 4.00 (m, 1H), 3.53 (m, 1H), 3.08 (m, 2H), 2.58 (m, 1H), 2.24 (m, 5H), 2.02 (m, 2H), 1.34 (m, 3H).
[0523] [0523] Intermediate P57: 1-Benzylazetidine-3-sulfonamide
[0524] [0524] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (intermediate P3) from azetidine-3-sulfonamide hydrochloride and benzyl bromide. The title compound (57 mg, 25% yield) was used without further purification.
[0525] [0525] 1H NMR (DMSO-d6): δ = 7.24 (m, 5 H), 6.93 (s, 2 H), 3.92 (m, 1 H), 3.58 (s, 2 H), 3.46 (t, 2 H), 3.35 (m, 2 H).
[0526] [0526] Intermediate P58: 1- (1-Ethylpiperidin-4-yl) azetidine-3-sulfonamide
[0527] [0527] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-ethyl-4-piperidone. The title compound (111 mg, 44% yield) was used without further purification.
[0528] [0528] 1H NMR (DMSO-d6): δ = 6.88 (s, 2 H), 3.85 (m, 1 H), 3.42 (t, 2 H), 3.22 (t, 2 H), 2.71 (m, 2 H), 2.27 (q, 2 H), 2.02 (m, 1 H), 1.87 (m, 2 H), 1.57 (dd, 2 H), 1.09 (m, 2 H), 0.95 (t, 3 H).
[0529] [0529] Intermediate P59: 1-Acetylazetidine-3-sulfonamide
[0530] [0530] Prepared as described for 1-acetylpiperidine-4-sulfonamide (Intermediate P7) from azetidine-3-sulfonamide hydrochloride.
[0531] [0531] 1H NMR (CD3OD): δ = 4.57 (m, 1 H), 4.50 (m, 2 H), 4.36 (m, 2 H), 1.98 (s, 3 H) .
[0532] [0532] Intermediate P60: 1- (Tetrahydro-2H-pyran-4-yl) azetidine-3-sulfonamide
[0533] [0533] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tetrahydro-4H-pyran-4-one. The title compound (112 mg, 50% yield) was used without further purification.
[0534] [0534] 1H NMR (DMSO-d6): δ = 6.89 (s, 2 H), 3.86 (m, 1 H), 3.77 (dt, 2 H), 3.44 (t, 2 H), 3.24 (m, 3 H), 2.98 (q, 1 H), 2.26 (tq, 1 H), 1.55 (dd, 2 H), 1.11 (m, 2 H).
[0535] [0535] Intermediate P61: 1-Propylazetidine-3-sulfonamide
[0536] [0536] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 1-bromopropane. The title compound (15 mg, 8% yield) was used without further purification.
[0537] [0537] 1H NMR (DMSO-d6): δ = 6.88 (s, 2 H), 3.87 (m, 1 H), 3.44 (t, 2 H), 3.22 (t, 2 H), 2.32 (t, 2 H), 1.24 (m, 2 H), 0.80 (t, 3 H).
[0538] [0538] Intermediate P62: 3-Sulfamoylazetidine-1-carboxylate tert-butyl
[0539] [0539] Step A: tert-butyl 3- (acetylthio) azetidine-1-carboxylate
[0540] [0540] To a solution of tert-butyl 3-iodoazetidine-1-carboxylate (17.2 g, 60.8 mmol, 1.0 equiv.) And thioacetic acid (8.7 mL, 121.6 mmol, 2 , 0 equiv.) In dimethylformamide (83 ml) cesium carbonate (39.6 g, 121.6 mmol, 2.0 equiv.) Was added in portions. The reaction was exothermic during this addition. Then, the reaction mixture was heated to 70 ° C for 1 hour to provide complete conversion. The mixture was diluted with water (600 ml) and then extracted with diethyl ether (600 ml). The organic layer was washed twice with water (600 ml), once with brine (500 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was subjected to normal phase flash chromatography on silica gel using heptane and ethyl acetate as eluent to provide the title compound (8.76 g, 62% yield).
[0541] [0541] 1H NMR (CDCl3): δ = 4.35 (t, 2 H), 4.10 (m, 1 H), 3.78 (dd, 2 H), 2.28 (s, 3 H) , 1.39 (s, 9 H).
[0542] [0542] Step B: tert-Butyl 3- (Chlorosulfonyl) azetidine-1-carboxylate
[0543] [0543] To a solution of tert-butyl 3- (acetylthio) azetidine-1-carboxylate (8.76 g, 37.9 mmol, 1.0 equiv.) In water (38 mL) and acetic acid (380 mL ) N-chlorosuccinimide (15.2 g, 113.7 mmol, 3.0 equiv.) was added. The suspension was stirred for 20 minutes at room temperature to provide a clear solution and complete conversion. The reaction mixture was diluted with water (600 ml) and then extracted with dichloromethane (600 ml). The organic layer was washed twice with water (600 ml), once with brine (300 ml), dried over Na2SO4, filtered and then used as such for the next reaction without further concentrating the organic layer.
[0544] [0544] 1H NMR (CDCl3): δ = 4.57 (m, 1 H), 4.38 (m, 4 H), 1.42 (s, 9 H).
[0545] [0545] Step C: tert-butyl 3-Sulfamoylazetidine-1-carboxylate
[0546] [0546] To a solution of tert-butyl 3- (chlorosulfonyl) azetidine-1-carboxylate (maximum 37.9 mmol) in dichloromethane (600 mL) was added 7M ammonia in methanol (55 mL, 379 mmol, 10 equiv. ). The clear solution was stirred for half an hour at room temperature. The suspension was concentrated in vacuo. The crude product was dissolved in methanol, coated in hydromatrix and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol as the eluent to provide the title compound (2.67 g, 11.3 mmol, in two stages 30% yield).
[0547] [0547] 1H NMR (DMSO-d6): δ = 7.18 (s, 2 H), 4.10 (m, 2 H), 3.98 (m, 3 H), 1.39 (s, 9 H).
[0548] [0548] Intermediate P63: 2- (3-Sulfamoylazetidin-1-yl) methyl acetate
[0549] [0549] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine hydrochloride
[0550] [0550] 1H NMR (DMSO-d6): δ = 6.92 (s, 2 H), 3.92 (m, 1 H), 3.58 (m, 5 H), 3.41 (dd, 2 H), 3.29 (s, 2 H).
[0551] [0551] Intermediate P64: 1-Isopropyl-2-oxopyrrolidine-3-sulfonamide
[0552] [0552] Step A: 2-bromo-4-chlorobutanoyl Cl Cl
[0553] [0553] To a solution of 4-chlorobutanoyl chloride (25 g, 177.31 mmol, 1 eq) in DCM (45 ml) was added NBS (47.34 g, 265.97 mmol, 1.5 eq) and SOCl2 (1.05 g, 8.87 mmol, 643.13 µL, 0.05 eq) followed by HBr (1.33 g, 6.58 mmol, 892.86 µL, 40% purity, 0.037 eq) at 25 ° C. The mixture was stirred at 50 ° C for 1.5 hours. The reaction mixture was diluted with hexane (300 ml) and filtered. The filtrate was concentrated in vacuo to provide the title compound (35 g, crude), which was used in the next step without further purification.
[0554] [0554] 1H NMR (CDCl3): δ = 4.87-4.80 (m, 1 H), 3.76-3.74 (m, 2 H) and 2.59-2.44 (m, 2 H).
[0555] [0555] Step B: 2-Bromo-4-chloro-N-isopropylbutanamide Cl O O NH2 NH Br Cl Cl Br
[0556] [0556] To a solution of 2-bromo-4-chlorobutanoyl chloride (20 g, 90.95 mmol, 1 eq) in DCM (50 mL) was added propan-2-amine (6.45 g, 109.14 mmol, 9.38 mL, 1.2 eq) at 0 ° C. The mixture was heated to 25 ° C and stirred at 25 ° C for an additional 1 hour. The reaction mixture was diluted with DCM (200 ml) and washed with water (100 ml). The organic layer was dried over
[0557] [0557] Step C: 3-Bromo-1-isopropylpyrrolidin-2-one
[0558] [0558] To a solution of 2-bromo-4-chloro-N-isopropylbutanamide (19 g, 78.34 mmol, 1 eq) in THF (200 mL) was added NaH (6.27 g, 156.67 mmol, 60% purity, 2 eq) at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. Then, the reaction mixture was quenched with H2O (200 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with brine (200 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 20: 1 to 1: 1) to provide the title compound (11.5 g, 55.80 mmol, 71% yield).
[0559] [0559] 1H NMR (CDCl3): δ = 4.41 - 4.31 (m, 2 H), 3.46 - 3.43 (m, 1 H), 3.32 - 3.29 (m, 1 H), 2.55-2.49 (m, 1 H), 2.32-2.30 (m, 1 H) and 1.16-1.14 (m, 6 H).
[0560] [0560] Step D: Methyl methyl ((1-Isopropyl-2-oxopyrrolidin-3-yl) sulfonyl) propanoate THE
[0561] [0561] To a solution of 3-bromo-1-isopropylpyrrolidin-2-one (1 g, 4.85 mmol, 1 eq) in DMSO (10 ml) was added 3-methoxy-3-oxo-propane-1- sodium sulfinate (845 mg, 4.85 mmol, 1 eq). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was quenched with water (80 ml) and extracted with ethyl acetate (3 x 80 ml). The combined organic layers were washed with brine (60 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 10: 1 to 1: 1) to provide the title compound (1.1 g, 3.97 mmol, 82% yield).
[0562] [0562] 1H NMR (CDCl3): δ = 4.37-4.33 (m, 1 H), 3.97-3.93 (m, 1 H), 3.82-3.72 (m, 5 H), 3.58-3.51 (m, 1 H), 3.39-3.38 (m, 1H), 2.94-2.90 (m, 2 H), 2.77-2, 73 (m, 1 H), 2.44-2.34 (m, 1 H) and 1.18 (d, 6 H). LCMS: m / z 277.9 (M + H) + (ES +). Step E: Sodium 1-isopropyl-2-oxopyrrolidine-3-sulfinate
[0563] [0563] To a solution of methyl 3 - ((1-isopropyl-2-oxopyrrolidin-3-yl) sulfonyl) propanoate (0.6 g, 2.16 mmol, 1 eq) in a mixture of MeOH (4, 8 ml) and THF (4.8 ml) a solution of NaOMe in MeOH (6.2 M, 1.05 ml, 3 eq) was added at 25 ° C. The mixture was stirred at 25 ° C for 3 hours. Then, the reaction mixture was concentrated in vacuo to provide the title compound (461.3 mg, crude) as a brown solid, which was used in the next step without further purification.
[0564] [0564] 1H NMR (CD3OD): δ = 4.34-4.27 (m, 1 H), 3.53-3.41 (m, 1 H), 3.19-3.15 (m, 2 H), 2.54-2.51 (m, 1 H), 2.17-2.12 (m, 1 H) and 1.19-1.14 (m, 6 H). LCMS: m / z 192.0 (M + H) + (ES +).
[0565] [0565] Step F: 1-Isopropyl-2-oxopyrrolidine-3-sulfonamide NH2
[0566] [0566] To a solution of sodium 1-isopropyl-2-oxopyrrolidine-3-sulfinate (461 mg, 2.16 mmol, 1 eq) in DMSO (6 mL) was added a solution of sulfonic (aminooxy) acid (1 , 22 g, 10.82 mmol, 5 eq) and AcONa (709 mg, 8.65 mmol, 4 eq) in H2O (2 ml) at 0 ° C. The mixture was heated to 25 ° C and stirred at 25 ° C for 16 hours. The reaction mixture was filtered and the filter residue was washed with MeOH (10 ml). The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (see "Experimental methods", "Purification method 2") to provide the title compound (219.8 mg, 1.07 mmol, 49%, 100% pure) as a white solid .
[0567] [0567] 1H NMR (DMSO-d6): δ = 6.92 (br s, 2 H), 4.18-4.15 (m, 1 H), 3.91-3.88 (m, 1 H ), 3.33-3.27 (m, 2H), 2.38-2.30 (m, 2 H) and 1.10-1.03 (m, 6 H). LCMS: m / z 206.9 (M + H) + (ES +).
[0568] [0568] Intermediate P65: 1- (1-Acetylazetidin-3-yl) piperidine-4-sulfonamide
[0569] [0569] A suspension of 1- (azetidin-3-yl) piperidine-4-sulfonamide dihydrochloride salt (95%, 250 mg, 0.81 mmol) and triethylamine (0.23 mL, 164 mg, 1.63 mmol) in acetonitrile (10 mL) was stirred for 30 minutes. Acetic anhydride (0.08 mL, 87 mg, 0.85 mmol) was added to this paste and stirring was continued for 20 hours. The mixture was concentrated in vacuo and the residue dissolved in methanol, then applied to a silica column (40 g) and eluted with 0-30% methanol in DCM to provide the title compound (93 mg, 43% yield).
[0570] [0570] HPLC-MS: 100% (ELSD), M 261 +1 (ACPI pos.)
[0571] [0571] 1H NMR (DMSO-d6): δ = 6.72 (s, 2H), 4.08 (t, J = 7.8 Hz, 1H), 3.91 (dd, J = 8.6, 5.1 Hz, 1H), 3.81 (dd, J = 9.7, 7.2 Hz, 1H), 3.61
[0572] [0572] Intermediate P66: 1- (1-Methylazetidin-3-yl) piperidine-4-sulfonamide
[0573] [0573] A suspension of 1- (azetidin-3-yl) piperidine-4-sulfonamide dihydrochloride salt (95%, 200 mg, 0.65 mmol) and triethylamine (0.19 mL, 138 mg, 1.36 mmol) in acetonitrile (8 mL) was stirred for 30 minutes. A solution of formalin (37% w / w, 15% methanol, 0.09 mL, 0.81 mmol) and sodium triacetoxyborohydride (1.25 eq., 178 mg, 0.81 mmol) was added to the resulting paste in portions. Stirring was continued for 20 hours at room temperature, then the mixture was concentrated in vacuo. The residue was dissolved in 3.5N ammonia in methanol and applied to a silica cartridge (40 g, Silicycle). The title compound (65 mg, 38% yield) was isolated by elution with a 0-30% gradient of 3.5N (ammonia / methanol) in DCM.
[0574] [0574] HPLC-MS: 100% (ELSD), M 233 +1 (ACPI pos.)
[0575] [0575] 1H NMR (DMSO-d6): δ = 6.70 (s, 2H), 3.44 (s, 2H), 2.89 - 2.66 (m, 6H), 2.25 (s, 2H), 1.95 (dd, J = 13.0, 3.5 Hz, 2H), 1.81 - 1.67 (m, 3H), 1.56 (qd, J = 12.2, 3, 9 Hz, 2H).
[0576] [0576] Intermediate P67: 1- (Pentan-3-yl) pyrrolidine-3-sulfonamide
[0577] [0577] Prepared as described for 1- cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-
[0578] [0578] 1H NMR (DMSO-d6): δ = 6.80 (s, 2H), 3.53 (m, 1H), 2.90 (dd, 1H), 2.65 (m, 2H), 2 , 48 (m, 1H), 2.01 (m, 3H), 1.40 (m, 4H), 0.79 (m, 6H).
[0579] [0579] Intermediate P68: 1- (Sec-butyl) pyrrolidine-3-sulfonamide
[0580] [0580] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-sulfonamide and 2-butanone, but no triethylamine was required. The title compound (143 mg, 64% yield) was used without further purification.
[0581] [0581] 1H NMR (CD3OD): δ = 3.78 (m, 1H), 3.33 (m, 1H), 2.99 (m, 2H), 2.78 (m, 1H), 2.51 (m, 1H), 2.25 (q, 2H), 1.74 (m, 1H), 1.40 (m, 1H), 1.15 (dd, 3H), 0.93 (t, 3H) .
[0582] [0582] Intermediate P69: 1-Butylazetidine-3-sulfonamide
[0583] [0583] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and butylaldehyde. The title compound (82 mg, 42% yield) was used without further purification.
[0584] [0584] 1H NMR (DMSO-d6): δ = 6.88 (s, 2 H), 3.85 (m, 1 H), 3.43 (t, 2 H), 3.22 (m, 2 H), 2.34 (t, 2 H), 1.22 (m, 4 H), 0.83 (t, 3 H).
[0585] [0585] Intermediate P70: 1- (2-Hydroxy-2-methylpropyl) azetidine-3-sulfonamide
[0586] [0586] To a solution of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol, 1.0 equiv.) And potassium carbonate (691 mg, 5.0 mmol, 5.0 equiv.) In water (5 ml) and ethanol (5 ml) in a microwave flask (20 ml) was added 1,2-epoxy-2-methylpropane (88 µL, 1.0 mmol, 1.0 equiv.). The reaction mixture was heated in the microwave at 110 ° C for 30 minutes and then concentrated in vacuo. The crude material was suspended in methanol and filtered. The filtrate was coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (38 mg, 18% yield), which was used without further purification.
[0587] [0587] 1H NMR (DMSO-d6): δ = 6.86 (s, 2 H), 4.03 (s, 1 H), 3.88 (m, 1 H), 3.54 (t, 2 H), 3.36 (m, 2 H), 2.31 (s, 2 H), 1.00 (s, 6 H).
[0588] [0588] Intermediate P71: 1-Cyclopropylazetidine-3-sulfonamide
[0589] [0589] Prepared as described for 1-cyclopropylpyrrolidine-3-sulfonamide (Intermediate P30) from azetidine-3-sulfonamide hydrochloride, except that the reaction was stirred for 3 days at room temperature and another 8 hours at 50 ° C. The title compound (47 mg, 26% yield) was used without further purification.
[0590] [0590] 1H NMR (DMSO-d6): δ = 6.92 (s, 2H), 3.84 (m, 1 H), 3.50 (t, 2 H), 3.40 (t, 2 H ), 1.94 (m, 1 H), 0.32 (m, 2 H), 0.19 (m, 2 H).
[0591] [0591] Intermediate P72: 1- (1,3-Difluoropropan-2-yl) azetidine-3-sulfonamide
[0592] [0592] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1,3-pentanone. The title compound (87 mg, 40% yield) was used without further purification.
[0593] [0593] 1H NMR (DMSO-d6): δ = 6.93 (s, 2 H), 4.47 (m, 2 H), 4.32 (m, 2 H), 3.94 (m, 1 H), 3.59 (t, 2 H), 3.48 (t, 2 H), 2.80 (m, 1 H).
[0594] [0594] Intermediate P73: 1- (Cyanomethyl) azetidine-3-sulfonamide
[0595] [0595] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and bromoacetonitrile. The title compound (47 mg, 26% yield) was used without further purification.
[0596] [0596] 1H NMR (DMSO-d6): δ = 6.98 (s, 2 H), 3.91 (m, 1 H), 3.62 (s, 2 H), 3.53 (m, 4 H).
[0597] [0597] Intermediate P74: 1- (2-Methoxyethyl) azetidine-3-sulfonamide
[0598] [0598] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine hydrochloride
[0599] [0599] 1H NMR (DMSO-d6): δ = 6.89 (s, 2 H), 3.87 (m, 1 H), 3.47 (t, 2 H), 3.32 (m, 2 H), 3.25 (m, 2 H), 3.18 (s, 3 H), 2.54 (m, 2 H).
[0600] [0600] Intermediate P75: 1- (Cyclohexylmethyl) azetidine-3-sulfonamide
[0601] [0601] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclohexanecarboxaldehyde. The title compound (202 mg, 86% yield) was used without further purification.
[0602] [0602] 1H NMR (DMSO-d6): δ = 6.87 (s, 2 H), 3.86 (m, 1 H), 3.44 (t, 2 H), 3.22 (t, 2 H), 2.21 (d, 2 H), 1.63 (m, 5 H), 1.14 (m, 4 H), 0.81 (m, 2 H).
[0603] [0603] Intermediate P76: 1- (Pyridin-3-ylmethyl) azetidine-3-sulfonamide
[0604] [0604] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and pyridine-3-aldehyde. The title compound (131 mg, 58% yield) was used without further purification.
[0605] [0605] 1H NMR (DMSO-d6): δ = 8.44 (m, 2 H), 7.65 (dt, 1 H), 7.32 (dd, 1 H), 6.95 (s, 2 H), 3.92 (m, 1 H), 3.61 (s, 2 H), 3.48 (t, 2 H), 3.37 (m, 2 H).
[0606] [0606] Intermediate P77: N, N-dimethyl-2- (3-sulfamoylazetidin-1-yl) acetamide
[0607] [0607] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 2-chloro-N, N-dimethylacetamide, except potassium iodide (0.5 equiv.) was added to the reaction mixture. The title compound (40 mg, 18% yield) was used without further purification.
[0608] [0608] 1H NMR (DMSO-d6): δ = 7.17 (s, 2 H), 4.07 (m, 3 H), 3.90 (m, 4 H), 2.88 (s, 3 H), 2.80 (s, 3 H).
[0609] [0609] Intermediate P78: 1- (2-Chloroethyl) azetidine-3-sulfonamide
[0610] [0610] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and chloroacetaldehyde (~ 50% by weight in H2O). The title compound (100 mg, 50% yield) was used without further purification.
[0611] [0611] 1H NMR (DMSO-d6): δ = 6.91 (s, 2 H), 3.92 (m, 1 H), 3.53 (m, 4 H), 3.36 (t, 2 H), 2.73 (t, 2 H).
[0612] [0612] Intermediate P79: 1-Cyclobutylazetidine-3-sulfonamide
[0613] [0613] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclobutanone. The title compound (127 mg, 66% yield) was used without further purification.
[0614] [0614] 1H NMR (DMSO-d6): δ = 6.91 (s, 2 H), 3.86 (m, 1 H), 3.39 (t, 2 H), 3.30 (m, 2 H), 3.09 (q, 1 H), 1.87 (m, 2 H), 1.67 (m, 4 H).
[0615] [0615] Intermediate P80: 1-Isopropyl-N, N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide
[0616] [0616] Step A: 4-nitrobenzyl 2- (Dimethylcarbamoyl) -4-sulfamoylpyrrolidine-1-carboxylate
[0617] [0617] A suspension of 4-nitrobenzyl 2- (dimethylcarbamoyl) -4-mercaptopyrrolidine-1-carboxylate (1 g, 2.83 mmol) in acetic acid (5 mL) / water (1 mL) ice at 0 ° C. N-chlorosuccinimide (1.13 g, 8.49 mmol, 3.0 equiv.) Was added in portions over a period of 5 minutes. The mixture was allowed to stir for an additional hour at room temperature. The reaction was then poured into ammonia (50 mL, 25% solution in water). The resulting solution was stirred for 18 hours at room temperature. The solvents were evaporated and the residue was triturated with ethanol (50 ml). Sodium sulfate (15 g) was added and the mixture was filtered and evaporated. The residue was dissolved in methanol (50 ml) and Amberlite 400 (OH-) (20 g) was added. After 18 hours of stirring, the mixture was filtered and evaporated to provide the title compound (610 mg, 54% yield) as an oil which crystallized on standing.
[0618] [0618] 1H NMR (CD3OD): δ = 8.20 (m, 2 H), 7.62 (d, 1 H), 7.53 (d, 1 H), 5.26 (d, 2 H) , 4.08 - 3.66 (m, 4 H), 3.00 (m, 6 H), 2.12 (m, 2H).
[0619] [0619] Step B: N, N-Dimethyl-4-sulfamoylpyrrolidine-2-carboxamide
[0620] [0620] 4-Nitrobenzyl 2- (dimethylcarbamoyl) -4-sulfamoyl pyrrolidine-1-carboxylate (610 mg, 1.53 mmol) was dissolved in methanol (10 mL). Palladium (47 mg, 10% charcoal) was added and the mixture was stirred for 18 hours under a hydrogen atmosphere (flask). The mixture was filtered over Celite and evaporated. The residue was purified by reversed phase silica to produce white solids (0.5 g), which were ground with THF. The THF layer was decanted and evaporated to provide the title compound (350 mg, 100% yield) as a white solid.
[0621] [0621] 1H NMR (CD3OD): δ = 3.79 - 3.55 (m, 4 H), 3.00 (m, 6 H), 1.90 (m, 2H).
[0622] [0622] Step C: 1-Isopropyl-N, N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide
[0623] [0623] N, N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide (84 mg, 0.38 mmol) was dissolved in acetonitrile (10 ml). Acetone (90 mg, 1.5 mmol) was added followed by sodium triacetoxyborohydride. After 18 hours of stirring at room temperature, the solvents were evaporated and the residue was purified on silica to provide the title compound (10 mg, 10% yield) as an oil.
[0624] [0624] 1H NMR (CD3OD): δ = 3.92 (t, 1 H), 3.73 (m, 1 H), 3.46 (dd, 1 H), 3.18 (s, 3 H) , 3.05 (m, 1 H), 2.95 (s, 3 H), 2.88 (m, 1 H), 2.57 (m, 1 H), 2.14 (m, 1 H) , 1.08 (d, 3 H), 1.03 (d, 3 H).
[0625] [0625] Intermediate P81: 1-Ethyl-5-oxopyrrolidine-3-sulfonamide
[0626] [0626] 1-Ethyl-5-oxopyrrolidine-3-sulfonyl chloride (150 mg, 0.71 mmol) was dissolved in THF (3 mL) and ammonia (25% solution in water) was added dropwise , 5 mL) at 4 ° C. After 18 hours of stirring at room temperature, the solvents were evaporated. The residue was triturated in THF. The THF layer was decanted and evaporated to provide the title compound (30 mg, 22% yield) as a brown oil.
[0627] [0627] 1H NMR (CD3OD): δ = 3.80 (m, 2 H), 3.34 (m, 3 H), 2.78 (m, 2 H), 1.13 (t, 3 H) .
[0628] [0628] Intermediate P82: 1- (Terc-butyl) azetidine-3-sulfonamide
[0629] [0629] Step A: 1- (Terc-butyl) azetidin-3-yl methanesulfonate
[0630] [0630] To a suspension of N-tert-butyl-3-hydroxyacetidine hydrochloride (1.0 g, 6.0 mmol) in dichloromethane (30 mL) was added N, N-diisopropylethylamine (2.4 mL, 13, 8 mmol, 2.5 equiv.). After stirring for 20 minutes at room temperature, the clear solution was cooled to 0 ° C and mesyl chloride (0.5 mL, 6.6 mmol, 1.1 equiv) was added dropwise. The reaction mixture was stirred for 1 hour, while allowing to warm to room temperature. Then the solvent was removed by evaporation in vacuo. The crude product was dissolved in methanol, coated with Hydromatrix from
[0631] [0631] 1H NMR (CDCl3): δ = 5.10 (m, 1 H), 3.74 (m, 2 H), 3.47 (m, 2 H), 3.02 (s, 3 H) , 1.04 (s, 9 H).
[0632] [0632] Step B: S- (1- (Terc-butyl) azetidin-3-yl) ethanothioate
[0633] [0633] To a solution of 1- (tert-butyl) azetidin-3-yl methanesulfonate (269 mg, 1.3 mmol) in acetonitrile (20 mL) was added potassium thioacetate (447 mg, 3.9 mmol, 3 equiv.). The reaction mixture was stirred overnight at room temperature and then for another 7 hours at 50 ° C. The solvent was removed by evaporation in vacuo. The crude product was dissolved in methanol, coated with Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (90 mg, 37% yield).
[0634] [0634] 1H NMR (CDCl3): δ = 4.15 (m, 1 H), 3.80 (m, 2 H), 3.30 (m, 2 H), 2.31 (s, 3 H) , 1.03 (s, 9 H).
[0635] [0635] Step C: 1- (Terc-butyl) azetidine-3-sulfonamide
[0636] [0636] To a suspension of N-chlorosuccinimide (200 mg, 1.5 mmol, 3 equiv.) In acetonitrile (2.0 mL) was added hydrochloric acid (aqueous, 2 M, 0.2 mL, 0.38 mmol , 0.8 equiv.). The solution was cooled in an ice bath, after which a solution of S- (1- (tert-butyl (azetidine-3-yl) ethanothioate (90 mg, 0.48 mmol, 1.0 equiv.) Was added) in acetonitrile (1.0 ml) and the ice bath was removed.The reaction mixture was stirred for 1 hour and then added dropwise to a solution of ammonia in methanol (7 M, 50 ml, 350 mmol, 729 equiv The mixture was stirred for 30 minutes and concentrated in vacuo The crude product was dissolved in methanol, coated in Agilent's Hydromatrix (an inert high purity diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (11 mg, 10% yield).
[0637] [0637] 1H NMR (CD3OD): δ = 3.97 (m, 1 H), 3.68 (m, 2 H), 3.51 (m, 2 H), 1.02 (s, 9 H) .
[0638] [0638] Intermediate P83: 1- (Cyclopropylmethyl) azetidine-3-sulfonamide
[0639] [0639] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclopropanecarboxaldehyde. The crude product was dissolved in methanol, coated with Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (180 mg, 94% yield) which was used without further purification.
[0640] [0640] 1H NMR (DMSO-d6): δ = 6.90 (s, 2 H), 3.90 (m, 1 H), 3.49 (t, 2 H), 3.30 (t, 2 H), 2.26 (d, 2 H), 0.69 (m, 1 H), 0.37 (m, 2 H), 0.07 (m, 2 H).
[0641] [0641] Intermediate P84: 1-Isobutylazetidine-3-sulfonamide
[0642] [0642] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and isobutyraldehyde. The title compound (138 mg, 71% yield) was used without further purification.
[0643] [0643] 1H NMR (DMSO-d6): δ = 6.88 (s, 2 H), 3.88 (m, 1 H), 3.46 (t, 2 H), 3.23 (m, 2 H), 2.18 (d, 2H), 1.47 (m, 1 H), 0.80 (d, 6 H).
[0644] [0644] Intermediate P85: 1- (2-Azidoethyl) azetidine-3-sulfonamide
[0645] [0645] To a solution of 1- (2-chloroethyl) azetidine-3-sulfonamide (45 mg, 0.22 mmol, 1.0 equiv.) In acetonitrile (5 mL) was added sodium azide (14 mg, 0 , 22 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature over the weekend. Extra sodium azide (56 mg, 0.88 mmol, 4.0 equiv.) Was added and the reaction mixture was heated to 50 ° C. After stirring overnight, water (0.4 ml) was added and the reaction mixture was stirred for an additional 2 days. The solution was concentrated in vacuo. The residue was suspended in methanol, filtered and the filtrate was concentrated in vacuo to provide the crude title compound (45 mg, 0.22 mmol, quantitative yield). The crude title compound was used without further purification.
[0646] [0646] 1H NMR (DMSO-d6): δ = 6.93 (s, 2 H), 3.92 (m, 1 H), 3.53 (t, 2 H), 3.34 (m, 2 H), 3.21 (dd, 2 H), 2.59 (dd, 2 H).
[0647] [0647] Intermediate P86: 1- (2,2,2-Trifluoroethyl) azetidine-3-sulfonamide
[0648] [0648] To a suspension of azetidine-3-sulfonamide hydrochloride (333 mg, 1.92 mmol) and triethylamine (0.67 mL, 4.8 mmol, 2.5 equiv.) In acetonitrile (20 mL) was added trifluoroacetic anhydride (0.24 ml, 1.73 mmol, 0.9 equiv.). After stirring for 4 hours at room temperature, the reaction mixture was concentrated in vacuo. The crude intermediate 1- (2,2,2-trifluoroacetyl) azetidine-3-sulfonamide was dissolved in methanol, coated with Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol. The impure intermediate (max. 1.92 mmol) was dissolved in tetrahydrofuran (20 ml) and then cooled to 0 ° C. To this solution, borane-dimethyl sulfide (0.85 mL, 9.0 mmol, 4.5 equiv.) Was added dropwise. The mixture was refluxed overnight and then cooled to room temperature. . Methanol was added to the reaction mixture until no further gas evolution was observed and then the reaction mixture was concentrated in vacuo. The crude product was dissolved in methanol, coated with Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (20 mg, 5% yield). The title compound was used without further purification.
[0649] [0649] 1H NMR (DMSO-d6): δ = 7.07 (s, 2 H), 4.24 - 4.08 (m, 1 H), 3.65 (t, 2 H), 3.52 (dd, 2 H), 3.31 - 3.16 (m, 2 H).
[0650] [0650] Intermediate P87: 1- (2 - ((Terc-butyldimethylsilyl) oxy) ethyl) azetidine-3-sulfonamide
[0651] [0651] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (intermediate P3) from azetidine-3-sulfonamide hydrochloride and (2-bromoethoxy) -tert-butyldimethylsilane. The title compound (44 mg, 16% yield) was used without further purification.
[0652] [0652] 1H NMR (DMSO-d6): δ = 6.89 (s, 2 H), 3.88 (q, 1 H), 3.50 (m, 4 H), 3.31 (m, 2 H), 0.84 (s, 9 H), 0.01 (s, 6 H).
[0653] [0653] Intermediate P88: 1-Cyclohexylazetidine-3-sulfonamide
[0654] [0654] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclohexanone. The title compound (218 mg, quantitative yield) was used without further purification.
[0655] [0655] 1H NMR (DMSO-d6): δ = 6.86 (s, 2 H), 3.83 (p, 1 H), 3.41 (t, 2 H), 3.21 (dd, 2 H), 2.00 (m, 1 H), 1.59 (m, 6 H), 1.15 (q, 2 H), 0.93 (m, 2 H).
[0656] [0656] Intermediate P89: 1-Cyclopentylazetidine-3-sulfonamide
[0657] [0657] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclopentanone. The title compound (204 mg, quantitative yield) was used without further purification.
[0658] [0658] 1H NMR (DMSO-d6): δ = 6.86 (s, 2 H), 3.82 (m, 1 H), 3.41 (t, 2 H), 3.18 (m, 2 H), 2.72 (m, 1 H), 1.49 (m, 6 H), 1.24 (m, 2 H).
[0659] [0659] Intermediate P90: 1- (1-Iminoethyl) azetidine-3-sulfonamide
[0660] [0660] To a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol, 1.0 equiv.) And triethylamine (0.49 mL, 3.5 mmol, 3.5 equiv.) In acetonitrile (10 ml) ethyl acetimidate hydrochloride (123 mg, 1.0 mmol, 1.0 equiv.) Was added. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude compound (approx. 300 mg) was dissolved in water / methanol (1: 1 ratio) (3 ml). 1 ml of this solution was purified by reverse phase flash chromatography to provide the title compound (30 mg, 9% yield).
[0661] [0661] 1H NMR (DMSO-d6): δ = 10.25 (s, 1 H), 7.41 (s, 2 H), 4.61 (dd, 1 H), 4.44 (m, 2 H), 4.21 (m, 2 H), 2.08 (s, 3 H).
[0662] [0662] Intermediate P91: 1- (Oxetan-3-ylmethyl) azetidine-3-sulfonamide
[0663] [0663] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 3-oxetanecarboxaldehyde. The title compound (156 mg, 75% yield) was used without further purification.
[0664] [0664] 1H NMR (DMSO-d6): δ = 6.91 (s, 2 H), 4.57 (dd, 2 H), 4.22 (t, 2 H), 3.90 (m, 1 H), 3.47 (t, 2 H), 3.28 (m, 2 H), 2.90 (m, 1 H), 2.68 (d, 2 H).
[0665] [0665] Intermediate P92: 1- (2- (Dimethylamino) ethyl) azetidine-3-sulfonamide THE
[0666] [0666] To a solution of 1- (cyanomethyl) azetidine-3-sulfonamide (220 mg, 1.25 mmol) in tetrahydrofuran (15 mL), cooled to 0 ° C, was added dimethyl borane sulfide (0.16 mL, 1.63 mmol, 1.3 equiv.). The reaction mixture was refluxed overnight and then quenched with methanol. The solution was concentrated in vacuo. The crude intermediate was suspended in acetonitrile (20 mL) and formaldehyde (37% in water stabilized with methanol, 186 µL, 2.5 mmol, 2.1 equiv.) Followed by sodium triacetoxyborohydride (688 mg, 3.25 mmol, 2.6 equiv.). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude product was dissolved in methanol, coated with Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (28 mg, 14% yield).
[0667] [0667] 1H NMR (CD3OD): δ = 4.02 (m, 1 H), 3.67 (m, 2 H), 3.55 (m, 2 H), 2.74 (dt, 4 H) , 2.56 (s, 6 H).
[0668] [0668] Intermediate P93: 1- (Pyridin-4-ylmethyl) azetidine-3-sulfonamide
[0669] [0669] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 4-pyridinecarboxaldehyde. The title compound (130 mg, 57% yield) was used without further purification.
[0670] [0670] 1H NMR (DMSO-d6): δ = 8.47 (d, 2 H), 7.26 (d, 2 H), 6.97 (s, 2 H), 3.94 (m, 1 H), 3.64 (s, 2 H), 3.52 (t, 2 H), 3.39 (t, 2 H).
[0671] [0671] Intermediate P94: 1- (Pyridin-2-ylmethyl) azetidine-3-sulfonamide
[0672] [0672] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2-pyridinecarboxaldehyde. The title compound (196 mg, 86% yield) was used without further purification.
[0673] [0673] 1H NMR (DMSO-d6): δ = 8.46 (dd, 1 H), 7.73 (td, 1 H), 7.32 (d, 1 H), 7.24 (m, 1 H), 6.95 (s, 2 H), 3.94 (tt, 1 H), 3.70 (s, 2 H), 3.55 (t, 2 H), 3.44 (t, 2 H).
[0674] [0674] Intermediate P95: 1 - (((2-Bromopyridin-3-yl) methyl) azetidine-3-sulfonamide
[0675] [0675] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2-bromo-3-pyridinecarboxaldehyde. The title compound (137 mg, 45% yield) was used without further purification.
[0676] [0676] 1H NMR (DMSO-d6): δ = 8.27 (dd, 1 H), 7.79 (dd, 1 H), 7.44 (dd, 1 H), 7.02 (s, 2 H), 3.97 (m, 1 H), 3.67 (s, 2 H), 3.61 (t, 2 H), 3.49 (dd, 2 H).
[0677] [0677] Intermediate P96: 3-Sulfamoyl- [1,3'-biazetidine] -1'-tert-butyl carboxylate
[0678] [0678] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tert-butyl-3-oxoazetidine-1-carboxylate. The title compound (350 mg, 24% yield) was used without further purification.
[0679] [0679] 1H NMR (DMSO-d6): δ = 6.95 (s, 2 H), 3.92 (m, 1 H), 3.80 (t, 2 H), 3.57 (d, 2 H), 3.48 (t, 2 H), 3.36 (m, 3 H), 1.35 (s, 9 H).
[0680] [0680] Intermediate P97: 1'-Methyl- [1,3'-biazetidine] -3-sulfonamide
[0681] [0681] Step A: [1,3'-biazetidine] -3-sulfonamide dihydrochloride
[0682] [0682] To a solution of tert-butyl 3-sulfamoyl- [1,3'-biazetidine] -1'-carboxylate (intermediate P96; 315 mg, 1.08 mmol) in dichloromethane (10 mL) 4M in dioxane (2.7 mL 10.8 mmol). After stirring for 2 hours at room temperature, the reaction mixture was concentrated in vacuo to provide the title compound (285 mg, quantitative yield), which was used without further purification.
[0683] [0683] 1H NMR (DMSO-d6): δ = 9.50 (bs, 1 H), 9.18 (bs, 1 H), 7.42 (s, 2 H), 4.57 - 4.31 (m, 3 H), 4.31 - 4.00 (m, 8 H).
[0684] [0684] Step B: 1'-Methyl- [1,3'-biazetidine] -3-sulfonamide
[0685] [0685] Prepared as described for 1-methylazetidine-3-sulfonamide (intermediate P39) from [1,3'-biazetidine] -3-sulfonamide dihydrochloride. The title compound (63 mg, 61% yield) was used without further purification.
[0686] [0686] 1H NMR (CD3OD): δ = 4.10 - 3.94 (m, 1 H), 3.75 - 3.60 (m, 4 H), 3.59 - 3.51 (m, 2 H), 3.51 - 3.44 (m, 1 H), 3.41 - 3.32 (m, 2 H), 2.55 (s, 3 H).
[0687] [0687] Intermediate P98: 1- (2- (Methylthio) ethyl) azetidine-3-sulfonamide
[0688] [0688] To a solution of 0.5M hydrochloric acid in water (6.0 mL, 3.0 mmol) was added (methylthio) acetaldehyde dimethyl acetal (0.4 mL, 3.0 mmol). After heating the reaction for 1 hour at 50 ° C, the reaction mixture was cooled to room temperature and then extracted with dichloromethane (10 ml). The organic layer was added to a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol) and triethylamine (0.17 mL, 1.2 mmol) in acetonitrile. After that, sodium triacetoxyborohydride (265 mg, 1.25 mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude product was dissolved in methanol, coated with Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (89 mg, 42% yield).
[0689] [0689] 1H NMR (DMSO-d6): δ = 6.91 (s, 2 H), 3.89 (p, 1 H), 3.49 (t, 2 H), 3.33 - 3.25 (m, 2 H), 2.59 (dd, 2 H), 2.37 (dd, 2 H), 2.03 (s, 3 H).
[0690] [0690] Intermediate P99: 1- (2-Fluoroethyl) azetidine-3-sulfonamide
[0691] [0691] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 1-bromo-2-fluoroethane. The title compound (10% yield) was used without further purification.
[0692] [0692] 1H NMR (DMSO-d6): δ = 6.91 (s, 2 H), 4.44 (t, 1 H), 4.29 (t, 1 H), 3.90 (q, 1 H), 3.53 (t, 2 H), 3.36 (t, 2 H), 2.79 - 2.69 (m, 1 H), 2.64 (t, 1 H).
[0693] [0693] Intermediate P100: 1- (Tietan-3-yl) azetidine-3-sulfonamide
[0694] [0694] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tietan-3-one. The title compound (54 mg, 26% yield) was used without further purification.
[0695] [0695] 1H NMR (DMSO-d6): δ = 6.95 (s, 2 H), 3.98 - 3.83 (m, 2 H), 3.43 (p, 4 H), 3.19 (t, 2 H), 2.97 (t, 2 H).
[0696] [0696] Intermediate P101: 1- (2- (3- (But-3-in-1-yl) -3H-diazirin-3-yl) ethyl) azetidine-3-sulfonamide
[0697] [0697] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and (3- (but-3-in- 1-yl) -3- (2-iodoethyl) -3H-diazirine (0.8 equiv.), Except that a more diluted solution was used (0.02 M solution) .The title compound (10% yield) was used without further purification.
[0698] [0698] 1H NMR (CD3OD): δ = 4.09 - 3.92 (m, 1 H), 3.61 (td, 2 H), 3.47 - 3.35 (m, 2 H), 2 , 37 (dd, 2 H), 2.27 (t, 1 H), 2.02 (td, 2 H), 1.60 (t, 2 H), 1.51 - 1.39 (m, 2 H).
[0699] [0699] Intermediate P102: Terc-butyl (Z) - ((((tert-butoxycarbonyl) amino) (3-sulfamoylazetidin-1-yl) methylene) carbamate
[0700] [0700] To a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol), triethylamine (0.49 mmol, 3.5 mmol) and 1,3-bis (tert-butoxycarbonyl) -2- methyl-2-thiopseudourea (290 mg, 1.0 mmol) in acetonitrile (10 mL) mercury dichloride (271 mg, 1.0 mmol) was added. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (216 mg, 57% yield).
[0701] [0701] 1H NMR (DMSO-d6): δ = 10.24 (s, 1 H), 7.16 (s, 2 H), 4.41 - 3.94 (m, 5 H), 1.41 (s, 9 H), 1.35 (s, 9 H).
[0702] [0702] Intermediate P103: 1- (3-Methylcyclobutyl) azetidine-3-sulfonamide
[0703] [0703] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 3-methylcyclobutan-1-one. The title compound (79 mg, 39% yield) was used without further purification.
[0704] [0704] 1H NMR (DMSO-d6): δ = 6.88 (s, 2 H), 3.84 (td, 1 H), 3.44 - 3.18 (m, 4 H), 2.92 (m, 1 H), 2.10 - 1.96 (m, 1 H), 1.91 - 1.78 (m, 2 H), 1.59 - 1.45 (m, 1 H), 1 , 39 - 1.24 (m, 1 H), 1.00 (s, 3 H).
[0705] [0705] Intermediate P104: 1- (3,3-Dimethylcyclobutyl) azetidine-3-sulfonamide
[0706] [0706] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 3,3-dimethylcyclobutan-1-one. The title compound (96 mg, 44% yield) was used without further purification.
[0707] [0707] 1H NMR (DMSO-d6): δ = 6.88 (s, 2 H), 3.84 (m, 1 H), 3.34 (t, 2 H), 3.29 - 3.19 (m, 2 H), 3.08 (dq, 1 H), 1.77 - 1.62 (m, 2 H), 1.58 - 1.43 (m, 2 H), 1.03 (td , 6 H).
[0708] [0708] Intermediate P105: 1- (Pyrimidin-5-ylmethyl) azetidine-3-sulfonamide
[0709] [0709] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and pyrimidine-5-carboxaldehyde. The title compound (98 mg, 43% yield) was used without further purification.
[0710] [0710] 1H NMR (DMSO-d6): δ = 9.07 (s, 1 H), 8.69 (s, 2 H), 6.96 (s, 2 H), 3.93 (m, 1 H), 3.64 (s, 2 H), 3.52 (t, 2 H), 3.40 (t, 2 H).
[0711] [0711] Intermediate P106: 1- (Tetrahydrofuran-3-yl) azetidine-3-sulfonamide
[0712] [0712] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tetrahydrofuran-3-one. The title compound (31 mg, 15% yield) was used without further purification.
[0713] [0713] 1H NMR (DMSO-d6): δ = 6.90 (s, 2 H), 3.86 (m, 1 H), 3.70 - 3.54 (m, 2 H), 3.54 - 3.34 (m, 4 H), 3.29 - 3.19 (m, 2 H), 3.08 - 2.98 (m, 1 H), 1.83 - 1.67 (m, 1 H), 1.62 - 1.49 (m, 1 H).
[0714] [0714] Intermediate P107: 1- (Sec-butyl) azetidine-3-sulfonamide
[0715] [0715] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2-butanone. The title compound (191 mg, 85% yield) was used without further purification.
[0716] [0716] 1H NMR (DMSO-d6): δ = 6.87 (s, 2 H), 3.81 (m, 1 H), 3.41 (td, 2 H), 3.21 (t, 2 H), 2.45 - 2.34 (m, 1 H), 2.18 - 2.03 (m, 1 H), 1.42 - 1.25 (m, 1 H), 1.01 (t , 3 H), 0.78 (d, 3 H).
[0717] [0717] Intermediate P108: 1 - (((1-Methyl-1H-imidazol-2-yl) methyl) azetidine-3-sulfonamide
[0718] [0718] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-methylimidazole-2-carbaldehyde. The title compound (144 mg, 63% yield) was used without further purification.
[0719] [0719] 1H NMR (DMSO-d6): δ = 7.03 (d, 1 H), 6.91 (s, 2 H), 6.71 (d, 1 H), 3.96 - 3.80 (m, 1 H), 3.61 (s, 2 H), 3.57 (s, 3 H), 3.45 (t, 2 H), 3.37 (dd, 2 H).
[0720] [0720] Intermediate P109: 1- (2,2-Dimethylcyclobutyl) azetidine-3-sulfonamide
[0721] [0721] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2,2-dimethylcyclobutanone. The title compound (24 mg, 11% yield) was used without further purification.
[0722] [0722] 1H NMR (DMSO-d6): δ = 6.87 (s, 2 H), 3.90 (p, 1 H), 3.40 (dd, 2 H), 3.20 (dt, 2 H), 2.57 (d, 1 H), 1.86 - 1.72 (m, 1 H), 1.56 - 1.33 (m, 3 H), 1.00 (s, 3 H) , 0.92 (s, 3 H).
[0723] [0723] Intermediate P110: Terc-butyl (E) - (((tert-butoxycarbonyl) imino) (3-sulfamoylazetidin-1-yl) methyl) (methyl) carbamate
[0724] [0724] Step A: 1-Methyl-1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea
[0725] [0725] A solution of 1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea (435 mg, 1.5 mmol) in dimethylformamide (5 ml) was cooled to 0 ° C in a cooling bath and then sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol) was added. The cooling bath was removed. After stirring for 1 hour at room temperature, methyl iodide (0.19 ml, 3.0 mmol) was added. After stirring overnight, the reaction mixture was poured into water and then extracted once with dichloromethane and once with ethyl acetate. The organic layers were combined, washed twice with water, once with brine, dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound (230 mg, 50% yield), which was used without purification additional.
[0726] [0726] 1H NMR (CDCl3): δ = 3.12 (s, 3 H), 2.39 (s, 3 H), 1.51 (s, 9 H), 1.48 (s, 9 H) .
[0727] [0727] Step B: (E) - (((tert-butoxycarbonyl) imino) (3-sulfamoylazetidin-1-yl) methyl) (methyl) tert-butyl carbamate
[0728] [0728] Prepared as described for (Z) - ((((tert-butoxycarbonyl) amino) (3-sulfamoylazetidin-1-yl) methylene) tert-butyl carbamate (Intermediate P102) from 1-methyl-1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea, except that after stirring over the weekend, water was added to the reaction mixture.The mixture was extracted three times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo The crude product was suspended in methanol, coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture ammonia (3.5 M) in methanol to provide the title compound (48 mg, 16% yield).
[0729] [0729] 1H NMR (DMSO-d6): δ = 7.23 (s, 2 H), 4.20 (bs, 1 H), 4.09 (p, 4 H), 2.84 (s, 3 H), 1.41 (s, 9 H), 1.36 (s, 9 H).
[0730] [0730] Intermediate P111: 1- (Cyclobutylmethyl) azetidine-3-sulfonamide
[0731] [0731] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclobutanecarboxaldehyde. The title compound (145 mg, 11% yield) was used without further purification.
[0732] [0732] 1H NMR (DMSO-d6): δ = 6.88 (s, 2 H), 3.87 (m, 1 H), 3.43 (t, 2 H), 3.29 - 3.18 (m, 2 H), 2.39 (d, 2 H), 2.22 (dt, 1 H), 1.98 - 1.85 (m, 2 H), 1.77 (m, 2 H) , 1.67 - 1.49 (m, 2 H).
[0733] [0733] Intermediate P112: 1- (2- (Hydroxyimino) propyl) azetidine-3-sulfonamide
[0734] [0734] Step A: 1- (2-Oxopropyl) azetidine-3-sulfonamide
[0735] [0735] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and chloroacetone to provide the title compound (125 mg, 21% yield).
[0736] [0736] 1H NMR (CD3OD): δ = 4.06 (m, 1 H), 3.75 (td, 2 H), 3.60 - 3.49 (m, 4 H), 2.07 (s , 3 H).
[0737] [0737] Step B: 1- (2- (Hydroxyimino) propyl) azetidine-3-sulfonamide
[0738] [0738] A solution of 1- (2-oxopropyl) azetidine-3-sulfonamide (138 mg, 0.72 mmol) and 7M ammonia in methanol (4.1 mL, 28.7 mmol) was cooled to 0 ° C and then hydroxylamine-O-sulfonic acid (81 mg 0.72 mmol) was added. After stirring for 3 hours, the reaction mixture was filtered over cotton and the residue was washed extensively with methanol. The filtrates were combined and then concentrated in vacuo. The residue was dissolved in methanol (10 ml) and then triethylamine (0.1 ml, 0.72 mmol) was added. The mixture was cooled in an ice bath and iodine (183 mg, 0.72 mmol) was added in small portions. After being stirred for 5 minutes, the mixture was concentrated in vacuo. The crude product was suspended in methanol, coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (18 mg, 12% yield).
[0739] [0739] 1H NMR (CD3OD): δ = 4.16 - 4.01 (m, 1 H), 3.82 - 3.72 (m, 2 H), 3.60 (dd, 2 H), 3 , 33 (p, 2 H), 1.85 (s, 3 H).
[0740] [0740] Intermediate P113: 1- (1-Hydroxypropan-2-yl) azetidine-3-sulfonamide
[0741] [0741] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and hydroxyacetone. The title compound (36 mg, 18% yield) was used without further purification.
[0742] [0742] 1H NMR (DMSO-d6): δ = 6.85 (s, 2 H), 4.41 (t, 1 H), 3.83 (t, 1 H), 3.45 (dt, 2 H), 3.27 - 3.17 (m, 3 H), 3.05 (dd, 2 H), 0.78 (d, 3 H).
[0743] [0743] Intermediate P114: 1- (1,1-Difluoropropan-2-yl) azetidine-3-sulfonamide
[0744] [0744] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1,1-pentanone. The title compound (81 mg, 38% yield) was used without further purification.
[0745] [0745] 1H NMR (DMSO-d6): δ = 6.93 (s, 2 H), 5.73 (td, 1 H), 3.90 (m, 1 H), 3.55 (q, 2 H), 3.44 (dd, J 2 H), 2.68 - 2.57 (m, 1 H), 0.90 (d, 3 H).
[0746] [0746] Intermediate P115: 1-Allylazetidine-3-sulfonamide
[0747] [0747] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and allybromide to provide the title compound (56 mg, 32% yield).
[0748] [0748] 1H NMR (DMSO-d6): δ = 6.90 (s, 2 H), 5.77 - 5.57 (m, 1 H), 5.22 - 4.96 (m, 2 H) , 3.96 - 3.82 (m, 1 H), 3.44 (t, 2 H), 3.31 - 3.22 (m, 2 H), 3.01 (dt, 2 H).
[0749] [0749] Intermediate P116: 1- (Prop-2-in-1-yl) azetidine-3-sulfonamide
[0750] [0750] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and propargyl bromide (80% by weight of toluene ) to provide the title compound (21 mg, 15% yield).
[0751] [0751] 1H NMR (DMSO-d6): δ = 6.91 (s, 2 H), 3.86 (m, 1 H), 3.43 (dt, 4 H), 3.20 (d, 2 H), 3.16 - 3.12 (m, 1 H).
[0752] [0752] Intermediate P117: 1- (3-Hydroxypropyl) azetidine-3-sulfonamide
[0753] [0753] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 3-bromo-1-propanol title compound (60 mg, 38% yield).
[0754] [0754] 1H NMR (DMSO-d6): δ = 6.91 (s, 2 H), 3.89 (m, 1 H), 3.49 (t, 2 H), 3.37 (t, 2 H), 3.32 - 3.24 (m, 2 H), 2.47 - 2.41 (m, 2 H), 1.39 (p, 2 H).
[0755] [0755] Intermediate P118: 1-Neopentylazetidine-3-sulfonamide
[0756] [0756] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and pivalaldehyde. The title compound (71 mg, 35% yield) was used without further purification.
[0757] [0757] 1H NMR (DMSO-d6): δ = 6.90 (s, 2 H), 3.92 (m, 1 H), 3.57 (t, 2 H), 3.39 - 3.29 (m, 2 H), 2.20 (s, 2 H), 0.80 (s, 9 H).
[0758] [0758] Intermediate P119: 1 - ((Trimethylsilyl) methyl) azetidine-3-sulfonamide
[0759] [0759] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine hydrochloride
[0760] [0760] 1H NMR (DMSO-d6): δ = 6.92 (s, 2H), 3.89 (t, 1H), 3.61 (bs, 2H), 3.31 (bs, 2H), 2 , 07 (s, 2H), -0.01 (s, 9H).
[0761] [0761] Intermediate P120: 1- (2-Hydroxypropyl) azetidine-3-sulfonamide
[0762] [0762] To a solution of 1- (2-oxopropyl) azetidine-3-sulfonamide (Intermediate P112, step A, 125 mg, 0.65 mmol) in methanol (10 mL) was added sodium borohydride (29 mg , 0.78 mmol). After stirring for 4 hours at room temperature, more sodium borohydride (7.4 mg, 0.2 mmol) was added. After stirring overnight, the reaction mixture was quenched with water (1.0 ml) and then concentrated in vacuo. The crude product was suspended in methanol, coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (11 mg, 8% yield).
[0763] [0763] 1H NMR (CD3OD): δ = 4.09 - 3.96 (m, 1 H), 3.77 - 3.64 (m, 3 H), 3.61 - 3.48 (m, 2 H), 2.55 - 2.44 (m, 2 H), 1.12 (d, 3 H).
[0764] [0764] Intermediate P121: 1- (4-Hydroxybutyl) azetidine-3-sulfonamide
[0765] [0765] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 4-bromo-1-butanol to provide the title compound (41 mg, 20% yield).
[0766] [0766] 1H NMR (DMSO-d6): δ = 6.98 (s, 2 H), 3.93 (m, 1 H), 3.57 (t, 2 H), 3.36 (t, 4 H), 3.16 (d, 1 H), 2.50 - 2.42 (m, 2 H), 1.47 - 1.21 (m, 4 H).
[0767] [0767] Intermediate P122: 1- (2- (3-Methyl-3H-diazirin-3-yl) ethyl) azetidine-3-sulfonamide
[0768] [0768] Step A: 2- (3-Methyl-3H-diazirin-3-yl) ethan-1-ol
[0769] [0769] cooled liquid ammonia (-78 ° C, 30 ml) was added 4-hydroxy-2-butanone (5.3 ml, 60.5 mmol). The solution was stirred at - 40 ° C for 4 hours and then cooled back to -78 ° C. To the cooled mixture, a solution of hydroxylamine-O-sulfonic acid (7.6 g, 67 mmol) in methanol (60 ml) was added dropwise. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The suspension was filtered and the residue was washed extensively with methanol. The filtrates were combined and concentrated in vacuo to about 100 ml and then degassed by passing nitrogen through the filtrates for 20 minutes. The solution was cooled in an ice bath and then triethylamine (7.5 ml, 53.8 mmol) was added followed by iodine (5.0 g, 19.7 mmol). After stirring for 1 hour, another batch of iodine (4.0 g, 15.8 mmol) was added. After 5 minutes, the reaction mixture was concentrated in vacuo to about 100 ml, then brine was added. The aqueous solution was extracted three times with diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo. Vacuum distillation (90 ° C, 10-2 mbar) gave the title compound as a yellow oil (226 mg, 3% yield).
[0770] [0770] 1H NMR (CDCl3): δ = 3.53 (t, 2 H), 1.73 (s, 1 H), 1.64 (t, 2 H), 1.07 (s, 3 H) .
[0771] [0771] Step B: 2- (3-Methyl-3H-diazirin-3-yl) ethyl methanesulfonate
[0772] [0772] A solution of 2- (3-methyl-3H-diazirin-3-yl) ethan-1-ol (100 mg, 1.0 mmol) and triethylamine (160 µL, 1.15 mmol) in dichloromethane (5 ml) was cooled in an ice bath. To the cooled solution, methanesulfonyl chloride (93 µL, 1.2 mmol) was added. The reaction mixture was stirred for 1.5 hours in the ice bath, then saturated ammonium chloride was added and the organic layer was separated. The aqueous layer was extracted once with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound (178 mg, quantitative yield) which was used without further purification.
[0773] [0773] 1H NMR (CDCl3): δ = 4.13 (t, 2 H), 3.05 (s, 3 H), 1.79 (t, 2 H), 1.09 (s, 3 H) .
[0774] [0774] Step C: 1- (2- (3-Methyl-3H-diazirin-3-yl) ethyl) azetidine-3-sulfonamide
[0775] [0775] To a solution of 2- (3-methyl-3H-diazirin-3-yl) ethyl methanesulfonate (178 mg, 1.0 mmol) in acetonitrile (20 mL) was added azetidine-3-sulfonamide hydrochloride ( 344 mg, 2.0 mmol) and then potassium carbonate (1.1 g, 8.0 mmol). The reaction mixture was stirred overnight at 55 ° C and then potassium iodide (158 mg, 1.0 mmol) and N, N-dimethylformamide (2 ml) were added. The reaction mixture was stirred for 6 hours at 60 ° C, then filtered through a glass filter. The residue was washed with methanol. The filtrates were combined and concentrated in vacuo. The crude product was suspended in methanol, coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (16 mg, 7% yield).
[0776] [0776] 1H NMR (DMSO-d6): δ = 6.90 (s, 2 H), 3.92 - 3.82 (m, 1 H), 3.44 (t, 2 H), 3.21 (t, 2 H), 2.27 (t, 2 H), 1.25 (t, 2 H), 0.97 (s, 3 H).
[0777] [0777] Intermediate P123: 1 - (((1-Methyl-6-oxo-1,6-dihydropyridin-3-yl) methyl) azetidine-3-sulfonamide
[0778] [0778] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde. The title compound (116 mg, 62% yield) was used without further purification.
[0779] [0779] 1H NMR (DMSO-d6): δ = 7.54 (s, 1 H), 7.29 (d, 1 H), 6.93 (s, 2 H), 6.32 (d, 1 H), 3.97 - 3.79 (m, 1 H), 3.43 (t, 2 H), 3.37 (s, 3 H), 3.31 - 3.24 (m, 4 H) .
[0780] [0780] Intermediate P124: 1 - (((1-Methyl-2-oxo-1,2-dihydropyridin-4-yl) methyl) azetidine-3-sulfonamide
[0781] [0781] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-methyl-2-oxo-1,2-dihydropyridine-4-carbaldehyde. The title compound (51 mg, 27% yield) was used without further purification.
[0782] [0782] 1H NMR (DMSO-d6): δ = 7.57 (d, 1 H), 6.98 (s, 2 H), 6.23 (s, 1 H), 6.07 (d, 1 H), 4.00 - 3.79 (m, 1 H), 3.49 (t, 2 H), 3.42 (s, 3 H), 3.40 - 3.33 (m, 4 H) .
[0783] [0783] Intermediate P125: 1- (2- (Tetrahydrofuran-3-yl) ethyl) azetidine-3-sulfonamide
[0784] [0784] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2- (oxolan-3-yl) acetaldehyde. The title compound (90 mg, 27% yield) was used without further purification.
[0785] [0785] 1H NMR (DMSO-d6): δ = 6.93 (s, 2 H), 3.90 (m, 1 H), 3.75 (t, 1 H), 3.68 (dt, 1 H), 3.59 (q, 1 H), 3.47 (t, 2 H), 3.26 (t, 3 H), 2.45 - 2.33 (m, 2 H), 2.09 (m, 1 H), 2.00 - 1.86 (m, 1 H), 1.42 (dt, 1 H), 1.30 (q, 2 H).
[0786] [0786] Intermediate P126: 1 - (((Tetrahydrofuran-3-yl) methyl) azetidine-3-sulfonamide
[0787] [0787] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tetrahydrofuran-3-one. The title compound (85 mg, 39% yield) was used without further purification.
[0788] [0788] 1H NMR (CD3OD): δ = 4.06 (t, 1 H), 3.88 - 3.66 (m, 5 H), 3.59 (t, 2 H), 3.43 (dd , 1 H), 2.66 (d, 2 H), 2.35 - 2.22 (m, 1 H), 2.12 - 1.97 (m, 1 H), 1.65 - 1.52 (m, 1 H).
[0789] [0789] Intermediate P127: 1 - (((Tetrahydrofuran-2-yl) methyl) azetidine-3-sulfonamide
[0790] [0790] To a solution of (tetrahydrofuran-2-yl) methanol (291 µL, 3.00 mmol) in dichloromethane (30 mL) was added Dess-Martin periodinane (1.40 g, 3.30 mmol) . The reaction mixture was stirred at room temperature. After stirring for 1 hour, the solution was washed once with saturated sodium bicarbonate. To the organic solution was added acetonitrile (10 ml), azetidine-3-sulfonamide hydrochloride (172 mg, 1.00 mmol), triethylamine (0.17 ml, 1.20 mmol) and then sodium triacetoxyborohydride (265 mg, 1.25 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude product was suspended in methanol, coated in Agilent's Hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to provide the title compound (77 mg, 35% yield).
[0791] [0791] 1H NMR (DMSO-d6): δ = 6.90 (s, 2 H), 3.90 (m, 1 H), 3.69 (q, 2 H), 3.60 - 3.46 (m, 3 H), 3.43 - 3.33 (m, 2 H), 2.44 (d, 2 H), 1.89 - 1.68 (m, 3 H), 1.47 (q , 1 H).
[0792] [0792] Intermediate P128: (1R, 3R, 5S) -8- (1-Methylazetidin-3-yl) -8-azabicyclo [3.2.1] octane-3-sulfonamide
[0793] [0793] Step A: tert-butyl ((1R, 3R, 5S) -3-Sulfamoyl-8-azabicyclo [3.2.1] octan-8-yl) azetidine-1-carboxylate
[0794] [0794] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R *, 3R *, 5S *) - 8-azabicyclo [3.2.1] octane-3-sulfonamide and 1-boc -3-azetidinone. The title compound (286 mg, 41% yield) was used without further purification.
[0795] [0795] 1H NMR (DMSO-d6): δ = 6.62 (s, 2 H), 3.82 (s, 2 H), 3.49 (s, 2 H), 3.20 - 3.04 (m, 4 H), 2.36 - 2.18 (m, 2 H), 1.85 - 1.74 (m, 2 H), 1.72 - 1.64 (m, 2 H), 1 , 58 (dd, 2 H), 1.35 (s, 9 H).
[0796] [0796] Step B: (1R, 3R, 5S) -8- (Azetidin-3-yl) -8-azabicyclo [3.2.1] octane-3-sulfonamide dihydrochloride
[0797] [0797] To a solution of tert-butyl 3 - ((1R, 3R, 5S) -3-sulfamoyl-8-azabicyclo [3.2.1] octan-8-yl) azetidine-1-carboxylate (286 mg, 0, 83 mmol) in dichloromethane (10 mL) hydrochloric acid (4 M in dioxane, 2.1 mL, 8.3 mmol) was added. After stirring for 2 hours, the reaction mixture was concentrated in vacuo to provide the title compound (237 mg, 89% yield), which was used without further purification.
[0798] [0798] 1H NMR (DMSO-d6): δ = 9.86 (bs, 1H), 9.01 (bs, 1H), 6.95 (d, J = 6.1 Hz, 2H), 4.46 (bs, 2H), 4.21 - 3.84 (m, 6H), 3.42 - 3.25 (m, 1H), 2.83 (bs, 2H), 2.30 (t, 2H), 2.20 - 1.97 (m, 4H).
[0799] [0799] Step C: (1R, 3R, 5S) -8- (1-Methylazetidin-3-yl) -8-azabicyclo [3.2.1] octane-3-sulfonamide
[0800] [0800] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R, 3R, 5S) -8- (azetidin-3-yl) -8-azabicyclo [3.2.1] octane-3 -sulfonamide dihydrochloride and formaldehyde
[0801] [0801] 1H NMR (CD3OD): δ = 4.15 (bs, 3 H), 3.92 (bs, 3 H), 2.93 (s, 3 H), 2.61 - 2.39 (m , 2 H), 2.03 - 1.89 (m, 4 H), 1.89 - 1.63 (m, 4 H).
[0802] [0802] Intermediate P129: 4-Methoxy-1-methylpyrrolidine-3-sulfonamide
[0803] [0803] Step A: Benzyl 3-methoxy-4-sulfamoylpyrrolidine-1-carboxylate
[0804] [0804] To a solution of ammonia in methanol (7M, 42 mL) was added a solution of benzyl 3- (chlorosulfonyl) -4-methoxypyrrolidine-1-carboxylate (500 mg, 1.49 mmol) in dichloromethane (10 mL). After stirring for 1.5 hours at room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and then concentrated in vacuo to provide the title compound (236 mg, 50% yield).
[0805] [0805] 1H NMR (DMSO-d6): δ = 7.43 - 7.28 (m, 5 H), 7.21 (s, 2 H), 5.08 (s, 2H), 4.24 ( bs, 1 H), 3.82 - 3.64 (m, 3 H), 3.66 - 3.55 (m, 1 H), 3.46 (d, 1 H), 3.29 (s, 3 H).
[0806] [0806] Step B: 4-Methoxypyrrolidine-3-sulfonamide
[0807] [0807] Prepared as described for azetidine-3-sulfonamide (Intermediate P33) from benzyl 3-methoxy-4-sulfamoyl pyrrolidine-1-carboxylate to provide the title compound (91 mg, 67% yield) which was used without additional purification.
[0808] [0808] 1H NMR (DMSO-d6): δ = 6.98 (s, 2 H), 4.08 (dt, 1 H), 3.76 - 3.62 (m, 1 H), 3.56 - 3.33 (m, 3 H), 3.30 - 3.15 (m, 3 H), 2.99 (dd, 1 H), 2.83 (t, 1 H).
[0809] [0809] Step C: 4-Methoxy-1-methylpyrrolidine-3-sulfonamide
[0810] [0810] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 4-methoxypyrrolidine-3-sulfonamide and formaldehyde (37% by weight in water). The title compound (mixture of diastereoisomers, 17 mg, 35% yield) was used without further purification.
[0811] [0811] 1H NMR (CD3OD) of the major diastereomer: δ = 4.21 - 4.11 (m, 1 H), 3.65 (td, 1 H), 3.40 - 3.35 (m, 2 H ), 3.27 - 3.18 (m, 1 H), 2.90 (d, 1 H), 2.81 (dd, 1 H), 2.70 - 2.52 (m, 2 H), 2.35 (s, 3 H).
[0812] [0812] Intermediate P130: 1-Ethyl-4-methoxypyrrolidine-3-sulfonamide
[0813] [0813] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 4-methoxypyrrolidine-3-sulfonamide and acetaldehyde. The title compound (mixture of diastereoisomers, 12 mg, 23% yield) was used without further purification.
[0814] [0814] 1H NMR (CD3OD) of the major diastereomer: δ = 4.18 (d, 1H), 3.75 - 3.56 (m, 1 H), 3.38 (s, 3 H), 3.13 - 2.94 (m, 2 H), 2.72 (dd, 2 H), 2.66 - 2.50 (m, 2 H), 1.14 (dd, 3 H).
[0815] [0815] Intermediate P131: 1- (Oxetan-3-yl) azetidine-3-sulfonamide
[0816] [0816] To a solution of azetidine-3-sulfonamide (22 mg, 0.16 mmol) in methanol (5 mL) was added oxetan-3-one (23 mg, 0.32 mmol) and 2 drops of acetic acid. Next, sodium cyanoborohydride (20 mg, 0.32 mmol) was added. The reaction mixture was stirred for 18 hours at room temperature. Then, the solvents were evaporated to provide the crude title compound (80 mg) as an oil, which was used without further purification.
[0817] [0817] The NMR data for the crude product was very complex. LCMS showed the desired mass.
[0818] [0818] LCMS: m / z 193 (M + H) + (ES +); 191 (M-H) - (ES-).
[0819] [0819] Intermediate P132: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide
[0820] [0820] Step A: 6-Chlorine-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide
[0821] [0821] Bis (4-methoxybenzyl) amine (3.71 g, 14.4 mmol) was added to a solution of 2-chloropyridine-5-sulfonyl chloride (3.00 g, 13.7 mmol) and triethylamine (2.49 mL, 17.8 mmol) in DCM (50 mL) at 0 ° C. The reaction was stirred at 0 ° C for 15 minutes and then allowed to warm to room temperature and stirred for 20 hours. Then, the reaction mixture was diluted with DCM (150 ml), washed with a saturated aqueous solution of NH4Cl (3x 40 ml) and brine (40 ml), dried over MgSO4, filtered and concentrated in vacuo to provide the crude product. like a cream solid. The crude product was triturated with TBME (70 ml), filtered and rinsed with TBME (2 x 40 ml) to provide the title compound (4.97 g, 83% yield) as an off-white solid.
[0822] [0822] 1H NMR (DMSO-d6) δ 8.76 (dd, J = 2.6, 0.7 Hz, 1H), 8.19 (dd, J = 8.4, 2.6 Hz, 1H) , 7.69 (dd, J = 8.4, 0.7 Hz, 1H), 7.08 - 7.02 (m, 4H), 6.83 - 6.76 (m, 4H), 4.29 (s, 4H), 3.71 (s, 6H). LCMS: m / z 433.3 (M + H) + (ES +).
[0823] [0823] Step B: 6-Hydroxy-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide
[0824] [0824] A suspension of 6-chloro-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide (0.508 g, 1.17 mmol) in ethane-1,2-diol (10 mL) was treated with KOH 2 M (aq) (2.4 mL, 4.80 mmol). The resulting suspension was stirred at 140 ° C for 18 hours. Then, the reaction mixture was treated with additional 2 M KOH (aq) (0.6 mL, 1.2 mmol, 1 eq) and heated at 140 ° C for an additional 6 hours, and additional 2 M KOH (aq) (aq) (0.6 mL, 1.2 mmol, 1 eq) and heated to 140 ° C for an additional 18 hours. Then, the reaction mixture was diluted with water (40 ml) and DCM (30 ml). Brine (5 ml) was added and the organic layer was collected. The aqueous phase was extracted with DCM (5 x 30 ml). The combined organic extracts were washed with water (10 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue was dried under reduced pressure at 50 ° C overnight to provide the title compound (542 mg, 100% yield).
[0825] [0825] 1H NMR (DMSO-d6) δ 12.17 (s, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.63 (dd, J = 9.6, 2, 9 Hz, 1H), 7.11 - 7.02 (m, 4H), 6.87 - 6.79 (m, 4H), 6.37 (d, J = 9.6 Hz, 1H), 4, 21 (s, 4H), 3.72 (s, 6H). LCMS: m / z 415.4 (M + H) + (ES +), 413.4 (M-H) - (ES-).
[0826] [0826] Step C: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide and 6-isopropoxy-N, N-bis (4-methoxybenzyl ) pyridine-3-sulfonamide
[0827] [0827] Sodium hydride (60 wt.% Dispersion in mineral oil) (36 mg, 0.91 mmol) was added to a mixture of 6-hydroxy-N, N-bis (4-methoxybenzyl) pyridine-3- sulfonamide (0.40 g, 0.869 mmol) and lithium bromide (0.154 g, 1.737 mmol) in DME: DMF (5 mL, 4: 1) at 0 ° C. The mixture was stirred at 0 ° C for 10 minutes and then at room temperature for another 10 minutes. Then, 2-iodopropane (0.10 ml, 1.04 mmol) was added and the mixture was stirred at room temperature for 46 hours. The reaction mixture was heated to 65 ° C for 17 hours, cooled to room temperature and quenched with saturated aqueous NH4Cl (5mL) and diluted with EtOAc (100 ml). The organic layer was washed with water (15 ml) and brine (3 x 15 ml), dried over MgSO 4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-100% EtOAc / isohexane) to provide 1-isopropyl-N, N-bis (4-methoxybenzyl) -6-oxo-1,6- dihydropyridine-3-sulfonamide (0.28 g, 70% yield) as a white solid and 6-isopropoxy-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide (0.11 g, 27% income).
[0828] [0828] 1-Isopropyl-N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide:
[0829] [0829] 1H NMR (CDCl3) δ 7.91 (d, J = 2.7 Hz, 1H), 7.41 (dd, J = 9.6, 2.6 Hz, 1H), 7.09 - 7 , 04 (m, 4H), 6.84 - 6.79 (m, 4H), 6.54 (dd, J = 9.6, 0.5 Hz, 1H), 5.17 (sept, J = 6 , 8 Hz, 1H), 4.26 (s, 4H), 3.79 (s, 6H), 1.34 (d, J = 6.8 Hz, 6H). LCMS: m / z 457.4 (M + H) + (ES +).
[0830] [0830] 6-Isopropoxy-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide:
[0831] [0831] 1H NMR (CDCl3) δ 8.60 - 8.55 (m, 1H), 7.84 - 7.79 (m, 1H), 7.06 - 6.99 (m, 4H), 6, 81 - 6.75 (m, 4H), 6.72 - 6.67 (m, 1H), 5.43 - 5.33 (m, 1H), 4.26 (s, 4H), 3.78 ( s, 6H), 1.37 (d, J = 6.2 Hz, 6H). LCMS: m / z 457.4 (M + H) + (ES +).
[0832] [0832] Step D: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide
[0833] [0833] TFA (0.43 ml, 5.64 mmol) was added to a solution of 1-isopropyl-N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-
[0834] [0834] Intermediate P133: 4-Isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide
[0835] [0835] Step A: 2- (Benzylthio) -5-chloropyrazine
[0836] [0836] To a solution of NaH (0.755 g, 18.88 mmol) in THF (55 mL) was added benzyl mercaptan (1.5 mL, 12.68 mmol) at 0 ° C. The reaction mixture was diluted with THF (20 ml) and stirred at 0 ° C for 10 minutes. Then, a solution of 2,5-dichloropyrazine (1.370 ml, 13.42 mmol) in THF (10 ml) was added dropwise. The reaction mixture was stirred at 0 ° C for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0 ° C, MeOH (1 ml) was added carefully and stirred for 5 minutes. Water (20 ml) was added, then DCM (150 ml) and the biphasic mixture was passed through a phase separator. The organic phase was concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-3% EtOAc / isohexane) to provide the title compound (2.373 g, 72% yield) as a light yellow oil.
[0837] [0837] 1H NMR (DMSO-d6) δ 8.68 (d, J = 1.5 Hz, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.34 - 7.29 (m, 2H), 7.28 - 7.23 (m, 1H), 4.46 (s, 2H).
[0838] [0838] Step B: 5-Chlorine-N, N-bis (4-methoxybenzyl) pyrazine-2-sulfonamide Cl Cl N N N N PMB O S N s The PMB
[0839] [0839] A solution of 2- (benzylthio) -5-chloropyrazine (0.916 g, 3.87 mmol) in DCM (15 mL, 233 mmol) was treated with water (1.5 mL) and the resulting suspension was cooled between -5 and 0 ° C. Sulfuryl chloride (2.2 ml, 26.2 mmol) was added and the reaction mixture was stirred for 2 hours, maintaining the temperature between -5 and 0 ° C. An ice / water paste (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (2 x 10 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to provide crude 5-chloropyrazine-2-sulfonyl intermediate chloride as a pale yellow liquid (1.198 g).
[0840] [0840] A suspension of bis (4-methoxybenzyl) amine hydrochloride (1.198 g, 4.08 mmol) and TEA (1.2 mL, 8.61 mmol) in DCM (15 mL) at 0 ° C was treated with a solution of 5-chloropyrazine-2-sulfonyl chloride (0.824 g, 3.87 mmol) in DCM (5 mL) dropwise. The resulting solution was stirred at 0 ° C for 15 minutes and then allowed to warm to room temperature over 16 hours. A saturated aqueous solution of NH4Cl (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (2 x 10 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc / isohexane) to provide the title compound (1.312 g, 77% yield) as a white solid.
[0841] [0841] 1H NMR (CDCl3) δ 8.78 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.11 - 7.07 (m , 4H), 6.79 - 6.75 (m, 4H), 4.43 (s, 4H), 3.79 (s, 6H).
[0842] [0842] Step C: N, N-Bis (4-methoxybenzyl) -5-oxo-4,5-dihydropyrazine-2-sulfonamide
[0843] [0843] A suspension of 5-chloro-N, N-bis (4-methoxybenzyl) pyrazine-2-sulfonamide (1.31 g, 2.99 mmol) in glycol (15 mL) was treated with 2 M KOH (aq. ) (7.5 mL, 15 mmol). The resulting suspension was stirred at 140 ° C for 18 hours. The reaction mixture was then allowed to cool to room temperature, diluted with water (100 ml) and neutralized with saturated aqueous NH4Cl solution (30 ml). The white precipitate was collected by filtration, washed with water and dried at 60 ° C under vacuum to provide the title compound (1.094 g, 79% yield) as a pale yellow solid.
[0844] [0844] 1H NMR (DMSO-d6) δ 7.94 (d, J = 1.2 Hz, 1H), 7.89 (br s, 1H), 7.10 - 7.06 (m, 4H), 6.84 - 6.79 (m, 4H), 4.28 (s, 4H), 3.71 (s, 6H). A proton exchange was not observed. LCMS: m / z 438.2 (M + Na) + (ES +); 414.2 (M-H) - (ES-).
[0845] [0845] Step D: 4-Isopropyl-N, N-bis (4-methoxybenzyl) -5-oxo- 4,5-dihydropyrazine-2-sulfonamide
[0846] [0846] A suspension of N, N-bis (4-methoxybenzyl) -5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.503 g, 1.090 mmol) and lithium bromide (0.192 g, 2.167 mmol) in DME: DMF (6 mL, 4: 1) at 0 ° C was treated with NaH
[0847] [0847] 1H NMR (DMSO-d6) δ 8.07 (d, J = 1.0 Hz, 1H), 7.96 (d, J = 0.9 Hz, 1H), 7.13 - 7.09 (m, 4H), 6.83 - 6.79 (m, 4H), 4.78 (sept, J = 6.5 Hz, 1H), 4.33 (s, 4H), 3.71 (s, 6H), 1.34 (d, J = 6.8 Hz, 6H). LCMS: m / z 480.3 (100, [M + Na] +), 458.5 (9, [M + H] +) (ES +).
[0848] [0848] Step E: 4-Isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide
[0849] [0849] A solution of 4-isopropyl-N, N-bis (4-methoxybenzyl) -5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.287 g, 0.565 mmol) in DCM (1 ml) was treated with TFA (1 mL, 12.98 mmol) at room temperature. The resulting solution was stirred for 28 hours. Then, the reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (4 g column, 0-10% MeOH / DCM) to provide the title compound (0.116 g, 94% yield) as a white solid.
[0850] [0850] 1H NMR (DMSO-d6) δ 8.14 (d, J = 1.0 Hz, 1H), 8.08 (d, J = 1.0 Hz, 1H), 7.40 (s, 2H ), 4.88 (sept, J = 6.7 Hz, 1H), 1.36 (d, J = 6.8 Hz, 6H). LCMS: 216.1 (M-H) - (ES-).
[0851] [0851] Intermediate P134: 1-Isopropylazetidine-3-sulfonamide
[0852] [0852] Step A: tert-Butyl 3-Hydroxy-azetidine-1-carboxylate OH
[0853] [0853] To a solution of azetidin-3-ol hydrochloride (45 g, 410.75 mmol, 1 eq) in MeOH (1.2 L) was added TEA (83.13 g, 821.51 mmol, 2 eq ) and di-tert-butyl dicarbonate (89.65 g, 410.75 mmol, 1 eq). The mixture was stirred at 25 ° C for 16 hours. Then, the reaction mixture was concentrated in vacuo. The residue was redissolved in EtOAc (1 L). The mixture was washed with H2O (3 x 500 ml) and brine (3 x 500 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide the title compound (65 g, 91% yield) as a yellow oil, that was used directly in the next step.
[0854] [0854] 1H NMR (CDCl3) δ 4.59 (s, 1 H), 4.19-4.12 (m, 2 H), 3.84-3.79 (m, 2 H), 1.45 (s, 9 H).
[0855] [0855] Step B: tert-butyl ((methylsulfonyl) oxy) azetidine-1-carboxylate THE OH The S
[0856] [0856] To a solution of tert-butyl 3-hydroxy-azetidine-1-carboxylate (65 g, 375.27 mmol, 1 eq) and TEA (113.92 g, 3 eq) in THF (650 ml) Methanesulfonyl chloride (51.58 g, 450.32 mmol, 1.2 eq) is added at 0 ° C. Then, the mixture was stirred at 25 ° C for 12 hours. The reaction mixture was diluted with EtOAc (2 L), washed with water (3 x 1.5 L) and brine (3 x 1.5 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide the title compound (90 g, 95% yield) as a yellow oil, which was used directly in the next step.
[0857] [0857] 1H NMR (CDCl3) δ 5.25-5.20 (m, 1 H), 4.32-4.27 (m, 2 H), 4.14-4.10 (m, 2 H) , 3.08 (s, 3 H) and 1.46 (s, 9 H).
[0858] [0858] Step C: tert-butyl 3- (acetylthio) azetidine-1-carboxylate The S The S
[0859] [0859] To a solution of tert-butyl 3- ((methylsulfonyl) oxy) azetidine-1-carboxylate (90 g, 358.14 mmol, 1 eq) in DMF (1.5 L) was added potassium ethanothioate (49 , 08 g, 429.77 mmol, 1.2 eq). The mixture was stirred at 80 ° C for 12 hours. Then, the reaction mixture was diluted with EtOAc (3 L), washed with saturated aqueous NH4Cl solution (3 x 2 L) and brine (3 x 2 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 100: 1 to 20: 1) to provide the title compound (54 g, 65% yield) as a yellow oil.
[0860] [0860] 1H NMR (CDCl3) δ 4.37 (t, 2 H), 4.17-4.14 (m, 1 H), 3.82 (dd, 2 H), 2.34 (s, 3 H) and 1.44 (s, 9 H).
[0861] [0861] Step D: tert-Butyl 3- (Chlorosulfonyl) azetidine-1-carboxylate
[0862] [0862] To a solution of tert-butyl 3- (acetylthio) azetidine-1-carboxylate (5 g, 21.62 mmol, 1 eq) in AcOH (200 mL) and H2O (20 mL) was added NCS (8 , 66 g, 64.85 mmol, 3 eq). The reaction mixture was stirred at 25 ° C for 1 hour. Then, the reaction mixture was diluted with DCM (300 ml), washed with water (3 x 300 ml) and brine (3 x 300 ml), dried over anhydrous Na2SO4 and filtered. The solution was used directly in the next step.
[0863] [0863] Step E: tert-Butyl 3-Sulfamoylazetidine-1-carboxylate
[0864] [0864] Using a solution of tert-butyl 3- (chlorosulfonyl) azetidine-1-carboxylate (55.28 g, crude) in DCM (1.5 L), NH3 was bubbled through for 30 minutes at 0 ° C . Then, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and EtOAc (21 ml, 20: 1) to provide the title compound (27 g, 53% yield) as a white solid.
[0865] [0865] 1H NMR (DMSO-d6) δ 7.16 (br s, 2 H), 4.18-4.03 (m, 2 H), 4.03-3.90 (m, 3 H) and 1.38 (s, 9 H).
[0866] [0866] Step F: tert-butyl 3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) azetidine-1-carboxylate THE
[0867] [0867] To a solution of tert-butyl 3-sulfamoylazetidine-1-carboxylate (1 g, 4.23 mmol, 1 eq) in DMF (10 mL) was added NaH (507 mg, 12.69 mmol, 60% by weight of mineral oil, 3 eq) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes. Then, 1- (chloromethyl) -4-methoxybenzene (1.99 g, 12.69 mmol, 3 eq) was added. The mixture was stirred at 25 ° C for 14 hours. Then, the reaction mixture was diluted with EtOAc (50 ml), washed with a saturated aqueous solution of NH4Cl (3 x 30 ml) and brine (3 x 30 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with MeOH (10 ml) to provide the title compound (1 g, 50% yield) as a white solid.
[0868] [0868] 1H NMR (CDCl3) δ 7.17 (d, 4 H), 6.91-6.88 (m, 4 H), 4.30 (s, 4 H), 4.22 (dd, 2 H), 4.01 (t, 2 H), 3.83 (s, 6 H), 3.75-3.62 (m, 1 H) and 1.44 (s, 9 H). LCMS: m / z 499.2 (M + Na) + (ES +).
[0869] [0869] Step G: N, N-Bis (4-methoxybenzyl) azetidine-3-sulfonamide O O O N O N S S O O N HN THE O O THE
[0870] [0870] To a solution of tert-butyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) azetidine-1-carboxylate (7 g, 14.69 mmol, 1 eq) and 2,6-lutidine ( 4.72 g, 44.06 mmol, 3 eq) in DCM (80 ml) trimethylsilyl trifluoromethanesulfonate (9.79 g, 44.06 mmol, 3 eq) was added at 0 ° C. Then, the reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (20 ml) and extracted with DCM (3 x 50 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (40 ml, 1: 1) to provide the title compound (4 g, 72% yield) as a white solid.
[0871] [0871] 1H NMR (CD3OD) δ 7.21 (d, 4 H), 6.94-6.85 (m, 4 H), 4.35 (s, 4 H), 4.28-4.11 (m, 5 H) and 3.81 (s, 6 H). LCMS: m / z 377.2 (M + H) + (ES +).
[0872] [0872] Step H: 1-Isopropyl-N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide
[0873] [0873] To a solution of N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (2.5 g, 6.64 mmol, 1 eq) and K2CO3 (1.38 g, 9.96 mmol, 1 , 5 eq) in MeCN (5 ml) 2-bromopropane (1.63 g, 13.28 mmol, 2 eq) was added. The mixture was stirred at 70 ° C for 12 hours. Then, H2O (10 ml) was added and the reaction mixture was extracted with EtOAc (3 x 30 ml). The combined organic layers were dried over anhydrous Na2SO4,
[0874] [0874] 1H NMR (CDCl3) δ 7.12-7.07 (m, 4 H), 6.83-6.76 (m, 4 H), 4.16 (s, 4 H), 3.74 (s, 6 H), 3.68-3.64 (m, 1 H), 3.43 (t, 2 H), 3.28 (t, 2 H), 2.38-2.29 (m , 1 H) and 0.82 (d, 6 H). LCMS: m / z 419.2 (M + H) + (ES +).
[0875] [0875] Step I: 1-Isopropylazetidine-3-sulfonamide
[0876] [0876] A solution of 1-isopropyl-N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (1 g, 2.39 mmol, 1 eq) in TFA (7.70 g, 67.53 mmol, 28.27 eq) was stirred at 25 ° C for 12 hours. Then, the reaction mixture was concentrated in vacuo. The residue was treated with MeOH (10 ml), filtered and the filtrate was adjusted with NH3, H2O (30% NH3, H2O in water) until pH = 8-9, The resulting mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.1% NH3, H2O) -MeCN) to provide the title compound (220 mg, 52% yield) as a white solid.
[0877] [0877] 1H NMR (CD3OD) δ 4.05-3.98 (m, 1 H), 3.67 (t, 2 H), 3.46 (t, 2 H), 2.59-2.48 (m, 1 H) and 0.97 (d, 6 H). Two exchangeable protons not observed. LCMS: m / z 179.1 (M + H) + (ES +).
[0878] [0878] Intermediate P135: 1-Cyclobutylazetidine-3-sulfonamide
[0879] [0879] Step A: Azetidine-3-sulfonamide
[0880] [0880] To a solution of tert-butyl 3-sulfamoylazetidine-1-carboxylate (3 g, 12.70 mmol, 1 eq, obtained according to Step E of the synthesis of intermediate P134) in DCM (10 mL) was HCl / EtOAc (12.70 mmol, 20 mL, 1 eq) is added. The mixture was stirred at 25 ° C for 1 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.05% NH3, H2O) -MeCN) to provide the title compound (0.8 g, 46% yield) as a white solid.
[0881] [0881] 1H NMR (DMSO-d6) δ 6.92 (s, 1 H), 4.23-4.19 (m, 2 H) and 3.77-3.70 (m, 3 H). Two exchangeable protons not observed. LCMS: m / z 137.1 (M + H) + (ES +).
[0882] [0882] Step B: 1-Cyclobutylazetidine-3-sulfonamide
[0883] [0883] To a solution of azetidine-3-sulfonamide (50 mg, 367.18 μmol, 1 eq) in MeOH (1 ml) was added cyclobutanone (31 mg, 440.62 μmol, 1.2 eq) and NaBH ( OAc) 3 (97 mg, 458.98 μmol, 1.25 eq). The reaction mixture was stirred at 20 ° C for 2 hours. Then, the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.05% NH3, H2O) -MeCN) to provide the title compound (12.25 mg, 18% yield) as a white solid.
[0884] [0884] 1H NMR (DMSO-d6) δ 6.92 (s, 2 H), 3.88-3.85 (m, 1 H), 3.41-3.33 (m, 2 H), 3 , 32-3.29 (m, 2 H), 3.12-3.09 (m, 1 H), 1.89-1.86 (m, 2 H) and 1.77-1.60 (m , 4 H).
[0885] [0885] Intermediate P136: 1-Ethylazetidine-3-sulfonamide
[0886] [0886] Step A: 1-Ethyl-N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide O O O O O O S I S N N HN N O O
[0887] [0887] To a solution of N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (1 g, 2.66 mmol, 1 eq, obtained according to Step G of the synthesis of intermediate P134) and K2CO3 ( 367 mg, 2.66 mmol, 1 eq) in MeCN (2 ml) iodoethane (414 mg, 2.66 mmol, 1 eq) was added. The mixture was stirred at 70 ° C for 1 hour. The reaction mixture was quenched with water (30 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over anhydrous Na2 SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (water (0.1% NH3, H2O) -MeCN) to provide the title compound (0.7 g, 22% yield, 100% purity in LCMS) as a white solid.
[0888] [0888] 1H NMR (CD3OD) δ 7.20 (d, 4 H), 6.90 (d, 4 H), 4.28 (s, 4 H), 4.00-3.93 (m, 1 H), 3.81 (s, 6 H), 3.51 (t, 2 H), 3.40 (t, 2 H), 2.53 (q, 2 H) and 0.96 (t, 3 H). LCMS: m / z 405.2 (M + H) + (ES +).
[0889] [0889] Step B: 1-Ethylazetidine-3-sulfonamide THE O O O O
[0890] [0890] A solution of 1-ethyl-N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (800 mg, 1.98 mmol, 1 eq) in TFA (82.13 g, 720.32 mmol, 364 eq) was stirred at 50 ° C for 1 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.1% NH3, H2O) -MeCN) to provide the title compound (160 mg, 47% yield, 95% purity in LCMS) as a solid White.
[0891] [0891] 1H NMR (DMSO-d6) δ 6.94 (s, 2 H), 3.95-3.86 (m, 1 H), 3.47 (t, 2 H), 3.31-3 , 25 (m, 2 H), 2.43 (q, 2 H) and 0.86 (t, 3 H). LCMS: m / z 165.1 (M + H) + (ES +).
[0892] [0892] Intermediate P137: 1- (Pyridin-3-ylmethyl) azetidine-3-sulfonamide
[0893] [0893] Step A: N, N-Bis (4-methoxybenzyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide O O O O N N
[0894] [0894] To a solution of N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (1 g, 2.66 mmol, 1 eq, obtained according to Step G of the synthesis of intermediate P134) in MeCN ( 20 ml) nicotinaldehyde (341 mg, 3.19 mmol, 1.2 eq) and NaBH (OAc) 3 (1.13 g, 5.31 mmol, 2 eq) were added. The mixture was stirred at 15 ° C for 1 hour. Then, the reaction mixture was quenched with water (80 ml) and extracted with EtOAc (6 × 100 ml). The combined organic layers were dried over Na2 SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 1: 1 to 0: 1) to provide the title compound (1.1 g, 89% yield) as an oil yellow.
[0895] [0895] 1H NMR (DMSO-d6) δ 8.53 (s, 1 H), 8.46 (s, 1 H), 7.72 (d, 1 H), 7.37-7.33 (m , 1 H), 7.13 (d, 4 H), 6.88 (d, 4 H), 4.21 - 4.17 (m, 5 H), 3.73 (s, 6 H), 3 , 61 (s, 2 H), 3.47-3.41 (m, 2 H) and 3.33-3.31 (m, 2 H).
[0896] [0896] Step B: 1- (Pyridin-3-ylmethyl) azetidine-3-sulfonamide
[0897] [0897] A solution of N, N-bis (4-methoxybenzyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (1 g, 2.14 mmol, 1 eq) in TFA (10 mL) was stirred at 10 ° C for 36 hours. Then, the reaction mixture was concentrated in vacuo. The residue was treated with MeOH (80 ml) and the mixture was stirred for an additional hour. Then, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.1% NH3, H2O) -MeCN) to provide the title compound (240 mg, 49% yield) as a white solid.
[0898] [0898] 1H NMR (DMSO-d6) δ 8.52-8.45 (m, 2 H), 7.67 (d, 1 H), 7.35 (dd, 1 H), 6.98 (s , 2 H), 3.99-3.94 (m, 1 H), 3.64 (s, 2 H), 3.54-3.49 (m, 2 H) and 3.44-3.35 (m, 2 H). LCMS: m / z 228.1 (M + H) + (ES +).
[0899] [0899] Intermediate P138: 1-Isopropylpiperidine-4-sulfonamide
[0900] [0900] Step A: Benzyl 4-Hydroxypiperidine-1-carboxylate H Cbz N N OH OH
[0901] [0901] To a solution of piperidin-4-ol (100 g, 988.66 mmol, 1 eq) in DCM (1 L) was added TEa (100.04 g, 988.66 mmol, 1 eq) and chloroformate of benzyl (168.66 g, 988.66 mmol, 1 eq) at 0 ° C. The mixture was heated to 25 ° C and stirred for 12 hours. Then, the reaction mixture was diluted with DCM (500 ml), washed with brine (3 x 500 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (220 g, 95% yield) as a yellow oil, which was used in the next step without further purification.
[0902] [0902] 1H NMR (CDCl3) δ 7.36-7.29 (m, 5 H), 5.10 (s, 2 H), 3.90-3.81 (m, 3 H), 3.15 -3.08 (m, 2 H), 1.83-1.81 (m, 2 H) and 1.47-1.45 (m, 2 H). An unobserved exchangeable proton. LCMS: m / z 258.1 (M + Na) + (ES +).
[0903] [0903] Step B: 4 - ((Methylsulfonyl) oxy) benzyl piperidine-1-carboxylate Cbz Cbz
[0904] [0904] To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (220 g, 935.06 mmol, 1 eq) in DCM (1.7 L) was added TEA (189.24 g, 1.87 mol, 2 eq). Then, mesyl chloride (128.54 g, 1.12 mol, 1.2 eq) was added dropwise at 0 ° C. The solution was heated to 25 ° C and stirred for 1 hour. Then, the reaction mixture was quenched with saturated aqueous NaHCO3 solution (1.2 L) and the two layers were separated. The organic layer was washed with a saturated aqueous solution of
[0905] [0905] Step C: Benzyl 4- (acetylthio) piperidine-1-carboxylate
[0906] [0906] To a solution of benzyl 4 - ((methylsulfonyl) oxy) piperidine-1-carboxylate (290 g, 925.43 mmol, 1 eq) in DMF (1.4 L) was added Cs2CO3 (331.67 g , 1.02 mol, 1.1 eq) and thioethanic acid (77.49 g, 1.02 mol, 1.1 eq). The mixture was stirred at 80 ° C for 12 hours. Some solid was precipitated. The reaction mixture was filtered. The filtrate was concentrated in vacuo to remove most of the DMF. The residue was diluted with EtOAc (1.5 L), washed with H2O (3 x 1 L) and brine (2 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 50: 1 to 40: 1) to provide the title compound (146 g, crude) as a yellow oil.
[0907] [0907] 1H NMR (CDCl3) δ 7.37-7.35 (m, 5 H), 5.13 (s, 2 H), 4.07-3.93 (m, 2 H), 3.66 -3.61 (m, 1 H), 3.19-3.12 (m, 2 H), 2.33 (s, 3 H), 1.94- 1.91 (m, 2 H) and 1 , 59-1.56 (m, 2 H). LCMS: m / z 294.1 (M + H) + (ES +).
[0908] [0908] Step D: Benzyl 4- (Chlorosulfonyl) piperidine-1-carboxylate
[0909] [0909] To a solution of benzyl 4- (acetylthio) piperidine-1-carboxylate (30.00 g, 102.26 mmol, 1 eq) in AcOH (1 L) and H2O (100 mL) was added NCS (40 , 96 g, 306.77 mmol, 3 eq). The reaction mixture was stirred at 25 ° C for 40 minutes. Then, the reaction mixture was poured into water (1 L) and extracted with DCM (1 L). The organic layer was washed with water (3 x 1 L) and brine (1 L), dried over Na2SO4 and filtered to provide the title compound in DCM solution (1 L) (theoretical amount: 32.4 g, crude), that was used in the next step without further purification.
[0910] [0910] Step E: Benzyl 4-sulfamylpiperidine-1-carboxylate Cbz Cbz N N
[0911] [0911] NH3 was bubbled into a solution of benzyl 4- (chlorosulfonyl) piperidine-1-carboxylate (theoretical amount: 30 g, crude) in DCM (1 L) at 0 ° C for 20 minutes. Then, the reaction mixture was stirred at 25 ° C for 40 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of EtOAc (50 ml) and petroleum ether (40 ml) to provide the title compound (21 g, 75% yield) as a yellow solid.
[0912] [0912] 1H NMR (DMSO-d6) δ 7.38-7.32 (m, 5 H), 6.79 (br s, 2 H), 5.10 (s, 2 H), 4.12- 4.01 (m, 2 H), 3.09-3.02 (m, 1 H), 3.01-2.75 (m, 2 H), 2.02-1.96 (m, 2 H ) and 1.51-1.41 (m, 2 H).
[0913] [0913] Step F: Piperidine-4-sulfonamide
[0914] [0914] To a solution of benzyl 4-sulfamoylpiperidine-1-carboxylate (21 g, 70.39 mmol, 1 eq) in MeOH (200 mL) was added Pd / C (10% by weight of activated carbon charge, 4 g) under nitrogen. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 25 ° C for 30 hours. Then, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with EtOAc (200 ml) to provide the title compound (11.2 g, 97% yield, 100% purity in LCMS) as a white solid.
[0915] [0915] 1H NMR (DMSO-d6 + D2O) δ 3.06-2.90 (m, 2 H), 2.89-2.86 (m, 1 H), 2.50-2.46 (m , 2 H), 1.95-1.91 (m, 2 H) and 1.53-1.46 (m, 2 H). Three exchangeable protons not observed. LCMS: m / z 165.1 (M + H) + (ES +).
[0916] [0916] Step G: 1-Isopropylpiperidine-4-sulfonamide H
[0917] [0917] To a solution of piperidine-4-sulfonamide (1.2 g, 7.31 mmol, 1 eq) in acetonitrile (20 ml) was added 2-bromopropane (3.59 g, 29.23 mmol, 4 eq ) and NaHCO3 (1.84 g, 21.92 mmol, 3 eq). Then, the reaction mixture was stirred at 70 ° C for 18 hours. The hot mixture was filtered and the filtrate was concentrated in vacuo to provide the title compound (1.05 g, 69% yield, 98.5% purity in LCMS) as a white solid.
[0918] [0918] 1H NMR (DMSO-d6) δ 6.61 (s, 2 H), 2.81-2.77 (m, 2 H), 2.66-2.61 (m, 2 H), 2 , 05-1.99 (m, 2 H), 1.91-1.87 (m, 2 H), 1.50-1.45 (m, 2 H) and 0.89 (dd, 6 H) . LCMS: m / z 207.1 (M + H) + (ES +).
[0919] [0919] Intermediate P139: (4- (Dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl) sulfonyl) amide
[0920] [0920] Step A: 5-Bromo-1-isopropylpyrimidin-2 (1H) -one
[0921] [0921] A suspension of 5-bromopyrimidin-2 (1H) -one (10.07 g, 57.5 mmol) and K2CO3 (8.35 g, 60.4 mmol) in DMF (200 mL) was treated with 2 -iodopropane (6.4 ml, 62.7 mmol) under nitrogen. The resulting suspension was stirred at room temperature for 40 hours, concentrated in vacuo and the residue was partitioned between EtOAc (100 ml) and water (50 ml). The organic layer was collected and the aqueous layer was extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with 20% v / v brine (3 x 50 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo to provide the crude product as a yellow oil (4.71 g) . The crude product was purified by chromatography on silica gel (dry charge) (40 g cartridge, 0-5% MeOH / DCM) to provide the title compound (1.34 g, 10% yield) as a yellow oil of course it solidified at rest.
[0922] [0922] 1H NMR (CDCl3) δ 8.52 (dd, J = 3.3, 1.6 Hz, 1H), 7.76 (d, J = 3.2 Hz, 1H), 4.99 (pd , J = 6.8, 1.6 Hz, 1H), 1.40 (dd, J = 6.8, 1.0 Hz, 6H). LCMS: m / z 217.0 (MBr79 + H) + (ES +).
[0923] [0923] Step B: 5- (Benzylthio) -1-isopropylpyrimidin-2 (1H) - one
[0924] [0924] A solution of 5-bromo-1-isopropylpyrimidin-2 (1H) -one (1.217 g, 5.05 mmol), DIPEA (1.8 ml, 10.31 mmol) and benzyl mercaptane (0.6 ml , 5.07 mmol) in dioxane (25 ml) was sparged with nitrogen for 15 minutes before Pd2 (dba) 3 (0.233 g, 0.254 mmol) and Xantphos (0.294 g, 0.508 mmol) were added. The reaction mixture was heated to 100 ° C for 22 hours and then concentrated in vacuo. The residue was partitioned between EtOAc (30 ml) and saturated aqueous NaHCO3 (20 ml). The aqueous layer was extracted with EtOAc (3 x 30 ml) and the combined organic extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to provide the crude product as a brown oil (2.3 g) . The crude product was purified by chromatography on silica gel (dry charge) (40 g cartridge, 0-5% MeOH / DCM) to provide the title compound (1.49 g, 99% yield) as a brown oil .
[0925] [0925] 1H NMR (CDCl3) δ 8.46 (d, J = 3.1 Hz, 1H), 7.30 - 7.22 (m, 3H), 7.15 (d, J = 3.2 Hz , 1H), 7.09 - 7.06 (m, 2H), 4.84 (sept, J = 6.8 Hz, 1H), 3.80 (s, 2H), 1.13 (d, J = 6.8 Hz, 6H). LCMS; m / z 261.1 (M + H) + (ES +).
[0926] [0926] Step C: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo- 1,2-dihydropyrimidine-5-sulfonamide
[0927] [0927] A suspension of 5- (benzylthio) -1- isopropylpyrimidin-2 (1H) -one (1.012 g, 3.69 mmol) in DCM (15 mL) and water (1.5 mL) at 0 ° C was treated with SO2Cl2 (2 ml, 23.86 mmol) dropwise. The resulting yellow suspension was stirred at 0 ° C for 1 hour. An ice / water paste (20 mL) was added and the organic phase was collected and retained. The aqueous layer was extracted with DCM (2 x 10 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to provide intermediate crude sulfonyl chloride as a pale yellow liquid (1.024 g) which was used without further purification. A solution of bis (4-methoxybenzyl) amine (1.007 g, 3.91 mmol) and Et3N (0.6 ml, 4.30 mmol) in DCM (20 ml) at 0 ° C was treated with a solution of the intermediate crude sulfonyl chloride in DCM (10 mL). The resulting solution was allowed to warm to room temperature, stirred for 1 hour and then diluted with DCM (20 ml) and saturated aqueous NH4Cl (20 ml). The organic layer was collected and washed with saturated aqueous NH4Cl (20 ml) and water (20 ml), dried (MgSO4) and concentrated in vacuo to provide the crude product as an orange oil (2.0 g). The crude product was triturated with TBME (30 ml), filtered, washed with TBME and dried in vacuo to provide the crude product which was purified by chromatography on silica gel (24 g cartridge, 0-5% MeOH / DCM) to provide the title compound (0.941 g, 44% yield) as an orange sticky oil.
[0928] [0928] 1H NMR (CDCl3) δ 8.65 (d, J = 3.3 Hz, 1H), 7.96 (d, J = 3.3 Hz, 1H), 7.15 - 7.10 (m , 4H), 6.85 - 6.82 (m, 4H), 4.88 (sept, J = 6.8 Hz, 1H), 4.32 (s, 4H), 3.79 (s, 6H) , 1.34 (d, J = 6.8 Hz, 6H). LCMS: m / z 458.1 (M + H) + (ES +).
[0929] [0929] Step D: 1-Isopropyl-2-oxo-1,2-dihydropyrimidine-5-sulfonamide
[0930] [0930] 1-Isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.941 g, 1.625 mmol) was treated with TFA (15 ml, 195 mmol) and the resulting solution was stirred at room temperature for 64 hours. Then the reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (dry charge) (12 g cartridge, 0-10% MeOH / DCM) to provide the title compound (0.350 g , 94% yield) as a white tan solid.
[0931] [0931] 1H NMR (DMSO-d6) δ 8.81 (d, J = 3.2 Hz, 1H), 8.51 (d, J = 3.3 Hz, 1H), 7.45 (s, 2H ), 4.77 (sept, J = 6.8 Hz, 1H), 1.37 (d, J = 6.8 Hz, 6H). LCMS; m / z 218.1 (M + H) + (ES +); 215.8 (M-H) - (ES-).
[0932] [0932] Step E: (4- (Dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl) sulfonyl) amide
[0933] [0933] A suspension of 1-isopropyl-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.150 g, 0.690 mmol) and DMAP (0.169 g, 1.383 mmol) in dry MeCN (2 mL) was stirred at room temperature for 10 minutes before adding diphenyl carbonate (0.163 g, 0.761 mmol) in one portion. The reaction was stirred for 18 hours, diluted with TBME (20 ml) and DCM (2 ml) and the precipitate was collected by filtration and used crude in the next step.
[0934] [0934] Intermediate P140: 1-Isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide
[0935] [0935] Step A: Lithium 2-chloropyridine-4-sulfinate
[0936] [0936] A solution of 4-bromo-2-chloropyridine (5.8 ml, 52.3 mmol) in dry THF (100 ml) at -78 ° C was treated with 2.5 M BuLi (in hexanes) (22 ml, 55.0 mmol) dropwise under nitrogen. The resulting solution was stirred at -78 ° C for 10 minutes and then the SO2 gas was bubbled through the solution for 20 minutes. The reaction was allowed to warm to room temperature and then concentrated in vacuo. The residue was triturated with TBME (100 ml). The resulting solid was filtered, washed with TBME and dried in vacuo to provide the title compound (8.80 g, 92% yield) as a dark purple solid which was used crude in the next step.
[0937] [0937] Step B: 2-Chlorine-N, N-bis (4-methoxybenzyl) pyridine-4-sulfonamide
[0938] [0938] A suspension of lithium 2-chloropyridine-4-sulfinate (6.55 g, 35.7 mmol) in DCM (100 mL) at 0 ° C was treated with NCS (4.862 g, 35.7 mmol) in a portion.
[0939] [0939] The resulting suspension was stirred at 0 ° C for 2 hours, quenched with water (50 mL) and the organic layer was collected. The aqueous layer was extracted with DCM (2 x 50 ml) and the combined organic extracts were washed with water (50 ml), dried (MgSO4) concentrated in vacuo to provide the crude sulfonyl chloride intermediate. A solution of the sulfonyl chloride intermediate in DCM (10 mL) was added dropwise to a suspension of bis (4-methoxybenzyl) amine (9.42 g, 36.6 mmol) and triethylamine (15.92 mL, 114 mmol ) in DCM (100 mL) at 0 ° C. The reaction mixture was allowed to warm to room temperature, stirred for 16 hours and then water (100 ml) was added. The organic layer was collected and the aqueous layer was extracted with DCM (2 x 50 ml). The combined organic extracts were washed with water (100 ml), 1 M HCl (aq) (2 x 100 ml), water (100 ml), dried (MgSO4) and concentrated in vacuo to provide the crude product which was purified by chromatography. on silica gel (dry charge) (80 g cartridge, 0-50% EtOAc / isohexane) to provide the title compound (0.677 g, 4% yield) as an orange solid.
[0940] [0940] 1H NMR (CDCl3) δ 8.51 (dd, J = 4.8, 1.9 Hz, 1H),
[0941] [0941] Step C: N, N-Bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-4-sulfonamide
[0942] [0942] A suspension of 2-chloro-N, N-bis (4-methoxybenzyl) pyridine-4-sulfonamide (0.365 g, 0.759 mmol) in ethane-1,2-diol (5 ml, 0.759 mmol) was treated with 2 M KOH (aq) (1.9 ml, 3.80 mmol). The resulting suspension was stirred at 140 ° C for 72 hours, allowed to cool to room temperature and then diluted with saturated aqueous NH4Cl (30 ml) and EtOAc (20 ml). The organic layer was collected and the aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to provide the crude product as a yellow solid (510 mg). The crude product was purified by chromatography on silica gel (dry charge) (12 g cartridge, 0-100% EtOAc / isohexane) to provide the title compound (0.437 g, 68%) as a pale yellow solid. LCMS: m / z 437.3 (M + Na) + (ES +); 413.1 (MH) - (ES-).
[0943] [0943] Step D: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo- 1,2-dihydropyridine-4-sulfonamide
[0944] [0944] A suspension of N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-4-sulfonamide (0.437 g, 0.949 mmol) and lithium bromide (0.171 g, 1.930 mmol) in DME: DMF (7.5 mL, 4: 1) at 0 ° C was treated with NaH in one portion. The resulting suspension was stirred at 0 ° C for 15 minutes, treated with 2-iodopropane (0.194 ml, 1.988 mmol) and heated to 65 ° C for 65 hours. More lithium bromide (0.171 g, 1.930 mmol) was added followed by NaH (0.053 g, 1.328 mmol) and the reaction mixture was stirred at 65 ° C for 10 minutes. Then, 2-iodopropane (0.194 ml, 1.988 mmol) was added and the reaction mixture was stirred at 65 ° C for 18 hours. EtOAc (10 mL) and saturated aqueous NH4Cl (5 mL) were added and the organic layer was collected. The aqueous layer was extracted with EtOAc (2 x 10 ml) and the combined organic extracts were washed with 20% v / v brine (3 x 10 ml) and brine (10 ml), dried (MgSO4) and concentrated in vacuo to provide the crude product as a yellow oil. The crude product was purified by chromatography on silica gel (dry charge) (12 g cartridge, 0-100% EtOAc / isohexane) to provide the title compound (0.385 g, 77%) as a pale yellow solid.
[0945] [0945] 1H NMR (DMSO-d6) δ 8.06 (dd, J = 6.8, 2.1 Hz, 1H), 7.99 (dd, J = 7.2, 2.0 Hz, 1H) , 7.07 -7.03 (m, 4H), 6.82 -6.78 (m, 4H), 6.39 (t, J = 7.0 Hz, 1H), 4.99 (sept, J = 6.8 Hz, 1H), 4.34 (s, 4H), 3.71 (s, 6H), 1.28 (d, J = 6.8 Hz, 6H). LCMS: m / z 479.3 (M + Na) + (ES +).
[0946] [0946] Step E: 1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide
[0947] [0947] 1-Isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-4-sulfonamide (0.375 g, 0.715 mmol) was treated with TFA (2 ml, 26 , 0 mmol) and the resulting red solution was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo, azeotroped with DCM (2 x 5 mL) and the crude product was purified by chromatography on silica gel (dry charge) (4 g cartridge, 0-10% MeOH / DCM) to provide the title compound (0.160 g, 100%) as a white solid.
[0948] [0948] 1H NMR (CDCl3) δ 8.09 (dd, J = 7.1, 2.1 Hz, 1H), 7.61 (dd, J = 6.9, 2.1 Hz, 1H), 6 , 42 (t, J = 7.0 Hz, 1H), 5.38 (br s, 2H), 5.32 (sept, J = 7.0 Hz, 1H), 1.41 (d, J = 6 , 8 Hz, 6H). LCMS: m / z 217.3 (M + H) + (ES +); 215.1 (M-H) - (ES-).
[0949] [0949] Intermediate P141: 1-isopropyl-2-oxo-1,2-dihydropyridine-3-sulfonamide
[0950] [0950] Step A: 2-chloro-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide
[0951] [0951] Bis (4-methoxybenzyl) amine (3.78 g, 14.41 mmol) and triethylamine (2.49 ml, 17.8 mmol) in anhydrous DCM (15 ml) were added to a solution of chloride 2-chloropyridine-3-sulfonyl (3.00 g, 13.72 mmol) in anhydrous DCM (35 mL) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hour, then heated to room temperature. After 19 hours, the reaction mixture was diluted with an additional portion of DCM (150 ml), washed with saturated aqueous NH4Cl (2x 50 ml), water (50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to offer the crude product as a pale orange solid. The crude product was triturated with TBME (50 ml), filtered, washed with TBME (2 x 40 ml), to provide the title compound (5.10 g, 80%) as a cream colored solid.
[0952] [0952] 1H NMR (DMSO-d6) δ 8.61 (dd, J = 4.8, 1.8 Hz, 1H), 8.27 (dd, J = 7.8, 1.8 Hz, 1H) , 7.55 (dd, J = 7.8, 4.8 Hz, 1H), 7.05 -6.98 (m, 4H), 6.86 -6.78 (m, 4H), 4.37 (s, 4H), 3.72 (s, 6H). LCMS: m / z 433.3 (M + H) + (ES +).
[0953] [0953] Step B: 2-hydroxy-N, N-bis (4-methoxybenzyl) pyridine-
[0954] [0954] 2 M KOH (aq) (2.15 ml, 4.30 mmol) was added to a suspension of 2-chloro-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide (0.50 g , 1.074 mmol) in ethane-1,2-diol (10 mL). The reaction mixture was stirred at 140 ° C for 66 hours, cooled to room temperature and neutralized with saturated aqueous NH4Cl (10 mL). The mixture was then extracted with DCM (5 x 40 ml) and the combined organics were washed with brine (20 ml), dried over MgSO4, filtered and concentrated in vacuo to provide a cream solid, which was ground with TBME (15 ml) to provide the title compound (0.38 g, 84% yield) as a pale cream solid.
[0955] [0955] 1H NMR (DMSO-d6) δ 12.29 (br s, 1H), 8.03 (dd, J = 7.2, 2.2, 1H), 7.70 (dd, J = 6, 3, 2.2, 1H), 7.07 -7.02 (m, 4H), 6.82 -6.77 (m, 4H), 6.29 (dd, J = 7.2, 6.3 , 1H), 4.32 (s, 4H), 3.71 (s, 6H). LCMS: m / z 437.4 (M + Na) + (ES +).
[0956] [0956] Step C: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-3-sulfonamide
[0957] [0957] Sodium hydride (60% dispersion in mineral oil) (0.026 g, 0.645 mmol) was added at 0 ° C for a mixture of 2-hydroxy-N, N-bis (4-methoxybenzyl) pyridine-3- sulfonamide (0.26 g, 0.615 mmol) and lithium bromide (0.109 g, 1.230 mmol) in a mixture of anhydrous DME / anhydrous DMF (3 mL, 4: 1). The reaction mixture was stirred at room temperature for 15 minutes before adding 2-iodopropane (0.07 ml, 0.74 mmol) and the reaction mixture was stirred at 60 ° C for 27 hours. The reaction was quenched with
[0958] [0958] 1H NMR (CDCl3) δ 8.06 (dd, J = 7.2, 2.1 Hz, 1H), 7.50 (dd, J = 6.8, 2.1 Hz, 1H), 7 , 11 -7.06 (m, 4H), 6.77 -6.72 (m, 4H), 6.26 (t, J = 7.0 Hz, 1H), 5.21 (sept, J = 6 , 8 Hz, 1H), 4.47 (s, 4H), 3.76 (s, 6H), 1.34 (d, J = 6.8 Hz, 6H). LCMS: m / z 479.4 (M + Na) + (ES +).
[0959] [0959] Step D: 1-isopropyl-2-oxo-1,2-dihydropyridine-3-sulfonamide
[0960] [0960] TFA (0.43 ml, 5.64 mmol) was added to a solution of 1-isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-3- sulfonamide (0.27 g, 0.591 mmol) in anhydrous DCM (3 mL) at room temperature. The reaction mixture was stirred for 66 hours, concentrated in vacuo, then redissolved in DCM (5 ml), pre-adsorbed on silica and purified by silica gel chromatography (12 g cartridge, 0-10% MeOH / DCM ) to provide the title compound (0.11 g, 82%) as a light brown solid. LCMS: m / z 217.1 (M + H) + (ES +).
[0961] [0961] Intermediate P142: (R) -1- (2-hydroxypropyl) -6-oxo- 1,6-dihydropyridine-3-sulfonamide
[0962] [0962] Step A: 6-chloro-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide
[0963] [0963] Bis (4-methoxybenzyl) amine (3.71 g, 14.41 mmol) was added to a solution of 2-chloropyridine-5-sulfonyl chloride (3.00 g, 13.72 mmol) and triethylamine (2.49 mL, 17.8 mmol) in anhydrous DCM (50 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 minutes and then allowed to warm to room temperature for 20 hours. Then, the reaction mixture was diluted with an additional portion of DCM (150 mL), washed with saturated aqueous NH4Cl (3x 40 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated in vacuo to offer the crude product as a cream solid. Trituration with TBME (70 ml) and collecting the solid by filtration followed by washing with TBME (2 x 40 ml) gave the title compound (4.97 g, 83%) as an off-white solid.
[0964] [0964] 1H NMR (DMSO-d6) δ 8.76 (dd, J = 2.6, 0.7 Hz, 1H), 8.19 (dd, J = 8.4, 2.6 Hz, 1H) , 7.69 (dd, J = 8.4, 0.7 Hz, 1H), 7.08 -7.02 (m, 4H), 6.83 -6.76 (m, 4H), 4.29 (s, 4H), 3.71 (s, 6H). LCMS: m / z 433.3 (M + H) + (ES +).
[0965] [0965] Step B: N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide
[0966] [0966] A suspension of 6-chloro-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide (4.07 g, 9.40 mmol) in ethane-1,2-diol (90 ml, 9, 40 mmol) was treated with 2 M KOH (aq) (23.50 ml, 47.0 mmol) and the resulting suspension was stirred at 140 ° C for 42 hours. Then, the reaction mixture was diluted with water (200 ml) and DCM (300 ml). Brine (5 ml) was added and the organic layer was collected. The aqueous layer was extracted with DCM (5 x 100 ml) and the combined organic extracts were washed with water (100 ml), dried (MgSO4) and concentrated in vacuo to provide the title compound (2.764 g, 61%) as a white. solid.
[0967] [0967] 1H NMR (DMSO-d6) δ 7.87 (d, J = 2.8 Hz, 1H), 7.60 (dd, J = 9.6, 2.9 Hz, 1H), 7.09 -7.03 (m, 4H), 6.84 -6.79 (m, 4H), 6.34 (d, J = 9.6 Hz, 1H), 4.19 (s, 4H), 3, 71 (s, 6H). An unobserved exchangeable proton. LCMS: m / z 415.4 (M + H) + (ES +); 413.3 (MH) - (ES-).
[0968] [0968] Step C: (R) -1- (2-hydroxypropyl) -N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide
[0969] [0969] A mixture of N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide (0.206 g, 0.427 mmol) and lithium bromide (0.076 g, 0.855 mmol) in a mixture of DME: DMF (2 mL, 4: 1) at 0 ° C was treated with NaH (0.026 g, 0.641 mmol). The reaction mixture was stirred at 0 ° C for 10 minutes, then at room temperature for 10 minutes. (R) -2-methyloxyrane (0.3 ml, 4.24 mmol) was added, and the reaction mixture was heated to 30 ° C and stirred for 16 hours. An additional portion of (R) -2-methyloxyrane (0.3 ml, 4.24 mmol) was added and the reaction was stirred at 30 ° C for 6 hours. More lithium bromide (0.076 g, 0.855 mmol) was added followed by NaH (0.026 g, 0.641 mmol) and the reaction mixture was stirred at 30 ° C for 5 minutes. (R) -2-methyloxyrane (0.3 ml, 4.24 mmol) was added and the reaction mixture was stirred at 30 ° C for 16 hours. Saturated aqueous NH 4Cl (4mL) was added, followed by EtOAc (10 ml). The organic layer was collected and the aqueous layer was extracted with EtOAc (2 x 5 ml). The combined organic extracts were washed with water (2 x 5 ml), brine (2 x 5 ml), dried (MgSO4), filtered and concentrated in vacuo to provide the crude product which was purified by silica gel chromatography (dry charge ) (4 g cartridge, 50-
[0970] [0970] 1H NMR (CDCl3) δ 7.86 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.6, 2.7 Hz, 1H), 7.09 -7 , 06 (m, 4H), 6.83 -6.80 (m, 4H), 6.55 (d, J = 9.7 Hz, 1H), 4.26 (s, 4H), 4.17 - 4.07 (m, 2H), 3.79 (s, 6H), 3.62 (dd, J = 13.3, 8.1 Hz, 1H), 1.25 (d, J = 6.3 Hz , 3H). An unobserved exchangeable proton. LCMS: m / z 473.4 (M + H) + (ES +); 471.3 (MH) - (ES-).
[0971] [0971] Step D: (R) -1- (2-Hydroxypropyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide
[0972] [0972] (R) -1- (2-hydroxypropyl) -N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide (0.182 g, 0.366 mmol) was suspended in DCM (1 ml, 15.54 mmol) and then treated with TFA (1 ml, 12.98 mmol). The resulting solution was stirred at room temperature for 24 hours. The DCM was evaporated and the reaction mixture was stirred at room temperature for 24 hours, then at 40 ° C for 21 hours. The reaction mixture was concentrated in vacuo and azeotroped with DCM (3 x 5 ml) to provide the crude product as a brown foam (0.241 g). The crude product was purified by chromatography on silica gel (dry charge) (12 g cartridge, 0-10% MeOH / DCM) to provide the title compound (0.049 g, 56%) as a white solid.
[0973] [0973] 1H NMR (DMSO-d6) δ 8.10 (d, J = 2.7 Hz, 1H), 7.69 (dd, J = 9.6, 2.7 Hz, 1H), 7.33 (s, 2H), 6.53 (d, J = 9.5 Hz, 1H), 4.92 (d, J = 5.5 Hz, 1H), 4.07 (dd, J = 13.0, 3.3 Hz, 1H), 3.91 -3.81 (m, 1H), 3.62 (dd, J = 13.0, 8.4 Hz, 1H), 1.08 (d, J = 6 , 3 Hz, 3H).
[0974] [0974] LCMS: m / z 233.0 (M + H) + (ES +); 230.9 (M-H) - (ES-).
[0975] [0975] Intermediate P143: 1- (2- (dimethylamino) ethyl) -6-oxo- 1,6-dihydropyridine-3-sulfonamide
[0976] [0976] Step A: 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide
[0977] [0977] A mixture of N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P142, Step B) (0.15 g, 0.355 mmol) and bromide of lithium (0.063 g, 0.709 mmol) in DME: DMF (2 mL, 4: 1) at room temperature was treated with sodium hydride (0.021 g, 0.532 mmol). The reaction mixture was stirred for 10 minutes, treated with 2-bromoethanol (0.030 ml, 0.426 mmol) and then stirred at 50 ° C for 69 hours. The reaction was quenched with saturated aqueous NH4Cl (2mL) and diluted with EtOAc (10 ml). The combined organic extracts were washed with water (2 x 5 ml), brine (2 x 5 ml), dried (MgSO4), filtered and concentrated in vacuo to provide the crude product which was purified by silica gel chromatography (dry charge ) (4 g cartridge, 50-100% EtOAc / isohexane) to provide the title compound (0.124 g, 75%) as a white solid.
[0978] [0978] 1H NMR (DMSO-d6) δ 8.16 (d, J = 2.7 Hz, 1H), 7.63 (dd, J = 9.6, 2.8 Hz, 1H), 7.10 -7.05 (m, 4H), 6.84 -6.80 (m, 4H), 6.44 (d, J = 9.6 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.21 (s, 4H), 3.99 (t, J = 5.2 Hz, 2H), 3.71 (s, 6H), 3.62 (app, q, J = 5 , 3 Hz, 2H). LCMS: m / z 459.4 (M + H) + (ES +).
[0979] [0979] Step B: N, N-Bis (4-methoxybenzyl) -6-oxo-1- (2-oxoethyl) -1,6-dihydropyridine-3-sulfonamide
[0980] [0980] A solution of 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide (0.177 g, 0.363 mmol) in DCM ( 5 ml) was treated with Dess-Martin periodinane (0.18 g, 0.424 mmol) and stirred at room temperature for 1 hour. More Dess-Martin periodinane (0.09 g, 0.212 mmol) was added and the reaction mixture was stirred for 0.5 hour. Saturated aqueous NaHCO3 (5 ml) and DCM (5 ml) were added and the reaction mixture was stirred vigorously for 10 minutes. The organic layer was collected and the aqueous layer was extracted with DCM (10 ml). The combined organic extracts were washed with saturated aqueous sodium thiosulfate (10 ml) and water (10 ml), dried (MgSO4), filtered and concentrated in vacuo to provide the title compound as a yellow oil (183 mg, 94%).
[0981] [0981] 1H NMR (CDCl3) δ 9.65 (s, 1H), 7.61 -7.58 (m, 1H), 7.47 (dd, J = 9.7, 2.6 Hz, 1H) , 7.13 -7.09 (m, 4H), 6.86 -6.82 (m, 4H), 6.57 (d, J = 9.7 Hz, 1H), 4.67 (s, 2H ), 4.29 (s, 4H), 3.80 (s, 6H).
[0982] [0982] Step C: 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide
[0983] [0983] Solution of N, N-bis (4-methoxybenzyl) -6-oxo-1- (2-oxoethyl) -1,6-dihydropyridine-3-sulfonamide (0.183 g, 0.341 mmol) in 1.2 - dichloroethane (3 ml, 38.1 mmol) was treated with 2M dimethylamine (in THF) (0.35 ml, 0.700 mmol). The resulting yellow / green solution was stirred for 30 minutes, before adding sodium triacetoxyborohydride (0.15 g, 0.708 mmol) in one portion. The reaction mixture was stirred at room temperature for 16 hours, then saturated aqueous NaHCO3 (5 mL) was added and the organic layer was collected. The aqueous layer was extracted with DCM (2 x 5 ml) and the combined organic extracts were washed with water (5 ml), dried (MgSO4), filtered and concentrated in vacuo to provide the crude product as a yellow oil (196 mg) . The crude product was loaded onto a SCX column (1.8 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to provide the title compound (0.162 g, 96%) as a light yellow oil.
[0984] [0984] 1H NMR (DMSO-d6) δ 8.23 (d, J = 2.7 Hz, 1H), 7.61 (dd, J = 9.6, 2.8 Hz, 1H), 7.08 -7.03 (m, 4H), 6.85 -6.79 (m, 4H), 6.43 (d, J = 9.6 Hz, 1H), 4.21 (s, 4H), 4, 03 (t, J = 6.0 Hz, 2H), 3.71 (s, 6H), 2.51 -2.45 (m, 2H), 2.15 (s, 6H). The 2.51-2.45 multiplet is obscured by the solvent signal DMSO-d6.
[0985] [0985] Step D: 1- (2- (dimethylamino) ethyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide
[0986] [0986] Solution of 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide (0.159 g, 0.321 mmol) in DCM (3 ml, 46.6 mmol) was treated with TFA (0.25 ml, 3.24 mmol) dropwise at room temperature and the reaction mixture was stirred for 16 hours. Additional TFA (0.25 ml, 3.24 mmol) was added. The resulting mixture was stirred for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (0.5 ml) and TFA (0.5 ml). The reaction mixture was stirred for 4 hours and then concentrated in vacuo. The residue was treated with TFA (2 ml) and water (0.2 ml). The reaction mixture was stirred for 24 hours at room temperature and then heated to 40 ° C for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was loaded onto a SCX column (1.9 g) in DCM. The column was washed with DCM and then the product was eluted with 0.7 M ammonia in MeOH / DCM (1: 1). The resulting mixture was concentrated in vacuo to provide the title compound (0.038 g, 35%) as a pale brown solid. LCMS: m / z 246.1 (M + H) + (ES +); 244.0 (MH) - (ES-).
[0987] [0987] Intermediate P144: 1-ethylazepano-4-sulfonamide
[0988] [0988] Step A: tert-butyl 4 - ((methylsulfonyl) oxy) azepane-1-carboxylate
[0989] [0989] For a solution of tert-butyl 4-hydroxyazpane-1-carboxylate (3.0 g, 14.0 mmol, 1.0 equiv.) And N, N-diisopropylethylamine (3.2 mL, 18.0 mmol, 1.3 equiv.) in dichloromethane (70 ml) methanesulfonyl chloride (1.2 ml, 15.0 mmol, 1.1 equiv) was added. The reaction mixture was stirred at room temperature for 1 hour and then water was added. The organic layer was separated and then washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound (3.87 g, 95% yield).
[0990] [0990] 1H NMR (CDCl3) δ 4.97 - 4.76 (m, 1 H), 3.62 - 3.24 (m, 4 H), 3.00 (s, 3 H), 2.14 - 1.83 (m, 4 H), 1.68 (q, 2 H), 1.45 (s, 9 H).
[0991] [0991] Step B: 4- (tert-butyl 4- (acetylthio) azepane-1-carboxylate
[0992] [0992] For a solution of tert-butyl 4 - ((methylsulfonyl) oxy) azepano-1-carboxylate (3.87 g, 13.2 mmol, 1.0 equiv.) In dimethylformamide (50 mL) and acetonitrile ( 13 ml) potassium thioacetate (4.52 g 39.6 mmol, 3.0 equiv.) Was added. The reaction mixture was heated to 90 ° C for 50 minutes and then cooled to room temperature. To the suspension, brine and ethyl acetate were added. The organic layer was separated, then washed three times with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to normal phase flash column chromatography using heptane and ethyl acetate as the eluant to provide the title compound (2.3 g, 64%). LC-MS: m / z 174.4 (M + H-C5H9O2) + (ES +).
[0993] [0993] Step C: tert -butyl 4-sulfamoylazepan-1-carboxylate
[0994] [0994] For a solution of tert-butyl 4- (acetylthio) azepane-1-carboxylate (2.2 g, 8.0 mmol, 1.0 equiv.) In water (8.0 ml) and acetic acid ( 80 ml) N-chlorosuccinimide (3.2 g, 24.1 mmol, 3.0 equiv.) Was added. The reaction mixture was stirred at room temperature for one hour and then added dropwise to a solution of ammonia in water (25% by weight, 500 ml) cooled in an ice bath. The mixture was adjusted to pH 9 by adding concentrated hydrochloric acid and then extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was subjected to normal phase flash column chromatography using dichloromethane and methanol as the eluant to give the title compound (250 mg, 11%).
[0995] [0995] 1H NMR (CDCl3) δ 4.47 (s, 2 H), 3.71 - 3.46 (m, 2 H), 3.48 - 3.35 (m, 1 H), 3.36 - 3.16 (m, 1 H), 2.97 (dt, 1 H), 2.55 - 2.36 (m, 2 H), 2.07 - 1.96 (m, 1 H), 1 , 94 - 1.80 (m, 1 H), 1.70 - 1.60 (m, 2 H), 1.46 (s, 9 H).
[0996] [0996] Step D: Azepano-4-sulfonamide hydrochloride
[0997] [0997] To a solution of tert -butyl 4-sulfamoylazepan-1-carboxylate (252 mg, 0.9 mmol, 1.0 equiv.) In dichloromethane (10 mL) 4M hydrochloric acid in dioxane (5.0 mL, 18.1 mmol, 20.0 equiv.). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo to provide the title compound (194 mg, quantitative yield).
[0998] [0998] 1H NMR (CD3OD) δ 3.47 (ddd, 1 H), 3.29 - 3.16 (m, 4 H), 2.57 - 2.34 (m, 2 H), 2.31 - 2.08 (m, 2 H), 2.06 - 1.80 (m, 2 H).
[0999] [0999] Step E: 1-ethylazepano-4-sulfonamide
[1000] [1000] To a suspension of azepano-4-sulfonamide hydrochloride (97 mg, 0.45 mmol, 1.0 equiv.) In acetonitrile (10 mL), acetaldehyde (28 µL, 0.5 mmol, 1.1 was added) equiv.), triethylamine (69 µL, 0.5 mmol, 1.1 equiv.) and then sodium triacetoxyborohydride (120 mg, 0.56 mmol, 1.25 equiv.). The suspension was stirred overnight at room temperature and then concentrated in vacuo. The crude product was dissolved in methanol,
[1001] [1001] 1H NMR (DMSO-d6) δ 6.69 (s, 2 H), 3.07 - 2.93 (m, 1 H), 2.81 - 2.51 (m, 4 H), 2 , 22 - 2.00 (m, 2 H), 1.91 - 1.42 (m, 6 H), 1.00 (t, J = 7.1 Hz, 3 H).
[1002] [1002] Intermediate P145: 1- (Ethyl-d5) piperidine-4-sulfonamide D D D D H D N N I
[1003] [1003] To a solution of piperidine-4-sulfonamide hydrochloride (733 mg, 3.65 mmol, 1 eq) and K2CO3 (2.02 g, 14.6 mmol, 4 eq) in acetonitrile (30 ml) was added 1-iodoethane-1,1,2,2,2-d5 (588 mg, 3.65 mmol, 1 eq) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. The residue was suspended in methanol, coated with Agilient hydromatrix (an inert high purity inert diatomaceous earth) and then subjected to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to offer the title compound (63 mg, 9%) as an off-white solid. LCMS: m / z 198 (M + H) + (ES +).
[1004] [1004] Preparation of Examples
[1005] [1005] Example 1: N - (((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) -1-methylpiperidine-4-sulfonamide, potassium salt.
[1006] [1006] To a cooled (0C) solution of 1-methylpiperidine-4-sulfonamide (55 mg, 0.31 mmol) in THF (2 mL), potassium tert-butoxide (38 mg, 0.34 mmol) was added ). The reaction mixture was stirred and allowed to warm to room temperature for 40 minutes and then a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1; 68 mg, 0.34 mmol) in THF (1 mL) was added. The mixture was stirred overnight at room temperature and the resulting precipitate was isolated by filtration and washed with THF (1 ml). The solid was triturated with EtOAc (2 ml) for 1 hour, filtered and dried in vacuo to provide the title compound (17 mg; 13%) as a white solid.
[1007] [1007] 1H NMR (CD3OD) δ 6.83 (s, 1 H), 4.58 (br s, 2 H), 3.2 (m, 1 H), 3.02 (m, 2 H), 2.82 (m, 8 H), 2.3 (s, 3 H) and 1.82-2.1 (m, 10 H). LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1008] [1008] Example 2: N - ((1,2,3,5,6,7-Hexahydro-s indacen- 4-yl) carbamoyl) -1- (prop-2-in-1-yl) azetidine -4-sulfonamide, potassium salt
[1009] [1009] For a cooled (0C) solution of 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P3; 64 mg, 0.31 mmol) in THF (3 mL) was Potassium tert-butoxide (39 mg, 0.35 mmol) is added. 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; 69 mg, 0.35 mmol) in THF (1 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and water (2 ml) was added. The suspension was filtered over cotton and subsequently subjected to purification by reverse phase column chromatography (see "Experimental methods", "Purification method 1")
[1010] [1010] 1H NMR (CD3OD) δ 6.83 (s, 1 H), 3.38 (m, 1 H), 3.02 (m, 2 H), 2.82 (m, 10 H), 2 , 63 (s, 1 H), 2.27 (m, 2 H), 2.16 (m, 2 H), 2.02 (m, 4 H) and 1.88 (m, 2 H). LCMS: m / z 402 (M + H) + (ES +); 400 (M-H) - (ES-).
[1011] [1011] Example 3: 1-Acetyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt.
[1012] [1012] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-acetylpiperidine-4-sulfonamide (Intermediate P7) to provide the title compound (73%) as a white solid.
[1013] [1013] 1H NMR (CD3OD) δ 6.84 (s, 1 H), 4.6 (m, 2 H), 4.02 (m, 1 H), 3.62 (m, 1 H), 3 , 15 (m, 1 H), 2.82 (m, 8 H), 2.64 (m, 1 H), 2.17 (m, 1 H), 2.09 (s, 3 H), 2 , 02 (m, 4 H) and 1.6-1.85 (m, 2 H). LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1014] [1014] Example 4: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -piperidine-4-sulfonamide, potassium salt.
[1015] [1015] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (example2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2,2,2 -trifluoroacetyl) piperidine-4-sulfonamide
[1016] [1016] 1H NMR (CD3OD) δ 6.83 (s, 1 H), 4.6 (br s, 1 H), 3.6 (m, 1 H), 2.82 (m, 10 H), 2.21 (m, 2 H), 2.02 (m, 4 H) and 1.86 (m, 4 H). LCMS: m / z 364 (M + H) + (ES +); 362 (M-H) - (ES-).
[1017] [1017] Example 5: 4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N-isopropylpiperidine-1-carboxamide, potassium salt.
[1018] [1018] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (example 2) of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-iso-propyl-4 -sulfamoylpiperidine-1-carboxamide (Intermediate P5) to provide the title compound (39%) as a white solid.
[1019] [1019] 1H NMR (CD3OD) δ 6.84 (s, 1 H), 4.14 (m, 2 H), 3.85 (m, 1 H), 3.53 (m, 1 H), 2 , 82 (m, 10 H), 2.05 (m, 6 H), 1.7 (m, 2 H) and 1.12 (d, 6 H). LCMS: m / z 449 (M + H) + (ES +); 447 (M-H) - (ES-).
[1020] [1020] Example 6: 1-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt.
[1021] [1021] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide,
[1022] [1022] 1H NMR (CD3OD) δ 6.83 (s, 1 H), 4.6 (br s, 1 H), 3.18 (m, 2 H), 2.82 (m, 8 H), 2.55 (q, 2 H), 2.17 (m, 4 H), 1.85-2.08 (m, 6 H) and 1.16 (t, 3 H). LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1023] [1023] Example 7: 1- (Cyclopropanecarbonyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, salt potassium.
[1024] [1024] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) from 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (cyclopropanecarbonyl) piperidine-4-sulfonamide (Intermediate P8) to provide the title compound (72%) as a white solid.
[1025] [1025] 1H NMR (CD3OD) δ 6.84 (s, 1 H), 4.58 (m, 1 H), 4.42 (m, 1 H), 3.6 (m, 1 H), 3 , 18 (m, 1 H), 2.82 (m, 8 H), 2.64 (m, 1 H), 2.08 (m, 1 H), 2.02 (m, 6 H), 1 , 8-1.94 (m, 2 H) and 0.92 (m, 4 H). LCMS: m / z 432 (M + H) + (ES +); 430 (M-H) - (ES-).
[1026] [1026] Example 8: N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (2,2,2-trifluoroacetyl) piperidine- 4-sulfonamide, potassium salt.
[1027] [1027] Prepared as described for N - ((1,2,3,5,6,7-
[1028] [1028] 1H NMR (CD3OD) δ 6.84 (s, 1 H), 4.51 (m, 2 H), 4.09 (m, 1 H), 3.7 (m, 1 H), 2 , 92 (m, 1 H), 2.82 (m, 8 H), 2.12 (m, 2 H), 2.02 (m, 4 H) and 1.8 (m, 2 H). LCMS: m / z 460 (M + H) + (ES +); 458 (M-H) - (ES-).
[1029] [1029] Example 9: 1-Acetyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-3-sulfonamide, potassium salt.
[1030] [1030] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethylpiperidine-3-sulfonamide (Intermediate P15) to provide the title compound (23%) as a white solid.
[1031] [1031] 1H NMR (CD3OD) δ 6.83 (s, 1 H), 3.61 (m, 1 H), 3.45 (m, 1 H), 2.94 (m, 1 H), 2 , 82 (m, 8 H), 2.55 (q, 2 H), 2.23 (m, 2 H), 2.03 (m, 6 H), 1.83 (m, 1 H), 1 , 63 (m, 2 H) and 1.16 (t, 3 H). LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1032] [1032] Example 10: N - ((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) -1-propionylpiperidine-4-sulfonamide, potassium salt.
[1033] [1033] Prepared as described for 1-ethyl-N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -piperidine-3-sulfonamide, salt potassium (example 9) of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-propionylpiperidine-4-sulfonamide (Intermediate P10) to provide the title compound (32%) as a white solid.
[1034] [1034] 1H NMR (CD3OD) δ 6.83 (s, 1 H), 4.62 (m, 1 H), 4.04 (m, 1 H), 3.61 (m, 1 H), 3 .09 (m, 1 H), 2.82 (m, 8 H), 2.65 (m, 1 H), 2.42 (q, 2 H), 2.17 (m, 2 H), 2 , 02 (m, 4 H), 1.7 (m, 2 H) and 1.12 (t, 3 H). LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1035] [1035] Example 11: N - (((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) -1-isobutyryl piperidine-4-sulfonamide, potassium salt.
[1036] [1036] Prepared as described for 1-ethyl-N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -piperidine-3-sulfonamide, salt potassium (example 9) of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-iso-butyrylpiperidine-4-sulfonamide (Intermediate P11) to provide the title compound (9%) as a white solid.
[1037] [1037] 1H NMR (CD3OD) δ 6.83 (s, 1 H), 4.62 (m, 1 H), 4.18 (m, 1 H), 3.65 (m, 1 H), 3 , 07 (m, 1 H), 2.96 (m, 1 H), 2.82 (m, 8 H), 2.65 (m, 1 H), 2.17 (m, 2 H), 2 , 02 (m, 4 H), 1.7 (m, 2 H) and 1.09 (t, 6 H). LCMS: m / z 434 (M + H) + (ES +).
[1038] [1038] Example 12: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1- (2-methoxyacetyl) piperidine-4-sulfonamide, potassium salt.
[1039] [1039] Prepared as described for 1-ethyl-N-
[1040] [1040] 1H NMR (CD3OD) δ 6.91 (s, 1 H), 4.19 (q, 2 H), 4.0 (m, 1 H), 3.7 (m, 1 H), 3 , 41 (s, 3 H), 3.23-3.03 (m, 2 H), 2.82 (m, 8 H), 2.7 (m, 1 H), 2.19 (m, 2 H), 2.02 (m, 4 H) and 1.77 (m, 2 H). LCMS: m / z 436 (M + H) + (ES +).
[1041] [1041] Example 13: Methyl 4- (N (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) piperidine-1-carboxylate, potassium salt
[1042] [1042] Prepared as described for 1-ethyl-N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -piperidine-3-sulfonamide, salt of potassium (example 9) of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl 4-sulfamoylpiperidine-1-carboxylate (Intermediate P13) to provide the compound holder (32%) as a solid white.
[1043] [1043] 1H NMR (CD3OD) δ 6.85 (s, 1 H), 4.2 (m, 2 H), 3.68 (s, 3 H), 3.55 (m, 1 H), 2 , 82 (m, 10 H), 2.03 (m, 6 H) and 1.7 (m, 2 H). LCMS: m / z 422 (M + H) + (ES +); 420 (M-H) - (ES-).
[1044] [1044] Example 14: 1- (cyanomethyl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, salt potassium
[1045] [1045] Prepared as described for 1-ethyl-N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -piperidine-3-sulfonamide, salt of potassium (example 9) from 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (cyanomethyl) piperidine-4-sulfonamide (Intermediate P9) to provide the title compound (51%) as a white solid.
[1046] [1046] 1H NMR (CD3OD) δ 6.87 (s, 1 H), 3.64 (s, 2 H), 3.38 (m, 1 H), 2.96 (m, 2 H), 2 , 82 (m, 8 H), 2.3 (m, 2 H), 2.18 (m, 2 H), 2.02 (m, 5 H) and 1.88 (m, 2 H). LCMS: m / z 403 (M + H) + (ES +); 401 (M-H) - (ES-).
[1047] [1047] Example 15: 1-Cyclobutyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt
[1048] [1048] Prepared as described for 1-ethyl-N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -piperidine-3-sulfonamide, salt of potassium (example 9) of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 1-cyclobutylpiperidine-4-sulfonamide (intermediate P14) to provide the title compound (20%) as a white solid.
[1049] [1049] 1H NMR (CD3OD) δ 6.87 (s, 1 H), 5.2 (s, 1 H), 3.47 (q, 2 H), 3.02 (m, 2 H), 2 , 82 (m, 8 H), 2.18-1.97 (m, 6 H), 1.97-1.82 (m, 4 H), 1.72 (m, 2 H) and 1.35 (m, 4 H), LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[1050] [1050] Example 16: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1,3-dimethyl-2,4-dioxo-1 , 2,3,4-tetrahydropyrimidine-5-sulfonamide, potassium salt
[1051] [1051] Prepared as described for 1-ethyl-N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -piperidine-3-sulfonamide, salt potassium (example 9) of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1,2,3,4-tetrahydro-1,3- dimethyl-2,4-dioxo-pyrimidine-5-sulfonate to provide the title compound (50%) as a white solid.
[1052] [1052] 1H NMR (CD3OD) δ 8.22 (s, 1 H), 6.83 (s, 1 H), 3.43 (s, 3 H), 3.35 (s, 3 H), 2 , 8 (t, 4 H), 2.75 (t, 4 H) and 2.0 (m, 4 H). LCMS: m / z 419 (M + H) + (ES +); 417 (M-H) - (ES-).
[1053] [1053] Example 17: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-hexyl-2,4-dioxo-1,2 , 3,4-tetrahydropyrimidine-5-sulfonamide, potassium salt
[1054] [1054] Prepared as described for 1-ethyl-N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -piperidine-3-sulfonamide, salt potassium (example 9) from 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-hexyl-1,2,3,4-tetra- hydro-2,4-dioxo-pyrimidine-5-sulfonamide to provide the title compound (30%) as a white solid.
[1055] [1055] 1H NMR (CD3OD) δ 8.19 (s, 1 H), 6.83 (s, 1 H), 3.78 (t, 2 H), 2.8 (t, 4 H), 2 , 7 (t, 4 H), 1.98 (m, 4 H), 1.67 (m, 2 H), 1.29 (m, 6 H) and 0.88 (t, 3 H) LCMS: m / z 475 (M + H) + (ES +); 473 (M-H) - (ES-).
[1056] [1056] Example 18: 1-Cyclobutyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1057] [1057] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclobutylazetidine-3-sulfonamide (Intermediate P79) to provide the title compound (25%) as a white solid.
[1058] [1058] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.34 (t, 1H), 3.63 (dd, 4H), 2.81 (m, 11H), 2.02 (m, 4H), 1.95 - 1.82 (m, 2H), 1.82 - 1.65 (m, 2H). LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[1059] [1059] Example 19: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-propylpiperidine-4-sulfonamide, potassium salt
[1060] [1060] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-propylpiperidine-4-sulfonamide (Intermediate P16) to provide the title compound (2%) as a white solid. LCMS: m / z 406 (M + H) + (ES +); 404 (MH) - (ES-).
[1061] [1061] Example 20: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (oxetan-3-yl) piperidine-4- sulfonamide, potassium salt
[1062] [1062] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (oxetan-3- il) piperidine-4-sulfonamide (Intermediate P17) to provide the title compound (12%) as a white solid.
[1063] [1063] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.62 (m, 4 H), 3.47 (m, 1 H), 3.4 (m, 1 H), 2 , 82 (m, 10 H), 2.18 (m, 2 H), 2.02 (m, 4 H) and 1.87 (m, 4 H). LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1064] [1064] Example 21: Methyl 2- (4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) piperidine-1-yl ) acetate, potassium salt
[1065] [1065] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl 2- (4-sulfamoylpiperidin -1-yl) acetate (Intermediate P18) to provide the title compound (46%) as a white solid.
[1066] [1066] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.69 (s, 3 H), 3.3 (m, 2 H), 3.24 (s, 2 H), 3 , 03 (m, 2 H), 2.82 (m, 8 H), 2.22 (m, 2 H) and 2.03 (m, 8 H).
[1067] [1067] Example 22: 1- (2-Fluoroethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt
[1068] [1068] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2-fluoroethyl) piperidine-4-sulfonamide to provide the title compound (14%) as a white solid.
[1069] [1069] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.65 (m, 1 H), 4.48 (m, 1 H), 3.4 (m, 1 H), 3 , 08 (m, 2 H), 2.82 (m, 8 H), 2.74 (m, 1 H), 2.64 (m, 1 H), 2.13 (m, 4 H), 2 , 02 (m, 4 H) and 1.9 (m, 2 H). LCMS: m / z 410 (M + H) + (ES +).
[1070] [1070] Example 23: 1-Cyclopropyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt
[1071] [1071] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclopropylpiperidine-4-sulfonamide (Intermediate P19) to provide the title compound (17%) as a white solid.
[1072] [1072] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.43 (m, 1 H),
[1073] [1073] Example 24: 1- (1-ethylazetidin-3-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine- 4-sulfonamide, potassium salt
[1074] [1074] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1-ethylazetidine- 3-yl) piperidine-4-sulfonamide (Intermediate P20) to provide the title compound (34%) as a white solid.
[1075] [1075] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.65 (m, 2 H), 3.33 (m, 1 H), 3.05 (m, 3), 2, 82 (m, 10 H), 2.63 (m, 2 H), 2.14 (m, 2 H), 2.02 (m, 4 H), 1.83 (m, 4 H), and 1 , 01 (t, 3 H). LCMS: m / z 447 (M + H) + (ES +); 445 (M-H) - (ES-).
[1076] [1076] Example 25: 1- (Cyclobutanocarbonyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, salt potassium
[1077] [1077] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide,
[1078] [1078] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.58 (m, 1 H), 3.91 (m, 1 H), 3.40 (m, 1 H), 3 , 02 (m, 1 H), 2.82 (m, 8 H), 2.63 (m, 1 H), 2.2 (m, 6 H), 2.02 (m, 6 H), 1 , 83 (m, 1 H) and 1.67 (m, 2 H). LCMS: m / z 446 (M + H) + (ES +); 444 (M-H) - (ES-).
[1079] [1079] Example 26: N-ethyl-4- (N - (((1,2,3,5,6,7-hexahydro-sindacen-4-yl) carbamoyl) sulfamoyl) piperidine-1-carboxamide, salt potassium
[1080] [1080] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-ethyl-4-sulfamoylpiperidine -1-carboxamide (Intermediate P22) to provide the title compound (5%) as a white solid.
[1081] [1081] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.13 (m, 2 H), 3.56 (m, 1 H), 3.18 (m, 2 H), 2 , 82 (m, 10 H), 2.02 (m, 6 H), 1.7 (m, 2 H) and 1.1 (t, 3 H). LCMS: m / z 435 (M + H) + (ES +).
[1082] [1082] Example 27: N-cyclobutyl-3- (N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) piperidine-1-carboxamide , potassium salt
[1083] [1083] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-cyclobutyl-3-sulfamoylpiperidine -1-carboxamide to provide the title compound (11%) as a white solid.
[1084] [1084] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.3 (m, 2 H), 4.03 (m, 2 H), 3.46 (m, 1 H), 2 , 99 (m, 2 H), 2.82 (m, 8 H), 2.65 (m, 2 H), 2.27 (m, 1 H), 2.02 (m, 4 H), 1 , 8 (m, 4 H), 1.6 (m, 2 H), 1.44 (m, 1 H). LCMS: m / z 461 (M + H) + (ES +).
[1085] [1085] Example 28: 4-N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N-methylpiperidine-1-carboxamide, salt of potassium.
[1086] [1086] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-ethyl-4-sulfamoylpiperidine -1-carboxamide (Intermediate P23) to provide the title compound (9%) as a white solid.
[1087] [1087] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.11 (m, 2 H), 3.55 (m, 1 H), 3.02 (m, 1 H), 2 , 82 (m, 9 H), 2.73 (m, 1 H), 2.7 (s, 3 H), 2.02 (m, 6 H) and 1.7 (m, 2 H).
[1088] [1088] Example 29: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (methylsulfonyl) piperidine-4-sulfonamide, salt potassium
[1089] [1089] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (methylsulfonyl) piperidine- 4-sulfonamide (Intermediate P24) to provide the title compound (33%) as a white solid.
[1090] [1090] 1H NMR (CD3OD) δ 6.86 (s, 1H) rotamer mixture, 3.92 (m, 2 H, rotamer a), 3.82 (m, 2 H, rotamer b), 3, 55 (m, 1 H), 3.0 (m, 1 H) 2.82 (m, 12 H), 2.22 (m, 2 H), 2.02 (m, 4 H), 1.87 (m, 2 H). LCMS: m / z 442 (M + H) + (ES +).
[1091] [1091] Example 30: N-ethyl-3- (N - (((1,2,3,5,6,7-hexahydro-sindacen-4-yl) carbamoyl) sulfamoyl) piperidine-1-carboxamide, salt potassium
[1092] [1092] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-ethyl-3-sulfamoylpiperidine -1-carboxamide (Intermediate P25) to provide the title compound (48%) as a white solid.
[1093] [1093] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.25 (m, 1 H), 3.63 (m, 3 H), 3.18 (m, 2 H), 2 , 82 (m, 10 H), 2.39 (m, 1 H), 2.23 (m, 1 H), 2.02 (m, 4 H) and 1.08 (t, 3 H). LCMS: m / z 421 (M + H) + (ES +); 419 (M-H) - (ES-).
[1094] [1094] Example 31: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-iso-propyl-piperidine-3-sulfonamide, salt potassium
[1095] [1095] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropylpiperidine-3-sulfonamide to provide the title compound (18%) as a white solid.
[1096] [1096] 1H NMR (CD3OD) δ 6.89 (s, 1 H), 3.78 (m, 1 H), 3.5 (m, 1 H), 3.05 (m, 1 H), 2 , 8 (m, 8 H), 2.7 (m, 2 H), 2.45 (m, 1 H), 2.21 (m, 1 H), 2.02 (m, 4 H), 1 , 86 (m, 1 H), 1.67 (m, 2 H) and 1.17 (d, 6 H). LCMS: m / z 406 (M + H) + (ES +).
[1097] [1097] Example 32: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-propionylpiperidine-3-sulfonamide, potassium salt
[1098] [1098] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-propionylpiperidine-3-sulfonamide to provide the title compound (27%) as a white solid.
[1099] [1099] 1 H NMR (CD3 OD) δ 6.87 (s, 1H) rotamer mixture, 4.96 (m, 1H, rotamer a), 4.4 (m, 1H, rotamer b), 4.28 (m, 1H, rotamer a), 3.87 (m, 1 H, rotamer b), 3.52 (m, 1 H), 3.01 (m, 1 H), 2.82 (m, 8 H ), 2.64 (m, 1 H), 2.42 (m, 2 H), 2.28 (m, 1 H), 2.02 (m, 4 H), 1.85 (m, 2 H ), 1.5 (m, 1 H) and 1.1 (t, 3 H). LCMS: m / z 420 (M + H) + (ES +); 418 (MH) - (ES-).
[1100] [1100] Example 33: 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N-isopropylpiperidine-1-carboxamide, potassium salt
[1101] [1101] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-isopropyl-3-sulfamoylpiperidine -1-carboxamide (Intermediate P26) to provide the title compound (55%) as a white solid.
[1102] [1102] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.35 (m, 1 H), 4.0 (m, 1 H), 3.85 (m, 1 H), 3 , 42 (m, 1 H), 2.82 (m, 9 H), 2.68 (m, 2 H), 2.28 (m, 1 H), 2.02 (m, 4 H), 1 , 79 (m, 2 H), 1.45 (m, 1 H) and 1.1 (d, 6 H). LCMS: m / z 449 (M + H) + (ES +); 447 (M-H) - (ES-).
[1103] [1103] Example 34: 1- (2-Fluoroethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-3-sulfonamide, potassium salt
[1104] [1104] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2-fluoroethyl) piperidine-3-sulfonamide to provide the title compound (2%) as a white solid.
[1105] [1105] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.84 (m, 1 H), 4.64 (m, 1 H), 3.61 (m, 1 H), 3 , 41 (m, 1 H), 2.91 (m, 1 H), 2.82 (m, 8 H), 2.69 (m, 2 H), 2.31 (m, 1 H), 2 , 21 (m, 1 H), 2.02 (m, 5 H), 1.79 (m, 1 H) and 1.61 (m, 2 H). LCMS: m / z 410 (M + H) + (ES +); 408 (M-H) - (ES-).
[1106] [1106] Example 35: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1,2,3,4-tetrahydroquinoline-3 -sulfonamide, potassium salt
[1107] [1107] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1,2,3,4 -tetrahydroquinoline-3-sulfonamide to provide the title compound (13%) as a white solid.
[1108] [1108] 1H NMR (CD3OD) δ 6.92 (m, 3 H), 6.58 (m, 2 H), 3.92 (m, 2 H), 3.73 (m, 2 H), 3 , 11 (m, 2 H), 2.82 (m, 8 H) and 2.02 (m, 4 H). LCMS: m / z 412 (M + H) + (ES +).
[1109] [1109] Example 36: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-methylpyrrolidine-3-sulfonamide, potassium salt
[1110] [1110] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-methyl-pyrrolidine-3 -sulfonamide (Intermediate P27) to provide the title compound (19%) as a white solid.
[1111] [1111] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.21 (m, 1 H), 3.1 (m, 1 H), 2.9 (m, 1 H), 2 , 82 (m, 9 H), 2.62 (m, 1 H), 2.42 (s, 3 H), 2.33 (m, 1 H), 2.19 (m, 1 H) and 2 , 02 (m, 4 H). LCMS: m / z 364 (M + H) + (ES +); 362 (M-H) - (ES-).
[1112] [1112] Example 37: 1-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) pyrrolidine-3-sulfonamide, potassium salt
[1113] [1113] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-pyrrolidine-3 -sulfonamide (Intermediate P28) to provide the title compound (30%) as a white solid.
[1114] [1114] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.21 (m, 1 H), 3.0 (m, 2 H), 2.82 (m, 10 H), 2 , 7 (m, 2 H), 2.38 (m, 1 H), 2.22 (m, 1 H), 2.02 (m, 4 H) and 1.18 (t, 3 H). LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1115] [1115] Example 38: 1-acetyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) pyrrolidine-3-sulfonamide, potassium salt
[1116] [1116] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-acetyl-pyrrolidine-3 -sulfonamide (Intermediate P29) to provide the title compound (21%) as a white solid.
[1117] [1117] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.24 (m, 1 H), 3.9 (m, 1 H), 3.75 (m, 1 H), 3 , 57 (m, 1 H), 3.45 (m, 1 H), 2.82 (m, 8 H), 2.38 (m, 2 H) and 2.02 (m, 7 H). LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1118] [1118] Example 39: 1-Cyclopropyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) pyrrolidine-3-sulfonamide, potassium salt
[1119] [1119] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and and 1-cyclopropyl-pyrrolidine-3 -sulfonamide (Intermediate P30) to provide the title compound (30%) as a white solid.
[1120] [1120] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.18 (m, 1 H), 3.22 (m, 1 H), 3.02 (m, 1 H), 2 , 82 (m, 10 H), 2.29 (m, 1 H), 2.16 (m, 1 H), 2.02 (m, 4 H), 1.81 (m, 1 H) and 1 , 45 (m, 4 H). LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[1121] [1121] Example 40: 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N, N-dimethylpyrrolidine-1- carboxamide
[1122] [1122] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N, N-dimethyl-3 -sulfamoylpyrrolidine-1-carboxamide (Intermediate P31) to provide the title compound as a white solid.
[1123] [1123] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.18 (m, 1 H), 3.82 (m, 1 H), 3.64 (m, 2 H), 3 , 44 (m, 1 H), 2.86 (s, 6 H), 2.82 (m, 8 H), 2.34 (m, 1 H), 2.19 (m, 1 H) and 2 , 02 (m, 4 H). LCMS: m / z 421 (M + H) + (ES +); 419 (M-H) - (ES-).
[1124] [1124] Example 41: N - (((1,2,3,5,6,7-hexahydro-s-indacent-4-yl) carbamoyl) -1-iso-propylpyrrolidine-3-sulfonamide, potassium salt
[1125] [1125] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropylpyrrolidine-3-sulfonamide (Intermediate P32) to provide the title compound (36%) as a white solid.
[1126] [1126] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.21 (m, 1 H),
[1127] [1127] Example 42: N - ((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) azetidine-3-sulfonamide.
[1128] [1128] For a solution of benzyl 3- (N- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) azamoidyl) azetidine-1-carboxylate , potassium salt (Example 71) in methanol Pd / C was added and the reaction was heated to 65 ° C under a hydrogen atmosphere. After cooling, the mixture was filtered and purified by reverse phase chromatography (see "Experimental methods", "Purification method 1") to provide the title compound (28%) as a white solid.
[1129] [1129] 1H NMR (CD3OD) δ 6.84 (s, 1 H), 4.8 (s, 1 H), 4.58 (m, 1 H), 4.04 (m, 1 H), 3 , 7 (m, 1 H), 3.3 (m, 1 H), 2.8 (m, 8 H) and 2.02 (m, 4 H). LCMS: m / z 337 (M + H) + (ES +).
[1130] [1130] Example 43: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) quinuclidine-3-sulfonamide, potassium salt
[1131] [1131] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and quinuclidine-3-sulfonamide (Intermediate P34)
[1132] [1132] 1H NMR (300 MHz, CD3OD) δ 6.86 (s, 1 H), 4.18 (m, 1 H), 3.97 (m, 1 H), 3.82 (m, 1 H ), 3.62 (m, 1 H), 3.58 (m, 2 H), 3.08 (m, 1 H), 2.82 (m, 8 H), 2.41 (m, 2 H ), 2.02 (m, 4 H), 1.77 (m, 2 H) and 1.48 (m, 1 H). LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[1133] [1133] Example 44: 1- (1-ethylpiperidine-4-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) pyrrolidine- 3-sulfonamide, potassium salt
[1134] [1134] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1-ethylpiperidin-4 -yl) pyrrolidine-3-sulfonamide (Intermediate P35) to provide the title compound (29%) as a white solid.
[1135] [1135] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.18 (m, 1 H), 3.72 (m, 1 H), 3.2 (m, 2 H), 3 , 08 (m, 2 H), 2.93 (m, 1 H), 2.82 (m, 8 H), 2.71 (m, 2 H), 2.6 (m, 2 H), 2 , 48 (m, 1 H), 2.23 (m, 4 H), 2.02 (m, 4 H), 1.65 (m, 2 H) and 1.18 (t, 3 H). LCMS: m / z 461 (M + H) + (ES +); 459 (M-H) - (ES-).
[1136] [1136] Example 45: (1R *, 3R *, 5S *) - N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -8- isopropyl-8-azabicyclo [3.2.1] octane-3-sulfonamide, potassium salt
[1137] [1137] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R *, 3R *, 5S *) - 8-isopropyl-8-azabicyclo [3.2.1] octane-3-sulfonamide (Intermediate P36) to provide the title compound (12%) as a white solid.
[1138] [1138] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.02 (m, 1 H), 2.82 (m, 8 H), 2.68 (m, 1 H), 2 , 22 (m, 10 H), 2.02 (m, 4 H) and 1.38 (d, 6 H). LCMS: m / z 432 (M + H) + (ES +); 430 (M-H) - (ES-).
[1139] [1139] Example 46: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-iso-propylazetidine-3-sulfonamide, potassium salt
[1140] [1140] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropylazetidine-3-sulfonamide (Intermediate P37) to provide the title compound (57%) as a white solid.
[1141] [1141] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.33 (m, 1 H), 3.88 (m, 4 H), 2.82 (m, 9 H), 2 , 02 (m, 4 H), and 1.03 (d, 6 H). LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1142] [1142] Example 47: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-iso-propylpyrrolidine-4-sulfonamide, potassium salt
[1143] [1143] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropylpiperidine-4-sulfonamide (Intermediate P138) to provide the title compound (59%) as a white solid.
[1144] [1144] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.03 (m, 2 H), 2.82 (m, 8 H), 2.72 (m, 1 H), 2 , 18 (m, 5 H), 2.02 (m, 4 H), 1.88 (m, 2 H) and 1.07 (d, 6 H). LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1145] [1145] Example 48: 1'-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) - [1,4'-bipiperidine] -4-sulfonamide, potassium salt
[1146] [1146] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (IntermediateA1) and 1'-ethyl- [1,4 '-bipiperidine] -4-sulfonamide (Intermediate P38) to provide the title compound (22%) as a white solid.
[1147] [1147] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.4 (m, 1 H), 3.19 (m, 4 H), 2.82 (m, 8 H), 2 , 7 (m, 2 H), 2.58 (m, 1 H), 2.38 (m, 4 H), 2.18 (m, 2 H), 2.02 (m, 4 H), 1 , 93 (m, 4 H), 1.7 (m, 2 H) and 1.18 (t, 3 H).
[1148] [1148] Example 49: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-methylazetidine-3-sulfonamide, potassium salt
[1149] [1149] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-methylazetidine-3-sulfonamide (Intermediate P39) to provide the title compound (13%) as a white solid.
[1150] [1150] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.35 (m, 1 H), 4.18 (m, 4 H), 2.82 (m, 8 H), 2 , 77 (s, 3 H) and 2.02 (m, 4 H). LCMS: m / z 350 (M + H) + (ES +); 348 (M-H) - (ES-).
[1151] [1151] Example 50: 2-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -2-azaspiro [3.3] heptane-6 -sulfonamide, potassium salt
[1152] [1152] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-ethyl-2-azaspiro [3.3] heptane-6-sulfonamide (Intermediate P40) to provide the title compound (35%) as a white solid.
[1153] [1153] 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).
[1154] [1154] Example 51: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (1-isopropylazetidin-3-yl) pyrrolidine- 3-sulfonamide, potassium salt
[1155] [1155] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1-isopropyl- azetidin-3-yl) pyrrolidine-3-sulfonamide (Intermediate P41) to provide the title compound (21%) as a white solid.
[1156] [1156] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.19 (m, 1 H), 3.72 (m, 2 H), 3.35 (m, 1 H), 3 , 21 (m, 1 H), 2.97 (m, 1 H), 2.82 (m, 10 H), 2.8 (m, 1 H), 2.63 (m, 2 H), 2 , 33 (m, 1 H), 2.17 (m, 1 H), 2.02 (m, 4 H) and 1.03 (d, 6 H). LCMS: m / z 447 (M + H) + (ES +).
[1157] [1157] Example 52: (1R *, 3R *, 5S *) - 8-Ethyl-N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl ) -8-azabicyclo [3.2.1] octane-3-sulfonamide, potassium salt
[1158] [1158] Prepared as described for N - ((1,2,3,5,6,7-
[1159] [1159] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.91 (m, 1 H), 3.64 (m, 2 H), 2.82 (m, 10 H), 2 , 5 (m, 3 H), 2.29 (m, 3 H), 2.02 (m, 6 H) and 1.12 (t, 3 H). LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[1160] [1160] Example 53: 1-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1161] [1161] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethylazetidine-3-sulfonamide (Intermediate P43) to provide the title compound (18%) as a white solid.
[1162] [1162] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.35 (m, 1 H), 3.78 (m, 2 H), 3.63 (m, 2 H), 2 , 82 (m, 8 H), 2.68 (m, 2 H), 2.02 (m, 4 H) and 1.01 (t, 3 H). LCMS: m / z 364 (M + H) + (ES +); 362 (M-H) - (ES-).
[1163] [1163] Example 54: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1- (2,2,2-trifluoroacetyl) pyrrolidine- 3-sulfonamide, potassium salt
[1164] [1164] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2,2, 2-trifluoroacetyl) pyrrolidine-3-sulfonamide (Intermediate P44) to provide the title compound (15%) as a white solid.
[1165] [1165] 1H NMR (CD3OD) δ 6.96 (s, 1 H), 4.42 (m, 1 H), 4.14 (m, 1 H), 3.85 (m, 2 H), 3 , 58 (m, 1 H), 2.8 (m, 8 H), 2.5 (m, 2 H) and 2.04 (m, 4 H). LCMS: m / z 446 (M + H) + (ES +); 444 (M-H) - (ES-).
[1166] [1166] Example 55: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl pyrrolidine-3-sulfonamide, potassium salt
[1167] [1167] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2,2, 2-trifluoroacetyl) pyrrolidine-3-sulfonamide (Intermediate P44) to provide the unprotected title compound (5%) as a white solid.
[1168] [1168] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 4.58 (m, 1 H), 4.22 (m, 1 H), 3.65 (m, 1 H), 3 , 38 (m, 1 H), 3.19 (m, 1 H), 2.82 (m, 8 H), 2.45 (m, 1 H), 2.29 (m, 1 H), and 2.02 (m, 4 H). LCMS: m / z 350 (M + H) + (ES +); 348 (M-H) - (ES-).
[1169] [1169] Example 56: 1-Acetyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-3-sulfonamide, potassium salt
[1170] [1170] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-acetyl-piperidine-3 -sulfonamide to provide the title compound (33%) as a white solid.
[1171] [1171] 1H NMR (CD3OD) δ 6.87 (s, 1H), 4.96 (m, 1 H, rotamer), 4.32 (m, 1 H, rotamer), 4.25 ( m, 1 H, rotamer), 3.85 (m, 1 H, rotamer), 3.55 (m, 1 H), 3.05 (m, 1 H), 2.82 (m, 8 H), 2.69 (m, 1 H), 2.27 (m, 1 H), 2.17 (s, 3H, rotamer), 2.09 (s, 3H, rotamer), 2.02 (m, 4H) , 1.85 (m, 2H), 1.5 (m, 1H). LCMS: m / z 406 (M + H) + (ES +); 404 (MH) - (ES-).
[1172] [1172] Example 57: 1- (Cyclopropylmethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-3-sulfonamide, salt potassium
[1173] [1173] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (cyclopropylmethyl) piperidine- 3-sulfonamide (Intermediate P45) to provide the title compound (21%) as a white solid.
[1174] [1174] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.72 (m, 2 H), 3.06 (m, 1 H), 2.8 (m, 8 H), 2 , 5 (m, 3 H), 2.22 (m, 2 H), 2.02 (m, 4 H), 1.85 (m, 2
[1175] [1175] Example 58: 1- (cyanomethyl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-3-sulfonamide, salt potassium
[1176] [1176] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (cyanomethyl) piperidine- 3-sulfonamide to provide the title compound (41%) as a white solid.
[1177] [1177] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.67 (s, 2 H), 3.6 (m, 1 H), 3.29 (m, 2 H), 2 , 82 (m, 8 H), 2.47 (t, 1 H), 2.21 (m, 2 H), 2.02 (m, 4 H), 1.84 (m, 1 H) and 1 , 58 (m, 2 H). LCMS: m / z 403 (M + H) + (ES +); 401 (M-H) - (ES-).
[1178] [1178] Example 59: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1- (prop-2-in-1-yl) piperidine-3-sulfonamide potassium salt
[1179] [1179] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (prop-2- in-1-yl) piperidine-3-sulfonamide to provide the title compound (44%) as a white solid.
[1180] [1180] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.57 (m, 1 H), 3.33 (m, 4 H), 2.82 (m, 8 H), 2 , 65 (m, 1 H), 2.42 (t, 1 H), 2.2 (m, 2 H), 2.02 (m, 4
[1181] [1181] Example 60: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-methylpiperidine-3-sulfonamide, potassium salt
[1182] [1182] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-methylpiperidine-3-sulfonamide (Intermediate P46) to provide the title compound (11%) as a white solid.
[1183] [1183] 1H NMR (CD3OD) δ 6.88 (s, 1 H), 3.68 (m, 1 H), 3.4 (m, 1 H), 2.82 (m, 9 H), 2 , 43 (m, 1 H), 2.42 (s, 3 H), 2.2 (m, 2 H), 2.02 (m, 4 H), 1.9 (m, 1 H), and 1.64 (m, 2 H). LCMS: m / z 378 (M + H) + (ES +).
[1184] [1184] Example 61: 4- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N, N-dimethylpiperidine-1- carboxamide
[1185] [1185] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N, N-dimethyl-4 -sulfamoylpiperidine-1-carboxamide (Intermediate P48) to provide the title compound (46%) as a white solid.
[1186] [1186] 1H NMR (CD3OD) δ 6.86 (s, 1 H), 3.78 (m, 2 H), 3.50 (m, 1 H), 2.82 (m, 10 H), 2 , 80 (s, 6 H), 2.05 (m, 6 H) and 1.8 (m, 2 H). LCMS: m / z 435 (M + H) + (ES +); 433 (M-H) - (ES-).
[1187] [1187] Example 62: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1- (1-isopropylazetidine-3-yl) piperidine- 4-sulfonamide, potassium salt
[1188] [1188] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1-isopropylazetidin- 3-yl) piperidine-4-sulfonamide (Intermediate P49) to provide the title compound (37%) as a white solid.
[1189] [1189] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.59 (s, 1H), 3.75 (t, 2H), 3.02 (d, 2H), 2.99 - 2.69 (m, 12H), 2.13 (d, 2H), 2.02 (m, 4H), 1.95 - 1.76 (m, 4H), 1.05 (d, 6H). LCMS: m / z 461 (M + H) + (ES +); 459 (M-H) - (ES-).
[1190] [1190] Example 63: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -2-isopropyl-2-azaspiro [3.3] heptane-6 -sulfonamide, potassium salt
[1191] [1191] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-isopropyl-2-azaspiro [3.3] heptane-6-sulfonamide
[1192] [1192] 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). LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[1193] [1193] Example 64: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -2-methyl-2-azaspiro [3.3] heptane-6 -sulfonamide, potassium salt
[1194] [1194] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-methyl-2-azaspiro [3.3] heptane-6-sulfonamide (Intermediate P51) to provide the title compound (14%) as a white solid.
[1195] [1195] 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). LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[1196] [1196] Example 65: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (pentan-3-yl) azetidine-3- sulfonamide, potassium salt
[1197] [1197] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-
[1198] [1198] 1H NMR (CD3OD): δ = 6.86 (s, 1 H), 4.31 (m, 1H), 4.16 (m, 4H), 2.82 (m, 9H), 2, 04 (q, 4H), 1.78 - 1.41 (m, 4H), 0.92 (t, 6H). LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1199] [1199] Example 66: 1-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1,2,3,4-tetra -hydroquinoline-3-sulfonamide, potassium salt
[1200] [1200] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-1,2 , 3,4-tetrahydroquinoline-3-sulfonamide (Intermediate P53) to provide the title compound (33%) as a white solid.
[1201] [1201] 1H NMR (CD3OD): δ = 6.95 (m, 3H), 6.81 - 6.51 (m, 2H), 3.76 - 3.41 (m, 2H), 3.21 - 3.01 (m, 2H), 2.83 (m, 10H), 2.29 - 1.91 (m, 5H), 1.15 (t, 3H). LCMS: m / z 440 (M + H) + (ES +); 438 (M-H) - (ES-).
[1202] [1202] Example 67: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1- (2,2,2-trifluoroethyl) piperidine- 4-sulfonamide, potassium salt
[1203] [1203] Prepared as described for N - ((1,2,3,5,6,7-
[1204] [1204] 1H NMR (CD3OD): δ = 6.96 (s, 1H), 3.66 - 3.39 (m, 1H), 3.09 (dt, 5H), 2.82 (dt, 9H) , 2.44 (t, 2H), 2.05 (m, 4H), 1.90 (dd, 2H). LCMS: m / z 446 (M + H) + (ES +); 444 (M-H) - (ES-).
[1205] [1205] Example 68: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-isopropyl-2-oxopyrrolidine-3-sulfonamide, salt potassium
[1206] [1206] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropyl-2-oxopyrrolidine -3-sulfonamide (Intermediate P64) to provide the title compound (64%) as a white solid.
[1207] [1207] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.47 - 4.13 (m, 2H), 3.52 (dt, 1H) 3.32 (dt, 1H), 2.82 (q, 8H), 2.68 - 2.46 (m, 1H), 2.46 - 2.25 (m, 1H), 2.15 - 1.89 (m, 4H), 1, 15 (d, 6H). LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1208] [1208] Example 69: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -8-isopropyl-8-azabicyclo [3.2.1] octane -3-sulfonamide exo isomer, potassium salt
[1209] [1209] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R *, 3S *, 5S *) - 8-iso-propyl-8-azabicyclo [3.2.1] octane-3-sulfonamide (Intermediate P55) to provide the title compound (40%) as a white solid.
[1210] [1210] 1H NMR (CD3OD): δ = 6.95 (s, 1H), 4.57 (s, 1H), 4.34 (s, 1H), 4.12 (s, 1H), 2.85 (dt, 9H), 2.59 (s, 1H), 2.47 - 2.16 (m, 5H), 2.06 (m, 6H), 1.41 (d, 6H). LCMS: m / z 432 (M + H) + (ES +); 430 (M-H) - (ES-).
[1211] [1211] Example 70: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -8-ethyl-8-azabicyclo [3.2.1] octane -3-sulfonamide exo isomers, potassium salt
[1212] [1212] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R *, 3S *, 5S *) - 8-ethyl-8-azabicyclo [3.2.1] octane-3-sulfonamide (Intermediate P56) to provide the title compound (23%) as a white solid.
[1213] [1213] 1H NMR (CD3OD): δ = 6.91 (s, 1H), 4.57 (s, 1H),
[1214] [1214] Example 71: Benzyl 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) azetidine-1-benzyl carboxylate, potassium salt
[1215] [1215] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-sulfamoylazetidine-1-carboxylate benzyl (Intermediate P47) to provide the title compound (41%) as a white solid.
[1216] [1216] 1H NMR (CD3OD): δ = 7.51 - 7.15 (m, 5H), 6.93 (s, 1H), 5.09 (s, 2H), 4.31 (m, 4H) , 2.80 (dt, 9H), 2.03 (m, 4H). LCMS: m / z 470 (M + H) + (ES +); 468 (M-H) - (ES-).
[1217] [1217] Example 72: 1-benzyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1218] [1218] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-benzylazetidine-3-sulfonamide (Intermediate
[1219] [1219] 1H NMR (CD3OD): δ = 7.41 - 7.15 (m, 5H), 6.86 (s, 1H), 4.33 (t, 1H), 3.69 (s, 2H) , 3.60 (d, 4H), 2.80 (dt, 8H), 2.02 (q, 4H). LCMS: m / z 426 (M + H) + (ES +); 424 (M-H) - (ES-).
[1220] [1220] Example 73: 1- (1-ethylpiperidin-4-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine- 3-sulfonamide, potassium salt
[1221] [1221] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1-ethylpiperidin- 4-yl) azetidine-3-sulfonamide (Intermediate P58) to provide the title compound (59%) as a white solid.
[1222] [1222] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.31 (q, 1H), 3.65 (t, 2H), 3.54 (t, 2H), 3.00 (d, 2H), 2.83 (q, 9H), 2.51 (q, 2H), 2.25 - 1.93 (m, 6H), 1.81 (d, 2H), 1.34 ( q, 2H), 1.12 (t, 3H). LCMS: m / z 447 (M + H) + (ES +); 445 (M-H) - (ES-).
[1223] [1223] Example 74: 1-acetyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1224] [1224] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-acetylazetidine-3-sulfonamide (Intermediate
[1225] [1225] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.54 - 4.32 (m, 2H), 4.32 - 4.07 (m, 2H), 3.55 ( m, 1H), 2.82 (m, 8H), 2.02 (m, 4H), 1.87 (d, 3H). LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1226] [1226] Example 75: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1- (tetrahydro-2H-pyran-4- il) azetidine-3-sulfonamide potassium salt
[1227] [1227] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (tetrahydro- 2H-pyran-4-yl) azetidine-3-sulfonamide (Intermediate P60) to provide the title compound (29%) as a white solid.
[1228] [1228] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.32 (m, 1H), 3.92 (ddd, 2H), 3.74 - 3.48 (m, 4H) , 3.48 - 3.33 (m, 2H), 2.82 (m, 8H), 2.45 (dt, 1H), 2.02 (m, 4H), 1.70 (dt, 2H), 1.24 (dd, 2H). LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1229] [1229] Example 76: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-propylazetidine-3-sulfonamide, potassium salt
[1230] [1230] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-
[1231] [1231] 1H NMR (CD3OD): δ = 6.91 (s, 1H), 4.39 (m, 1H), 4.29 (d, 4H), 3.17 - 3.01 (m, 2H) , 2.83 (m, 8H), 2.04 (m, 4H), 1.57 (m, 2H), 0.99 (t, 3H). LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1232] [1232] Example 77: tert-Butyl 3- (N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) azetidine-1-carboxylate , potassium salt
[1233] [1233] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-sulfamoylazetidine-1-carboxylate tert-butyl (Intermediate P62) to provide the title compound (9%) as a white solid
[1234] [1234] 1H NMR (CD3OD): δ = 6.93 (s, 1H), 4.43 (d, 1H), 4.33 - 4.03 (m, 4H), 2.82 (m, 8H) , 2.04 (m, 4H), 1.44 (s, 9H). LCMS: m / z 434 (M-H) - (ES-).
[1235] [1235] Example 78: Methyl 2- (3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) azeditin-1-yl ) acetate, potassium salt
[1236] [1236] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide,
[1237] [1237] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.36 (m, 1H), 3.87 - 3.74 (m, 2H), 3.69 (s, 3H) , 3.61 (dd, 2H), 3.39 (s, 2H), 2.81 (m, 8H), 2.03 (m, 4H). LCMS: m / z 408 (M + H) + (ES +); 406 (M-H) - (ES-).
[1238] [1238] Example 79: 1- (1-acetyl-azetidine-3-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt
[1239] [1239] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1-acetyl- azeditin-3-yl) piperidine-4-sulfonamide (Intermediate P65) to provide the title compound (20%) as a white solid.
[1240] [1240] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.23 (m, 1H), 4.03 (m, 2H), 3.82 (dd, 1H), 3.45 (s, 1H), 3.20 (q, 1H), 2.99 (s, 2H), 2.84 (m, 10H), 2.17 (d, 2H), 2.04 (m, 5H) , 1.97 - 1.78 (m, 4H). LCMS: m / z 461 (M + H) + (ES +); 459 (M-H) - (ES-).
[1241] [1241] Example 80: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (1-methylazetidine-3-yl) piperidine- 4-sulfonamide, potassium salt
[1242] [1242] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1-methyl- azetidine-3-yl) piperidine-4-sulfonamide (Intermediate P66) to provide the title compound (29%) as a white solid.
[1243] [1243] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 3.59 (m, 2H), 3.40 (m, 2H), 3.00 (dq, 3H), 2.83 (m, 11H), 2.40 (s, 3H), 2.04 (m, 4H), 1.89 (q, 4H). LCMS: m / z 433 (M + H) + (ES +); 431 (M-H) - (ES-).
[1244] [1244] Example 81: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (pentan-3-yl) pyrrolidine-3- sulfonamide, potassium salt
[1245] [1245] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (pentan-3- il) pyrrolidine-3-sulfonamide (Intermediate P67) to provide the title compound (33%) as a white solid.
[1246] [1246] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.22 (s, 1H), 3.07 (m, 2H), 2.82 (m, 8H), 2.62 -2.18 (m, 5H), 2.03 (m, 4H), 1.86 - 1.48 (m, 4H), 0.94 (td, 6H). LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1247] [1247] Example 82: 1- (sec-butyl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) pyrrolidine-3-sulfonamide, potassium salt
[1248] [1248] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and and 1-cyclopropyl-pyrrolidine-3 -sulfonamide (Intermediate P68) to provide the title compound (34%) as a white solid.
[1249] [1249] 1H NMR (CD3OD): δ = 6.90 (s, 1H), 4.21 (d, 1H), 3.62 - 3.40 (m, 1H), 3.23 - 3.07 ( m, 1H), 2.98 (s, 1H), 2.84 (q, 10H), 2.35 (dd, 2H), 2.04 (m, 4H), 1.85 (d, 1H), 1.45 (s, 1H), 1.21 (s, 3H), 1.10 - 0.82 (m, 3H). LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1250] [1250] Example 83: 1-butyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1251] [1251] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-butylazetidine-3-sulfonamide (Intermediate P69) to provide the title compound (43%) as a white solid.
[1252] [1252] 1H NMR (CD3OD): δ = 6.87 (s, 1 H), 4.36 (m, 1H), 3.93 - 3.59 (m, 4H), 2.81 (q, 8H ), 2.66 (t, 2H), 2.02 (m, 4H), 1.48 - 1.16 (m, 4H), 0.93 (t, 3H).
[1253] [1253] Example 84: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (2-hydroxy-2-methylpropyl) azetidine- 3-sulfonamide, potassium salt
[1254] [1254] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2-hydroxy- 2-methylpropyl) azetidine-3-sulfonamide (Intermediate P70) to provide the title compound (54%) as a white solid.
[1255] [1255] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.37 (m, 1H), 3.77 (m, 2H), 3.68 (m, 2H), 2.83 (m, 8H), 2.57 (s, 2H), 2.04 (m, 4H), 1.15 (s, 6H). LCMS: m / z 408 (M + H) + (ES +); 406 (M-H) - (ES-).
[1256] [1256] Example 85: 1-Cyclopropyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1257] [1257] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclopropylpiperidine-3-sulfonamide (Intermediate P71) to obtain the title compound (27% yield) as a white solid.
[1258] [1258] 1H NMR (CD3OD): δ = 6.86 (s, 1 H), 4.35 (m, 1 H), 3.67 (m, 4 H), 2.81 (m, 8 H) , 2.02 (m, 5 H), 0.43 (m, 2H), 0.33 (m, 2 H). LCMS: m / z 376 (M + H) + (ES +); 374 (M-H) - (ES-).
[1259] [1259] Example 86: 1- (1,3-Difluoropropan-2-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1260] [1260] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1,3- difluoropropan-2-yl) azetidine-3-sulfonamide (Intermediate P72) to obtain the title compound (91% yield) as a white solid.
[1261] [1261] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.52 (m, 2H), 4.37 (m, 3H), 3.72 (d, 4H), 3.30 (m, 1H), 2.81 (m, 8H), 2.03 (m, 4H). LCMS: m / z 414 (M + H) + (ES +); 412 (M-H) - (ES-).
[1262] [1262] Example 87: 1- (Cyanomethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, salt potassium
[1263] [1263] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (cyanomethyl) azetidine- 3-sulfonamide (Intermediate P73) to obtain the title compound (57% yield) as a white solid.
[1264] [1264] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.32 (m, 1H), 3.85 - 3.62 (m, 4H), 3.56 (s, 2H) , 2.81 (m, 8H), 2.02 (m, 4H). LCMS: m / z 375 (M + H) + (ES +); 373 (M-H) - (ES-).
[1265] [1265] Example 88: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (2-methoxyethyl) azetidine-3-sulfonamide, potassium salt
[1266] [1266] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2-methoxyethyl) azetidine-3-sulfonamide (Intermediate P74) to obtain the title compound (35% yield) as a white solid.
[1267] [1267] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.36 (m, 1H), 3.82 - 3.58 (m, 4H), 3.41 (t, 2H) , 3.3 (s, 3H), 2.81 (m, 10H), 2.13 - 1.92 (m, 4H). LCMS: m / z 394 (M + H) + (ES +).
[1268] [1268] Example 89: 1- (cyclohexylmethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1269] [1269] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (cyclohexylmethyl) azetidine-3-sulfonamide
[1270] [1270] 1H NMR (CD3OD): δ = 6.89 (s, 1H), 4.37 (t, 1H), 3.93-3.67 (m, 4H), 2.83 (m, 9H) , 2.61 (m, 1H), 2.12 - 1.95 (m, 4H), 1.73 (d, 5H), 1.27 (d, 4H), 0.95 (d, 2H). LCMS: m / z 432 (M + H) + (ES +); 430 (M-H) - (ES-).
[1271] [1271] Example 90: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (pyridin-3-ylmethyl) azetidine-3- sulfonamide, potassium salt
[1272] [1272] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (pyridin-3- ilmethyl) azetidine-3-sulfonamide (Intermediate P76) to obtain the title compound (51% yield) as a white solid.
[1273] [1273] 1H NMR (CD3OD): δ = 8.57 - 8.37 (m, 2H), 7.82 (d, 1H), 7.41 (dd, 1H), 6.87 (s, 1H) , 4.36 (q, 1H), 3.76 (s, 2H), 3.70 - 3.51 (m, 4H), 2.96 - 2.70 (m, 8H), 2.03 (m , 4H). LCMS: m / z 427 (M + H) + (ES +); 425 (M-H) - (ES-).
[1274] [1274] Example 91: 2- (3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) azetidin-1-yl) -N, N-dimethylacetamide, potassium salt
[1275] [1275] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N, N-dimethyl-2 - (3-sulfamoylazetidin-1-yl) acetamide (Intermediate P77) to obtain the title compound (15% yield) as a white solid.
[1276] [1276] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.39 (m, 1H), 3.82 (t, 2H), 3.59 (t, 2H), 3.50 (s, 2H), 2.97 (s, 3H), 2.89 (s, 3H), 2.81 (m, 8H), 2.11 - 1.92 (m, 4H). LCMS: m / z 421 (M + H) + (ES +); 419 (M-H) - (ES-).
[1277] [1277] Example 92: 1- (2-Chloroethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1278] [1278] Prepared as described for N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl ) piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2-chloroethyl) azetidine-3-sulfonamide (Intermediate P78) to obtain the title compound (55% yield) as a white solid.
[1279] [1279] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.35 (t, 1H), 3.72 (t, 2H), 3.61 (t, 2H), 3.52 (t, 2H), 2.98 - 2.69 (m, 10H), 2.02 (m, 4H). LCMS: m / z 398 (M + H) + (ES +); 396 (M-H) - (ES-).
[1280] [1280] Example 93: 1- (tert-butyl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1281] [1281] To a solution of 1- (tert-butyl) azetidine-3-sulfonamide (Intermediate P82; 10 mg, 0.052 mmol) in THF (3 mL) was added potassium tert-butoxide (6 mg, 0.052 mmol). The mixture was stirred at room temperature for 40 minutes. A solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1; 10 mg, 0.052 mmol) in THF (1 mL) was added and the mixture was stirred for the night at room temperature. 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 1") to obtain the title compound (5 mg, 25% yield) like a white solid.
[1282] [1282] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.28 (m, 1H), 3.76 (t, 2H), 3.41 (t, 2H), 2.81 (m, 8H), 2.02 (m, 4H), 1.01 (s, 9H). LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1283] [1283] Example 94: 1- (Cyclopropylmethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, salt potassium
[1284] [1284] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (cyclopropylmethyl) azetidine-3-sulfonamide (Intermediate P83 ) to obtain the title compound (34% yield) as a white solid.
[1285] [1285] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.38 (t, 1H), 4.09 (q, 4H), 2.83 (m, 10H), 2.02 (m, 4H), 0.89 (d, 1H), 0.58 (q, 2H), 0.28 (q, 2H). LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[1286] [1286] Example 95: 1- (2-Azidoethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1287] [1287] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2-azidoethyl) azetidine-3-sulfonamide ( Intermediate P85) to obtain the title compound (33% yield) as a white solid.
[1288] [1288] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.36 (p, 1H), 3.71 (td, 2H), 3.58 (dd, 2H), 2.81 (m, 10H), 2.77 - 2.63 (m, 2H), 2.03 (m, 4H). LCMS: m / z 405 (M + H) + (ES +); 403 (M-H) - (ES-).
[1289] [1289] Example 96: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1- (2,2,2-trifluoroethyl) azetidine- 3-sulfonamide, potassium salt
[1290] [1290] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2,2,2-trifluoroethyl) azetidine- 3-sulfonamide (Intermediate P86) to obtain the title compound (11% yield) as a white solid.
[1291] [1291] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.35 (t, 1H), 3.73 (dt, 4H), 3.16 (q, 2H), 2.81 (m, 8H), 2.02 (m, 4H). LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[1292] [1292] Example 97: N - ((1,2,3,5,6,7-Hexahydro-s-indacen- 4-yl) carbamoyl) -1-isobutylazetidine-3-sulfonamide, potassium salt
[1293] [1293] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isobutylazetidine-3-sulfonamide (Intermediate P84) to obtain the title compound (19% yield) as a white solid.
[1294] [1294] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.36 (p, 1H), 3.92 (dt, 4H), 2.92 - 2.74 (m, 8H) , 2.67 (d, 2H), 2.02 (m, 4H), 1.77 (dt, 1H), 0.92 (dd, 6H). LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1295] [1295] Example 98: 1-Cyclohexyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, salt potassium
[1296] [1296] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclohexylazetidine-3-sulfonamide
[1297] [1297] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.32 (p, 1H), 3.79 (dt, 4H), 2.82 (m, 8H), 2.44 (s, 1H), 2.02 (m, 4H), 1.94 - 1.54 (m, 5H), 1.41 - 0.84 (m, 5H). LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[1298] [1298] Example 99: 1-Cyclopentyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1299] [1299] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclopentylazetidine-3-sulfonamide (Intermediate P89) the title compound (10% yield) as a white solid.
[1300] [1300] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.32 (q, 1H), 3.78 (dt, 4H), 2.82 (m, 9H), 2.02 (m, 4H), 1.94 - 1.49 (m, 6H), 1.48 - 1.24 (m, 2H). LCMS: m / z 404 (M + H) + (ES +); 402 (M-H) - (ES-).
[1301] [1301] Example 100: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-iminoethyl) azetidine-3-sulfonamide, potassium salt
[1302] [1302] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equivalents) and 1- ( -1- iminoethyl) azetidine-3-sulfonamide (Intermediate P90) to obtain the title compound (8% yield) as a white solid.
[1303] [1303] 1H NMR (CD3OD) (tautomeric mixture): δ = 6.89 (s, 1H), 4.60 (q, 2H), 4.53 - 4.31 (m, 2H), 3.68 - 3.43 (m, 1H), 2.82 (m, 8H), 2.13 (s, 3H), 2.02 (m, 4H). LCMS: m / z 377 (M + H) + (ES +); 375 (MH) - (ES-).
[1304] [1304] Example 101: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (oxetan-3-ylmethyl) azetidine-3- sulfonamide, potassium salt
[1305] [1305] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (oxetan-3-ylmethyl) azetidine-3- sulfonamide (Intermediate P91) to obtain the title compound (53% yield) as a white solid.
[1306] [1306] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.75 (dd, 2H), 4.39 (t, 2H), 4.31 (d, 1H), 3.73 - 3.59 (m, 2H), 3.52 (t, 2H), 3.05 (dt, 1H), 2.82 (m, 10H), 2.02 (m, 4H). LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1307] [1307] Example 102: 1- (2- (Dimethylamino) ethyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3 -sulfonamide, potassium salt
[1308] [1308] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2- (dimethylamino) ethyl) azetidine-3 -sulfonamide (Intermediate P92) to obtain the title compound (20% yield) as a white solid.
[1309] [1309] 1H NMR (D2O): δ = 6.94 (s, 1H), 4.20 (t, 1H), 3.55 (t, 2H), 3.41 (t, 2H), 2.72 (m, 8H), 2.60 (t, 5H), 2.54 (s, 6H), 2.05 - 1.81 (m, 3H). LCMS: m / z 407 (M + H) + (ES +); 405 (M-H) - (ES-).
[1310] [1310] Example 103: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (pyridin-4-ylmethyl) azetidine-3- sulfonamide, potassium salt
[1311] [1311] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (pyridin-4-ylmethyl) azetidine-3- sulfonamide (Intermediate P93) to obtain the title compound (60% yield) as a white solid.
[1312] [1312] 1H NMR (D2O): δ = 8.38 (d, 2H), 7.24 (d, 2H), 6.96 (s, 1H), 4.25 (t, 1H), 3.69 (s, 2H), 3.61 (t, 2H), 3.50 (t, 2H), 2.75 (t, 4H), 2.63 (t, 4H), 1.91 (m, 4H) . LCMS: m / z 427 (M + H) + (ES +); 425 (M-H) - (ES-).
[1313] [1313] Example 104: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (pyridin-2-ylmethyl) azetidine-3- sulfonamide, potassium salt
[1314] [1314] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (pyridin-2-ylmethyl) azetidine-3- sulfonamide (Intermediate P94) to obtain the title compound (47% yield) as a white solid.
[1315] [1315] 1H NMR (D2O): δ = 8.32 (d, 1H), 7.71 (t, 1H), 7.23 (d, 2H), 6.93 (s, 1H), 4.20 (t, 1H), 3.69 (s, 2H), 3.53 (dt, 4H), 2.71 (t, 4H), 2.59 (t, 4H), 1.87 (p, 4H) . LCMS: m / z 427 (M + H) + (ES +); 425 (M-H) - (ES-).
[1316] [1316] Example 105: 1 - ((2-Bromopyridin-3-yl) methyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl ) azetidine-3-sulfonamide, potassium salt
[1317] [1317] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2-bromopyridin-3-yl) methyl) azetidine-3-sulfonamide (Intermediate P95) to obtain the title compound (46% yield) as a white solid.
[1318] [1318] 1H NMR (D2O): δ = 8.14 (dd, 1H), 7.64 (dd, 1H), 7.35 (dd, 1H), 6.96 (s, 1H), 4.25 (p, 1H), 3.76 (s, 2H), 3.62 (dt, 4H), 2.75 (t, 4H), 2.64 (t, 4H), 1.91 (m, 4H) . LCMS: m / z 505 (M + H) + (ES +); 503 (M-H) - (ES-).
[1319] [1319] Example 106: tert-butyl 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - [1,3 ' -biazetidine] -1'-carboxylate, potassium salt
[1320] [1320] Prepared as described for 1- (tec-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-sulfamoyl- [1,3'-biazetidine] - Tert-Butyl 1'-carboxylate (Intermediate P96) to obtain the title compound (33% yield) as a white solid.
[1321] [1321] 1H NMR (D2O): δ = 6.94 (s, 1H), 4.19 (t, 1H), 3.86 (d, 2H), 3.64 - 3.48 (m, 4H) , 3.40 (m, 3H), 2.72 (t, 4H), 2.60 (t, 4H), 1.89 (m, 4H), 1.27 (d, 9H). LCMS: m / z 491 (M + H) + (ES +); 489 (M-H) - (ES-).
[1322] [1322] Example 107: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (methylthio) eyl) azetidine-3 -sulfonamide, potassium salt
[1323] [1323] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2- (methylthio) ethyl) azetidine-3 -sulfonamide
[1324] [1324] 1H NMR (D2O): δ = 6.99 (s, 1H), 4.26 (p, 1H), 3.80 - 3.64 (m, 2H), 3.54 (t, 2H) , 2.78 (m, 6H), 2.66 (t, 4H), 2.46 (t, 2H), 2.02 (s, 3H), 1.94 (m, 4H). LCMS: m / z 410 (M + H) + (ES +); 408 (M-H) - (ES-).
[1325] [1325] Example 108: 1- (2-Fluoroethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1326] [1326] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2-fluoroethyl) azetidine-3-sulfonamide ( Intermediate P99) to obtain the title compound (61% yield) as a white solid.
[1327] [1327] 1H NMR (D2O): δ = 6.94 (s, 1H), 4.42 (t, 1H), 4.26 (t, 1H), 4.20 (d, 1H), 3.58 (t, 2H), 3.40 (t, 2H), 2.84 - 2.67 (m, 6H), 2.67 - 2.52 (m, 4H), 1.88 (m, 4H). LCMS: m / z 382 (M + H) + (ES +); 380 (M-H) - (ES-).
[1328] [1328] Example 109: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (tietan-3yl) azetidine-3-sulfonamide, potassium salt
[1329] [1329] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (tietan-3-yl) azetidine-3- sulfonamide (Intermediate P100) to obtain the title compound (16% yield) as a white solid.
[1330] [1330] 1H NMR (D2O): δ = 6.94 (s, 1H), 4.17 (p, 1H), 3.89 (t, 1H), 3.44 (p, 4H), 3.09 (t, 2H), 2.97 (t, 2H), 2.72 (t, 4H), 2.60 (t, 4H), 1.89 (m, 4H). LCMS: m / z 408 (M + H) + (ES +); 406 (M-H) - (ES-).
[1331] [1331] Example 110: N - (((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) -1'-methyl- [1,3'-biazetidine] -3-sulfonamide, potassium salt
[1332] [1332] Prepared as described for 1- (tec-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1'-methyl- [1,3'-biazetidine] -3-sulfonamide (Intermediate P97) to obtain the title compound (13% yield) as a white solid.
[1333] [1333] 1H NMR (D2O): δ = 6.95 (s, 1H), 4.20 (p, 1H), 3.84 - 3.67 (m, 2H), 3.66 - 3.36 ( m, 7H), 2.72 (t, 4H), 2.61 (t, 4H), 2.50 (s, 3H), 1.89 (m, 4H). LCMS: m / z 405 (M + H) + (ES +); 403 (M-H) - (ES-).
[1334] [1334] Example 111: 1- (2- (3- (But-3-in-1-yl) -3H-diazirin-3-yl) ethyl) -N - ((1,2,3,5,6 , 7-hexahydro-s-indacen-4-yl) carbamoyl) axetidine-3-sulfonamide, potassium salt
[1335] [1335] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2- (3- (but-3- in-1-yl) -3H-diazirin-3-yl) ethyl) azetidine-3-sulfonamide (Intermediate P101) to obtain the title compound (58% yield) as a white solid.
[1336] [1336] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.30 (t, 1H), 3.61 (t, 2H), 3.55 - 3.40 (m, 2H) , 2.81 (m, 8H), 2.38 (t, 2H), 2.28 (t, 1H), 2.01 (m, 6H), 1.59 (t, 2H), 1.44 ( t, 2H). LCMS: m / z 456 (M + H) + (ES +); 454 (M-H) - (ES-).
[1337] [1337] Example 112: tert-Butyl - ((((tert-butoxycarbonyl) imino) (3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl ) carbamoyl) sulfamoyl) azetidin-1-yl) methyl) carbamate, potassium salt
[1338] [1338] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and tert-butyl (Z) - (((tert-butoxycarbonyl ) amino) 3-sulfamoylazetidin-1-yl) methylene) carbamate (Intermediate P102) to obtain the title compound (31% yield) as a white solid.
[1339] [1339] 1H NMR (CDCl3): δ = 6.85 (s, 1H), 6.68 (s, 1H), 4.62 - 4.08 (m, 5H), 2.90 - 2.56 ( m, 8H), 1.96 (m, 4H), 1.41 (d, 18H). LCMS: m / z 578 (M + H) + (ES +); 576 (M-H) - (ES-).
[1340] [1340] Example 113: 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) sulfamoyl) azetidine-1-carboxyidamide, salt from TFA
[1341] [1341] Terc-Butyl - (((tert-butoxycarbonyl) imino) (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) azetidin-1-yl) methyl) carbamate, potassium salt (Example 112; 100 mg, 0.17 mmol) in DCM (0.5 ml) was treated with trifluoroacetic acid (0.5 ml) and stirred for 2 hours. Then, the reaction mixture was concentrated in vacuo and DMSO (0.5-1 ml) was added. The mixture was subjected to purification by reverse phase column chromatography (see "Experimental Method", "Purification Method 1") to obtain the title compound (28% yield) as a white solid.
[1342] [1342] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.49 - 4.24 (m, 5H), 2.82 (m, 8H), 2.02 (m, 4H) . 19F-NMR indicated the presence of TFA. LCMS: m / z 378 (M + H) + (ES +); 376 (M-H) - (ES-).
[1343] [1343] Example 114: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) - [1,3'-biazetidine] -3-sulfonamide, TFA salt
[1344] [1344] Prepared as described for 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) azetidine-1-carboxyidamide, salt 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - [1,3'-biazetidine] TFA (Example 113) Tert-butyl -1'-carboxylate, potassium salt (Example 106) to generate the title compound (24% yield) as a white solid.
[1345] [1345] 1H NMR (D2O): δ = 6.96 (s, 1H), 4.32 - 4.15 (m, 1H), 4.09 - 3.91 (m, 2H), 3.91 - 3.67 (m, 3H), 3.54 (m, 4H), 2.73 (t, 4H), 2.62 (t, 4H), 1.91 (m, 4H). LCMS: m / z 391 (M + H) + (ES +); 389 (M-H) - (ES-).
[1346] [1346] Example 115: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (methylsulfonyl) ethyl) azetidine-3 -sulfonamide, potassium salt and N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (methylsulfinyl) ethyl) azetidine- 3-sulfonamide, potassium salt
[1347] [1347] N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (methylthio) ethyl) azetidine-3-sulfonamide, potassium salt (Example 107; 20 mg, 0.05 mmol) was dissolved in THF (2 ml) and cooled on ice. M-Chloroperbenzoic acid (75% by weight, 13 mg, 0.057 mmol) was added in one portion and the mixture was stirred for 2 hours at 0 ° C. Then, the reaction mixture was concentrated in vacuo and DMSO (0.5-1 ml) was added. The mixture was subjected to purification by reverse phase column chromatography (see "Experimental Methods", "Purification Method 1") to obtain the title compounds (38% yield) as a white solid.
[1348] [1348] 1H NMR (CD3OD) (sulfonyl / sulfinyl mixture, ratio 2/1): δ = 7.01 (sulfonyl) 6.95 (sulfinyl) (s, 1H), 4.36 (m, 1H), 3.94 - 3.58 (m, 4H), 3.19 - 2.97 (m, 4H), 2.97 - 2.73 (m, 8H), 2.73 - 2.59 (m, 3H ), 2.23 - 1.97 (m, 4H). LCMS: m / z 442 (M + H) + (ES +); 440 (M-H) - (ES-), sulfonyl. LCMS: m / z 426 (M + H) + (ES +); 424 (M-H) - (ES-), sulfinyl.
[1349] [1349] Example 116: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (oxetan-3-yl) azetidine-3- sulfonamide, potassium salt
[1350] [1350] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (oxetan-3-yl) azetidine-3- sulfonamide (Intermediate P131) to obtain the title compound (1% yield) as a white solid. LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1351] [1351] Example 117: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-oxidotietan-3-yl) azetidine- 3-sulfonamide, potassium salt THE s s N N THE O S O O O S NH O NH NH NH
[1352] [1352] N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (tietan-3-yl) azetidine-3-sulfonamide, salt potassium (Example 109; 25 mg, 0.06 mmol) was dissolved in THF (2 mL) and cooled on ice. M-Chloroperbenzoic acid (75% by weight, 17 mg, 0.74 mmol) was added in one portion and the mixture was stirred for 2 hours at 0 ° C. Then, the reaction mixture was concentrated in vacuo and DMSO (0.5-1 ml) was added. The mixture was subjected to purification by reverse phase column chromatography (see
[1353] [1353] 1H NMR (CD3OD): δ = 7.00 (s, 1H), 4.69 (s, 1H), 4.14 (t, 1H), 3.61 (t, 1H), 3.49 (d, 1H), 3.03 (dt, 3H), 2.95 - 2.78 (m, 8H), 2.78 - 2.66 (m, 3H), 2.06 (m, 4H). LCMS: m / z 424 (M + H) + (ES +); 422 (M-H) - (ES-).
[1354] [1354] Example 118: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (3-methylcyclobutyl) azetidine-3-sulfonamide, potassium salt
[1355] [1355] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (3-methylcyclobutyl) azetidine-3-sulfonamide ( Intermediate P103) to obtain the title compound (22% yield) as a white solid.
[1356] [1356] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.31 (qd, 1H), 3.73 - 3.53 (m, 4H), 2.93 - 2.71 ( m, 8H), 2.37 (d, 1H), 2.20 (td, 1H), 2.02 (m, 6H), 1.79 - 1.62 (m, 1H), 1.47 (dt , 1H), 1.08 (dd, 3H). LCMS: m / z 404 (M + H) + (ES +); 402 (M-H) - (ES-).
[1357] [1357] Example 119: 1- (3,3-dimethylcyclobutyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3- sulfonamide, potassium salt
[1358] [1358] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (3,3-dimethylcyclobutyl) azetidine-3- sulfonamide (Intermediate P104) to obtain the title compound (9% yield) as a white solid.
[1359] [1359] 1H NMR (CD3OD): δ = 6.89 (s, 1H), 4.34 (t, 1H), 4.25 - 3.94 (m, 4H), 3.94 - 3.69 ( m, 1H), 2.81 (m, 8H), 2.04 (m, 6H), 1.82 (t, 2H), 1.15 (d, 6H). LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[1360] [1360] Example 120: 1- (1,1-Dioxidotietan-3-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt THE S O s N N THE O S O O O S NH O NH NH NH
[1361] [1361] N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (tietan-3-yl) azetidine-3-sulfonamide, salt potassium (Example 109; 18 mg, 0.044 mmol) was dissolved in THF (2 mL) and cooled on ice.
[1362] [1362] 1H NMR (CD3OD): δ = 7.00 (s, 1H), 4.21 (m, 1H), 3.88 (s, 2H), 3.65 (m, 2H), 3.13 (dd, 1H), 2.83 (m, 12H), 2.07 (m, 4H). LCMS: m / z 440 (M + H) + (ES +); 438 (M-H) - (ES-).
[1363] [1363] Example 121: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (tetrahydrofuran-3-yl) azetidine- 3-sulfonamide, potassium salt
[1364] [1364] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (tetrahydrofuran-3-yl) azetidine- 3-sulfonamide (Intermediate P106) to obtain the title compound (27% yield) as a white solid.
[1365] [1365] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.31 (p, 1H), 3.87 (q, 1H), 3.79 - 3.43 (m, 7H) , 2.81 (m, 9H), 2.03 (m, 4H), 1.98 - 1.84 (m, 1H), 1.82 - 1.62 (m, 1H). LCMS: m / z 405 (M + H) + (ES +); 403 (M-H) - (ES-).
[1366] [1366] Example 122: 1- (sec-butyl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1367] [1367] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (sec-butyl) azetidine-3-sulfonamide ( Intermediate P107) to obtain the title compound (43% yield) as a white solid.
[1368] [1368] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.29 (p, 1H), 3.70 (t, 2H), 3.63 - 3.45 (m, 2H) , 2.82 (m, 8H), 2.38 (m, 1H), 2.02 (m, 4H), 1.65 - 1.45 (m, 1H), 1.21 - 1.02 (m , 1H), 1.02 - 0.82 (m, 6H). LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1369] [1369] Example 123: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((1-methyl-1H-imidazole-2 -yl) methyl) azetidine-3-sulfonamide, potassium salt
[1370] [1370] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1 - ((1-methyl-1H-imidazole-2 -yl) methyl) azetidine-3-sulfonamide (Intermediate P108) to obtain the title compound (49% yield) as a white solid.
[1371] [1371] 1H NMR (CD3OD): δ = 7.00 (s, 1H), 6.84 (d, 2H), 4.34 (p, 1H), 3.74 (s, 2H), 3.70 (s, 3H), 3.68 - 3.52 (m, 4H), 2.80 (m, 8H), 2.01 (m, 4H). LCMS: m / z 430 (M + H) + (ES +); 428 (M-H) - (ES-).
[1372] [1372] Example 124: 1- (2,2-Dimethylcyclobutyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3- sulfonamide, potassium salt
[1373] [1373] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2,2-dimethylcyclobutyl) azetidine-3- sulfonamide (Intermediate P109) to obtain the title compound (16% yield) as a white solid.
[1374] [1374] 1H NMR (CD3OD): δ = 6.89 (s, 1H), 4.40 (t, 1H), 3.73 (dq, 4H), 3.02 (t, 1H), 2.83 (m, 8H), 2.04 (m, 4H), 1.79 - 1.63 (m, 2H), 1.63 - 1.46 (m, 2H), 1.10 (d, 6H). LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[1375] [1375] Example 125: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (pyrimidin-5-ylmethyl) azetidine-3- sulfonamide, potassium salt
[1376] [1376] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (pyrimidin-5-ylmethyl) azetidine-3- sulfonamide (Intermediate P105) to obtain the title compound (8% yield) as a white solid.
[1377] [1377] 1H NMR (CD3OD): δ = 9.06 (s, 1H), 8.76 (s, 2H), 6.88 (s, 1H), 4.38 (t, 1H), 3.77 (s, 2H), 3.74 - 3.59 (m, 4H), 2.96 - 2.73 (m, 8H), 2.03 (m, 4H). LCMS: m / z 428 (M + H) + (ES +); 426 (M-H) - (ES-).
[1378] [1378] Example 126: 1- (Cyclobutylmethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, salt potassium
[1379] [1379] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (cyclobutylmethyl) azetidine-3-sulfonamide (Intermediate P111 ) to obtain the title compound (14% yield) as a white solid.
[1380] [1380] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.34 (p, 1H),
[1381] [1381] Example 127: tert-Butyl - ((((tert-butoxycarbonyl) imino) (3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl ) carbamoyl) sulfamoyl) azetidin-1-yl) methyl) (methyl) carbamate, potassium salt
[1382] [1382] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and tert-butyl (E) - (((tert-butoxycarbonyl ) imino) 3-sulfamoylazetidin-1-yl) methyl) (methyl) carbamate (Intermediate P110) to obtain the title compound (49% yield) as a white solid.
[1383] [1383] 1H NMR (CDCl3): δ = 6.83 (s, 1H), 6.81 (s, 1H), 4.51 (d, 1H), 4.24 (dd, 4H), 2.91 (s, 3H), 2.75 (m, 8H), 1.95 (m, 4H), 1.41 (d, 18H). LCMS: m / z 592 (M + H) + (ES +); 590 (M-H) - (ES-).
[1384] [1384] Example 128: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (hydroxyimino) propyl) azetine -3-sulfonamide, potassium salt
[1385] [1385] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equivalents) and 1- ( 2- (hydroxyimino) propyl) azetidine-3-sulfonamide (Intermediate P112) to obtain the title compound (6% yield) as a white solid.
[1386] [1386] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.47 - 4.26 (m, 1H), 3.59 (dt, 4H), 3.19 (s, 2H) , 2.81 (m, 8H), 2.02 (m, 4H), 1.81 (s, 3H). LCMS: m / z 407 (M + H) + (ES +); 405 (M-H) - (ES-).
[1387] [1387] Example 129: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N-methylazetidine-1-carboxyidamide, salt of TFA
[1388] [1388] Prepared as described for 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) azetidine-1-carboxyidamide, salt TFA (Example 113) of tert-butyl - ((((tert-butoxycarbonyl) imino) (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl ) carbamoyl) sulfamoyl) azetidin-1-
[1389] [1389] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.46 - 4.35 (m, 2H), 4.35 - 4.23 (m, 2H), 2.93 - 2.71 (m, 11H), 2.71 - 2.50 (m, 1H), 2.02 (m, 4H). LCMS: m / z 392 (M + H) + (ES +).
[1390] [1390] Example 130: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-hydroxypropan-2-yl) azetidine- 3-sulfonamide, potassium salt
[1391] [1391] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equivalents) and 1- ( 1-hydroxypropan-2-yl) azetidine-3-sulfonamide (Intermediate P113) to obtain the title compound (12% yield) as a white solid.
[1392] [1392] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.33 (p, 1H), 3.63 (tt, 4H), 3.43 (dd, 1H), 2.81 (m, 9H), 2.52 (q, 1H), 2.03 (m, 4H), 0.94 (d, 3H). LCMS: m / z 394 (M + H) + (ES +); 392 (M-H) - (ES-).
[1393] [1393] Example 131: 1- (1,1-Difluoropropan-2-yl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1394] [1394] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (1,1-difluoropropan-2-yl) azetidine-3-sulfonamide (Intermediate P114) to obtain the title compound (46% yield) as a white solid.
[1395] [1395] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 5.58 (td, 1H), 4.30 (p, 1H), 3.82 - 3.51 (m, 4H) , 2.81 (m, 8H), 2.69 (ddd, 1H), 2.02 (m, 4H), 1.00 (d, 3H). LCMS: m / z 414 (M + H) + (ES +); 412 (M-H) - (ES-).
[1396] [1396] Example 132: 1-Allyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1397] [1397] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-allylazetidine-3-sulfonamide (Intermediate P115) to obtain the title compound (15% yield) as a white solid.
[1398] [1398] 1H NMR (CD3OD): δ = 6.89 (s, 1H), 5.77 (ddt, 1H), 5.54 - 5.30 (m, 2H), 4.36 (q, 1H) , 4.20 - 3.97 (m, 4H), 3.55 (d, 2H), 2.81 (m, 8H), 2.17 - 1.93 (m, 4H). LCMS: m / z 376 (M + H) + (ES +); 374 (M-H) - (ES-).
[1399] [1399] Example 133: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (prop-2-in-1-yl) azetidine-3-sulfonamide, potassium salt
[1400] [1400] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (prob-2-in-1-yl) azetidine-3-sulfonamide (Intermediate P116) to obtain the title compound (14% yield) as a white solid.
[1401] [1401] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.31 (q, 1H), 3.66 (d, 4H), 3.31 (s, 2H), 2.81 (q, 8H), 2.71 - 2.57 (m, 1H), 2.02 (m, 4H). LCMS: m / z 374 (M + H) + (ES +); 372 (M-H) - (ES-).
[1402] [1402] Example 134: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (3-hydroxypropyl) azetidine-3-sulfonamide, potassium salt
[1403] [1403] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equivalents) and 1- ( 3-hydroxypropyl) azetidine-3-sulfonamide (Intermediate P117) to obtain the title compound (3% yield) as a white solid. LCMS: m / z 394 (M + H) + (ES +); 392 (M-H) - (ES-).
[1404] [1404] Example 135: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1-neopentylazetidine-3-sulfonamide, potassium salt
[1405] [1405] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-neopentylazetidine-3-sulfonamide (Intermediate P118) to obtain the title compound (12% yield) as a white solid.
[1406] [1406] 1H NMR (CD3OD): δ = 6.92 (s, 1H), 4.54 - 4.29 (m, 5H), 3.06 (s, 2H), 2.79 (m, 8H) , 2.16 - 1.93 (m, 4H), 1.00 (s, 9H). LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1407] [1407] Example 136: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((trimethylsilyl) methyl) azetidine-3-sulfonamide , potassium salt
[1408] [1408] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1 - ((trimethylsilyl) methyl) azetidine-3-sulfonamide (Intermediate P119) to obtain the title compound (32% yield) as a white solid.
[1409] [1409] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.32 (t, 1H), 3.89 (t, 2H), 3.70 (t, 2H), 2.81 (m, 8H), 2.33 (s, 2H), 2.02 (m, 4H), 0.08 (s, 9H). LCMS: m / z 422 (M + H) + (ES +); 420 (M-H) - (ES-).
[1410] [1410] Example 137: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2-hydroxypropyl) azetidine-3-sulfonamide, potassium salt
[1411] [1411] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equivalents) and 1- ( 2-hydroxypropyl) azetidine-3-sulfonamide (Intermediate P120) to obtain the title compound (14% yield) as a white solid.
[1412] [1412] 1H NMR (CD3OD): δ = 6.86 (s, 1H), 4.37 (p, 1H),
[1413] [1413] Example 138: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (4-hydroxybutyl) azetidine-3-sulfonamide, potassium salt
[1414] [1414] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equivalents) and 1- ( 4-hydroxybutyl) azetidine-3-sulfonamide (Intermediate P121) to obtain the title compound (4% yield) as a white solid.
[1415] [1415] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.41 - 4.23 (m, 1H), 3.67 (t, 2H), 3.61 - 3.45 ( m, 4H), 2.82 (m, 8H), 2.57 (t, 2H), 2.15 - 1.91 (m, 4H), 1.50 (m, 4H). LCMS: m / z 408 (M + H) + (ES +); 406 (M-H) - (ES-).
[1416] [1416] Example 139: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (3-methyl-3H-diazirin -3-yl) ethyl) azetidine-3-sulfonamide, potassium salt
[1417] [1417] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2- (3-methyl-3H-diazirin -3-yl) ethyl) azetidine-3-sulfonamide (Intermediate P122) to obtain the title compound (3% yield) as a white solid.
[1418] [1418] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.33 (p, 1H), 3.64 (t, 2H), 3.49 (q, 2H), 2.82 (m, 8H), 2.46 (t, 2H), 2.03 (m, 4H), 1.35 (t, 2H), 1.00 (s, 3H). LCMS: m / z 418 (M + H) + (ES +); 416 (M-H) - (ES-).
[1419] [1419] Example 140: N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1 - ((1-methyl-6-oxo-1 , 6-dihydropyridin-3-yl) methyl) azetidine-3-sulfonamide, potassium salt
[1420] [1420] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1 - ((1-methyl-6-oxo-1 , 6-dihydropyridin-3-
[1421] [1421] 1H NMR (CD3OD): δ = 7.59 (d, 1H), 7.50 (dd, 1H), 6.87 (s, 1H), 6.51 (d, 1H), 4.32 (p, 1H), 3.71 - 3.57 (m, 3H), 3.53 (d, 4H), 3.47 (s, 2H), 2.80 (m, 8H), 2.01 ( m, 4H). LCMS: m / z 457 (M + H) + (ES +); 455 (M-H) - (ES-).
[1422] [1422] Example 141: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((1-methyl-2-oxo-1 , 2-dihydropyridin-4-yl) methyl) azetidine-3-sulfonamide, potassium salt
[1423] [1423] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1 - ((1-methyl-2-oxo-1 , 2-dihydropyridin-4-yl) methyl) azetidine-3-sulfonamide (Intermediate P124) to obtain the title compound (13% yield) as a white solid.
[1424] [1424] 1H NMR (CD3OD): δ = 7.56 (d, 1H), 6.86 (s, 1H), 6.55 - 6.42 (m, 1H), 6.34 (dd, 1H) , 4.37 (p, 1H), 3.68 (t, 2H), 3.59 (t, 4H), 3.52 (s, 3H), 2.93 - 2.73 (m, 8H), 2.01 (m, 4H). LCMS: m / z 457 (M + H) + (ES +); 455 (M-H) - (ES-).
[1425] [1425] Example 142: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (tetrahydrofuran-3-yl ) ethyl) azetidine-3-sulfonamide, potassium salt
[1426] [1426] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2- (tetrahydrofuran-3-yl ) ethyl) azetidine-3-sulfonamide (Intermediate P125) to obtain the title compound (26%) as a white solid.
[1427] [1427] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.43 - 4.24 (m, 1H), 3.97 - 3.77 (m, 2H), 3.77 - 3.63 (m, 4H), 3.55 (dd, 2H), 2.82 (m, 8H), 2.71 - 2.49 (m, 2H), 2.17 (td, 1H), 2 , 11 - 1.95 (m, 5H), 1.62 - 1.37 (m, 3H). LCMS: m / z 434 (M + H) + (ES +); 432 (M-H) - (ES-).
[1428] [1428] Example 143: 1- (sec-Butyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) azetidine-3-sulfonamide
[1429] [1429] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A3) and 1- (sec-butyl) azetidine-3-sulfonamide (Intermediate P107) to obtain the title compound (26%) as a white solid.
[1430] [1430] 1H NMR (CD3OD): δ = 6.82 (d, 2H), 4.27 (p, 1H), 3.89 (p, 4H), 3.22 (q, 2 H), 2, 70 (m, 1 H), 1.61 (m, 1H), 1.18 (d, 14H), 1.03 (d,
[1431] [1431] Example 144: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((tetrahydrofuran-3-yl) methyl ) azetidine-3-sulfonamide, potassium salt
[1432] [1432] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1 - ((tetrahydrofuran-3-yl) methyl ) azetidine-3-sulfonamide (Intermediate P126) to obtain the title compound (51%) as a white solid.
[1433] [1433] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.34 (p, 1H), 3.82 (ddd, 2H), 3.77 - 3.61 (m, 2H) , 3.51 (td, 2H), 3.39 (dd, 2H), 2.82 (m, 8H), 2.56 (dd, 2H), 2.39 - 2.18 (m, 1H), 2.02 (m, 5H), 1.57 (dq, 1H). LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1434] [1434] Example 145: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((tetrahydrofuran-2-yl) methyl ) azetidine-3-sulfonamide, potassium salt
[1435] [1435] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1 - ((tetrahydrofuran-2-yl) methyl ) azetidine-3-sulfonamide (Intermediate P127) to obtain the title compound (22%) as a white solid.
[1436] [1436] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.34 (p, 1H), 3.98 - 3.78 (m, 2H), 3.68 (m, 5H) , 2.81 (m, 8H), 2.73 - 2.56 (m, 2H), 2.02 (m, 5H), 1.87 (dt, 2H), 1.50 (dd, 1H). LCMS: m / z 420 (M + H) + (ES +); 418 (M-H) - (ES-).
[1437] [1437] Example 146: (1R *, 3R *, 5S *) - N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -8- (1-methylazetidin-3-yl) -8-azabicyclo [3.2.1] octane-3-sulfonamide, potassium salt
[1438] [1438] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R, 3R, 5S) -8- (1- methylazetidin-3-yl) -8-azabicyclo [3.2.1] octane-3-sulfonamide (Intermediate P128) to obtain the title compound (8%) as a white solid.
[1439] [1439] 1H NMR (CD3OD): δ = 6.89 (s, 1H), 3.96 (m, 4H), 3.61 (m, 2H), 2.97 - 2.66 (m, 11H) , 2.43 (m, 2H), 2.03 (m, 4H), 1.91 (m, 4H), 1.67 (m, 2H), 1.32 (m, 2H). LCMS: m / z 459 (M + H) + (ES +); 457 (M-H) - (ES-).
[1440] [1440] Example 147: 1-Ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -5-oxopyrrolidine-3-sulfonamide, salt potassium
[1441] [1441] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-5-oxopyrrolidine-3-sulfonamide (Intermediate P81) to obtain the title compound (62%) as a white solid.
[1442] [1442] 1H NMR (CD3OD): δ = 6.87 (s, 1H), 4.43 - 4.24 (m, 1H), 3.86 (dd, 1H), 3.74 (dd, 1H) , 3.33 (m, 2H), 2.95 - 2.70 (m, 10H), 2.15 - 1.94 (m, 4H), 1.13 (t, 3H). LCMS: m / z 392 (M + H) + (ES +); 390 (M-H) - (ES-).
[1443] [1443] Example 148: 4- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-isopropyl-N, N- dimethylpyrrolidine-2-carboxamide, potassium salt
[1444] [1444] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropyl-N, N-dimethyl-4-sulfamoylpyrrolidine -2- carboxamide (Intermediate P80) to obtain the title compound (25%) as a white solid.
[1445] [1445] 1H NMR (D2O): δ = 6.96 (s, 1H), 4.07 (m, 2H), 3.36 (m, 1H), 3.18 (m, 1H), 3.02 (d, 6H), 2.68 (m, 8H), 2.46 (m, 1H), 1.90 (m, 4H), 1.75 (m, 2H), 1.01 - 0.83 ( m, 6H). LCMS: m / z 463 (M + H) + (ES +); 461 (M-H) - (ES-).
[1446] [1446] Example 149: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -4-methoxy-1-methylpyrrolidine-3-sulfonamide, salt potassium
[1447] [1447] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4-methoxy-1-methylpyrrolidine-3-sulfonamide (Intermediate P129) to obtain the title compound (53%) as a white solid.
[1448] [1448] 1H NMR (CD3OD) (mixture of isomers, ratio 2.5: 1): δ = 6.90 (s, 1H), 4.50 (smallest), 4.57 - 4.19 (largest) ( m, 2H), 3.67 (dt, 1H), 3.45 (lowest), 3.40 (largest) (s, 3H), 3.14 (dd, 2H), 3.10 - 2.96 ( m, 1H), 2.83 (m, 8H), 2.74 (smallest), 2.70 (largest) (s, 3H), 2.04 (m, 4H). LCMS: m / z 394 (M + H) + (ES +); 392 (M-H) - (ES-).
[1449] [1449] Example 150: 1-Ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -4-methoxypyrrolidine-3-sulfonamide, salt potassium
[1450] [1450] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-4-methoxypyrrolidine-3-sulfonamide (Intermediate P130) to obtain the title compound (26%) as a white solid.
[1451] [1451] 1H NMR (CD3OD) (mixture of isomers, 6: 1 ratio): δ = 6.85 (s, 1H), 4.27 (m, 2H), 3.54 (m, 1H), 3 , 42 (smallest), 3.39 (largest) (s, 3H), 3.16-2.89 (m, 2H), 2.82 (m, 11H), 2.04 (m, 4H), 1 , 18 (t, 3H). LCMS: m / z 408 (M + H) + (ES +); 406 (M-H) - (ES-).
[1452] [1452] Example 151: 1- (2 - ((tert-Butyldimethylsilyl) oxy) ethyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1453] [1453] Prepared as described for 1- (tert-butyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide , potassium salt (Example 93) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (2 - ((tert-butyldimethylsilyl) oxy) ethyl) azetidine-3-sulfonamide (Intermediate P87) to obtain the title compound (50%) as a white solid.
[1454] [1454] 1H NMR (CD3OD): δ = 6.88 (s, 1 H), 4.40 (m, 1 H), 3.88 (t, 2 H), 3.68 (m, 2 H) , 3.55 (m, 2 H), 3.13 (m, 2H), 2.84 (m, 8H), 2.00 (m, 4H), 1.18 (s, 9 H), 0, 1 (s, 6 H). LCMS: m / z 494 (M + H) + (ES +); 492 (M-H) - (ES-).
[1455] [1455] Example 152: 1- (2-Hydroxyethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1456] [1456] After reverse phase purification of 1- (2 - ((tert-butyldimethylsilyl) oxy) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4 - yl) carbamoyl) azetidine-3-sulfonamide, potassium salt (Example 151), the deprotected product was also isolated (10%) as a white solid.
[1457] [1457] 1H NMR (CD3OD): δ = 6.88 (s, 1H), 4.40 (s, 1H), 3.73 (t, 2H), 3.66 (t, 2H) (3.55 (t, 2H), 3.23 (m, 2H), 2.83 (m, 8H), 2.70 (t, 2H), 2.04 (m, 4H) LCMS: m / z 380 (M + H) + (ES).
[1458] [1458] Example 153: 1-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -6-oxo-1 , 6-dihydropyridine-3-sulfonamide
[1459] [1459] 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A4) (0.30 g, 1.25 mmol) was dissolved in THF ( 10 mL). TEA (0.20 ml, 1.43 mmol) was added, followed by a solution of bis (trichloromethyl) carbonate (0.35 g, 1.18 mmol) in THF (2 ml). The mixture was stirred at room temperature for 1 hour, then concentrated in vacuo and dried for 30 minutes to obtain intermediate 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2- methoxypyridine as a light yellow solid that was used without further purification.
[1460] [1460] 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (45 mg, 0.21 mmol) was dissolved in dry THF (2 mL). NaOtBu (2M in THF) (0.125 mL, 0.250 mmol) was added and the mixture was stirred at room temperature for 1 hour. A solution of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (prepared above) (55 mg) in THF (2 ml) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in DMSO (2 ml) and purified by basic preparative HPLC to obtain the title compound (41 mg, 40%) as a colorless powder.
[1461] [1461] 1H NMR (DMSO-d6) δ 10.76 (s, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.03 (dd, J = 5.3, 0, 7 Hz, 1H), 7.91 (s, 1H), 7.60 (dd, J = 9.5, 2.6 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H) , 7.10 (d, J = 7.6 Hz, 1H), 6.83 (dd, J = 5.3, 1.5 Hz, 1H), 6.65 (s, 1H), 6.47 ( d, J = 9.6 Hz, 1H), 4.99 (sept, J = 6.8 Hz, 1H), 3.84 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.98 (p, J = 7.4 Hz, 2H), 1.29 (d, J = 6.8 Hz, 6H) . LCMS: m / z 483.3 (M + H) + (ES +); 481.5 (M-H) - (ES-).
[1462] [1462] Example 154: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropyl-6-oxo-1 , 6-dihydropyridine-3-sulfonamide, sodium salt
[1463] [1463] Step A: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropyl-6-oxo-1 , 6-dihydropyridine-3-sulfonamide
[1464] [1464] Prepared according to the general procedure of 1-isopropyl-N - (((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) - 6- oxo-1,6-dihydropyridine-3-sulfonamide (Example 153) of 4- (4-amino-2,3-di-
[1465] [1465] 1H NMR (DMSO-d6) δ 8.56 (d, J = 5.1 Hz, 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.75 (br s, 1H), 7.59 (dd, J = 5.1, 1.8 Hz, 1H), 7.51 (dd, J = 9.5 , 2.5 Hz, 1H), 7.17 - 7.12 (m, 2H), 6.32 (d, J = 9.4 Hz, 1H), 4.96 (sept, J = 6.7 Hz , 1H), 2.91 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 1.98 (p, J = 7.5 Hz, 2H ), 1.25 (d, J = 6.8 Hz, 6H). An unobserved exchangeable proton. LCMS: m / z 478.3 (M + H) + (ES +); 476.2 (M-H) - (ES-).
[1466] [1466] Step B: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropi-6-oxo-1 , 6-dihydropyridine-3-sulfonamide, sodium salt Free acid Sodium salt
[1467] [1467] N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropyl-6-oxo-1,6- dihydropyridine-3-sulfonamide (0.025 g, 0.052 mmol) was treated with 0.1 M NaOH solution (520 μL) and the resulting solution lyophilized to obtain the title compound (26 mg, 99%) as a solid White.
[1468] [1468] 1H NMR (DMSO-d6) δ 8.54 (dd, J = 5.1, 0.8 Hz, 1H), 7.91 - 7.89 (m, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.60 (dd, J = 5.1, 1.8 Hz, 1H),
[1469] [1469] Example 155: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4-isopropyl-5-oxo-4 , 5-dihydropyrazine-2-sulfonamide, sodium salt
[1470] [1470] Step A: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4-isopropyl-5-oxo-4 , 5-dihydropyrazine-2-sulfonamide
[1471] [1471] Prepared according to the general procedure of 1-isopropyl-N - (((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) - 6- oxo-1,6-dihydropyridine-3-sulfonamide (Example 153) of 4- (4-amino-2,3-dihydro-1H-inden-5-yl) picolinonitrile (Intermediate A5) (0 , 03g, 0.123mmol) and 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P133) (0.027 g, 0.123 mmol) and purified by C18 reverse phase flash chromatography (12 g of column, 0-60% MeCN / 10 mM ammonium bicarbonate) to obtain the title compound (0.023 g, 19%) as a yellow flocculent solid.
[1472] [1472] 1H NMR (DMSO-d6) δ 8.58 (d, J = 5.1 Hz, 1H), 7.93 (s, 2H), 7.89 (d, J = 1.7 Hz, 1H ), 7.76 (br s, 1H), 7.59 (dd, J = 5.2, 1.7 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.84 (p , J = 6.8 Hz, 1H), 2.91 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 1.99 (p, J = 7.5 Hz, 2H), 1.28 (d, J = 6.8 Hz, 6H). LCMS: m / z 479.3 (M + H) + (ES +); 477.2 (M-H) - (ES-).
[1473] [1473] Step B: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4-isopropyl-5-oxo-4 , 5-dihydropyrazine-2-sulfonamide, sodium salt
[1474] [1474] N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4-isopropyl-5-oxo-4,5- dihydropyrazine-2-sulfonamide (0.015 g, 0.031 mmol) was treated with 0.1 M NaOH solution (310 μL) and the resulting solution was lyophilized to obtain the title compound (16 mg, quantum yield) as a solid yellow.
[1475] [1475] 1H NMR (DMSO-d6) δ 8.56 (d, J = 5.1 Hz, 1H), 7.89 (t, J = 1.6 Hz, 2H), 7.84 (d, J = 1.1 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.13 - 7.09 (m, 2H), 4.85 (sept, J = 6.8 Hz, 1H) , 2.90 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 1.98 (p, J = 7.5 Hz, 2H), 1 , 28 (d, J = 6.8 Hz, 6H). LCMS: m / z 479.3 (M + H) + (ES +); 477.1 (M-H) - (ES-).
[1476] [1476] Example 156: 4-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -5-oxo-4 , 5-dihydropyrazine-2-sulfonamide
[1477] [1477] Prepared according to the general procedure of 1-isopropyl-N - (((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) - 6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 153) of 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P133) (26 mg, 0.12 mmol) and 5- (2-
[1478] [1478] 1H NMR (DMSO-d6) δ 8.09 (s, 1H), 8.05 (d, J = 5.3 Hz, 1H), 7.98 (s, 1H), 7.71 (s , 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 5.3 Hz, 1H ), 6.65 (s, 1H), 4.86 (sept, J = 7.2, 6.7 Hz, 1H), 3.86 (s, 3H), 2.90 (t, J = 7, 4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 1.98 (p, J = 7.4 Hz, 2H), 1.30 (d, J = 6.7 Hz , 6H). Partial ammonium salt. LCMS: m / z 484.3 (M + H) + (ES +).
[1479] [1479] Example 157: N - ((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1-isopropylazetidine-3-sulfonamide
[1480] [1480] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (70 mg, 392.70 μmol, 1 eq) in THF (2 ml) was added t-BuONa (37 mg, 392.70 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A6) (110 mg, 392.70 μmol, 1 eq) was added. The reaction mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 12% - 42%, 11.5 min) to give the title compound (80.02 mg, 43% yield, 96% purity in LCMS) as a white solid.
[1481] [1481] 1H NMR (DMSO-d6) δ 8.75 (d, 1 H), 8.06 (s, 1 H), 7.77-7.66 (m, 2 H), 7.21 (dd , 1 H), 7.12 (dd, 1 H), 3.78-3.49 (m, 4 H), 3.26-3.22 (d, 2 H), 2.83-2.79 (m, 1 H), 1.15 (d, 6 H) and 0.95 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 460.2 (M + H) + (ES +).
[1482] [1482] Example 158: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-isopropylazetidine-3-sulfonamide
[1483] [1483] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (70 mg, 392.70 μmol, 1 eq) in THF (2 ml) was added t-BuONa (38 mg, 392.70 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A7) (112 mg, 392.70 μmol, 1 eq) was added. The mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 12% -42%, 11.5 min) to give the title compound (87.88 mg, 48% yield, 99% LCMS purity) as a white solid.
[1484] [1484] 1H NMR (DMSO-d6) δ 8.11 (d, 1 H), 7.17 (br s, 1 H), 7.11 (d, 1 H), 7.01 (s, 1 H ), 6.93 (d, 1 H), 6.85 (s, 1 H), 3.86 (s, 3 H), 3.81 - 3.77 (m, 1 H), 3.26- 3.22 (m, 1 H), 3.18-3.15 (m, 2 H), 3.03-3.00 (m, 2 H), 2.22 - 1.98 (m, 1 H ), 1.16-1.12 (m, 6 H) and 0.80 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 465.2 (M + H) + (ES +).
[1485] [1485] Example 159: 1-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide
[1486] [1486] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (70 mg, 392.70 μmol, 1 eq) in THF (2 ml) was added t-BuONa (38 mg, 392.70 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A8) (104 mg, 392.70 μmol, 1 eq) was added. The mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (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 give the title compound (56.2 mg, 32% yield, 100% LCMS purity) as a white solid.
[1487] [1487] 1H NMR (DMSO-d6) δ 8.13 (d, 1 H), 7.49 (br s, 1 H), 7.12 (d, 1 H), 7.07 (d, 1 H ), 6.98 (d, 1 H), 6.79 (s, 1 H), 4.00-3.94 (m, 1 H), 3.87 (s, 3 H), 3.70- 3.64 (m, 2 H), 3.58-3.54 (m, 2 H), 2.91 (t, 2 H), 2.83 (t, 2 H), 2.76-2, 73 (m, 1 H), 2.04-1-97 (m, 2 H) and 0.94 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 445.2 (M + H) + (ES +).
[1488] [1488] Example 160: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropylazetidine-3-sulfonamide O O O O O S S F F
[1489] [1489] A mixture of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (50 mg, 280.50 μmol, 1 eq) and t-BuONa (27 mg, 280.50 μmol, 1 eq) in THF (2 ml ) was stirred at 25 ° C for 10 minutes. 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A9) (71 mg, 280.50 μmol, 1 eq) was added and the resulting mixture it was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 12% -42%, 10 min) to give the title compound (7.96 mg, 7% yield, 100% LCMS purity) as a white solid.
[1490] [1490] 1H NMR (DMSO-d6) δ 8.55 (d, 2 H), 7.41-7.38 (m, 3 H), 6.95 (d, 1 H), 3.94-3 .88 (m, 1 H), 3.70-3.67 (m, 2 H), 3.61-3.58 (m, 2 H), 2.95 (t, 2 H), 2.86 (t, 2 H), 2.82-2.75 (m, 1 H), 2.10-2.02 (m, 2 H) and 0.96 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 433.2 (M + H) + (ES +).
[1491] [1491] Example 161: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1-cyclobutylazetidine-3-sulfonamide THE
[1492] [1492] A solution of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P135) (30 mg, 157.68 μmol, 1 eq) and t-BuONa (15 mg, 157.68 μmol, 1 eq) in THF (1 ml ) was stirred at 25 ° C for 10 minutes. 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) picolinonitrile (Intermediate A6) (44 mg, 157.68 μmol, 1 eq) was added and the resulting mixture was stirred at 25 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (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, 10 min) to give the title compound (6.35 mg, 8% yield, 97% purity in LCMS) as a white solid.
[1493] [1493] 1H NMR (DMSO-d6) δ 8.75 (d, 1 H), 8.05 (s, 1 H), 7.77-7.75 (m, 1 H), 7.67-7 , 65 (m, 1 H), 7.23-7.18 (m, 1 H), 7.12 (d, 1 H), 3.95 - 3.68 (m, 2 H), 3.67 -3.56 (m, 2 H), 3.55-3.42 (m, 2 H), 3.25-3.21 (m, 1 H), 1.99- 1.97 (m, 2 H), 1.86-1.84 (m, 2 H), 1.71-1.62 (m, 2 H) and 1.16 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 472.2 (M + H) + (ES +).
[1494] [1494] Example 162: 1-Cyclobutyl-N - (((4-fluoro-2-isopropyl- 6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) azetidine-3-sulfonamide
[1495] [1495] To a solution of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P135) (25 mg, 131.40 μmol, 1 eq) in THF (1 ml) was added t-BuONa (13 mg, 131.40 μmol, 1 eq). The reaction mixture was stirred at 20 ° C for 10 minutes. Then 4- (5-fluoro-2-isocyanate-3 isopropylphenyl) -2-methoxypyridine (Intermediate A7) (38 mg, 131.40 μmol, 1 eq) was added and the resulting mixture was stirred at 20 ° C 20 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 15% -45%, 10 min ) to give the title compound (41.16 mg, 66% yield, 100% purity in LCMS) as a white solid.
[1496] [1496] 1H NMR (DMSO-d6) δ 8.16 (d, 1 H), 7.61 (br s, 1 H), 7.16 (d, 1 H), 7.03-6.96 ( m, 2 H), 6.83 (s, 1 H), 4.02-3.92 (m, 1 H), 3.88 (s, 3
[1497] [1497] Example 163: 1-Cyclobutyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide THE THE S O The HN The N
[1498] [1498] A mixture of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P135) (40 mg, 210.24 μmol, 1 eq) and t-BuONa (20 mg, 210.24 μmol, 1 eq) in THF (2 ml ) was stirred at 25 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A8) (56 mg, 210.24 μmol, 1 eq) was added and the mixture The resulting mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (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 give the title compound (20.06 mg, 21% yield, 100% purity in LCMS) as a white solid.
[1499] [1499] 1H NMR (DMSO-d6) δ 8.13 (d, 1 H), 7.40 (br s, 1 H), 7.12 (d, 1 H), 7.06 (d, 1 H ), 6.96 (d, 1 H), 6.77 (s, 1 H), 4.06-3.98 (m, 1 H), 3.87 (s, 3 H), 3.49- 3.44 (m, 3 H), 3.38-3.35 (m, 2 H), 2.91 (t, 2 H), 2.82 (t, 2 H), 2.03-1, 99 (m, 2 H), 1.98-1.94 (m, 2 H), 1.85-1.81 (m, 2 H) and 1.71-1.62 (m, 2 H). An unobserved exchangeable proton. LCMS: m / z 457.3 (M + H) + (ES +).
[1500] [1500] Example 164: 1-Cyclobutyl-N - (((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3- sulfonamide O O O O O F S F s
[1501] [1501] A mixture of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P135) (37 mg, 194.47 μmol, 1 eq) and t-BuONa (19 mg, 194.47 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 A9) (49 mg, 194.47 μmol, 1 eq) was added and the The resulting mixture was stirred at 25 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18, 250mm * 50mm * 10μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B%: 0% -30%, 10 min) to give the title compound (18.09 mg, 20% yield, 97% purity in LCMS) as a solid.
[1502] [1502] 1H NMR (DMSO-d6) δ 8.57 (d, 2 H), 7.57 (br s, 1 H), 7.39 (d, 2 H), 6.97 (d, 1 H ), 4.02-3.95 (m, 1 H), 3.70-3.66 (m, 3 H), 3.57-3.54 (m, 1 H), 3.37-3, 27 (m, 1 H), 2.96 (t, 2 H), 2.86 (t, 2 H), 2.11 - 2.00 (m, 4 H), 1.92-1.87 ( m, 2 H) and 1.72-1.65 (m, 2 H). An unobserved exchangeable proton. LCMS: m / z 445.2 (M + H) + (ES +).
[1503] [1503] Example 165: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1-ethylazetidine-3-sulfonamide F F O O O O
[1504] [1504] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P136) (40 mg, 243.57 μmol, 1 eq) in THF (1 ml) was added t-BuONa (23 mg, 243.57 μmol, 1 eq). The mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -picolinonitrile (Intermediate A6) (68 mg, 243.57 μmol, 1 eq) was added and the mixture was stirred at 70 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% -38, 11.5 min) to give the title compound (48.97 mg, 45% yield, 100% LCMS purity) as a white solid.
[1505] [1505] 1H NMR (DMSO-d6) δ 8.75 (d, 1 H), 8.05 (s, 1 H), 7.76 (s, 1 H), 7.66 (s, 1 H) , 7.22-7.18 (m, 1 H), 7.12-7.09 (m, 1 H), 3.83-3.76 (m, 5 H), 3.24-3.20 (m, 1 H), 2.93-2.88 (m, 2 H), 1.16 (d, 6 H) and 0.99 (t, 3 H). An unobserved exchangeable proton. LCMS: m / z 446.2 (M + H) + (ES +).
[1506] [1506] Example 166: 1-Ethyl-N - (((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) azetidine-3-sulfonamide F F O O O O
[1507] [1507] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P136) (40 mg, 243.57 μmol, 1 eq) in THF (1 ml) was added t-BuONa (23 mg, 243.57 μmol, 1 eq). The mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A7) (69 mg, 243.57 μmol, 1 eq) was added and the mixture was stirred at 75 ° C for other 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% -38%, 11.5 min) to give the title compound (46.05 mg, 42% yield, 100% purity in LCMS) as a white solid.
[1508] [1508] 1H NMR (DMSO-d6) δ 8.15 (d, 1 H), 7.48 (s, 1 H), 7.17-7.12 (m, 1 H), 7.03-6 , 94 (m, 2 H), 6.84 (s, 1 H), 3.99-3.77 (m, 8 H), 3.24-3.20 (m, 1 H), 2.95 -2.92 (m, 2 H), 1.15 (d, 6 H) and 1.00 (t, 3 H). An unobserved exchangeable proton. LCMS: m / z 451.2 (M + H) + (ES +).
[1509] [1509] Example 167: 1-Ethyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide O O O O
[1510] [1510] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P136) (40 mg, 243.57 μmol, 1 eq) in THF (1 ml) was added t-BuONa (23 mg, 243.57 μmol, 1 eq). The mixture was stirred at 25 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A8) (64 mg, 243.57 μmol, 1 eq) was added and the mixture it was stirred at 70 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% -38%, 11.5 min) to give the title compound (52.99 mg, 51% yield, 100% LCMS purity) as a white solid.
[1511] [1511] 1H NMR (DMSO-d6) δ 8.13 (d, 1 H), 7.43 (br s, 1 H), 7.12 (d, 1 H), 7.06 (d, 1 H ), 6.97 (dd, 1 H), 6.79 (s, 1 H), 4.08-4.00 (m, 1 H), 3.88 (s, 3 H), 3.85- 3.80 (m, 2 H), 3.77-3.72 (m, 2 H), 2.91 (t, 2 H), 2.87-2.80 (m, 4 H), 2, 04-1.96 (m, 2 H) and 0.98 (t, 3 H). An unobserved exchangeable proton. LCMS: m / z 431.2 (M + H) + (ES +).
[1512] [1512] Example 168: 1-Ethyl-N - (((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3- sulfonamide
[1513] [1513] A solution of 1-ethylazetidine-3-sulfonamide (Intermediate P136) (50 mg, 304.46 μmol, 1 eq) and t-BuONa (29 mg, 304.46 μmol, 1 eq) in THF (1 ml ) was stirred at 25 ° C for 10 minutes. Then, a solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A9) (77 mg, 304.46 μmol, 1 eq) in THF (2 ml) was added and the reaction mixture was stirred at 25 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (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%, 10 min) to give the title compound (9.59 mg, 8% yield, 100% LCMS purity) as a white solid.
[1514] [1514] 1H NMR (DMSO-d6) δ 8.57 (d, 2 H), 7.43 (br s, 1 H), 7.40 (d, 2 H), 6.96 (d, 1 H ), 4.01-3.88 (m, 5 H), 2.98-2.93 (m, 4 H), 2.86 (t, 2 H), 2.11-2.03 (m, 2 H) and 1.01 (t, 3 H). An unobserved exchangeable proton. LCMS: m / z 419.2 (M + H) + (ES +).
[1515] [1515] Example 169: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide
[1516] [1516] A solution of 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (Intermediate P137) (50 mg, 219.99 μmol, 1 eq), 4- (5-fluoro-2-isocyanate-3- isopropylphenyl) picolinonitrile (Intermediate A6) (68 mg, 241.99 μmol, 1.1 eq) and t-BuONa (25 mg, 263.99 μmol, 1.2 eq) in THF (1.5 ml) was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3 v / v); B: MeCN]; B%: 15% - 45%, 12 min) to give the title compound (10 mg, 9%) as a white solid.
[1517] [1517] 1H NMR (DMSO-d6) δ 8.74 (d, 1 H), 8.50-8.47 (m, 2 H), 8.05 (s, 1 H), 8.00 (br s, 1 H), 7.73 (d, 1 H), 7.68 (d, 1 H), 7.39-7.35 (m, 1 H), 7.29-7.25 (m, 1 H), 7.16 (d, 1 H), 4.03-3.97 (m, 1 H), 3.73-3.68 (m, 2 H), 3.45-3.38 ( m, 4 H), 3.19-3.15 (m, 1 H) and 1.14 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 509.3 (M + H) + (ES +).
[1518] [1518] Example 170: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide
[1519] [1519] A solution of 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (Intermediate P137) (50 mg, 219.99 μmol, 1 eq), 4- (4-isocyanate-2,3-di- hydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A8) (64 mg, 241.99 μmol, 1.1 eq) and t-BuONa (25 mg, 263.99 μmol, 1.2 eq) in THF (1.5 ml) it was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05%
[1520] [1520] 1H NMR (DMSO-d6) δ 8.49- 8.45 (m, 2 H), 8.12 (d, 1 H), 7.79 (br s, 1 H), 7.67 ( d, 1 H), 7.38-7.33 (m, 1 H), 7.18 (d, 1 H), 7.09 (d, 1 H), 6.92 (d, 1 H), 6.73 (s, 1 H), 4.19-4.15 (m, 1 H), 3.80 (s, 3 H), 3.66 (s, 2 H), 3.50-3, 43 (m, 2 H), 3.38-3.34 (m, 2 H), 2.91 (t, 2 H), 2.78 (t, 2 H) and 2.04-1.98 ( m, 2 H). An unobserved exchangeable proton. LCMS: m / z 494.2 (M + H) + (ES +).
[1521] [1521] Example 171: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (pyridin-3- ylmethyl) azetidine-3-sulfonamide THE F HN AT THE O S HN F
[1522] [1522] To a solution of 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (Intermediate P137) (54 mg, 235.98 μmol, 1 eq) in THF (5 ml) was added t-BuONa (27 mg, 283.18 μmol, 1.2 eq) and a solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A9) (60 mg, 235.98 μmol, 1 eq) in THF (5 ml) and DCM (5 ml). The reaction mixture was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3 v / v); B: MeCN]; B%: 5% -50 %, 10 min) to give the title compound (35.53 mg, 31% yield, 99.4% LCMS purity) as a white solid.
[1523] [1523] 1H NMR (DMSO-d6) δ 8.56-8.54 (m, 2 H), 8.49-8.47 (m, 2 H), 7.76 (br s, 1 H), 7.68 (d, 1 H), 7.36 (dd, 3 H), 7.00 (d, 1 H), 4.17-4.12 (m, 1 H), 3.68 (s, 2 H), 3.47 (t, 2 H), 3.40 (t, 2 H), 2.96 (t, 2 H), 2.84 (t, 2 H) and
[1524] [1524] LCMS: m / z 482.2 (M + H) + (ES +).
[1525] [1525] Example 172: N - ((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1-isopropyl-6-oxo-1,6-dihydropyridine-3 -sulfonamide
[1526] [1526] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (60 mg, 225.09 μmol, 1 eq), 4- (5-fluoro-2 -isocyanate-3-isopropylphenyl) -picolinonitrile (Intermediate A6) (70 mg, 247.60 μmol, 1.1 eq) and t-BuONa (26 mg, 270.11 μmol, 1.2 eq) in THF (1, 5 ml) was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3 v / v); B: MeCN]; B%: 15% -45 %, 12 min) to give the title compound (30 mg, 26%) as a white solid.
[1527] [1527] 1H NMR (DMSO-d6) δ 8.57 (d, 1 H), 7.99-7.92 (m, 3 H), 7.64-7.62 (m, 1 H), 7 , 47-7.45 (m, 1 H), 7.25-7.22 (m, 1 H), 7.14-7.11 (m, 1 H), 6.36 (d, 1 H) , 4.99-4.91 (m, 1 H), 3.10-3.05 (m, 1 H), 1.25 (d, 6 H) and 1.09 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 498.3 (M + H) + (ES +).
[1528] [1528] Example 173: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-isopropyl-6-oxo-1,6-dihydropyridine- 3- sulfonamide
[1529] [1529] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (60 mg, 225.09 μmol, 1 eq), 4- (5-fluoro-2 -isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A7) (71 mg, 247.60 μmol, 1.1 eq) and t-BuONa (26 mg, 270.11 μmol, 1.2 eq) in THF ( 1.5 ml) was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18, 250mm * 50mm * 10μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B%: 2% -32%, 10 min) to give the title compound (61 mg, 54%) as a white solid.
[1530] [1530] 1H NMR (DMSO-d6) δ 7.97 (d, 2 H), 7.51 (d, 2 H), 7.13 (dd, 1 H), 6.96-6.89 (m , 2 H), 6.73 (s, 1 H), 6.35 (d, 1 H), 5.00-4.95 (m, 1 H), 3.83 (s, 3 H), 3 , 09-3.04 (m, 1 H), 1.25 (d, 6 H) and 1.05 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 503.2 (M + H) + (ES +).
[1531] [1531] Example 174: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropyl-6-oxo -1,6-dihydropyridine-3-sulfonamide
[1532] [1532] 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide solution (Intermediate P132) (50 mg, 187.58 μmol, 1 eq), 4- (7-fluoro-4-
[1533] [1533] 1H NMR (DMSO-d6) δ 8.46 (d, 2 H), 8.08 (s, 1 H), 7.83 (br s, 1 H), 7.58 (dd, 1 H ), 7.26 (d, 2 H), 6.99 (d, 1 H), 6.45 (d, 1 H), 5.02 - 4.94 (m, 1 H), 2.94 ( t, 2 H), 2.71 (t, 2 H), 2.07-2.01 (m, 2 H) and 1.28 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 471.2 (M + H) + (ES +).
[1534] [1534] Example 175: N - (((4-Fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-isopropylazetidine-3-sulfonamide
[1535] [1535] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (200 mg, 1.12 mmol, 1 eq) in THF (5 mL) was added MeONa (60 mg, 1.12 mmol, 1 eq ). The reaction mixture was stirred at 25 ° C for 30 minutes. Then 3- (5-fluoro-2-isocyanate-3-isopropylphenyl) pyridine (Intermediate A10) (431 mg, 1.68 mmol, 1.5 eq) was added and the resulting mixture was stirred at 70 ° C for 30 minutes . Then, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: Welch Ultimate XB_C18, 35mm * 235mm * 20 / 35μm, mobile phase: [A: water (0.05% ammonium hydroxide); B: MeCN]; B%: 0% -40%, 10 min) to give the title compound (33 mg, 7% yield, 100% LCMS purity) as a white solid.
[1536] [1536] 1H NMR (DMSO-d6) δ 8.60-8.51 (m, 2 H), 7.92-7.77 (m, 1 H), 7.57 (s, 1 H), 7 , 44-7.40 (m, 1 H), 7.14 (d, 1 H), 7.00 (d, 1 H), 3.92-3.74 (m, 3 H), 3.29 -2.95 (m, 4 H), 1.26-1.10 (m, 6 H) and 1.02 (d, 6 H). An unobserved exchangeable proton.
[1537] [1537] LCMS: m / z 435.2 (M + H) + (ES +).
[1538] [1538] Example 176: N - (((4-Fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-isopropylpiperidine-4-sulfonamide F N F
[1539] [1539] To a solution of 1-isopropylpiperidine-4-sulfonamide (Intermediate P138) (720 mg, 3.49 mmol, 1 eq) in THF (10 mL) was added NaOMe (226 mg, 4.19 mmol, 1, 2 eq) and 3- (5-fluoro-2-isocyanato-3-isopropylphenyl) pyridine (Intermediate A10) (805 mg, 3.14 mmol, 0.9 eq). The reaction mixture was then stirred at 70 ° C for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 250mm * 50mm * 10μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 15% -45%, 10 min ) to give the title compound (69.36 mg, 4% yield, 100% purity in LCMS) as a white solid.
[1540] [1540] 1H NMR (DMSO-d6) δ 8.57 (s, 1 H), 8.48 (d, 1 H), 7.87-7.80 (m, 1 H), 7.36-7 , 32 (m, 1 H), 7.25 (s, 1 H), 7.10 (d, 1 H), 6.95 (d, 1 H), 6.09 (s, 1 H), 2 , 95-2.85 (m, 1 H), 2.79-2.76 (m, 2 H), 2.70-2.63 (m, 2 H), 1.98-1.85 (m , 2 H), 1.65-1.61 (m, 2 H), 1.42-1.38 (m, 2 H), 1.14 (d, 6 H) and 0.94 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 463.4 (M + H) + (ES +).
[1541] [1541] Example 177: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide
[1542] [1542] A solution of 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (Intermediate P137) (50 mg, 219.99 μmol, 1 eq), 4- (5-fluoro-2-isocyanate-3- isopropylphenyl) -2-methoxypyridine (Intermediate A7) (69 mg, 241.99 μmol, 1.1 eq) and t-BuONa (25 mg, 263.99 μmol, 1.2 eq) in THF (1.5 ml) it was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% -38%, 11.5 min) to give the title compound (44 mg, 38%) as a white solid.
[1543] [1543] 1H NMR (DMSO-d6) δ 8.47 (s, 2 H), 8.12 (d, 1 H), 7.67 (d, 2 H), 7.35 (dd, 1 H) , 7.19 (d, 1 H), 7.01-6.95 (m, 2 H), 6.80 (s, 1 H), 4.04-3.98 (m, 1 H), 3 , 78 (s, 3 H), 3.64 (s, 2 H), 3.43-3.36 (m, 4 H), 3.16-3.12 (m, 1 H) and 1.12 (d, 6 H). An unobserved exchangeable proton. LCMS: m / z 514.3 (M + H) + (ES +).
[1544] [1544] Example 178: 1-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-oxo-1 , 2-dihydropyrimidine-5-sulfonamide, sodium salt
[1545] [1545] A suspension of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (0.033 g, 0.137 mmol) (Intermediate A4) and (4-
[1546] [1546] 1H NMR (DMSO-d6) δ 8.65 (d, J = 3.0 Hz, 1H), 8.35 (d, J = 3.1 Hz, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.24 (br s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H) , 6.88 (dd, J = 5.3, 1.4 Hz, 1H), 6.70 (t, J = 1.0 Hz, 1H), 4.76 (sept, J = 6.7 Hz, 1H), 3.82 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.30 (d, J = 6.8 Hz, 6H). LCMS: m / z 484.1 (M + H) + (ES +); 482.1 (M-H) - (ES-).
[1547] [1547] Example 179: 1-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-oxo-1 , 2-dihydropyridine-4-sulfonamide, sodium salt
[1548] [1548] To a solution of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A4) (0.156 g, 0.65 mmol) in DCM ( 5 ml) and saturated aqueous NaHCO3 (5 ml) a solution of bis (trichloromethyl) carbonate (0.079 g, 0.264 mmol) in toluene (1 ml) was added to the DCM layer without stirring. The reaction mixture was stirred for 1 hour,
[1549] [1549] A solution of 1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Intermediate P140) (0.050 g, 0.224 mmol) in dry THF (3 mL) was treated with tert-butoxide sodium (2 M in THF) (0.120 ml, 0.24 mmol). The reaction mixture was stirred at room temperature for 1 hour, treated with a solution of the crude isocyanate intermediate in dry THF (4 ml) and then stirred at room temperature for 22 hours. The reaction mixture was concentrated in vacuo and the residue purified by C18 reverse phase flash chromatography (liquid charge) (12 g cartridge, 5-50% MeCN / 10 mM ammonium bicarbonate) to provide 1-isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-oxo-1,2-dihydropyridine-4-sulfonamide ( 0.079 g, 70%) as a white flocculent solid. The free acid (0.071 g, 0.141 mmol) was treated with 0.1 M NaOH (aq) (1.410 ml, 0.141 mmol) and the mixture was dried by lyophilization to obtain the title compound (0.073 g, 102%) as a white solid.
[1550] [1550] 1H NMR (DMSO-d6) δ 8.06 (dd, J = 5.3, 0.7 Hz, 1H), 7.87 (dd, J = 6.9, 2.1 Hz, 1H) , 7.76 (dd, J = 7.0, 2.1 Hz, 1H), 7.30 (br s, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.76 (t, J = 1.0 Hz, 1H), 6 , 30 (t, J = 6.9 Hz, 1H), 5.14 (sept, J = 6.8 Hz, 1H), 3.85 (s, 3H), 2.85 (t, J = 7, 4 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 1.90 (p, J = 7.5 Hz, 2H), 1.30 (d, J = 6.8 Hz , 6H). LCMS: m / z 483.1 (M + H) + (ES +); 481.0 (M-H) - (ES-).
[1551] [1551] Example 180: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl-2-oxo-1,2-di -hydropyridine-4-sulfonamide, sodium salt
[1552] [1552] A solution of 1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Intermediate P140) (0.05 g, 0.224 mmol) in dry THF (4 mL) was treated with 2 M of sodium tert-butoxide in THF (0.12 mL, 0.240 mmol) under nitrogen. The resulting suspension was stirred at room temperature for 1 hour, then treated with a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.049 g, 0.247 mmol) in dry THF (1 mL) and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by C18 reverse phase flash chromatography (liquid charge) (12 g cartridge, 0-75% MeCN / 10 mM ammonium bicarbonate) to obtain N - (( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (0.059 g, 63%) as a white flocculent solid. The free acid (0.05 g, 0.119 mmol) was treated with 0.1 M NaOH (1.191 ml, 0.119 mmol) and the resulting solution was lyophilized to obtain the title compound (0.052 g, 99%) as a white solid. .
[1553] [1553] 1H NMR (DMSO-d6) δ 7.88-7.84 (m, 2H), 7.47 (s, 1H), 6.75 (s, 1H), 6.33 (t, J = 6.9 Hz, 1H), 5.11 (sept, J = 6.8 Hz, 1H), 2.73 (t, J = 7.4 Hz, 4H), 2.61 (t, J = 7, 4 Hz, 4H), 1.87 (p, J = 7.4 Hz, 4H), 1.29 (d, J = 6.9 Hz, 6H). LCMS: m / z 438.3 (M + Na) + (ES +); 414.2 (M-H) - (ES-).
[1554] [1554] Example 181: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -4-isopropyl-5-oxo-4,5-di -hydropyrazine-2-sulfonamide, sodium salt
[1555] [1555] A solution of 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P133) (0.06 g, 0.273 mmol) in dry THF (4 mL) was treated with 2M of sodium tert-butoxide in THF (0.15 ml, 0.300 mmol) under nitrogen. The resulting suspension was stirred at room temperature for 45 minutes, then treated with a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.061 g, 0.306 mmol) in dry THF (1 mL) and stirred for 21 hours. The reaction mixture was diluted with EtOAc (10 ml) and washed with water (2 x 2 ml). The aqueous layer was collected and retained. The organic layer was concentrated in vacuo and the residue was dissolved in MeCN (2 ml) and combined with the aqueous layer. The resulting suspension was filtered through cotton and then purified by C18 reverse phase flash chromatography (12 g cartridge, 5-75% MeCN / 10 mM ammonium bicarbonate) to obtain N - ((1,2,3, 5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.075 g, 66%) as a white flocculent solid . The free acid (0.05 g, 0.120 mmol) was treated with 0.1 M NaOH (1,200 ml, 0.120 mmol) and the resulting solution was lyophilized to obtain the title compound (0.053 g, 101%) as a white solid. .
[1556] [1556] 1H NMR (DMSO-d6) δ 7.96 (d, J = 1.1 Hz, 1H), 7.90 (d, J = 1.0 Hz, 1H), 7.46 (s, 1H ), 6.76 (s, 1H), 4.88 (sept, J = 6.8 Hz, 1H), 2.74 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.3 Hz, 4H), 1.88 (p, J = 7.4 Hz, 4H), 1.31 (d, J = 6.8 Hz, 6H). LCMS: m / z 417.3 (M + H) + (ES +); 415.2 (M-H) - (ES-).
[1557] [1557] Example 182: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl-2-oxo-1,2-di -hydropyridine-3-sulfonamide
[1558] [1558] 2M sodium tert-butoxide in THF (0.138 ml, 0.277 mmol) was added to a solution of 1-isopropyl-2-oxo-1,2-di-
[1559] [1559] 1H NMR (DMSO-d6) δ 8.19 - 8.00 (m, 3H), 6.89 (s, 1H), 6.46 (t, J = 7.0 Hz, 1H), 5 , 11 (sept, J = 6.8 Hz, 1H), 2.76 (t, J = 7.4 Hz, 4H), 2.56 (t, J = 7.2 Hz, 4H), 1.91 (p, J = 7.4 Hz, 4H), 1.32 (d, J = 6.8 Hz, 6H). An unobserved exchangeable proton. LCMS: m / z 416.2 (M + H) + (ES +), 438.3 (M + Na) + (ES +).
[1560] [1560] Example 183: (R) -N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2-hydroxypropyl) -6 -oxo-1,6-dihydropyridine-3-sulfonamide
[1561] [1561] A solution of (R) -1- (2-hydroxypropyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P142) (0.047 g, 0.196 mmol) in dry THF (4 mL ) was treated with 2M sodium tert-butoxide in THF (0.103 ml, 0.206 mmol) under nitrogen. The resulting suspension was stirred at room temperature for 1 hour and then treated with a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.043 g, 0.216 mmol) in dry THF (1 mL) and stirred for 20 hours. The reaction mixture was concentrated in vacuo to obtain the crude product as a green solid which was purified by preparative HPLC (column: Waters Xbridge C18, 19 mm * 15 mm * 5 μm; mobile phase: [A: water (0.1 % NH4HCO3); B: MeCN]; B%: 10% -40%) to obtain the title compound (0.016 g, 19%) as a white flocculent solid.
[1562] [1562] 1H NMR (DMSO-d6) δ 8.17 (d, J = 2.6 Hz, 1H), 7.85 (br s, 1H), 7.75 (dd, J = 9.6, 2 , 7 Hz, 1H), 6.88 (s, 1H), 6.44 (d, J = 9.6 Hz, 1H), 4.92 (d, J = 5.5 Hz, 1H), 4, 04 (dd, J = 12.9, 3.7 Hz, 1H), 3.85 (ddd, J = 9.4, 7.0, 4.7 Hz, 1H), 3.64 (dd, J = 12.9, 8.0 Hz, 1H), 2.77 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7.4 Hz, 4H), 1.92 (p, J = 7.5 Hz, 4H), 1.06 (d, J = 6.3 Hz, 3H). An unobserved exchangeable proton. LCMS: m / z 432.3 (M + H) + (ES +); 430.1 (M-H) - (ES-).
[1563] [1563] Example 184: 1- (2- (Dimethylamino) ethyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -6- oxo-1,6-dihydropyridine-3-sulfonamide
[1564] [1564] A solution of 1- (2- (dimethylamino) ethyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P143) (0.034 g, 0.100 mmol) in dry THF (3 mL) was treated with 2M sodium tert-butoxide in THF (0.07 ml, 0.140 mmol) under nitrogen. The resulting suspension was stirred at room temperature for 1 hour and then treated with a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.035 g, 0.176 mmol) in dry THF (1 mL) and stirred for 20 hours. The reaction mixture was concentrated in vacuo to obtain the crude product as an off-white solid which was purified by C18 reverse phase flash chromatography (liquid charge in water) (12 g cartridge, 5-75% MeCN / 10 mM bicarbonate ammonium) to provide the title compound (0.017 g, 38%) as a flocculent white solid.
[1565] [1565] 1H NMR (DMSO-d6) δ 8.28 (d, J = 2.6 Hz, 1H), 7.85 (s, 1H), 7.75 (dd, J = 9.6, 2, 7 Hz, 1H), 6.88 (s, 1H), 6.46 (d, J = 9.6 Hz, 1H), 4.11 (t, J = 6.3 Hz, 2H), 2.80 -2.70 (m, 6H), 2.60 (t, J = 7.4 Hz, 4H), 2.34 (s, 6H), 1.92 (p, J = 7.4 Hz, 4H) . An unobserved exchangeable proton. LCMS: m / z 445.3 (M + H) + (ES +); 443.3 (M-H) - (ES-).
[1566] [1566] Example 185: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl-6-oxo-1,6-di -hydropyridine-3-sulfonamide, sodium salt
[1567] [1567] Sodium terc-butoxide (2 M in THF) (0.048 mL, 0.096 mmol) was added to a solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (19.7 mg, 0.091 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature for 1 hour. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (20 mg, 0.100 mmol) was added and the reaction mixture was stirred at room temperature during night. The resulting white precipitate was collected by filtration, washed with THF. The solid was dissolved in MeCN, filtered and dried in vacuo to obtain the title compound (5 mg, 12%) as a white solid.
[1568] [1568] 1H NMR (DMSO-d6) δ 8.00 (d, J = 2.5 Hz, 1H), 7.66 (dd, J = 9.4, 2.5 Hz, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 6.32 (d, J = 9.3 Hz, 1H), 5.01 (sept, J = 6.8 Hz, 1H), 2.75 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.3 Hz, 4H), 1.88 (p, J = 7.4 Hz, 4H), 1.28 (d , J = 6.8 Hz, 6H). LCMS: m / z 416.3 (M + H) + (ES +).
[1569] [1569] Example 186: 1-Ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine- 4-sulfonamide, potassium salt
[1570] [1570] To a solution of 1-ethylpiperidine-4-sulfonamide (Intermediate P6; 90 mg, 0.37 mmol) in THF (5 mL) was added potassium tert-butoxide (49 mg, 0.44 mmol). The mixture was stirred at room temperature for 45 minutes. Then, 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A11; 90 mg, 0.32 mmol) was added and the mixture it was stirred for 2 hours at room temperature. 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 1") to obtain the title compound (18 mg, 10%) as a white solid.
[1571] [1571] 1H NMR (methanol-d4) δ 8.10 (d, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 6.84 (s, 1H), 3.92 (s, 3H), 3.23 (m, 2H), 3.07 (m, 1H), 3.00 (m, 4H), 2.68 (m, 2H), 2.32-2.08 ( m, 4H), 2.03 (m, 2H), 1.86 (m, 2H), 1.18 (t, 3H). LCMS: m / z 477 (M + H) + (ES +); 475 (M-H) - (ES-).
[1572] [1572] Example 187: 1- (sec-Butyl) -N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) azetidine-3-sulfonamide, potassium salt
[1573] [1573] Prepared as described for 1-ethyl-N - ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 5-chloro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A15) and 1- (sec-butyl) azetidine-3-sulfonamide (Intermediate P107) to obtain the title compound (25%) as a white solid.
[1574] [1574] 1H NMR (CD3OD) δ 7.08 (m, 2 H), 4.28 (t, 1 H), 3.70 (t, 2 H), 3.58 (t, 2 H), 3 , 24 (m, 2 H), 2.42 (d, 1H), 1.55 (s, 1H), 1.18 (d, 13 H), 0.95 (d, 3 H), 0.89 (t, 3 H). LCMS: m / z 431 (M + H) + (ES +); 429 (M-H) - (ES-).
[1575] [1575] Example 188: 1-Ethyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt
[1576] [1576] Prepared as described for 1-ethyl-N - ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A8) and 1-ethylpiperidine-4 - sulfonamide (Intermediate P6) to obtain the title compound (54 mg, 30%) as a white solid.
[1577] [1577] 1H NMR (methanol-d4) δ 8.08 (d, 1H), 7.25 - 7.08 (m, 2H), 7.03 (dd, 1H), 6.86 (s, 1H) , 3.92 (s, 3H), 3.39 - 3.17 (m, 3H), 2.95 (m, 4H), 2.71 (q, 2H), 2.33 (t, 2H), 2.22 - 1.97 (m, 4H), 1.97 - 1.72 (m, 2H), 1.18 (t, 3H). LCMS: m / z 459 (M + H) + (ES +); 457 (M-H) - (ES-).
[1578] [1578] Example 189: 1-Ethyl-N - ((1,2,3,7-tetrahydro-s-
[1579] [1579] Prepared as described for 1-ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 8-isocyanate-1,2,3,5-tetrahydro-s-indacene (Intermediate A14) and 1-ethylpiperidine-4-sulfonamide (Intermediate P6) to obtain the title compound (77 mg, 34%) as a white solid.
[1580] [1580] 1H NMR (methanol-d4) (mixture of isomers) δ 7.14, 7.06 (s, 1H), 6.91, 6.77 (m, 1H), 6.46, 6.41 ( m, 1H), 3.64 - 3.44 (m, 2H), 3.31 (m, 2H), 3.23 (m, 1H), 2.89 (m, 4H), 2.74 - 2 , 54 (m, 2H), 2.31 (d, 2H), 2.25 - 1.85 (m, 6H), 1.16 (t, 3H). LCMS: m / z 390 (M + H) + (ES +); 388 (M-H) - (ES-).
[1581] [1581] Example 190: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-ethylpiperidine-4-sulfonamide, salt potassium
[1582] [1582] Prepared as described for 1-ethyl-N - ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) picolinonitrile (Intermediate A12) and 1-ethylpiperidine-4-
[1583] [1583] 1H NMR (methanol-d4) δ 8.66 (dd, 1H), 7.95 (d, 1H), 7.73 (dd, 1H), 7.20 (q, 2H), 3.55 (m, 1H), 3.09 (q, 2H), 2.98 (m, 4H), 2.85 (m, 4H), 2.13 (m, 2H), 2.1-1.97 ( m, 4H), 1.31 (t, 3H). LCMS: m / z 454 (M + H) + (ES +); 452 (M-H) - (ES-).
[1584] [1584] Example 191: 1-Ethyl-N - (((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) piperidine-4-sulfonamide, potassium salt
[1585] [1585] Prepared as described for 1-ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A7) and 1-ethylpiperidine-4-sulfonamide (Intermediate P6) the title compound (23 mg, 14%) as a white solid.
[1586] [1586] 1H NMR (methanol-d4) δ 8.09 (d, 1H), 7.06 (dd, 2H), 6.88 (m, 2H), 3.92 (s, 3H), 3.72 (m, 1H), 3.19 (m, 1H), 3.08 (m, 2H), 2.49 (d, 2H), 1.87 (m, 6H), 1.23 (d, 6H) , 1.12 (t, 3H). LCMS: m / z 479 (M + H) + (ES +); 477 (M-H) - (ES-).
[1587] [1587] Example 192: 1-Ethyl-N - ((5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine-4-sulfonamide, salt potassium
[1588] [1588] Prepared as described for 1-ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A13) and 1-ethylpiperidine-4-sulfonamide ( Intermediate P6) to obtain the title compound (11 mg, 13%) as a white solid.
[1589] [1589] 1H NMR (methanol-d4) δ 8.55 - 8.42 (m, 2H), 7.58 - 7.44 (m, 2H), 7.24 - 7.05 (m, 2H), 3.22 (d, 2H), 3.07 (m, 1H), 2.97 (m, 4H), 2.65 (t, 2H), 2.23 (t, 2H), 2.10 (m , 2H), 2.04 - 1.67 (m, 4H), 1.18 (t, 3H). LCMS: m / z 429 (M + H) + (ES +); 427 (M-H) - (ES-).
[1590] [1590] Example 193: 1- (Ethyl-d5) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt
[1591] [1591] Prepared as described for 1-ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1- (ethyl-d5) piperidine- 4-sulfonamide (Intermediate P145) to obtain the title compound (75 mg, 38%) as a white solid.
[1592] [1592] 1H NMR (methanol-d4) δ 6.87 (s, 1H), 3.44 (m, 1H), 3.16 (d, 2H), 2.82 (m, 8H), 2.15 (m, 4H), 2.10 - 1.84 (m, 6H). LCMS: m / z 397 (M + H) + (ES +); 395 (M-H) - (ES-).
[1593] [1593] Example 194: 1-Ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azepano-4-sulfonamide, potassium salt
[1594] [1594] Prepared as described for 1-ethyl-N - ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethylazepano-4-sulfonamide (Intermediate P144) to obtain the title compound (17 mg, 27%) as a white solid.
[1595] [1595] 1H NMR (methanol-d4) δ 6.89 (s, 1H), 3.72 (sd, 1H), 3.37 - 3.18 (m, 2H), 3.13 - 2.91 ( m, 3H), 2.85 (dq, 8H), 2.41 (ddt, 1H), 2.24 (ddd, 2H), 2.03 (m, 6H), 1.92 - 1.70 (m , 2H), 1.21 (t, 3H). LCMS: m / z 406 (M + H) + (ES +); 404 (M-H) - (ES-).
[1596] [1596] Example 195: N - (((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-methylazepano-4-sulfonamide, potassium salt
[1597] [1597] Prepared as described for 1-ethyl-N - ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 186) using 4-isocyanate-1,2,3,5,6,7-
[1598] [1598] 1H NMR (methanol-d4) δ 6.89 (s, 1H), 3.83 - 3.66 (m, 1H), 3.14 - 2.95 (m, 4H), 2.83 ( m, 8H), 2.66 (s, 3H), 2.47 - 2.19 (m, 2H), 2.18 - 1.93 (m, 6H), 1.83 (dd, 2H). LCMS: m / z 392 (M + H) + (ES +).
[1599] [1599] Examples - biological studies
[1600] [1600] NLRP3 and Pyroptosis
[1601] [1601] It is well established that 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.
[1602] [1602] THP-1 Cells: Culture and Preparation
[1603] [1603] 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% yield) was checked for trypan blue (Sigma # T8154). Appropriate dilutions were made to give a concentration of 625,000 cells / ml. To this diluted cell solution, LPS (Sigma # L4524) was added to give 1 µg / ml of Final Assay Concentration (FAC). 40µl of the final preparation was aliquoted in each well of a 96-well plate. The prepared plate was then used for screening compounds.
[1604] [1604] Pyroptosis Assay with THP-1 Cells
[1605] [1605] The following step-by-step assay method was followed for screening compounds.
[1606] [1606] The results of the pyroptosis assay performed are summarized in Table 1 below as THP IC50.
[1607] [1607] Human Blood IL1β Release Assay
[1608] [1608] 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.
[1609] [1609] Human whole blood in Li-heparin tubes was obtained from healthy donors from a panel of voluntary donors.
[1610] [1610] The results of the human whole blood assay are summarized in Table 1 below as HWB IC50. THP No. IC50 HWB IC50 THP No. IC50 HWB IC50 Example Example 1 ++ ++ 99 +++ +++ 2 ++ ++ 100 ++ ND 3 ++ ++ 101 +++ +++ 4 ++ ++ 102 ++ ND 5 +++ ++ 103 +++ ++ 6 +++ +++ 104 +++ ND 7 +++ ++ 105 +++ + 8 ++ +++ 106 ++ ND
[1611] [1611] PK Protocol
[1612] [1612] Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-300g; or Vital River Laboratory Animal Technology Co., Beijing, China, 7-9 weeks old). The animals were housed individually during the study and maintained on a 12-hour light / dark cycle. The animals had free access to food and water, except that the animals administered orally were deprived of food during the night before the study.
[1613] [1613] 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 water or DMSO: water [10:90] in a dosage volume of 5 ml / kg and administered orally.
[1614] [1614] Serial blood samples (about 120-300 μL) were collected from each animal at each of the 8 moments after the dose (0.083, 0.25, 0.5, 1, 2, 4, 8 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. The PK parameters were generated from LC-MS / MS data using the Dotmatics or Phoenix WinNonlin 6.3 software. Dose No. AUC T½ (hr) Vdss Cl Example (mg / kg) (ng hr / mL) (L / kg) (mL / min · kg) 1 1 1949.4 1.2 0.58 8.5 6 1 2344.0 2.7 0.61 7.2 9 1 2669.0 3.9 0.63 6.5 18 1 1531.6 0.9 0.42 10.9 31 1 2753.6 4.5 0, 47 6.1 37 1.46 2247.9 2.1 0.59 10.8 41 1 1853.9 2.9 0.78 9.1 45 0.66 703.1 3.3 2.06 15.6 46 1 2077.2 1.2 0.45 8.2 70 1.86 2552.9 1.7 0.53 12.1 76 1 2647.5 1.0 0.25 6.3 94 2.09 1407, 8 1.1 1.62 25.2 99 1 1670.9 0.6 0.42 10.0 109 1 1732.0 1.3 0.64 9.6 153 1 510.7 1.1 1.21 32 , 6 156 1 1518.0 1.0 0.31 11.0 Table 2: PK data (intravenous administration)
[1615] [1615] As is evident from the results shown in Table 1, surprisingly, despite 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.
[1616] [1616] 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 compounds prior art.
[1617] [1617] It will be understood that the present invention has been described above for 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 (23)
[1]
1. Compound of formula (I):
O O Q S R2 1
R N N
H H Formula (I) characterized by the fact that: Q is selected from O or S; R1 is a non-aromatic heterocyclic group comprising at least one ring nitrogen atom, where R1 is attached to the sulfonylurea group sulfur atom by a ring carbon atom and where R1 can optionally be substituted; and R2 is a cyclic group substituted at position a, where R2 can optionally be additionally substituted.
[2]
2. A compound according to claim 1, characterized by the fact that R1 is a monocyclic or bicyclic non-aromatic heterocyclic group, in which R1 can be optionally substituted.
[3]
3. A compound according to claim 2, characterized by the fact that R1 is a 4, 5, 6 or 7 membered monocyclic non-aromatic heterocyclic group or a 7, 8, 9 or 10 membered non-aromatic heterocyclic group, where R1 can be replaced.
[4]
Compound according to any one of claims 1 to 3, characterized in that the heterocyclic group of R1 is fully saturated.
[5]
Compound according to any one of claims 1 to 4, characterized in that R1 comprises one, two or three atoms of nitrogen, oxygen or sulfur in the ring.
[6]
6. Compound according to claim 5, 1 characterized by the fact that R comprises one or two nitrogen or oxygen atoms in the ring.
[7]
7. Compound according to claim 6, characterized by the fact that R1 comprises one or two nitrogen atoms in the ring.
[8]
8. A compound according to any one of claims 1 to 7, characterized by the fact that R1 is selected from:
O O
THE
NH
NH NH
NH NH
NH
O O O O O
NH HN NH HN NH HN NH HN NH
O O
HN
N HN
H N where R1 is linked to the sulfonyl group of sulfonylurea by a carbon atom in the non-aromatic ring and where R1 can optionally be substituted or additionally substituted.
[9]
Compound according to any one of claims 1 to 8, characterized in that R1 is substituted by one or more substituents independently selected 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; -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; -NRβ-Rα-N (Rβ) 2; a C3-C7 cycloalkyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a C3-C7 cycloalkenyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a 3- to 7-membered non-aromatic heterocyclic group optionally substituted by C1-C6 alkyl or C1-C3 haloalkyl groups; oxo (= O); or a C1-C4 alkylene bridge; 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 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 where each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and where any -Rβ optionally can be replaced by one or more C1- groups C3 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, -O (C1-C3 alkyl), halo, -CN, -C≡CH or oxo (= O).
[10]
10. A compound according to claim 9, characterized by the fact that R1 is substituted on one or more nitrogen atoms in the ring by a substituent independently selected 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; -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; a C3-C7 cycloalkyl group optionally substituted by one or more groups
C1-C3 alkyl or C1-C3 haloalkyl; a C3-C7 cycloalkenyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; (CH2) m (CH2) m 
N R (CH2) n; (CH2) n; oxo (= O); or a C1-C4 alkylene bridge; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains 1 to 6 carbon atoms in its main chain and where the alkylene, alkenylene or alkynylene group can optionally be replaced by one or more halo and / or -Rβ groups; where each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and where any -Rβ can optionally be substituted by one or more C1-C3 alkyl groups , C1-C3 haloalkyl, C3-C7 cycloalkyl, -O (C1-C3 alkyl), halo, - CN, -C≡CH or oxo (= O); wherein each -Rδ is independently selected from a C1-C6 alkyl or C1-C3 haloalkyl group; where each m is independently selected from 1, 2 or 3; and where each n is independently selected from 1, 2 or 3.
[11]
A compound according to any one of claims 1 to 10, 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.
[12]
A compound according to claim 11, characterized by the fact that R2 is an aryl or heteroaryl group, in which the aryl or heteroaryl group is substituted in the α and α 'positions, and in which R2 can optionally be additionally substituted.
[13]
13. A compound according to claim 12, 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 in the positions α, β and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl is fused to the aryl or heteroaryl group through positions α ', β', and where R2 can optionally be additionally substituted.
[14]
Compound according to any one of claims 1 to 10, characterized in that R2 is a cyclic group substituted at positions α and α ', in which R2 can optionally be additionally substituted.
[15]
15. A compound according to any one of claims 1 to 14, characterized by the fact that Q is O.
[16]
16. A compound characterized by the fact that it is selected from the group consisting of:
O O O
s
N N
H H
N
O O O
s
N N
H H
N
O O O
s
N N
H H
N
THE
O O O
s
N N
H H
HN
O O O
s
N N
H H H
N N
THE
O O O
s
N N
H H
N Et
O O O
s
N N
H H
N
THE
O O O
s
N N
H H F3C N
THE
O O O
s
N N
H H
N Et
O O O
s
N N
H H
N
THE
O O O
s
N N
H H
N
THE
O O O
s
N N
H H
N MeO
THE
O O O
s
N N
H H MeO N
THE
O O O
s
N N
H H
NC N
O O O
s
N N
H H
N
O O O
s
N N N
H H
O N O
O O O n-hex S
N N N
H H
O N O
H
O O O
s
N N
N H H
O O O
s
N N
H H
N
O O O
s
N N
H H
N
THE
O O O
s
The N N
H H
N MeO
O O O
s
N N
H H
N
F
O O O
s
N N
H H
N
O O O
s
N N
H H
N
N Et
O O O
s
N N
H H
N
THE
O O O
s
N N
H H EtHN N
THE
O O O O
s
N N N N
H H H
O O O
s
N N
H H MeHN N
THE
O O O
s
N N
H H
N
s
O O
O O O
s
N N
H H
N EtHN
THE
O O O O
O O
S S
N N N N
H H H H
N N Et O
O O O
O O O
s
N N S
H H N N
H H
N
N
N O H CH2F
O O O O O O
S S
N N N N
H H H H
N N
H
O O O
O O O S
N N
S H H
N N
H H N
Grandson
O O O
s
N N
H H
N
O O O
s
N N
H H
N Me2N
THE
O O O
s
N N
H H O O O
N S
N N
HN H H
O O O
s
N N
H H
N
O O O
s
N N
H H
N
N
O O O
s
N N
H H
N
O O O
s
N N
N H H
O O O
s
N N
H H
N
O O O
s
N N
H H
N
O O O
s
N N
H H Me2N N
THE
O O O
s
N N
H H
N
N
O O O
s
N N
H H
N
O O O
s
N N
H H
N
O O O
s
N N
N H H
O O O
s
N N N
H H
O O O
s
N N
H H F3C N
O O O O
s
N N
N H H
O O O
s
N N
H H
N
O O O
s
N N
H H
N
O O O
s
N N
O N H H
THE
O O O
s
N N
N H H
O O O
s
N N
N H H
N
O O O
s
N N
O N H H
O O O
s
N N
N H H
THE
O O O
s
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s
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s
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s
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N H H Cl
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NH NH N
N
NH NH
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O O O S N3 O S F
NH NH F
N N
NH NH F
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NH N NH N
NH NH
NH
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NH NH
NH NH
THE
N
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NH
NH
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NH NH
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N N N N Br
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THE
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NH NH
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NH
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NH
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NH
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NH
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NH H2N 1-2
THE
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THE
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N
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NH NH
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HN
NH
N
THE
The S
THE
NH
NH
F
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NH NH
NH NH
N
THE
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THE
NH
NH
N N OH
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NH NH
NH NH
N
THE
The S
THE
NH
NH
Si
N N OH
O O
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OH
N
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NH
NH
N
N
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THE
N
THE
The S
F O
NH
N O O NH
s
N N
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HN
N O HN
THE
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THE
NH
N
NH
N
HN
HN HN
THE
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N
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THE
HN
HN
THE
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HN
THE
S O O Si
AT THE
O O O
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N N
N H H
HO
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H H H H
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Y N Y N
N H H N H H N CN N OMe
N N
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F
HN HN F
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OH OH
N NC N O
N
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THE
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N
THE
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S F HN
N
N HN F
H N
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NC
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N HN N HN
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N H S
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N
N NC N
F
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THE
s
N N
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N
The N
O O O
S F
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Y N H
N N
H H
N
The N N
F
O O
THE
s
N N
H H
N
NC N
N
O O
THE
s
N N
H H
N
The N
N
F
O O
THE
HN O
The S
S HN F N N
The H H
N N N
The NC N
N
F
F O O
O O
O O S
Y N N
N H H
N
H H
The N N
The N
The N
F
O O
THE
s
N N
H H
N
N
F
O O O
S NH N
N
H
N
F
O O O
S NH N
N
H
N
O O O
s
N N N
H H
The N
AT THE
O O O
s
N N
H H
N
THE
AT THE
O O O O O O
Y N Y
N N N N
H H H H
N O N
THE
O O O
s
O O O N N
S H H
N N O N
H H
AT THE
OH
O O O
s
N N O O O
H H
s
O N N N
H H
The N
N
N N
O O S O
S O
HN O
HN
HN F
HN O Cl
N
N
THE
S O
THE
HN
HN
THE
N
N
N
THE
S O
O O
HN
S O
The HN
HN
HN
NC
N
N
THE
S O
THE
HN
HN F
THE
N
D D
N D
D
D N
THE
S O
O O
HN
S O
HN O
HN
HN
N
N
THE
S O
THE
HN
HN
N
THE
S O
THE
HN
HN e.
[17]
17. Pharmaceutically acceptable salt, solvate or prodrug characterized by the fact that it is of a compound according to any one of claims 1 to 16.
[18]
Pharmaceutical composition characterized by the fact that it comprises a compound according to any one of claims 1 to 16, or a salt, solvate or prodrug, according to claim 17, and a pharmaceutically acceptable excipient.
[19]
A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or prodrug according to claim 17, or a pharmaceutical composition according to claim 18, characterized in that which is for medical use.
[20]
20. A pharmaceutically acceptable compound, salt, solvate, prodrug or pharmaceutical composition according to claim 19 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.
[21]
21. A pharmaceutically acceptable compound, salt, solvate, prodrug or pharmaceutical composition according to claim 19 or 20, for use in the treatment or prevention of a disease, disorder or condition, characterized by the fact that 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; (xvi) allodynia; and (xvii) any disease in which an individual has been determined to have a germline or somatic non-silent mutation in NLRP3.
[22]
22. A pharmaceutically acceptable compound, salt, solvate, prodrug or pharmaceutical composition according to claim 19 or 20, for use in the treatment or prevention of a disease, disorder or condition, characterized by the fact that the disease, disorder or condition is selected from: (i) cryopyrin-associated periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii) family cold 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).
[23]
23. Method of inhibiting NLRP3, the method characterized by the fact that it comprises the use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or prodrug according to claim 17 , or a pharmaceutical composition according to claim 18, for inhibiting NLRP3.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

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

---

FR3046933B1|2016-01-25|2018-03-02|Galderma Research & Development|NLRP3 INHIBITORS FOR THE TREATMENT OF INFLAMMATORY SKIN CONDITIONS|

---

WO2017140778A1|2016-02-16|2017-08-24|The University Of Queensland|Sulfonylureas and related compounds and use of same|

---

AU2017253937B2|2016-04-18|2021-08-05|Novartis Ag|Compounds and compositions for treating conditions associated with NLRP activity|WO2016131098A1|2015-02-16|2016-08-25|The University Of Queensland|Sulfonylureas and related compounds and use of same|

---

PE20191615A1|2017-01-23|2019-11-05|Genentech Inc|CHEMICAL COMPOUNDS AS INHIBITORS OF INTERLEUQUIN-1 ACTIVITY|

---

BR112020001476A2|2017-07-24|2020-09-15|Novartis Inflammasome Research, Inc.|compounds and compositions to treat conditions associated with nlrp activity|

---

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

---

US20200407340A1|2018-03-02|2020-12-31|Inflazome Limited|Sulfonamide derivates as nlrp3 inhibitors|

---

EP3759102A1|2018-03-02|2021-01-06|Inflazome Limited|Novel compounds|

---

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

---

WO2021002887A1|2019-07-02|2021-01-07|Novartis Inflammasome Research, Inc.|Gut-targeted nlrp3 antagonists and their use in therapy|

---

CN112654350A|2018-07-03|2021-04-13|诺华股份有限公司|Methods of treating a subject resistant to a TNF inhibitor or selecting a treatment for said subject using an NLRP3 antagonist|

---

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

---

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

---

WO2020157069A1|2019-01-28|2020-08-06|NodThera Limited|Amino heterocyclic compounds and uses thereof|

---

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

---

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

---

CN111848461A|2019-04-29|2020-10-30|苏州大学|NLRP3 inflammasome inhibitor and preparation method and application thereof|

---

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|

---

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

---

US20210292336A1|2020-03-16|2021-09-23|Zomagen Biosciences Ltd|Nlrp3 modulators|

---

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:

---

申请号 | 申请日 | 专利标题

---

GB1710943.0|2017-07-07|

---

GBGB1710943.0A|GB201710943D0|2017-07-07|2017-07-07|Novel Compounds|

---

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

---

GB1713082.4|2017-08-15|

---

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

---

GB1713079.0|2017-08-15|

---

GB1718563.8|2017-11-09|

---

GB1718561.2|2017-11-09|

---

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

---

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

---

GB1721726.6|2017-12-22|

---

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

---

PCT/EP2018/068077|WO2019008025A1|2017-07-07|2018-07-04|Novel sulfonamide carboxamide compounds|

---