sulfonylureas and sulfonylthioureas as inhibitors of vnlrp3

专利摘要:
The present invention relates to sulfonylureas and sulfonylthioureas comprising a 5-membered heteroaryl ring containing nitrogen attached to the sulfonyl group, wherein the heteroaryl ring is replaced by a nitrogen-containing group R1, where R1 contains from 1 to 7 atoms that are not hydrogen or halogen. 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:BR112020003014A2
申请号:R112020003014-7
申请日:2018-08-15
公开日:2020-07-28
发明作者:Matthew Cooper；Jokin Carrillo Arregui；David Miller；Angus Macleod；Stephen Thom；Stephen St-Gallay；Jonathan Shannon；Thomas Alanine；Stuart Onions；Ian STRUTT
申请人:Inflazome Limited；
IPC主号:

专利说明:

[0001] [0001] The present invention relates to sulfonylureas and sulfonylthioureas comprising a 5-membered heteroaryl ring containing nitrogen attached to the sulfonyl group, wherein the heteroaryl ring is replaced by a group R1 containing nitrogen, where R1 contains from 1 to 7 atoms other than hydrogen or halogen, and associated salts, solvates, prodrugs and pharmaceutical compositions. The present invention also relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, mainly by inhibiting NLRP3. FUNDAMENTALS
[0002] [0002] The NOD-like receptor family (NLR), the inflammasome of protein 3 containing the pyrin domain (NLRP3) is a component of the inflammatory process, and its aberrant activity is pathogenic in hereditary diseases such as periodic syndromes associated with crypirin (CAPS ) and complex diseases like multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.
[0003] [0003] NLRP3 is an intracellular signaling molecule that detects many factors derived from pathogens, environmental and host derivatives. After activation, NLRP3 binds to a particle-like 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 cysteine-protease caspase-1 to form a complex called inflammasome. This results in the activation of caspase-1, which cleaves the parental forms of the pro-inflammatory cytokines IL-1β and IL-18 (called pro-IL-1 and pro-IL-18, respectively) to activate these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC particle can also recruit and activate caspase-8, which can process pro-IL-1 and pro-IL-18 and trigger apoptotic cell death.
[0004] [0004] Caspase-1 cleaves pro-IL-1 and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. By controlling the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmine molecules, such as IL-33 and protein 1 of 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 IL-17 production 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 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 NLRP3 activation, but not NLRC4 or NLRP1. Other weak NLRP3 inhibitors previously characterized include parthenolide, 3,4-methylenedioxy-β-nitrostyrene and dimethyl sulfoxide (DMSO), although these agents have limited potency and are non-specific.
[0010] [0010] Current treatments for diseases related to NLRP3 include biological agents that target IL-1. These are the anakinra recombinant IL-1 receptor antagonist, the neutralizing IL-1β cannabinumab antibody and the soluble decoy IL-1 receptor rilonacept. These approaches have proven to be successful in the treatment of CAPS, and these biological agents have been used in clinical trials for other diseases associated with IL-1β.
[0011] [0011] Some compounds containing diaylsulfonylureas have been identified as cytokine release inhibiting drugs (CRIDs) (Perregaux et al .; J. Pharmacol. Exp. Ther. 299, 187-197, 2001). CRIDs are a class of compounds containing diarylsulfonylurea that inhibit post-translational processing of IL-1β. Post-translational processing of IL-1β is accompanied by activation of caspase-1 and cell death. CRIDs arrest activated monocytes so that caspase-1 remains inactive and plasma membrane latency is preserved.
[0012] [0012] Certain sulfonylurea-containing compounds are also disclosed as NLRP3 inhibitors (see, for example, Baldwin et al., J. Med. Chem., 59 (5), 1691-1710, 2016; and WO 2016/131098 A1, WO 2017/129897 A1, WO 2017/140778 A1, WO 2017/184604 A1, WO 2017/184623 A1, WO 2017/184624 A1, WO 2018/136890 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 this specification, a "hydrocarbyl" substituent group or a hydrocarbyl moiety in a substituent group includes only carbon and hydrogen atoms, but, unless otherwise stated, does not include hetero atoms, such as N, O or S, in your carbon skeleton. A hydrocarbyl group / moiety 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 hetero atoms, such as N, O or S , in its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups / moieties and combinations of all these groups / moieties. Typically, a hydrocarbyl group is a C1-C20 hydrocarbyl group. More typically, a hydrocarbyl group is a C1-C15 hydrocarbyl group. More typically, a hydrocarbyl group is a C 1- C10 hydrocarbyl group. A "hydrocarbilene" group is defined in the same way as a divalent hydrocarbyl group.
[0016] [0016] An "alkyl" substituent group or an alkyl moiety in a substituent group can be straight-chain (i.e. straight-chain) or branched. Examples of alkyl groups / moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups / moieties. Unless 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 / moieties include ethylene, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl groups and moieties 4-hexadienyl. Unless otherwise specified, the term "alkenyl" does not include "cycloalkenyl". Typically, an alkenyl group is a C2-C12 alkenyl group. More typically, an alkenyl group is a C2-C6 alkenyl group. An "alkenylene" group is similarly defined as a divalent alkenyl group.
[0018] [0018] An "alkynyl" substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl moiety or moiety with one or more carbon-carbon triple bonds. Examples of alkynyl groups / moieties include ethinyl, propargyl, but-1-inyl and but-2-inyl groups / moieties. 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 moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated (including aromatic) and may include one or more hetero atoms, for example, N, O or S, in your carbon skeleton. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups, as discussed below. A cyclic group can be monocyclic, bicyclic (for example, bridged, fused or spiro) or polycyclic. Typically, a cyclic group is a cyclic group with 3 to 12 members, which means that it contains 3 to 12 ring atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means that it contains 3 to 7 ring atoms.
[0020] [0020] A "heterocyclic" substituent group or a heterocyclic moiety in a substituent group refers to a cyclic moiety or moiety including one or more carbon atoms and one or more (such as one, two three or four) hetero atoms, for example , N, O or S, in the ring structure. Examples of heterocyclic groups include heteroaryl groups, as discussed below, and non-aromatic heterocyclic groups such as azetinyl, azetidinyl, oxetanyl, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, pyridine, pyrolanyl, pyrolanyl, dioxolanil, pyrolanil, pyrolanil, pyridine, pyrolanil, pyridine, pyrolanyl, pyridine, pyrolanyl, pyridine. -hydropyranyl, thianyl, piperazinyl, dioxanil, morpholinyl and thiomorphoryl.
[0021] [0021] 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 cyclohexyl. Unless otherwise indicated, a cycloalkyl substituting group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
[0022] [0022] A "cycloalkenyl" substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring with one or more carbon-carbon double bonds and containing, for example, 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex-1,3-dien-1-yl. Unless otherwise indicated, a cycloalkenyl substituting group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
[0023] [0023] An "aryl" substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring. The term "aryl" includes monocyclic aromatic hydrocarbons and 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".
[0024] [0024] A "heteroaryl" substituent group or a heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety. The term "heteroaryl" includes monocyclic aromatic heterocycles and 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 / portions 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
[0025] [0025] For the purposes of this specification, where a combination of portions is referred to as a group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alquinylaryl, the last portion mentioned contains the atom by which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl.
[0026] [0026] For the purposes of this specification, in an optionally substituted group or portion: (i) each hydrogen atom may optionally be substituted by a group selected independently 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; - β β β β β β α β α C (= NR) NHR; -C (= NR) N (R) 2; -C (= NOH) R; -C (N2) R; -R -C (= NH) R; -R - C (= NH) NH2; -Rα-C (= NH) NHRβ; -Rα-C (= NH) N (Rβ) 2; -Rα-C (= NRβ) Rβ; -Rα- C (= NRβ) NHRβ; -Rα-C (= NRβ) N (Rβ) 2; -Rα-C (= NOH) Rβ; -Rα-C (N2) Rβ; -NH-CHO; - NRβ-CHO; -NH-CORβ; -NRβ-CORβ; -CONH2; -CONHRβ; -CON (Rβ) 2; -Rα-NH-CHO; -Rα-NRβ-CHO; -Rα-NH-CORβ; -Rα-NRβ-CORβ; -Rα-CONH2; -Rα-CONHRβ; -Rα- CON (Rβ) 2; -O-Rα-OH; -O-Rα-ORβ; -O-Rα-NH2; -O-Rα-NHRβ; -O-Rα-N (Rβ) 2; -O-Rα- N (O) (Rβ) 2; -O-Rα-N + (Rβ) 3; -NH-Rα-OH; -NH-Rα-ORβ; -NH-Rα-NH2; -NH-Rα-NHRβ; - NH-Rα-N (Rβ) 2; -NH-Rα-N (O) (Rβ) 2; -NH-Rα-N + (Rβ) 3; -NRβ-Rα-OH; -NRβ-Rα-ORβ; - NRβ-Rα-NH2; -NRβ-Rα-NHRβ; -NRβ-Rα-N (Rβ) 2; -NRβ-Rα-N (O) (Rβ) 2; -NRβ-Rα- N + (Rβ) 3; -N (O) Rβ-Rα-OH; -N (O) Rβ-Rα-ORβ; -N (O) Rβ-Rα-NH2; -N (O) Rβ-Rα-NHRβ; - N (O) Rβ-Rα-N (Rβ) 2; -N (O) Rβ-Rα-N (O) (Rβ) 2; -N (O) Rβ-Rα-N + (Rβ) 3; -N + (Rβ) 2-Rα-OH; - N + (Rβ) 2-Rα-ORβ; -N + (Rβ) 2-Rα-NH2; -N + (Rβ) 2-Rα-NHRβ; -N + (Rβ) 2-Rα-N (Rβ) 2; or - N + (Rβ) 2-Rα-N (O) (Rβ) 2; and / or (ii) any two hydrogen atoms attached to the same atom can optionally be replaced by a substituent linked 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 moiety, may optionally be substituted by a bridged substituent independently selected from -O-, -S-, -NH -, -N = N-, -N (Rβ) -, -N (O) (Rβ) -, -N + (Rβ) 2- or -Rα-;
[0027] [0027] Typically, the compounds of the present invention comprise at most one group of quaternary ammonium such as -N + (Rβ) 3 or -N + (Rβ) 2-.
[0028] [0028] Where reference is made to a group-Rα-C (N2) Rβ, what is intended is:
[0029] [0029] Typically, in an optionally substituted portion or group: (i) each hydrogen can be optionally substituted by a group independently selected from halo; -CN; -NO2; -N3; -Rβ; -OH; -ORβ; -Rα- halo; -Rα-CN; -Rα-NO2; -Rα-N3; -Rα-Rβ; -Rα-OH; -Rα-ORβ; -SH; -SRβ; -SORβ; - SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; - Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -
[0030] [0030] Alternatively, in the optionally substituted β groups or portions defined immediately above, each-R can be selected independently from a cyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 or any other -Rβ-linked group to the same nitrogen atom it can, together with the nitrogen atom to which they are attached, form a cyclic C2-C7 group, in which any -Rβ can optionally be replaced by one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, -O (C1-C4 alkyl), -O (C1-C4 haloalkyl), -O (C3-C7 cycloalkyl), -O (C3-C7 halocycloalkyl), halo, -OH , -NH2, -CN, -C≡CH, oxo (= O), or a 4- to 6-membered heterocyclic group.
[0031] [0031] More typically, in an optionally substituted moiety or group: (i) each hydrogen atom can be optionally substituted by a group selected independently from halo; -CN; -NO2; -N3; -Rβ; -OH; -ORβ; - Rα-halo; -Rα-CN; -Rα-NO2; -Rα-N3; -Rα-Rβ; -Rα-OH; -Rα-ORβ; -SH; -SRβ; -SORβ; - SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; - Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; - N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα-COORβ; or -Rα-OCORβ; and / or (ii) any two hydrogen atoms attached to the same carbon atom 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 moiety, may optionally be substituted by a bridged substituent independently selected from -O-, -S-, -NH -, -N (Rβ) - or -Rα-; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and where each -Rβ is independently selected from a cyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 group, and where any -Rβ can be optionally substituted by one or more C 1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O (C1-C4 alkyl), -O (C1-C4 haloalkyl), -O (C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -C≡CH, oxo (= O), or 4- to 6-membered heterocyclic group.
[0032] [0032] Alternatively, in the optionally substituted groups or portions defined immediately above, each -Rβ can be selected independently from a cyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 or any other linked -Rβ group to the same nitrogen atom it can, together with the nitrogen atom to which they are attached, form a cyclic C2-C7 group, in which any -Rβ can optionally be replaced by one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, -O (C1-C4 alkyl), -O (C1-C4 haloalkyl), -O (C3-C7 cycloalkyl), -O (C3-C7 halocycloalkyl), halo, -OH , -NH2, -CN, -C≡CH, oxo (= O), or a 4- to 6-membered heterocyclic group.
[0033] [0033] More typically, in an optionally substituted moiety or group: (i) each hydrogen atom can be optionally substituted by a group selected independently from halo; -CN; -Rβ; -OH; -ORβ; -Rα-halo; - Rα-CN; -Rα-Rβ; -Rα-OH; -Rα-ORβ; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; - SO2NHRβ; -SO2N (Rβ) 2; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; - Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα- N (Rβ) 2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα- COOH; -Rα-COORβ; or -Rα-OCORβ; and / or (ii) any two hydrogen atoms attached to the same carbon atom 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 moiety, may optionally be substituted by a bridged substituent independently selected from -O-, -S-, -NH -, -N (Rβ) - or -Rα-; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and where each -Rβ is independently selected from a cyclic group C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6, and where any -Rβ can be optionally substituted by a C1-C4 alkyl, halo , -OH, or 4- to 6-membered heterocyclic group.
[0034] [0034] Alternatively from the optionally substituted groups or portions defined immediately above, each -Rβ can be selected independently from a cyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 group, or any two -Rβ linked to the same nitrogen atom they can, together with the nitrogen atom to which they are attached, form a C2-C7 cyclic group, where any -Rβ can be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, halo, -OH, or 4- to 6-membered heterocyclic group.
[0035] [0035] 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.
[0036] [0036] Unless otherwise specified, any divalent bridge substituent (for example, -O-, -S-, -NH-, -N = N-, -N (Rβ) -, -N (O) (Rβ) -, -N + (Rβ) 2- or - Rα-) of an optionally substituted group or portion (for example, R 1) must be attached only to the specified group or portion and cannot be attached to a second group or potion (for example, R2), even though the second group or portion can be optionally substituted.
[0037] [0037] The term "halo" includes fluorine, chlorine, bromine and iodine.
[0038] [0038] Unless otherwise specified, where a group is prefixed by the term "halo", such as a haloalkyl or halomethyl group, it should be understood that the group in question is replaced by one or more halo groups independently selected from fluoro, chloro , bromine and iodine. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution in the corresponding group without the prefix halo. For example, a halomethyl group can contain one, two or three halo substituents. A haloethyl or halophenyl group can contain one, two, three, four or five halo substituents. Likewise, unless otherwise specified, where a group is prefixed by a specific halo group, it must be understood that the group in question is replaced by one or more specific halo groups. For example, the term "fluoromethyl" refers to a methyl group substituted by one, two or three fluoro groups.
[0039] [0039] Unless otherwise indicated, where it is said that a group is "substituted with halo", it should be understood that the group in question is replaced by one or more halo groups selected independently from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution in the group said to be substituted by halo. For example, a halo-substituted methyl group may contain one, two or three halo substituents. A halo-substituted ethyl group or halo-substituted phenyl may contain one, two, three, four or five halo substituents.
[0040] [0040] 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.
[0041] [0041] Where reference is made to a hydrocarbyl or another 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:
[0042] [0042] When reference is made to a CH2- group in the main chain of a hydrocarbyl or another group being replaced by a -N (O) (Rβ) - or - N + (Rβ) 2- group, what is intended is that : OR
[0043] [0043] 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 parent group replaced 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 C x-Cy group. For example, a morpholinyl group should be considered a C4 heterocyclic group, not a C6 heterocyclic group.
[0044] [0044] As will be understood, ring A is a 5-membered heteroaryl group containing at least one nitrogen atom in the 5-membered ring structure.
[0045] [0045] In one embodiment, ring A is monocyclic. In such an embodiment, the groups R1 and, if present, R3 are monovalent, but can be or include cyclic groups. Examples of 5-membered monocyclic heteroaryl groups containing at least one nitrogen atom in the 5-membered ring structure include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl groups.
[0046] [0046] As indicated, W, X, Y and Z are each independently N, O, S, NH or CH, where at least one of W, X, Y and Z is N or NH. Typically, at least two of W, X, Y and Z are N or NH. Usually, at least one of W, X, Y and Z is CH. For the purposes of this specification, where it is stated that W, X, Y or Z can be NH or CH, it should be understood that this refers to W, X, Y and Z before it is possible to consider replacing R1 or R3 . Thus, where it is stated that W, X, Y or Z can be NH, it must be understood that W, X, Y or Z can be NH, N-R3 or N-R1 after the substitution is considered. Likewise, where it is stated that W, X, Y or Z can be CH, it must be understood that W, X, Y or Z can be CH, C-R3 or C-R1 after the substitution is considered.
[0047] [0047] In one embodiment, W, X, Y and Z are each independently N, NH or CH. Typically, in such an embodiment, at least two of W, X, Y and Z are N or NH and at least one of W, X, Y and Z is CH. Examples of such groups include imidazolyl, pyrazolyl and triazolyl groups. More typically, at least one of W and Z is CH. More typically, two from W, X, Y and Z are N or NH and two from W, X, Y and Z are CH. Thus, in this more typical embodiment, ring A is an imidazolyl or pyrazolyl group.
[0048] [0048] As will be understood, R1 can be directly linked to any ring atom represented by W, X, Y or Z. Generally, where R 1 is a monovalent group, -R1 is directly linked to X or Y. Typically, where R1 is a divalent group, -R1- is directly linked to at least one of X and Y. Generally, where R1 is a divalent group, -R1-is directly linked to X and Y.
[0049] [0049] For the purposes of this specification, in which it is stated that a first atom or group is "directly linked" to a second atom or group, it must be understood that the first atom or group is covalently linked to the second atom or group with no atom (s) or intervening groups present. So, for example, for the group - (C = ON (CH3) 2, the carbon atom of each methyl group is directly linked to the nitrogen atom and the carbon atom of the carbonyl group is directly linked to the nitrogen atom, but the carbon atom of the carbonyl group is not directly linked to the carbon atom of the two methyl groups.
[0050] [0050] In one embodiment, R1 is directly linked to a nitrogen atom in ring A. For example, where R1 is a monovalent group, -R1 can be directly linked to X where X is NH or -R1 can be directly linked to Y where Y is NH.
[0051] [0051] In another embodiment, R1 is directly linked to a carbon atom in ring A. For example, where R1 is a monovalent group, -R1 can be directly linked to X where X is CH or -R1 can be directly linked to Y where Y is CH.
[0052] [0052] In another embodiment, where R1 is a divalent group, -R1-is directly linked to a ring carbon atom and a nitrogen atom of the ring A. For example, -R1-can be directly linked to X and Y , where X is CH and Y is NH, or -R1- can be directly linked to X and Y, where X is NH and Y is CH.
[0053] [0053] Typically, in any mode where W, X, Y or Z is NH, NH is replaced by R1 or R3.
[0054] [0054] In one embodiment, R1 is a monovalent group comprising at least one nitrogen atom, where -R1 contains from 1 to 7 atoms other than hydrogen or halogen. Typically, -R1 contains 4 to 6 atoms other than hydrogen or halogen.
[0055] [0055] In another embodiment, where R1 is a monovalent group comprising at least one nitrogen atom, and typically where ring A is monocyclic, -R1 contains 2 to 6 atoms other than hydrogen or halogen. More typically in this modality, -R1 contains 3 to 5 atoms other than hydrogen or halogen.
[0056] [0056] Typically, where R1 is a monovalent group comprising at least one nitrogen atom, and especially where ring A is monocyclic, -R1 contains from 2 to 6 carbon atoms. More typically, -R1 contains 2, 3 or 4 carbon atoms.
[0057] [0057] In one embodiment, where R1 is a monovalent group, -R1 can be a saturated or unsaturated hydrocarbyl group, where the hydrocarbyl group can be straight or branched chain or be or include cyclic groups, where the hydrocarbyl group it can optionally be substituted, where the hydrocarbyl group includes at least one N heteroatom in its carbon backbone and where the hydrocarbyl group can optionally include one or more other N, O or S heteroatoms in its carbon backbone. When the hydrocarbyl group of R1 is optionally substituted, it is usually substituted by one or more groups selected from halo, -CN, -OH, -NH2, oxo (= O) and = NH.
[0058] [0058] More typically, where R1 is a monovalent group, -R1 is a saturated hydrocarbyl group, where the hydrocarbyl group is straight or branched, or is or includes cyclic groups, where the hydrocarbyl group can optionally be substituted by one or more groups selected from halo, -CN, -OH, -NH2 and oxo (= O), where the hydrocarbyl group includes at least one N heteroatom in its carbon backbone and where the hydrocarbyl group can optionally include another N or O heteroatom in its carbon skeleton. Optionally, where -R1 is a saturated hydrocarbyl group, and especially where ring A is monocyclic, the hydrocarbyl group is unsubstituted or substituted by one or more halo groups.
[0059] [0059] In one embodiment, where R1 is a monovalent group, -R1 is a straight or branched chain group, such as a straight or branched chain hydrocarbyl group, as described above. In one aspect of such an embodiment, ring A is a pyrazolyl group, typically a monocyclic pyrazolyl group.
[0060] [0060] In a modality, where R1 is a monovalent group, -R1 has the formula: R13 R14 R15 10 R
[0061] [0061] Normally, p is 1, q is 0 or 1 and r is 0, that is, -R1 has the formula: R13 R14 R13 10 10 R R
[0062] [0062] In one embodiment: R10 is hydrogen or a C1-C4 alkyl or C3-C4 cycloalkyl group; R11 is a C1-C4 alkyl or C3-C4 cycloalkyl group, or R11 together with any R13, R14 or R15 forms a C1-C4 alkylene group; or R10 and R11 together form a C2-C4 alkylene group; wherein any alkyl or alkylene group can optionally be substituted by one or more halo, -CN, -OH, oxo (= O), -OMe and / or -O-halomethyl groups, and where any cycloalkyl group can optionally be substituted by one or more halo, -CN, -OH, oxo (= O), methyl, halomethyl, - OMe and / or -O-halomethyl groups.
[0063] [0063] More typically: R10 is a C1-C3 alkyl group or a cyclopropyl group; R11 is a C1-C3 alkyl or cyclopropyl group, or R11 together with any of R13 or R14 forms a C1-C3 alkylene group; or R10 and R11 together form a C2-C4 alkylene group;
[0064] [0064] More typically still: R10 is a methyl or ethyl group; R11 is a methyl, ethyl, isopropyl or cyclopropyl group; or R10 and R11 together form a C2-C4 alkylene group; wherein any methyl, ethyl, isopropyl or alkylene group can optionally be substituted by one or more fluoro, -OH or oxo groups (= O), and any cyclopropyl group can optionally be substituted by one or more fluoro or -OH groups .
[0065] [0065] In one aspect of any of the above, R 10R11N- is monovalent. Typically, where R10R11N- is monovalent, R10R11N- contains 2 to 6 atoms other than hydrogen or halogen. More typically, where R10R11N- is monovalent, R10R11N- contains 3, 4 or 5 atoms other than hydrogen or halogen.
[0066] [0066] More typically, R10 and R11 are both methyl groups, or R10 and R11 together form a -CH2CH2- or -CH2CH2CH2- group.
[0067] [0067] In another typical modality, in which ring A is monocyclic: R10 is hydrogen or a C1-C3 alkyl or cyclopropyl group; R11 is a C1-C3 alkyl or cyclopropyl group, or R11 together with any of R13 or R14 forms a C1-C3 alkylene group; or R10 and R11 together form a C2-C4 alkylene group; wherein any alkyl or alkylene group can optionally be substituted by one or more fluoro, chloro, -CN, -OH, oxo (= O), -OMe and / or - OEt groups, where any cyclopropyl group can optionally be substituted by one or more fluoro, chloro, -CN, -OH, methyl, ethyl, -OMe and / or -OEt groups, and in which any methyl (Me) or ethyl (Et) group can optionally be substituted by one or more fluoro groups and / or chlorine.
[0068] [0068] Typically, in such a modality, p is 1, q is 0 or 1 and r is 0.
[0069] [0069] More typically in such a modality: R10 is hydrogen or a methyl or ethyl group; R11 is a methyl, ethyl, isopropyl or cyclopropyl group; or R10 and R11 together form a C2-C4 alkylene group; wherein any methyl, ethyl, isopropyl or alkylene group can optionally be substituted by one or more fluoro, -OH or oxo groups (= O), and any cyclopropyl group can optionally be substituted by one or more fluoro or -OH groups .
[0070] [0070] In one aspect of the above modality, R10R11N- is monovalent. Typically in such a modality, where R10R11N- is monovalent, R10R11N- contains 2 to 6 atoms other than hydrogen or halogen. More typically in such an embodiment, where R10R11N- is monovalent, R10R11N- contains 2, 3, 4 or 5 atoms other than hydrogen or halogen.
[0071] [0071] More typically in this modality, R10 is hydrogen or a methyl group and R11 is a methyl group.
[0072] [0072] In one embodiment, each R13, R14 and R15 is independently selected from hydrogen or a halo group, -OH, C1-C3 alkyl or -O- (C1-C3 alkyl) and / or any two R13, two R14 or two R15 can, together with the carbon atom to which they are attached, form a C = O group and / or any two R13, R14 or R15 can together form a C1-C3 alkylene group, where the C1-C3 group alkylene may optionally include an oxygen atom in its carbon backbone, and any alkyl or alkylene group may optionally be substituted by one or more halo, -OH or oxo (= O) groups. Alternatively or in addition, R11, together with any one of R13, R14 or R15, can form a C1-C4 alkylene group, wherein the C1-C4 alkylene group can optionally be substituted by one or more halo groups, -CN, - OH, oxo (= O), -OMe and / or -O-halomethyl.
[0073] [0073] In another embodiment, p is 1, q is 0 or 1 and r is 0, and each R 13 and R14 is independently selected from hydrogen or a fluoro, chloro, - CN, -OH, methyl, ethyl, -OMe or -OEt, and / or any two R13 or two R14 may, together with the carbon atom to which they are attached, form a C = O group and / or any two R13 or R14 may together form a C1-C2 group alkylene, where the C1-C2 alkylene group can optionally include an oxygen atom in its carbon backbone and where any methyl, ethyl or alkylene group can optionally be substituted by one or more fluoro, chloro, -OH or oxo groups ( = O). Alternatively or in addition, R11, together with any R13 or R14, can form a C1-C3 alkylene group, wherein the C1-C3 alkylene group can optionally be substituted by one or more fluoro, chloro, -CN, -OH, oxo (= O), -OMe and / or -OEt, where any -OMe or -OEt group can be optionally substituted with one or more fluoro or chloro groups.
[0074] [0074] More typically, p is 1, q is 0 or 1 and r is 0, R10R11N- is monovalent and each R13 and R14 is independently selected from hydrogen or a fluoro, methyl, ethyl, fluoromethyl or fluoroethyl group and / or two R 13 or two R14 can, together with the carbon atom to which they are attached, form a C = O or cyclopropyl group, wherein the cyclopropyl group can optionally be replaced by one or more fluoro groups.
[0075] [0075] Typically, in any of the above modalities, all or all, except one or two of R13, R14 and R15, are hydrogen or halogen. More typically, all or all, except one or two of R13, R14 and R15, are hydrogen or fluoro. More typically, all or all, except one or two of R 13, R14 and R15, are hydrogen.
[0076] [0076] Normally, where R10R11N- is monovalent, the group: R13 R14 R15
[0077] [0077] In another modality, where R1 is a monovalent group, -R1 has the formula:
[0078] Alternatively, in the above modality, R10, R11 and R12 may, together with the nitrogen atom to which they are attached, form a saturated heterocyclic group, such as a saturated C5-C8 heterocyclic group.
[0079] [0079] In one embodiment, R10R11R12N + - is monovalent. Typically, where R10R11R12N + - is monovalent, R10R11R12N + - contains 4 to 6 atoms, other than hydrogen or halogen. More typically, where R10R11R12N + - is monovalent, R10R11R12N + - contains 4 or 5 atoms other than hydrogen or halogen.
[0080] [0080] Typically, R12 is a C1-C4 alkyl or C3-C4 cycloalkyl group, where the alkyl group can optionally be substituted by one or more halos groups, -CN, -OH, oxo (= O), -OMe and / or -O- halomethyl and where the cycloalkyl group can optionally be substituted with one or more halo groups, - CN, -OH, oxo (= O), methyl, halomethyl, -OMe and / or -O-halomethyl.
[0081] [0081] In a typical embodiment, in which ring A is monocyclic, R12 is a C1-C3 alkyl group or a cyclopropyl, in which the alkyl group can optionally be replaced by one or more fluoro, chloro, -CN, - OH, oxo (= O) -OMe and / or -OEt, where the cyclopropyl group can optionally be replaced by one or more fluoro, chloro, -CN, -OH, methyl, ethyl, -OMe and / or -OEt groups and wherein any methyl (Me) or ethyl (Et) group can optionally be substituted by one or more fluoro and / or chloro groups.
[0082] [0082] More typically, R12 is a C1-C3 alkyl or cyclopropyl group, where the alkyl group can optionally be substituted by one or more fluoro, chloro, -CN, -OH, oxo (= O) and / or - groups OMe, in which the cyclopropyl group can optionally be substituted by one or more fluoro, chloro, -CN, -OH, methyl and / or -OMe groups, and in which any methyl group can optionally be substituted by one or more fluoro groups and / or chlorine.
[0083] [0083] More typically, R12 is a methyl, fluoromethyl, ethyl or fluoroethyl group.
[0084] [0084] More typically, R12 is a methyl group. More typically, where R12 is a methyl group, R10 and R11 are also methyl groups, i.e., R10R11R12N + - is Me3N + -.
[0085] [0085] In another modality, where R1 is a monovalent group, -R1 has the formula: R13 R14 R15
[0086] [0086] In another embodiment, where R1 is a monovalent group, -R1 has the formula: R13 R14 R15 R16 CCC R13 R14 R15 pqr where p, q, r, R13 R14 and R15 are as defined above, and where R16 is a 5- or 6-membered heteroaryl group, where the heteroaryl group contains at least one nitrogen atom in the 5- or 6-membered ring structure and where the heteroaryl group is optionally substituted with one or more halo groups, - CN, -OH, methyl, halomethyl, ethyl, haloethyl, -OMe and / or -O-halomethyl.
[0087] [0087] Typically, R16 is a 5- or 6-membered heteroaryl group, where the heteroaryl group contains one nitrogen atom and, optionally, a second nitrogen, oxygen or sulfur atom in the 5- or 6-membered ring structure. For example, R16 can be a pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group.
[0088] [0088] Typically, where the heteroaryl group of R16 is substituted, it is substituted by one or more chlorine, fluoro, methyl and / or -OMe groups, where any methyl group can optionally be substituted by one or more chlorine and / or groups or fluoro.
[0089] [0089] As will be understood, in any of the above modalities in which R1 is a monovalent group, -R1 must still contain from 1 to 7 atoms other than hydrogen or halogen.
[0090] [0090] In one embodiment, where R1 is a monovalent group, -R1 is selected from the group consisting of: THE THE O O O N
[0091] [0091] In another embodiment, R1 is a divalent group comprising at least one nitrogen atom, where -R1- contains 1 to 7 atoms other than hydrogen or halogen, and where -R1- is directly linked to any two W, X, Y or adjacent Z. Typically, where R 1 is a divalent group, -R1 contains 3 to 7 atoms other than hydrogen or halogen. More typically, where R1 is a divalent group, -R1- contains 5 to 7 atoms other than hydrogen or halogen.
[0092] [0092] For example, where R1 is a divalent group, -R1 can be a saturated or unsaturated hydrocarbilene group, where the hydrocarbilene group can be straight or branched chain or be or include cyclic groups, where the hydrocarbilene group can optionally be substituted, where the hydrocarbilene group includes at least one N heteroatom in its carbon backbone and where the hydrocarbilene group can optionally include one or more other N, O or S heteroatoms in its carbon backbone. When the hydrocarbilene group of R 1 is optionally substituted, it is usually substituted by one or more groups selected from halo, -CN, -OH, -NH2, oxo (= O) and = NH.
[0093] [0093] More typically, where R1 is a divalent group, -R1-is a saturated hydrocarbilene group, where the saturated hydrocarbilene group is straight or branched, where the saturated hydrocarbilene group can optionally be substituted by one or more groups selected from halo, - CN, -OH, - NH2 and oxo (= O), where the saturated hydrocarbilene group includes at least one N heteroatom in its carbon backbone and where the saturated hydrocarbilene group can optionally include another heteroatom N or O in its carbon skeleton.
[0094] [0094] In one embodiment, where R1 is a divalent group, -R1- is a C2-C5 alkylene group, where the alkylene group is replaced by a monovalent group -NR10R11 or a monovalent group R10R11R12N + -, where R10, R11 and R12 are as defined above, and wherein the alkylene group can optionally be further substituted with one or more halo, -CN, -OH, oxo (= O), -O-alkyl and / or -O-haloalkyl groups.
[0095] [0095] More typically, -R1- is a C3-C4 alkylene group, where the alkylene group is replaced by a monovalent group -NR10R11, where: R10 is hydrogen or a C1-C4 alkyl or C3-C4 cycloalkyl group; R11 is a C1-C4 alkyl or C3-C4 cycloalkyl group; or
[0096] [0096] More typically, -R1- is a C3-C4 alkylene group, in which the alkylene group is replaced by a monovalent group -NR10R11, in which: R10 is a methyl or ethyl group; R11 is a methyl, ethyl, isopropyl or cyclopropyl group; or R10 and R11 together form a C2-C4 alkylene group; wherein any methyl, ethyl, isopropyl or alkylene group can optionally be substituted by one or more fluoro, -OH or oxo groups (= O), and any cyclopropyl group can optionally be substituted by one or more fluoro or -OH groups .
[0097] [0097] In another modality, where R1 is a divalent group, -R1 has the formula: R18 R17 R19
[0098] [0098] Normally, s is 1 or 2 and t is 1 or 2.
[0099] [0099] In one embodiment: R17 is a C1-C4 alkyl or C3-C4 cycloalkyl group, or R 17 together with any 19 or any R or R form a C1-C4 alkylene group; each R18 and R19 is independently selected from hydrogen or a halo group, -OH, C1-C3 alkyl or -O- (C1-C2 alkyl) and / or any two R18 or two R19 bonded to the same carbon atom can together with the carbon atom to which they are attached form a C = O group and / or any two R 18 or two R19 attached to the same carbon atom can together form a C 12 -C 13 alkylene group; and wherein any alkyl or alkylene group can optionally be substituted by one or more halo, -CN, -OH, oxo (= O), -OMe and / or -O-halomethyl groups, and where any cycloalkyl group can optionally be replaced by one or more halo, -CN, -OH, oxo (= O), methyl, halomethyl, - OMe and / or -O-halomethyl groups.
[0100] [0100] More typically: R17 is a C1-C3 alkyl group or a cyclopropyl group; each R18 and R19 is independently selected from hydrogen or a fluoro, chloro, -OH, methyl, ethyl, -OMe or -OEt group and / or any two R18 or two R19 linked to the same carbon atom can, together with the carbon atom to which they are attached, form a C = O or cyclopropyl group; wherein the C1-C3 alkyl group can optionally be substituted with one or more fluoro, chloro, -OH, oxo (= O), -OMe and / or -OEt groups; wherein any cyclopropyl group can optionally be substituted by one or more fluoro, chloro, -OH or methyl groups; and wherein any methyl or ethyl group can optionally be substituted by one or more fluoro and / or chloro groups.
[0101] [0101] More typically still: R17 is a methyl, ethyl, isopropyl or cyclopropyl group; each R18 and R19 is independently selected from hydrogen or a fluoro, methyl or ethyl group and / or any two R18 or two R19 attached to the same carbon atom can, together with the carbon atom to which they are attached, form a group C = O or cyclopropyl; and any methyl, ethyl, isopropyl or cyclopropyl group can optionally be substituted by one or more fluoro groups.
[0102] [0102] As will be understood, in any of the above modalities in which R1 is a divalent group, -R1 must still contain from 1 to 7 atoms other than hydrogen or halogen.
[0103] [0103] In one embodiment, where R1 is a divalent group, -R1 is selected from the group consisting of: The NMe2 MeN MeN, e.
[0104] [0104] In one embodiment, R1 (monovalent or divalent) contains only atoms selected from the group consisting of carbon, hydrogen, nitrogen, oxygen and halogen atoms. In another embodiment, R 1 contains only atoms selected from the group consisting of carbon, hydrogen, nitrogen and halogen atoms.
[0105] [0105] In one embodiment, R1 comprises at least one nitrogen atom that is not directly linked to a sp2 hybridized carbon atom. Typically, R1 comprises at least one nitrogen atom that is not directly linked to a sp2 hybridized atom.
[0106] [0106] In another embodiment, no nitrogen atom within the R group is directly linked to a sp2 hybridized atom. 1
[0107] [0107] In an additional embodiment, no nitrogen atom within the R1 group is directly linked to a sp2 or sp3 hybridized atom.
[0108] [0108] In yet another embodiment, no oxygen or nitrogen atom within the R1 group is directly linked to a sp2 or sp3 hybridized atom.
[0109] [0109] In one embodiment, the R1 group does not include an aromatic group.
[0110] [0110] In one embodiment, the group R1 does not include an amide group. In another embodiment, the R1 group does not include a carbonyl group.
[0111] [0111] In an additional modality, the group: R1 W
[0112] [0112] Without wishing to be bound by theory, it is currently believed that where the group R1 does not include an amide group, and / or no nitrogen atom within the group R1 is directly linked to a sp2 hybridized atom, the compounds of the invention are particularly suitable for oral or intravenous administration due to its pharmacokinetic properties. This is thought to apply particularly where: (i) 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, heterocyclic ring, aryl or non-aromatic heteroaryl are fused to the aryl or heteroaryl group through the α ', β' positions, where R 2 can optionally be further substituted, as discussed below; or (ii) R2 is a fused aryl or fused heteroaryl group, in which a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group at positions α, β, where the aryl or heteroaryl group is still substituted in the α 'position by an alkyl or cycloalkyl group, and where R2 can optionally be further substituted; or
[0113] [0113] Normally, where the group R1 does not include an amide group, and / or no nitrogen atom within the group R1 is directly linked to a sp2 hybridized atom, R1 is a saturated hydrocarbyl group, where the hydrocarbyl group is chain linear or branched, or is or includes cyclic groups, in which the hydrocarbyl group can optionally be substituted by one or more groups selected from halo, -CN, -OH, -NH2 and oxo (= O), where the hydrocarbyl group includes at least one heteroatom N in its carbon backbone and the hydrocarbyl group may optionally include another N or O heteroatom in its carbon backbone. For example, in such an embodiment R 1 may be a saturated hydrocarbyl group, in which the saturated hydrocarbyl group is unsubstituted or optionally substituted by one or more fluoro and / or chlorine groups, in which the saturated hydrocarbyl group includes at least one N heteroatom in its carbon backbone and the saturated hydrocarbyl group may optionally include one or more additional N or O heteroatoms in its carbon backbone.
[0114] [0114] Normally, where the R1 group does not include an amide group, and / or no nitrogen atom within the R1 group is directly linked to a sp2 hybridized atom, no oxygen or nitrogen atom within the R 1 group is directly linked to a sp2 or sp3 hybridized atom.
[0115] [0115] Typically, where the R1 group does not include an amide group, and / or no nitrogen atom within the R1 group is directly linked to a sp2 hybridized atom, ring A is monocyclic.
[0116] [0116] Typically, where the R1 group does not include an amide group, and / or no nitrogen atom within the R1 group is directly linked to a sp2 hybridized atom, each R3, when present, contains from 1 to 6 atoms, except hydrogen or halogen, and each R3 is a saturated hydrocarbyl group, where the saturated hydrocarbyl group can be straight or branched, or be or include cyclic groups, where the saturated hydrocarbyl group can optionally be substituted by one or more halo groups and wherein the saturated hydrocarbyl group can optionally include one or two oxygen atoms in its carbon skeleton. Typically, m is 0 or 1.
[0117] [0117] In contrast, where the group R1 includes an amide group, it is currently believed that the compounds of the invention are particularly suitable for topical administration due to their pharmacokinetic properties.
[0118] [0118] For the purposes of this specification, an "amide group" is considered to be any group that comprises the structure: THE N.
[0119] [0119] Accordingly, the term "amide group" includes urea groups.
[0120] [0120] As stated above, m is 0, 1, 2 or 3. More typically, m is 0, 1 or 2. Usually, m is 0 or 1.
[0121] [0121] In one mode, m is 0.
[0122] [0122] Typically, where m is 0 or 1, ring A is monocyclic.
[0123] [0123] As will be understood, each R3-, when present, can be directly linked to any atom in the ring represented by W, X, Y or Z. Typically, each R3-, when present, is directly linked to X or Y. More typically, where m is 1 and R1 is monovalent, R1- is directly linked to one of X or Y and R3- is directly linked to the other of X or Y.
[0124] [0124] In any of the above modes, each R3 can be selected independently from a 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; - β β β β β β α β α C (= NR) NHR; -C (= NR) N (R) 2; -C (= NOH) R; -C (N2) R; -R -C (= NH) R; -R -
[0125] [0125] In one mode, each R3 is independently selected from a halo; -CN; -NO2; -N3; -Rβ; -OH; -ORβ; -Rα-halo; -Rα-CN; -Rα-NO2; -Rα-N3; -
[0126] [0126] In another modality, cadad R3 is independently selected from halo; -CN; -NO2; -N3; -Rβ; -OH; -ORβ; -Rα-halo; -Rα-CN; -Rα-NO2; -Rα- N3; -Rα-Rβ; -Rα-OH; -Rα-ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; - SO2NHRβ; -SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα- SO2NH2; -Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα- COOH; -Rα-COORβ; or -Rα-OCORβ; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and where each -Rβ is independently selected from a cyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 group, and where any -Rβ can be optionally substituted by one or more C 1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O (C1-C4 alkyl), -O (C1-C4 haloalkyl), -O (C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -C≡CH, oxo (= O), or 4- to 6-membered heterocyclic group.
[0127] [0127] Alternatively, each R3 can be independently selected from halo; -CN; -Rβ; -OH; -ORβ; -Rα-halo; -Rα-CN; -Rα-Rβ; -Rα- OH; -Rα-ORβ; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; - Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; -Rα- SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; -CORβ; - COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα-COORβ; or -Rα- OCORβ; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and where each -Rβ is independently selected from a cyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 group, and any -Rβ can be optionally substituted by a C1-C4 alkyl, halo , -OH, or 4- to 6-membered heterocyclic group.
[0128] [0128] In one modality, each R3 is monovalent. Alternatively or in addition, any R3, and any two adjacent W, X, Y or Z can together form a saturated or unsaturated cyclic group of 3 to 12 members fused to ring A, where the cyclic group fused to ring A can optionally be substituted . Thus, it will be understood that in such an embodiment that the group -R3- forms a divalent bridge substituent between two adjacent W, X, Y and Z. In such an embodiment, part or all of R3 can form the fused cyclic group. Typically, in such an embodiment, -R3- and any two adjacent W, X, Y or Z together form a 4- to 7-membered saturated or unsaturated cyclic group fused to ring A, where the cyclic group fused to ring A can optionally be replaced, so that ring A and the fused cyclic group together form a fused bicyclic group.
[0129] [0129] In any aspect of any of the foregoing modalities, R3 contains from 1 to 12 atoms other than hydrogen or halogen. More typically, R3 contains 1 to 7 atoms other than hydrogen or halogen. More typically, R3 contains 1 to 6 atoms other than hydrogen or halogen. More typically, R3 contains 1 to 3 atoms other than hydrogen or halogen.
[0130] [0130] In one embodiment, each R3 is independently a halo, -OH, -NO2, -NH2, -N3, -SH, -SO2H, -SO2NH2 group, or a saturated or unsaturated hydrocarbyl group, where the hydrocarbyl group can be straight or branched chain or be or include cyclic groups, where the hydrocarbyl group can optionally be substituted, and where the hydrocarbyl group can include one or more N, O or S heteroatoms in its carbon backbone.
[0131] [0131] In one embodiment, each R3 is a monovalent group and each R3 contains 1 to 7 atoms other than hydrogen or halogen. Typically in such an embodiment, R3 is a saturated or unsaturated hydrocarbyl group, where the hydrocarbyl group can be straight or branched, or be or include cyclic groups, where the hydrocarbyl group can optionally be substituted, and where the hydrocarbyl group it can optionally include one or more N, O or S heteroatoms in its carbon skeleton. When the hydrocarbyl group of R3 is optionally substituted, it is usually substituted by one or more groups selected from halo, -CN, -OH, -NH2, oxo (= O) and = NH.
[0132] [0132] More typically, each R3 contains 1 to 6 atoms, other than hydrogen or halogen, each R3 is a saturated hydrocarbyl group, where the saturated hydrocarbyl group can be straight or branched, or be or include cyclic groups , in which the saturated hydrocarbyl group can optionally be substituted by one or more groups selected from halo, -CN, -OH, - NH2 and oxo (= O), and in which the saturated hydrocarbyl group can optionally include one or two heteroatoms N or O in their carbon skeleton.
[0133] [0133] Even more typically, each R3 contains 1 to 6 atoms, other than hydrogen or halogen, each R3 is a saturated hydrocarbyl group, where the saturated hydrocarbyl group can be straight or branched, or be or include groups cyclic, in which the saturated hydrocarbyl group the group can optionally be replaced by one or more halo groups, and in which the saturated hydrocarbyl group can optionally include one or two oxygen atoms in its carbon skeleton.
[0134] [0134] More typically, each R3 is independently selected from a C1-C4 alkyl or C3-C4 cycloalkyl group, wherein any C1-C4 alkyl or C3-C4 cycloalkyl group can optionally be replaced by one or more fluoro and / or chlorine.
[0135] [0135] More typically, each R3 is independently selected from a methyl, ethyl, isopropyl or cyclopropyl group.
[0136] [0136] Alternatively or in addition, any group R3 can be another group R1, where R1 is as defined above. The other group R1 can be the same or different from the first group R1.
[0137] [0137] R2 is a cyclic group substituted at the α position, where R2 can optionally be further 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.
[0138] [0138] In an embodiment of the first aspect of the invention, R 2 is an aryl or heteroaryl group, in which the aryl or heteroaryl group is substituted in the α position and in which R2 can optionally be additionally substituted. Typically, R2 is a phenyl or a 5- or 6-membered heteroaryl group, where the phenyl or heteroaryl group is substituted in the α position and where R 2 can optionally be additionally 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, R 2 can be a substituted phenyl group at 2- and 6- positions or a substituted phenyl group at 2-, 4- and 6- positions.
[0139] [0139] In one embodiment, the phenyl or the parent 5- or 6-membered heteroaryl group of R2 can be selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl , isotazolyl, triazolyl or oxadiazolyl. Typically, the phenyl or the 5- or 6-membered parental heteroaryl group of R2 can be selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl or triazolyl. Typically, the phenyl or the parent 5- or 6-membered heteroaryl group of R2 can be selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazolyl.
[0140] [0140] As used in this document, the nomenclature α, β, α ', β' refers to the position of the atoms of a cyclic group, such as -R2, in relation to the point of attachment of the cyclic group to the rest of the molecule. For example, where -R2 is a 1,2,3,5,6,7-hexahydro-s-indacen-4-yl portion, the positions α, β, α 'and β' are as follows:    ''
[0141] [0141] For the avoidance of doubt, when it is stated that a cyclic group, such as an aryl or heteroaryl group, is substituted in the α and / or α 'positions, it should be understood that one or more hydrogen atoms in the α and / or positions α 'respectively are replaced by one or more substituents, like any optional substituent as defined above. Unless otherwise indicated, the term "substituted" does not include the replacement of one or more ring carbon atoms by one or more ring hetero atoms.
[0142] [0142] In another embodiment, R2 is a cyclic group substituted in positions α and α ', where R2 can optionally be additionally substituted. For example, R2 can be a non-aromatic cycloalkyl, cycloalkenyl or heterocyclic group substituted at the α and α 'positions.
[0143] [0143] In any of the above modalities, typical substituents at the α and / or α 'positions of the precursor cyclic group of R2 comprise a carbon atom. For example, typical substituents at positions α and / or α 'can be selected independently from the groups -R4, -OR4 and -COR4, where each R4 is independently selected from a cyclic C1-C6 alkyl, C2-C6 alkenyl group , C2-C6 alkynyl or C2-C6 and wherein each R4 is optionally substituted further 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 additionally substituted by one or more fluoro and / or chloro groups.
[0144] [0144] In one aspect of any of the above modalities, each substituent at positions α and α 'comprises a carbon atom.
[0145] [0145] Other typical substituents at the α and / or α 'positions of the precursor cyclic group of R2 may include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings that are fused to the precursor cyclic group through the α, β and / or groups α ', β' positions respectively. Such fused cyclic groups are described in more detail below.
[0146] [0146] In one embodiment, R2 is a fused aryl or fused heteroaryl group, where the aryl or heteroaryl group is fused to one or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings, where R2 can optionally be additionally substituted. Typically, a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group through the α, β positions. Typically, the aryl or heteroaryl group is also substituted at the α 'position, for example, by a substituent selected from -R4, -OR4 and -COR4, where each R4 is selected independently from a cyclic C1-C6 alkyl group, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 and wherein each R4 is optionally additionally substituted by one or more halo groups. Typically, in such an embodiment, R2 is bicyclic or tricyclic.
[0147] [0147] More typically, R2 is a fused phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group is fused to one or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings, where R2 can optionally be further substituted. Typically, a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 5- or 6-membered heteroaryl group at the α, β positions, to form a 4- to 6-membered fused ring structure. Typically, the phenyl or the 5- or 6-membered heteroaryl group is also substituted in the α 'position, for example, by a substituent selected from -R4, -OR4 and -COR4, where each R4 is independently selected from a group cyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 and wherein each R4 is optionally additionally substituted by one or more halo groups. Typically, in such an embodiment, R2 is bicyclic or tricyclic.
[0148] [0148] 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, non-aromatic heterocyclic, aryl or heteroaryl rings independently selected, where R2 2 can optionally be additionally 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, non-aromatic heterocyclic, fused aryl or heteroaryl ring has only two atoms and a common connection with the aryl or heteroaryl group. Normally, R 2 is tricyclic.
[0149] [0149] 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 in the α, β and a second cycloalkyl positions , 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 additionally substituted. Typically, in such an embodiment, R2 is tricyclic.
[0150] [0150] More typically, R2 is a fused phenyl or a 5- or 6-membered heteroaryl group, in which a first non-aromatic cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 5- or 6-membered heteroaryl group in positions α, β, so as to form a first 4- to 6-membered fused ring structure, and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to phenyl or to the 5- or 6 heteroaryl group with members through positions α ', β' so as to form a second fused ring structure of 4 to 6 members, where R2 can optionally be additionally substituted. Typically, in such an embodiment, R2 is tricyclic.
[0151] [0151] In one mode, -R2 has a formula selected from: Ra Rb A1 A1 Ra Rb Rc Rc Rc Rc
[0152] [0152] Normally, any ring containing A1 or A2 is a 5- or 6-membered ring. Typically, A1 and A2 are each independently selected from an optionally substituted straight chain alkylene group or an optionally substituted straight chain alkylene group, where one or two carbon atoms in the main chain of the alkylene or alkenylene group can optionally be replaced by one or two heteroatoms selected independently of nitrogen and oxygen. More typically, A1 and A2 are each independently selected from an optionally substituted straight chain alkylene group, in which a carbon atom in the main chain of the alkylene group can optionally be replaced by an oxygen atom. Normally, no heteroatom at A1 or A2 is directly linked to another ring heteroatom. Normally, A 1 and A2 are unsubstituted or substituted by one or more substituents independently selected from halo, -OH, -CN, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, -O (C1-C4alkyl) or -O (C1-C4 haloalkyl). More typically, A1 and A2 are unsubstituted or replaced by one or more fluoro and / or chlorine groups. Where R2 contains both groups A1 and A2, A1 and A2 can be the same or different. Normally, A1 and A2 are the same.
[0153] [0153] Where Raa is a substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, usually the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group is replaced by one or more (for example , one or two) substituents independently selected from halo, -OH, -CN, -NO2, -O (C1-C4 alkyl) or -O (C1-C4 haloalkyl).
[0154] [0154] Where Raa is a 3- to 7-membered cyclic group substituted, normally the 3- to 7-membered cyclic group is replaced by one or more (eg one or two) substituents independently selected from halo, -OH, -NH2, -CN, -NO2, -B1, -OB1, -NHB1, -N (B1) 2, -CONH2, -CONHB1, - CON (B1) 2, -NHCOB1, -NB1COB1, or -B11-; where each B1 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl or phenyl group or a 4- to 6-membered heterocyclic group containing one or two heteroatoms in the N ring and / or O, or two B1 together with the nitrogen atom to which they are attached, can form a 4- to 6-membered heterocyclic group containing one or two N and / or O ring heteroatoms, where any B 1 can optionally be replaced by halo and / or substituted with one or two substituents independently selected from -OH, -NH2, -OB12, -NHB12 or - N (B12) 2; wherein each B11 is independently selected from a C1-C8 alkylene or C2-C8 alkenylene group, where one or two carbon atoms in the main chain of the alkylene or alkenylene group can optionally be replaced by one or two N and / or O heteroatoms , and wherein the alkylene or alkenylene group can optionally be substituted with halo and / or substituted with one or two substituents independently selected from -OH, -NH2, - OB12, -NHB12 or -N (B12) 2; and wherein each B12 is independently selected from a C1-C3 alkyl or C1-C3 haloalkyl group; Typically, any divalent group -B11- forms a 4- to 6-membered fused ring.
[0155] [0155] Normally, each Ra is -Raa. More typically, each Ra is independently selected from a C1-C6 alkyl group (in particular C3-C6 branched alkyl) or C3-C6 cycloalkyl, where each Ra is optionally further substituted with one or more halo groups. More typically, each R a is independently selected from a C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl group. Where a group Ra is present at positions α and α ', each Ra can be the same or different. Normally, each Ra is the same.
[0156] [0156] Normally, each Rb is selected independently from hydrogen or halo. More typically, each Rb is hydrogen.
[0157] [0157] Typically, each Rc is independently selected from hydrogen, halo, -OH, -NO2, -CN, -Rcc or -ORcc. More typically, each Rc is independently selected from hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclopropyl. More typically, each Rc is independently selected from hydrogen or halo.
[0158] [0158] Normally, each Rcc is selected independently from a C1-C4 alkyl or C3-C6 cycloalkyl group, or any two Rcc attached to the same nitrogen atom can, together with the nitrogen atom to which they are attached, form a heterocyclic group saturated 3 to 6 members, where each Rcc is optionally replaced. Where Rcc is substituted, normally Rcc is substituted by one or more halo, -OH, -CN, -NO2, -O (C1-C4 alkyl) groups or -O (C1-C4 haloalkyl) groups. More typically, each Rcc is independently selected from a C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl C3-C4 group.
[0159] [0159] In one embodiment, -R2 has a formula selected from: R5 Rd R6, where R5 and R6 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl and C3-C4 halocycloalkyl, and Rd is hydrogen, halo, -OH, -NO2, -CN, -Rdd, -ORdd, -CORdd, -COORdd, -CONH2, - CONHRdd or -CON (Rdd) 2, where each -Rdd is independently selected from from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl and C3-C4 halocycloalkyl. Typically, R5 and R6 are independently selected from C1-C4 alkyl, and Rd is hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclopropyl. More typically, R5 and R6 are independently selected from C1-C4 alkyl, and Rd is hydrogen or halo. In one aspect of such an embodiment, R5 and R 6 are independently selected from C1-C4 alkyl, and Rd is halo. Typically, -R2 has a formula selected from: Cl F, or.
[0160] [0160] In one mode, -R2 has a formula selected from: A1 A1 A1
[0161] [0161] In one embodiment, Re is hydrogen, halo, -OH, -NO2, -CN, -Ree, - ORee, -CORee, -COORee, -CONH2, -CONHRee or -CON (Ree) 2, where each -Ree is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl and C3-C4 halocycloalkyl. Typically, Re is hydrogen or a halo, hydroxyl, -CN, -NO2, -Ree or -ORee group, where Ree is a C1-C4 alkyl group that can optionally be substituted by halo. More typically, R e is hydrogen or a halo, hydroxyl, -CN, -Ree or -ORee group, where Ree is a C1-C4 alkyl group that can optionally be substituted by halo. More typically, Re is hydrogen or halo.
[0162] [0162] Normally, any ring containing A1 or A2 is a 5- or 6-membered ring.
[0163] [0163] Typically, A1 and A2 are each independently selected from an optionally substituted straight chain alkylene group or an optionally substituted straight chain alkylene group,
[0164] [0164] In another mode, -R2 has a formula selected from:
[0165] [0165] Normally, -R2 has the formula: N N N N,,,,,, N N
[0166] [0166] More normally, -R2 has the formula:.
[0167] [0167] Yet other typical substituents at the α position of the parent cyclic 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 α of the parent cyclic group, in which the heterocyclic or aromatic group can optionally be substituted and in which the cyclic parent group can optionally be additionally substituted. These R 2 groups are described in more detail below.
[0168] [0168] In one embodiment, the parent cyclic group substituted by 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 parent cyclic group substituted by α from R2 is an aryl or heteroaryl group, all of which can optionally be additionally substituted. In one embodiment, the parent cyclic group substituted by α from R2 is a phenyl or a 5- or 6-membered heteroaryl group, all of which can optionally be additionally substituted. In one embodiment, the parent cyclic group substituted by α from R2 is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl group, all triazolyl or triazolyl, triazolyl or triazolyl. which can optionally be replaced additionally. In one embodiment, the parent cyclic group substituted by α from R2 is a phenyl or pyrazolyl group, both of which can optionally be additionally substituted. In one embodiment, the parent cyclic group substituted by α from R2 is a phenyl group, which can optionally be substituted further.
[0169] [0169] In one embodiment, the parent cyclic group substituted by α from R2 is substituted in positions α and α 'and can optionally be additionally substituted. For example, the parent cyclic group substituted by α from R 2 can be a substituted phenyl group in positions 2- and 6- or a substituted phenyl group in positions 2-, 4- and 6-.
[0170] [0170] In one embodiment, R2 is a cyclic parent 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 parent cyclic group can optionally be additionally substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl or a 5- or 6-membered heterocyclic group, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, isothiazolyl, triazolyl, isothiazolyl, triazole, azetidinyl, oxetanil, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, 1,4-piperazinil dioxanil, thianyl, morpholinyl, thiomorpholinyl or 1-methyl-2-oxo-1,2-dihydropyridinyl, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, isothiazolyl, isothiazolyl, isothiazolyl, triazole, azetidinyl, oxetanil, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanyl, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, tianyl, pianil, piperine 4-dioxatanil, morpholinyl, all of which can optionally be replaced. 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, oxazolyl, isoxazolyl, thiazolyl, piperidinol, pyridinyl, pyridinyl, pyridine group. all of which can optionally be replaced. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl or tetrahydropyranyl or 1-methyl-2oxo-1,2-dihydropyridine group, all which can optionally be replaced. In one embodiment, the monovalent heterocyclic or aromatic group in the α position is a phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl or tetrahydropyranyl group, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyrimidinyl, pyrazolyl group, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group at the α position is an unsubstituted phenyl, pyridinyl, pyrimidinyl or pyrazolyl group. In one embodiment, the monovalent heterocyclic group at the α position is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, all of which can optionally be substituted. In one embodiment, the monovalent heterocyclic group at the α position is an unsubstituted pyridin-3-yl group or an optionally substituted pyridin-4-yl group.
[0171] [0171] For any of these monovalent heterocyclic or aromatic groups in the α position mentioned in the immediately preceding paragraph, the monovalent heterocyclic or aromatic group can optionally be substituted by one or two substituents independently selected from halo, -OH, - NH2, -CN, -NO2, -B4, -OB4, -NHB4, -N (B4) 2, -CONH2, -CONHB4, -CON (B4) 2, - NHCOB4, -NB4COB4, or -B44-; wherein each B4 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl or phenyl group or a 4- to 6-membered heterocyclic group containing one or two heteroatoms in the N ring and / or O, or two B4s together with the nitrogen atom to which they are attached, can form a 4- to 6-membered heterocyclic group containing one or two N and / or O ring heteroatoms, where any B 4 can optionally be substituted by halo and / or substituted with one or two substituents independently selected from -OH, -NH2, -OB45, -NHB45 or - N (B45) 2; wherein each B44 is independently selected from a C1-C8 alkylene or C2-C8 alkenylene group, where one or two carbon atoms in the main chain of the alkylene or alkenylene group can optionally be substituted by one or two N and / or O heteroatoms , and wherein the alkylene or alkenylene group can optionally be substituted with halo and / or substituted with one or two substituents independently selected from -OH, -NH2, - OB45, -NHB45 or -N (B45) 2; and wherein each B45 is independently selected from a C1-C3 alkyl or C1-C3 haloalkyl group;
[0172] [0172] Typically, any divalent group -B44- forms a 4- to 6-membered fused ring.
[0173] [0173] In one embodiment, the monovalent heterocyclic or aromatic group at the α position is a phenyl, pyridinyl, pyrimidinyl or pyrazolyl group, all of which can optionally be substituted by one or two substituents independently selected from halo, -OH, - NH2, -CN, -B4, -OB4, - NHB4 or -N (B4) 2, where B4 is independently selected from a C1- C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, all of which can be optionally substituted by halo. In one embodiment, the monovalent heterocyclic group at the α position is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, all of which can optionally be substituted by one or two substituents independently selected from halo , -OH, -NH2, -CN, -B4, -OB4, -NHB4 or -N (B4) 2, where each B4 is independently selected from a C 1 -C4 alkyl, C2-C4 alkenyl or C2 group -C4 alkynyl, all of which can be optionally substituted by halo. In one embodiment, the monovalent heterocyclic group at the α position is an unsubstituted pyridin-3-yl group or a pyridin-4-yl group optionally substituted by one or two substituents independently selected from halo, -OH, -NH2, - CN, -B4, -OB4, - NHB4 or -N (B4) 2, where each B4 is independently selected from a group C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl all of which can be optionally replaced by halo.
[0174] [0174] In one embodiment, R2 is a cyclic parent 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 parent cyclic group can optionally be additionally substituted. In one embodiment, these additional substituents are in the α 'position of the parent cyclic 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 cyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 group and in which each Rδ is optionally substituted with one or more halo groups. Typically, these additional substituents on the α-substituted parent cyclic group of R2 are independently selected from halo, C1-C6 alkyl (in particular C3-C6 branched alkyl) or C3-C6 cycloalkyl groups, for example, fluoro, chloro, isopropyl groups , cyclopropyl, cyclohexyl or t-butyl, where the alkyl and cycloalkyl groups are optionally further substituted by one or more fluoro and / or chloro groups.
[0175] [0175] In one embodiment, -R2 has a formula selected from: R7 Rg R8, where R7 is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl, R8 is a heterocyclic or aromatic group optionally substituted 5- or 6-membered, and Rg is hydrogen, halo, -OH, -NO2, -CN, -Rgg, - ORgg, -CORgg, -COORgg, -CONH2, -CONHRgg or -CON (Rgg) 2 , where each -Rgg is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl and C3-C4 halocycloalkyl. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, -OH, -NH2, -CN, -NO2, -B5, -OB5, -NHB5, - N (B5) 2, -CONH2 , -CONHB5, -CON (B5) 2, -NHCOB5, -NB5COB5, or B55-; wherein each B5 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl or phenyl group or a 4- to 6-membered heterocyclic group containing one or two heteroatoms in the N ring and / or O, or two B5s together with the nitrogen atom to which they are attached, can form a 4- to 6-membered heterocyclic group containing one or two N and / or O ring heteroatoms, where any B 5 can optionally be substituted by halo and / or substituted with one or two substituents independently selected from -OH, -NH2, -OB56, -NHB56 or - N (B56) 2; wherein each B55 is independently selected from a C1-C8 alkylene or C2-C8 alkenylene group, where one or two carbon atoms in the main chain of the alkylene or alkenylene group can optionally be replaced by one or two N and / or O heteroatoms , and wherein the alkylene or alkenylene group can optionally be substituted with halo and / or substituted with one or two substituents independently selected from -OH, -NH2, - OB56, -NHB56 or -N (B56) 2; and wherein each B56 is independently selected from a C1-C3 alkyl or C1-C3 haloalkyl group;
[0176] [0176] Typically, any divalent group -B55- forms a 4- to 6-membered fused ring. Typically, R7 is C1-C4 alkyl, R8 is an optionally substituted 5- or 6-membered heterocyclic or aromatic group, and Rg is hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclopropyl. More typically, R7 is C1-C4 alkyl, R8 is an optionally substituted 5- or 6-membered heterocyclic or aromatic group and Rg is hydrogen or halo. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, -OH, -NH2, -CN, -B5, -OB5, - NHB5 or -N (B5) 2, where each B5 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, all of which can be optionally substituted by halo.
[0177] [0177] Normally, -R2 has a formula selected from:
[0178] [0178] Typically, any divalent B66-group forms a 4- to 6- membered fused ring. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, -OH, -NH2, -CN, -B6, -OB6, -NHB6 or -N (B6) 2, where each B6 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, all of which can be optionally substituted by halo.
[0179] [0179] In one embodiment, R2 is a parent 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 parent cyclic group can optionally be additionally substituted. The other substituents on the α-substituted parent cyclic 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 from R2, that is, each cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring has only two atoms and a common bond with the 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 from R2 through positions α ', β'.
[0180] [0180] In one mode, -R2 has a formula selected from: Rh N Rh Rh N Rh
[0181] [0181] Typically, any divalent group -B77- forms a 4- to 6-membered fused ring. Typically, Rh is hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclopropyl. More typically, Re is hydrogen or halo. Typically, the optional substituents on the heterocyclic or aromatic group are selected independently from halo, -OH, -NH2, -CN, -B7, -OB7, -NHB7 or -N (B7) 2, where each B7 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, all of which can be optionally substituted by halo.
[0182] [0182] In one mode, -R2 has a formula selected from: N N
[0183] [0183] Typically, any divalent group -B88- forms a 4- to 6-membered fused ring. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, -OH, -NH2, -CN, -B8, -OB8, -NHB8 or -N (B8) 2, where each B8 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, all of which can be optionally substituted by halo.
[0184] [0184] Normally, -R2 has a formula selected from:
[0185] [0185] Typically, any divalent group -B99- forms a 4- to 6-membered fused ring. Typically, Rh is hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclopropyl. More typically, Ri is hydrogen or halo. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, -OH, -NH2, -CN, -B9, -OB9, -NHB9 or -N (B9) 2, where each B9 is independently selected from of a C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, all of which can optionally be substituted by halo.
[0186] [0186] 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 a C1-C6 alkyl, C2-C6 alkenyl group , 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 in the α 'position by a substituent selected from -R24, -OR24 and - COR24, where R24 is selected from a C1-C6 alkyl, C2 group -C6 alkenyl, C2-C6 alkynyl or C2-C6 and wherein R24 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, -COOR25, -CONH2, -CONHR25 or - CON ( R25) 2, wherein each -R25 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 cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring that is fused to the phenyl or the parent 5 or 6-membered heteroaryl group through the α positions, β and which is optionally substituted by one or more halo groups; and optionally, the 5- or 6-membered phenyl or heteroaryl group is further substituted in the α 'position by a substituent selected from -R4, -OR4 and -COR4, where R4 is selected from a cyclic C1-C6 alkyl group, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 and wherein R4 is optionally substituted by one or more halo groups; and optionally, the 5- or 6-membered phenyl or heteroaryl group is further substituted (usually by one, two or three substituents independently selected from halo, -NO2, -CN, -COOR25, -CONH2, -CONHR25 or - CON ( R25) 2, wherein each -R25 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 cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring that is fused to the phenyl or the parent 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 phenyl or the parent 5- or 6-membered heteroaryl group through the α ', β positions 'and which is optionally substituted by one or more halo groups; and optionally, the phenyl group is additionally substituted (usually by a substituent selected from halo, -NO2, -CN, -COOR25, -CONH2, -
[0187] [0187] In the modality directly above, where a group or portion 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.
[0188] [0188] In one aspect of any of the above, R 2 contains 10 to 50 atoms other than hydrogen. More typically, R2 contains 10 to 40 atoms other than hydrogen. More typically, R 2 contains 10 to 35 atoms other than hydrogen. More typically, R2 contains 12 to 30 atoms other than hydrogen.
[0189] [0189] In one aspect of any of the foregoing modalities, R2 contains 5 to 30 atoms other than hydrogen or halogen. More typically, R2 contains 7 to 25 atoms other than hydrogen or halogen. More typically, R2 contains 9 to 20 atoms other than hydrogen or halogen. More typically, R2 contains 10 to 20 atoms other than hydrogen or halogen. More typically, R2 contains 12 to 18 atoms other than hydrogen or halogen.
[0190] [0190] Q is selected from O or S. In an embodiment of the first aspect of the invention, Q is O.
[0191] [0191] In one aspect of any of the above, 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 300 to 900 Da. More typically, the compound of formula (I) has a molecular weight of 350 to 600 Da.
[0192] [0192] A second aspect of the invention provides a compound selected from the group consisting of: THE THE O O O O O S N O O N H Y N Y N H N H N H H H N N N N N N O O N N HN THE THE THE Y N N H H AT THE THE AT THE Y N N H The H N N N N THE O O O O O O Y N Y N N H N H The H H N N N N HO HN N O O O O O O Y N Y N N H N H N H H N HO N N N N N O O O O O O N Y N Y N N H H The H H THE The N N Y N N N N H H N N N N N O O O O O O O O O Y N Y N Y N H N H N H H H H N N N N N N HN N N H O O O O F O O O O O Y N Y N Y N H N H N H H H H N N N N N N N N N O O O O O O O O O N Y N Y N Y N H N N H H H H H N N N N N N N N N O O O O O O Y N Y N N N O H N H O H H S O N N N HN N N HN N N N N O O O N S N N H H N N O O O N S N N H H N N O O O N S N N H H N N O O O O O O N Y N Y N N N N H H H H N N N N O O O N S N N H H N N O O O s N N H H N N N CN O O O F S O O N N O H H S N N N N H H
[0193] [0193] 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.
[0194] [0194] 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, maleic or galactonic, gluconic, galactic, 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 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.
[0195] [0195] 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.
[0196] [0196] 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.
[0197] [0197] 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.
[0198] [0198] 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.
[0199] [0199] In some embodiments of the present invention, therapeutically inactive prodrugs are provided. Prodrugs 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 modalities, prodrugs 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 portion of the active compound. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated and / or dephosphorylated to produce the active compound. The present invention also encompasses salts and solvates of such prodrugs, as described above.
[0200] [0200] The compounds, salts, solvates and prodrugs of the present invention can contain at least one chiral center. The compounds, salts, solvates and
[0201] [0201] The compounds, salts, solvates and prodrugs of the present invention 12 13 may contain any stable isotope, including, but not limited to C, C, 1 H, 2H (D), 14 N, 15 N, 16 O , 17 O, 18 O, 19 F and 127 I, and any radioisotope including but not limited to 11C, 14C, 3H (T), 13N, 15O, 18F, 123I, 124I, 125I and 131I.
[0202] [0202] The compounds, salts, solvates and prodrugs of the present invention can be in any polymorphic or amorphous form.
[0203] [0203] 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.
[0204] [0204] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Aulton’s Pharmaceutics - The Design and Manufacture of Medicines", M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier, 4th Ed., 2013.
[0205] [0205] Pharmaceutically acceptable excipients, including adjuvants, diluents or carriers 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 vegetable saturated 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, sodium carboxymethyl cellulose , polyacrylates, waxes, polyoxypropylene-polyethylene-, polyethylene-gly block polymers ol and wool fat.
[0206] [0206] In one embodiment, the pharmaceutical composition of the fourth aspect of the invention further comprises one or more additional active agents.
[0207] [0207] 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.
[0208] [0208] 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.
[0209] [0209] The term "treatment", as used in this document, 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 in this document, 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 non-administration of a composition, salt, solvate,
[0210] [0210] 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.
[0211] [0211] 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.
[0212] [0212] 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 a disease, disorder or condition in an individual, where the individual has a germline or a non-silent somatic mutation in NLRP3. The mutation can be, for example, a gain in function or another mutation resulting in increased NLRP3 activity. Typically, the use comprises administering the compound, salt, solvate, prodrug or pharmaceutical composition to an individual. In one embodiment, the use comprises co-administration of one or more additional active agents. The use may also comprise the diagnosis of an individual with a non-silent somatic germline or somatic mutation in NLRP3, in which the compound, salt, solvate, prodrug or pharmaceutical composition is administered to an individual based on a positive diagnosis for the mutation. Typically, the identification of the mutation in the NLRP3 in the individual can be by any suitable genetic or biochemical means.
[0213] [0213] 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 germline or somatic mutation in the
[0214] [0214] 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.
[0215] [0215] In general modalities, the disease, disorder or condition can be a disease, disorder or condition of the immune system, the cardiovascular system, the endocrine system, the gastrointestinal tract, the renal system, the hepatic system, the metabolic system, the respiratory system, the central nervous system, may be cancer or other malignancy and / or may be caused or associated with a pathogen.
[0216] [0216] 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.
[0217] [0217] In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is responsive to NLRP3 inhibition. 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.
[0218] [0218] 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).
[0219] [0219] 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 increasing order of severity, are cold-induced familial autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and 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.
[0220] [0220] Various autoimmune diseases have been shown to involve NLRP3, including, in particular, 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), erythematous systemic lupus (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.
[0221] [0221] The inflammasome, and NLRP3 specifically, has also been proposed as a target for modulation by several pathogens, including viruses such as DNA viruses (Amsler et al., Future Virol. (2013) 8 (4), 357–370).
[0222] [0222] NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al., Clinical and Experimental Immunology 166: 1-15, 2011; and Masters Clin. Immunol. 2013). For example, several previous studies have suggested a role for IL-1β in cancer invasion, growth and metastasis, and inhibition of IL-1β with Canaquinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomized study, double-blind, placebo-controlled (Ridker et al. Lancet, S0140-6736 (17) 32247-X, 2017). Inhibition of NLRP3 or IL-1β inflammasome has also been shown to inhibit lung cancer cell proliferation and migration in vitro (Wang et al. Oncol Rep. 2016; 35 (4): 2053-64). A role for NLRP3 inflammasome has been suggested in myelodysplastic syndromes (Basiorka et al. Blood. December 22, 2016; 128 (25): 2960-2975) and also in the carcinogenesis of several other types of cancer, including glioma (Li et al Am J Cancer Res. 2015; 5 (1): 442-449), inflammation-induced tumors (Allen et al. J Exp Med. 2010; 207 (5): 1045-56 and Hu et al. PNAS. 2010; 107 (50): 21635-40), multiple myeloma (Li et al. Hematology 2016 21 (3): 144-51) and squamous cell carcinoma of the head and neck (Huang et al. J
[0223] [0223] 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).
[0224] [0224] Therefore, examples of diseases, disorders or conditions that can respond to NLRP3 inhibition and that can be treated or prevented according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention include: (i ) inflammation, including inflammation that occurs as a result of an inflammatory disorder, for example, an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs as a result of infection or inflammation secondary to trauma, injury or autoimmunity ; (ii) autoimmune disease such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis , celiac disease, Crohn's disease, diabetes type 1 (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, erythematous lupus including systemic lupus erythematosus ( SLE), multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and recurrent remitting multiple sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus syndrome (WHO), optic neuritis, Ord thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, idiopathic juvenile arthritis or d disease and Still, refractory gout arthritis, arthritis, Reiter's syndrome, Sjogren's syndrome, systemic sclerosis, a systemic connective tissue disorder, arteritis of
[0225] [0225] In one embodiment, the disease, disorder or condition is selected from: (i) inflammation; (ii) an infection; (iii) cardiovascular disease; (iv) a respiratory disease; (v) a liver disease; (vi) a kidney disease; (vii) an eye disease; (viii) a skin disease; (ix) a psychological disorder; (x) a lymphatic condition; and / or (xi) any disease, disorder or condition in which an individual has been determined to have a germline or non-silent somatic mutation in NLRP3.
[0226] [0226] 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
[0227] [0227] 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.
[0228] [0228] In one embodiment, the disease, disorder or condition is selected from: (i) acne conglobata; (ii) atopic dermatitis; (iii) Alzheimer's disease; (iv) amyotrophic lateral sclerosis; (v) age-related macular degeneration (AMD); (vi) anaplastic thyroid cancer; (vii) cryopyrin-associated periodic syndromes (CAPS); (viii) contact dermatitis; (ix) cystic fibrosis; (x) congestive heart failure; (xi) chronic kidney disease; (xii) Crohn's disease; (xiii) cold-induced familial autoinflammatory syndrome (FCAS); (xiv) Huntington's disease; (xv) heart failure; (xvi) heart failure with preserved ejection fraction; (xvii) ischemic reperfusion injury; (xviii) juvenile idiopathic arthritis; (xix) myocardial infarction; (xx) macrophage activation syndrome; (xxi) myelodysplastic syndrome; (xxii) multiple myeloma; (xxiii) motor neuron disease;
[0229] [0229] 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 (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, pummel rhinitis, sicca rhinitis, drug rhinitis, membranous rhinitis, seasonal rhinitis, for example, hay fever and vasomotor rhinitis) sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis or idiopathic interstitial pneumonia; (vi) a vascular condition such as atherosclerosis, Behcet's disease, vasculitis or wegener's granulomatosis; (vii) an autoimmune condition, such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic purple thrombocytopenia or Graves' disease; (viii) an eye condition such as uveitis, allergic conjunctivitis or vernal conjunctivitis; (ix) a nervous condition such as multiple sclerosis or encephalomyelitis; (x) an infection or condition related to the infection, such as Acquired Immunodeficiency Syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis, intracellular mycobacterium avium, pneumocystis carinii pneumonia, orchitis / epididymitis, legionella disease, legionella, A, epstein-barr virus, viral encephalitis / aseptic meningitis or pelvic inflammatory disease; (xi) a renal condition such as mesangial proliferative glomerulonephritis, nephratic syndrome, nephritis, glomerular nephritis, acute renal failure, uremia or nephrotic syndrome; (xii) a lymphatic condition such as Castleman's disease; (xiii) a condition or involvement of the immune system, such as hyper IgE syndrome, lepromatous leprosy, familial haemophagocytic lymphohistiocytosis or graft versus host disease; (xiv) a liver condition, such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH) or primary biliary cirrhosis; (xv) a cancer, including the cancers listed above; (xvi) burn, wound, trauma, hemorrhage or stroke; (xvii) radiation exposure; and / or (xviii) obesity; and / or (xix) pain such as inflammatory hyperalgesia.
[0230] [0230] 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 multisystemic inflammatory disease (NOMID), tumor necrosis factor (TNF), periodic receptor-associated syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis, gangrenous pyoderma and acne syndrome (PAPA), adult Still's disease (AOSD), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), antibody deficiency and PLCG2-associated immune dysregulation (PLAID), PLCG2-associated autoinflammatory, antibody deficiency and immune dysregulation (APLA ID) or sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD).
[0231] [0231] Examples of diseases, disorders or conditions that can respond to NLRP3 inhibition and that can be treated or prevented according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention are listed above. Some of these diseases, disorders or conditions are substantially or totally mediated by NLRP3 and IL-1β and / or IL-18 inflammasome activity. As a result, such diseases, disorders or conditions may be particularly responsive to inhibition of NLRP3 and may be particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention. Examples of such diseases, disorders or conditions include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial autoinflammatory syndrome (FCAS), neonatal onset multisystemic inflammatory disease (NOMID), familial Mediterranean fever ( FMF), pyogenic arthritis, gangrenous pyoderma and acne syndrome (PAPA), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic juvenile idiopathic arthritis, Adult Still (AOSD), relapsing polychondritis, Schnitzler's syndrome, Sweet's syndrome, Behcet's disease, anti-synthase syndrome, interleukin 1 receptor antagonist (DIRA) deficiency and A20 haploinsufficiency (HA20) insufficiency.
[0232] [0232] 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).
[0233] [0233] An eleventh aspect of the invention provides a method of inhibiting NLRP3, the method comprising using a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to inhibit NLRP3.
[0234] [0234] In an eleventh aspect of the present invention, the method comprises using a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention or a product pharmaceutical composition of the fourth aspect of the invention, in combination with one or more additional active agents.
[0235] [0235] 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.
[0236] [0236] 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.
[0237] [0237] 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.
[0238] [0238] 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.
[0239] [0239] 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.
[0240] [0240] 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.
[0241] [0241] 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.
[0242] [0242] 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;
[0243] [0243] 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.
[0244] [0244] 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, flutamide, gencitabine, hydroxyane, hydroxyane, hydroxyane, hydroxyane lonidamine, lomustine (CCNU), larotaxel (RPR109881), meclorethamine, mercaptopurine, methotrexate, mitomycin C, mitoxantrone, melphalan, mivobulin, 3 ', 4'-dideshydro-4'-deoxy-8'-norvin-kaleucoblastine, nil da, oxaliplatin, onapristone, prednimustine, procarbazine, paclitaxel, anticancer agents containing platinum, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-
[0245] [0245] Alternatively or in addition, one or more chemotherapeutic agents can be selected from complement fragment CD59, fragment of fibronectin, gro-beta (CXCL2), heparinases, fragment of heparin hexasaccharide, human chorionic 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 factor beta (TGF -β), vasculostatin, vasostatin (fragment of calreticulin) and / or cytokines (including interleukins, such as interleukin-2 (IL-2) or IL-10).
[0246] [0246] 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.
[0247] [0247] 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.
[0248] [0248] 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.
[0249] [0249] In some embodiments, one or more antiangiogenic agents are selected from among endostatin, angiogenin, angiostatin, angioarrestin, angiostatin (plasminogen fragment), antiangiogenic factors derived from basement membrane collagen (tumstatin, canstatin or cravine), antiantithrombin III angiogenic and / or cartilage-derived inhibitor (ICD).
[0250] [0250] 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 vinca, 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.
[0251] [0251] 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
[0252] [0252] 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.
[0253] [0253] 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, hemsleianol D, hopeafenol, transdiptoindonesin B, astringine, piceid and / or diptoindonesin A.
[0254] [0254] 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 (for example, 2 'protection -OH with a methyl group or replacement of 2'-OH by -F or -N3).
[0255] [0255] In some modalities, one or more vaccines against cancer are selected from an HPV vaccine, a vaccine against hepatitis B, Oncophage and / or Provenge.
[0256] [0256] In some embodiments, one or more immunomodulating agents may comprise an immune checkpoint inhibitor. The immune checkpoint inhibitor may target an immune checkpoint receptor or combination of receptors comprising, for example, CTLA-4, PD-1, PD-L1, PD-L2, T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9, phosphatidylserine, lymphocyte activation gene 3 protein (LAG3), MHC class I, MHC class II, 4-1BB, 4-1BBL, OX40, OX40L, GITR, GITRL, CD27, CD70 , TNFRSF25, TL1A, CD40, CD40L, HVEM, LIGHT, BTLA, CD160, CD80, CD244, CD48, ICOS, ICOSL, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2, TMIGD2, butyrophylline (including BTNL2), one member of the Siglec family, TIGIT, PVR, a killer cell immunoglobulin-type receptor, a
[0257] [0257] In some embodiments, the immune checkpoint inhibitor is selected from urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDDL3280A) (PDDL3280A) -L1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertibe, ulocuplumab, BKT140, bavituxima, and / or MNRP1685A.
[0258] [0258] In some embodiments, one or more antibiotics are selected from amikacin, gentamycin, kanamycin, neomycin, netilmycin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, meripenem, imipenopen, meripenem, imipenopenem, meripenem, , cefadroxil, cefazoline, cephalothin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodine, ceftaxine, ceftaxine, ceftaxine, ceftaxima, ceftaxine vancomycin, telavancin, dalbavancin, oritavancin, clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone, nitrofurantoin, amide, zolazole, zolol, zolol carbenicillin, cloxacillin, dicloxacillin, fluclox acylin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, ticarcilin, calvulanate, ampicillin, subbactam, tazobactam, ticarcilin, clavulanate, bacitracin, levacycline, cystacycline, colystin, polycycline, colystin, colystin , lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, spparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxamine, sulfamethoxazamine, sulfamethoxazole, sulfamethoxazole minocycline, ocitetracycline, tetracycline, clofazimine, dapsone, dapreomycin,
[0259] [0259] 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.
[0260] [0260] In some embodiments, one or more antifungal agents are selected from bifonazole, butoconazole, clotrimazole, econazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, flaconazole, ezaconazole, flaconazole, flaconazol, , itraconazole, posaconazole, propiconazole, ravusconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naphthphine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, cyclopyroxy, flucytosine, flucytosine, 5 / or balm from Peru.
[0261] [0261] In some embodiments, one or more anthelmintic agents are selected from benzimidazoles (including albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole and flubendazole), abamectin, diethylcarbamazine, ivermectin, suramine, piramide, pyrantelanamide, piramide, pyrantelanamide, piramide, pyrantelanamide, pyrantelanamide, piramide, pyrantelanamide, pyrantylamine, niclosamide and oxyclozanide) and / or nitazoxanide.
[0262] [0262] 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).
[0263] [0263] 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. More typically, the subject is a human.
[0264] [0264] Any of the medications employed in the present invention can be administered by oral, parenteral administration (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), air (aerosol), rectal, vaginal, ocular or topical (including transdermal, buccal, mucous, sublingual and ocular).
[0265] [0265] 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.
[0266] [0266] 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, tablets, sweetener or lozenges, as a powder or granules or as an aqueous solution, suspension or dispersion.
[0267] [0267] 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.
[0268] [0268] 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.
[0269] [0269] Powders or granules for oral use can be supplied in sachets or tubes. Aqueous solutions, suspensions or dispersions can be prepared by adding water to powders, granules or tablets.
[0270] [0270] Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavoring agents, dyes and / or preservatives.
[0271] [0271] Formulations for rectal administration can be presented as a suppository with a suitable base, which comprises, for example, cocoa butter or a salicylate.
[0272] [0272] Formulations suitable for vaginal administration may be presented as pessaries, absorbents, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers known in the art to be appropriate.
[0273] [0273] For parenteral use, the compounds, salts, solvates or prodrugs of the present invention will generally be supplied in a sterile aqueous solution or suspension, buffered at an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solutions and isotonic sodium chloride or glucose. The aqueous suspensions according to the invention can include suspending agents, such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and tragacanth gum and a wetting agent, such as lecithin. Preservatives suitable for aqueous suspensions include n-propyl p-hydroxybenzoate and ethyl. The compounds of the invention can also be presented as liposome formulations.
[0274] [0274] For ocular administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in a form suitable for topical administration, for example, as eye drops. Suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels and eye inserts. Alternatively, the compounds, salts, solvates or prodrugs of the invention can be supplied in a form suitable for other types of ocular administration, for example, as intraocular preparations (including irrigation solutions, such as intraocular injection formulations, intravitreal or juxta-scleral or as intravitreal implants), as corneal packs or shields, as intracameral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations.
[0275] [0275] 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.
[0276] [0276] Suitable suspensions and solutions can be used in inhalers for administration of airways (aerosol).
[0277] [0277] The dose of the compounds, salts, solvates or prodrugs of the present invention will vary, of course, with the disorder, disease or condition being treated or prevented. In general, an adequate dose will be in the range of 0.01 to 500 mg per kilogram of the recipient's body weight per day. The desired dose can be presented at an appropriate interval, such as once every two days, once a day, twice a day, three times a day or four times a day. The desired dose can be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.
[0278] [0278] To avoid doubts, as far as possible, any modality of a given aspect of the present invention can occur in combination with any other modality of the same aspect of the present invention. Furthermore, as far as possible, it should be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention.
[0279] [0279] As an example, combinations of aspects and typical embodiments of the present invention include the following.
[0280] [0280] In a first combination, a compound of the first aspect of the invention is provided in which R2 is a cyclic group substituted at the α and α 'positions, where each substituent at the α and α' positions comprises a carbon atom and in which R2 can optionally be further replaced.
[0281] [0281] In a second combination, a compound of the first aspect of the invention is provided in which R1 is a monovalent straight or branched chain group and where R2 is a cyclic group substituted at the α and α 'positions, where each substituent on α and α 'positions comprise a carbon atom and where R2 can optionally be further substituted.
[0282] [0282] In a third combination, a compound of the first aspect of the invention is provided in which R1 is directly attached to a nitrogen atom in ring A and where R2 is a cyclic group substituted at positions α and α ', where each substituent at positions α and α 'comprise a carbon atom and where R2 can optionally be further substituted. Usually, in this combination, ring A is monocyclic.
[0283] [0283] In a fourth combination, a compound of the first aspect of the invention is provided in which W, X, Y and Z are each independently N, NH or CH, and where R2 is a cyclic group substituted at the α and α positions ', where R2 can optionally be further replaced. Usually, in this combination, ring A is monocyclic.
[0284] [0284] In a fifth combination, a compound of the first aspect of the invention is provided in which W, X, Y and Z are each independently N, NH or CH, where R1 is a monovalent straight or branched chain group and in that R2 is a cyclic group substituted at positions α and α ', where R 2 can optionally be additionally substituted. Usually, in this combination, ring A is monocyclic.
[0285] [0285] In a sixth combination, a compound of the first aspect of the invention is provided in which W, X, Y and Z are each independently N, NH or CH, where R1 is directly attached to the nitrogen atom of ring A, and where R2 is a cyclic group substituted at positions α and α ', where R2 can optionally be further substituted. Usually, in this combination, ring A is monocyclic.
[0286] [0286] In a seventh combination, a compound of the first aspect of the invention is provided in which R1 is directly attached to a nitrogen atom in ring A and in which R2 is a cyclic group substituted at positions α and α ', where R2 can optionally be further replaced. Usually, in this combination, ring A is monocyclic.
[0287] [0287] In an eighth combination, a compound of the first aspect of the invention is provided in which R1 is directly attached to a nitrogen atom in ring A, where R1 is a monovalent straight or branched chain group and where R2 is a cyclic group substituted at positions α and α ', where R 2 can optionally be further substituted. Usually, in this combination, ring A is monocyclic.
[0288] [0288] In a ninth combination, a compound of the first aspect of the invention is provided in which W, X, Y and Z are each independently N, NH or CH, R1 is a monovalent straight or branched chain group and R 1 contains only atoms selected from the group consisting of carbon, hydrogen, nitrogen, oxygen and halogen atoms. Usually, in this combination, ring A is monocyclic.
[0289] [0289] In a tenth combination, a compound of the first aspect of the invention is provided in which R1 is a monovalent straight or branched chain group and R1 contains only atoms selected from the group consisting of carbon, hydrogen, nitrogen and halogen atoms. Usually, in this combination, ring A is monocyclic.
[0290] [0290] In an eleventh combination, a compound of the first aspect of the invention is provided in which R1 does not include an amide group, where R2 is a cyclic group substituted at the α and α 'positions, and where R 2 can optionally be additionally replaced.
[0291] [0291] In a twelfth combination, a compound of the first aspect of the invention is provided in which no nitrogen atom within the R1 group is directly linked to a sp2 hybridized atom, and where R2 is a cyclic group substituted at the α and e positions α ', where R2 can optionally be further substituted. Usually, in this combination, ring A is monocyclic. Typically in such a combination, 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 positions α, β and a second cycloalkyl ring, 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 additionally substituted.
[0292] [0292] In a thirteenth combination, a compound of the first aspect of the invention is provided in which:
[0293] [0293] R1 is a monovalent saturated hydrocarbyl group, in which the saturated hydrocarbyl group is straight or branched, or is or includes cyclic groups, in which the saturated hydrocarbyl group is unsubstituted or substituted by one or more fluoro groups and / or chlorine, in which the saturated group the saturated hydrocarbyl group includes at least one N hetero atom in its carbon backbone and where the saturated hydrocarbyl group can optionally include another N or O hetero atom in its carbon backbone; and
[0294] [0294] R2 is an aryl or heteroaryl group, where the aryl or heteroaryl group is substituted at the α and α 'positions, where each substituent at the α and α' positions comprises a carbon atom and where R 2 can optionally be further replaced. Usually, in this combination, ring A is monocyclic. Typically in such a combination, 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 positions α, β and a second cycloalkyl ring, 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 additionally substituted.
[0295] [0295] In a fourteenth combination, a compound of the first aspect of the invention is provided in which R1 is a monovalent straight or branched chain group, in which R1 does not include an amide group, and in which R2 is a cyclic group substituted in α and α ', and where R2 can optionally be further substituted.
[0296] [0296] In a fifteenth combination, a compound of the first aspect of the invention is provided in which R1 is a monovalent straight or branched chain group, in which no nitrogen atom within the group R1 is directly linked to a sp2 hybridized atom, and where R2 is a cyclic group substituted at the α and α 'positions, where each substituent at the α and α' positions comprises a carbon atom, and where R2 can optionally be additionally substituted. Usually, in this combination, ring A is monocyclic. Typically in such a combination, 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 positions α, β and a second cycloalkyl ring, 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 additionally substituted.
[0297] [0297] In a sixteenth combination, a compound of the first aspect of the invention is provided in which:
[0298] [0298] R1 is a monovalent saturated hydrocarbyl group, in which the saturated hydrocarbyl group is straight or branched, in which the saturated hydrocarbyl group is unsubstituted or substituted by one or more fluoro and / or chlorine groups, in which the group saturated hydrocarbyl includes at least one N heteroatom in its carbon backbone and wherein the saturated hydrocarbyl group can optionally include another N or O heteroatom in its carbon backbone; and
[0299] [0299] R2 is an aryl or heteroaryl group, where the aryl or heteroaryl group is substituted at the α and α 'positions, where each substituent at the α and α' positions comprises a carbon atom and where R2 can optionally be more replaced. Usually, in this combination, ring A is monocyclic. Typically in such a combination, R2 is a fused aryl or fused heteroaryl group, in which a first cycloalkyl, cycloalkenyl ring,
[0300] [0300] A seventeenth combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, wherein: the ring A is monocyclic; W, X, Y and Z are each independently N, NH or CH, where at least two of W, X, Y and Z are N or NH and at least one of W, X, Y and Z is CH; -R1 has the formula: R13 R14 R13 10 10 R R
[0301] [0301] An eighteenth combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, where R 1 is a monovalent straight or branched chain group, ring A is a pyrazolyl group and R 2 is a cyclic group substituted at the α and α 'positions, where R 2 can optionally be additionally substituted. Usually, in this combination, ring A is monocyclic.
[0302] [0302] A nineteenth combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, wherein W, X , Y and Z are each independently N, NH or CH, for use in medicine.
[0303] [0303] A twentieth combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, where R 1 does not include an amide group, for use in medicine. Usually, in this combination, ring A is monocyclic.
[0304] [0304] A twenty-first combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, wherein R1 comprises at least least one nitrogen atom that is not directly linked to a sp2 hybridized atom, for use in medicine.
[0305] [0305] A twenty-second combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, where R 1 is directly attached to an A ring nitrogen atom for use in medicine.
[0306] [0306] A twenty-third combination 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 composition pharmaceutical product of the fourth aspect of the invention, wherein R1 is a monovalent straight or branched chain group. Usually, in this combination, ring A is monocyclic.
[0307] [0307] A twenty-fourth combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, where R 1 is a monovalent group of straight or branched chain (and typically where ring A is monocyclic), for use in the treatment or prevention of a disease, disorder or condition, in which the disease, disorder or condition is selected from: (i) inflammation; (ii) an infection; (iii) cardiovascular disease; (iv) a respiratory disease; (iv) a liver disease; (vi) a kidney disease; (vii) an eye disease; (viii) a skin disease; (ix) a psychological disorder; (x) a lymphatic condition; and / or (xi) any disease, disorder or condition in which an individual has been determined to have a germline or non-silent somatic mutation in NLRP3.
[0308] [0308] A twenty-fifth combination provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, where R 1 is a monovalent group of straight or branched chain (and typically where ring A is monocyclic), for use in the treatment or prevention of a disease, disorder or condition, in which the disease, disorder or condition is selected from: (i) cryopyrin-associated periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii) familial cold-induced autoinflammatory syndrome (FCAS); (iv) neonatal onset multisystemic inflammatory disease (NOMID); (v) familial Mediterranean fever (FMF); (vi) pyogenic arthritis, gangrenous pyoderma and acne syndrome (PAPA); (vii) hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); (viii) Periodic Syndrome Associated with the Tumor Necrosis Factor (TNF) Receptor (TRAPS); (ix) Systemic Juvenile Idiopathic Arthritis; (x) Adult onset Still's disease (AOSD); (xi) Recurrent Polyondritis; (xii) Schnitzler syndrome; (xiii) Sweet's syndrome; (xiv) Behçet's disease; (xv) Antisynthetase Syndrome; (xvi) Deficiency of the Interleukin 1 Receptor Antagonist (DIRA); and (xvii) Haploinsufficiency of A20 (HA20).
[0309] [0309] Typically, in any of the above exemplary combinations, Q is O.
[0310] [0310] Typically, in any of the exemplary combinations, 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 substituted further. Typically, each substituent at the α and α 'positions comprises a carbon atom. Typically, in any of the above exemplary combinations, R2 contains 9 to 20 atoms other than hydrogen or halogen.
[0311] [0311] Typically, in any of the above exemplary combinations, m is 0 or 1 and R3, where present, is independently selected from a C1-C4 alkyl or C3-C4 cycloalkyl group, where any C1-C4 alkyl or C3 group -C4 cycloalkyl can optionally be substituted by one or more fluoro and / or chloro groups. In one mode, m is 0.
[0312] [0312] As will be appreciated, the above combinations are exemplary only and other combinations of aspects and modalities, including combinations of the above combinations, can be readily considered. EXAMPLES - SUMMARY OF COMPOUNDS
[0313] [0313] All solvents, reagents and compounds were purchased and used without further purification, unless otherwise specified. Abbreviations 2-MeTHF 2-methyltetrahydrofuran Ac2O acetic anhydride AcOH aqueous acetic acid Boc tert-butyloxycarbonyl broad Cbz carboxybenzyl CDI 1,1-carbonyl-di-imidazole conc concentrate doublet DABCO 1,4-diazabicyclo [2,2, 2] octane DCE 1,2-dichloroethane, also called ethylene dichloride DCM dichloromethane DIPEA N, N-diisopropylethylamine, also called Hünig DMA dimethylacetamide DMAP 4-dimethylaminopyridine, also called N, N-dimethylpyridin-4-amine DME dimetoxyethane DMF N, N-dimethylformamide DMSO dimethyl sulfoxide eq or equivalent equiv
[0314] [0314] NMR spectra were recorded at 300, 400 or 500 MHz. Spectra were measured at 298 K, unless otherwise stated, and were referenced in relation to the resonance of the solvent. Chemical shifts are reported in parts per million. The spectra were recorded using one of the following machines: - a 400 MHz Bruker Avance III spectrometer adjusted with a 5mm BBO liquid probe, - a 400 MHz Bruker spectrometer using ICON-NMR, under the control of the TopSpin program, - a Bruker spectrometer Advance III HD at 500 MHz, equipped with a Bruker 5 mm SmartProbeTM, - an Agilent VNMRS 300 instrument fitted with a Oxford Instruments Tesla 7.05 magnet, indirect detection probe and direct drive console, including the PFG module, or - an Agilent MercuryPlus 300 instrument fitted with a Tesla 7.05 magnet from Oxford Instruments, a 4-core probe with automatic switching and a Mercury plus console. LC-MS
[0315] [0315] LC-MS methods: 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 2,1X30 mm, 5 µm. Reverse phase HPLC conditions for LCMS analytical methods
[0316] [0316] Methods 1a and 1b: Waters Xselect CSH C18 XP column (4.6 x 30 mm, 2.5 µm) at 40 ° C; flow rate 2.5-4.5 mL min-1 eluted with an H2O-MeCN gradient containing 0.1% v / v formic acid (Method 1a) or 10 mM NH4HCO3 in water (Method 1b) over 4 minutes, using UV detection at 254 nm. Gradient information: 0-3.00 min, increased from 95% water - 5% acetonitrile to 5% water - 95% acetonitrile; 3.00-3.01 min, maintained at 5% water and 95% acetonitrile, the flow rate increased to 4.5 mL min -1; 3.01-3.50 min, maintained at 5% water and 95% acetonitrile; 3.50-3.60 min, returned to 95% water-5% acetonitrile, flow rate reduced to 3.50 mL min-1; 3.60-3.90 min, maintained at 95% water and 5% acetonitrile; 3.90-4.00 min, maintained at 95% water and 5% acetonitrile, flow rate reduced to 2.5 mL min-1.
[0317] [0317] Method 1c: Agilent 1290 series with UV detector and HP 6130 MSD mass detector using the Waters XBridge BEH C18 XP column (2.1 x 50 mm, 2.5 μm) at 35 ° C; flow rate 0.6 ml / min; 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); for 4 minutes using UV detection at 215 and 238 nm. Gradient information: 0-0.5 min, maintained at 80% A-20% B; 0.5-2.0 min, increased from 80% A-20% B to 100% B. Reverse phase HPLC conditions for UPLC analytical methods
[0318] [0318] Methods 2a and 2b: Waters BEH C18 (2.1 x 30 mm, 1.7 µm) at 40 ° C;
[0319] [0319] Method 1 (acid preparation): Waters X-Select CSH C18 column, 5 µm (19 x 50 mm), flow rate of 28 mL / min-1 eluting with a gradient of H2O-MeCN containing 0.1% v / v formic acid for 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 20% MeCN; 0.2-5.5 min, increased from 20% MeCN to 40% MeCN; 5.5-5.6 min, increased from 40% MeCN to 95% MeCN; 5.6-6.5 min, maintained at 95% MeCN.
[0320] [0320] Method 2 (basic preparation): Waters X-Bridge Prep C18 column, 5 µm (19 x 50 mm), flow rate 28 mL min-1 eluting with a gradient of 10 mM NH4HCO3-MeCN over 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 10% MeCN; 0.2-5.5 min, increased from 10% MeCN to 40% MeCN; 5.5-5.6 min, increased from 40% MeCN to 95% MeCN; 5.6-6.5 min, maintained at 95% MeCN.
[0321] [0321] Method 3: Phenomenex Gemini column, 10 µm (150 x 25 mm), flow rate = 25 mL / min eluting with a water-acetonitrile gradient containing 0.04% NH3 at pH 10 for 9 minutes using detection UV at 220 and 254 nm. Gradient information: 0-9 minutes, increased from 8% to 35% acetonitrile; 9 - 9.2 minutes, increased from 35% to 100% acetonitrile; 9.2-15.2 minutes, maintained at 100% acetonitrile.
[0322] [0322] Method 4 (water-methanol preparation): Revelis C18 reverse phase 12 g cartridge [18% carbon load; surface area 568 m 2 / g; pore diameter 65 Angstrom; pH of 5.1 (5% paste); average particle size 40 µm], flow rate = 30 mL / min eluting with a water-
[0323] [0323] A solution of n-BuLi (100 mL, 250 mmol, 2.5M in hexanes) was added slowly to a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (36 , 2 g, 238 mmol) in THF (500 mL), keeping the temperature below -65 ° C. The mixture was stirred for 1.5 hours, then sulfur dioxide was bubbled through for 10 minutes. The mixture was allowed to warm to room temperature, the solvent was evaporated and the residue was triturated with TBME (300 ml) and filtered. The solid was washed with TBME and isohexane and dried to generate the crude title compound (54.89 g, 99%).
[0324] [0324] 1H NMR (DMSO-d6) δ 7.26 (d, J = 1.6Hz, 1H), 6.10 (d, J = 1.7Hz, 1H), 5.99 (dd, J = 10 , 0, 2.5Hz, 1H), 3.92-3.87 (m, 1H), 3.56-3.49 (m, 1H), 2.25-2.15 (m, 1H), 2 .00-1.91 (m, 1H), 1.75-1.69 (m, 1H), 1.66-1.46 (m, 3H).
[0325] [0325] LCMS; m / z 215 (MH) - (ES-). Step B: N, N-Bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide
[0326] [0326] NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfinate (20 g, 90 mmol ) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 hours, suppressed with water (100 ml) and then partitioned between DCM (300 ml) and water (200 ml). The organic phase was washed with water (200 ml), dried (MgSO 4), filtered and evaporated to ~ 50 ml. The solution was added to a mixture of bis (4-methoxybenzyl) amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature and then partitioned between DCM (300 ml) and water (250 ml). The organic layer was washed with water (250 ml), 1M aq HCl (2 x 250 ml), water (250 ml), dried (MgSO4), filtered and evaporated to generate the crude title compound (41.02 g, 97%) as a brown oil.
[0327] [0327] LCMS; m / z 494.2 (M + Na) + (ES +). Step C: N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0328] [0328] A mixture of N, N-bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide (41 g, 87 mmol) and 1M of Aq HCl (30 ml) in THF (300 ml) and MeOH (50 ml) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between EtOAc (400 ml) and 1M aq HCl (200 ml). The organic layer was washed with 10% saline (200 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with TBME, filtered and dried to generate the title compound (24.87 g, 69%) as an off-white solid.
[0329] [0329] 1H NMR (CDCl3) δ 7.88 (d, J = 2.4 Hz, 1 H), 7.06-7.02 (m, 4 H), 6.79-6.75 (m, 4 H), 6.63 (d, J = 2.4 Hz, 1 H), 4.31 (s, 4 H), 3.78 (s, 6 H). Interchangeable proton not visible.
[0330] [0330] LCMS: m / z 388 (M + H) + (ES +); 386 (M-H) - (ES-). Step D: 2- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide
[0331] [0331] Under nitrogen, a mixture of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (500 mg, 1.290 mmol) and K2CO3 (350 mg, 2.53 mmol) was suspended in dry acetonitrile (10 mL). 2-chloro-N, N-dimethylacetamide (0.133 mL, 1.290 mmol) was added in a single part and the cloudy mixture was heated to 65 ° C (bath temperature) for 3 hours. The mixture was diluted with water (5 ml) and extracted with DCM (3 x 25 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 (40g column, 0-100% EtOAc / isohexane) to generate the title compound (420g, 65%) as a light yellow oil.
[0332] [0332] 1H NMR (CDCl3) δ 7.65 (d, J = 2.4 Hz, 1H), 7.09-6.99 (m, 4H), 6.85-6.76 (m, 4H) , 6.72 (d, J = 2.4 Hz, 1H), 5.08 (s, 2H), 4.32 (s, 4H), 3.80 (s, 6H), 3.10 (s, 3H), 3.04 (s, 3H).
[0333] [0333] LCMS; m / z 473 (M + H) + (ES +). Step E: N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide
[0334] [0334] 2- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (440 mg, 0.931 mmol) was dissolved in DCM (1 mL ) and water (0.5 ml) and TFA (2 ml, 26.0 mmol) added. The reaction mixture was then stirred at room temperature for 15 hours. The mixture was concentrated in vacuo and the crude product purified by chromatography (Companion apparatus, RP Flash C18, 12 g column, 0-10% acetonitrile / 10 mM ammonium bicarbonate) to generate the title compound (195 mg, 88%) as a white solid.
[0335] [0335] 1H NMR (DMSO-d6) δ 7.76 (d, J = 2.4 Hz, 1H), 7.35 (s, 2H), 6.59 (d, J = 2.4 Hz, 1H ), 5.20 (s, 2H), 3.04 (s, 3H), 2.86 (s, 3H). Intermediate P2: N-Methyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide Step A: 2- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1 -il) -N- methylacetamide
[0336] [0336] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 2-chloro-N-methylacetamide to generate the title compound (449 g, 72%) as a colorless crystalline solid.
[0337] [0337] 1H NMR (CDCl3) δ 7.54 (d, J = 2.4 Hz, 1H), 7.09-7.02 (m, 4H), 6.81-6.76 (m, 4H) , 6.71 (d, J = 2.4 Hz, 1H), 5.91 (s, 1H), 4.83 (s, 2H), 4.32 (s, 4H), 3.79 (s, 6H), 2.75 (d, J = 4.6 Hz, 3H).
[0338] [0338] LCMS; m / z 480 (M + Na) + (ES +), 457 (M-H) + (ES-). Step B: N-methyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide
[0339] [0339] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) of 2- (3- (N, N bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) methyl) -N-methylacetamide to generate the title compound (146 mg, 70%) as a colorless crystalline solid.
[0340] [0340] 1H NMR (DMSO-d6) δ 8.22-8.11 (br s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.41 (s, 2H), 6.59 (d, J = 2.4 Hz, 1H), 4.85 (s, 2H), 2.64 (d, J = 4.6 Hz, 3H). Intermediate P3: 1- (2- (Pyrrolidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide Step A: 1- (2-Hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazole -3-sulfonamide
[0341] [0341] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 2-bromoethanol to generate the title compound (3.50 g, 68%) as a yellow oil .
[0342] [0342] 1H NMR (DMSO-d6) δ 7.93 (d, J = 2.3 Hz, 1H), 7.03-6.98 (m, 4H), 6.84-6.78 (m, 4H), 6.71 (d, J = 2.4 Hz, 1H), 5.01 (t, J = 5.2 Hz, 1H), 4.27 (t, J = 5.5 Hz, 2H) , 4.19 (s, 4H), 3.81 - 3.74 (m, 2H), 3.72 (s, 6H).
[0343] [0343] LCMS; m / z 454.5 (M + Na) + (ES +). Step B: N, N-bis (4-methoxybenzyl) -1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide
[0344] [0344] 1- (2-Hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (0.5 g, 1.159 mmol) and DIPEA (0.28 mL, 1.608 mmol) were dissolved in THF (5 ml) and cooled to 0 ° C in an ice bath. Methanesulfonyl chloride (0.10 ml, 1.292 mmol) was added and the mixture was stirred at 0 ° C for 1 hour. Pyrrolidine (0.29 mL, 3.47 mmol) was added and the mixture was stirred at room temperature over the weekend and then at 50 ° C for 6 hours. The reaction mixture was diluted with water (10 ml) and poured into EtOAc (10 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 10 ml). The combined organic layers were dried (MgSO4), filtered and evaporated to produce an orange oil. The crude product was purified by chromatography on silica gel (24 g column, 0-100% EtOAc / isohexane followed by 0-20% MeOH / DCM) to generate the title compound (395 mg, 68%) as a thick yellow oil.
[0345] [0345] 1H NMR (DMSO-d6) δ 7.97 (d, J = 2.3 Hz, 1H), 7.07-6.96 (m, 4H), 6.86-6.75 (m, 4H), 6.69 (d, J = 2.3 Hz, 1H), 4.31 (t, J = 6.5 Hz, 2H), 4.18 (s, 4H), 3.71 (s, 6H), 2.83 (t, J = 6.5 Hz, 2H), 2.48 - 2.41 (m, 4H), 1.72 - 1.58 (m, 4H).
[0346] [0346] LCMS; m / z 486 (M + H) + (ES +). Step C: 1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide
[0347] [0347] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) from N, N-bis (4 -methoxybenzyl) -1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide to generate the title compound (187 mg, 94%) as a standing yellow solid.
[0348] [0348] 1H NMR (DMSO-d6) δ 7.88 (d, J = 2.3 Hz, 1H), 7.37 (s, 2H), 6.55 (d, J = 2.3 Hz, 1H ), 4.26 (t, J = 6.6 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.49-2.39 (m, 4H), 1.73 -1.58 (m, 4H).
[0349] [0349] LCMS; m / z 245 (M + H) + (ES +). Intermediate P4: tert-butyl 1- (1-acetylazetidin-3-yl) -1H-pyrazol-3-sulfonamide Step A: tert-butyl 3- (3-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate
[0350] [0350] Under nitrogen, a mixture of 3-nitro-1H-pyrazole (3 g, 26.5 mmol) and K2CO3 (11.00 g, 80 mmol) was suspended in dry DMF (75 mL). Tert-butyl 3-iodoazetidine-1-carboxylate (5.52 mL, 31.8 mmol) was added in a single part and the cloudy mixture was heated at 100 ° C for 4 hours. The mixture was diluted with water (5 ml) and extracted with DCM (3 x 50 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, 0-100% EtOAc / isohexane) to generate the title compound (5.3 g, 74%) as a colorless solid.
[0351] [0351] 1H NMR (DMSO-d6) δ 8.20 (d, J = 2.6 Hz, 1H), 7.11 (d, J = 2.6 Hz, 1H), 5.43-5.28 (m, 1H), 4.35 (t, J = 8.6 Hz, 2H), 4.22-4.03 (m, 2H), 1.42 (s, 9H).
[0352] [0352] LCMS; m / z 269 (M + H) + (ES +). Step B: 1- (Azetidin-3-yl) -3-nitro-1H-pyrazole, HCl
[0353] [0353] 4M hydrogen chloride in dioxane (24.70 mL, 99 mmol) was added to a solution of tert-butyl 3- (3-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate ( 5.3 g, 19.76 mmol) in 1,4-dioxane (20 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to generate the title compound (4.1 g, 96%) as an off-white solid.
[0354] [0354] LCMS; m / z 169 (M + H) + (ES +). Step C: 1- (3- (3-nitro-1H-pyrazol-1-yl) azetidin-1-yl) ethanone
[0355] [0355] A suspension of 1- (azetidin-3-yl) -3-nitro-1H-pyrazole hydrochloride (2.59 g, 12.66 mmol) in DCM (36 mL) was treated with triethylamine (5.26 mL, 38.0 mmol) and stirred at room temperature for 10 minutes. The mixture was then cooled on ice to 0 ° C and acetyl chloride (1.084 ml, 15.19 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred for 10 minutes at 0 ° C, then the reaction mixture was allowed to warm to room temperature with stirring for 18 hours. The solvent was removed under reduced pressure and the residue was suspended in acetonitrile and then filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g column, 0-20% MeOH / DCM) to generate the title compound (1.02 g, 35%) as a yellow solid.
[0356] [0356] 1H NMR (DMSO-d6) δ 8.22 (d, J = 2.6 Hz, 1H), 7.12 (d, J = 2.6 Hz, 1H), 5.46-5.34 (m, 1H), 4.66-4.56 (m, 1H), 4.46-4.37 (m, 1H), 4.36-4.27 (m, 1H), 4.11 (dd , J = 10.3, 5.2 Hz, 1H), 1.83 (s, 3H).
[0357] [0357] LCMS; m / z 211 (M + H) + (ES +). Step D: 1- (3- (3-amino-1H-pyrazol-1-yl) azetidin-1-yl) ethanone
[0358] [0358] 1- (3- (3-nitro-1H-pyrazol-1-yl) azetidin-1-yl) ethanone (1.02 g, 4.46 mmol) and 10% palladium on carbon (wet type 87 L) (0.024 g) were suspended in MeOH (10 ml) and EtOAc (10 ml). The reaction mixture was stirred at room temperature under 2 bar of H2 for 17 hours. The reaction mixture was filtered through a pad of Celite® and the filter cake was washed with EtOAc (2 x 10 ml). The filtrate was concentrated to dryness to produce the title compound (0.95 g, 92%) as a viscous yellow oil.
[0359] [0359] 1H NMR (DMSO-d6) δ 7.42 (d, J = 2.3 Hz, 1H), 5.41 (d, J = 2.3 Hz, 1H), 4.94 (ddd, J = 8.0, 5.3, 2.7 Hz, 1H), 4.80 (s, 2H), 4.43 (ddd, J = 9.0, 8.0, 1.1 Hz, 1H), 4.29 (dd, J = 8.6, 5.4 Hz, 1H), 4.15 (ddd, J = 9.4, 8.1, 1.1 Hz, 1H), 4.07 - 3.93 (m, 1H) , 1.78 (s, 3H).
[0360] [0360] LCMS; m / z 181 (M + H) + (ES +). Step E: 1- (1-acetylazetidin-3-yl) -1H-pyrazol-3-sulfonyl chloride
[0361] [0361] A mixture of concentrated HCl (1.5 ml) in water (1 ml) and acetonitrile (5.0 ml) was cooled to -10 ° C and treated with a sodium nitrite solution (0.338 g, 4, 90 mmol) in water (0.6 mL) dropwise keeping the internal temperature below 0 ° C. The solution was stirred for 10 minutes and then treated with a solution of 1- (3- (3-amino-1H-pyrazol-1-yl) azetidin-1-yl) ethanone (0.95 g, 4.09 mmol) in acetonitrile (5.1 ml) (which has been pre-cooled to 0 ° C) to 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 50 minutes. Cold AcOH (2 mL), CuCl2.2H2O (0.275 g, 2.043 mmol) and CuCl (0.02 g, 0.204 mmol) were added sequentially to the reaction mixture and the reaction mixture was purged with SO2 gas for 20 minutes at 0 ° C. The reaction was stirred for another 45 minutes, diluted with water (20 ml) and extracted with EtOAc (2 x 20 ml). The organic phase was washed with water (25 ml) and saturated saline (25 ml), dried over Na2SO4, filtered and concentrated in vacuo to generate a brown oil. The crude product was purified by chromatography on silica gel (24 g column, 0-10% MeOH / DCM) to generate the title compound (528 mg, 32%) as a yellow oil.
[0362] [0362] 1H NMR (CDCl3) δ 7.69 (d, J = 2.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 5.25 (p, J = 6 , 7 Hz, 1H), 4.74-4.27 (m, 4H), 1.96 (s, 3H). Step F: 1- (1-acetylazetidin-3-yl) -1H-pyrazol-3-sulfonamide
[0363] [0363] 1- (1-Acetylazetidin-3-yl) -1H-pyrazol-3-sulfonyl chloride (0.52 g, 1.301 mmol) in THF (8 mL) was treated with 0.5 M ammonia in dioxane (7.8 mL, 3.90 mmol) and the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH / DCM) to generate the title compound (136 mg, 42%) as a white powder .
[0364] [0364] 1H NMR (DMSO-d6) δ 8.06 (d, J = 2.4 Hz, 1H), 7.50 (s, 2H), 6.64 (d, J = 2.4 Hz, 1H ), 5.34 (ddd, J = 8.1, 5.3, 2.9 Hz, 1H), 4.75-4.43 (m, 1H), 4.50-4.12 (m, 2H ), 4.09 (dd, J = 10.0, 5.3 Hz, 1H), 1.82 (s, 3H).
[0365] [0365] LCMS; m / z 245 (M + H) + (ES +). Intermediate P5: 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide Step A: 2-Amino-5-methyl-6,7-di -hydropyrazolo [1,5-a] apirazin-4 (5H) -one
[0366] [0366] Zinc (167 mg, 2.55 mmol) was added in parts to 5-methyl-2-nitro-6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one ( 1.4 g, 7.14 mmol) in AcOH (1.0 mL) and THF (1.5 mL). The reaction mixture was then stirred at room temperature for 2 days. The reaction mixture was filtered through a pad of Celite ®, washed with DCM (2 x 15 mL) and the filtrate concentrated under reduced pressure to produce a yellow solid. The solid was suspended in DCM (5 ml), filtered and the filtrate was evaporated to dryness to yield the title compound (2.2 g, 74%) as a yellow solid.
[0367] [0367] 1H NMR (DMSO-d6) δ 5.80 (s, 1H), 4.83 (s, 2H), 4.10-3.93 (m, 2H), 3.72-3.55 ( m, 2H), 2.97 (s, 3H).
[0368] [0368] LCMS; m / z 167 (M + H) + (ES +). Step B: 5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonyl chloride
[0369] [0369] A mixture of aqueous HCl (2.2 ml) in water (8 ml) and acetonitrile (8 ml) was cooled to -10 ° C and treated with a NaNO2 solution (0.50 g, 7.25 mmol ) in water (0.9 mL), drop by drop, keeping the internal temperature below 0 ° C. The solution was stirred for 10 minutes and then treated with a solution of 2-amino-5-methyl-6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one (0.997 g, 6 mmol ) in acetonitrile (8 ml) (which has been pre-cooled to 0 ° C) to 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 50 minutes. Cold AcOH (4.8 mL), dehydrated CuCl2 (0.30 g, 2.23 mmol) and CuCl (0.03 g, 0.30 mmol) were added sequentially to the reaction mixture and the reaction mixture was purged with SO2 gas for 20 minutes at 0 ° C. The reaction was stirred for another 45 minutes, diluted with water (20 ml) and extracted with EtOAc (2 x 20 ml). The organic phase was washed with water (25 ml) and saturated saline (25 ml), dried (MgSO 4), filtered and concentrated in vacuo to generate a brown oil. The brown oil was purified by chromatography on silica gel (40 g column, 0-100% EtOAc / isohexane) to generate the title compound (577 mg, 30%) as a yellow crystalline solid.
[0370] [0370] 1H NMR (CDCl3) δ 7.39 (s, 1H), 4.63-4.45 (m, 2H), 3.95-3.83 (m, 2H), 3.19 (s, 3H). Step C: 5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide
[0371] [0371] 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonyl chloride (577 mg, 1.826 mmol) in THF (4 mL) was treated with 0.5 M ammonium in 1,4-dioxane (11.00 mL, 5.50 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was suspended in water (10 ml) and filtered. The yellow powder obtained was then washed with DCM (2 x 5 ml) and dried in vacuo to generate the title compound (332 mg, 77%) as a white powder.
[0372] [0372] 1H NMR (DMSO-d6) δ 7.57 (s, 2H), 6.93 (s, 1H), 4.59-4.34 (m, 2H), 3.90-3.71 ( m, 2H), 3.01 (s, 3H).
[0373] [0373] LCMS; m / z 231 (M + H) + (ES +). Intermediate P6: 1- (2- (dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide Step A: 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazole- 3- sulfonamide
[0374] [0374] Prepared according to the general procedure of N, N-bis (4-methoxybenzyl) -1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P3, Step B ) of 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P3, Step A) and dimethylamine to generate the title compound (208 mg, 62%) like a pale yellow oil.
[0375] [0375] 1H NMR (CDCl3) δ 7.58 (d, J = 2.3 Hz, 1H), 7.11 - 7.05 (m, 4H), 6.82 - 6.76 (m, 4H) , 6.65 (d, J = 2.3 Hz, 1H), 4.34 (t, J = 6.5 Hz, 2H), 4.32 (s, 4H), 3.81 (s, 6H) , 2.84 (t, J = 6.5 Hz, 2H), 2.33 (s, 6H).
[0376] [0376] LCMS; m / z 459 (M + H) + (ES +). Step B: 1- (2- (Dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide
[0377] [0377] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) from 1- (2- (dimethylamino ) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (78 mg, 81%) as a pale yellow oil.
[0378] [0378] 1H NMR (DMSO-d6) δ 7.87 (d, J = 2.3 Hz, 1H), 7.37 (s, 2H), 6.55 (d, J = 2.2 Hz, 1H ), 4.25 (t, J = 6.5 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.17 (s, 6H). Intermediate P7: 1- (2- (Dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide Step A: 1- (tetrahydro-2H-pyran-2-yl) -1H -pyrazol-5-lithium sulfinate
[0379] [0379] A solution of n-BuLi (100 mL, 250 mmol, 2.5M in hexanes) was added slowly to a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (36 , 2 g, 238 mmol) in THF (500 mL), keeping the temperature below -65 ° C. The mixture was stirred for 1.5 hours, then sulfur dioxide was bubbled through for 10 minutes. The mixture was allowed to warm to room temperature, the solvent was evaporated and the residue was triturated with TBME (300 ml) and filtered. The solid was washed with TBME and isohexane and dried to generate the crude title compound (54.89 g, 99%).
[0380] [0380] 1H NMR (DMSO-d6) δ 7.26 (d, J = 1.6Hz, 1H), 6.10 (d, J = 1.7Hz, 1H), 5.99 (dd, J = 10.0 , 2.5Hz, 1H), 3.92-3.87 (m, 1H), 3.56-3.49 (m, 1H), 2.25-2.15 (m,
[0381] [0381] LCMS; m / z 215 (M-H) - (ES-). Step B: N, N-Bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide
[0382] [0382] NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfinate (20 g, 90 mmol ) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 hours, suppressed with water (100 ml) and then partitioned between DCM (300 ml) and water (200 ml). The organic phase was washed with water (200 ml), dried (MgSO 4), filtered and evaporated to ~ 50 ml. The solution was added to a mixture of bis (4-methoxybenzyl) amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature and then partitioned between DCM (300 ml) and water (250 ml). The organic layer was washed with water (250 ml), 1M aq HCl (2 x 250 ml), water (250 ml), dried (MgSO4), filtered and evaporated to generate the crude title compound (41.02 g, 97%) as a brown oil.
[0383] [0383] LCMS; m / z 494.2 (M + Na) + (ES +). Step C: N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0384] [0384] A mixture of N, N-bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide (41 g, 87 mmol) and 1M Aq HCl (30 ml) in THF (300 ml) and MeOH (50 ml) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between EtOAc (400 ml) and 1M aq HCl (200 ml). The organic layer was washed with 10% saline solution (200 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with TBME, filtered and dried to generate the title compound (24.87 g, 69%) as an off-white solid.
[0385] [0385] 1H NMR (CDCl3) δ 7.88 (d, J = 2.4Hz, 1H), 7.06-7.02 (m, 4H), 6.79- 6.75 (m, 4H), 6.63 (d, J = 2.4 Hz, 1H), 4.31 (s, 4H), 3.78 (s, 6H). Exchangeable proton not visible.
[0386] [0386] LCMS; m / z 388 (M + H) + (ES +); 386 (M-H) - (ES-). Step D: 1- (2-Hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0387] [0387] N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (3.94 g, 10.17 mmol) and potassium carbonate (4.22 g, 30.5 mmol) were suspended in dry acetonitrile (30 ml). 2-bromoethanol (0.937 ml, 13.22 mmol) was added, the mixture was heated to 50 ° C overnight, then water (20 ml) was added and the organic layer was collected. The aqueous layer was extracted with EtOAc (3 x 20 ml) and the combined organic layers were dried (MgSO 4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g column, 0-75% EtOAc / isohexane) to generate the title compound (3 g, 66%) as a clear colorless oil.
[0388] [0388] 1H NMR (CDCl3) δ 7.50 (d, J = 2.3 Hz, 1H), 7.12-7.01 (m, 4H), 6.82- 6.74 (m, 4H) , 6.66 (d, J = 2.3 Hz, 1H), 4.32 (s, 4H), 4.30-4.24 (m, 2H), 4.01-3.94 (m, 2H ), 3.78 (s, 6H). OH proton not visible.
[0389] [0389] LCMS; m / z 454.4 (M + Na) + (ES +). Step E: 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0390] [0390] 1- (2-Hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (2.00 g, 4.63 mmol) and DIPEA (1.4 mL, 8, 04 mmol) were dissolved in THF (20 mL) and cooled to 0 ° C. Methanesulfonyl chloride (0.40 ml, 5.17 mmol) was added and the mixture was stirred at 0 ° C for 1 hour. Dimethylamine (40% in water) (3 ml, 23.69 mmol) was added and the reaction mixture was stirred at room temperature over the weekend. The mixture was concentrated to dryness and the yellow residue was partitioned between water (30 ml) and EtOAc (70 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 70 ml). The combined organic layers were dried (MgSO 4) and evaporated to produce a yellow oil. The crude product was loaded onto a SCX column (7 g) in MeOH. The column was washed with DCM: MeOH (9: 1) and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to generate the title compound (1.36 g, 61%) as a thick orange oil.
[0391] [0391] 1H NMR (CDCl3) δ 7.54 (d, J = 2.3 Hz, 1H), 7.14-6.97 (m, 4H), 6.81-6.71 (m, 4H) , 6.62 (d, J = 2.3 Hz, 1H), 4.35-4.21 (m, 6H), 3.78 (s, 6H), 2.77 (t, J = 6.5 Hz, 2H), 2.29 (s, 6H).
[0392] [0392] LCMS; m / z 459.5 (M + H) + (ES +). Step F: 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0393] [0393] A solution of n-BuLi (2.5M in hexanes) (0.44 mL, 1,100 mmol) was added dropwise to a stirred solution of 1- (2- (dimethylamino) ethyl) -N, N- bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (0.5 g, 1.090 mmol) in THF (14 mL) at -78 ° C. The reaction was stirred for 1 hour and N-methyl-N-methylene methanamine iodide (0.403 g, 2.181 mmol) was added. The reaction mixture was left at - 78 ° C for 1 hour. Then the reaction mixture was suppressed with water (20 ml) and extracted with EtOAc (2 x 20 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified by chromatography on silica gel (24 g column, 0-10% MeOH / DCM) to generate the title compound (208 mg, 35%) as a yellow oil.
[0394] [0394] 1H NMR (DMSO-d6) δ 7.09-6.94 (m, 4H), 6.89-6.73 (m, 4H), 6.56 (s, 1H), 4.28 ( t, J = 6.9 Hz, 2H), 4.20 (s, 4H), 3.71 (s, 6H), 3.48 (s, 2H), 2.63 (t, J = 6.9 Hz, 2H), 2.19 (s, 6H), 2.16 (s, 6H).
[0395] [0395] LCMS; m / z 517 (M + H) + (ES +). Step G: 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide
[0396] [0396] 1- (2- (Dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (207 mg, 0.401 mmol) was dissolved in TFA (3 ml) and stirred at room temperature for 17 hours. The mixture was evaporated to dryness, dissolved in DCM: MeOH (9: 1) and loaded into SCX (1 g). The column was washed with DCM: MeOH (9: 1) (2 x 20 ml), then the product was eluted with 0.7 NH3 in DCM: MeOH (9: 1) (2 x 10 ml). The resulting mixture was concentrated in vacuo to generate the title compound (82 mg, 73%) as a white solid.
[0397] [0397] 1H NMR (DMSO-d6) δ 7.35 (s, 2H), 6.46 (s, 1H), 4.25 (t, J = 7.0 Hz, 2H), 3.47 (s, 2H ), 2.64 (t, J = 7.0 Hz, 2H), 2.19 (s, 6H), 2.16 (s, 6H).
[0398] [0398] LCMS; m / z 276 (M + H) + (ES +). Intermediate P8: 1- (2- (Dimethylamino) ethyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-sulfonamide Step A: 1- (2- (dimethylamino) ethyl) -5- ( 2-hydroxypropan-2-yl) -N, N-bis (4methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0399] [0399] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P6, Step A) and acetone to generate the compound title (373 mg, 33%) as a white solid.
[0400] [0400] 1H NMR (DMSO-d6) δ 7.10-6.94 (m, 4H), 6.88-6.72 (m, 4H), 6.40 (s, 1H), 5.63 ( s, 1H), 4.54-4.45 (m, 2H), 4.20 (s, 4H), 3.72 (s, 6H), 2.69 (t, J = 7.3 Hz, 2H ), 2.20 (s, 6H), 1.50 (s, 6H).
[0401] [0401] LCMS; m / z 518 (M + H) + (ES +). Step B: 1- (2- (Dimethylamino) ethyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-sulfonamide
[0402] [0402] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P7, Step G) of 1- (2 - (dimethylamino) ethyl) -5- (2-hydroxypropan-2-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (140 mg, 67%) like a pale yellow solid at rest.
[0403] [0403] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.38 (s, 1H), 5.63 (s, 1H), 4.64 - 4.35 (m, 2H) , 2.79-2.65 (m, 2H), 2.21 (s, 6H), 1.52 (s, 6H).
[0404] [0404] LCMS; m / z 277 (M + H) + (ES +). Intermediate P9: 5-Methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide
[0405] [0405] The borane-tetrahydrofuran complex (0.87 mL, 0.87 mmol) was added to a solution of 5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1.5 -
[0406] [0406] 1H NMR (DMSO-d6) δ 7.35 (s, 2H), 6.36 (s, 1H), 4.14 (t, J = 5.6 Hz, 2H), 3.60 (s , 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.40 (s, 3H). Intermediate P10: 1 - ((1- (dimethylamino) cyclopropyl) methyl) -1H-pyrazol-3-sulfonamide Step A: 1 - ((1- (dimethylamino) cyclopropyl) methyl) -N, N-bis (4-methoxybenzyl ) -1H-pyrazol-3-sulfonamide
[0407] [0407] Ethylmagnesium bromide (1M in THF) (2.2 mL, 2,200 mmol) was added dropwise over 20 seconds to a stirred solution of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl ) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D) (500 mg, 1.058 mmol) and triisopropoxy (methyl) titanium (1.3 mL, 1,300 mmol) in THF (3 mL ) at room temperature. The mixture was then stirred at room temperature for 23 hours. The reaction was suppressed with water (5 ml) and aqueous sodium bicarbonate (10 ml). The reaction mixture was filtered and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 20 ml) and the combined organic layers were dried (MgSO 4), filtered and concentrated to dryness to produce a yellow oil. The crude product was loaded onto a SCX column (3 g) in MeOH. The column was washed with DCM: MeOH (9: 1) and then the product was eluted with 0.7 M ammonia in DCM: MeOH
[0408] [0408] 1H NMR (DMSO-d6) δ 8.03 (d, J = 2.4 Hz, 1H), 7.12-6.99 (m, 4H), 6.85-6.75 (m, 4H), 6.73 (d, J = 2.3 Hz, 1H), 4.30 (s, 2H), 4.19 (s, 4H), 3.71 (s, 6H), 2.13 ( s, 6H), 0.78-0.64 (m, 2H), 0.67-0.52 (m, 2H).
[0409] [0409] LCMS; m / z 485 (M + H) + (ES +). Step B: 1 - ((1- (dimethylamino) cyclopropyl) methyl) -1H-pyrazol-3-sulfonamide
[0410] [0410] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) of 1 - ((1- (dimethylamino) cyclopropyl) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (169 mg, 82%) as a standing orange solid.
[0411] [0411] 1H NMR (DMSO-d6) δ 7.91 (d, J = 2.3 Hz, 1H), 7.37 (s, 2H), 6.58 (d, J = 2.3 Hz, 1H ), 4.26 (s, 2H), 2.14 (s, 6H), 0.74-0.67 (m, 2H), 0.61-0.53 (m, 2H).
[0412] [0412] LCMS; m / z 245 (M + H) + (ES +). Intermediate P11: 1- (1-Methylazetidin-3-yl) 1H-pyrazol-3-sulfonamide Step A: 3- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl ) tert-butyl azetidine-1-carboxylate
[0413] [0413] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and tert-butyl 3-iodoazetidine-1-carboxylate to generate the title compound (2.45 g, 79%) as a thick colorless oil.
[0414] [0414] 1H NMR (DMSO-d6) δ 8.10 (d, J = 2.4 Hz, 1H), 7.13-6.94 (m, 4H), 6.91-6.78 (m, 4H), 6.76 (d, J = 2.4 Hz, 1H), 5.39-5.18 (m, 1H), 4.33 (t, J = 8.6 Hz, 2H), 4, 22 (s, 4H), 4.14 - 4.04 (m, 2H), 3.72 (s, 6H), 1.40 (s, 9H).
[0415] [0415] LCMS; m / z 443 (M + H-Boc) + (ES +). Step B: 1- (Azetidin-3-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0416] [0416] 2M lithium aluminum hydride in THF (3.04 mL, 6.07 mmol) was added dropwise to a stirred solution of 3- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl ) Tert-butyl -1H-pyrazol-1-yl) azetidine-1-carboxylate (1.22 g, 2.023 mmol) in THF (30 mL) at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction was cooled to 0 ° C and suppressed sequentially with H2O (0.6 ml), 2M NaOH (1.5 ml) and H2O (3 ml). Na2SO4 was added, the mixture was stirred for 30 minutes and then filtered through a plug of Celite® with EtOAc. The filtrate was evaporated to produce the title compound (1.1 g, 100%) as a yellow oil.
[0417] [0417] LCMS; m / z 443 (M + H) + (ES +). Step C: N, N-Bis (4-methoxybenzyl) -1- (1-methylazetidin-3-yl) -1H-pyrazol-3-sulfonamide
[0418] [0418] A mixture of 1- (azetidin-3-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (1.1 g, 2.02 mmol), formaldehyde (37% in H2O, 10% MeOH) (1.50 mL, 20.15 mmol) and formic acid (0.78 mL, 20.34 mmol) was stirred at 60 ° C overnight. The mixture was concentrated to dryness to produce a yellow oil. The crude product was loaded onto a SCX column (4 g) in MeOH. The column was washed with MeOH (2 x 20 ml) and then the product was eluted with 0.7 M ammonia in DCM: MeOH (9: 1) (50 ml) and concentrated in vacuo to generate a yellow oil. The crude product was purified by chromatography on silica gel (40 g column, 0-20% MeOH / DCM) to generate the title compound (630 mg, 40%) as a thick colorless oil.
[0419] [0419] 1H NMR (DMSO-d6) δ 8.09 (d, J = 2.4 Hz, 1H), 7.09-7.01 (m, 4H), 6.84-6.77 (m, 4H), 6.74 (d, J = 2.4 Hz, 1H), 5.08-4.99 (m, 1H), 4.22 (s, 4H), 3.71 (s, 6H), 3.70-3.66 (m, 2H), 3.37-3.32 (m, 2H), 2.32 (s, 3H).
[0420] [0420] LCMS; m / z 457 (M + H) + (ES +). Step D: 1- (1-methylazetidin-3-yl) -1H-pyrazol-3-sulfonamide
[0421] [0421] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) from N, N-bis (4 -methoxybenzyl) -1- (1- (methylazetidin-3-yl) ethyl) -1H-pyrazol-3-sulfonamide to generate the title compound (115 mg, 49%) as a pale yellow solid.
[0422] [0422] 1H NMR (CDCl3) δ 7.66 (d, J = 2.5 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 4.96 (p, J = 6 , 5 Hz, 1H), 3.83-3.72 (m, 2H), 3.58 - 3.50 (m, 2H), 2.43 (s, 3H). Two interchangeable protons not visible.
[0423] [0423] LCMS; m / z 217 (M + H) + (ES +). Intermediate P12: 2,2,2-trifluoro-N-methyl-N- (2- (3-sulfamoyl-1H-pyrazol-1-yl) ethyl) acetamide Step A: N, N-Bis (4-methoxybenzyl) - 1- (2- (methylamino) ethyl) -1H-pyrazol-3-sulfonamide
[0424] [0424] Dess-Martin periodinane (0.541 g, 1.275 mmol) was added to a solution of 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P3, Step A) (0.5 g, 1.159 mmol) in DCM (8 mL) at room temperature. The reaction mixture was stirred for 1 hour and then methylamine (2M in THF) (3 mL, 6.00 mmol) was added, followed by solid sodium triacetoxyhydroborate (0.368 g, 1.738 mmol). The mixture was stirred at room temperature for 16 hours. The DCM was removed in vacuo, the residue was dissolved in MeOH (30 ml) and SCX (8 g) was added and the mixture was stirred at room temperature for 2 hours. The SCX was filtered and washed with water (100 ml), DCM (100 ml) and MeOH (100 ml). The product was then eluted with 0.7 M ammonia in MeOH (150 mL). The solvent was concentrated in vacuo to generate the title compound (211 mg, 31%) as a yellow oil.
[0425] [0425] LCMS; m / z 445 (M + H) + (ES +), 443 (M-H) - (ES -). Step B: N- (2- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) ethyl) - 2,2,2-trifluoro-N-methylacetamide
[0426] [0426] N, N-Bis (4-methoxybenzyl) -1- (2- (methylamino) ethyl) -1H-pyrazol-3-sulfonamide (205 mg, 0.346 mmol) was dissolved in DCM (5 mL) and pyridine ( 50 µL, 0.621 mmol) was added followed by 2,2,2-trifluoroacetic anhydride (75 µL, 0.532 mmol). After stirring for 1 hour, the mixture was removed with water (2 ml). The organic phase was separated by passing through a hydrophobic frit and then concentrated in vacuo to produce an orange oil. The crude product was purified by chromatography on silica gel (12 g column, 0-100% EtOAc / isohexane) to generate the title compound (106 g, 53%) as a colorless oil.
[0427] [0427] 1H NMR (CDCl3) δ 7.42 (d, J = 2.3 Hz, 1H), 7.16-7.07 (m, 4H), 6.84- 6.77 (m, 4H) , 6.67 (d, J = 2.2 Hz, 1H), 4.44 (t, J = 5.8 Hz, 2H), 4.33 (s, 4H), 3.88 (t, J = 5.9 Hz, 2H), 3.81 (s, 6H), 2.84-2.78 (m, 3H).
[0428] [0428] LCMS; m / z 563 (M + Na) + (ES +). Step C: 2,2,2-trifluoro-N-methyl-N- (2- (3-sulfamoyl-1H-pyrazol-1-yl) ethyl) acetamide
[0429] [0429] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) of N- (2- (3- ( N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) ethyl) -2,2,2-trifluoro-N-methylacetamide to generate the title compound (46 mg, 80%) as a yellow solid at rest.
[0430] [0430] LCMS; m / z 301 (M + H) + (ES +). 299 (M-H) - (ES -). Intermediate P13: Benzyl 3- (3-sulfamoyl-1H-pyrazol-1-yl) azetidine-1-carboxylate Step A: 1- (Azetidin-3-yl) -1H-pyrazol-3-sulfonamide
[0431] [0431] 3- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) azetidine-1-tert-butyl carboxylate (Intermediate P11, Step A) (1.06 g, 1.953 mmol) was dissolved in TFA (5 ml) and stirred at room temperature for 19 hours. The solvent was evaporated and the residue loaded onto an SCX column (3 g) in DCM: MeOH (9: 1). The column was washed with DCM: MeOH (9: 1) and then the product was eluted with 0.7 M ammonia in DCM: MeOH (9: 1). The resulting mixture was concentrated in vacuo to generate the title compound (0.38 mg, 87%) as a colorless solid.
[0432] [0432] 1H NMR (DMSO-d6) δ 8.01 (d, J = 2.4 Hz, 1H), 7.48 (s, 2H), 6.61 (d, J = 2.4 Hz, 1H ), 5.25 (p, J = 7.4 Hz, 1H), 4.06 (br s, 1H), 3.93-3.86 (m, 2H), 3.80-3.72 (m , 2H).
[0433] [0433] LCMS; m / z 203.2 (M + H) + (ES +). Step B: Benzyl 3- (3-sulfamoyl-1H-pyrazol-1-yl) azetidine-1-carboxylate
[0434] [0434] To a stirred suspension of 1- (azetidin-3-yl) -1H-pyrazol-3-sulfonamide (0.38 g, 1.691 mmol) and DIPEA (0.66 mL, 3.79 mmol) in DCM ( 5 ml) benzyl chloroformate (0.35 ml, 2.452 mmol) was added dropwise at 0 ° C. The reaction mixture was then stirred at room temperature for 17 hours. The reaction mixture was suppressed with saturated aqueous sodium bicarbonate (5 ml) and stirred for 15 minutes. The solvent was removed under reduced pressure and the residue was triturated with DCM (3 ml) and purified by silica gel chromatography (24 g column, 0-10% MeOH / DCM) to generate the title compound (283 mg, 17%) as a brown tar.
[0435] [0435] 1H NMR (DMSO-d6) δ 8.06 (d, J = 2.4 Hz, 1H), 7.49 (s, 2H), 7.44 - 7.19 (m, 5H), 6 , 63 (d, J = 2.4 Hz, 1H), 5.41 - 5.29 (m, 1H), 5.07 (s, 2H), 4.58-4.28 (m, 2H), 4.32-3.97 (m, 2H).
[0436] [0436] LCMS; m / z 337.2 (M + H) + (ES +). Intermediate P14: 1- (2- (dimethylamino) ethyl) -5-isopropyl-1H-pyrazol-3-sulfonamide Step A: 1- (2- (dimethylamino) ethyl) -5-iodine-N, N-bis (4 -methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0437] [0437] n-BuLi (2.5 M in hexanes) (0.951 ml, 2.377 mmol) was added dropwise to a solution of 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl ) -1H-pyrazol-3-sulfonamide (Intermediate P6, Step A) (1.09 g, 2.377 mmol) in anhydrous THF (15 mL) at -78 ° C, keeping the temperature below -65 ° C. The solution was stirred for 1 hour at -78 ° C, before a solution of diiodine (0.784 g, 3.09 mmol) in THF (5 mL) was added. The mixture was stirred for 5 minutes at this temperature, then the temperature was raised to room temperature and the reaction mixture was stirred for 1 hour. The reaction mixture was suppressed with saturated aqueous ammonium chloride (15 ml) and diluted with DCM (20 ml), then the mixture was poured over 10% by weight aqueous sodium thiosulfate (30 ml). The organic layer was separated and the aqueous layer was extracted with DMC (2 x 20 ml). The combined organic layers were dried (Na 2SO4), filtered and concentrated to dryness to produce a yellow oil. The crude product was purified by chromatography on silica gel (24 g column, 0-5% MeOH / DCM) to generate the title compound (0.48 mg, 32%) as a yellow wax.
[0438] [0438] 1H NMR (DMSO-d6) δ 7.07-7.00 (m, 4H), 6.84 (s, 1H), 6.83-6.77 (m, 4H), 4.28 ( t, J = 6.8 Hz, 2H), 4.20 (s, 4H), 3.72 (s, 6H), 2.63 (t, J = 6.8 Hz, 2H), 2.20 ( s, 6H).
[0439] [0439] LCMS; m / z 585.4 (M + H) + (ES +). Step B: 1- (2- (Dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -5- (prop-1-en-2-yl) - 1H-pyrazol-3-sulfonamide
[0440] [0440] Nitrogen was bubbled through a mixture of 1- (2- (dimethylamino) ethyl) -5-iodine-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (0.48 g , 0.772 mmol), 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane (0.185 mL, 0.984 mmol), palladium acetate (0.037 g , 0.164 mmol), tricyclohexylphosphine in toluene (20% by weight) (0.460 g, 0.328 mmol) and cesium carbonate (2.67 g, 8.20 mmol) in toluene (10 mL) and water (5 mL) for 15 minutes and then the reaction mixture was heated to 100 ° C for 18 hours. Then, the reaction mixture was cooled to room temperature and filtered through a pad of Celite®. The filter cake was washed with DCM (3 x 10 mL) and the organic layer was separated, dried (Na2SO4), filtered and evaporated to produce a brown residue which was purified by chromatography on silica gel (24 g column, 0- 10% MeOH / DCM) to produce the title compound (191 mg, 35%) as an orange oil.
[0441] [0441] 1H NMR (DMSO-d6) δ 7.09-7.01 (m, 4H), 6.84-6.76 (m, 4H), 6.65 (s, 1H), 5.53- 5.40 (m, 1H), 5.35-5.21 (m, 1H), 4.26 (t, J = 6.7 Hz, 2H), 4.21 (s, 4H), 3.71 (s, 6H), 2.61 (t, J = 6.7 Hz, 2H), 2.13 (s, 6H), 2.07-2.02 (m, 3H).
[0442] [0442] LCMS; m / z 499.5 (M + H) + (ES +). Step A: 1- (2- (dimethylamino) ethyl) -5-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0443] [0443] 1- (2- (Dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -5- (prop-1-en-2-yl) - 1H-pyrazol-3-sulfonamide (191 mg, 0.287 mmol) and 5% palladium on carbon (61 mg, 0.014 mmol) were suspended in EtOH (3 mL) and hydrogenated at 5 bar for 17 hours. The reaction mixture was filtered through a pad of Celite ® and washed with EtOH (2 x 5 ml). The filtrate was evaporated to dryness, redissolved in MeOH (3 ml) and loaded onto a SCX column (1 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 generate the title compound (174 g, 92%) as a thick orange oil.
[0444] [0444] 1H NMR (DMSO-d6) δ 7.15-6.96 (m, 4H), 6.90-6.77 (m, 4H), 6.44 (s, 1H), 4.29- 4.15 (m, 6H), 3.72 (s, 6H), 3.09 (sept, J = 6.8 Hz, 1H), 2.63 (t, J = 6.6 Hz, 2H), 2.19 (s, 6H), 1.21 (d, J = 6.8 Hz, 6H).
[0445] [0445] LCMS; m / z 501.5 (M + H) + (ES +). Step D: 1- (2- (dimethylamines) ethyl) -5-isopropyl-1H-pyrazol-3-sulfonamide
[0446] [0446] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P7, Step G) of 1- (2 - (dimethylamino) ethyl) -5-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (68 mg, 73%) as a colorless glass.
[0447] [0447] 1H NMR (DMSO-d6) δ 7.33 (s, 2H), 6.39 (s, 1H), 4.16 (t, J = 6.9 Hz, 2H), 3.08 (sept , J = 6.7 Hz, 1H), 2.63 (t, J = 6.9 Hz, 2H), 2.18 (s, 6H), 1.21 (d, J = 6.8 Hz, 6H ).
[0448] [0448] LCMS; m / z 261.3 (M + H) + (ES +). Intermediate P15: 1- (1- (Dimethylamino) -2-methylpropan-2-yl) -1H-pyrazol-3-sulfonamide Step A: 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole -5-lithium sulfinate
[0449] [0449] A solution of n-BuLi (100 mL, 250 mmol, 2.5M in hexanes) was added slowly to a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (36 , 2 g, 238 mmol) in THF (500 mL), keeping the temperature below -65 ° C. The mixture was stirred for 1.5 hours, then sulfur dioxide was bubbled through for 10 minutes. The mixture was allowed to warm to room temperature, the solvent was evaporated and the residue was triturated with TBME (300 ml) and filtered. The solid was washed with TBME and isohexane and dried to generate the crude title compound (54.89 g, 99%).
[0450] [0450] 1H NMR (DMSO-d6) δ 7.26 (d, J = 1.6Hz, 1H), 6.10 (d, J = 1.7Hz, 1H), 5.99 (dd, J = 10.0 , 2.5Hz, 1H), 3.92-3.87 (m, 1H), 3.56-3.49 (m, 1H), 2.25-2.15 (m, 1H), 2.00 -1.91 (m, 1H), 1.75-1.69 (m, 1H), 1.66-1.46 (m, 3H).
[0451] [0451] LCMS; m / z 215 (M-H) - (ES-). Step B: N, N-Bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide
[0452] [0452] NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfinate (20 g, 90 mmol ) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 hours, suppressed with water (100 ml) and then partitioned between DCM (300 ml) and water (200 ml). The organic phase was washed with water (200 ml), dried (MgSO 4), filtered and evaporated to ~ 50 ml. The solution was added to a mixture of bis (4-methoxybenzyl) amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature and then partitioned between DCM (300 ml) and water (250 ml). The organic layer was washed with water (250 ml), 1M aq HCl (2 x 250 ml), water (250 ml), dried (MgSO4), filtered and evaporated to generate the crude title compound (41.02 g, 97%) as a brown oil.
[0453] [0453] LCMS; m / z 494.2 (M + Na) + (ES +). Step C: N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0454] [0454] A mixture of N, N-bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide (41 g, 87 mmol) and 1M of Aq HCl (30 ml) in THF (300 ml) and MeOH (50 ml) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between EtOAc (400 ml) and 1M aq HCl (200 ml). The organic layer was washed with 10% saline (200 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with TBME, filtered and dried to generate the title compound (24.87 g, 69%) as an off-white solid.
[0455] [0455] 1H NMR (CDCl3) δ 7.88 (d, J = 2.4Hz, 1H), 7.06-7.02 (m, 4H), 6.79- 6.75 (m, 4H), 6.63 (d, J = 2.4 Hz, 1H), 4.31 (s, 4H), 3.78 (s, 6H). Interchangeable proton not visible.
[0456] [0456] LCMS; m / z 388 (M + H) + (ES +); 386 (M-H) - (ES-). Step D: Methyl 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoate
[0457] [0457] N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (2.00 g, 5.16 mmol) and potassium carbonate (2.140 g, 15.49 mmol) were suspended in dry DMF (30 mL). Methyl 2-bromo-2-methylpropanoate (1.002 ml, 7.74 mmol) was added and the mixture was heated to 80 ° C overnight. The reaction mixture was cooled to room temperature, diluted with water (20 ml), poured into saline solution (200 ml) and extracted with MTBE (2 x 50 ml). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness to produce a yellow oil. The crude product was purified by chromatography on silica gel (80 g column, 0-70% EtOAc / isohexane) to generate the title compound (2.45 g, 94%) as a clear colorless oil.
[0458] [0458] 1H NMR (DMSO-d6) δ 8.18 (d, J = 2.5 Hz, 1H), 7.05-6.95 (m, 4H), 6.85-6.78 (m, 4H), 6.78 (d, J = 2.5 Hz, 1H), 4.18 (s, 4H), 3.72 (s, 6H), 3.65 (s, 3H), 1.81 ( s, 6H).
[0459] [0459] LCMS; m / z 511 (M + Na) + (ES +). Step E: 2- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoic acid
[0460] [0460] A mixture of methyl 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoate (2.4 g, 4.92 mmol) and 2M aq NaOH (5 mL, 10.00 mmol) in THF (5 mL) and MeOH (3 mL) was stirred at room temperature for 20 hours. The mixture was partitioned between EtOAc (100 ml) and 1 M aq HCl (100 ml), the organic layer was washed with brine (50 ml), dried (MgSO 4), filtered and evaporated to generate the title compound ( 2.38 g, 95%) as a gum which solidified on standing.
[0461] [0461] 1H NMR (CDCl3) δ 7.64 (d, J = 2.5Hz, 1H), 7.09-7.05 (m, 4H), 6.80- 6.77 (m, 4H), 6.73 (d, J = 2.5 Hz, 1H), 4.32 (s, 4H), 3.80 (s, 6H), 1.91 (s, 6H). Interchangeable proton not visible.
[0462] [0462] LCMS; m / z 472 (M-H) - (ES-). Step F: 2- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N, 2-trimethylpropanamide
[0463] [0463] A mixture of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoic acid (2.1 g, 4.43 mmol), N, N-diisopropylethylamine (3.1 mL, 17.75 mmol) and HATU (1.9 g, 5.00 mmol) in DMF (30 mL) was stirred at 0-5 ° C for 10 minutes and then , dimethylamine hydrochloride (0.723 g, 8.87 mmol) was added. The mixture was warmed to room temperature, stirred for 20 hours and then partitioned between TBME (200 ml) and 1M aq HCl (200 ml). The organic layer was washed with water (100 ml), dried (MgSO 4), filtered, evaporated to dryness and then purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / heptane) to generate the compound of the title (2.2 g, 98%) as a clear gum.
[0464] [0464] 1H NMR (CDCl3, rotamers) δ 7.48 (d, J = 2.4Hz, 1H), 7.14-7.10 (m, 4H), 6.82-6.78 (m, 5H ), 4.33 (s, 4H), 3.81 (s, 6H), 2.97 (br s, 3H), 2.37 (br s, 3H), 1.82 (s, 6H).
[0465] [0465] LCMS; m / z 501 (M + H) + (ES +). Step G: N, N, 2-trimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) propanamide
[0466] [0466] A mixture of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N, 2-trimethylpropanamide (0.8 g, 1.558 mmol) and TFA (6 mL) was stirred for 4 hours. The reaction mixture was concentrated and the crude product was purified by chromatography on silica gel (12 g column, 0-10% MeOH / DCM) to generate the title compound (360 mg, 86%) as a colorless solid.
[0467] [0467] 1H NMR (DMSO-d6, rotamers) δ 8.02 (d, J = 2.5 Hz, 1H), 7.47 (s, 2H), 6.68 (d, J = 2.4 Hz , 1H), 2.82 (br s, 3H), 2.30 (br s, 3H), 1.71 (s, 6H). Step H: 1- (1- (Dimethylamino) -2-methylpropan-2-yl) -1H-pyrazol-3-sulfonamide O O
[0468] [0468] Borane tetrahydrofuran complex (2.3 mL, 2.30 mmol) was added to a solution of N, N, 2-trimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) propanamide (200 mg, 0.768 mmol) in THF (5 mL) at room temperature. The mixture was stirred for 5 minutes and then heated to reflux overnight. The reaction mixture was cooled to room temperature and 1M aq HCl (2 ml) was added slowly and stirred for 2 hours at 50 ° C. The solvent was evaporated and the crude product was loaded onto a SCX column (3 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in
[0469] [0469] 1H NMR (DMSO-d6) δ 7.90 (d, J = 2.4 Hz, 1H), 7.36 (s, 2H), 6.56 (d, J = 2.4 Hz, 1H ), 2.58 (s, 2H), 1.95 (s, 6H), 1.52 (s, 6H).
[0470] [0470] LCMS; m / z 247 (M + H) + (ES +). Intermediate P16: (S) -1- (2-Dimethylamino) propyl) -1H-pyrazol-3-sulfonamide Step A: (R) -1- (2-Hydroxypropyl) -N, N-bis (4-methoxybenzyls) - 1H-pyrazol-3-sulfonamide
[0471] [0471] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and (R) -2-chloro-N-methyloxirane to generate the title compound (210 g, 46 %) as a clear colorless oil.
[0472] [0472] 1H NMR (CDCl3) δ 7.50 (d, J = 2.3 Hz, 1H), 7.13-7.05 (m, 4H), 6.87- 6.75 (m, 4H) , 6.69 (d, J = 2.3 Hz, 1H), 4.35 (s, 4H), 4.28-3.99 (m, 3H), 3.81 (s, 6H), 1, 28 (d, J = 6.3 Hz, 3H).
[0473] [0473] LCMS; m / z 446 (M + H) + (ES +). Step B: (R) -1- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) - 1H-pyrazol-1-yl) propan-2-yl methanesulfonate
[0474] [0474] Methanesulfonyl chloride (0.22 mL, 2.80 mmol) was added to a solution of (R) -1- (2-hydroxypropyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazole -3- sulfonamide (1.07 g, 2.378 mmol) and DIPEA (0.57 mL, 3.27 mmol) in an anhydrous DCM solution (10 mL) at 0 ° C. The reaction mixture was stirred for 30 minutes at 0 ° C, then the temperature was raised to room temperature and the reaction mixture was stirred for 17 hours. The reaction mixture was suppressed by adding saturated aq NaHCO3 solution (10 ml), then diluted with DCM (40 ml), and the layers were separated. The aqueous phase was extracted with more portions of DCM (2 x 40 ml) and the combined organics were washed with saturated aqueous NaHCO3 solution (20 ml), H2O (20 ml) and saline solution (20 ml), dried over MgSO4, filtered and concentrated in vacuo to produce an orange oil. The crude product was purified by chromatography on silica gel (12 g column, 0-100% EtOAc / isohexane) to generate the title compound (1.39 g, 100%) as a yellow oil.
[0475] [0475] 1H NMR (DMSO-d6) δ 7.99 (d, J = 2.4 Hz, 1H), 7.07-7.00 (m, 4H), 6.86-6.78 (m, 4H), 6.76 (d, J = 2.3 Hz, 1H), 5.16-4.98 (m, 1H), 4.59-4.40 (m, 2H), 4.19 (s , 4H), 3.71 (s, 6H), 2.95 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H). Step C: (S) -1- (2- (dimethylamino) propyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0476] [0476] (R) -1- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) - 1H-pyrazol-1-yl) propan-2-yl methanesulfonate (1.00 g, 1.757 mmol) and DIPEA (0.306 mL, 1.757 mmol) were dissolved in DMF (10 mL) in a sealed microwave flask. 2M dimethylamine in THF (2.64 mL, 5.27 mmol) was added and the mixture was stirred at 70 ° C (conventional heating) for 24 hours. The reaction mixture was poured into saline solution (100 ml) and extracted with DCM (2 x 30 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated to produce a yellow oil. The crude product was loaded onto a SCX column (4 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 generate the title compound (0.32 g, 36%) as a brown gum.
[0477] [0477] 1H NMR (DMSO-d6) δ 7.93 (d, J = 2.3 Hz, 1H), 7.15-6.93 (m, 4H), 6.90-6.75 (m, 4H), 6.69 (d, J = 2.3 Hz, 1H), 4.27 (dd, J = 13.7, 7.4 Hz, 1H), 4.18 (s, 4H), 4, 09 (dd, J = 13.7, 6.8 Hz, 1H), 3.71 (s, 6H), 3.12-2.99 (m, 1H), 2.18 (s, 6H), 0 , 85 (d, J = 6.6 Hz, 3H).
[0478] [0478] LCMS; m / z 473.5 (M + H) + (ES +). Step D: (S) -1- (2- (Dimethylamino) propyl) -1H-pyrazol-3-sulfonamide
[0479] [0479] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) from (S) -1- ( 2- (dimethylamino) propyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (130 mg, 75%) as an orange gum.
[0480] [0480] 1H NMR (DMSO-d6) δ 7.83 (d, J = 2.3 Hz, 1H), 7.36 (s, 2H), 6.55 (d, J = 2.3 Hz, 1H ), 4.22 (dd, J = 13.7, 7.4 Hz, 1H), 4.03 (dd, J = 13.7, 6.8 Hz, 1H), 3.05 (app h, J = 6.8 Hz, 1H), 2.17 (s, 6H), 0.84 (d, J = 6.7 Hz, 3H).
[0481] [0481] LCMS; m / z 233.3 (M + H) + (ES +). Intermediate P17: 1 - ((1-methylazetidin-3-yl) methyl) -1H-pyrazol-3-sulfonamide Step A: 3 - ((3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H- pyrazol-1-yl) methyl) azetidine-1-carboxylate tert-butyl
[0482] [0482] To a solution of tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (500 mg, 2.67 mmol) in DCM (10 mL) at 0 ° C was added DIPEA (0.6 mL, 3 , 44 mmol) and methanesulfonyl chloride (0.25 mL 3.21 mmol). The mixture was warmed to room temperature and stirred for 2 hours, suppressed with NaHCO3 solution (20 ml) and extracted with DCM (2 x 30 ml). The combined organic extracts were passed through a phase separator and the solvent was removed in vacuo. The residue was dissolved in THF (10 mL), N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) (1 g, 2.58 mmol) and cesium carbonate ( 2.5 g, 7.67 mmol) were added and the mixture was stirred at 50 ° C overnight. After cooling to room temperature, the mixture was diluted with H2O (30 ml) and extracted with EtOAc (3x 60 ml). The combined organic extracts were washed with saline (50 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by silica gel chromatography (40 g column, 0-100% EtOAc / isohexane) to generate the title compound (1.28 g, 85%) as a pale yellow oil.
[0483] [0483] 1H NMR (DMSO-d6) δ 8.01 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.71 (d, J = 2.4 Hz, 1H), 4.44 (d, J = 7.3 Hz, 2H), 4.19 (s, 4H), 3.87 (app t, J = 8.5 Hz, 2H), 3.72 (s, 6H), 3.70-3.63 (m, 2H), 3.04-2.93 (m, 1H ), 1.36 (s, 9H).
[0484] [0484] LCMS; m / z 579.4 (M + Na) + (ES +). Step B: N, N-Bis (4-methoxybenzyl) -1 - ((1-methylazetidin-3-yl) methyl) -1H-pyrazol-3-sulfonamide
[0485] [0485] To a solution of tert-butyl 3 - ((3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) methyl) azetidine-1-carboxylate (1.28 g, 2.184 mmol) in THF (50 mL) at 0 ° C LiAlH4 (2M in THF) (4.5 mL, 9.00 mmol) was added and the mixture was stirred at the same temperature for 1 hour and then at room temperature during the night. The reaction was suppressed sequentially with H 2O (0.2 ml), 2M NaOH (0.5 ml) and H2O (1mL). Na2SO4 was added, and the mixture was stirred for 30 minutes and then filtered through a plug of Celite ® with EtOAc. The filtrate was evaporated and the residue loaded on silica and purified by silica gel chromatography (40 g column, 0-10% MeOH / DCM) to generate the title compound (463 mg, 44%) as a clear colorless oil .
[0486] [0486] 1H NMR (DMSO-d6) δ 7.97 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.70 (d, J = 2.4 Hz, 1H), 4.38 (d, J = 7.4 Hz, 2H), 4.19 (s, 4H), 3.72 (s, 6H), 3.19 (app t, J = 7.2 Hz, 2H), 2.97-2.87 (m, 2H), 2.81 2.71 (m, 1H ), 2.18 (s, 3H).
[0487] [0487] LCMS; m / z 471.5 (M + H) + (ES +). Step C: 1 - (((1-methylazetidin-3-yl) methyl) -1H-pyrazol-3-sulfonamide
[0488] [0488] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) from N, N-bis (4 -methoxybenzyl) -1- (1- (methylazetidin-3-yl) ethyl) -1H-pyrazol-3-sulfonamide to generate the title compound (187 mg, 84%) as a pale yellow gum.
[0489] [0489] 1H NMR (DMSO-d6) δ 7.88 (d, J = 2.3 Hz, 1H), 7.39 (s, 2H), 6.58 (d, J = 2.3 Hz, 1H ), 4.38 (d, J = 7.3 Hz, 2H), 3.42 (app t, J = 7.9 Hz, 2H), 3.25-3.15 (m, 2H), 2, 94-2.82 (m, 1H), 2.34 (s, 3H).
[0490] [0490] LCMS; m / z 231.3 (M + H) + (ES +). Intermediate P18: (S) -1 - ((1-methylazetidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide Step A: 2 - ((3- (N, N-bis (4-methoxybenzyl) sulfamoyl (S) -tert-butyl) -1H-pyrazol-1-yl) methyl) azetidine-1-carboxylate
[0491] [0491] Prepared according to the general procedure of tert-butyl 3 - ((3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) methyl) azetidine-1-carboxylate (Intermediate P17, Step A) from N, N-bis (4-methoxybenzyl) -1H-pyrazole-3-
[0492] [0492] 1H NMR (DMSO-d6) δ 7.89 (d, J = 2.3 Hz, 1H), 7.03 (d, J = 8.7 Hz, 4H), 6.80 (d, J = 8.7 Hz, 4H), 6.76 (d, J = 2.3 Hz, 1H), 4.53-4.42 (m, 3H), 4.26- 4.14 (m, 4H) , 3.71 (s, 6H), 3.69-3.63 (m, 1H), 3.39 (s, 1H), 2.23-2.13 (m, 1H), 1.97-1 , 86 (m, 1H), 1.37 (s, 9H).
[0493] [0493] LCMS; m / z 579.1 (M + Na) + (ES +). Step B: (S) -N, N-Bis (4-methoxybenzyl) -1 - (((1-methylazetidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[0494] [0494] Prepared according to the general procedure of N, N-bis (4-methoxybenzyl) -1 - ((1-methylazetidin-3-yl) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P17, Step B ) of (S) -tert-butyl 2 - ((3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) methyl) azetidine-1-carboxylate to generate the compound titer (623 mg, 59%) as a pale yellow oil.
[0495] [0495] 1H NMR (DMSO-d6) δ 7.94 (d, J = 2.3 Hz, 1H), 7.03 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.72 (d, J = 2.3 Hz, 1H), 4.24 (d, J = 5.7 Hz, 2H), 4.18 (s, 4H), 3.71 (s, 6H), 3.30-3.24 (m, 1H), 3.24-3.17 (m, 1H), 2.73-2.64 (m, 1H), 1, 99 (s, 3H), 1.97-1.87 (m, 1H), 1.85-1.72 (m, 1H).
[0496] [0496] LCMS; m / z 471.2 (M + H) + (ES +). Step C: (S) 1 - ((1-methylazetidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[0497] [0497] Prepared according to the general procedure of N, N-dimethyl-2- (3-
[0498] [0498] 1H NMR (DMSO-d6) δ 7.83 (d, J = 2.3 Hz, 1H), 7.38 (s, 2H), 6.57 (d, J = 2.3 Hz, 1H ), 4.27-4.13 (m, 2H), 3.31-3.23 (m, 1H), 3.23-3.17 (m, 1H), 2.74-2.63 (m , 1H), 2.01 (s, 3H), 1.99-1.89 (m, 1H), 1.86-1.74 (m, 1H).
[0499] [0499] LCMS; m / z 231.3 (M + H) + (ES +). Intermediate P19: (R) -1 - ((1-methylpyrrolidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide Step A: 2 - ((3- (N, N-bis (4-methoxybenzyl) sulfamoyl (R) -tert-butyl) -1H-pyrazol-1-yl) methyl) pyrrolidine-1-carboxylate
[0500] [0500] Prepared according to the general procedure of tert-butyl 3 - ((3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) methyl) azetidine-1-carboxylate (Intermediate P17, Step A) from N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 2- (hydroxymethyl) pyrrolidine-1-carboxylate -tert-butyl to generate the title compound (2.40 g, 93%) as a colorless oil.
[0501] [0501] LCMS; m / z 471.5 (M-Boc + H) + (ES +). Step B: (R) -N, N-Bis (4-methoxybenzyl) -1 - (((1-methylpyrrolidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[0502] [0502] Prepared according to the general procedure of N, N-bis (4-methoxybenzyl) -1 - ((1-methylazetidin-3-yl) methyl) -1H-pyrazol-3-sulfonamide
[0503] [0503] LCMS; m / z 485.5 (M + H) + (ES +). Step C: (R) -1 - ((1-methylpyrrolidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[0504] [0504] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) from (R) - N, N -bis (4-methoxybenzyl) -1 - (((1-methylpyrrolidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide to generate the title compound (0.48 g, 56%) as a slightly white solid gummy.
[0505] [0505] LCMS; m / z 245.3 (M + H) + (ES +). Intermediate P20: 1- (pyrimidin-2-ylmethyl) -1H-pyrazol-3-sulfonamide Step A: 1- (lithium tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfinate
[0506] [0506] A solution of n-BuLi (100 mL, 250 mmol, 2.5M in hexanes) was added slowly to a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (36 , 2 g, 238 mmol) in THF (500 mL), keeping the temperature below -65 ° C. The mixture was stirred for 1.5 hours, then sulfur dioxide was bubbled through for 10 minutes. The mixture was allowed to warm to room temperature, the solvent was evaporated and the residue was triturated with TBME (300 ml) and filtered. The solid was washed with TBME and isohexane and dried to generate the crude title compound (54.89 g, 99%).
[0507] [0507] 1H NMR (DMSO-d6) δ 7.26 (d, J = 1.6Hz, 1H), 6.10 (d, J = 1.7Hz, 1H), 5.99 (dd, J = 10.0 , 2.5Hz, 1H), 3.92-3.87 (m, 1H), 3.56-3.49 (m, 1H), 2.25-2.15 (m, 1H), 2.00 -1.91 (m, 1H), 1.75-1.69 (m, 1H), 1.66-1.46 (m, 3H).
[0508] [0508] LCMS; m / z 215 (M-H) - (ES-). Step B: N, N-Bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide
[0509] [0509] NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfinate (20 g, 90 mmol ) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 hours, suppressed with water (100 ml) and then partitioned between DCM (300 ml) and water (200 ml). The organic phase was washed with water (200 ml), dried (MgSO 4), filtered and evaporated to ~ 50 ml. The solution was added to a mixture of bis (4-methoxybenzyl) amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature and then partitioned between DCM (300 ml) and water (250 ml). The organic layer was washed with water (250 ml), 1M aq HCl (2 x 250 ml), water (250 ml), dried (MgSO4), filtered and evaporated to generate the crude title compound (41.02 g, 97%) as a brown oil.
[0510] [0510] LCMS; m / z 494.2 (M + Na) + (ES +). Step C: N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0511] [0511] A mixture of N, N-bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide (41 g, 87 mmol) and 1M of Aq HCl (30 ml) in THF (300 ml) and MeOH (50 ml) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between EtOAc (400 ml) and 1M aq HCl (200 ml). The organic layer was washed with 10% saline (200 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with TBME, filtered and dried to generate the title compound (24.87 g, 69%) as an off-white solid.
[0512] [0512] 1H NMR (CDCl3) δ 7.88 (d, J = 2.4Hz, 1H), 7.06-7.02 (m, 4H), 6.79- 6.75 (m, 4H), 6.63 (d, J = 2.4 Hz, 1H), 4.31 (s, 4H), 3.78 (s, 6H). Exchangeable proton not visible.
[0513] [0513] LCMS; m / z 388 (M + H) + (ES +); 386 (M-H) - (ES-). Step D: N, N-Bis (4-methoxybenzyl) -1- (pyrimidine-2-ylmethyl) -1H-pyrazol-3-sulfonamide
[0514] [0514] K2CO3 (0.535 g, 3.87 mmol) was added to a solution of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (0.5 g, 1.290 mmol) and hydrochloride of 2 - (chloromethyl) pyrimidine (0.213 g 1.290 mmol) in DMF (8 mL). The reaction mixture was then heated to 70 ° C and stirred for 16 hours. Then, the reaction mixture was washed with saturated saline solution (3 x 20 ml), the washes were combined and extracted with DCM (3 x 20 ml). The extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-100% EtOAc / isohexane), then purified by silica gel chromatography (40 g column, 0-100% EtOAc / isohexane and 0-10 % MeOH / DCM) to generate the title compound (62 mg, 6%) as a yellow oil.
[0515] [0515] 1H NMR (DMSO-d6) δ 8.83 (d, J = 4.9 Hz, 2H), 8.11 (d, J = 2.3 Hz, 1H), 7.50 (t, J = 4.9 Hz, 1H), 7.02-6.95 (m, 4H), 6.80-6.74 (m, 5H), 5.72 (s, 2H), 4.16 (s, 4H), 3.72 (s, 6H).
[0516] [0516] LCMS; m / z 502.4 (M + Na) + (ES +). Step E: 1- (Pyrimidin-2-ylmethyl) -1H-pyrazol-3-sulfonamide
[0517] [0517] N, N-Bis (4-methoxybenzyl) -1- (pyrimidin-2-ylmethyl) -1H-pyrazol-3-sulfonamide (60 mg, 0.079 mmol) was dissolved in DCM (1 mL) and TFA (1 ml) was added. The solution was stirred for 16 hours. The reaction mixture was concentrated in vacuo, suspended in toluene (5 ml) and concentrated again. The crude product was purified by chromatography on silica gel (12 g column, 0-5% MeOH / DCM) to generate the title compound (16 mg, 84%) as a brown solid.
[0518] [0518] 1H NMR (DMSO-d6) δ 8.81 (d, J = 4.9 Hz, 2H), 7.98 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 4.9 Hz, 1H), 7.15 (s, 2H), 6.61 (d, J = 2.3 Hz, 1H), 5.63 (s, 2H).
[0519] [0519] LCMS; m / z 240.2 (M + H) + (ES +). Intermediate P21: 1- (2- (dimethylamino) ethyl) -1H-imidazole-4-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1H-imidazole-4-sulfonamide
[0520] [0520] A solution of 1H-imidazole-4-sulfonyl chloride (2.5 g, 15.01 mmol) in DCM (10 mL) was added slowly to a solution of bis (4-methoxybenzyl) amine (4 g, 15.54 mmol) and Et3N (4.5 mL, 32.3 mmol) in DCM (50 mL) cooled in an ice bath. The mixture was stirred for 30 minutes, warmed to room temperature and stirred for 2 hours. The DCM was removed under pressure and replaced with dioxane (50 ml). Then, the reaction mixture was heated under reflux for 48 hours, cooled and partitioned between EtOAc (200 ml) and water (200 ml). The organic layer was dried (MgSO 4), filtered and evaporated to produce an oil which was purified by chromatography on silica gel (120 g column, 0-100% EtOAc / isohexane column). The product was triturated in TBME / EtOAc, filtered and dried to generate the title compound (2.864 g, 48%) as a solid.
[0521] [0521] 1H NMR (CDCl3) δ 7.92 (d, J = 1.3Hz, 1H), 7.52 (d, J = 1.3Hz, 1H), 7.06-7.02 (m, 4H ), 6.79-6.75 (m, 4H), 4.30 (s, 4H), 3.77 (s, 6H). Exchangeable proton not visible.
[0522] [0522] LCMS; m / z 388 (M + H) + (ES +); 386 (M-H) - (ES-). Step B: 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-imidazole-4-sulfonamide
[0523] [0523] A mixture of N, N-bis (4-methoxybenzyl) -1H-imidazole-4-sulfonamide (1 g, 2.58 mmol), oxirane (2.5 M in THF) (2 mL, 5.00 mmol) and K 2 CO3 (1.07 g, 7.74 mmol) in acetonitrile (20 mL) was stirred at 50 ° C for 3 days. After cooling to room temperature, the mixture was diluted with H 2 O (40 ml) and extracted with EtOAc (3x 80 ml). The combined organic extracts were washed with saline (50 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by silica gel chromatography (40 g column, 0-100% EtOAc / isohexane, eluting at 100%) to generate the title compound (679 mg, 61%) as a clear colorless solid .
[0524] [0524] 1H NMR (DMSO-d6) δ 7.85 (d, J = 1.3 Hz, 1H), 7.84 (d, J = 1.3 Hz, 1H), 7.03 (d, J = 8.7 Hz, 4H), 6.80 (d, J = 8.7 Hz, 4H), 5.04 (t, J = 5.1 Hz, 1H), 4.18 (s, 4H), 4.08 (t, J = 5.3 Hz, 2H), 3.71 (s, 6H), 3.70-3.66 (m, 2H).
[0525] [0525] LCMS; m / z 432.4 (M + H) + (ES +). Step C: 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-imidazole-4-sulfonamide
[0526] [0526] To a solution of 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-imidazole-4-sulfonamide (675 mg, 1.564 mmol) in DCM (8 mL) at 0 ° C DIPEA (0.41 ml, 2.348 mmol) and methanesulfonyl chloride (0.16 ml, 2.053 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 2 hours before being suppressed by adding aqueous NaHCO 3 (10 ml). The reaction mixture was extracted twice with DCM (15 ml) and the combined organic extracts were passed through a phase separator and concentrated in vacuo. The orange residue was dissolved in THF (8 ml), dimethylamine (2M in THF) (2.4 ml, 4.80 mmol) and potassium iodide (130 mg, 0.782 mmol) were added and the reaction mixture was heated to 60 ° C and stirred overnight. Additional dimethylamine (2 M in THF) (2.4 ml, 4.80 mmol) was added and stirring was continued overnight. The reaction mixture was diluted with aqueous NaHCO3 (20 ml) and extracted with EtOAc (3 x 40 ml). The combined organic extracts were passed through a phase separator and the solvent was removed in vacuo. The residue was dissolved in MeOH (30 ml), SCX (~ 12 g) was added and the suspension was stirred at room temperature for 30 minutes. The mixture was transferred to a cartridge, washed sequentially with DCM / MeOH (9: 1) and MeOH, and the product was eluted with 0.7M NH3 in MeOH to generate the title compound (585 mg, 73%) as a yellow oil.
[0527] [0527] 1H NMR (DMSO-d6) δ 7.87 (s, 2H), 7.02 (d, J = 8.7 Hz, 4H), 6.79 (d, J = 8.7 Hz, 4H ), 4.18 (s, 4H), 4.12 (t, J = 6.2 Hz, 2H), 3.71 (s, 6H), 2.58 (t, J = 6.2 Hz, 2H ), 2.18 (s, 6H).
[0528] [0528] LCMS; m / z 459.0 (M + H) + (ES +). Step D: 1- (2- (dimethylamino) ethyl) -1H-imidazole-4-sulfonamide
[0529] [0529] A mixture of 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-imidazole-4-sulfonamide (585 mg, 1.135 mmol) and TFA (4 mL, 62, 8 mmol) was stirred at room temperature overnight. The mixture was evaporated and the residue was dissolved in MeOH (30 ml) and DCM (10 ml). SCX (~ 8 g) was added and the mixture was stirred for 30 minutes at room temperature, transferred to a cartridge and the solid washed sequentially with DCM: MeOH (9: 1) and MeOH. The product was eluted with 0.7 M NH3 in MeOH to produce the crude product, which was further purified by chromatography on silica gel (24 g column, 0-10% (0.7 M ammonia / MeOH / DCM) to generate the title compound (180 mg, 72%) as a pale yellow oil.
[0530] [0530] 1H NMR (DMSO-d6) δ 7.77 (d, J = 1.4 Hz, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.11 (s, 2H ), 4.09 (t, J = 6.1 Hz, 2H), 2.56 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H).
[0531] [0531] LCMS; m / z 219.3 (M + H) + (ES +). Intermediate P22: 1-Cyclopropyl-5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide Step A: 1-Cyclopropyl-3-nitro-1H-pyrazole N NO2 NO2 N HN N
[0532] [0532] To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol, 1.1 eq) in 1,2-dichloroethane (500 mL) was added 3-nitro-1H-pyrazole (44 g, 389, 12 mmol, 1 eq), 2,2-bipyridine (60.77 g, 389.12 mmol, 1 eq) and Na2CO3 (64.59 g, 609.44 mmol, 1.57 eq) at 25 ° C. The mixture was stirred at 25 ° C for 30 minutes. Then Cu (OAc) 2 (70.68 g, 389.12 mmol, 1 eq) was added and the reaction mixture was heated to 70 ° C and stirred at 70 ° C for 15.5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 30: 1 to 3: 1) to produce the crude product (26.7 g). The crude product was dissolved in pyrrolidine (10 ml) and the resulting mixture was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the pyrrolidine. The residue was diluted with H2O (33 ml) and the pH was adjusted to 5-6 with aqueous HCl solution (1N). The mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (2 × 33 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce the title compound (17.7 g, 29.7%) as a yellow oil.
[0533] [0533] 1H NMR (CDCl3) δ 7.54 (d, 1 H), 6.84 (d, 1 H), 3.73-3.67 (m, 1 H), 1.24-1.22 (m, 2 H), 1.13-1.07 (m, 2 H). Step B: 1-cyclopropyl-1H-pyrazol-3-amine N NO2 N NH2 N N
[0534] [0534] To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36 g, 235.08 mmol, 1 eq) in EtOH (400 mL) was added a solution of NH4Cl (62.87 g, 1, 18 mol, 41.09 ml, 5 eq) in H2O (150 ml). Then, the reaction mixture was heated to 60 ° C and iron powder (39.38 g, 705.24 mmol, 3 eq) was added to the reaction mixture in parts. The reaction mixture was stirred at 60 ° C for 16 hours and then concentrated under reduced pressure. The residue was diluted with H 2 O (500 ml) and extracted with EtOAc (3 × 500 ml). The combined organic layers were washed with saline (2 x 250mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 30: 1 to 1: 1) to produce the title compound (20 g, 69.08%) as a yellow oil.
[0535] [0535] 1H NMR (CDCl3) δ 7.14 (d, 1 H), 5.11 (d, 1 H), 3.57 (br s, 2 H), 3.38-3.32 (m, 1 H), 0.99-0.95 (m, 2 H), 0.90-0.87 (m, 2 H).
[0536] [0536] LCMS: m / z 124.2 (M + H) + (ES +). Step C: 1-cyclopropyl-1H-pyrazol-3-sulfonyl chloride N NH2 O
[0537] [0537] To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol, 1 eq) in acetonitrile (500 ml) and H2O (50 ml) at 0 ° C was added concentrated solution HCl (50 mL). Then, an aqueous solution of NaNO 2 (12.77 g, 185.13 mmol, 1.2 eq) in H2O (50 mL) was added slowly. The resulting solution was stirred at 0 ° C for 40 minutes. AcOH (50 mL), CuCl2 (10.37 g, 77.14 mmol, 0.5 eq) and CuCl (763 mg, 7.71 mmol, 0.05 eq) were added to the reaction mixture. Then SO2 gas (15 psi) was bubbled into the reaction mixture for 20 minutes at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour and then concentrated under reduced pressure. The residue was diluted with H 2 O (250 ml) and extracted with EtOAc (3 x 250 ml). The combined organic layers were washed with brine (2 x 150 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100: 0 to 1: 1) to produce the title compound (14 g, 43.91%) as a yellow oil.
[0538] [0538] 1H NMR (CDCl3) δ 7.62 (d, 1 H), 6.83 (d, 1 H), 3.78-3.72 (m, 1 H), 1.28-1.24 (m, 2 H), 1.16-1.12 (m, 2 H). Step D: 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide PMB O O
[0539] [0539] To a solution of 1-cyclopropyl-1H-pyrazol-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (300 mL) was added triethylamine (27.42 g, 270.99 mmol, 37.72 mL, 2 eq) and bis (4-methoxybenzyl) amine (34.87 g, 135.49 mmol, 1 eq). The mixture was stirred at 25 ° C for 1 hour. Then, the reaction mixture was diluted with H2O (500 ml) and extracted with EtOAc (3 x 500 ml). The combined organic layers were washed with brine (2 x 500 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (acetonitrile / NH3 H2O (0.5% NH3 H2O)) and the collected elution solution was concentrated under reduced pressure to remove most of the acetonitrile. Then, the mixture was extracted with EtOAc (3 x 1000 ml). The combined organic layers were washed with brine (2 x 500 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce the title compound (30 g, 51.69% yield, 99.8% HPLC purity) ).
[0540] [0540] 1H NMR (CDCl3) δ 7.49 (d, 1 H), 7.08-7.06 (m, 4 H), 6.79-6.77 (m, 4 H), 6.62 (d, 1 H), 4.32 (s, 4 H), 3.80 (s, 6 H), 3.68-3.64 (m, 1 H), 1.15-1.13 (m , 2 H), 1.09-1.06 (m, 2 H).
[0541] [0541] LCMS: m / z 428.2 (M + H) + (ES +). Step E: 1-Cyclopropyl-5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide PMB THE PMB N The N S PMB N N O N S PMB AT THE N
[0542] [0542] A solution of n-BuLi (2.5 M, 8.89 mL, 1 eq) was added dropwise to a stirred solution of 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H- pyrazole-3-sulfonamide (10 g, 22.22 mmol, 1 eq) in THF (250 mL) at -78 ° C. The reaction mixture was stirred for 1 hour at -78 ° C. Then, N- iodide was added
[0543] [0543] 1H NMR (DMSO-d6) δ 7.03-7.00 (m, 4 H), 6.83-6.78 (m, 4 H), 6.56 (s, 1 H), 4 , 20 (s, 4 H), 3.82-3.76 (m, 1 H), 3.71 (s, 6 H), 3.57 (s, 2 H), 2.19 (s, 6 H), 1.09-0.99 (m, 4 H).
[0544] [0544] LCMS: m / z 485.2 (M + H) + (ES +). Step F: 1-Cyclopropyl-5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide PMB
[0545] [0545] To a solution of 1-cyclopropyl-5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide (9 g, 18.57 mmol, 1 eq ) in DCM (30 ml) TFA (154.0 g, 1.35 mol, 100 ml, 72.73 eq) was added. The reaction mixture was stirred at 25 ° C for 12 hours and then concentrated under reduced pressure. The residue was treated with MeOH (300 ml) and a solid formed. The mixture was filtered, the filtrate was collected. The pH of the filtrate was adjusted to 8-9 with ion exchange resin (Amberlyst® A-21). The mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase prep HPLC (column: Phenomenex Gemini; C18 250 mm * 50 mm * 10 µm; mobile phase: [water (0.05% v / v ammonium hydroxide) -MeCN]; B% : 1% -45%, 35 minutes) to produce the title compound (3.97 g, 87.6% yield, 100% purity 1H NMR) as a white solid, 1 H NMR (DMSO-d6) δ 7.34 (br s, 2 H), 6.48 (s, 1 H), 3.78-3.74 (m, 1 H), 3.56 (s, 2 H), 2.20 (s , 6 H), 1.11-1.02 (m, 4 H).
[0546] [0546] A mixture of 4- (benzylthio) -1H-1,2,3-triazole (5.9 g, 30.8 mmol), K2CO3 (13 g, 94 mmol) and ((2-bromoethoxy) methyl) benzene (5.5 ml, 34.8 mmol) in MeCN (100 ml) was stirred at room temperature for 6 hours and then heated to 55 ° C for 24 hours. The mixture was partitioned between EtOAc (400mL) and water (300 ml). The organic layer was washed with brine (300 ml), dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel (120 g column, 0-50% MTBE / isohexane) to generate the title compound (1.71 g, 16%) as a clear oil.
[0547] [0547] 2- (2- (Benzyloxy) ethyl) -4- (benzylthio) -2H-1,2,3-triazole (4.99 g, 48%) and 1- (2- (benzyloxy) ethyl) - 5- (benzylthio) -1H-1,2,3-triazole (2.07 g, 16%) were also isolated as clear oils.
[0548] [0548] 1H NMR (CDCl3) δ 7.40 (s, 1H), 7.39-7.19 (m, 10H), 4.50 (t, J = 5.2 Hz, 2H), 4.48 (s, 2H), 4.13 (s, 2H), 3.79 (t, J = 5.4 Hz, 2H). LCMS; m / z 326.2 (M + H) + (ES +). Step B: 1- (2- (Benzyloxy) ethyl) -N, N-bis (4-methoxybenzyl) -1H-1,2,3-triazole-4-sulfonamide
[0549] [0549] NCS (2.80 g, 20.96 mmol) was added to a solution of 1- (2- (benzyloxy) ethyl) -4- (benzylthio) -1H-1,2,3-triazole (1.705 g , 5.24 mmol) in AcOH (20 mL) and water (10 mL). The mixture was stirred for 1 hour and then partitioned between EtOAc (100 ml) and water (100 ml). The organic layer was washed with saturated aqueous NaHCO3 (2 x 60 ml) and brine (100 ml), dried (MgSO 4), filtered and evaporated to generate 1- (2- (benzyloxy) ethyl) -1H-1,2 chloride , Crude 3-triazole-4-sulfonyl. A solution of crude 1- (2- (benzyloxy) ethyl) -1H-1,2,3-triazol-4-sulfonyl chloride in DCM (5 mL) was added to a solution of bis (4-methoxybenzyl) amine (1.48 g, 5.75 mmol) and pyridine (5 ml) in DCM (5 ml). The mixture was stirred at room temperature for 16 hours. The organic phase was washed with 0.1 M aqueous hydrochloric acid (2 x 20 ml), dried over MgSO 4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-10% MeOH / DCM) to generate the title compound (964 mg, 34%) as a yellow oil.
[0550] [0550] 1H NMR (DMSO-d6) δ 8.75 (s, 1H), 7.33 - 7.26 (m, 3H), 7.24 - 7.19 (m, 2H), 7.08 - 7.01 (m, 4H), 6.85 - 6.77 (m, 4H), 4.67 (t, J = 5.2 Hz, 2H), 4.51 (s, 2H), 4.24 (s, 4H), 3.88 (t, J = 5.2 Hz, 2H), 3.71 (s, 6H).
[0551] [0551] LCMS; m / z 523.4 (M + H) + (ES +). Step C: 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-1,2,3-triazole-4-sulfonamide
[0552] [0552] A mixture of 1- (2- (benzyloxy) ethyl) -N, N-bis (4-methoxybenzyl) -1H- 1,2,3-triazole-4-sulfonamide (964 mg, 1.845 mmol) and 5 % Pd-C (189 mg, 0.037 mmol) Type 87L (58.5% moisture) in EtOH (4 mL) was hydrogenated at 3 bar for 16 hours. Then the mixture was filtered through Celite ® and evaporated. The crude product was purified by chromatography on silica gel (24 g column, 0-10% MeOH / DCM) to generate the title compound (717 mg, 78%) as a colorless oil.
[0553] [0553] 1H NMR (DMSO-d6) δ 8.71 (s, 1H), 7.09 - 7.03 (m, 4H), 6.85 - 6.79 (m, 4H), 5.12 ( t, J = 5.3 Hz, 1H), 4.48 (t, J = 5.4 Hz, 2H), 4.26 (s, 4H), 3.83 (app. q, J = 5.3 Hz, 2H), 3.72 (s, 6H).
[0554] [0554] LCMS; m / z 433.3 (M + H) + (ES +).
[0555] [0555] Prepared according to the general procedure of 2,2,2-trifluoro-N-methyl-N- (2- (3-sulfamoyl-1H-pyrazol-1-yl) ethyl) acetamide (Intermediate P12, Step A ) of 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-1,2,3-triazol-4-sulfonamide and dimethylamine (2M in THF) to generate the title compound (151 mg, 17%) as a yellow oil.
[0556] [0556] 1H NMR (DMSO-d6) δ 8.73 (s, 1H), 7.09 - 7.02 (m, 4H), 6.86 - 6.78 (m, 4H), 4.52 ( t, J = 6.2 Hz, 2H), 4.26 (s, 4H), 3.73 (s, 6H), 2.72 (t, J = 6.2 Hz, 2H), 2.19 ( s, 6H). LCMS; m / z 460.5 (M + H) + (ES +). Step E: 1- (2- (Dimethylamino) ethyl) -1H-1,2,3-triazole-4-sulfonamide
[0557] [0557] Prepared according to the general procedure of 1- (azetidin-3-yl) - 1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) from 1- (2- (dimethylamino) ethyl) -N , N-bis (4-methoxybenzyl) -1H-1,2,3-triazole-4-sulfonamide to generate the title compound (53 mg, 71%) as a colorless oil.
[0558] [0558] 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 7.69 (s, 2H), 4.53 (t, J = 6.1 Hz, 2H), 2.72 (t , J = 6.1 Hz, 2H), 2.18 (s, 6H).
[0559] [0559] LCMS; m / z 220.3 (M + H) + (ES +). Intermediate P24: 1- (2- (dimethylamino) ethyl) -1H-1,2,4-triazol-3-sulfonamide Step A: 1- (2- (Benzyloxy) ethyl) -3- (benzylthio) -1H-1 , 2,4-triazole
[0560] [0560] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -1H-1,2,3-triazol-4-sulfonamide (Intermediate P23, Step A) from 3- (benzylthio) -1H-1,2,4-triazole to generate the title compound (1.69 g, 43%) as a colorless oil. 4- (2- (Benzyloxy) ethyl) -3- (benzylthio) -4H-1,2,4-triazole (1.08 g, 28%) was also isolated as a colorless oil.
[0561] [0561] 1H NMR (DMSO-d6) δ 8.51 (s, 1H), 7.43 - 7.16 (m, 10H), 4.46 (s, 2H), 4.37 - 4.30 ( m, 4H), 3.76 (t, J = 5.2 Hz, 2H).
[0562] [0562] LCMS; m / z 326.3 (M + H) + (ES +). Step B: 1- (2- (Benzyloxy) ethyl) -N, N-bis (4-methoxybenzyl) -1H-1,2,4-triazole-3-sulfonamide
[0563] [0563] NCS (2.77 g, 20.74 mmol) was added to a solution of 1- (2- (benzyloxy) ethyl) -3- (benzylthio) -1H-1,2,4-triazole (1.687 g , 5.18 mmol) in AcOH (20 mL) and water (10 mL). The mixture was stirred for 1 hour and then partitioned between EtOAc (100 ml) and water (100 ml). The organic layer was washed with NaHCO3 (2 x 60 ml) and brine (100 ml), dried (MgSO4), filtered and evaporated to generate 1- (2- (benzyloxy) ethyl) -1H-1,2,4 chloride crude triazole-3-sulfonyl. A solution of crude 1- (2- (benzyloxy) ethyl) -1H-1,2,4-triazol-3-sulfonyl chloride (1.56 g, 5.17 mmol) in DCM (5 mL) was added to a solution of bis (4-methoxybenzyl) amine (1.46 g, 5.67 mmol) and pyridine (5 ml) in DCM (5 ml). The mixture was stirred at room temperature for 48 hours. The organic phase was washed with 0.1 M aqueous hydrochloric acid (2 x 20 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 and after 0-10% MeOH / DCM) to generate the title compound (725 mg, 24%) as a yellow oil.
[0564] [0564] 1H NMR (DMSO-d6) δ 8.79 (s, 1H), 7.35 - 7.21 (m, 5H), 7.06 - 6.99 (m, 4H), 6.85 - 6.77 (m, 4H), 4.55 - 4.49 (m, 4H), 4.27 (s, 4H), 3.83 (t, J = 5.1 Hz, 2H), 3.71 (s, 6H).
[0565] [0565] LCMS; m / z 523.5 (M + H) + (ES +). Step C: 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-1,2,4-triazole-3-sulfonamide
[0566] [0566] Prepared according to the general procedure of 1- (2-hydroxyethyl) - N, N-bis (4-methoxybenzyl) -1H-1,2,3-triazole-4-sulfonamide (Intermediate P23, Step C) 1- (2- (benzyloxy) ethyl) -N, N-bis (4-methoxybenzyl) -1H-1,2,4-triazol-3-sulfonamide to generate the title compound (294 mg, 46%) as a colorless oil.
[0567] [0567] 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 7.07 - 7.00 (m, 4H), 6.86 - 6.80 (m, 4H), 5.09 ( t, J = 5.3 Hz, 1H), 4.33 (t, J = 5.3 Hz, 2H), 4.28 (s, 4H), 3.78 (q, J = 5.3 Hz, 2H), 3.73 (s, 6H).
[0568] [0568] LCMS; m / z 433.4 (M + H) + (ES +). Step D: 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-1,2,4-triazole-3-sulfonamide
[0569] [0569] Prepared according to the general procedure of 2,2,2-trifluoro-N-methyl-N- (2- (3-sulfamoyl-1H-pyrazol-1-yl) ethyl) acetamide (Intermediate P12, Step A ) of 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-1,2,4-triazol-3-sulfonamide and dimethylamine (2M in THF) to generate the title compound (157 mg, 43%) as a yellow oil.
[0570] [0570] 1H NMR (DMSO-d6) δ 8.74 (s, 1H), 7.07 - 7.00 (m, 4H), 6.86 - 6.79 (m, 4H), 4.37 ( t, J = 6.2 Hz, 2H), 4.28 (s, 4H), 3.73 (s, 6H), 2.67 (t, J = 6.2 Hz, 2H), 2.19 ( s, 6H).
[0571] [0571] LCMS; m / z 460.3 (M + H) + (ES +). Step E: 1- (2- (Dimethylamino) ethyl) -1H-1,2,4-triazole-3-sulfonamide
[0572] [0572] Prepared according to the general procedure of 1- (azetidin-3-yl) - 1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) from 1- (2- (dimethylamino) ethyl) -N , N-bis (4-methoxybenzyl) -1H-1,2,4-triazole-3-sulfonamide to generate the title compound (57 mg, 79%) as a colorless oil.
[0573] [0573] 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 7.69 (s, 2H), 4.53 (t, J = 6.1 Hz, 2H), 2.72 (t , J = 6.1 Hz, 2H), 2.18 (s, 6H).
[0574] [0574] LCMS; m / z 220.3 (M + H) + (ES +). Intermediate P25: 1- (1-Methylpiperidin-4-yl) -1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1- (1-methylpiperidin-4-yl) -1H- pyrazol-3-sulfonamide
[0575] [0575] To a solution of 1-methylpiperidine-4-ol (0.156 g, 1.355 mmol) in THF (4 mL) at 0 ° C was added N-ethyl-N-isopropylpropan-2-amine (0.293 mL, 1.678 mmol ) and methanesulfonyl chloride (0.111 ml, 1.420 mmol). The mixture was warmed to room temperature and stirred for 2 hours before a solution of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) (0.5 g, 1.290 mmol ) in THF (4 ml) was added. Cs2CO3 (1.261 g, 3.87 mmol) was added to the mixture, heated to 60 ° C and stirred for 16 hours. The mixture was diluted with H2O (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic extracts were washed with brine (20 ml), passed through a phase separator and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (12 g column, 0-10% MeOH / DCM) to generate a mixture of regioisomers (17% regioisomer). The crude product was purified by chromatography on silica gel (4 g column, 0-10% (0.7 M ammonia / MeOH) / DCM) to generate the title compound (110 mg, 18%) as a colorless oil.
[0576] [0576] 1H NMR (DMSO-d6) δ 8.03 (d, J = 2.4 Hz, 1H), 7.05 - 7.00 (m, 4H), 6.84 - 6.78 (m, 4H), 6.72 (d, J = 2.4 Hz, 1H), 4.28 - 4.23 (m, 1H), 4.20 (s, 4H), 3.72 (s, 6H), 2.90 - 2.84 (m, 2H), 2.21 (s, 3H), 2.10 - 1.94 (m, 6H).
[0577] [0577] LCMS; m / z 485.4 (M + H) + (ES +). Step B: 1- (1-methylpiperidine-4-yl) -1H-pyrazol-3-sulfonamide
[0578] [0578] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) from N, N-bis (4-methoxybenzyl) -1 - (1-methylpiperidine-4-yl) -1H-pyrazol-3-sulfonamide to generate the title compound (50 mg, 84%) as a white solid.
[0579] [0579] 1H NMR (DMSO-d6) δ 7.95 (d, J = 2.4 Hz, 1H), 7.40 (s, 2H), 6.59 (d, J = 2.4 Hz, 1H ), 4.30 - 4.19 (m, 1H), 2.95 (d, J = 11.6 Hz, 2H), 2.29 (s, 3H), 2.22 - 1.97 (m, 6H).
[0580] [0580] LCMS; m / z 245.1 (M + H) + (ES +). Intermediate P26: 1- (3- (Dimethylamino) propyl) -1H-pyrazol-3-sulfonamide Step A: 1- (3-Hydroxypropyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0581] [0581] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 3-bromopropane-1-ol to generate the title compound (1.13 g, 59%) like a colorless oil.
[0582] [0582] 1H NMR (DMSO-d6) δ 7.96 (d, J = 2.3 Hz, 1H), 7.06 - 6.96 (m, 4H), 6.86 - 6.77 (m, 4H), 6.71 (d, J = 2.3 Hz, 1H), 4.66 (t, J = 5.0 Hz, 1H), 4.27 (t, J = 7.1 Hz, 2H), 4 , 20 (s, 4H), 3.72 (s, 6H), 3.46 - 3.37 (m, 2H), 1.98 - 1.90 (m, 2H).
[0583] [0583] LCMS; m / z 468.4 (M + Na) + (ES +). Step B: 1- (3- (Dimethylamino) propyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0584] [0584] Prepared according to the general procedure of N, N-bis (4-methoxybenzyl) -1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P3, Step B ) of 1- (3-hydroxypropyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide and 2M dimethylamine in THF to generate the title compound (383 mg, 33%) as an oil thick yellow.
[0585] [0585] 1H NMR (DMSO-d6) δ 7.95 (d, J = 2.3 Hz, 1H), 7.06 - 6.99 (m, 4H), 6.85 - 6.76 (m, 4H), 6.71 (d, J = 2.3 Hz, 1H), 4.28 - 4.15 (m, 6H), 3.72 (s, 6H), 2.21 - 2.07 (m , 8H), 1.97 - 1.85 (m, 2H).
[0586] [0586] LCMS; m / z 473.5 (M + H) + (ES +). Step C: 1- (3- (dimethylamino) propyl) -1H-pyrazol-3-sulfonamide
[0587] [0587] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) from 1- (3- (dimethylamino) propyl) -N , N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (168 mg, 85%) as a pale yellow oil.
[0588] [0588] 1H NMR (DMSO-d6) δ 7.86 (d, J = 2.3 Hz, 1H), 7.38 (s, 2H), 6.57 (d, J = 2.3 Hz, 1H ), 4.18 (t, J = 7.1 Hz, 2H), 2.17 (t, J = 6.9 Hz, 2H), 2.12 (s, 6H), 1.96 - 1.84 (m, 2H).
[0589] [0589] LCMS; m / z 233.2 (M + H) + (ES +). Intermediate P27: 1- (2-cyanopropane-2-yl) -1H-pyrazol-3-sulfonamide Step A: 1- (1-Cyanomethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3- sulfonamide
[0590] [0590] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 2-bromopropanonitrile to generate the title compound (1.48 g, 81%) as a white solid .
[0591] [0591] 1H NMR (CDCl3) δ 7.66 (d, J = 2.5Hz, 1H), 7.12-7.08 (m, 4H), 6.84- 6.80 (m, 4H), 6.75 (d, J = 2.5 Hz, 1H), 5.35 (q, J = 7.3 Hz, 1H), 4.36 (s, 4H), 3.81 (s, 6H), 1 , 95 (d, J = 7.3 Hz, 3H).
[0592] [0592] LCMS; m / z 463.4 (M + Na) + (ES +). Step B: 1- (2-cyanopropane-2-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0593] [0593] NaH (120 mg, 3.00 mmol) (60% in mineral oil) was added to a solution of 1- (1-cyanoethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazole-3 -sulfonamide (1.25 g, 2.84 mmol) in DMF (20 mL) cooled in an ice bath. The mixture was stirred for 20 minutes and then methyl iodide (230 µL, 3.68 mmol) was added. The reaction mixture was stirred for 2 hours and then warmed to room temperature. The reaction mixture was suppressed with water, then partitioned between EtOAc (100 ml) and 10% brine (100 ml). The organic layer was washed with water (50 ml), dried (MgSO4), filtered and evaporated. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc / isohexane) to generate the title compound (1.08 g, 80%) as a white solid.
[0594] [0594] 1H NMR (CDCl3) δ 7.75 (d, J = 2.5Hz, 1H), 7.13-7.09 (m, 4H), 6.84- 6.80 (m, 4H), 6.76 (d, J = 2.5 Hz, 1H), 4.36 (s, 4H), 3.81 (s, 6H), 2.00 (s, 6H).
[0595] [0595] LCMS; m / z 477.2 (M + Na) + (ES +). Step C: 1- (2-cyanopropane-2-yl) -1H-pyrazol-3-sulfonamide
[0596] [0596] 1- (2-Cyanopropan-2-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (693 mg, 1.525 mmol) was dissolved in TFA (5 ml) and stirred for 17 hours at room temperature. The reaction mixture was concentrated to dryness and the crude product was purified by chromatography on silica gel (12 g column, 0-10% MeOH / DCM, 5% elution) to generate the title compound (0, 24 g, 66%) as a white solid.
[0597] [0597] 1H NMR (DMSO-d6) δ 8.19 (d, J = 2.6 Hz, 1H), 7.58 (s, 2H), 6.73 (d, J = 2.6 Hz, 1H ), 2.01 (s, 6H).
[0598] [0598] LCMS; m / z 215.2 (M + H) + (ES +). Intermediate P28: 1- (Cyanomethyl) -1H-pyrazol-3-sulfonamide Step A: 1- (Cyanomethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0599] [0599] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 2-bromoacetonitrile to generate the title compound (0.41 g, 72%) as a crystalline solid colorless.
[0600] [0600] 1H NMR (CDCl3) δ 7.59 (d, J = 2.5 Hz, 1H), 7.11 - 7.05 (m, 4H), 6.83 - 6.78 (m, 4H) , 6.71 (d, J = 2.4 Hz, 1H), 5.11 (s, 2H), 4.34 (s, 4H), 3.79 (s, 6H).
[0601] [0601] LCMS; m / z 449 (M + Na) + (ES +), 425 (M-H) - (ES-). Step B: 1- (cyanomethyl) -1H-pyrazol-3-sulfonamide
[0602] [0602] 1- (Cyanomethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (0.41 g, 0.913 mmol) was dissolved in DCM (2 mL) and TFA (5 mL) was added. The reaction was stirred overnight and then concentrated in vacuo. DCM (3 ml) was added, followed by isohexanes (15 ml), resulting in the precipitation of the title compound (158 mg, 92%) as a pale brown solid which was dried in vacuo for 3 hours.
[0603] [0603] 1H NMR (DMSO-d6) δ 8.00 (d, J = 2.4 Hz, 1H), 7.57 (s, 2H), 6.68 (d, J = 2.4 Hz, 1H ), 5.61 (s, 2H).
[0604] [0604] LCMS; m / z 187 (M + H) + (ES +), 185 (M-H) - (ES-). Intermediate P29: 1- (Oxazol-2-ylmethyl) -1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1- (oxazol-2-ylmethyl) -1H-pyrazol-3-
[0605] [0605] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 2- (chloromethyl) oxazole to generate the title compound (523 g, 83%) as a solid colorless crystalline.
[0606] [0606] 1H NMR (CDCl3) δ 7.68 (d, J = 0.9 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 1.0 Hz, 1H), 7.06 - 6.99 (m, 4H), 6.79 - 6.72 (m, 4H), 6.69 (d, J = 2.4 Hz, 1H), 5.50 (s, 2H), 4.30 (s, 4H), 3.78 (s, 6H).
[0607] [0607] LCMS; m / z 491 (M + Na) + (ES +). Step B: 1- (Oxazol-2-ylmethyl) -1H-pyrazol-3-sulfonamide
[0608] [0608] Prepared according to the general procedure of 1- (2-cyanopropan-2-yl) -1H-pyrazol-3-sulfonamide (Intermediate P27, Step C) from N, N-bis (4-methoxybenzyl) -1- (oxazol-2-ylmethyl) -1H-pyrazol-3-sulfonamide to give the title compound (146 mg, 59%) as a colorless crystalline solid.
[0609] [0609] 1H NMR (DMSO-d6) δ 8.14 (d, J = 0.9 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.45 (s, 2H ), 7.25 (d, J = 0.8 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 5.64 (s, 2H). Intermediate P30: 5 - ((Dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide Step A: N, N-Bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0610] [0610] To a solution of 1-ethyl-1H-pyrazol-3-sulfonyl chloride (41.0 g, 210 mmol) in THF (400 mL) was added TEA (63.9 g, 631 mmol) and bis ( 4-methoxybenzyl) amine (10.8 g 42.1 mmol). The mixture was stirred at 25 ° C for 1.5 hours. The reaction mixture was diluted with cold water (800 ml) and extracted with EtOAc (3x800 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (0.1% NH3 in water / MeCN) to yield the title compound (18.7 g, 21%) as a yellow oil.
[0611] [0611] 1H NMR (CDCl3) δ 7.44 (d, 1H), 7.06 (d, 4H), 6.77 (d, 4H), 6.64 (d, 1H), 4.32 (s , 4H), 4.27-4.21 (m, 2H), 3.79 (s, 6H), 1.52 (t, 3H).
[0612] [0612] LCMS: m / z 416.1 (M + H) + (ES +). Step B: 5 - ((Dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0613] [0613] A den-BuLi solution (2.5 M in hexanes) (3 mL, 7.50 mmol) was added dropwise to a stirred solution of 1-ethyl-N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide (3 g, 7.22 mmol) in THF (45 mL) at -78 ° C. The reaction was stirred for 1 hour and then N, N-dimethylmethyleneimonium iodide ( 2.67 g, 14.44 mmol). The reaction mixture was left at - 78 ° C for 1 hour, suppressed with water (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layers were dried over MgSO 4, filtered and concentrated in vacuo. The crude product was purified by chromatography on SiO2 (120 g column, 0-10% MeOH / DCM) to generate the title compound (1.75 g, 49%) as a yellow solid.
[0614] [0614] 1H NMR (DMSO-d6) δ 7.06 - 6.99 (m, 4H), 6.85 - 6.78 (m, 4H), 6.57 (s, 1H), 4.27 - 4.17 (m, 6H), 3.72 (s, 6H), 3.47 (s, 2H), 2.16 (s, 6H), 1.35 (t, J = 7.2 Hz, 3H ).
[0615] [0615] LCMS; m / z 473.5 (M + H) + (ES +). Step C: 5 - ((Dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide
[0616] [0616] 5 - ((Dimethylamino) methyl) -1-ethyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (1.75 g, 3.70 mmol) was dissolved in DCM ( 5 ml) and TFA (5 ml) was added. The solution was stirred for 16 hours, concentrated in vacuo, suspended in toluene (5 ml) and concentrated again. The residue was dissolved in a mixture of DCM (10 ml) and MeOH (20 ml). SCX (14 g) was added and the suspension was stirred at room temperature for 1 hour. The SCX was filtered off and washed with MeOH (3 x 10 mL) and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to generate the title compound (705 mg, 81%) as a white solid.
[0617] [0617] 1H NMR (DMSO-d6) δ 7.35 (s, 2H), 6.47 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.47 (s , 2H), 2.17 (s, 6H), 1.35 (t, J = 7.2 Hz, 3H).
[0618] [0618] LCMS; m / z 233.4 (M + H) + (ES +). Intermediate P31: 1- (1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) -N, N, N-trimethylethane-1-amine 2,2,2-trifluoroacetate Step A: N, N-Bis- (4-methoxybenzyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[0619] [0619] Prepared according to the general procedure of N, N-bis- (4-methoxybenzyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P30, Step A) from 1-isopropyl chloride 1H-pyrazol-3-sulfonyl to generate the title compound (16.6 g, 80%) as a white solid.
[0620] [0620] 1H NMR (DMSO-d6) δ 8.00 (d, J = 2.4 Hz, 1H), 7.07 - 6.96 (m, 4H), 6.85 - 6.76 (m, 4H), 6.70 (d, J = 2.4 Hz, 1H), 4.61 (sept, J = 6.7 Hz, 1H), 4.20 (s, 4H), 3.71 (s, 6H), 1.44 (d, J = 6.7 Hz, 6H).
[0621] [0621] LCMS; m / z 452.2 (M + Na) + (ES +). Step B: 5- (1-hydroxyethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-
[0622] [0622] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) from N, N-bis- (4-methoxybenzyl) -1- isopropyl-1H-pyrazol-3-sulfonamide and acetaldehyde to generate the title compound (2.14 g, 65%) as a white solid.
[0623] [0623] 1H NMR (DMSO-d6) δ 7.07 - 6.99 (m, 4H), 6.84 - 6.78 (m, 4H), 6.51 (s, 1H), 5.49 ( d, J = 6.0 Hz, 1H), 4.96 - 4.76 (m, 2H), 4.19 (s, 4H), 3.72 (s, 6H), 1.44 (d, J = 6 , 5 Hz, 3H), 1.39 (t, J = 6.4 Hz, 6H).
[0624] [0624] LCMS; m / z 496.4 (M + Na) + (ES +). Step C: 5- (1- (Dimethylamino) ethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0625] [0625] 5- (1-Hydroxyethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (1 g, 2,112 mmol) and N-ethyl-N-isopropylpropan-2 -amine (1.103 ml, 6.33 mmol) were dissolved in THF (20 ml) and cooled to 0 ° C. MsCl (0.327 ml, 4.22 mmol) was added and the mixture was stirred at 0 ° C for 1 hour. Dimethylamine (2 M in THF) (10 mL, 20.00 mmol) and KI (0.175 g, 1.056 mmol) were added and the reaction mixture was stirred at room temperature over the weekend. The mixture was concentrated to dryness and the yellow residue was partitioned between water (20 ml) and EtOAc (30 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were dried (MgSO4) and evaporated to produce a yellow oil. The crude product was purified by chromatography on SiO 2 (40 g column, 0-10% MeOH / DCM) to generate the crude product (800 mg) as a brown oil. The crude product was loaded onto a SCX column (4 g) in MeOH.
[0626] [0626] 1H NMR (DMSO-d6) δ 7.07 - 6.96 (m, 4H), 6.86 - 6.76 (m, 4H), 6.49 (s, 1H), 4.93 - 4.84 (m, 1H), 4.21 (s, 4H), 4.01 - 3.90 (m, 1H), 3.72 (s, 6H), 2.13 (s, 6H), 1 , 43 - 1.32 (m, 6H), 1.24 (d, J = 6.7 Hz, 3H).
[0627] [0627] LCMS; m / z 501.5 (M + H) + (ES +). Step D: 1- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H-pyrazol-5-yl) -N, N, N-trimethylethane-1-aminium iodide
[0628] [0628] MeI (0.139 mL, 2.217 mmol) was added to a stirred solution of 5- (1- (dimethylamino) ethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3- sulfonamide (555 mg, 1.109 mmol) in MeCN (7.5 mL). The reaction mixture was then stirred at room temperature for 16 hours. The resulting colorless precipitate was collected by filtration, washed with MeCN (5 ml) and dried in vacuo to generate the title compound (241 mg, 34%) as a colorless solid. The filtrate and the wash were combined and concentrated to generate additional material (450 mg, 60%) as a yellow solid.
[0629] [0629] 1H NMR (DMSO-d6) δ 7.26 (s, 1H), 7.12 - 7.02 (m, 4H), 6.88 - 6.80 (m, 4H), 5.13 ( q, J = 6.8 Hz, 1H), 5.09 - 4.97 (m, 1H), 4.31 (d, J = 15.4 Hz, 2H), 4.23 (d, J = 15 , 4 Hz, 2H), 3.73 (s, 6H), 3.02 (s, 9H), 1.69 (d, J = 6.8 Hz, 3H), 1.51 (d, J = 6 , 4 Hz, 3H), 1.29 (d, J = 6.3 Hz, 3H).
[0630] [0630] LCMS; m / z 515.5 (M) + (ES +). Step E: 1- (1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) -N, N, N-trimethylethane-1-amine 2,2,2-trifluoroacetate O O O O
[0631] [0631] 1- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H-pyrazol-5-yl) -N, N, N-trimethylethan-1-aminium iodide (150 mg, 0.233 mmol) was dissolved in DCM (1.5 ml) and TFA (1.5 ml) was added. The solution was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, suspended in toluene (5 ml) and concentrated again. The crude product was dissolved in MeOH, filtered and dried in vacuo to give the title compound (100 mg, 99%) as a solid.
[0632] [0632] 1H NMR (DMSO-d6) δ 7.52 (s, 2H), 7.15 (s, 1H), 5.22 - 5.08 (m, 1H), 5.08 - 4.98 ( m, 1H), 3.04 (s, 9H), 1.73 (d, J = 6.8 Hz, 3H), 1.53 (d, J = 6.4 Hz, 3H), 1.32 ( d, J = 6.3 Hz, 3H).
[0633] [0633] LCMS; m / z 275.4 (M) + (ES +). Intermediate P32: N, N, N-Trimethyl-1- (1-methyl-3-sulfamoyl-1H-pyrazol-5-yl) ethane-1-amine 2,2,2-trifluoroacetate Step A: N, N-Bis - (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0634] [0634] A solution of 1-methyl-1H-pyrazol-3-sulfonyl chloride (13.0 g, 72.0 mmol) in DCM (30 mL) was added slowly to a solution of bis- (4-methoxybenzyl) amine (20 g, 78 mmol) and triethylamine (20 mL, 143 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 30 minutes, warmed to room temperature and stirred for 2 hours. The mixture was washed with water (200 ml), hydrochloric acid (aqueous, 1 M, 200 ml) and water (200 ml), then dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was triturated with TBME (250 ml), filtered and then purified by silica gel chromatography (330 g column, 0-60% EtOAc / isohexane column) to generate the title compound (27.7 g, 93%) as a white solid.
[0635] [0635] 1H NMR (CDCl3) δ 7.42 (d, J = 2.3 Hz, 1 H), 7.11-7.07 (m, 4 H), 6.81-6.77 (m, 4 H), 6.65 (d, J = 2.3 Hz, 1 H), 4.33 (s, 4 H), 3.99 (s, 3 H) and 3.81 (s, 6 H) .
[0636] [0636] LCMS; m / z 402 (M + H) + (ES +). Step B: 5- (1-hydroxyethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-
[0637] [0637] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) from N, N-bis- (4-methoxybenzyl) -1- methyl-1H-pyrazol-3-sulfonamide and acetaldehyde to generate the title compound (1.9 g, 38%) as a colorless oil.
[0638] [0638] 1H NMR (DMSO-d6) δ 7.11 - 6.90 (m, 4H), 6.86 - 6.74 (m, 4H), 6.53 (s, 1H), 5.49 ( d, J = 5.7 Hz, 1H), 4.86 (dt, J = 12.5, 6.4 Hz, 1H), 4.20 (s, 4H), 3.91 (s, 3H), 3.71 (s, 6H), 1.42 (d, J = 6.5 Hz, 3H). Step C: 5- (1- (Dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H - pyrazol-3-sulfonamide
[0639] [0639] Prepared according to the general procedure of 5- (1- (dimethylamino) ethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P31, Step C ) of 5- (1-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide and 2M dimethylamine in THF to generate the title compound (0.39 g, 96%) as a very pale yellow viscous oil.
[0640] [0640] LCMS; m / z 473.5 (M + H) + (ES +). Step D: 1- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-yl) -N, N, N-trimethylmethanamine iodide
[0641] [0641] Prepared according to the general procedure of 1- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H-pyrazol-5-yl) -N, N, N -trimetiletan-
[0642] [0642] 1H NMR (DMSO-d6) δ 7.28 (s, 1H), 7.10 - 7.05 (m, 4H), 6.87 - 6.81 (m, 4H), 5.04 ( q, J = 6.8 Hz, 1H), 4.28 (d, J = 15.4 Hz, 2H), 4.23 (d, J = 15.3 Hz, 2H), 4.04 (s, 3H), 3.73 (s, 6H), 3.02 (s, 9H), 1.68 (d, J = 6.8 Hz, 3H).
[0643] [0643] LCMS; m / z 487.4 (M) + (ES +). Step E: N, N, N-Trimethyl-1- (1-methyl-3-sulfamoyl-1H-pyrazol-5-yl) ethane-1-amine 2,2,2-trifluoroacetate
[0644] [0644] Prepared according to the general procedure of 1- (1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) -N, N, N-trimethylethane-1-aminium 2,2,2-trifluoroacetate ( Intermediate P31, Step E) of 1- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-yl) -N, N, N-trimethylmethanamine, to generate the title compound (70 mg, 101%) as an orange oil.
[0645] [0645] 1H NMR (DMSO-d6) δ 7.51 (s, 2H), 7.16 (s, 1H), 5.04 (q, J = 6.8 Hz, 1H), 4.02 (s , 3H), 3.04 (s, 9H), 1.71 (d, J = 6.8 Hz, 3H).
[0646] [0646] LCMS; m / z 247.3 (M) + (ES +). Intermediate P33: 1-Cyclopropyl-5- (1- (dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide Step A: 1-Cyclopropyl-5- (1-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0647] [0647] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -
[0648] [0648] 1H NMR (DMSO-d6) δ 7.06 - 7.01 (m, 4H), 6.83 - 6.78 (m, 4H), 6.55 (s, 1H), 5.50 ( d, J = 5.7 Hz, 1H), 5.01 (p, J = 6.4 Hz, 1H), 4.19 (s, 4H), 3.85 - 3.77 (m, 1H), 3.72 (s, 6H), 1.46 (d, J = 6.5 Hz, 3H), 1.18 - 0.95 (m, 4H).
[0649] [0649] LCMS; m / z 494.4 (M + Na) + (ES +). Step B: 1-Cyclopropyl-5- (1- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0650] [0650] MsCl (0.11 mL, 1.47 mmol) was added to a solution of 1- cyclopropyl-5- (1-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3- sulfonamide (0.60 g, 1.221 mmol) and DIPEA (0.30 mL, 1.71 mmol) in anhydrous DCM (6 mL) at 0 ° C. The reaction mixture was stirred for 1 hour at 0 ° C. Then the temperature was raised to room temperature and the reaction mixture was stirred overnight. The reaction was quenched by adding saturated aqueous NaHCO3 solution (10 ml), then diluted with DCM (40 ml), and the layers were separated. The aqueous phase was extracted with more parts of DCM (2 x 40 ml) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (20 ml), H2O (20 ml) and brine (20 ml), dried over MgSO4, filtered and concentrated in vacuo to produce an orange oil (0.523 g). The oil was dissolved in anhydrous THF (4 ml) at room temperature, treated with dimethylamine (2 M in THF) (2.27 ml, 4.55 mmol), heated to 50 ° C and stirred overnight. The mixture was transferred to a microwave flask and stirred at 60 ° C over the weekend. The mixture was suppressed with aqueous NaHCO3 (15 ml) and extracted with EtOAc (3 x 25 ml). The combined organic extracts were washed with brine (20 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was dissolved in MeOH (20 ml), SCX (~ 8 g) was added and the suspension was stirred for 30 minutes at room temperature. The mixture was transferred to a cartridge, washed with MeOH and the product was eluted with NH 3
[0651] [0651] 1H NMR (DMSO-d6) δ 7.03 (d, J = 8.6 Hz, 4H), 6.81 (d, J = 8.6 Hz, 4H), 6.53 (s, 1H ), 4.19 (s, 4H), 4.05 (q, J = 6.8 Hz, 1H), 3.91 - 3.82 (m, 1H), 3.72 (s, 6H), 2 , 15 (s, 6H), 1.27 (d, J = 6.8 Hz, 3H), 1.18 - 1.09 (m, 1H), 1.08 - 1.01 (m, 2H), 1.01 - 0.92 (m, 1H).
[0652] [0652] LCMS; m / z 499.5 (M + H) + (ES +). Step C: 1-Cyclopropyl-5- (1- (dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide
[0653] [0653] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) from 1-cyclopropyl- 5- (1- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (103 mg, 80%) as a brown oil.
[0654] [0654] 1H NMR (DMSO-d6) δ 7.33 (s, 2H), 6.48 (s, 1H), 4.05 (q, J = 6.8 Hz, 1H), 3.88 - 3 , 78 (m, 1H), 2.16 (s, 6H), 1.28 (d, J = 6.8 Hz, 3H), 1.23 - 1.15 (m, 1H), 1.08 - 0.96 (m, 3H).
[0655] [0655] LCMS; m / z 259.3 (M + H) + (ES +). Intermediate P34: 5- (1- (Azetidine-1-yl) propyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide Step A: 1-Cyclopropyl-5- (1-hydroxypropyl) -N, N-bis- bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0656] [0656] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -
[0657] [0657] 1H NMR (DMSO-d6) δ 7.04 - 7.00 (m, 4H), 6.83 - 6.78 (m, 4H), 6.53 (s, 1H), 5.48 ( d, J = 5.8 Hz, 1H), 4.76 (q, J = 6.2 Hz, 1H), 4.18 (s, 4H), 3.84 - 3.76 (m, 1H), 3.72 (s, 6H), 1.84 - 1.72 (m, 2H), 1.16 - 0.95 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H) .
[0658] [0658] LCMS; m / z 508.4 (M + Na) + (ES +). Step B: 5- (1- (Azetidine-1-yl) propyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide
[0659] [0659] Prepared according to the general procedure of 1-cyclopropyl-5- (1- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P33, Step B ) of 1-cyclopropyl-5- (1-hydroxypropyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide and azetidine to generate the title compound as a pale yellow oil (178 mg, 72 %).
[0660] [0660] 1H NMR (DMSO-d6) δ 7.00 (d, J = 8.7 Hz, 4H), 6.80 (d, J = 8.7 Hz, 4H), 6.47 (s, 1H ), 4.19 (s, 4H), 3.96 - 3.87 (m, 1H), 3.72 (s, 6H), 3.68 (dd, J = 8.2, 4.1 Hz, 1H), 3.10 (q, J = 6.7 Hz, 2H), 3.03 - 2.96 (m, 2H), 1.99 - 1.85 (m, 2H), 1.77 - 1 , 63 (m, 1H), 1.61 - 1.49 (m, 1H), 1.14 - 0.98 (m, 4H), 0.69 (t, J = 7.4 Hz, 3H).
[0661] [0661] LCMS; m / z 525.5 (M + Na) + (ES +). Step C: 5- (1- (Azetidine-1-yl) propyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide
[0662] [0662] Prepared according to the general procedure of 1- (azetidin-3-yl) - 1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (1- (azetidine-1-yl) propyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound as a white foam (70 mg, 78%).
[0663] [0663] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.41 (s, 1H), 3.92 - 3.81 (m, 1H), 3.68 (dd, J = 8.0, 4.1 Hz, 1H), 3.11 (q, J = 6.8 Hz, 2H), 3.03 (q, J = 6.8 Hz, 2H), 1.93 (p, J = 6.8 Hz, 2H), 1.74 - 1.62 (m, 1H), 1.62 - 1.49 (m, 1H), 1.23 - 1.13 (m, 1H), 1.12 - 1.00 (m, 3H), 0.70 (t, J = 7.4 Hz, 3H).
[0664] [0664] LCMS; m / z 285.3 (M + H) + (ES +). Intermediate P35: 1-Cyclopropyl-5- (1- (dimethylamino) propyl) -1H-pyrazol-3-sulfonamide Step A: 1-Cyclopropyl-5- (1- (dimethylamino) propyl) -N, N-bis (4 -methoxybenzyl) - 1H-pyrazol-3-sulfonamide
[0665] [0665] Prepared according to the general procedure of 1-cyclopropyl-5- (1- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P33, Step B ) of 1-cyclopropyl-5- (1-hydroxypropyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P34, Step A) and dimethylamine (2M in THF) for compound generation of the title (147 mg, 62%) as a brown oil.
[0666] [0666] 1H NMR (DMSO-d6) δ 7.01 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.55 (s, 1H ), 4.20 (s, 4H), 3.91 - 3.84 (m, 1H), 3.84 - 3.78 (m, 1H), 3.72 (s, 6H), 2.14 ( s, 6H), 1.87 - 1.77 (m, 1H), 1.76 - 1.63 (m, 1H), 1.16 - 0.94 (m, 4H), 0.79 (t, J = 7.3 Hz, 3H).
[0667] [0667] LCMS; m / z 513.5 (M + H) + (ES +). Step B: 1-Cyclopropyl-5- (1- (dimethylamino) propyl) -1H-pyrazol-3-sulfonamide
[0668] [0668] Prepared according to the general procedure of 1- (azetidine-3-
[0669] [0669] 1H NMR (DMSO-d6) δ 7.35 (s, 2H), 6.47 (s, 1H), 3.86 (dd, J = 9.2, 5.4 Hz, 1H), 3 , 82 - 3.74 (m, 1H), 2.16 (s, 6H), 1.90 - 1.77 (m, 1H), 1.76 - 1.62 (m, 1H), 1.20 - 1.11 (m, 1H), 1.11 - 0.98 (m, 3H), 0.80 (t, J = 7.3 Hz, 3H).
[0670] [0670] LCMS; m / z 273.3 (M + H) + (ES +). Intermediate P36: 5- (1- (Azetidine-1-yl) ethyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide Step A: 5- (1- (Azetidine-1-yl) ethyl) -1-cyclopropyl -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0671] [0671] Prepared according to the general procedure of 1-cyclopropyl-5- (1- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P33, Step B ) of 1-cyclopropyl-5- (1-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P33, Step A) and azetidine to generate the title compound as an oil pale yellow (246 mg, 91%).
[0672] [0672] 1H NMR (DMSO-d6) δ 7.00 (d, J = 8.7 Hz, 4H), 6.80 (d, J = 8.7 Hz, 4H), 6.44 (s, 1H ), 4.19 (s, 4H), 3.92 - 3.81 (m, 1H), 3.77 (q, J = 6.5 Hz, 1H), 3.72 (s, 6H), 3 , 16 - 3.00 (m, 4H), 1.93 (p, J = 6.9 Hz, 2H), 1.17 (d, J = 6.5 Hz, 3H), 1.15 - 0, 95 (m, 4H).
[0673] [0673] LCMS; m / z 511.5 (M + H) + (ES +). Step B: 5- (1- (Azetidine-1-yl) ethyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide
[0674] [0674] Prepared according to the general procedure of 1- (azetidine-3-
[0675] [0675] 1H NMR (DMSO-d6) δ 7.33 (s, 2H), 6.40 (s, 1H), 3.87 - 3.80 (m, 1H), 3.77 (q, J = 6.5 Hz, 1H), 3.16 - 3.02 (m, 4H), 1.93 (p, J = 7.0 Hz, 2H), 1.17 (d, J = 6.5 Hz, 3H) , 1.16 - 1.01 (m, 4H).
[0676] [0676] LCMS; m / z 271.3 (M + H) + (ES +). Intermediate P37: 5- (1- (Azetidine-1-yl) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide, enantiomer A and Intermediate P38: 5- (1- (Azetidine-1-yl) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide, enantiomer B Enantiomer A Enantiomer B
[0677] [0677] Prepared by chiral resolution of 5- (1- (azetidine-1-yl) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P63): racemic 5- (1- (azetidine-1- il) ethyl) -1- methyl-1H-pyrazol-3-sulfonamide (Intermediate P63) (16 g) was separated by SFC to produce Intermediate P37, Enantiomer A (5.45 g, 98.34% ee) and Intermediate P38, Enantiomer B (5.49 g, 99.72% ee). SFC separation method: Instrument: Waters UPC2 analytical SFC (SFC-H) Column: ChiralPak AD, 150 × 4.6mm ID, 3µm Mobile phase: A for CO2 and B for MeOH (0.05% DEA) Gradient: B 5 -40% Flow rate: 2.5 mL / min Back pressure: 100 bar Column temperature: 35 ° C Wavelength: 220 nm
[0678] [0678] Intermediate P37: 1H NMR (DMSO-d6) δ 7.39 (br s, 2H), 6.46 (s, 1H), 3.90 (s, 3H), 3.80-3.60 ( m, 1H), 3.18-2.96 (m, 4H), 2.05-1.90 (m, 2H), 1.10 (s, 3H).
[0679] [0679] LCMS; m / z 245.0 (M + H) + (ES +).
[0680] [0680] SFC: retention time: 3.026 min. Intermediate P38: 1H NMR (DMSO-d6) δ 7.36 (s, 2H), 6.42 (s, 1H), 3.89 (s, 3H), 3.75-3.61 (m, 1H) , 3.10-2.96 (m, 4H), 1.96-1.92 (m, 2H), 1.13 (d, 3H).
[0681] [0681] LCMS; m / z 245.0 (M + H) + (ES +).
[0682] [0682] SFC: retention time: 3,132 min. Intermediate P39: 5 - ((Dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((Dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl- 1H-pyrazol-3-sulfonamide
[0683] [0683] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step A) and N-methyl-N-methylenemethanamine to generate the compound title (1.9 g, 38%) as a colorless oil.
[0684] [0684] 1H NMR (DMSO-d6) δ 7.07 - 7.01 (m, 4H), 6.84 - 6.78 (m, 4H), 6.58 (s, 1H), 4.21 ( s, 4H), 3.89 (s, 3H), 3.72 (s, 6H), 3.47 (s, 2H) and 2.16 (s, 6H).
[0685] [0685] LCMS; m / z 459.8 (M + H) + (ES +). Step B: 5 - ((Dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0686] [0686] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (337 mg, 79%) as a white solid.
[0687] [0687] 1H NMR (DMSO-d6) δ 7.36 (br s, 2H), 6.51 (s, 1H), 3.86 (s, 3H), 3.32 (s, 2H) and 2, 23 (s, 6H).
[0688] [0688] LCMS; m / z 219.3 (M + H) + (ES +). Intermediate P40: 1-Methyl-5- (1- (3-methylazetidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1-methyl-5 - (1- (3-methylazetidine-1-yl) ethyl) -1H-pyrazol-3-sulfonamide
[0689] [0689] Prepared according to the general procedure of 5- (1- (dimethylamino) ethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P31, Step C ) of 5- (1-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step B) and 3-methylazetidine hydrochloride to generate the compound title (867 mg, 67%) as a yellow oil.
[0690] [0690] 1H NMR (DMSO-d6) δ 7.01 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.43 (s, 1H ), 4.19 (s, 4H), 3.91 (s, 3H), 3.71 (s, 6H), 3.59 (q, J = 6.5 Hz, 1H), 3.35 - 3 , 31 (m, 1H), 3.21 - 3.14 (m, 1H), 2.67 - 2.58 (m, 2H), 2.44 - 2.32 (m, 1H), 1.12 (d, J = 6.5 Hz, 3H), 1.10 (d, J = 6.7 Hz, 3H).
[0691] [0691] LCMS; m / z 499.5 (M + H) + (ES +). Step B: 1-Methyl-5- (1- (3-methylazetidine-1-yl) ethyl-1H-pyrazol-3-sulfonamide
[0692] [0692] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of N, N-bis (4-methoxybenzyl) -1-methyl -5- (1- (3-methylazetidine-1-yl) ethyl) -1H-pyrazol-3-sulfonamide to generate the title compound (283 mg, 66%) as a light brown solid.
[0693] [0693] 1H NMR (DMSO-d6) δ 7.35 (s, 2H), 6.39 (s, 1H), 3.88 (s, 3H), 3.58 (q, J = 6.6 Hz , 1H), 3.38 - 3.30 (m, 1H), 3.24 - 3.16 (m, 1H), 2.64 (app. Q, J = 6.8
[0694] [0694] LCMS; m / z 259.3 (M + H) + (ES +). Intermediate P41: 5- (Azetidin-1-ylmethyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide Step A: 1-Cyclopropyl-5-formyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol- 3- sulfonamide
[0695] [0695] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of 1-cyclopropyl-N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide (Intermediate P22, Step D) and morpholine-4-carbaldehyde to generate the title compound (732 mg, 33%) as a colorless oil that slowly solidified.
[0696] [0696] 1H NMR (DMSO-d6) δ 10.02 (s, 1H), 7.35 (s, 1H), 7.05 (d, J = 8.7 Hz, 4H), 6.82 (d , J = 8.7 Hz, 4H), 4.32 - 4.25 (m, 1H), 4.24 (s, 4H), 3.72 (s, 6H), 1.14 (s, 2H) , 1.13 - 1.11 (m, 2H).
[0697] [0697] LCMS; m / z 456.2 (M + H) + (ES +). Step B: 5- (Azetidin-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0698] [0698] To a solution of 1-cyclopropyl-5-formyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (730 mg, 1.603 mmol) in THF (10 mL) was added hydrochloride azetidine (300 mg, 3.21 mmol), triethylamine (0.44 mL, 3.16 mmol) and 4Å molecular sieves. The mixture was stirred for 1 hour before adding NaBH (OAc) 3 (509 mg, 2.404 mmol) and stirring was continued overnight. The mixture was filtered over a pad of Celite® with EtOAc and the solvent was removed in vacuo. The residue was dissolved in MeOH (10 ml), SCX was added and the suspension was stirred for 30 minutes and transferred to a cartridge. The solid was washed with MeOH and the product was eluted with 0.7 M NH3 in MeOH. The solvent was evaporated to generate the title compound (691 mg, 84%) as a pale yellow oil.
[0699] [0699] 1H NMR (DMSO-d6) δ 7.01 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.50 (s, 1H ), 4.17 (s, 4H), 3.76 - 3.70 (m, 7H), 3.68 (s, 2H), 3.18 (t, J = 7.0 Hz, 4H), 2.00 (p, J = 7.0 Hz, 2H), 1.04 (s, 2H), 1.02 (s, 2H).
[0700] [0700] LCMS; m / z 497.6 (M + H) + (ES +). Step C: 5- (Azetidine-1-ylmethyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide
[0701] [0701] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (azetidine-1-ylmethyl) - 1-cyclopropyl- N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the compound title (345 mg, 95%) as a solid beige.
[0702] [0702] 1H NMR (DMSO-d6) δ 7.36 (s, 2H), 6.43 (s, 1H), 3.78 - 3.62 (m, 4H), 3.26 - 3.16 ( m, 3H), 2.01 (p, J = 7.0 Hz, 2H), 1.11 - 0.97 (m, 4H).
[0703] [0703] LCMS; m / z 257.3 (M + H) + (ES +). Intermediate P42: 5 - ((Dimethylamino) methyl) -1-neopentyl-1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1-neopentyl-1H-pyrazol-3-sulfonamide
[0704] [0704] A mixture of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) (500 mg, 1.290 mmol), K2CO3 (360 mg, 2.60 mmol), KI
[0705] [0705] 1H NMR (CDCl3) δ 7.38 (d, J = 2.3 Hz, 1H), 7.11 - 7.07 (m, 4H), 6.80 - 6.76 (m, 4H) , 6.68 (d, J = 2.3Hz, 1H), 4.34 (s, 4H), 3.98 (s, 2H), 3.80 (s, 6H), 0.97 (s, 9H ). Step B: 5 - ((Dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-neopentyl-1H-pyrazol-3-sulfonamide
[0706] [0706] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis (4-methoxybenzyl) -1-neopentyl-1H-pyrazol-3-sulfonamide and N-methyl-N-methylene methanamine to generate the title compound (198 g, 42 %) as a colorless oil.
[0707] [0707] 1H NMR (CDCl3) δ 7.14 - 7.06 (m, 4H), 6.83 - 6.75 (m, 4H), 6.68 (s, 1H), 4.36 (s, 4H), 4.13 (s, 2H), 3.80 (s, 6H), 3.76 (s, 2H), 2.42 (s, 6H), 0.97 (s, 9H).
[0708] [0708] LCMS; m / z 515.3 (M + H) + (ES +); 513.5 (M-H) - (ES-). Step C: 5 - ((Dimethylamino) methyl) -1-neopentyl-1H-pyrazol-3-sulfonamide
[0709] [0709] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5-
[0710] [0710] 1H NMR (CDCl3) δ 6.60 (s, 1H), 4.95 (s, 2H), 4.07 (s, 2H), 3.45 (s, 2H), 2.23 (s , 6H), 0.99 (s, 9H).
[0711] [0711] LCMS; m / z 275.3 (M + H) + (ES +). Intermediate P43: 5- (1- (Dimethylamino) cyclopropyl) -1-isopropyl-1H-pyrazol-3-sulfonamide Step A: 3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-N, N-dimethyl-1H-pyrazol-5-carboxamide
[0712] [0712] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis- (4-methoxybenzyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P31, Step A) and carbamoyl chloride to generate the title compound (0, 6 g, 50%) as a yellow gum.
[0713] [0713] 1H NMR (DMSO-d6) δ 7.09 - 6.98 (m, 4H), 6.88 (s, 1H), 6.85 - 6.77 (m, 4H), 4.69 ( sept, J = 6.6 Hz, 1H), 4.24 (s, 4H), 3.72 (s, 6H), 3.01 (s, 3H), 2.95 (s, 3H), 1, 39 (d, J = 6.6 Hz, 6H).
[0714] [0714] LCMS; m / z 523.4 (M + Na) + (ES +). Step B: 5- (1- (Dimethylamino) cyclopropyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide
[0715] [0715] 1M ethylmagnesium bromide in THF (2.0 mL, 2,000 mmol) was added dropwise over 20 seconds to a stirred solution of 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) - 1-isopropyl-N, N-dimethyl-1H-pyrazol-5-carboxamide (0.5 g, 0.999 mmol) and 1 M triisopropoxy (methyl) titanium (1.2 mL,
[0716] [0716] 1H NMR (DMSO-d6) δ 7.07 - 6.95 (m, 4H), 6.82 - 6.73 (m, 4H), 6.47 (s, 1H), 4.92 ( sept, J = 6.0 Hz, 1H), 4.22 (s, 4H), 3.71 (s, 6H), 2.15 (s, 6H), 1.38 (d, J = 6.5 Hz, 6H), 1.06 - 0.97 (m, 2H), 0.86 - 0.77 (m, 2H).
[0717] [0717] LCMS; m / z 513.3 (M + H) + (ES +). Step C: 5- (1- (Dimethylamino) cyclopropyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[0718] [0718] 5- (1- (Dimethylamino) cyclopropyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide (0.37 g, 0.520 mmol) was dissolved in TFA ( 5 mL) and stirred at room temperature for 17 hours. The mixture was evaporated to dryness, dissolved in 9: 1 DCM: MeOH and loaded into SCX (2 g). The column was washed with 9: 1 DCM: MeOH (20 ml), then the product was eluted with 0.7NH3 in 1: 9 MeOH: DCM (20 ml). The resulting mixture was concentrated in vacuo to generate the crude product as a pale yellow solid. The crude product was purified by preparative reverse phase HPLC (General Methods, basic preparation) to generate the title compound (79 mg, 55%) as a white solid.
[0719] [0719] 1H NMR (DMSO-d6) δ 7.36 (s, 2H), 6.43 (s, 1H), 4.92 (sept, J = 6.5 Hz, 1H), 2.17 (s , 6H), 1.40 (d, J = 6.5 Hz, 6H), 1.10 - 0.96 (m, 2H), 0.86 - 0.73 (m,
[0720] [0720] LCMS; m / z 273.3 (M + H) + (ES +). Intermediate P44: 5- (2- (Dimethylamino) ethyl) -1-isopropyl-1H-pyrazol-3-sulfonamide Step A: 5- (2-Hydroxyethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0721] [0721] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis- (4-methoxybenzyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P31, Step A) and oxirane (2.5 M in THF) to generate the title of the compound (1.33 g, 56%) as a yellow oil.
[0722] [0722] 1H NMR (DMSO-d6) δ 7.06 - 6.97 (m, 4H), 6.85 - 6.78 (m, 4H), 6.51 (s, 1H), 4.87 ( t, J = 5.2 Hz, 1H), 4.68 (sept, J = 6.6 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 3.70 - 3.63 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.38 (d, J = 6.6 Hz, 6H).
[0723] [0723] LCMS; m / z 496.4 (M + Na) + (ES +). Step B: 5- (2- (Dimethylamino) ethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0724] [0724] Prepared according to the general procedure of 2,2,2-trifluoro-N-methyl-N- (2- (3-sulfamoyl-1H-pyrazol-1-yl) ethyl) acetamide (Intermediate P12, Step A ) of 5- (2-hydroxyethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide and dimethylamine (2 M in THF) to generate the title compound (162 mg, 61%) as a colorless oil.
[0725] [0725] 1H NMR (DMSO-d6) δ 7.05 - 6.97 (m, 4H), 6.86 - 6.77 (m, 4H), 6.48 (s, 1H), 4.65 ( sept, J = 6.7 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 2.84 (t, J = 7.4 Hz,
[0726] [0726] LCMS; m / z 501.5 (M + H) + (ES +). Step C: 5- (2- (Dimethylamino) ethyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[0727] [0727] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (2- (dimethylamino) ethyl) -1-isopropyl -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (55 mg, 84%) as a colorless oil.
[0728] [0728] 1H NMR (DMSO-d6) δ 7.31 (s, 2H), 6.41 (s, 1H), 4.61 (sept, J = 6.5 Hz, 1H), 2.81 (t , J = 7.3 Hz, 2H), 2.19 (s, 6H), 1.38 (d, J = 6.5 Hz, 6H). CH2 triplet was not observed under DMSO.
[0729] [0729] LCMS; m / z 261.3 (M + H) + (ES +). Intermediate P45: 5- (2- (Dimethylamino) propan-2-yl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1 -methyl-1H-pyrazol-5-carboxylate
[0730] [0730] Prepared according to the general procedure of N, N-bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step A) of ethyl 3- (chlorosulfonyl) -1 -methyl-1H -pyrazol-5-carboxylate to generate the title compound (15.9 g, 91%) as a white solid.
[0731] [0731] 1H NMR (DMSO-d6) δ 7.19 - 7.00 (m, 5H), 6.85 - 6.77 (m, 4H), 4.33 (q, J = 7.1 Hz, 2H), 4.25 (s, 4H), 4.15 (s, 3H), 3.71 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H).
[0732] [0732] LCMS; m / z 496.4 (M + Na) + (ES +). Step B: 5- (2-Hydroxypropan-2-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0733] [0733] Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylate (2 g, 3.67 mmol) was dissolved in dry THF (70 mL) under nitrogen atmosphere and cooled to -78 ° C (bath temperature). Methylmagnesium chloride (3 M in THF) (6.2 mL, 18.60 mmol) was added via syringe over 5 minutes and the mixture was warmed to room temperature and stirred over the weekend. The yellow reaction mixture was cooled in an ice bath and suppressed by cautious addition of saturated aqueous ammonium chloride (20 mL). Water (20 ml) and EtOAc (80 ml) were added and the phases separated. The aqueous layer was extracted with EtOAc (2 x 80 ml). The combined organic extracts were passed through a phase separator and concentrated in vacuo to produce a pale yellow oil. The crude product was loaded onto silica and purified by SiO2 chromatography (40 g column, 0-70% EtOAc / isohexane) to generate the title compound (1.56 g, 87%) as a colorless crystalline solid after drying in the desiccator overnight.
[0734] [0734] 1H NMR (DMSO-d6) δ 7.05 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.41 (s, 1H ), 5.48 (s, 1H), 4.21 (s, 4H), 4.03 (s, 3H), 3.72 (s, 6H), 1.49 (s, 6H).
[0735] [0735] LCMS; m / z 482.1 (M + Na) + (ES +). Step C: 5- (2-Aminopropan-2-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0736] [0736] To a mixture of 5- (2-hydroxypropan-2-yl) -N, N-bis (4-methoxybenzyl) -1- methyl-1H-pyrazol-3-sulfonamide (1 g, 2.176 mmol) and azidotrimethylsilane (0.58 mL, 4.37 mmol) in toluene (5 mL) BF3.OEt2 (4 mL, 15.07 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 2 hours. The mixture was suppressed with aqueous NaHCO3 (30 ml) and extracted with DCM (3 x 30 ml). The combined organic extracts were passed through a phase separator and the solvent was removed in vacuo to produce a brown oil. The residue was dissolved in EtOH (45 ml) and hydrogenated using an H-Cube (10% Pd / C at 35 ° C, 1 cycle). After evaporation of the solvent, the residue was loaded into SCX with MeOH, washed with MeOH and the product was eluted with 0.7 M NH 3 in MeOH to produce the title compound (322 mg, 29%) as a clear colorless oil.
[0737] [0737] 1H NMR (DMSO-d6) δ 7.05 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.36 (s, 1H ), 4.21 (s, 4H), 4.12 (s, 3H), 3.72 (s, 6H), 2.00 (s, 2H), 1.42 (s, 6H).
[0738] [0738] LCMS; m / z 459.2 (M + H) + (ES +). Step D: 5- (2- (Dimethylamino) propan-2-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0739] [0739] A mixture of 5- (2-aminopropan-2-yl) -N, N-bis (4-methoxybenzyl) -1- methyl-1H-pyrazol-3-sulfonamide (320 mg, 0.698 mmol), formaldehyde ( 37% in H 2 O, 10% MeOH) (1.1 ml, 14.77 mmol) and formic acid (0.54 ml, 14.08 mmol) was stirred at 60 ° C overnight. After cooling to room temperature, the mixture was diluted with EtOAc (15 ml), basified with 2 M aqueous NaOH (2 ml) and diluted H2O (5 ml). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 15 ml). The combined organic extracts were passed through a phase separator and the solvent was removed in vacuo. To the residue, SCX was added and the mixture was stirred for 30 minutes before being transferred to a cartridge. The suspension was washed with MeOH and the product subsequently eluted with 0.7 M NH3 in MeOH. The solvent was evaporated to generate the title compound (275 mg, 75%) as a pale yellow oil.
[0740] [0740] 1H NMR (DMSO-d6) δ 7.06 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.36 (s, 1H ), 4.21 (s, 4H), 4.06 (s, 3H), 3.71 (s, 6H), 2.08 (s, 6H), 1.31 (s, 6H).
[0741] [0741] LCMS; m / z 487.6 (M + H) + (ES +). Step E: 5- (2- (Dimethylamino) propan-2-yl) -1-methyl-1H-pyrazol-3-sulfonamide
[0742] [0742] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (2- (dimethylamino) propan-2-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (135 mg, 78%) as a sticky yellow oil.
[0743] [0743] 1H NMR (DMSO-d6) δ 7.32 (s, 2H), 6.40 (s, 1H), 4.05 (s, 3H), 2.10 (s, 6H), 1.34 (s, 6H).
[0744] [0744] LCMS; m / z 247.4 (M + H) + (ES +). Intermediate P46: 1- (tert-Butyl) -5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide Step A: 1- (tert-Butyl) -N, N-bis (4-methoxybenzyl) -1H -pyrazol-3-sulfonamide
[0745] [0745] To a solution of 1- (tert-butyl) -1H-pyrazol-3-sulfonyl chloride (40 g, 179.6 mmol) in THF (400 mL) was added TEA (54.53 g, 538, 9 mmol, 75.00 mL) and bis (4-methoxybenzyl) amine (13.87 g, 53.9 mmol). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into H2O (1 L) and extracted with EtOAc (3 x 1 L). The combined organic layers were dried over (Na 2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether 30: 1 to 2: 1 / EtOAc) and then purified by flash reverse phase chromatography (0.1% NH3.H2O / CH3CN) to produce the compound title (15 g, 19%) as a yellow oil.
[0746] [0746] 1H NMR (CDCl3) δ 7.54 (d, 1 H), 7.07 (d, 4 H), 6.77 (d, 4 H), 6.66 (d, 1 H), 4 , 32 (s, 4 H), 3.79 (s, 6 H) and 1.60 (s, 9 H). Step B: 1- (tert-Butyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0747] [0747] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of 1- (tert-butyl) -N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide and N-methyl-N-iodide of methylene methanamine to generate the title compound ( 266 g, 23%).
[0748] [0748] 1H NMR (DMSO-d6) δ 7.05 - 7.00 (m, 4H), 6.83 - 6.78 (m, 4H), 6.60 (s, 1H), 4.22 ( s, 4H), 3.72 (s, 6H), 3.52 (s, 2H), 2.17 (s, 6H), 1.60 (s, 9H).
[0749] [0749] LCMS; m / z 501.6 (M + H) + (ES +). Step C: 1- (tert-Butyl) -5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide
[0750] [0750] 1- (tert-Butyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (266 mg, 0.531 mmol) was dissolved in DCM ( 1.5 ml) and TFA (1.5 ml) was added. The solution was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, suspended in toluene (5 ml) and concentrated again. The crude product was loaded onto a SCX column (2 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The product was further purified by SiO2 chromatography (12 g column, 0-10% MeOH / DCM) to generate the title compound (30 mg, 19%) as a white solid.
[0751] [0751] 1H NMR (DMSO-d6) δ 7.42 (s, 2H), 6.62 (s, 1H), 3.61 (s, 2H), 2.26 (s, 6H), 1.71 (s, 9H).
[0752] [0752] LCMS; m / z 261.3 (M + H) + (ES +). Intermediate P47: 5- (Azetidine-1-ylmethyl) -1- (tert-butyl) -1H-pyrazol-3-sulfonamide Step A: 1- (tert-Butyl) -5-formyl-N, N-bis (4 -methoxybenzyl) -1H-pyrazol-3-
[0753] [0753] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of 1- (tert-butyl) -N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide (Intermediate P46, Step A) and morpholine-4-carbaldehyde to generate the compound of the title (713 mg, 31%) as a colorless oil.
[0754] [0754] 1H NMR (DMSO-d6) δ 9.97 (s, 1H), 7.54 (s, 1H), 7.14 - 7.03 (m, 4H), 6.91 - 6.75 ( m, 4H), 4.29 (s, 4H), 3.72 (s, 6H), 1.61 (s, 9H).
[0755] [0755] LCMS; m / z 494.5 (M + Na) + (ES +). Step B: 5- (Azetidine-1-ylmethyl) -1- (tert-butyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0756] [0756] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) 1- (tert-butyl) -5-formyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide and azetidine hydrochloride to generate the title compound (690 mg, 73%) as a white oil.
[0757] [0757] 1H NMR (DMSO-d6) δ 7.05 - 6.99 (m, 4H), 6.84 - 6.78 (m, 4H), 6.57 (s, 1H), 4.20 ( s, 4H), 3.72 (s, 6H), 3.70 (s, 2H), 3.16 (t, J = 7.0 Hz, 4H), 2.01 (p, J =
[0758] [0758] LCMS; m / z 513.5 (M + H) + (ES +). Step C: 5- (Azetidine-1-ylmethyl) -1- (tert-butyl) -1H-pyrazol-3-sulfonamide
[0759] [0759] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (azetidine-1-ylmethyl) - 1- (tert -butyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title of the compound (284 mg, 63%).
[0760] [0760] 1H NMR (DMSO-d6) δ 7.31 (s, 2H), 6.51 (s, 1H), 3.70 (s, 2H), 3.18 (t, J = 7.0 Hz, 4H ), 2.01 (p, J = 7.0 Hz, 2H), 1.60 (s, 9H).
[0761] [0761] LCMS; m / z 273.4 (M + H) + (ES +). Intermediate P48: 5 - ((Dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((Dimethylamino) methyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide
[0762] [0762] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis- (4-methoxybenzyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P31, Step A) and N-methyl-N-iodide of methylene methanamine to generate the title compound (2.43 g, 69%) as a solid white.
[0763] [0763] 1H NMR (CDCl3) δ 7.13 - 7.04 (m, 4H), 6.83 - 6.76 (m, 4H), 6.58 (s, 1H), 4.86 (sept, J = 6.5 Hz, 1H), 4.34 (s, 4H), 3.81 (s, 6H), 3.51 (s, 2H) 2.38 (s, 6H), 1.51 (d , J = 6.5 Hz, 6H).
[0764] [0764] LCMS; m / z 487 (M + H) + (ES +); 485 (M-H) - (ES-). Step B: 5 - ((Dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[0765] [0765] 5 - ((Dimethylamino) methyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (2.43 g, 4.84 mmol) was dissolved in DCM ( 20 ml) and TFA (10 ml, 130 mmol) was added. The mixture was stirred over the weekend at room temperature. The reaction solvent was removed in vacuo. DCM (50 ml) and MeOH (50 ml) were added together with SCX (25 g, ~ 3 eq). The mixture was stirred for 2 hours at room temperature. The SCX was filtered and washed with MeOH (3 x 100 ml). The product was then eluted with 0.7 M ammonia in MeOH (3 x 100 mL). The concentration of the ammoniacal washes in vacuo produced a pale yellow semi-solid. This residue was dissolved in a minimal amount of DCM / MeOH (9: 1, ~ 10 mL). Then the product was precipitated by adding an excess of isohexanes (100 ml). After filtration, the title compound (1.04 g, 86%) was isolated as a colorless solid which was dried in vacuo and used without further purification.
[0766] [0766] 1H NMR (DMSO-d6) δ 7.35 (s, 2H), 6.46 (s, 1H), 4.78 (sept, J = 6.6 Hz, 1H), 3.47 (s , 2H), 2.16 (s, 6H), 1.38 (d, J = 6.6 Hz, 6H).
[0767] [0767] LCMS; m / z 247 (M + H) + (ES +); 245 (M-H) - (ES-). Intermediate P49: N, N, N-Trimethyl-1- (1-methyl-3-sulfamoyl-1H-pyrazol-5-yl) methanamine 2,2,2-trifluoroacetate Step A: 1- (3- (N, N -Bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-yl) - N, N, N-trimethylmethanamine iodide
[0768] [0768] MeI (0.136 mL, 2.181 mmol) was added to a stirred solution of 5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide ( Intermediate P39, Step A) (500 mg, 1.090 mmol) in MTBE (5 mL). The reaction mixture was stirred at room temperature for 16 hours. Additional MeI (0.136 mL, 2.181 mmol) was added and the reaction mixture was stirred for 48 hours. The precipitate was filtered and washed with MTBE (10 ml) to generate the title compound (490 mg, 69%).
[0769] [0769] 1H NMR (DMSO-d6) δ 7.12 - 7.03 (m, 5H), 6.87 - 6.78 (m, 4H), 4.74 (s, 2H), 4.26 ( s, 4H), 4.04 (s, 3H), 3.73 (s, 6H), 3.09 (s, 9H).
[0770] [0770] LCMS; m / z 473.3 (M) + (ES +). Step B: N, N, N-Trimethyl-1- (1-methyl-3-sulfamoyl-1H-pyrazol-5-yl) methanamine 2,2,2-trifluoroacetate I O O O O
[0771] [0771] Prepared according to the general procedure of 1- (1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) -N, N, N-trimethylethane-1-aminium 2,2,2-trifluoroacetate ( Intermediate P31, Step E) from 1- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-yl) -N, N, N-trimethylmethanamine iodide, for generate the title compound (182 mg, 47%) as a brown solid.
[0772] [0772] 1H NMR (DMSO-d6) δ 7.61 (s, 2H), 7.01 (s, 1H), 4.81 (s, 2H), 4.08 (s, 3H), 3.18 (s, 9H).
[0773] [0773] LCMS; m / z 233.0 (M) + (ES +). Intermediate P50: 5- (Azetidine-1-ylmethyl) -1-ethyl-1H-pyrazol-3-sulfonamide Step A: 1-Ethyl-5-formyl-N, N-bis (4-methoxybenzyl) -1H-pyrazole- 3-sulfonamide
[0774] [0774] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of 1-ethyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P30, Step A) and morpholine-4-carbaldehyde to generate the title compound (960 mg, 45%) as a solid white.
[0775] [0775] 1H NMR (DMSO-d6) δ 9.90 (s, 1H), 7.44 (s, 1H), 7.10 - 7.04 (m, 4H),
[0776] [0776] LCMS; m / z 466.3 (M + Na) + (ES +). Step B: 5- (Azetidine-1-ylmethyl) -1-ethyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0777] [0777] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 1-ethyl-5-formyl-N, N-bis (4-methoxybenzyl) -1H -pyrazol-3-sulfonamide and azetidine hydrochloride to generate the title compound (555 mg, 49%) as a white oil.
[0778] [0778] 1H NMR (DMSO-d6) δ 7.04 - 6.99 (m, 4H), 6.84 - 6.78 (m, 4H), 6.53 (s, 1H), 4.23 - 4.15 (m, 6H), 3.72 (s, 6H), 3.60 (s, 2H), 3.14 (t, J = 7.0 Hz, 4H), 1.99 (p, J = 7.0 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).
[0779] [0779] LCMS; m / z 485.3 (M + H) + (ES +). Step C: 5- (Azetidine-1-ylmethyl) -1-ethyl-1H-pyrazol-3-sulfonamide
[0780] [0780] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (azetidine-1-ylmethyl) - 1-ethyl- N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title of the compound (255 mg, 98%).
[0781] [0781] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.45 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.60 (s , 2H), 3.21 - 3.10 (m, 4H), 2.00 (p, J = 7.0 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).
[0782] [0782] LCMS; m / z 245.4 (M + H) + (ES +).
[0783] [0783] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of 1-isopropyl-N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide (Intermediate P31, Step A) and morpholine-4-carbaldehyde to generate the title compound (3 , 45 g, 80%) as a solid white.
[0784] [0784] 1H NMR (DMSO-d6) δ 9.90 (s, 1H), 7.44 (s, 1H), 7.10 - 7.03 (m, 4H), 6.86 - 6.80 ( m, 4H), 5.34 (sept, J = 6.6 Hz, 1H), 4.26 (s, 4H), 3.72 (s, 6H), 1.42 (d, J = 6.5 Hz, 6H).
[0785] [0785] LCMS; m / z 480.3 (M + Na) + (ES +). Step B: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -5 - ((methylamino) methyl) -1H-pyrazol-3-sulfonamide
[0786] [0786] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide and methylamine (2 M in THF) to generate the title compound (388 mg, 68%) as a yellow oil.
[0787] [0787] 1H NMR (DMSO-d6) δ 7.05 - 6.98 (m, 4H), 6.84 - 6.78 (m, 4H), 6.56 (s, 1H), 4.78 ( sept, J = 6.6 Hz, 1H), 4.19 (s, 4H), 3.73 (s, 2H), 3.72 (s, 6H), 3.32 (br s, 1H), 2 , 27 (s, 3H), 1.39 (d, J = 6.6 Hz, 6H).
[0788] [0788] LCMS; m / z 473.3 (M + H) + (ES +).
[0789] [0789] To a solution of 1-isopropyl-N, N-bis (4-methoxybenzyl) -5- ((methylamino) methyl) -1H-pyrazol-3-sulfonamide (388 mg, 0.739 mmol) in DCM (2, 5 ml) pyridine (0.131 ml, 1.626 mmol) was added and the mixture was cooled to 0 ° C. Trifluoroacetic anhydride (0.157 ml, 1.108 mmol) was added dropwise and the resulting mixture was stirred at 0 ° C for 15 minutes before warming to room temperature for 2 hours. The mixture was suppressed with saturated aqueous sodium bicarbonate (5 ml) and the layers were separated. The aqueous layer was extracted with DCM (2 x 10 ml) and EtOAc (10 ml) and the combined organics were dried with MgSO4. The solvent was removed under reduced pressure. The crude product was purified by SiO2 chromatography (24 g column, 0-100% EtOAc / isohexane) to generate the title compound (366 mg, 86%) as a white solid.
[0790] [0790] 1H NMR (DMSO-d6) δ 7.02 (d, J = 8.7 Hz, 4H), 6.85 - 6.79 (m, 4H), 6.73 (s, 1H), 4 , 81 (s, 2H), 4.70 - 4.62 (m, 1H), 4.22 (s, 4H), 3.72 (s, 6H), 3.11 - 3.07 (m, 3H ), 1.36 (d, J = 6.5 Hz, 6H).
[0791] [0791] LCMS; m / z 591.3 (M + Na) + (ES +). Step D: 2,2,2-Trifluoro-N - (((1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) methyl) -N-methylacetamide
[0792] [0792] Prepared according to the general procedure of 1- (pyrimidine-2-ylmethyl) -1H-pyrazol-3-sulfonamide (Intermediate P20, Step E) (N ((3- (N, N-bis (4 -
[0793] [0793] 1H NMR (DMSO-d6) δ 7.42 (br s, 2H), 6.57 (s, 1H), 4.80 (s, 2H), 4.70 - 4.56 (m, 1H ), 3.13 - 3.10 (m, 3H), 1.38 (d, J = 6.5 Hz, 6H).
[0794] [0794] LCMS; m / z 329.6 (M + H) + (ES +). Intermediate P52: 5- (Azetidine-1-ylmethyl) -1-isopropyl-1H-pyrazol-3-sulfonamide Step A: 5- (Hydroxymethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H- pyrazol-3-sulfonamide
[0795] [0795] A suspension of 5-formyl-1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P51, Step A) (500 mg, 1.093 mmol) in MeOH (11 mL) was treated with NaBH4 (70.3 mg, 1.858 mmol). The solution was stirred at room temperature for 3 hours and then evaporated in vacuo. The crude product was redissolved in EtOAc (10 ml) and washed with brine (5 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to generate the title compound (514 mg, 98%).
[0796] [0796] 1H NMR (DMSO-d6) δ 7.04 - 7.00 (m, 4H), 6.83 - 6.79 (m, 4H), 6.60 (s, 1H), 5.48 ( d, J = 5.3 Hz, 1H), 4.73 (sept, J = 6.4 Hz, 1H), 4.57 (d, J = 5.0 Hz, 2H), 4.19 (s, 4H) , 3.72 (s, 6H), 1.41 (d, J = 6.6 Hz, 6H).
[0797] [0797] LCMS; m / z 482.3 (M + Na) + (ES +). Step B: 5- (Azetidine-1-ylmethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0798] [0798] MsCl (62.0 µL, 0.796 mmol) was added to a solution of 5- (hydroxymethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (305 mg , 0.663 mmol) and DIPEA (151 µL, 0.862 mmol) in anhydrous DCM (3 mL) at 0 ° C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (10 ml) and saturated aqueous NaHCO3 solution was added (10 ml). The phases were separated and the aqueous phase was extracted with an additional portion of DCM (10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4, filtered and concentrated in vacuo to yield the crude intermediate as a brown oil. The crude intermediate was redissolved in anhydrous THF (3 ml) and azetidine (303 mg, 5.30 mmol) was added. The reaction mixture was heated to 60 ° C and stirred for 1 hour. The solvent was removed in vacuo. The crude product was loaded onto a SCX column (2 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The product was further purified by chromatography on SiO2 (12 g column, 0-10% MeOH / DCM) to generate the title compound (212 mg, 55%) as a white solid.
[0799] [0799] 1H NMR (DMSO-d6) δ 7.03 - 6.98 (m, 4H), 6.84 - 6.79 (m, 4H), 6.53 (s, 1H), 4.74 ( sept, J = 6.6 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 3.61 (s, 2H), 3.13 (t, J = 7.0 Hz, 4H), 1.99 (p, J = 7.0 Hz, 2H), 1.39 (d, J = 6.6 Hz, 6H).
[0800] [0800] LCMS; m / z 499.5 (M + H) + (ES +). Step C: 5- (Azetidine-1-ylmethyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[0801] [0801] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (azetidine-1-ylmethyl) - 1-isopropyl- N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title of the compound (91 mg, 94%) as a solid white.
[0802] [0802] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.43 (s, 1H), 4.71 (sept, J = 6.6 Hz, 1H), 3.60 (s , 2H), 3.14 (t, J = 7.0 Hz, 4H), 1.99 (p, J = 7.0 Hz, 2H), 1.38 (d, J = 6.6 Hz, 6H).
[0803] [0803] LCMS; m / z 259.4 (M + H) + (ES +). Intermediate P53: 5 - ((((2,2-Difluoroethyl) (methyl) amino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((((2,2-Difluoroethyl) (methyl) amino) methyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0804] [0804] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P51, Step A) and methyl ethylamine 2,2-difluoro-N-hydrochloride to generate the compound of the title (374 mg, 60%) as a colorless oil.
[0805] [0805] 1H NMR (DMSO-d6) δ 7.03 - 6.97 (m, 4H), 6.85 - 6.78 (m, 4H), 6.62 (s, 1H), 6.16 ( tt, J = 55.6, 4.2 Hz, 1H), 4.80 (sept, J = 6.5 Hz, 1H), 4.20 (s, 4H), 3.72 (s, 8H), 2.83 (td, J = 15.6, 4.2 Hz, 2H), 2.26 (s, 3H), 1.39 (d, J = 6.6 Hz, 6H).
[0806] [0806] LCMS; m / z 537.5 (M + H) + (ES +). Step B: 5 - ((((2,2-Difluoroethyl) (methyl) amino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[0807] [0807] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5 - ((((2,2-difluoroethyl) (methyl) amino) methyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (145 mg, 81%) as a white solid.
[0808] [0808] 1H NMR (DMSO-d6) δ 7.37 (s, 2H), 6.50 (s, 1H), 6.15 (tt, J = 55.7, 4.3 Hz, 1H), 4 , 76 (sept, J = 6.6 Hz, 1H), 3.71 (s, 2H), 2.81 (td, J = 15.6, 4.3 Hz, 2H), 2.27 (s, 3H), 1.38 (d, J = 6.6 Hz, 6H).
[0809] [0809] LCMS; m / z 297.3 (M + H) + (ES +). Intermediate P54: 5 - ((((2-Fluoroethyl) (methyl) amino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((((2-Fluoroethyl) (methyl) amino) methyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0810] [0810] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P51, Step A) and 2-fluoro-N-methylethylamine hydrochloride to generate the title compound (279 mg, 48%) as a colorless oil.
[0811] [0811] 1H NMR (DMSO-d6) δ 7.06 - 6.97 (m, 4H), 6.86 - 6.77 (m, 4H), 6.59 (s, 1H), 4.83 ( sept, J = 6.5 Hz, 1H), 4.55 (dt, J = 47.8, 4.8 Hz, 2H), 4.20 (s, 4H), 3.72 (s, 6H), 3.65 (s, 2H), 2.68 (dt, J = 28.4, 4.9 Hz, 2H), 2.21 (s, 3H), 1.39 (d, J = 6.6 Hz , 6H).
[0812] [0812] LCMS; m / z 519.2 (M + H) + (ES +). Step B: 5 - ((((2-Fluoroethyl) (methyl) amino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[0813] [0813] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5 - (((2-
[0814] [0814] 1H NMR (DMSO-d6) δ 7.36 (s, 2H), 6.48 (s, 1H), 4.79 (sept, J = 6.6 Hz, 1H), 4.54 (dt , J = 47.8, 4.9 Hz, 2H), 3.63 (s, 2H), 2.68 (dt, J = 28.3, 4.9 Hz, 2H), 2.22 (s, 3H), 1.38 (d, J = 6.6 Hz, 6H).
[0815] [0815] LCMS; m / z 279.4 (M + H) + (ES +). Intermediate P55: 5- (1- (Dimethylamino) cyclopropyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -N, N, 1- trimethyl-1H-pyrazole-5-carboxamide
[0816] [0816] Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylate (Intermediate P45, Step A) (2 g, 4.22 mmol) was suspended in EtOH (20 ml) and THF (5 ml) and 2 M aqueous NaOH (4.22 ml, 8.45 mmol). The reaction was left to stir at room temperature for 20.5 hours. The reaction was then evaporated to dryness under reduced pressure to produce a white solid. The obtained solid was suspended in THF (25 ml) to which T3P, 50 wt% EtOAc (4.8 ml, 8.06 mmol), 2 M dimethylamine in THF (2.5 ml, 5.00 mmol) and DIPEA (1.4 mL, 8.02 mmol) was added. The reaction mixture was stirred at room temperature for 90 h. A gel was obtained, then additional THF (10 mL) was added and the mixture was stirred for an additional 17 hours. Additional T3P, 50 wt% EtOAc (4.8 mL, 8.06 mmol), DIPEA (1.4 mL, 8.02 mmol) and 2 M dimethylamine in THF (2.5 mL, 5.00 mmol) were added and the mixture was stirred for another 24 hours at room temperature. The mixture was suppressed with 1 M aqueous HCl (50 ml) and extracted with EtOAc (50 ml). The organic layer was washed with 1M aqueous HCl (50 ml), dried (MgSO 4), filtered and concentrated to dryness to produce a yellow oil. The yellow oil was dissolved in THF (25 mL) and 2 M dimethylamine in THF (2.5 mL, 5.00 mmol), DIPEA (1.4 mL, 8.02 mmol) and T3P, 50 wt% EtOAc (4.8 mL, 8.06 mmol) were added sequentially. The mixture was stirred at room temperature for an additional hour. The mixture was suppressed with 1 M aqueous HCl (50 ml) and extracted with EtOAc (50 ml). The organic layer was washed with 1 M aqueous HCl (50 ml), 2 M aqueous NaOH and then dried (MgSO 4), filtered and concentrated to dryness to produce an orange oil. The crude product was purified by chromatography on SiO2 (40 g column, 0-100% EtOAc / isohexane) to generate the title compound (1.64 g, 85%) as a beige solid.
[0817] [0817] 1H NMR (DMSO-d6) δ 7.20 - 7.01 (m, 4H), 6.95 (s, 1H), 6.88 - 6.70 (m, 4H), 4.23 ( s, 4H), 3.91 (s, 3H), 3.71 (s, 6H), 3.01 (s, 3H), 3.00 (s, 3H).
[0818] [0818] LCMS; m / z 495.2 (M + Na) + (ES +). Step B: 5- (1- (Dimethylamino) cyclopropyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0819] [0819] Prepared according to the general procedure 5- (1- (dimethylamino) cyclopropyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P43, Step B) 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) - N, N, 1-trimethyl-1H-pyrazol-5-carboxamide to generate the title compound (345 mg, 48.3%) as a solid White.
[0820] [0820] 1H NMR (DMSO-d6) δ 7.08 - 6.97 (m, 4H), 6.85 - 6.74 (m, 4H), 6.49 (s, 1H), 4.22 ( s, 4H), 3.94 (s, 3H), 3.72 (s, 6H), 2.15 (s, 6H), 1.04 - 0.95 (m, 2H), 0.88 - 0 , 80 (m, 2H).
[0821] [0821] LCMS; m / z 485.6 (M + H) + (ES +). Step C: 5- (1- (Dimethylamino) cyclopropyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0822] [0822] Prepared according to the general procedure of 5- (1- (dimethylamino) cyclopropyl) -1-methyl-1H-pyrazol-3-sulfonamids (Intermediate P43, Step C) of 5- (1- (dimethylamino) cyclopropyl ) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-
[0823] [0823] 1H NMR (DMSO-d6) δ 7.32 (br s, 2H), 6.47 (s, 1H), 3.93 (s, 3H), 2.18 (s, 6H), 1, 07 - 0.95 (m, 2H), 0.93 - 0.71 (m, 2H).
[0824] [0824] LCMS; m / z 245.4 (M + H) + (ES +). Intermediate P56: 5- (2- (Dimethylamino) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5- (2-Hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1-methyl -1H-pyrazol-3-sulfonamide
[0825] [0825] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamids ( Intermediate P7, Step F) of N, N-bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamids (Intermediate P32, Step A) and oxirane (2.5 M in THF) to generate the compound title (0.55 g, 25%) as a yellow oil.
[0826] [0826] 1H NMR (CDCl3) δ 7.10 - 7.05 (m, 4H), 6.80 - 6.74 (m, 4H), 6.41 (d, J = 0.6 Hz, 1H) , 4.30 (s, 4H), 3.88 (t, J = 6.3 Hz, 2H), 3.87 (s, 3H), 3.78 (s, 6H), 2.87 (t, J = 6.3 Hz, 2H). OH signal not observed.
[0827] [0827] LCMS; m / z 468.4 (M + Na) + (ES +). Step B: 5- (2- (Dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0828] [0828] Dess-Martin periodinane (0.540 g, 1.210 mmol) was added to a solution of 5- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazole-3- sulfonamide (0.50 g 1,100 mmol) in anhydrous DCM (8 mL) at room temperature. The mixture was stirred for 2.5 hours at room temperature and then suppressed by adding 5% aqueous NaS 2O3 solution (3 ml), followed by a saturated aqueous NaHCO3 solution (5 ml). This mixture was then stirred for 15 minutes and extracted with EtOAc (3 x 25 ml). The combined organic phases were washed with saturated aqueous NaHCO 3 solution (2 x 10 ml), H2O (10 ml) and brine (10 ml), dried over MgSO4, filtered and concentrated in vacuo to produce a yellow oil. NaCNBH3 (0.086 g, 1.299 mmol) was added to a pre-stirred solution (10 minutes at room temperature) of this oil and dimethylamine (2 M in THF) (2.71 mL, 5.41 mmol) in anhydrous MeOH (5 mL ) at room temperature. The reaction mixture was stirred at room temperature over the weekend. The mixture was concentrated under reduced pressure, redissolved in MeOH (3 ml) and loaded into SCX (ca. 5 g), which was then washed with MeOH (15 ml) and eluted with 0.7 M NH 3 / MeOH (15 mL). The eluent was concentrated in vacuo to produce a pale yellow oil. The residue was redissolved in anhydrous MeOH (5 ml), NaBH 4 (0.082 g, 2.165 mmol) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was suppressed with 14% w / v aqueous NaOH (0.928 mL, 3.25 mmol) and stirred for 20 minutes at room temperature before being concentrated under reduced pressure. The residue was partitioned between EtOAc (30 ml) and brine (10 ml), and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 30 ml). The combined organic phases were washed with brine (2 x 10 ml), dried over MgSO4, filtered and concentrated in vacuo to produce a pale yellow oil. The crude product was purified by chromatography on SiO2 (12 g column, 0-10% (0.7 M ammonia / MeOH) / DCM) to generate the title compound (0.24 g, 43%) as an oil very pale yellow.
[0829] [0829] 1H NMR (DMSO-d6) δ 7.06 - 7.00 (m, 4H), 6.84 - 6.77 (m, 4H), 6.48 (s, 1H), 4.18 ( s, 4H), 3.84 (s, 3H), 3.71 (s, 6H), 2.79 (t, J = 7.4 Hz, 2H), 2.20 (s, 6H). 2H triplet directly under DMSO peak. LCMS; m / z 473.5 (M + H) + (ES +). Step C: 5- (2- (Dimethylamino) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0830] [0830] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Phase A) of 5- (2-
[0831] [0831] LCMS; m / z 233.4 (M + H) + (ES +). Intermediate P57: 4- (Dimethylamino) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-sulfonamide Step A: Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl ) -1H-pyrazol-5-carboxylate
[0832] [0832] Prepared according to the general procedure of N, N-bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step A) of ethyl 3- (chlorosulfonyl) -1H -pyrazol-5-carboxylate to generate the title compound (5.7 g, 81%) as a white solid.
[0833] [0833] 1H NMR (DMSO-d6) δ 14.87 (s, 1H), 7.28 - 6.98 (m, 5H), 6.98 - 6.47 (m, 4H), 4.35 ( q, J = 7.1 Hz, 2H), 4.24 (br s, 4H), 3.71 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H).
[0834] [0834] LCMS; m / z 482.1 (M + Na) + (ES +). Step B: Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1- (4-methoxy-4-oxobutyl) -1H-pyrazol-5-carboxylate
[0835] [0835] A mixture of ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-5-carboxylate (1 g, 2.176 mmol), ethyl 4-bromobutanoate (0.50 g, 2.61 mmol ) and K2CO3 (600 mg, 4.34 mmol) in DMF (10 mL) was stirred at room temperature for 72 hours. The mixture was partitioned between EtOAc (100 ml) and water (100 ml), the organic layer washed with water (100 ml), dried (MgSO 4), filtered and evaporated to generate the title compound (1.09 g, 85 %) as an oil.
[0836] [0836] 1H NMR (CDCl3) δ 7.14 (s, 1H), 7.13-7.09 (m, 4H), 6.82-6.78 (m,
[0837] [0837] LCMS; m / z 582 (M + Na) + (ES +). Step C: Methyl 2- (N, N-bis (4-methoxybenzyl) sulfamoyl) -4-oxo-4,5,6,7-tetrahydroprazolo [1,5-a] pyridine-5-carboxylate and ethyl 2 - (N, N-bis (4-methoxybenzyl) sulfamoyl) - 4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-5-carboxylate
[0838] [0838] Toluene (15 mL) was added to 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1- (4-methoxy-4-oxobutyl) -1H-pyrazol-5-carboxylate (1.06 g, 1.894 mmol) and the solution evaporated under reduced pressure. A solution of sodium tert-butoxide (1 mL, 2,000 mmol) (2 M in THF) was added to a solution of ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1- (4-methoxy- 4-oxobutyl) -1H-pyrazol-5-carboxylate (1.06 g, 1.894 mmol) in toluene (15 mL). The reaction mixture was stirred at room temperature for 10 minutes and then heated to 80 ° C for 3 hours. The mixture was cooled and partitioned between EtOAc (80 ml) and 1 M aqueous HCl (50 ml). The organic layer was washed with water (40 ml), dried (MgSO 4), filtered and evaporated. The residue was purified by chromatography on silica gel (40 g column, 0-50% EtOAc / isohexane) to generate methyl 2- (N, N-bis (4-methoxybenzyl) sulfamoyl) -4-oxo-4, 5,6,7-tetrahydropyrazolo [1,5-a] pyridine-5-carboxylate (510 mg, 45%) and ethyl 2- (N, N-bis (4-methoxybenzyl) sulfamoyl) -4-oxo- 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-5-carboxylate (264 mg, 24%) as solids.
[0839] [0839] Methyl ester: 1 H NMR (CDCl3) δ 11.93 (s, 1H), 7.13-7.09 (m, 4H), 6.92 (s, 1H), 6.82-6, 78 (m, 4H), 4.35 (s, 4H), 4.28 (t, J = 7.5 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 6H), 2.93 (t, J = 7.4 Hz, 2H).
[0840] [0840] LCMS; m / z 514 (M + H) + (ES +); 512 (MH) - (ES-).
[0841] [0841] Ethyl ester: LCMS; m / z 528 (M + H) + (ES +); 526 (M-H) - (ES -). Step D: N, N-Bis (4-methoxybenzyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a]
[0842] [0842] A mixture of methyl 2- (N, N-bis (4-methoxybenzyl) sulfamoyl) -4-oxo- 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-5-carboxylate (450 mg, 0.876 mmol), ethyl 2- (N, N-bis (4-methoxybenzyl) sulfamoyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5- a] pyridine-5 -carboxylate (260 mg, 0.493 mmol) and LiCl (120 mg, 2.83 mmol) in DMSO (10 mL) and water (1 mL) were heated to 120 ° C for 3 hours. The mixture was partitioned between EtOAc (80 ml) and 10% brine (50 ml), the organic layer was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by chromatography on silica gel (40 g column, 0-70% EtOAc / isohexane) to generate the title compound (525 g, 80%) as a solid.
[0843] [0843] 1H NMR (CDCl3) δ 7.13-7.10 (m, 5H), 6.81-6.77 (m, 4H), 4.42-4.39 (m, 2H), 4, 36 (s, 4H), 3.80 (s, 6H), 2.77-2.73 (m, 2H), 2.45-2.39 (m, 2H).
[0844] [0844] LCMS; m / z 478 (M + Na) + (ES +); 454.3 (M-H) - (ES-). Step E: 4- (Dimethylamino) -N, N-bis (4-methoxybenzyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-sulfonamide
[0845] [0845] To a mixture of N, N-bis (4-methoxybenzyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-sulfonamide (200 mg, 0.439 mmol), dimethylamine (2 M in THF) (280 µL, 0.560 mmol) and triethylamine (200 µL, 1.435 mmol) in DCM (4 mL) at 0 ° C titanium (IV) chloride (1 M in DCM) was added (220 µL, 0.220 mmol) slowly through the syringe. The resulting mixture was warmed to room temperature and stirred overnight. NaBH (OAc) 3 (240 mg, 1.113 mmol) and MeOH (1 mL) were added and stirring was continued over the weekend. The reaction was suppressed with H2O (5 ml) and brine (10 ml) and the mixture was extracted with EtOAc (3 x 30 ml). The combined organic extracts were washed with brine (15 ml), passed through a phase separator and the solvent was removed under reduced pressure. The residue was loaded onto a column
[0846] [0846] 1H NMR (DMSO-d6) δ 7.03 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.7 Hz, 4H), 6.44 (d, J = 0.9 Hz, 1H), 4.28 - 4.11 (m, 5H), 4.12 - 3.96 (m, 1H), 3.94 - 3.85 (m, 1H), 3, 71 (s, 6H), 2.21 (s, 6H), 2.21 - 2.11 (m, 1H), 2.03 - 1.82 (m, 2H), 1.76 - 1.61 ( m, 1H).
[0847] [0847] LCMS; m / z 485.2 (M + H) + (ES +). Step F: 4- (Dimethylamino) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-sulfonamide
[0848] [0848] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 4- (dimethylamino) -N, N-bis (4- methoxybenzyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-sulfonamide to generate the title compound (58 mg, 81%) as a beige solid.
[0849] [0849] 1H NMR (DMSO-d6) δ 7.33 (s, 2H), 6.42 (s, 1H), 4.18 - 4.07 (m, 1H), 4.07 - 3.94 ( m, 1H), 3.93 - 3.85 (m, 1H), 2.23 (s, 6H), 2.19 - 2.08 (m, 1H), 1.99 - 1.80 (m, 2H), 1.75 - 1.60 (m, 1H).
[0850] [0850] LCMS; m / z 245.4 (M + H) + (ES +). Intermediate P58: 5- (1- (Dimethylamino) propyl) -1-isopropyl-1H-pyrazol-3-sulfonamide Step A: 5- (1-Hydroxypropyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0851] [0851] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis- (4-methoxybenzyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P31, Step A) and proprionaldehyde to generate the compound title (1.79 g , 77%) as a very pale yellow oil.
[0852] [0852] LCMS m / z 488.3 (M + H) + (ES +). Step B: 5- (1- (Dimethylamino) propyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0853] [0853] MsCl (0.158 mL, 2.026 mmol) was added to a solution of 5- (1-hydroxypropyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (0, 84 g, 1.688 mmol) and DIPEA (0.413 mL, 2.364 mmol) in anhydrous DCM (8 mL) at 0 ° C. After 20 minutes, the solution was allowed to warm to room temperature and stirred overnight. Dimethylamine (2 M in THF) (5.06 mL, 10.13 mmol) was added and the mixture was heated at 40 ° C for 23 hours. The mixture was concentrated under reduced pressure and the flask was refilled with dimethylamine (2 M in THF) (5.06 ml, 10.13 mmol) and heated to 50 ° C overnight. After an additional 24 hours, the reaction mixture was transferred to a microwave flask, dimethylamine (2 M in THF) (1.688 mL, 3.38 mmol) was added and the vessel was sealed and heated to 40 ° C over the weekend . To the reaction mixture was added saturated aqueous NaHCO3 (20 ml) and EtOAc (30 ml). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 30 ml). The combined organic extracts were washed with brine (30 ml), passed through a phase separator and the solvent was removed in vacuo to produce a brown oil. The residue was loaded onto an SCX column with MeOH and the column was washed further with MeOH (15 ml). The product was eluted with 0.7 M NH3 in MeOH (~ 20 mL) and the solvent was removed in vacuo to generate the title compound (428 mg, 48%) as a light brown oil.
[0854] [0854] 1H NMR (DMSO-d6) δ 6.99 (d, J = 8.7 Hz, 4H), 6.80 (d, J = 8.7 Hz, 4H), 6.53 (s, 1H ), 4.89 - 4.80 (m, 1H), 4.21 (s, 2H), 4.20 (s, 2H), 3.71 (s, 6H), 3.70 - 3.65 ( m, 1H), 2.10 (s, 6H), 1.88 - 1.76 (m, 1H), 1.72 - 1.61 (m, 1H), 1.40 (d, J = 6, 5 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H).
[0855] [0855] LCMS; m / z 515.5 (M + H) + (ES +).
[0856] [0856] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (1- (dimethylamino) propyl) -1-isopropyl -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide to generate the title compound (202 mg, 91%) as a light brown solid.
[0857] [0857] 1H NMR (DMSO-d6) δ 7.35 (s, 2H), 6.43 (s, 1H), 4.88 - 4.75 (m, 1H), 3.66 (dd, J = 4.8, 9.8 Hz, 1H), 2.12 (s, 6H), 1.91 - 1.78 (m, 1H), 1.71 - 1.59 (m, 1H), 1.40 (d, J = 6.5 Hz, 3H), 1.35 (d, J = 6.5 Hz, 3H), 0.79 (t, J = 7.3 Hz, 3H).
[0858] [0858] LCMS; m / z 275.1 (M + H) + (ES +). Intermediate P59: 5- (1- (Dimethylamino) propyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5- (1-Hydroxypropyl) -N, N-bis (4-methoxybenzyl) -1-methyl -1H-pyrazol-3-sulfonamide
[0859] [0859] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step A) and proprionaldehyde to generate the compound title (3.4 g , 84%) as a colorless viscous oil.
[0860] [0860] 1H NMR (DMSO-d6) δ 7.08 - 7.02 (m, 4H), 6.84 - 6.80 (m, 4H), 6.53 (s, 1H), 5.50 ( d, J = 5.8 Hz, 1H), 4.60 (q, J = 6.4 Hz, 1H), 4.20 (s, 4H), 3.91 (s, 3H), 3.72 ( s, 6H), 1.73 (td, J = 7.7, 6.5 Hz, 2H), 0.95 - 0.81 (m, 3H).
[0861] [0861] LCMS; m / z 460 (M + H) + (ES +). Step B: 5- (1- (Dimethylamino) propyl) -1-methyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0862] [0862] MsCl (0.094 mL, 1,200 mmol) was added to a solution of 5- (1-hydroxypropyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (0.484 g , 1,000 mmol) and DIPEA (0.245 mL, 1,400 mmol) in anhydrous DCM (5 mL) at 0 ° C. The mixture was warmed to room temperature and stirred for 2.5 hours. Then the pale yellow solution was cooled to 0 ° C and dimethylamine (2M in THF) (12.50 ml, 25.00 mmol) was added. The reaction mixture was heated to 40 ° C and stirred for 17 hours. An additional portion of dimethylamine (2 M in THF) (1.0 mL, 2,000 mmol) was added and the reaction was stirred at 40 ° C for an additional 2 hours. The mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in EtOAc (50 ml) and saturated aqueous NaHCO 3 solution (10 ml), the layers were separated and the aqueous phase was extracted with additional parts of EtOAc (2 x 20 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution (10 ml) and brine (2 x 10 ml), dried over MgSO4, filtered and concentrated in vacuo to produce the crude product as a yellow oil. The crude product was redissolved in MeOH (3 ml) and loaded into SCX (ca. 4 g), which was then washed with MeOH (15 ml) and eluted with 0.7 M NH3 / MeOH (15 ml) and concentrated in vacuo to generate the title compound (0.27 g, 48%) as a pale yellow oil.
[0863] [0863] LCMS; m / z 487.5 (M + H) + (ES +). Step C: 5- (1- (Dimethylamino) propyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0864] [0864] TFA (1.412 mL, 18.45 mmol) was added to a solution of 5- (1- (dimethylamino) propyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazole-3 -sulfonamide (0.630 g 1.230 mmol) in anhydrous DCM (4 ml) at room temperature. The mixture was stirred at room temperature for 19 hours. A second part of TFA (0.471 ml, 6.15 mmol) was added and the reaction was stirred for an additional 2 hours at room temperature. The reaction mixture was concentrated in vacuo and co-evaporated with parts of MeCN (2 x 10 ml). The residue was then redissolved in MeOH (3 ml) and loaded into SCX (ca. 5 g), which was rinsed with MeOH (15 ml) and eluted with 0.7 M NH3 / MeOH (15 ml) to produce a yellow solid. after concentration in a vacuum. This material was pre-adsorbed on silica and purified by SiO2 chromatography (12 g column, 0-10% (0.7 M ammonia / MeOH) / DCM) to generate the title compound (0.14 g, 45% ) as an off-white solid.
[0865] [0865] LCMS; m / z 247.4 (M + H) + (ES +). Intermediate P60: 2,2,2-Trifluoro-N-methyl-N - (((1-methyl-3-sulfamoyl-1H-pyrazol-5-yl) methyl) acetamide Step A: 5-Formyl-N ,, N- bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0866] [0866] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step A) and DMF to generate the title compound (4 g, 93 %) as a white solid.
[0867] [0867] 1H NMR (DMSO-d6) δ 9.90 (s, 1H), 7.41 (s, 1H), 7.11 - 7.02 (m, 4H), 6.87 - 6.78 ( m, 4H), 4.25 (s, 4H), 4.17 (s, 3H), 3.72 (s, 6H).
[0868] [0868] LCMS; m / z 452.4 (M + Na) + (ES +). Step B: N, N-Bis (4-methoxybenzyl) -1-methyl-5 - ((methylamino) methyl) -1H-pyrazol-3-sulfonamide
[0869] [0869] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-
[0870] [0870] 1H NMR (DMSO-d6) δ 7.06 - 7.01 (m, 4H), 6.83 - 6.78 (m, 4H), 6.59 (s, 1H), 4.19 ( s, 4H), 3.90 (s, 3H), 3.72 (s, 8H), 3.34 (br s, 1H), 2.27 (s, 3H).
[0871] [0871] LCMS; m / z 445.771 (M + H) + (ES +). Step C: 1-Methyl-5 - ((methylamino) methyl) -1H-pyrazol-3-sulfonamide
[0872] [0872] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of N, N-bis (4-methoxybenzyl) -1-methyl -5 - ((methylamino) methyl) -1H-pyrazol-3-sulfonamide to generate the title compound (110 mg, 91%) as a brown solid.
[0873] [0873] 1H NMR (DMSO-d6) δ 7.33 (br s, 2H), 6.47 (s, 1H), 3.84 (s, 3H), 3.69 (s, 2H), 2, 27 (s, 3H). N-H not observed.
[0874] [0874] LCMS; m / z 205.3 (M + H) + (ES +). Step D: 2,2,2-Trifluoro-N-methyl-N - (((1-methyl-3-sulfamoyl-1H-pyrazol-5-yl) methyl) acetamide
[0875] [0875] Prepared according to the general procedure of N - ((3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H-pyrazol-5-yl) methyl) -2,2, 2-trifluoro-N-methylacetamide (Intermediate P51, Step C) of 1-methyl-5 - ((methylamino) methyl) -1H-pyrazol-3-sulfonamide to generate the title compound (27 mg, 21%) as a white solid.
[0876] [0876] 1H NMR (DMSO-d6) δ 7.42 (br s, 2H), 6.56 (s, 1H), 4.75 (s, 2H), 3.86 (s, 3H), 3, 18 - 3.07 (m, 3H).
[0877] [0877] LCMS; m / z 301.2 (M + H) + (ES +). Intermediate P61: 5- (1- (Dimethylamino) ethyl) -1-isopropyl-1H-pyrazol-3-
[0878] [0878] 5- (1- (Dimethylamino) ethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P31, Step C) (88 mg, 0.176 mmol) it was dissolved in TFA (5 ml) and stirred for 16 hours. The reaction mixture was concentrated and the crude product was loaded onto a SCX column (2 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 generate the title compound (38 mg, 76%) as a brown solid.
[0879] [0879] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.45 (s, 1H), 4.86 (sept, J = 6.6 Hz, 1H), 3.94 (q , J = 6.8 Hz, 1H), 2.14 (s, 6H), 1.38 (app t, J = 6.2 Hz, 6H), 1.25 (d, J = 6.8 Hz, 3H).
[0880] [0880] LCMS; m / z 261.5 (M + H) + (ES +). Intermediate P62: 5- (3-Hydroxy-1-methylazetidine-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: Benzyl 3- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-yl) -3-hydroxyazetidine-1-carboxylate
[0881] [0881] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step A) and benzyl 3-oxoazetidine-1-carboxylate to generate the compound titer (4.20 g, 83%) as a pale yellow oil.
[0882] [0882] 1H NMR (DMSO-d6) δ 7.39 - 7.35 (m, 4H), 7.07 - 7.02 (m, 4H), 6.91
[0883] [0883] LCMS; m / z 607.0 (M + H) + (ES +). Step B: 5- (3-Hydroxyazetidine-3-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0884] [0884] A Pd / C paste (Type J&M 39, 50% paste with water) (0.631 g, 2.97 mmol) in EtOH (2 mL) was added to a solution of benzyl3- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-prazol-5-yl) -3-hydroxyazetidine-1-carboxylate (2.00 g, 2.97 mmol) in EtOH (18 mL). The container was charged with hydrogen (5 bar) and stirred at room temperature for 17 hours. The mixture was filtered through a plug of Celite® (ca. 6 g), rinsed with additional parts of EtOH (3 x 20 ml) and concentrated in vacuo to produce a pale yellow oil. The residue was then redissolved in MeOH (5 ml) and loaded into SCX (ca. 5 g), which was washed with MeOH (15 ml) and then eluted with 0.7 M NH3 / MeOH (15 ml) and concentrated in vacuo to produce a colorless oil, which solidified on standing to produce the title compound (0.61 g, 41%) as a white solid.
[0885] [0885] 1H NMR (DMSO-d6) δ 7.18 - 6.97 (m, 4H), 6.84 - 6.78 (m, 4H), 6.77 (s, 1H), 6.34 ( br s, 1H), 4.22 (br s, 4H), 3.84 (s, 3H), 3.75 (br s, 3H), 3.71 (s, 6H), 3.17 (s, 2H).
[0886] [0886] LCMS; m / z 473.0 (M + H) + (ES +). Step C: 5- (3-Hydroxy-1-methylazetidine-3-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0887] [0887] NaCNBH3 (0.160 g, 2.54 mmol) was added to a mixture of 5-
[0888] [0888] LCMS; m / z 487.4 (M + H) + (ES +). Step D: 5- (3-Hydroxy-1-methylazetidine-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide
[0889] [0889] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (3-hydroxy-1-methylazetidine-3-yl ) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (0.09 g, 107%) as a white solid.
[0890] [0890] LCMS m / z 247.3 (M + H) + (ES +). Intermediate P63: 5- (1- (Azetidine-1-yl) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide StepA: 5- (1- (Azetidine-1-yl) ethyl) -N, N- bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0891] [0891] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P52, Step B) 5- (1-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step B) and azetidine to generate the title compound (0.58 g, 55%) as a yellow oil.
[0892] [0892] LCMS; m / z 485.1 (M + H) + (ES +). Step B: 5- (1- (Azetidine-1-yl) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0893] [0893] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (1- (azetidine-1-yl) ethyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title of the compound (0.26 g, 89%) as a cream colored solid.
[0894] [0894] 1H NMR (DMSO-d6) δ 7.33 (s, 2H), 6.40 (s, 1H), 3.89 (s, 3H), 3.65 - 3.56 (m, 1H) , 3.18 - 2.98 (m, 4H), 1.97 - 1.89 (m, 2H), 1.12 (d, J = 6.6 Hz, 3H).
[0895] [0895] LCMS; m / z 245.1 (M + H) + (ES +). Intermediate P64: 5- (1- (Dimethylamino) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0896] [0896] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5- (1- (dimethylamino) ethyl) -N, N bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step C) to generate the title compound (0.17 g, 83%) as a cream colored solid.
[0897] [0897] 1H NMR (MeOH-d4) δ 6.51 (s, 1H), 3.84 (s, 3H), 3.83 (q, J = 6.8 Hz, 1H), 2.16 (s , 6H), 1.27 (d, J = 6.8 Hz, 3H). NH2 signal not observed.
[0898] [0898] LCMS; m / z 233.1 (M + H) + (ES +). Intermediate P65: 1-Methyl-5- (pyrrolidine-1-ylmethyl) -1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1-methyl-5- (pyrrolidine-1-ylmethyl ) -1H-pyrazol-3-sulfonamide
[0899] [0899] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P60, Step A) and pyrrolidine to generate the title compound (211 mg, 46%) as a clear colorless gum.
[0900] [0900] 1H NMR (DMSO-d6) δ 7.10 - 6.95 (m, 4H), 6.87 - 6.73 (m, 4H), 6.56 (s, 1H), 4.19 ( s, 4H), 3.88 (s, 3H), 3.71 (s, 6H), 3.65 (s, 2H), 2.45 - 2.35 (m, 4H), 1.77 - 1 , 62 (m, 4H).
[0901] [0901] LCMS; m / z 485.2 (M + H) + (ES +). Step B: 1-Methyl-5- (pyrrolidine-1-ylmethyl) -1H-pyrazol-3-sulfonamide
[0902] [0902] Prepared according to the general procedure of 5- (1- (dimethylamino) ethyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P61) of N, N-bis (4-methoxybenzyl) -1 -methyl-5- (pyrrolidine-1-ylmethyl) -1H-pyrazol-3-sulfonamide to generate the title compound (100 mg, 84%) as a waxy orange solid.
[0903] [0903] 1H NMR (DMSO-d6) δ 7.31 (s, 2H), 6.46 (s, 1H), 3.84 (s, 3H), 3.64 (s, 2H), 2.47 - 2.40 (m, 4H), 1.73 - 1.64 (m, 4H).
[0904] [0904] LCMS; m / z 245.1 (M + H) + (ES +). Intermediate P66: 5 - (((3-Fluoroazetidin-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5 - (((3-Fluoroazetidine-1-yl) methyl) -N, N -bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0905] [0905] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0906] [0906] 1H NMR (DMSO-d6) δ 7.10 - 6.97 (m, 4H), 6.85 - 6.75 (m, 4H), 6.57 (s, 1H), 5.30 - 5.04 (m, 1H), 4.18 (s, 4H), 3.85 (s, 3H), 3.71 (s, 8H), 3.65 - 3.49 (m, 2H), 3 , 25 - 3.11 (m, 2H).
[0907] [0907] LCMS; m / z 489.2 (M + H) + (ES +). Step B: 5 - (((3-Fluoroazetidine-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0908] [0908] 5 - ((3-Fluoroazetidine-1-yl) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (0.34 g, 0.696 mmol) dissolved in TFA (5 ml, 64.9 mmol) and stirred for 4 hours. The solution was diluted with toluene (20 ml) and evaporated in vacuo to generate a colorless gum. The gum was dissolved in THF, absorbed in SCX and eluted with THF / MeOH / DCM (1: 1: 3) followed by (1 M NH3 / MeOH) / THF / DCM (1: 1: 3). The solvent was evaporated in vacuo to generate the title compound (0.17 g, 95%) as a white solid.
[0909] [0909] 1H NMR (DMSO-d6) δ 7.35 (s, 2H), 6.49 (s, 1H), 5.32 - 5.04 (m, 1H), 3.82 (s, 3H) , 3.71 (s, 2H), 3.57 (m, 2H), 3.21 (m, 2H).
[0910] [0910] LCMS; m / z 249.1 (M + H) + (ES +). Intermediate P67: 5 - ((Diethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((Diethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl- 1H-pyrazol-3-sulfonamide
[0911] [0911] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[0912] [0912] 1H NMR (DMSO-d6) δ 7.08 - 6.99 (m, 4H), 6.86 - 6.77 (m, 4H), 6.59 (s, 1H), 4.20 ( s, 4H), 3.90 (s, 3H), 3.72 (s, 6H), 3.61 (s, 2H), 2.47 (q, J = 7.1 Hz, 4H), 0, 98 (t, J = 7.1 Hz, 6H).
[0913] [0913] LCMS; m / z 487.2 (M + H) + (ES +). Step B: 5 - ((Diethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0914] [0914] Prepared according to the general procedure of 5 - (((3-fluoroazetidine-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P66, Step B) of 5 - ((diethylamino ) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (0.17 g, 94%) as a white solid.
[0915] [0915] 1H NMR (DMSO-d6) δ 7.33 (s, 2H), 6.49 (s, 1H), 3.86 (s, 3H), 3.59 (s, 2H), 2.47 (q, J = 7.1 Hz, 4H), 0.98 (t, J = 7.1 Hz, 6H).
[0916] [0916] LCMS; m / z 247.1 (M + H) + (ES +). Intermediate P68: 5 - ((Ethyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((Ethyl (methyl) amino) methyl) -N, N-bis (4 -methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0917] [0917] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P60, Step A) and N-methylethhanamine to generate the title compound (0.42 g, 76%), as a colorless gum.
[0918] [0918] 1H NMR (DMSO-d6) δ 7.03 (m, 4H), 6.81 (m, 4H), 6.58 (s, 1H), 4.20 (s, 4H), 3.89 (s, 3H), 3.72 (s, 6H), 3.53 (s, 2H), 2.40 (q, J = 7.1 Hz, 2H), 2.11 (s, 3H), 1 , 03 (t, J = 7.1 Hz, 3H).
[0919] [0919] LCMS; m / z 473.2 (M + H) + (ES +). Step B: 5 - ((Ethyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0920] [0920] Prepared according to the general procedure of 5 - (((3-fluoroazetidine-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P66, Step B) of 5 - ((ethyl (methyl) amino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (0.23 g, 103%) as a white solid.
[0921] [0921] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.48 (s, 1H), 3.85 (s, 3H), 3.52 (s, 2H), 2.40 (q, J = 7.1 Hz, 2H), 2.12 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H).
[0922] [0922] LCMS; m / z 233.1 (M + H) + (ES +). Intermediate P69: 5 - ((Cyclopropyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((cclopropyl (methyl) amino) methyl) -N, N-bis (4 -methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0923] [0923] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P60, Step A) and N-methylcyclopropanamine hydrochloride to generate the title compound (0.42 g , 72%), as a colorless gum.
[0924] [0924] 1H NMR (DMSO-d6) δ 7.10 - 7.00 (m, 4H), 6.85 - 6.77 (m, 4H), 6.59 (s, 1H), 4.19 ( s, 4H), 3.85 (s, 3H), 3.72 (s, 6H), 3.71 (m, 2H), 2.20 (s, 3H), 1.72 (tt,
[0925] [0925] LCMS; m / z 485.2 (M + H) + (ES +). Step B: 5 - ((Cyclopropyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0926] [0926] Prepared according to the general procedure of 5 - (((3-fluoroazetidine-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P66, Step B) of 5 - ((cyclopropyl (methyl) amino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (200 mg, 94%) as a colorless gum.
[0927] [0927] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.48 (s, 1H), 3.80 (s, 3H), 3.70 (s, 2H), 2.21 (s, 3H), 1.73 (tt, J = 3.6, 6.7 Hz, 1H), 0.45 (m, 2H), 0.31 (m, 2H).
[0928] [0928] LCMS; m / z 245.1 (M + H) + (ES +). Intermediate P70: 5- (Azetidine-1-methyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5- (Azetidine-1-ylmethyl) -N, N-bis (4-methoxybenzyl) -1- methyl-1H-pyrazol-3-sulfonamide
[0929] [0929] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P60, Step A) and azetidin hydrochloride to generate the title compound (0.46 g, 84%) as a colorless gum.
[0930] [0930] 1H NMR (DMSO-d6) δ 7.08 - 6.98 (m, 4H), 6.85 - 6.77 (m, 4H), 6.54 (s, 1H), 4.19 ( s, 4H), 3.86 (s, 3H), 3.72 (s, 6H), 3.59 (s, 2H), 3.15 (t, J = 7.0 Hz, 4H), 1.99 ( p, J = 7.0 Hz, 2H).
[0931] [0931] LCMS; m / z 471.2 (M + H) + (ES +). Step B: 5- (Azetidine-1-ylmethyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0932] [0932] Prepared according to the general procedure of 5 - ((3-fluoroazetidine1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P66, Step B) of 5- (azetidine-1- ylmethyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (220 mg, 98%) as a white solid.
[0933] [0933] 1H NMR (DMSO-d6) δ 7.33 (s, 2H), 6.44 (s, 1H), 3.82 (s, 3H), 3.58 (s, 2H), 3.15 (t, J = 7.0 Hz, 4H), 1.99 (p, J = 7.0 Hz, 2H).
[0934] [0934] LCMS; m / z 231.0 (M + H) + (ES +). Intermediate P71: 5 - ((Isopropyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((Isopropyl (methyl) amino) methyl) -N, N-bis (4 -methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0935] [0935] Prepared according to the general procedure of 5- (azetidine-1-imethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P60, Step A) and N-methylpropane-2-amine to generate the title compound (0 , 46 g, 88%), as a colorless gum.
[0936] [0936] 1H NMR (DMSO-d6) δ 7.03 (m, 4H), 6.81 (m, 4H), 6.57 (s, 1H), 4.20 (s, 4H), 3.89 (s, 3H), 3.72 (s, 6H), 3.57 (s, 2H), 2.84 (sept, J = 6.6 Hz, 1H), 2.05 (s, 3H), 1 , 02 (d, J = 6.5 Hz, 6H).
[0937] [0937] LCMS; m / z 487.2 (M + H) + (ES +). Step B: 5 - ((Isopropyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0938] [0938] Prepared according to the general procedure of 5 - (((3-fluoroazetidine-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P66, Step B) of 5 - ((isopropyl (methyl) amino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (0.24 g, 104%) as a white solid.
[0939] [0939] 1H NMR (DMSO-d6) δ 7.33 (s, 2H), 6.47 (s, 1H), 3.85 (s, 3H), 3.56 (s, 2H), 2.83 (sept, J = 6.6 Hz, 1H), 2.07 (s, 3H), 1.01 (d, J = 6.6 Hz, 6H).
[0940] [0940] LCMS; m / z 247.1 (M + H) + (ES +). Intermediate P72: 5- (1- (Dimethylamino) -2,2,2-trifluoroethyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1-methyl- 5- (2,2,2-trifluoroacetyl) -1H-pyrazol-3-sulfonamide
[0941] [0941] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P32, Step A) and ethyl 2,2,2-trifluoroacetate to generate the compound title (1.23 g, 53%) as a colorless solid.
[0942] [0942] 1H NMR (DMSO-d6) δ 7.06 - 7.00 (m, 4H), 6.83 - 6.79 (m, 4H), 6.74 (s, 1H), 4.22 ( s, 4H), 4.01 (s, 3H), 3.72 (s, 6H).
[0943] [0943] LCMS; m / z not found, without ionization. Step B: N, N-Bis (4-methoxybenzyl) -1-methyl-5- (2,2,2-trifluoro-1-hydroxyethyl) -1H-pyrazol-3-sulfonamide
[0944] [0944] A solution of N, N-bis (4-methoxybenzyl) -1-methyl-5- (2,2,2-trifluoroacetyl) -1H-pyrazol-3-sulfonamide (0.6 g, 1.206 mmol) in MeOH (5 mL) was stirred at 0 ° C under nitrogen. NaBH4 (0.046 g, 1.206 mmol) was added in small parts over 5 minutes, then the reaction was left at 0 ° C for 1 hour. After concentration under reduced pressure, the residue was treated with a concentrated solution of aqueous ammonium chloride, assimilated in EtOAc (50 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc / isohexane) to generate the title compound (510g, 82%) as a colorless, sticky oil.
[0945] [0945] 1H NMR (DMSO-d6) δ 7.32 (d, J = 6.6 Hz, 1H), 7.07 - 6.98 (m, 4H), 6.87 - 6.77 (m, 4H), 6.74 (s, 1H), 5.71 - 5.53 (m, 1H), 4.28 - 4.16 (m, 4H), 3.97 (s, 3H), 3.72 (s, 6H).
[0946] [0946] LCMS; m / z 522.4 (M + H) + (ES +). Step C: 5- (1- (Dimethylamino) -2,2,2-trifluoroethyl) -N, N-bis (4-methoxybenzl) -1- methyl-1H-pyrazol-3-sulfonamide
[0947] [0947] Triflic anhydride (1 M in DCM) (2 mL, 2,000 mmol) was added to a solution of N, N-bis (4-methoxybenzyl) -1-methyl-5- (2,2,2-trifluoro- 1-hydroxyethyl) -1H-pyrazol-3-sulfonamide (500 mg, 1.001 mmol) and 2,6-dimethylpyridine (0.233 mL, 2.002 mmol) in anhydrous DCM (5 mL) at 0 ° C. The reaction was allowed to warm to room temperature, stirred for 2 hours and then cooled to 0 ° C. A solution of dimethylamine (5 mL, 10.00 mmol) was added and the mixture was stirred at 40 ° C for 18 hours. The mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in EtOAc (50 ml) and saturated aqueous NaHCO3 solution (10 ml), the layers were separated and the aqueous phase was extracted with additional parts of EtOAc (2 x 20 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution (10 ml) and brine (2 x 10 ml), dried over MgSO 4, filtered and concentrated in vacuo to produce the crude product as a yellow oil. The crude product was redissolved in MeOH (3 ml) and loaded into SCX (ca. 4 g), which was then washed with MeOH (15 ml) and eluted with 0.7 M NH3 / MeOH (15 ml) and concentrated in vacuo to produce the title compound (200 mg, 32%) as a pale yellow solid.
[0948] [0948] 1H NMR (DMSO-d6) δ 7.10 - 6.99 (m, 4H), 6.86 - 6.77 (m, 4H), 6.59 (s, 1H), 5.15 ( q, J = 8.5 Hz, 1H), 4.24 (s, 4H), 3.95 (s, 3H), 3.72 (s, 6H), 2.36 (s, 6H).
[0949] [0949] LCMS; m / z 549.4 (M + Na) + (ES +). Step D: 5- (1- (Dimethylamino) -2,2,2-trifluoroethyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0950] [0950] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P7, Step G) of 5- (1 - (dimethylamino) -2,2,2-trifluoroethyl) -N, N-bis (4-methoxybenzyl) -1- methyl-1H-pyrazol-3-sulfonamide to generate the title compound (85 mg, 98%) as a yellow oil.
[0951] [0951] LCMS; m / z 287.5 (M + H) + (ES +). Intermediate P73: 1-Isopropyl-5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide Step A: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide
[0952] [0952] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P51, Step A) and 2,2,2-trifluoro-N-methylethamine (114 mg, 1.005 mmol) and sodium triacetoxyborohydride to generate the title compound (170 mg, 60%) as a colorless oil.
[0953] [0953] 1H NMR (DMSO-d6) 7.04 - 6.99 (m, 4H), 6.84 - 6.78 (m, 4H), 6.64 (s, 1H), 4.78 (sept , J = 6.6 Hz, 1H), 4.20 (s, 4H), 3.82 (s, 2H), 3.72 (s, 6H), 3.37 - 3.25 (m, 2H) , 2.31 (s, 3H), 1.39 (d, J = 6.6 Hz, 6H).
[0954] [0954] LCMS; m / z 577.9 (M + Na) + (ES +). Step B: 1-Isopropyl-5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide
[0955] [0955] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) of 1-isopropyl-N, N-bis (4-methoxybenzyl) -5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide to generate the title compound (15 mg, 14%) as a white solid.
[0956] [0956] 1H NMR (DMSO-d6) δ 7.38 (bs, 2H), 6.53 (s, 1H), 4.74 (sept, J = 6.6 Hz, 1H), 3.81 (s , 2H), 3.32 - 3.25 (m, 2H), 2.33 (s, 3H), 1.39 (d, J = 6.6 Hz, 6H).
[0957] [0957] LCMS; m / z 315.1 (M + H) + (ES +). Intermediate P74: 1-Methyl-5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1-methyl -5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide
[0958] [0958] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P60, Step A) and 2,2,2-trifluoro-N-methylethhanamine to generate the compound of the title (148 mg, 50%) as a colorless oil.
[0959] [0959] 1H NMR (DMSO-d6) δ 7.06 - 7.00 (m, 4H), 6.84 - 6.78 (m, 4H), 6.66 (s, 1H), 4.20 ( s, 4H), 3.89 (s, 3H), 3.82 (s, 2H), 3.72 (s, 6H), 3.30 (q, J = 10.1 Hz, 2H), 2, 34 (s, 3H).
[0960] [0960] LCMS; m / z 549.4 (M + Na) + (ES +). Step B: 1-Methyl-5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide
[0961] [0961] Prepared according to the general procedure of N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1, Step E) of N, N-bis (4-methoxybenzyl ) -1-methyl-5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide to generate the title compound (74 mg, 39%) as a white solid.
[0962] [0962] 1H NMR (DMSO-d6) δ 7.37 (bs, 2H), 6.55 (s, 1H), 3.85 (s, 3H), 3.80 (s, 2H), 3.30 - 3.24 (m, 2H), 2.35 (s, 3H).
[0963] [0963] LCMS; m / z 287.2 (M + H) + (ES +). Intermediate P75: 1 - (((1-Methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1 - ((1-methyl -1H-imidazol-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[0964] [0964] Prepared according to the general procedure of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (Intermediate P1, Step D ) of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 2- (chloromethyl) -1-methyl-1H-imidazole, HCl salt to generate the title compound (270 mg, 37%) as a yellow oil.
[0965] [0965] 1H NMR (DMSO-d6) δ 7.98 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 1.2 Hz,
[0966] [0966] LCMS; m / z 482.8 (M + H) + (ES +). Step B: 1 - ((1-Methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[0967] [0967] Prepared according to the general procedure of 1- (pyrimidine-2-ylmethyl) -1H-pyrazol-3-sulfonamide (Intermediate P20, Step E) of N, N-bis (4-methoxybenzyl) -1 - (( 1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-3-sulfonamide to generate the title compound (105 mg, 85%) as a yellow oil.
[0968] [0968] 1H NMR (DMSO-d6) δ 7.90 (d, J = 2.4 Hz, 1H), 7.42 (s, 2H), 7.15 (d, J = 1.2 Hz, 1H ), 6.85 (d, J = 1.2 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 5.50 (s, 2H), 3.68 (s, 3H ).
[0969] [0969] LCMS; m / z 242.3 (M + H) + (ES +). Intermediate P76: 1- (Pyridine-2-yl) -1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1- (pyridine-2-yl) -1H-pyrazol-3- sulfonamide
[0970] [0970] N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) (196 mg, 0.556 mmol) was dissolved in dry DMF (5 mL). Potassium carbonate (140 mg, 1.012 mmol) and 2-bromopyridine (96 mg, 0.607 mmol) were added and the reaction mixture was heated at 120 ° C for 40 hours. Then the reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on SiO2 (12 g column, 0-50% EtOAc / isohexane) to generate the title compound (210 mg, 83%) as an oil.
[0971] [0971] LCMS; m / z 465 (M + H) + (ES +). Step B: 1- (Pyridine-2-yl) -1H-pyrazol-3-sulfonamide
[0972] [0972] N, N-Bis (4-methoxybenzyl) -1- (pyridin-2-yl) -1H-pyrazol-3-sulfonamide (210 mg, 0.452 mmol) was dissolved in DCM (0.5 mL) and TFA (1 ml) was added. The solution was stirred for 25 hours. The reaction mixture was concentrated in vacuo, suspended in toluene (5 ml) and concentrated again. The residue was triturated with MTBE (2 ml) for 16 hours and the suspension was filtered. The collected solid was dried under reduced pressure for 1 hour to generate the title compound (82 mg, 67%) as a white solid.
[0973] [0973] LCMS; m / z 225 (M + H) + (ES +). Intermediate P77: 1- (thiazol-2-yl) -1H-pyrazol-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1- (thiazol-2-yl) -1H-pyrazol-3- sulfonamide
[0974] [0974] Prepared according to the general procedure of N, N-bis (4-methoxybenzyl) -1- (pyridine-2-yl) -1H-pyrazol-3-sulfonamide (Intermediate P76, Step A) of N, N -bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) and 2-bromothiazole to generate the title compound (169 mg, 84%) as an oil.
[0975] [0975] 1H NMR (CDCl3) δ 8.38 (d, J = 2.6 Hz, 1H), 7.62 (d, J = 3.5 Hz, 1H), 7.23 (d, J = 3 , 4 Hz, 1H), 7.19 - 7.14 (m, 4H), 6.85 - 6.77 (m, 5H), 4.40 (s, 4H), 3.79 (s, 6H) .
[0976] [0976] LCMS; m / z 471 (M + H) + (ES +). Step B: 1- (Thiazol-2-yl) -1H-pyrazol-3-sulfonamide
[0977] [0977] Prepared according to the general procedure of 1- (pyridine-2-yl) - 1H-pyrazol-3-sulfonamide (Intermediate P76, Step B) of N, N-bis (4-methoxybenzyl) - 1- ( thiazol-2-yl) -1H-pyrazol-3-sulfonamide to generate the title compound (45 mg, 34%) as a white solid.
[0978] [0978] LCMS; m / z 231 (M + H) + (ES +). Intermediate P78: 1- (Pyridine-3-yl) -1H-pyrazola-3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -1- (pyridine-3-yl) -1H-pyrazol-3- sulfonamide
[0979] [0979] 3-bromopyridine (130 µL, 1.349 mmol) and N1, N2-dimethylethane-1,2-diamine (15 µL, 0.139 mmol) were added to a suspension of N, N-bis (4-methoxybenzyl) - 1H-pyrazol-3-sulfonamide (Intermediate P1, Step C) (495 mg, 1.278 mmol), K2CO3 (350 mg, 2.53 mmol) and CuI (15 mg, 0.079 mmol) in dry DMF (8 mL). The resulting mixture was heated to 140 ° C (bath temperature) for 3 days. The mixture was cooled to room temperature, diluted with EtOAc (50 ml) and filtered through Celite ®. The solution was concentrated in vacuo to produce a brown oil, which was purified by silica gel chromatography (40 g column of 0-50% EtOAc / isohexane) to produce the title compound as a colorless oil (127 mg, 20% ).
[0980] [0980] 1H NMR (CDCl3) δ 9.05 (d, J = 2.6 Hz, 1H), 8.67 (dd, J = 4.9, 1.4 Hz, 1H), 8.17 (ddd , J = 8.4, 2.6, 1.4 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.60 (dd, J = 8.4, 4.9 Hz, 1H), 7.16 - 7.11 (m, 4H), 6.90 (d, J = 2.6 Hz, 1H), 6.80 - 6.75 (m, 4H), 4.40 (s, 4H), 3.76 (s, 6H).
[0981] [0981] LCMS; m / z 465 (M + H) + (ES +). Step B: 1- (Pyridine-3-yl) -1H-pyrazol-3-sulfonamide
[0982] [0982] Prepared according to the general procedure of 1- (azetidine-3-yl) - 1H-pyrazola-3-sulfonamide (Intermediate P13, Step A) of N, N-bis (4-methoxybenzyl) -1- (pyridine -3-yl) -1H-pyrazol-3-sulfonamide to generate the title compound (51 mg, 86%) as a white solid.
[0983] [0983] 1H NMR (MeOH-d4) δ 9.12 (dd, J = 2.7, 0.8 Hz, 1H), 8.59 (dd, J = 4.9, 1.4 Hz, 1H) , 8.49 (d, J = 2.6 Hz, 1H), 8.33 (ddd, J = 8.4, 2.7, 1.4 Hz, 1H), 7.62 (ddd, J = 8 , 4, 4.8, 0.8 Hz, 1H), 6.95 (d, J = 2.6 Hz, 1H). NH2 Intermediate P79: 5- (3- (Dimethylamino) oxetan-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5- (3-Aminooxetan-3-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0984] [0984] A solution of n-BuLi (2.5 M in hexanes; 0.70 mL, 1.750 mmol) was added dropwise to a stirred solution of N, N-bis (4-methoxybenzyl) -1- methyl- 1H-pyrazol-3-sulfonamide (Intermediate P32, Step A) (0.70 g, 1.74 mmol) in THF (15 mL) at -78 ° C. The reaction was stirred for 1 hour, then a solution of 2-methyl-N- (oxetan-3-ylidene) propane-2-sulfinamide (0.40 g, 2.28 mmol) in THF (5 mL) was added . The reaction mixture was left at -78 ° C for 5 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction was suppressed with saturated aqueous ammonium chloride (15 ml) and extracted with DCM (3 x 20 ml). The extracts were dried (MgSO4), filtered and concentrated in vacuo. The resulting orange gum was dissolved in MeOH (18 ml) and HCl (3.7 M in 1,4-dioxane, 1.7 ml, 6.29 mmol) was added. The solution was stirred for 16 hours and then concentrated in vacuo. The crude product was loaded onto a column (SCX; 5 g) in MeOH and the column was washed with MeOH and then the product was eluted with 0.7 M ammonia in
[0985] [0985] 1H NMR (DMSO-d6) δ 7.09-7.04 (m, 4H), 6.86-6.80 (m, 4H), 6.79 (s, 1H), 4.87 ( d, J = 6.4 Hz, 2H), 4.65 (d, J = 6.4 Hz, 2H), 4.22 (s, 4H), 3.84 (s, 3H), 3.71 ( s, 6H), 3.16 (s, 2H).
[0986] [0986] LCMS; m / z 473.5 (M + H) + (ES +). Step B: 5- (3- (Dimethylamino) oxetan-3-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
[0987] [0987] Prepared according to the general procedure of 5- (2- (dimethylamino) propan-2-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P45, Step D) of 5- (3-aminooxetan-3-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (0.17 g, 61%) as an orange oil.
[0988] [0988] 1H NMR (DMSO-d6) δ 7.11-7.03 (m, 4H), 6.86-6.78 (m, 4H), 6.77 (s, 1H), 4.93 ( d, J = 7.2 Hz, 2H), 4.74 (d, J = 7.2 Hz, 2H), 4.23 (s, 4H), 3.75 (s, 3H), 3.72 ( s, 6H), 2.19 (s, 6H).
[0989] [0989] LCMS; m / z 501.4 (M + H) + (ES +). Step C: 5- (3- (Dimethylamino) oxetan-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide
[0990] [0990] 5- (3- (Dimethylamino) oxetan-3-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (0.17 g, 0.25 mmol ) was dissolved in TFA (3 ml) and stirred at room temperature for 23 hours. Additional TFA (3 ml) was added and the mixture was stirred for an additional 3 hours at room temperature. The mixture was then evaporated to dryness and purified by silica gel chromatography (12 g column, 0-10% MeOH / DCM) to generate an orange solid. The product was further purified by precipitation with the addition of isohexane to a 19: 1 DCM: MeOH solution of the product. The product was collected by filtration to produce the title compound (65 mg, 84%) as an orange solid.
[0991] [0991] 1H NMR (DMSO-d6) δ 7.46 (s, 2H), 6.79 (s, 1H), 5.00 (d, J = 7.6 Hz, 2H), 4.85 (d , J = 7.6 Hz, 2H), 3.76 (s, 3H), 2.38 (br s, 6H).
[0992] [0992] LCMS; m / z 261.1 (M + H) + (ES +). Intermediate P80: 5 - ((((2-Hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide Step A: 5 - ((((2-Hydroxyethyl) (methyl) amino) methyl) -N, N-bis (4-methoxybenzyl) -1- methyl-1H-pyrazol-3-sulfonamide
[0993] [0993] 2- (Methylamino) ethanol (112 µL, 1.40 mmol) was added to a solution of 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P60, Step A) (0.40 g, 0.93 mmol) in dry THF (20 mL) containing 4Å molecular sieves and stirred for 1 hour. Sodium triacetoxyborohydride (0.30 g, 1.42 mmol) and acetic acid (6 µL, 0.1 mmol) were added and the reaction was stirred at room temperature for 3 days. An additional part of acetic acid (54 µL, 0.94 mmol) was added and the reaction mixture was stirred for 20 hours at 60 ° C. Then, 2- (methylamino) ethanol (112 µL, 1.39 mmol) and more sodium triacetoxyborohydride (0.30 g, 1.42 mmol) and the reaction was heated to 60 ° C for another 20 hours. The reaction was suppressed with water (1 mL) and loaded onto a column (SCX). The column was washed with 20% MeOH in DCM and then the crude product was eluted with 0.7M ammonia in DCM: MeOH (9: 1, 50 ml). The resulting mixture was concentrated in vacuo and the crude product was further purified by chromatography on silica gel (12 g column, 0-20% (0.7 M ammonia in MeOH) / DCM) to generate the title compound (0, 19 g, 41%) as a colorless gum.
[0994] [0994] 1H NMR (DMSO-d6) δ 7.07-6.99 (m, 4H), 6.86-6.77 (m, 4H), 6.61 (s, 1H), 4.49 ( t, J = 5.3 Hz, 1H), 4.20 (s, 4H), 3.91 (s, 3H), 3.72 (s, 6H), 3.60 (s, 2H), 3, 54 (td, J = 5.2, 6.1 Hz, 2H), 2.47 (t, J = 6.1 Hz, 2H), 2.17 (s, 3H).
[0995] [0995] LCMS; m / z 489.2 (M + H) + (ES +). Step B: 5 - ((((2-Hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-
[0996] [0996] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of 5 - ((((2-hydroxyethyl) (methyl) amino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (95 mg, 95%) as a colorless gum.
[0997] [0997] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.49 (s, 1H), 4.47 (t, J = 5.3 Hz, 1H), 3.87 (s , 3H), 3.58 (s, 2H), 3.56-3.48 (m, 2H), 2.45 (t, J = 6.1 Hz, 2H), 2.17 (s, 3H) .
[0998] [0998] LCMS; m / z 249.1 (M + H) + (ES +). Intermediate P81: 5 - ((((2-Methoxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazoli- 3-sulfonamide Step A: N, N-Bis (4-methoxybenzyl) -5 - ((( 2-methoxyethyl) (methyl) amino) methyl) -1- methyl-1H-pyrazol-3-sulfonamide
[0999] [0999] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P60, Step A) and 2-methoxy-N-methylethhanamine to generate the title compound (0 , 41 g, 86%), as a pale colorless oil.
[1000] [1000] 1H NMR (DMSO-d6) δ 7.08-6.99 (m, 4H), 6.86-6.77 (m, 4H), 6.59 (s, 1H), 4.20 ( s, 4H), 3.90 (s, 3H), 3.72 (s, 6H), 3.60 (s, 2H), 3.46 (t, J = 5.7 Hz, 2H), 3, 24 (s, 3H), 2.55 (t, J = 5.7 Hz, 2H), 2.17 (s, 3H).
[1001] [1001] LCMS; m / z 503.4 (M + H) + (ES +). Step B: 5 - ((((2-Methoxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1002] [1002] Prepared according to the general procedure of 1- (azetidine-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P13, Step A) of N, N-bis (4-methoxybenzyl) -5- ( ((2-methoxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide to generate the title compound (0.20 g, 91%) as a white solid.
[1003] [1003] 1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.49 (s, 1H), 3.86 (s, 3H), 3.58 (s, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.24 (s, 3H), 2.54 (t, J = 5.8 Hz, 2H), 2.18 (s, 3H).
[1004] [1004] LCMS; m / z 263.1 (M + H) + (ES +). Intermediate P82: 1-Methyl-5- (morpholinomethyl) -1H-pyrazol-3-sulfonamide Step A: 5- (Hydroxymethyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1005] [1005] A solution of LiBH4 (2 M in THF; 4.3 mL, 8.6 mmol) was added dropwise over 5 minutes to a stirred solution of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole -5-carboxylate (1.00 g, 4.29 mmol) in THF (10 mL) at 0 ° C. The reaction was allowed to warm to room temperature, stirred for 3 hours and then heated to 40 ° C for 20 hours. The reaction was cooled to 0 ° C. LiAlH4 (2M in THF; 0.55 mL, 1.10 mmol) was added and the reaction was stirred for an additional 2 days at 40 ° C. The reaction was cooled to 0 ° C and saturated aqueous ammonium chloride (10 ml) was carefully added dropwise over 10 minutes. The mixture was allowed to warm to room temperature and EtOAc (30 ml) was added. The reaction mixture was stirred vigorously for 10 minutes and then filtered through a pad of Celite ®. The layers were separated and the aqueous layer was saturated with NaCl and further extracted with EtOAc (5 x 20 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to generate the title compound (0.67 g, 78%) as a white solid.
[1006] [1006] 1H NMR (DMSO-d6) δ 5.70 (s, 1H), 3.73 (s, 2H), 3.02 (s, 3H). Three interchangeable protons not observed.
[1007] [1007] LCMS; m / z 192.0 (M + H) + (ES +). Step B: 5-Formyl-1-methyl-1H-pyrazol-3-sulfonamide
[1008] [1008] Manganese (IV) oxide (1.00 g, 11.5 mmol) was added to a solution of 5- (hydroxymethyl) -1-methyl-1H-pyrazol-3-sulfonamide (0.55 g, 2 , 88 mmol) in 1,2-dimethoxyethane (30 ml). The reaction mixture was stirred for 20 hours at room temperature and then at 40 ° C for an additional 6 hours. Manganese (IV) oxide (0.50 g, 5.75 mmol) was added in addition and the reaction was heated at 40 ° C for 2 days. The mixture was cooled to room temperature and filtered through a pad of Celite®, washing with 1,2-dimethoxyethane. The filtrate was concentrated in vacuo to generate the title compound (0.29 g, 52%), as a yellow gum.
[1009] [1009] 1H NMR (DMSO-d6) δ 9.92 (s, 1H), 7.64 (s, 2H), 7.31 (s, 1H), 4.16 (s, 3H).
[1010] [1010] LCMS; m / z 189.9 (M + H) + (ES +). Step C: 1-Methyl-5- (morpholinomethyl) -1H-pyrazol-3-sulfonamide
[1011] [1011] Prepared according to the general procedure of 5- (azetidine-1-ylmethyl) -1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P41, Step B) of 5-formyl-1-methyl-1H-pyrazol-3-sulfonamide and morpholine to generate the title (73 mg, 25%) as a colorless gum.
[1012] [1012] 1H NMR (DMSO-d6) δ 7.36 (s, 2H), 6.50 (s, 1H), 3.87 (s, 3H), 3.57 (m, 4H), 3.56 (s, 2H), 2.37 (m, 4H).
[1013] [1013] LCMS; m / z 261.0 (M + H) + (ES +). Intermediate P83: N - (((1-Isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) methyl) -N-methylacetamide Step A: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -5- ( (methylamino) methyl) -1H-
[1014] [1014] Acetic acid (10 µL, 0.175 mmol) was added to a stirred suspension of 5-formyl-1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (Intermediate P51, Step A) (400 mg, 0.874 mmol), methylamine (2 M in THF) (874 µL, 1.748 mmol) and sodium triacetoxyborohydride (278 mg, 1.311 mmol) in THF (14 mL). The reaction mixture was then stirred at room temperature for 16 hours. Water (1 ml) was added and the volatiles were evaporated. The crude product was purified by chromatography on SiO2 (24 g column, 0-10% MeOH / DCM) to generate the title compound (130 mg, 24%) as a colorless oil.
[1015] [1015] 1H NMR (DMSO-d6) δ 7.05 - 6.98 (m, 4H), 6.85 - 6.79 (m, 4H), 6.57 (s, 1H), 4.77 ( sept, J = 6.5 Hz, 1H), 4.19 (s, 4H), 3.74 (s, 2H), 3.72 (s, 6H), 3.37 (bs, 1H), 2, 27 (s, 3H), 1.90 (s, 3H), 1.39 (d, J = 6.5 Hz, 6H). OH not observed.
[1016] [1016] LCMS; m / z 473.5 (M + H) + (ES +). Step B: N - ((3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H-pyrazol-5-yl) methyl) -N-methylacetamide
[1017] [1017] To a solution of 1-isopropyl-N, N-bis (4-methoxybenzyl) -5- ((methylamino) methyl) -1H-pyrazol-3-sulfonamide, acetic acid salt (130 mg, 0.248 mmol) in DCM (1 ml) pyridine (45 µL, 0.556 mmol) was added and the mixture was cooled to 0 ° C. Trifluoroacetic anhydride (53 µL, 0.375 mmol) was added dropwise and the resulting mixture was stirred at 0 ° C for 15 minutes, before warming to room temperature for 16 hours.
[1018] [1018] Additional pyridine (45 µL, 0.556 mmol) and trifluoroacetic anhydride (53 µL, 0.375 mmol) were added and the mixture was stirred for another 16 hours. The mixture was suppressed with saturated sodium bicarbonate (5 ml) and the layers were separated. The aqueous layer was extracted with DCM (2 x 10 ml) and EtOAc (10 ml) and the combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure. The crude product was purified by chromatography on SiO2 (12 g column, 0-10% MeOH / DCM) to generate the title compound (88 mg, 57%) as a brown oil.
[1019] [1019] 1H NMR (DMSO-d6); rotamers: δ 7.05 - 6.99 (m, 4H), 6.85 - 6.79 (m, 4H), 6.63 (s, 1H), 4.75 - 4.66 (m, 1H) , 4.63 (s, 2H), 4.21 (s, 4H), 3.73 (s, 6H), 3.32 (s, 3H), 2.07 (s, 3H), 1.35 ( d, J = 6.5 Hz, 6H).
[1020] [1020] LCMS; m / z 537.1 (M + Na) + (ES +). Step C: N - (((1-Isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) methyl) -N-methylacetamide
[1021] [1021] Prepared according to the general procedure of N - ((3- (N, N, N, N, N-bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H-pyrazol-5-yl) methyl) -N-methylacetamide to generate the title compound (30 mg, 78%) as a white solid.
[1022] [1022] 1H NMR (DMSO-d6) δ 7.37 (bs, 2H), 6.51 (s, 1H), 4.73 - 4.66 (m, 1H), 4.61 (s, 2H) , 2.95 (s, 3H), 2.06 (s, 3H), 1.35 (d, J = 6.5 Hz, 6H).
[1023] [1023] LCMS; m / z 275.2 (M + H) + (ES +). Intermediate P84: N, N, 1-Trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide Step A: 1-Methyl-3-sulfamoyl-1H-pyrazol-5-carboxylic acid, sodium salt
[1024] [1024] To a suspension of ethyl 1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxylate (3 g, 12.86 mmol) in ethanol (60 mL) was added a sodium hydroxide solution (2, 0 M, 13.5 mL) and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was removed by filtration, washed with ethanol and dried to generate the title compound (2.92 g, 99%) as a white solid.
[1025] [1025] 1H NMR (D2O) δ 6.79 (s, 1 H), 4.01 (s, 3 H). NH2 not observed.
[1026] [1026] To a mixture of 1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxylic acid, sodium salt (2.38 g, 10.48 mmol) was added T3P (50% in EtOAc, 12.47 mL, 20.95 mmol) and DIPEA (Hunig's Base, 3.66 mL, 20.95 mmol) in THF (50 mL). A 2.0 M solution of dimethylamine in THF (15.71 ml, 31.4 mmol) was added and the reaction was stirred for 20 hours before being suppressed with saturated aqueous ammonium chloride (10 ml) and extracted with EtOAc ( 3 x 20 mL). The combined extracts were dried (magnesium sulfate), filtered and evaporated in vacuo to generate a yellow gum. The crude product was triturated in DCM (20 ml) and filtered to obtain the title compound (900 mg) as a white solid. The mother layers were evaporated, dissolved in DCM / MeOH and purified by chromatography (Companion apparatus, 40 g column, 0-10% MeOH / DCM with the product eluted at ~ 5% MeOH) to generate an additional batch of the compound of the title (457 mg) as a white solid. The solids were combined to generate the title compound (1.36 g, 55%).
[1027] [1027] 1H NMR (DMSO-d6) δ 7.50 (s, 2H), 6.82 (s, 1H), 3.90 (s, 3H), 3.03 (s, 3H) and 3.01 (s, 3H).
[1028] [1028] LCMS; m / z 233.0 (M + H) + (ES +). Intermediate P85: 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5- carboxylic
[1029] [1029] Triphosgene (170 mg, 0.573 mmol) was added to a mixture of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (165 mg, 0.952 mmol) and triethylamine ( 0.36 mL, 2.58 mmol) in THF (8 mL) and stirred for 15 hours. The reaction mixture was evaporated in vacuo and azeotroped with toluene (3 x 1 ml). THF (8 ml) was added and the reaction mixture was filtered. The filtrate was added to a mixture of ethyl 1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxylate (200 mg, 0.857 mmol) and sodium hydride (86 mg, 2.150 mmol) in THF (8 mL) and stirred for 20 hours. The reaction was quenched with aqueous Na2CO3 (3.5 mL, 1.295 mmol) and evaporated in vacuo to remove THF. The residual aqueous was washed with MTBE (2 x 5 ml). The solid that precipitated from the aqueous was filtered off and dried to provide 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - Sodium 1-methyl-1H-pyrazol-5-carboxylate (100 mg) as a solid. The filtrate was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN / 10 mM ammonium bicarbonate) to give the title compound (180 mg) as a white solid. The solids were combined and dissolved in MeOH (3 ml). NaOH (0.25 mL, 0.500 mmol) was added and the reaction mixture was stirred for 20 hours. The MeOH was evaporated in vacuo. The remaining aqueous was adjusted to pH 8 with NaH2PO4 purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN / 10 mM ammonium bicarbonate) to generate the title compound (140 mg, 39%) as a white solid.
[1030] [1030] 1H NMR (DMSO-d6) δ 7.65 (s, 2H), 6.31 (s, 1H), 6.15 (s, 1H), 3.41 (s, 3H), 2.05 (t, J = 7.4 Hz, 4H), 1.90 (t, J = 7.3 Hz, 4H), 1.24 (quin, J = 7.4 Hz, 4H). An unobserved interchangeable proton.
[1031] [1031] LCMS; m / z 405.0 (M + H) + (ES +). Intermediate P86: 1-Methyl-5- (pyrrolidine-1-carbonyl) -1H-pyrazol-3-sulfonamide
[1032] [1032] Prepared according to the general procedure for N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (Intermediate P84, Step B) of 1-methyl-3-sulfamoyl-1H-pyrazole acid -5-carboxylic, sodium salt (Intermediate P84, Step A) and pyrrolidine to generate the title compound (204 mg, 54%) as a cream-colored solid.
[1033] [1033] LCMS; m / z 259.3 (M + H) + (ES +). Intermediate P87: 3- (N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt
[1034] [1034] 2 M sodium tert-butoxide in THF (1.005 mL, 2.009 mmol) was added to a solution of ethyl 1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxylate (0.5 g, 1.914 mmol) in THF (15 mL) and stirred at room temperature for 1 hour to produce a white suspension. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.419 mg, 2.105 mmol) in THF (5mL) was added and stirred at room temperature overnight . The resulting colorless precipitate was collected by filtration, washed with THF (4 ml) and dried in vacuo to generate the title compound (930 mg, 91%) as a colorless solid.
[1035] [1035] 1H NMR (DMSO-d6) δ 7.51 (s, 1H), 6.96 (s, 1H), 6.77 (s, 1H), 4.28 (q, J = 7.1 Hz , 2H), 4.05 (s, 3H), 2.74 (t, J = 7.4 Hz, 4H), 2.66 (t, J = 7.3 Hz, 4H), 1.90 (p , J = 7.4 Hz, 4H), 1.30 (t, J = 7.1 Hz, 3H).
[1036] [1036] LCMS; m / z 433.4 (M + H) + (ES +). Step B: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt
[1037] [1037] Ethyl 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1-methyl-1H-pyrazol-5- carboxylate, sodium salt (3.15 g, 6.24 mmol) were dissolved in MeOH (20 mL), 2 M aqueous NaOH (3.12 mL, 6.24 mmol) was added and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to generate the title compound (2.80 g, 99%) as a colorless solid.
[1038] [1038] 1H NMR (DMSO-d6) δ 7.57 (s, 1H), 6.76 (s, 1H), 6.44 (s, 1H), 4.02
[1039] [1039] LCMS; m / z 405.4 (M + H) + (ES +). Intermediate P88: 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt Step A: ethyl 3- (N - ((2,6 ethyl-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazole-5-carboxylate, sodium salt
[1040] [1040] Ethyl 1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxylate (2 g, 7.65 mmol) was dissolved in THF (80 mL, 986 mmol). Sodium hydride (0.367 g, 9.18 mmol) was added and stirred at room temperature for 30 minutes to produce a white suspension. Then 2-isocyanate-1,3-diisopropylbenzene (Intermediate A18) (1.712 g, 8.42 mmol) in THF (20 ml) was added and stirred at room temperature overnight. The resulting colorless precipitate was collected by filtration, washed with THF (2 x 20 ml) and dried in vacuo to generate the title compound (2.16 mg, 60%) as a colorless solid.
[1041] [1041] 1H NMR (DMSO-d6) δ 7.35 (s, 1H), 7.15 - 7.05 (m, 1H), 7.05 - 6.95 (m, 2H), 6.93 ( s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 3.20 - 3.02 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.03 (d, J = 6.9 Hz, 12H).
[1042] [1042] LCMS; m / z 437.4 (M + H) + (ES +). Step B: 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt
[1043] [1043] Prepared according to the general procedure for 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1 -methyl-1H-pyrazol-5 carboxylic, disodium salt (Intermediate P87, Step B) of ethyl 3- (N - ((- 2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazole-5 -carboxylate, sodium salt to generate the title compound (2.0 g, 99%) as a colorless solid.
[1044] [1044] 1H NMR (DMSO-d6) δ 7.44 (s, 1H), 7.13 - 7.05 (m, 1H), 7.05 - 6.94 (m, 2H), 6.42 ( s, 1H), 4.00 (s, 3H), 3.16 - 3.03 (m, 2H), 1.01 (d, J = 6.8 Hz, 12H).
[1045] [1045] LCMS; m / z 409.4 (M + H) + (ES +). Intermediate P89: 3- (N - (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt Step A: ethyl 3- (N- ( (4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylate, sodium salt
[1046] [1046] Prepared according to the general procedure for 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H ethyl-pyrazol-5-carboxylate, sodium salt (Intermediate P87, Step A) of ethyl 1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxylate and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (intermediate A2) to generate the title compound (1.7 g, 92%) as a colorless solid.
[1047] [1047] 1H NMR (DMSO-d6) δ 7.32 (s, 1H), 6.93 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 4.29 (q , J = 7.1 Hz, 2H), 4.05 (s, 3H), 3.21 - 2.94 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1 , 03 (d, J = 6.8 Hz, 12H).
[1048] [1048] LCMS; m / z 455.4 (M + H) + (ES +). Step B: 3- (N - (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt
[1049] [1049] Prepared according to the general procedure for 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1 -methyl-1H-pyrazol-5 carboxylic acid, disodium salt (Intermediate P87, Step B) of ethyl 3- (N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H- pyrazole-5-carboxylate, sodium salt to generate the title compound (1.65 g, 98%) as a colorless solid.
[1050] [1050] 1H NMR (DMSO-d6) δ 7.41 (s, 1H), 6.77 (d, J = 10.1 Hz, 2H), 6.45 (s, 1H), 4.01 (s , 3H), 3.15 - 3.02 (m, 2H), 1.10 - 0.93 (m, 12H).
[1051] [1051] LCMS; m / z 427.4 (M + H) + (ES +). Intermediate P90: 3- (N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt Step A: Ethyl 3- (N- ( (4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylate, sodium salt
[1052] [1052] Prepared according to the general procedure for ethyl 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl- 1H-pyrazol-5-carboxylate, sodium salt (Intermediate P87, Step A) of ethyl 1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxylate and 5-chloro-2-isocyanate-1,3-diisopropylbenzene ( Intermediate A22) to generate the title compound (1.32 g, 92%) as a colorless solid.
[1053] [1053] 1H NMR (DMSO-d6); δ 7.41 (s, 1H), 7.01 (s, 2H), 6.92 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 3.13 (br s, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.04 (d, J = 6.8 Hz, 12H).
[1054] [1054] LCMS; m / z 471.4 (M + H) + (ES +). Step B: 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt
[1055] [1055] Prepared according to the general procedure for 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1 acid -methyl-1H-pyrazole-5-carboxylate, disodium salt (Intermediate P87, Step B) of ethyl 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H pyrazole-5-carboxylate, sodium salt (Intermediate P90, Step A) to generate the title compound (1.0 g, 77%) as a colorless solid.
[1056] [1056] 1H NMR (DMSO-d6) δ 7.49 (s, 1H), 7.00 (s, 2H), 6.42 (s, 1H), 4.01 (s, 3H), 3.09 (br s, 2H), 1.02 (d, J = 6.8 Hz, 12H).
[1057] [1057] LCMS; m / z 443.4 (M + H) + (ES +). Intermediate P91: 5- (Azetidine-1-carbonyl) -1-isopropyl-1H-pyrazol-3-sulfonamide Step A: Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H- pyrazole-5-carboxylate
[1058] [1058] Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-5-carboxylate (Intermediate P57, Step A) (1 g, 2.176 mmol), K 2 CO3 (0.391 g, 2, 83 mmol) and 2-iodopropane (0.26 mL, 2.61 mmol) were stirred in DMF (10 mL) under a nitrogen atmosphere for 18 hours. The reaction was poured into brine (100 ml) and EtOAc (50 ml). The aqueous layer was discarded and the organic layer washed with brine (2 x 100 mL), dried (MgSO4), filtered and concentrated to dryness to produce a yellow oil which was purified by chromatography on silica gel (80 g column, column 0-40% EtOAc / isohexane) to produce the title compound (1.0 g, 85%) as a clear colorless oil which solidified on standing.
[1059] [1059] 1H NMR (DMSO-d6) δ 7.22 - 6.93 (m, 5H), 6.93 - 6.68 (m, 4H), 5.45 (sept, J = 6.6 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.25 (s, 4H), 3.71 (s, 6H), 1.42 (d, J = 6.6 Hz, 6H), 1.32 (t, J = 7.1 Hz, 3H).
[1060] [1060] LCMS; m / z 524.2 (M + Na) + (ES +). Step B: 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H-pyrazole-5-carboxylic acid, sodium salt
[1061] [1061] Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H-pyrazol-5-carboxylate (1 g, 1.994 mmol) was suspended in EtOH (10 mL) and 2 M aqueous sodium (1.994 ml, 3.99 mmol). The reaction was left to stir at room temperature for 17 hours, then it was evaporated to dryness under reduced pressure to generate the title compound as a colorless foam which was used without further purification.
[1062] [1062] LCMS; m / z 496.1 (M + Na) + (ES +). Step C: 5- (Azetidine-1-carbonyl) -1-isopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
[1063] [1063] T3P (50% by weight EtOAc) (2.28 mL, 3.83 mmol) was added to a mixture of 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-isopropyl-1H sodium pyrazole-5-carboxylate (0.99 g, 1.913 mmol) and azetidine hydrochloride (0.215 g, 2.296 mmol) in THF (10 mL). DIPEA (0.67 mL, 3.84 mmol) was added and the reaction was stirred at room temperature for 5 hours. Additional T3P (50% by weight EtOAc) (2.28 mL, 3.83 mmol), DIPEA (0.67 mL, 3.84 mmol) and azetidine hydrochloride (0.215 g, 2.296 mmol) were added and The reaction was stirred at room temperature for an additional 2 days. The reaction mixture was diluted with EtOAc (20 ml) and washed with 2 M aqueous NaOH (2 x 20 ml) followed by 1 M aqueous HCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated to dryness to produce the crude product still containing the initial acid. The mixture was subjected to the above reaction procedure, stirred for 2 days, then diluted with EtOAc (20 ml) and washed with water (2 x 30 ml) followed by 1 M aqueous HCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated to dryness to generate the title compound (786 mg, 75%) as an orange oil which was used without further purification in the next step.
[1064] [1064] 1H NMR (CDCl3) δ 7.17 - 6.99 (m, 4H), 6.85 - 6.73 (m, 4H), 6.70 (s, 1H), 5.46 (sept, J = 6.6 Hz, 1H), 4.37 - 4.24 (m, 6H), 4.20 (t, J = 7.8 Hz, 2H), 3.78 (s, 6H), 2, 50 - 2.29 (m, 2H), 1.47 (d, J = 6.6 Hz, 6H).
[1065] [1065] LCMS; m / z 513.2 (M + H) + (ES +). Step D: 5- (Azetidine-1-carbonyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[1066] [1066] Prepared according to the general procedure of 1- (pyrimidine-2-ylmethyl) -1H-pyrazol-3-sulfonamide (Intermediate P20, Step E) of 5- (azetidine-1-carbonyl) -1-isopropyl- N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (0.79 g, 1.54 mmol) to generate the title compound (201 mg, 47%) as a colorless foam.
[1067] [1067] 1H NMR (DMSO-d6) δ 7.51 (s, 2H), 6.85 (s, 1H), 5.28 (sept, J = 6.6 Hz, 1H), 4.30 (t , J = 7.7 Hz, 2H), 4.04 (t, J = 7.8 Hz, 2H), 2.27 (p, J = 7.8 Hz, 2H), 1.40 (d, J = 6.6 Hz, 6H).
[1068] [1068] LCMS; m / z 273.1 (M + H) + (ES +). Intermediate P92: (4- (Dimethylamino) pyridine-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) amide
[1069] [1069] A solution of N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (Intermediate P84) (459 mg, 1.976 mmol) in MeCN (2.3 mL) was treated with N, N -dimethylpyridin-4-amine (483 mg, 3.95 mmol) and the reaction mixture was stirred at room temperature until the sulfonamide dissolved. Diphenyl carbonate (466 mg, 2.174 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was filtered off, washed with MeCN and dried to generate the title compound (578 mg, 77%) which was used in the next step without further purification.
[1070] [1070] 1H NMR (DMSO-d6) δ 8.77 - 8.73 (m, 2H), 7.02 - 6.98 (m, 2H), 6.83 (s, 1H), 3.85 ( s, 3H), 3.26 (s, 6H), 3.05 (s, 3H), 3.00 (s, 3H). Intermediate P93: 2 - ((Dimethylamino) methyl) -1-methyl-1H-imidazole-4-sulfonamide, and
[1071] [1071] Prepared according to the general procedure of N, N-bis (4-methoxybenzyl) -1H-imidazole-4-sulfonamide (Intermediate P21, Step A) of 1-methyl-1H-imidazole-4-sulfonyl chloride and bis (4-methoxybenzyl) amino to generate the title compound (5.1 g, 55%) as a white solid.
[1072] [1072] 1H NMR (DMSO-d6) δ 7.87 - 7.78 (m, 2H), 7.09 - 6.99 (m, 4H), 6.91 - 6.73 (m, 4H), 4.19 (s, 4H), 3.72 (s, 6H), 3.33 (s, 3H).
[1073] [1073] LCMS; m / z 402.3 (M + H) + (ES +). Step B: 2 - ((Dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-imidazole-4-sulfonamide and 5 - ((dimethylamino) methyl) -N, N-bis ( 4-methoxybenzyl) -1-methyl-1H-imidazole-4-sulfonamide
[1074] [1074] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide ( Intermediate P7, Step F) of N, N-bis (4-methoxybenzyl) -1-methyl-1H-imidazole-4-sulfonamide and N-methyl-N-methylene methanedamide iodide to generate the title compounds as a mixture 85: 15 (374 mg, 28%) as a yellow oil.
[1075] [1075] 1H NMR (major product) (DMSO-d6) δ 7.83 (s, 1H), 7.05 - 6.98 (m, 4H), 6.83 - 6.74 (m, 4H), 4.24 (s, 4H), 3.71 (s, 6H), 3.70 (s, 3H), 3.68 (s, 2H), 2.16 (s, 6H).
[1076] [1076] LCMS; m / z 459.4 (M + H) + (ES +). Step C: 2 - ((Dimethylamino) methyl) -1-methyl-1H-imidazole-4-sulfonamide and 5-
[1077] [1077] An 85: 15 mixture of 2 - ((dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-imidazol-4-sulfonamide and 5 - ((dimethylamino) methyl) - N, N-bis (4-methoxybenzyl) -1-methyl-1H-imidazole-4-sulfonamide (552 mg, 1.204 mmol) was dissolved in TFA (5 ml, 1.204 mmol) and stirred overnight. Additional TFA (2 ml) was added and stirred for an additional 24 hours at room temperature. The mixture was concentrated in vacuo and the residue was suspended in a mixture of MeOH (50 ml) and DCM (10 ml). SCX (3 g) was added and the suspension was stirred at room temperature for 1 hour. The SCX was filtered and washed with MeOH (50 ml) and the product was then eluted with 0.7% ammonia in MeOH (50 ml). After concentration in vacuo, an 85: 15 mixture of 2 - ((dimethylamino) methyl) -1-methyl-1H-imidazole-4-sulfonamide and 5 - ((dimethylamino) methyl) -1-methyl-1H-imidazole-4 - sulfonamide (222 mg, 84%) was isolated as a pale yellow oil.
[1078] [1078] 1H NMR (major product) (DMSO-d6) δ 7.72 (s, 1H), 7.10 (s, 2H), 3.66 (s, 3H), 3.65 (s, 2H) , 2.15 (s, 6H). Intermediate P95: 1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-sulfonamide Step A: 4-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole N N O N HN O I I
[1079] [1079] To a mixture of 4-iodo-1H-pyrazole (50 g, 257.77 mmol, 1 eq) and pyridine-1-i 4-methylbenzenesulfonate (32.39 g, 128.88 mmol, 0.5 eq ) in DCM (500 ml) at 20 ° C 3,4-dihydro-2H-pyran (43.4 g, 515.54 mmol, 2 eq) was added. The mixture was stirred at 20 ° C for 12 hours. The mixture was concentrated in vacuo. The residue was purified by chromatography (SiO2, petroleum ether: ethyl acetate, 1: 0 to 20: 1) to produce the title compound (65 g, 91%) as a colorless oil.
[1080] [1080] 1H NMR (CDCl3): δ 7.67 (s, 1 H), 7.55 (s, 1 H), 3.8 (q, 1 H), 4.15- 4.01 (m, 1 H), 3.72-3.66 (m, 1 H), 2.07-2.04 (m, 2 H) and 1.69-1.62 (m, 4 H). Step B: S- (1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) benzothioate THE SH N N AT THE N
[1081] [1081] CuI (2.05 g, 10.79 mmol, 0.1 eq) was added to the mixture of 4-iodo- 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (30 g, 107.88 mmol, 1 eq), benzenocarbothioic acid S (17.89 g, 129.45 mmol, 1.2 eq), 1.10-phenanthroline (3.89 g, 21.58 mmol, 0.2 eq) and DIPEA (27.89 g, 215.76 mmol, 2 eq) in toluene (300 ml) at 20 ° C under N2. The mixture was stirred for 12 hours at 110 ° C under N2. The residue was poured into a 1 M HCl solution (500 mL). The aqueous phase was extracted with ethyl acetate (3 × 200 ml). The combined organic phases were washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO 2, petroleum ether: ethyl acetate 20: 1 to 5: 1) to produce the title compound (28 g, 85% yield, 94% purity in LCMS) as a yellow oil.
[1082] [1082] 1H NMR (CDCl3): δ 8.01 (d, 2 H), 7.83 (s, 1 H), 7.64-7.59 (m, 2 H), 7.49 (t, 2 H), 5.49 (t, 1 H), 4.09-4.05 (m, 1 H), 3.76-3.69 (m, 1 H), 2.16-2.13 ( m, 2 H), 1.74-1.62 (m, 4 H). Step C: 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-sulfonyl chloride N N NINTH
[1083] [1083] 1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (13.30 g, 57.22 mmol, 1.1 eq) was added to a solution of chloride benzyltrimethylammonium (31.88 g, 171.66 mmol, 29.79 mL, 3.3 eq) in MeCN (300 mL) at 20 ° C. The mixture was stirred for 30 minutes. The light yellow solution was added dropwise to a solution of S- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) benzothioate (15 g, 52.02 mmol, 1 eq) in MeCN (150 ml) at 0 ° C. An aqueous solution of sodium carbonate (1 M, 52.02 ml, 1 eq) was added dropwise to the mixture at 0 ° C. The mixture was stirred for 30 minutes. The reaction mixture was diluted with saturated aqueous sodium carbonate solution (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate,
[1084] [1084] 1H NMR (CDCl3): δ 8.29 (s, 1 H), 8.00 (s, 1 H), 5.45 (q, 1 H), 4.16 - 4.08 (m, 1 H), 3.78-3.74 (m, 1 H), 2.02-1.96 (m, 2 H) and 1.71 to 1.60 (m, 4 H). Step D: N, N-Bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-sulfonamide MeO MeO OMe
[1085] [1085] 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-sulfonyl chloride (2.5 g, 9.97 mmol, 1 eq) was added to the bis (4 -methoxybenzyl) amine (2.31 g, 8.97 mmol, 0.9 eq) and TEA (3.03 g, 29.92 mmol, 3 eq) in THF (50 ml) at 0 ° C. The reaction mixture was stirred at 20 ° C for 12 hours. The residue was poured into 1 M HCl solution (100 ml). The aqueous phase was extracted with ethyl acetate (2 × 30 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The solid was triturated with a mixture of petroleum ether and EtOAc (20 mL, v: v = 5: 1) to produce the title compound (3 g, 60% yield, 94.4% purity in LCMS) as a white solid.
[1086] [1086] 1H NMR (CDCl3): δ 7.76 (s, 1 H), 7.65 (s, 1 H), 7.11 (d, 4 H), 6.81 (d, 4 H), 3.36-3.33 (m, 1 H), 4.23 (s, 4 H), 4.05 (d, 1 H), 3.80 (s, 6 H), 3.73-3, 64 (m, 1 H), 2.10-1.97 (m, 2 H) and 1.76-1.64 (m, 4 H).
[1087] [1087] LCMS: m / z 472.1 (M + H) + (ES +). Step E: N, N-Bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide MeO MeO OMe OMe O O N N The S S N O HN O N N
[1088] [1088] HCl (1 M, 8.48 mL, 2 eq) was added to the mixture of N, N-bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H- pyrazol-4-sulfonamide (2 g, 4.24 mmol, 1 eq) in EtOH (20 ml) and THF (20 ml) at 20 ° C. The mixture was stirred at
[1089] [1089] 1H NMR (CDCl3): δ 7.78 (s, 2 H), 7.10 (d, 4 H), 6.81 (d, 4 H), 4.24 (s, 4 H) and 3.79 (s, 6 H).
[1090] [1090] LCMS: m / z 388.1 (M + H) + (ES +). Step F: 1- (2- (Dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide THE THE THE THE N
[1091] [1091] To a solution of N, N-bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide (500 mg, 1.29 mmol, 1 eq) in MeCN (10 mL) was added K 2CO3 (535 mg , 3.87 mmol, 3 eq) and 2-chloro-N, N-dimethel-ethanamine (223 mg, 1.55 mmol, 1.2 eq, HCl salt). The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 1: 1 to 0: 1) to produce the title compound (350 mg, 56% yield, 95% purity in LCMS) as a gray solid.
[1092] [1092] 1H NMR (DMSO-d6): δ 8.33 (s, 1 H), 7.79 (s, 1 H), 7.05 (d, 4 H), 6.81 (d, 4 H ), 4.23 (t, 2 H), 4.12 (s, 4 H), 3.76 (s, 6 H), 2.67-2.62 (m, 2 H) and 2.16 ( s, 6 H).
[1093] [1093] LCMS: m / z 459.0 (M + H) + (ES +). Step G: 1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-sulfonamide THE
[1094] [1094] A solution of 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide (0.3 g, 654.20 µmol, 1 eq) in TFA (7.70 g, 67.53 mmol, 103.23 eq) was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. Then, the residue was redissolved in MeOH (10 mL) and adjusted to pH = 7 ~ 8 with resin (Amberlyst® A-21, ion exchange resin). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (0.05% NH3 • H2O-MeCN) to produce the title compound (103 mg, 72% yield, 100% purity in LCMS) as a yellow oil.
[1095] [1095] LCMS: m / z 219.1 (M + H) + (ES +). Intermediate P96: 1- (1- (Dimethylamino) -2-methylpropan-2-yl) -1H-pyrazol-4-sulfonamide Step A: Methyl 2- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoate THE N PMB
[1096] [1096] To a solution of N, N-bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide (2.1 g, 5.42 mmol, 1 eq) (Intermediate P95, Step E) in DMF (30 ml) K2CO3 (1.12 g, 8.13 mmol, 1.5 eq) and methyl 2-bromo-2-methylpropanoate (1.28 g, 7.05 mmol, 1.3 eq) were added. The mixture was stirred for 2 hours at 90 ° C. The reaction mixture was cooled to 25 ° C and then poured into water (100 ml). The mixture was extracted with EtOAc (2 × 80 ml). The combined organic layers were washed with brine (2 x 60 ml), dried over Nas2SO4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and EtOAc (50 ml, v: v = 2: 1) to produce the title compound (2.35 g, 89%) as an off-white solid.
[1097] [1097] 1H NMR (CDCl3): δ 7.69 (d, 2 H), 7.15-7.13 (d, 4 H), 6.86-6.82 (m, 4 H), 4, 27 (s, 4 H), 3.81 (s, 6 H), 3.74 (s, 3 H) and 1.83 (s, 6 H).
[1098] [1098] LCMS: m / z 488.3 (M + H) + (ES +). Step B: 2- (4- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoic acid PMB PMB N O O O PMB N OH S The PMB S O N O N N N
[1099] [1099] To a solution of methyl 2- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoate (1.8 g, 3.69 mmol , 1 eq) in MeOH (20 ml), H2O (10 ml) and THF (10 ml) was added NaOH (442.98 mg, 11.08 mmol, 3 eq). The mixture was stirred for 2 hours at 25 ° C. The reaction mixture was poured into water (100 ml) and adjusted with 1 N HCl to pH = 3. The mixture was extracted with EtOAc (2 × 100 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound (1.7 g, 97%) as a white solid.
[1100] [1100] 1H NMR (DMSO-d6): δ 13.21 (br s, 1 H), 8.38 (s, 1 H), 7.85 (s, 1 H), 7.08-7.06 (d, 4 H), 6.84-6.82 (d, 4 H), 4.17 (s, 4 H), 3.72 (s, 6 H) and 1.76 (s, 6 H) .
[1101] [1101] LCMS: m / z 474.1 (M + H) + (ES +). Step C: 2- (4- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N, 2-trimethylpropanamide PMB The PMB O O O N N OH S N PMB Y N N The PMB The N N
[1102] [1102] To a solution of 2- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoic acid (2.1 g, 4.43 mmol, 1 eq) in DMF (30 ml) were added HATU (2.02 g, 5.32 mmol, 1.2 eq), TEA (2.24 g, 22.17 mmol, 5 eq) and Me2NH (1.08 g, 13.30 mmol, 3 eq, HCl salt). The reaction mixture was stirred for 3 hours at 25 ° C. The reaction mixture was poured into water (200 ml) and extracted with EtOAc (2 × 100 ml). The combined organic layers were washed with brine (80 ml) and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate 10: 1 to 1: 1) to obtain the title compound (1.33 g, 47% yield, 78.8 % purity in LCMS) as a yellow solid.
[1103] [1103] 1H NMR (CDCl3): δ 7.61 (s, 1 H), 7.48 (s, 1 H), 7.07-7.04 (m, 4 H), 6.76-6, 73 (m, 4 H), 4.17 (s, 4 H), 3.72 (s, 6 H), 2.90 (s, 3 H), 2.25 (s, 3 H) and 1, 67 (s, 6 H).
[1104] [1104] LCMS: m / z 501.1 (M + H) + (ES +). Step D: 1- (1- (Dimethylamino) -2-methylpropan-2-yl) -N, N-bis (4-methoxybenzyl) - 1H-pyrazol-4-sulfonamide O N PMB N THE Y N N N N Y NPMB N O PMB O PMB
[1105] [1105] To a solution of 2- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -N, N, 2-trimethylpropanamide (0.8 g, 1, 60 mmol, 1 eq) in THF (20 ml) BH3-Me2S (10 M, 479.42 µL, 3 eq) was added. The mixture was stirred for 2 hours at 80 ° C. The reaction mixture was stopped with MeOH (30 ml), diluted with water (100 ml) and extracted with EtOAc (3 × 80 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (0.1% TFA in H2O / MeCN) to produce the title compound (405 mg, 52%) as a yellow oil.
[1106] [1106] 1H NMR (CDCl3): δ 7.70 (s, 1 H), 7.56 (s, 1 H), 7.17-7.14 (m, 4 H), 6.86-6, 83 (m, 4 H), 4.23 (s, 4 H), 3.80 (s, 6 H), 3.38 (s, 2 H), 2.33 (s, 6 H) and 1, 17 (s, 6 H).
[1107] [1107] LCMS: m / z 487.1 (M + H) + (ES +). Step E: 1- (1- (Dimethylamino) -2-methylpropan-2-yl) -1H-pyrazol-4-sulfonamide
[1108] [1108] To a solution of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide (640 mg, 1.32 mmol, 1 eq) in DCM (5 ml) TFA (5 ml, 67.53 mmol, 51.35 eq) was added. The reaction mixture was stirred at 20 ° C for 12 hours and then concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (0.1% NH3.H2O / MeCN) to produce the title compound (260 mg, 80%) as a colorless oil.
[1109] [1109] 1H NMR (DMSO-d6): δ 8.11 (s, 1 H), 7.75 (s, 1 H), 7.19 (s, 2 H), 2.58 (s, 2 H ), 1.95 (s, 6 H) and 1.51 (s, 6 H).
[1110] [1110] LCMS: m / z 247.0 (M + H) + (ES +). Intermediate A1: 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene
[1111] [1111] To a solution of phosgene (4.45 ml, 20% by weight of 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 (756 mg, 100%) as a brown oil. The crude product was used directly in the next step without further purification.
[1112] [1112] 1H NMR (CDCl3) δ 6.8 (s, 1 H), 2.89 (m, 8 H) and 2.09 (m, 4 H). Intermediate A2: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene
[1113] [1113] 4-Fluoro-2,6-diisopropylaniline (1 g, 5.12 mmol) and triethylamine (0.785 mL, 5.63 mmol) were dissolved in THF (10 mL) and cooled to 0 ° C. Triphosgene (0.760 g, 2.56 mmol) was added to the mixture in portions and the reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated in vacuo. Isohexane (50 ml) was added and the suspension was filtered through silica (3 g). The filtrate was dried under reduced pressure to generate the title compound (900 mg, 75%) as a colorless oil.
[1114] [1114] 1H NMR (DMSO-d6) δ 6.80 (d, J = 9.4 Hz, 2H), 3.27-3.12 (m, 2H), 1.23 (d, J = 6, 8 Hz, 12H).
[1115] [1115] N- (2,3-dihydro-1H-inden-4-yl) pivalamide (1 g, 4.60 mmol), p-toluenesulfonic monohydrate (0.45 g, 2.366 mmol), Pd (OAc) 2 (0.05 g, 0.223 mmol), and NBS (0.9 g, 5.06 mmol) were suspended in toluene (20 mL) and stirred for 16 hours. The dark green mixture was diluted with EtOAc (20 ml) and then washed with 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 produce 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 reaction by-products.
[1116] [1116] LCMS; m / z 296.3 / 298.3 (M + H) + (ES +). Step B: 5-Bromo-2,3-dihydro-1H-inden-4-amine
[1117] [1117] 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 throughout the week. 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 phases were 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%).
[1118] [1118] 1H NMR (CDCl3) δ 7.23 (d, J = 7.9 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 3.92 (s, 2H), 2, 89 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.15 (p, J = 7.5 Hz, 2H). Step C: 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
[1119] [1119] 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. 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 produce a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc / isohexane) to generate the title compound (0.29 g, 87%) as a pale yellow crystalline solid.
[1120] [1120] 1H NMR (CDCl3) δ 8.26 (d, J = 5.4 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.97 (s, 1H), 6.80 (d, J = 7.6 Hz, 1H), 4.06 (s, 3H), 2.98 (t, J = 7.6 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.19 (p, J = 7.5 Hz, 2H). NH2 not observed.
[1121] [1121] LCMS; m / z 241.3 (M + H) + (ES +). Intermediate A4: 7-Fluoro-5- (pyridin-3-yl) -2,3-dihydro-1H-inden-4-amine Step A: N- (7-Fluoro-2,3-dihydro- 1H-inden-4-yl) pivalamide
[1122] [1122] To a solution of N- (2,3-dihydro-1H-inden-4-yl) pivalamide (2.5 g, 11.50 mmol) cooled on ice in dry DCM (50 mL) was added pyridine hydrofluoride (9 mL, 69.9 mmol). The pale yellow mixture was stirred for 30 minutes at 0 ° C. A solution of bis (tert-butylcarbonyloxy) iodobenzene (7.5 g, 17.91 mmol) in DCM (10 mL) was then added slowly over 10 minutes. The reaction was slowly allowed to reach room temperature and stirred overnight. It was then quenched with triethylamine (0.5 mL, 3.58 mmol) and the mixture was absorbed on silica gel and purified by silica gel chromatography (120 g column, 0-30% EtOAc / isohexane) to generate the title compound (0.64 g, 22%) as a yellow crystalline solid.
[1123] [1123] 1H NMR (CDCl3) δ 7.68 (dd, J = 8.8, 4.5 Hz, 1H), 7.14 (s, 1H), 6.87 (t, J = 8.6 Hz , 1H), 3.01 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.18 (p, J = 7.5 Hz, 2H ), 1.34 (s, 9H).
[1124] [1124] LCMS; m / z 236.3 (M + H) + (ES +); 234.2 (M-H) - (ES-). Step B: 7-Fluoro-2,3-dihydro-1H-inden-4-amine
[1125] [1125] N- (7-Fluoro-2,3-dihydro-1H-inden-4-yl) pivalamide (0.632 g, 2.69 mmol) was dissolved in ethanol (5 ml) and stirred at room temperature. H 2SO4 (95% aqueous) (5 ml, 89 mmol) was added slowly to water (5 ml) and this mixture was then added to the reaction mixture. The slurry was heated to 100 ° C (bath temperature) over the weekend. The reaction mixture was cooled to room temperature, diluted with water (10 ml) and basified with 2 M aqueous NaOH. The mixture was extracted with DCM (3 x 100 ml). The combined organic phases were washed by passing through a hydrophobic frit and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc / isohexane) to generate the title compound (350 mg, 82%) as a pale pink oil which solidified on standing.
[1126] [1126] 1H NMR (CDCl3) δ 6.71 (dd, J = 9.0, 8.2 Hz, 1H), 6.46 (dd, J = 8.5, 3.9 Hz, 1H), 3.45 (s, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.16 (p, J = 7.6 Hz , 2H).
[1127] [1127] LCMS; m / z 152.3 (M + H) + (ES +). Step C: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine
[1128] [1128] 7-Fluoro-2,3-dihydro-1H-inden-4-amine (345 mg, 2.282 mmol) was dissolved in DCM (10 mL). NBS (450 mg, 2.53 mmol) was added at room temperature in a single portion. The mixture was immediately dark brown and was stirred for 15 minutes at room temperature. The reaction mixture was partitioned between DCM (20 ml) and 1 M aqueous NaOH (20 ml) and stirred for 15 minutes. The organic phase was separated and washed with brine (10 ml) and then dried by passing through a hydrophobic frit. The solvent was removed in vacuo to produce a dark brown oil. The crude product was purified by chromatography on silica gel (24 g column, 0-20% EtOAc / isohexane) to generate the title compound (323 mg, 55%) as a dark purple oil.
[1129] [1129] 1H NMR (CDCl3) δ 7.08 (d, J = 7.8 Hz, 1H), 3.06 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 7 , 5 Hz, 2H), 2.20 (p, J = 7.6 Hz, 2H). NH2 not observed. Step D: 7-Fluoro-5- (pyridin-3-yl) -2,3-dihydro-1H-inden-4-amine
[1130] [1130] Prepared according to the general procedure of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A3, Step C) from Acid 5 -bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine and pyridin-3-ylboronic acid to generate the title compound (0.32 g, 68%) as a green crystalline solid.
[1131] [1131] 1H NMR (CDCl3) δ 8.79 (s, 1H), 8.65 (s, 1H), 8.00 (d, J = 7.1 Hz, 1H), 7.56 (s, 1H ), 6.71 (d, J = 8.9 Hz, 1H), 3.04 (t, J = 7.6 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.24 (p, J = 7.5 Hz, 2H). NH2 not observed.
[1132] [1132] LCMS; m / z 229.3 (M + H) + (ES +). Intermediate A5: 7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
[1133] [1133] Prepared according to the general procedure of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A3, Step C) from 5- bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (Intermediate A4, Step C) and boronic acid (2-methoxypyridin-4-yl) to generate the title compound (0.19 g, 49%) as a light brown oil that crystallized on standing.
[1134] [1134] 1H NMR (CDCl3) δ 8.27 (d, J = 5.4 Hz, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.95 (s, 1H), 6.73 (d, J = 9.0 Hz, 1H), 4.03 (s, 3H), 3.00 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.23 (p, J = 7.5 Hz, 2H). NH2 not observed.
[1135] [1135] LCMS; m / z 259.3 (M + H) + (ES +). Intermediate A6: 4-Fluoro-2-isopropyl-6- (pyridin-3-yl) aniline Step A: 2-Bromo-4-fluoro-6-isopropylaniline
[1136] [1136] N-Bromosuccinimide (5.64 g, 31.7 mmol) was added in portions to 4-fluoro-2-isopropylaniline (4.62 g, 30.2 mmol) in DCM (72 mL) at 0 ° Ç. The resulting mixture was stirred at 0 ° C for 1 hour and then allowed to warm to room temperature over 21 hours. The reaction mixture was washed with an aqueous sodium hydroxide solution (2 M, 2 x 50 mL), dried (MgSO 4), filtered and concentrated in vacuo to produce a brown residue. The crude product was then filtered through a plug of silica (50 g) and washed with 50% DCM in isohexane (500 ml). The red filtrate was concentrated to dryness and the crude product was purified by chromatography on silica gel (120 g column, 0-10% DCM / isohexane) to generate the title compound (4.99 g, 70% ) as a red oil.
[1137] [1137] 1H NMR (CDCl3) δ 7.07 (dd, 1H), 6.86 (dd, 1H), 4.14 (s, 2H), 2.93 (sept, 1H) and 1.25 (d , 6H). NH2 not observed.
[1138] [1138] LCMS; m / z 232.2 / 234.3 (M + H) + (ES +). Step B: 4-Fluoro-2-isopropyl-6- (pyridin-3-yl) aniline
[1139] [1139] To a stirred degassed nitrogen mixture of 2-bromo-4-fluoro-6-isopropylaniline (1.00 g, 4.27 mmol) was added pyridin-3-ylboronic acid (0.577 g, 4.69 mmol) , Pd (dppf) Cl2 (0.156 g, 0.213 mmol) and potassium carbonate (1.769 g, 12.80 mmol) in a 10: 1 mixture of 1,4-dioxane: water (33 mL). The reaction mixture was then heated to 80 ° C under a nitrogen atmosphere for 2 days, cooled to room temperature, filtered through a pad of Celite® (10 g) and the filter residue was washed with EtOAc (2 x 30 mL). The filtrate was poured into water (50 mL) and the organic layer was collected. The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to dryness. The crude product was purified by chromatography on silica gel (80 g column, 0-60% EtOAc / isohexane) to generate the title compound (273 mg, 27%) as a brown gum.
[1140] [1140] 1H NMR (CDCl3) δ 8.70 (dd, 1H), 8.63 (dd, 1H), 7.82 (ddd, 1H), 7.48
[1141] [1141] LCMS; m / z 231.1 (M + H) + (ES +).
[1142] [1142] The following intermediates were synthesized following the general procedure for Intermediate A6: Inter medi Structure Analytical data ar 1 H NMR (CDCl3) δ 7.50 - 7.32 (m, 5H), 6.90 (dd, 1 H), 6.74 (dd, 1H), 4.11 (br s, A7 2H), 3.15 - 2.80 (m, 1H) and 1.29 (d, 6H). LCMS; m / z 230.1 (M + H) + (ES +). 5-Fluoro-3-isopropyl- [1,1'- (161 mg, 82%) biphenyl] -2-amine 1 H NMR (CDCl3) δ 7.82 - 7.74 (m, 1H), 7.73 - 7.66 (m, 1H), 7.66 - 7.60 (m, 1H), 7.59 - 7.49 (m, 1H), 6.96 (dd, 1H), 6.69 A8 ( dd, 1 H), 3.10 - 2.84 (m, 1H) and 1.29 (d, 6H). 2'-Amino-5'-fluoro-3'-LCMS; m / z 255.1 (M + H) + (ES +). isopropyl- [1,1'-biphenyl] -3- (182 mg, 81%) carbonitrile 1 H NMR (CDCl3) δ 6.95 (dd, 1H), 6.68 (dd, 1H), 6.09 ( s, 1H), 3.69 (s, 3H), 2.98 - 2.81 A9 (m, 1H), 2.33 (s, 3H) and 1.28 (d, 6H). 2- (1,3-Dimethyl-1H-pyrazol-LCMS; m / z 248.1 (M + H) + (ES +). 5-yl) -4-fluoro-6- (72 mg, 34%) isopropylaniline
[1143] [1143] Nitrogen gas was bubbled through a mixture of 2,6-dibromo-4-fluoroaniline (5 g, 18.59 mmol), 4,4,5,5-tetramethyl-2- (prop-1-en -2-yl) - 1,3,2-dioxaborolane (4.2 mL, 22.34 mmol) and potassium triphosphate (7.9 g, 37.2 mmol) in dioxane (50 mL) and water (8 mL ) for 15 minutes. So (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) methanesulfonate [2- (2′-amino-1,1′-biphenyl)] palladium (II) methanesulfonate [XPhos G3 Pd cat (500 mg, 0.591 mmol)] was added. The mixture was heated at 90 ° C for 8 hours and then partitioned between hexane (200 ml) and water (100 ml). The organic layer was dried (magnesium sulfate), filtered, evaporated in vacuo and the residue purified by chromatography on silica gel (120 g column, 0-2% ethyl acetate / isohexane) to generate the compound title (1.95 g, 43%) as an oil.
[1144] [1144] 1H NMR (CDCl3) δ 7.13 (dd, 1 H), 6.77 (dd, 1 H), 5.37-5.35 (m, 1 H), 5.12-5.10 (m, 1 H), 3.52 (br s, 2 H) and 2.08-2.06 (m, 3 H).
[1145] [1145] LCMS; m / z 230.2 (M + H) + (ES +). Step B: 2- (3,6-Dihydro-2H-pyran-4-yl) -4-fluoro-6- (prop-1-en-2-yl) aniline
[1146] [1146] 2- (3,6-Dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (457 mg, 2.176 mmol), tetrakis ( triphenylphosphine) palladium (0) (251 mg, 0.218 mmol), sodium carbonate (923 mg, 8.70 mmol) and water (4 mL) were added to a sealed flask containing a solution of 2-bromo-4-fluoro- 6- (prop-1-en-2-yl) aniline (500 mg, 2.173 mmol) in DMF (22 mL). The reaction mixture was heated under nitrogen at 100 ° C overnight and then allowed to cool. The reaction mixture was diluted with EtOAc (50 ml), washed with brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by chromatography on silica (40 g column, 0-20% EtOAc / isohexanes) to generate the title compound (355 mg, 65%) as a brownish oil.
[1147] [1147] 1H NMR (CDCl3) δ 6.71 (dd, 1H), 6.67 (dd, 1H), 5.88 (m, 1H), 5.35 - 5.31 (m, 1H), 5 .09 (m, 1H), 4.32 (m, 2H), 3.95 (t, J = 5.4 Hz, 2H), 3.82 (br s, 2H), 2.42 (m, 2H ) and 2.09 - 2.07 (m, 3H). Step C: 4-Fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) aniline
[1148] [1148] A mixture of 2- (3,6-dihydro-2H-pyran-4-yl) -4-fluoro-6- (prop-1-en-2-yl) aniline (355 mg, 1.522 mmol ) and 5% palladium on carbon 156 mg, 0.03 mmol; type 87L (58.5% humidity)) in EtOAc (3.8 mL) was hydrogenated at 5 bar for 1 hour. The mixture was filtered through Celite® and evaporated to generate the title compound (340 mg, 91%).
[1149] [1149] 1H NMR (CDCl3) δ 6.80 (dd, 1H), 6.75 (dd, 1H), 4.16 - 4.14 (m, 1H), 4.13 - 4.10 (m, 1H), 3.65 - 3.51 (m, 4H), 3.01 - 2.89 (m, 1H), 2.85 - 2.74 (m, 1H), 1.86 - 1.78 ( m, 4H) and 1.28 (d, 6H).
[1150] [1150] LCMS; m / z 238.1 (M + H) + (ES +). Intermediate A15: 2-Isopropyl-5- (1-methyl-1H-pyrazol-4-yl) aniline
[1151] [1151] To a sealed flask was added 5-bromo-2-isopropylaniline (250 mg, 1.168 mmol) in DMF (11 mL), followed by the addition of (1-methyl-1H-pyrazol-4-yl) boronic acid ( 147 mg, 1.178 mmol), Pd (PPh3) 4 (135 mg, 0.117 mmol) and 2 M aqueous Na2CO3 (2.335 mL, 4.67 mmol). The reaction mixture is heated under argon to 100 ° C overnight. The reaction mixture was diluted with EtOAc (20 ml), washed with brine (20 ml), dried over anhydrous Na2SO4, filtered, concentrated and then purified by silica gel chromatography (40 g column, 0-60% EtOAc / iso hexane) to generate the title compound (90 mg, 36%) as a white solid.
[1152] [1152] 1H NMR (CDCl3) δ 7.70 (d, J = 0.9 Hz, 1H), 7.54 (s, 1H), 7.13 (d, J =
[1153] [1153] Prepared according to the general procedure for 2-isopropyl-5- (1-methyl-1H-pyrazol-4-yl) aniline (Intermediate A15) from 5-bromo-2-isopropylaniline and pyrimidin-5 acid -borboronic to obtain the title compound (130 mg, 51%) as a white solid.
[1154] [1154] 1H NMR (CDCl3) δ 9.16 (s, 1H), 8.91 (s, 2H), 7.28 (d, J = 7.9 Hz, 1H), 6.98 (dd, J = 8.0, 1.9 Hz, 1H), 6.87 (d, J = 1.9 Hz, 1H), 3.84 (bs, 2H), 2.95 (sept, J = 6.8 Hz, 1H ), 1.31 (d, J = 6.8 Hz, 6H). Intermediate A17: 2,5-Diisopropylaniline Step A: 2-isopropyl-5- (prop-1-en-2-yl) aniline
[1155] [1155] Nitrogen was bubbled through a mixture of 5-bromo-2-isopropylaniline (500 mg, 2,335 mmol), 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2- dioxaborolane (0.527 mL, 2.80 mmol) and Cs2CO3 (7609 mg, 23.35 mmol) in toluene (20 mL) and water (10 mL) for 15 minutes. Then, palladium (II) acetate (157 mg, 0.701 mmol) and tricyclohexylphosphine (327 mg, 1.168 mmol) were added. The mixture was heated at 100 ° C for 4 hours and then partitioned between hexane (50 ml) and water (20 ml). The organic layer was dried (MgSO 4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-30% EtOAc / isohexane) to generate the title compound (227 mg, 53%) as an oil.
[1156] [1156] 1H NMR (CDCl3) δ 7.13 (d, J = 8.0 Hz, 1H), 6.94 (dd, J = 8.0, 1.9 Hz, 1H), 6.83 (d, J = 1 , 9 Hz, 1H), 5.37 - 5.30 (m, 1H), 5.03 (p, J = 1.6 Hz, 1H), 3.69 (bs, 2H), 2.93 (sept , J = 6.8 Hz, 1H), 2.17 - 2.11 (m, 3H), 1.29 (d, J = 6.8 Hz,
[1157] [1157] A mixture of 2-isopropyl-5- (prop-1-en-2-yl) aniline (227 mg, 1.295 mmol) and 5% Pd / C (0.133 g, 0.026 mmol) (Type 87L, 58 , 5% humidity) in EtOAc (3 mL) was hydrogenated at 5 bar for 16 hours. The mixture was filtered through Celite® and evaporated to generate the title compound (209 mg, 88%).
[1158] [1158] 1H NMR (CDCl3) δ 7.06 (d, J = 7.9 Hz, 1H), 6.66 (dd, J = 7.9, 1.9 Hz, 1H), 6.56 (d , J = 1.9 Hz, 1H), 3.71 (bs, 2H), 2.88 (sept, J = 7.0 Hz, 1H), 2.78 (sept, J = 7.0 Hz, 1H), 1, 25 (d, J = 7.1 Hz, 6H), 1.21 (d, J = 6.9 Hz, 6H). Intermediate A18: 2-Isocyanate-1,3-diisopropylbenzene
[1159] [1159] 2,6-Diisopropylaniline (3.07 g, 17.14 mmol) was dissolved in dry THF (40 mL) and Et3N (3 mL, 21.52 mmol) was added. A solution of triphosgene (4.26 g, 14.35 mmol) in dry THF (12 mL) was added over 5 minutes, resulting in the formation of a thick colorless precipitate. The reaction mixture was stirred at room temperature overnight. THF was removed in vacuo and toluene (50 ml) was added. The mixture was filtered through a short silica plug eluting with toluene (150 ml). The filtrate was concentrated in vacuo to generate the title compound (2.76 g, 92%) as a colorless oil.
[1160] [1160] 1H NMR (CDCl3) δ 7.20 - 7.10 (m, 3H), 3.22 (hept, J = 6.9 Hz, 2H), 1.26 (d, J = 6.8 Hz , 12H). Intermediate A19: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) -2-isopropoxypyridine Step A: 4-Fluoro-2- (prop-1-en-2-yl) aniline
[1161] [1161] 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 an atmosphere of N2. 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 anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 0 to 100: 1) to obtain the title compound (27 g, 77% yield, 89% purity in LCMS ) as a yellow oil.
[1162] [1162] 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).
[1163] [1163] LCMS: m / z 152.2 (M + H) + (ES +). Step B: 4-Fluoro-2-isopropylaniline NH2 NH2 F F
[1164] [1164] 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 an atmosphere of N 2. The reaction mixture was degassed in vacuo and purged with H2 several times. The reaction mixture was stirred at 25 ° C for 12 hours under H2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the title compound (20 g, crude) as a yellow oil.
[1165] [1165] 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).
[1166] [1166] LCMS: m / z 154.2 (M + H) + (ES +). Step C: 2-Bromo-4-fluoro-6-isopropylaniline NH2 NH2 Br F F
[1167] [1167] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 ml) was added NBS (23.24 g, 130.55 mmol, 1 eq) to 25 ° C. The reaction mixture was stirred at 25 ° C for 10 minutes. Then, the reaction mixture was poured into H2O (300 ml) and extracted with EtOAc (2 x 250 ml). The organic phases were washed with brine (2 x 400 ml), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting only using petroleum ether) to obtain the title compound (30 g, 99%) as a black brown oil.
[1168] [1168] 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).
[1169] [1169] LCMS: m / z 232.1 (M + H) + (ES +). Step D: 4-Bromo-2-isopropoxypyridine Br Br Cl N O N
[1170] [1170] To a solution of 4-bromo-2-chloropyridine (20 g, 103.93 mmol, 1 eq) in THF (400 mL) was added NaH (6.24 g, 155.89 mmol, 60% purity , 1.5 eq) at 0 ° C. Then the mixture was stirred for 0.5 hour. Propan-2-ol (6.87 g, 114.32 mmol, 8.75 ml, 1.1 eq) was added and the resulting mixture was heated to 50 ° C and stirred for 12 hours. The reaction mixture was quenched with H 2 O (1 L) at 25 ° C and extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with brine (200 ml), dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 50: 1 to 40: 1) to obtain the title compound (22 g, 98%) as a yellow oil.
[1171] [1171] 1H NMR (CDCl3): δ 7.96 (d, 1 H), 6.98 (dd, 1 H), 6.89 (d, 1 H), 5.44-
[1172] [1172] To a solution of 4-bromo-2-isopropoxypyridine (19 g, 87.93 mmol, 1 eq) and 4.4.4 ', 4', 5.5.5 ', 5'-octamethyl-2 , 2'-bi (1,3,2-dioxaborolane) (22.33 g, 87.93 mmol, 1 eq) in 1,4-dioxane (300 mL) was added KOAc (25.89 g, 263.80 mmol, 3 eq) followed by Pd (dppf) Cl2 (1.93 g, 2.64 mmol, 0.03 eq) under nitrogen. The reaction mixture was heated to 80 ° C and stirred for 12 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate = 50: 1 to 20: 1) to produce the title compound (22 g, 95%) as a yellow oil.
[1173] [1173] 1H NMR (CDCl3): δ 8.16 (d, 1 H), 7.13 (d, 1 H), 7.08 (s, 1 H), 5.32 - 5.24 (m, 1H), 1.34 (s, 12 H) and 1.27 (s, 6 H).
[1174] [1174] LCMS: m / z 264.2 (M + H) + (ES +). Step F: 4-Fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropylaniline NH2 F Br O O B H2N F O N N O
[1175] [1175] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (10.94 g, 47.12 mmol, 1 eq) and 2-isopropoxy-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) pyridine (12.4 g, 47.12 mmol, 1 eq) in 1,4-dioxane (200 ml) and H2O (20 ml) Pd (dppf) Cl2 was added (1.72 g, 2.36 mmol, 0.05 eq) followed by K2CO3 (19.54 g, 141.37 mmol, 3 eq) at 25 ° C. Then, the reaction mixture was heated to 80 ° C and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate = 50: 1 to 20: 1) to obtain the title compound (10.3 g, 69% yield, 91% LCMS purity) as a brown oil.
[1176] [1176] 1H NMR (CDCl3): δ 8.21 (d, 1 H), 6.94-6.91 (m, 2 H), 6.76 (s, 1 H), 6.72 (dd, 1 H), 5.38-5.29 (m, 1 H), 3.64 (br s, 2 H), 2.98-2.89 (m, 1 H), 1.38 (d, 6 H) and 1.30-1.27 (m, 6 H).
[1177] [1177] LCMS: m / z 289.2 (M + H) + (ES +). Step G: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) -2-isopropoxypyridine F
[1178] [1178] To a solution of 4-fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropylaniline (4 g, 13.87 mmol, 1 eq) in THF (80 mL) was added TEA (2, 81 g, 27.74 mmol, 3.86 ml, 2 eq). The mixture was cooled to 0 ° C and then triphosgene (1.65 g, 5.55 mmol, 0.4 eq) was added to the mixture. The resulting mixture was heated to 70 ° C and stirred for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate = 100: 1 to 30: 1) to obtain the title compound (1.9 g, 44% yield) as a yellow oil, which was used directly in the next step. Intermediate A20: 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine Step A: 4-nitro-2,3-dihydro-1H-indene O2N
[1179] [1179] To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 62.50 mL, 1 eq) in concentrated H2SO4 (30 mL) was added a mixture of HNO 3 (50 ml, 69% by weight in water) and concentrated H2SO4 (50 ml) dropwise at 0 ° C over a period of 3.5 hours. The reaction mixture was stirred at 0 ° C for 0.5 hour. Then, the reaction mixture was poured into ice water (600 ml) and extracted with ethyl acetate (2 × 400 ml). The combined organic layers were washed with water (500 ml), saturated aqueous NaHCO3 solution (500 ml) and brine (2 × 500 ml). The organic layer was dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 1: 0 to 100: 1) to obtain the title compound (55 g, 66%) as a colorless oil.
[1180] [1180] 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.51 (d, 1 H), 7.30 (t, 1 H), 3.41 (t, 2 H), 302 (t, 2 H) and 2.22-2.20 (m, 2 H). Step B: 2,3-Dihydro-1H-inden-4-amine O2N H2N
[1181] [1181] To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd / C (5 g, 10 µl charge % by weight of activated carbon) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H 2 (50 psi) at 20 ° C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 1: 0 to 100: 4) to produce the title compound (19.82 g, 43% yield, 96.39 % purity in LCMS) as a brown oil.
[1182] [1182] 1H NMR (CDCl3): δ 7.01 (t, 1 H), 6.71 (d, 1 H), 6.51 (d, 1 H), 3.57 (br s, 2 H) , 2.93 (t, 2 H), 2.75 (t, 2 H) and 2.16-2.08 (m, 2 H).
[1183] [1183] LCMS: m / z 134.2 (M + H) + (ES +). Step C: N- (2,3-Dihydro-1H-inden-4-yl) acetamide
[1184] [1184] To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1 , 3 eq) in DCM (300 ml) Ac2O (17.45 g, 170.96 mmol, 1.15 eq) was added dropwise over 6 minutes at 0 ° C. Then, the reaction mixture was heated to 16 ° C and stirred for 1.4 hours. Then, the mixture was poured into water (500 ml) and extracted with DCM (2 x 300 ml). The combined organic phases were washed with brine (2 x 500 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain the title compound (25.74 g, 96% yield, 96.69% purity in LCMS) as a white solid.
[1185] [1185] 1H NMR (CDCl3): δ 7.70 (d, 1 H), 7.15 (t, 1 H), 7.02 (d, 1 H), 2.95 (t, 2 H), 2.81 (t, 2 H), 2.18 (s, 3 H) and 2.15-2.08 (m, 2 H).
[1186] [1186] LCMS: m / z 176.2 (M + H) + (ES +) Step D: N- (5-Bromo-2,3-dihydro-1H-inden-4-yl) acetamide THE THE N
[1187] [1187] N- (2,3-dihydro-1H-inden-4-yl) acetamide (34.6 g, 197.46 mmol, 1 eq), p-toluenesulfonic acid (18.70 g, 108, 60 mmol, 0.55 eq) and Pd (OAc) 2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in toluene (400 mL) and stirred at 20 ° C for 0.5 hour under air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. The reaction mixture was stirred at 20 ° C for 2 hours. The reaction mixture was poured into ice water (500 ml) and extracted with ethyl acetate (2 × 500 ml). The combined organic phases were washed with brine (2 x 500 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 10: 1 to 2: 1) to produce the title compound (13.9 g, 27% yield, 98.1 % purity in LCMS) as a brown solid.
[1188] [1188] 1H NMR (CDCl3): δ 7.33 (d, 1 H), 7.16 (s, 1 H), 6.98 (d, 1 H), 2.92 - 2.83 (m, 4 H), 2.21 (s, 3 H) and 2.10-2.02 (m, 2 H).
[1189] [1189] LCMS: m / z 254.1 (M + H) + (ES +). Step E: 5-Bromo-2,3-dihydro-1H-inden-4-amine
[1190] [1190] A mixture of N- (5-bromo-2,3-dihydro-1H-inden-4-yl) acetamide (45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl (300 mL, 36 wt.% in water) was stirred at 80 ° C for 36 hours. The reaction mixture was cooled to 0 ° C in an ice bath and some solid precipitated. The suspension was filtered. The filter residue was washed with ice water (50 ml) and dried in vacuo to obtain the title compound (34.1 g, 72% yield, 94.08% purity in LCMS, HCl salt) as a gray solid .
[1191] [1191] 1H NMR (DMSO-d6): δ 7.67 (br s, 2 H), 7.24 (d, 1 H), 6.69 (d, 1 H), 2.85 (t, 2 H), 2.79 (t, 2 H) and 2.04-1.96 (m, 2 H).
[1192] [1192] LCMS: m / z 212.0 (M + H) + (ES +). Step F: 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine HO OH
[1193] [1193] A solution of (2-methoxypyridin-4-yl) boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-indent 4-amine (34 g, 136.80 mmol, 1 eq, HCl salt) and K2CO3 (60.50 g, 437.74 mmol, 3.2 eq) in dioxane (500 mL) and H2O (100 mL) were degassed with nitrogen for 15 minutes before Pd (dppf) Cl2. CH2Cl2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80 ° C for 12 hours. The mixture was poured into ice water (500 ml) and extracted with ethyl acetate (2 × 500 ml). The combined organic phases were washed with brine (2 x 700 ml), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate, 1: 0 to 10: 1) to obtain the title compound (27.4 g, 79% yield, 95% yield). LCMS purity) as a brown solid.
[1194] [1194] 1H NMR (CDCl3): δ 8.22 (d, 1 H), 7.03-7.00 (m, 1 H), 6.99 (d, 1 H), 6.87 (s, 1 H), 6.77 (d, 1 H), 3.99 (s, 3 H), 3.77 (br s, 2 H), 2.97 (t, 2 H), 2.77 (t , 2 H) and 2.21 - 2.13 (m, 2 H).
[1195] [1195] LCMS: m / z 241.2 (M + H) + (ES +). Step G: 4- (4-isocyanate-2,3-dihydro-1H-iden-5-yl) -2-methoxypyridine H2N OCN O N O N
[1196] [1196] To a solution of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA (5 , 10 g, 50.35 mmol, 1.1 eq) in THF (275 ml) bis (trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) was added in parts 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 yield the title compound (9.04 g, 74%) as a light yellow solid.
[1197] [1197] 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). Intermediate A21: 8-Isocyanate-1,2,3,5-tetrahydro-s-indacene Step A: 1,2,3,7-Tetrahydro-s-indacen-4-amine
[1198] [1198] 8-nitro-1,2,3,5-tetrahydro-s-indacene (700 mg, 3.48 mmol) was dissolved in a dioxane / ethanol / water mixture (10 ml / 6 ml / 4 ml). Iron powder (1.17 g, 20.9 mmol) and ammonium chloride (0.93 g, 17.4 mmol) were added. The mixture was refluxed for 15 minutes. Ethyl acetate (50 ml) was added and the mixture was filtered over Celite ®. The solids were washed with ethyl acetate. The combined ethyl acetate layers were evaporated. The crude product was filtered over silica, using ethyl acetate as the eluent, to generate the title compound (580 mg, 97%) as a brown oil which solidified after standing.
[1199] [1199] 1H NMR (CDCl3) δ 6.88 (s, 1 H), 6.85 (m, 1H), 6.39 (m, 1H), 3.68 (s, br, 2H) 3.36 (s, 2 H), 2.93 (t, 2H), 2.75 (t, 2H), 2.14 (m, 2H).
[1200] [1200] To a solution of phosgene (1.4 mL, 20 wt% toluene, 2.6 mmol) in toluene (40 mL) was added dropwise a solution of 1,2,3,7-tetrahydro- s-indacen-4-amine (180 mg 1.05 mmol) in toluene (20 ml) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, was concentrated in vacuo to generate the title compound as a brown oil (207 mg, 100%). The crude product was used directly in the next step without further purification.
[1201] [1201] 1H NMR (CDCl3): mixture of δ isomers 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). Intermediate A22: 5-Chlorine-2-isocyanate-1,3-diisopropylbenzene
[1202] [1202] To a solution of 4-chloro-2,6-diisopropylaniline (0.105 g, 0.496 mmol) in toluene (1 mL) was added a solution of phosgene (0.65 mL, 20 wt% toluene, 1, 22 mmol) and the reaction mixture was refluxed for 1 hour. Upon cooling, the mixture was concentrated in vacuo to generate the title compound as an orange oil (0.111 g, 94%).
[1203] [1203] 1H NMR (CDCl3) δ 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H). Preparation of Examples Example 1: 2- (3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1H-pyrazol-1 -il) -N, N-dimethylacetamide, sodium salt
[1204] [1204] N, N-dimethyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P1) (67 mg, 0.287 mmol) was dissolved in dry THF (2 mL) and tert-butoxide sodium (2M in THF) (0.151 ml, 0.301 mmol) was added. After stirring for 1 hour, a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (60 mg, 0.301 mmol) in THF (1 mL) was added . The reaction mixture was then stirred at room temperature overnight. EtOAc (6 ml) was added and the suspension was stirred for 1 hour. The resulting colorless precipitate was collected by filtration, washed with EtOAc and dried in vacuo to generate the title compound (15 mg, 11%) as a white solid.
[1205] [1205] 1H NMR (DMSO-d6) δ 7.55-7.54 (m, 2H), 6.77 (s, 1H), 6.42 (d, J = 2.2 Hz, 1H), 5 .08 (s, 2H), 3.03 (s, 3H), 2.86 (s, 3H), 2.76 (t, J = 7.4 Hz, 4H), 2.67 (t, J = 7.3 Hz, 4H), 1.95-1.87 (m, 4H).
[1206] [1206] LCMS; m / z 432 (M + H) + (ES +). Example 2: 2- (3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1H-pyrazol-1-yl) -N-methylacetamide
[1207] [1207] N-Methyl-2- (3-sulfamoyl-1H-pyrazol-1-yl) acetamide (Intermediate P2) (58 mg, 0.251 mmol) was dissolved in dry THF (2 mL) and sodium tert-butoxide ( 2 M in THF) (0.125 mL, 0.251 mmol) was added. After stirring for 1 hour, a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (50 mg, 0.251 mmol) in THF (1 mL) was added ). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, dissolved in DMSO (2 ml) and purified by reverse phase prep HPLC (General Methods, basic preparation) to generate the title compound (29.6 mg, 27%) of a colorless powder .
[1208] [1208] 1H NMR (DMSO-d6) δ 8.06 (s, 1H), 7.84 (s, 1H), 7.81 (d, J = 1.5 Hz, 1H), 6.88 (s , 1H), 6.64 (d, J = 1.7 Hz, 1H), 4.84 (s, 2H), 2.78 (t, J = 7.4 Hz, 4H),
[1209] [1209] LCMS; m / z 418 (M + H) + (ES +), 416 (M-H) - (ES-). Example 3: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (pyrrolidin-1-yl) ethyl) -1H -pyrazol-3-sulfonamide, sodium salt
[1210] [1210] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide, sodium salt (Example 1) of 1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P3) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (30 mg, 27%) as a colorless solid.
[1211] [1211] 1H NMR (DMSO-d6) δ 7.65 (d, J = 2.3 Hz, 1H), 7.51 (s, 1H), 6.76 (s, 1H), 6.35 (d , J = 2.2 Hz, 1H), 4.17 (t, J = 6.8 Hz, 2H), 2.82-2.71 (m, 6H), 2.64 (t, J = 7, 3 Hz, 4H), 2.47-2.42 (m, 4H), 2.01-1.80 (m, 4H), 1.69-1.61 (m, 4H). One exchangeable proton not visible.
[1212] [1212] LCMS; m / z 444 (M + H) + (ES +), 442 (M-H) - (ES-). Example 4: 1- (1-Acetylazetidin-3-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazole- 3- sulfonamide
[1213] [1213] Prepared according to the general procedure of 2- (3- (N-
[1214] [1214] 1H NMR (DMSO-d6) δ 7.95 (s, 1H), 7.73 (s, 1H), 6.85 (s, 1H), 6.61 (s, 1H), 5.35 -5.22 (m, 1H), 4.63-4.54 (m, 1H), 4.41-4.22 (m, 2H), 4.09 (dd, J = 10.1, 5, 5 Hz, 1H), 2.77 (t, J = 7.4 Hz, 4H), 2.62 (t, J = 7.3 Hz, 4H), 1.99-1.87 (m, 4H) , 1.81 (s, 3H). One exchangeable proton not visible.
[1215] [1215] LCMS; m / z 444 (M + H) + (ES +). Example 5: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -5-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide, sodium salt
[1216] [1216] 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide (Intermediate P5) (59.8 mg, 0.260 mmol) was dissolved in THF: DMF (1: 1) (4 ml) and sodium tert-butoxide (2M in THF) (0.136 ml, 0.273 mmol) was added. After stirring for 1 hour, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (54.3 mg, 0.273 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. Ethyl acetate (6 mL) was added and the suspension was stirred for 15 hours. The resulting precipitate was collected by filtration, washed with ethyl acetate (2 ml), triturated with ethyl acetate (5 ml) for 1 hour, filtered and dried under reduced pressure to generate the title compound (73 mg, 60%) like a white solid.
[1217] [1217] 1H NMR (DMSO-d6) δ 7.47 (s, 1H), 6.79-6.74 (m, 2H), 4.38-4.32 (m, 2H), 3.80- 3.72 (m, 2H), 3.00 (s, 3H), 2.79-2.71 (m, 4H), 2.67 (t, J = 7.2 Hz, 4H), 1.95 -1.86 (m, 4H).
[1218] [1218] LCMS; m / z 430 (M + H) + (ES +). Example 6: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1- (2- (methylamino) ethyl) acid -1H-pyrazol-5-carboxylic
[1219] [1219] The 5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide (Intermediate P5) (80.5 mg, 0.350 mmol) was dissolved in THF (10 ml) and sodium tert-butoxide (2M in THF) (0.184 ml, 0.367 mmol) was added. After stirring for 1 hour, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (69.7 mg, 0.350 mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. The resulting precipitate was collected by filtration, washed with THF (1 ml), triturated with ethyl acetate (5 ml) for 1 hour, filtered and purified by chromatography (Companion apparatus, RP Flash C18, 13 g column, 0-50 % acetonitrile / 10 mM ammonium bicarbonate). The obtained compound was triturated with TBME (2 ml) for 2 hours, filtered and dried under reduced pressure to generate the title compound (91 mg, 56%) as a white solid. The ring opening occurred during purification.
[1220] [1220] 1H NMR (DMSO-d6) δ 7.58 (s, 1H), 6.77 (s, 1H), 6.44 (s, 1H), 4.72- 4.56 (m, 2H) , 3.57-3.38 (m, 2H), 2.83-2.58 (m, 11H), 1.98-1.82 (m, 4H). Three exchangeable protons not visible.
[1221] [1221] LCMS; m / z 448 (M + H) + (ES +). Example 7: 1- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3 -sulfonamide
[1222] [1222] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N-
[1223] [1223] 1H NMR (DMSO-d6) δ 10.69 (br s, 1H), 7.97 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 6.92 ( s, 1H), 6.70 (d, J = 2.3 Hz, 1H), 4.30 (t, J = 6.5 Hz, 2H), 2.79 (t, J = 7.4 Hz, 4H), 2.73 (t, J = 6.5 Hz, 2H), 2.61 (t, J = 7.4 Hz, 4H), 2.21 (s, 6H), 2.03-1, 87 (m, 4H).
[1224] [1224] LCMS; m / z 418 (M + H) + (ES +), 416 (M-H) - (ES-). Example 8: 1- (2- (Dimethylamino) ethyl) -5 - ((dimethylamino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl ) carbamoyl) -1H-pyrazol-3-sulfonamide
[1225] [1225] Prepared according to the general procedure of 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1- (2- (methylamino) ethyl) - 1H-pyrazol-5-carboxylic (Example 6) of 1- (2- (dimethylamino) ethyl) -5- ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P7) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (40.1 mg, 46%) as a white solid.
[1226] [1226] 1H NMR (DMSO-d6) δ 7.92 (s, 1H), 6.89 (s, 1H), 6.60 (s, 1H), 4.31 (t, J = 6.8 Hz , 2H), 3.51 (s, 2H), 2.83-2.71 (m, 6H), 2.59 (t, J = 7.4 Hz, 4H), 2.26 (s, 6H) , 2.18 (s, 6H), 1.98-1.85 (m, 4H). One exchangeable proton not visible.
[1227] [1227] LCMS; m / z 475 (M + H) + (ES +); 473 (M-H) - (ES-). Example 9: 1- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -5- (2- hydroxypropan-2-yl) -1H-pyrazol-3-sulfonamide
[1228] [1228] Prepared according to the general procedure of 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1- (2- (methylamino) ethyl) - 1H-pyrazol-5-carboxylic (Example 6) of 1- (2- (dimethylamino) ethyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-3- sulfonamide (Intermediate P8) and 4-isocyanate- 1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (23.7 mg, 27%) as a white solid.
[1229] [1229] 1H NMR (DMSO-d6) δ 7.93 (s, 1H), 6.90 (s, 1H), 6.48 (s, 1H), 4.53 (t, J = 7.2 Hz , 2H), 2.85 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.62 (t, J = 7.3 Hz, 4H ), 2.27 (s, 6H), 2.00-1.83 (m, 4H), 1.51 (s, 6H). Two exchangeable protons not visible.
[1230] [1230] LCMS; m / z 476 (M + H) + (ES +); 474 (M-H) - (ES-). Example 10: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -5-methyl- 4,5,6,7-tetrahydropyrazolo [ 1,5-a] pyrazine-2-sulfonamide
[1231] [1231] Prepared according to the general procedure of 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1- (2- (methylamino) ethyl) - 1H-pyrazol-5-carboxylic (Example 6) from 5-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide (Intermediate P9) and 4-isocyanate-1, 2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (16 mg, 26%) as a colorless solid.
[1232] [1232] 1H NMR (DMSO-d6) δ 10.78 (s, 1H), 7.94 (s, 1H), 6.92 (s, 1H), 6.49 (s, 1H), 4.15 (t, J = 5.6 Hz, 2H), 3.60 (s, 2H), 2.88 (t, J = 5.7 Hz, 2H), 2.79 (t, J = 7.4 Hz , 4H), 2.61 (t, J = 7.4 Hz, 4H), 2.39 (s, 3H), 2.05-1.86 (m, 4H).
[1233] [1233] LCMS; m / z 416 (M + H) + (ES +). Example 11: 1 - ((1- (Dimethylamino) cyclopropyl) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H- pyrazol-3-sulfonamide
[1234] [1234] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N-methylacetamide (Example 2) of 1 - ((1- (dimethylamino) cyclopropyl) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P10) and 4-isocyanate-1, 2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (16 mg, 78%) as a colorless solid.
[1235] [1235] 1H NMR (DMSO-d6) δ 10.88 (s, 1H), 7.75 (s, 1H), 7.60 (s, 1H), 6.80 (s, 1H), 6.47 (s, 1H), 4.20 (s, 2H), 2.75 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 2.13 (s, 6H), 1.95-1.85 (m, 4H), 0.69-0.64 (m, 2H), 0.55-0.50 (m, 2H).
[1236] [1236] LCMS; m / z 445 (M + H) + (ES +). Example 12: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-methylazetidin-3-yl) -1H-pyrazole- 3- sulfonamide
[1237] [1237] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 1- (1-methylazetidin-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P11) and 4-isocyanate-1,2 , 3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (25 mg, 25%) as a white solid.
[1238] [1238] 1H NMR (DMSO-d6) δ 11.28-9.98 (br s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 6.89 (s, 1H), 6.70 (d, J = 2.4 Hz, 1H), 5.13 (p, J = 7.0 Hz, 1H), 3.99-3.81 (m, 2H ), 3.66-3.48 (m, 2H), 2.77 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7.4 Hz, 4H), 2.46 (s, 3H), 2.07-1.80 (m, 4H).
[1239] [1239] LCMS; m / z 416 (M + H) + (ES +); 414 (M-H) - (ES-). Example 13: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (2- (methylamino) ethyl) -1H-pyrazol-3 -sulfonamide
[1240] [1240] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 2,2,2-trifluoro-N-methyl-N- (2- (3-sulfamoyl-1H-pyrazol-1-yl) ethyl) acetamide 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) (Intermediate P12) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (5.4 mg, 9%) as a solid colorless.
[1241] [1241] 1H NMR (DMSO-d6) δ 7.75 (d, J = 2.3 Hz, 1H), 7.69 (s, 1H), 6.81 (s, 1H), 6.49 (d , J = 2.3 Hz, 1H), 4.37 (t, J = 6.4 Hz, 2H), 3.19 (t, J = 6.4 Hz, 2H), 2.76 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 2.39 (s, 3H), 1.91 (p, J = 7.4 Hz, 4H). Two exchangeable protons not visible.
[1242] [1242] LCMS; m / z 404 (M + H) + (ES +); 402 (M-H) - (ES-). Example 14: 1- (Azetidin-3-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3- sulfonamide Step A: Benzyl 3- (3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1H-pyrazol-1- il) azetidine-1-carboxylate, sodium salt
[1243] [1243] Benzyl 3- (3-sulfamoyl-1H-pyrazol-1-yl) azetidine-1-carboxylate (Intermediate P13) (283 mg, 0.294 mmol) was dissolved in THF (5 mL) and 2M tert-butoxide sodium in THF (0.368 ml, 0.736 mmol) was added. After 1 hour, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (147 mg, 0.736 mmol) was added and the mixture was stirred at room temperature for 22 hours. The mixture was then concentrated to dryness to produce a yellow solid which was used without further purification in the next step.
[1244] [1244] LCMS; m / z 558.5 (M + Na) + (ES +). Step B: 1- (Azetidin-3-yl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3- sulfonamide
[1245] [1245] Benzyl 3- (3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1H-pyrazol-1-yl ) azetidine-1-carboxylate, sodium salt (162 mg, 0.29 mmol) and 5% Pd / C (61.7 mg) were suspended in EtOH (3 mL) and hydrogenated at 5 bar H2 at room temperature for 17 hours. The reaction showed ~ 50% conversion, so that the mixture was filtered through a pad of Celite® and the filter residue was washed with MeOH (2 x 10 mL). The filtrate was evaporated to dryness, additional 5% Pd / C (61.7 mg) was added and the reaction mixture was stirred under 5 bar H2 at room temperature for 67 hours. The mixture was filtered through a pad of Celite ® and the filter residue was washed with MeOH (2 x 10 mL). The filtrate was evaporated to dryness and purified by preparative reverse phase HPLC (General Methods, basic preparation) to generate the title compound (5 mg, 4%) as a white solid.
[1246] [1246] 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.61 (s, 1H), 6.79 (s , 1H), 6.50 (d, J = 2.3 Hz, 1H), 5.46 (p, J = 7.9 Hz, 1H), 4.37-4.21 (m, 4H), 2 , 75 (t, J = 7.3 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 2.00-1.85 (m, 4H). One exchangeable proton not visible.
[1247] [1247] LCMS; m / z 402.3 (M + H) + (ES +); 400.0 (M-H) - (ES-). Example 15: 1- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -5-isopropyl-1H -pyrazol-3-sulfonamide
[1248] [1248] Prepared according to the general procedure of 3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1- (2- (methylamino) ethyl) - 1H-pyrazol-5-carboxylic (Example 6) of 1- (2- (dimethylamino) ethyl) -5-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P14) and 4- isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (47 mg, 39%) as a white solid.
[1249] [1249] 1H NMR (DMSO-d6) δ 11.28-9.98 (br s, 1H), 7.94 (s, 1H), 6.91 (s, 1H), 6.52 (s, 1H ), 4.20 (t, J = 6.8 Hz, 2H), 3.09 (sept, J = 6.8 Hz, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.70 (t, J = 6.8 Hz, 2H), 2.60 (t, J = 7.4 Hz, 4H), 2.20 (s, 6H), 1.93 (p, J = 7 , 4 Hz, 4H), 1.21 (d, J = 6.8 Hz, 6H).
[1250] [1250] LCMS; m / z 460.5 (M + H) + (ES +); 458.3 (M-H) - (ES-). Example 16: 1- (2- (Dimethylamino) ethyl) -N - ((4-fluoro-2,6-diisopropyl-phenyl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1251] [1251] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N-methylacetamide (Example 2) of 1- (2- (dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P6) and 5-fluoro-2-isocyanate-1 , 3-diisopopylbenzene (Intermediate A2) to generate the title compound (30 mg, 29%) as a colorless solid.
[1252] [1252] 1H NMR (DMSO-d6) δ 10.90 (br s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.80 (s, 1H), 6.91 ( d, J = 9.9 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.02-2, 90 (m, 2H), 2.73 (t, J = 6.5 Hz, 2H), 2.22 (s, 6H), 1.05 (br s, 12H).
[1253] [1253] LCMS; m / z 440.3 (M + H) + (ES +). Example 17: 1- (1- (Dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl ) -1H-pyrazol-3-sulfonamide
[1254] [1254] Sodium tert-butoxide (2 M in THF) (0.23 mL, 0.460 mmol) was added to a solution of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -1H-pyrazole - 3-sulfonamide (Intermediate P15) (107 mg, 0.434 mmol) in THF (6 mL) and stirred at room temperature for 1 hour. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (95 mg, 0.478 mmol) was added and the reaction mixture was stirred at room temperature during night. The reaction mixture was concentrated and the crude product was purified by chromatography on RP Flash C18 (13 g cartridge, 5-50% MeCN / 10 mM ammonium bicarbonate) to generate the title compound (117 mg, 59%) as a colorless solid.
[1255] [1255] 1H NMR (DMSO-d6) δ 10.79 (s, 1H), 8.03-7.91 (m, 2H), 6.93 (s, 1H),
[1256] [1256] LCMS; m / z 446 (M + H) + (ES +). Example 18: (S) -1- (2- (Dimethylamino) propyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H -pyrazol-3-sulfonamide
[1257] [1257] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N- methylacetamide (Example 2) of (S) -1- (2- (dimethylamino) propyl) -1H-pyrazol-3-sulfonamide (Intermediate P16) and 4-isocyanate-1 , 2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (57 mg, 48%) as a white solid.
[1258] [1258] 1H NMR (DMSO-d6) δ 7.95 (s, 1H), 7.88 (d, J = 2.3 Hz, 1H), 6.91 (s, 1H), 6.69 (d , J = 2.4 Hz, 1H), 4.28 (dd, J = 13.7, 7.1 Hz, 1H), 4.11 (dd, J = 13.8, 6.9 Hz, 1H) , 3.16-3.08 (m, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7.3 Hz, 4H), 2.22 ( s, 6H), 1.94 (p, J = 7.4 Hz, 4H), 0.85 (d, J = 6.6 Hz, 3H). One exchangeable proton not visible.
[1259] [1259] LCMS; m / z 432.4 (M + H) + (ES +). Example 19: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - (((1-methylazetidin-3-yl) methyl) -1H -pyrazol-3-sulfonamide
[1260] [1260] Prepared according to the general procedure of 2- (3- (N-
[1261] [1261] 1H NMR (DMSO-d6) δ 7.83 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 6.82 (s, 1H), 6.49 (d , J = 2.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.86-3.77 (m, 2H), 3.72-3.62 (m, 2H), 3.12-3.00 (m, 1H), 2.75 (t, J = 7.4 Hz, 4H), 2.62 (t, J = 7.4 Hz, 4H), 2, 41 (s, 3H), 1.91 (p, J = 7.4 Hz, 4H). One exchangeable proton not visible.
[1262] [1262] LCMS; m / z 430.4 (M + H) + (ES +). Example 20: (S) -N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((1-methylazetidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[1263] [1263] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) of (S) -1 - ((1-methylazetidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P18) and 4- isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (24 mg, 23%) as a white solid.
[1264] [1264] 1H NMR (DMSO-d6) δ 10.63 (s, 1H), 7.92 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 6.89 (s , 1H), 6.67 (d, J = 2.3 Hz, 1H), 4.29 (d, J = 5.8 Hz, 2H), 3.51 (p, J = 6.2 Hz, 1H ), 3.38-3.28 (m, 1H), 2.88 (q, J = 8.3 Hz, 1H), 2.77 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7.4 Hz, 4H), 2.09 (s, 3H), 2.01-1.82 (m, 6H).
[1265] [1265] LCMS; m / z 430.4 (M + H) + (ES +). Example 21: (R) -N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((1-methylpyrrolidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[1266] [1266] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from (R) -1 - ((1-methylpyrrolidin-2-yl) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P19) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (96 mg, 59%) as a white solid.
[1267] [1267] 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 7.88 (d, J = 2.3 Hz, 1H), 6.91 (s, 1H), 6.68 (d , J = 2.3 Hz, 1H), 4.27 (dd, J = 13.7, 5.0 Hz, 1H), 4.14 (dd, J = 13.7, 6.5 Hz, 1H), 3 .00-2.94 (m, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.74-2.66 (m, 1H), 2.60 (t, J = 7 , 4 Hz, 4H), 2.27-2.19 (m, 1H), 2.23 (s, 3H), 1.93 (p, J = 7.4 Hz, 4H), 1.79-1 , 66 (m, 1H), 1.65-1.46 (m, 3H). One exchangeable proton not visible.
[1268] [1268] LCMS; m / z 444.4 (M + H) + (ES +). Example 22: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- (pyrimidin-2-ylmethyl) -1H-pyrazol-3- sulfonamide
[1269] [1269] Sodium tert-butoxide (2M in THF) (0.033 mL, 0.066 mmol) was added to a solution of 1- (pyrimidin-2-ylmethyl) -1H-pyrazol-3-sulfonamide (Intermediate P20) (15 mg , 0.063 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (14 mg, 0.070 mmol) was added and the reaction mixture was stirred at room temperature during night. The volatiles were evaporated and the crude product was purified by preparative reverse phase HPLC (Methods
[1270] [1270] 1H NMR (DMSO-d6) δ 10.81 (br s, 1H), 8.79 (d, J = 4.9 Hz, 2H), 8.04 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.48 (t, J = 4.9 Hz, 1H), 6.92 (s, 1H), 6.77 (d, J = 2.4 Hz, 1H), 5.66 (s, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 1.92 (p, J = 7.4 Hz, 4H).
[1271] [1271] LCMS; m / z 439.4 (M + H) + (ES +). Example 23: 1- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1H-imidazole-4 -sulfonamide
[1272] [1272] To a solution of 1- (2- (dimethylamino) ethyl) -1H-imidazol-4-sulfonamide (Intermediate P21) (105 mg, 0.481 mmol) in THF (2.5 mL) was added tert-butoxide sodium (2M in THF) (0.3 ml, 0.600 mmol) and the reaction mixture was stirred at room temperature for 1 hour. 4-Isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (105 mg, 0.527 mmol) in THF (2.5 mL) was added and the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo, the residue dissolved in DMSO (2 ml) and purified by preparative HPLC to generate the title compound (44 mg, 22%) as a white solid.
[1273] [1273] 1H NMR (DMSO-d6) δ 8.06 (s, 1H), 7.93 (d, J = 1.3 Hz, 1H), 7.86 (d, J = 1.3 Hz, 1H ), 6.92 (s, 1H), 4.11 (t, J = 6.2 Hz, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.63-2.55 (m, 6H), 2.17 (s, 6H), 1.94 (p, J = 7.4 Hz, 4H). One exchangeable proton not visible.
[1274] [1274] LCMS; m / z 418.4 (M + H) + (ES +). Example 24: 1-Cyclopropyl-5 - ((dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazole-3 -sulfonamide O O
[1275] [1275] To a solution of 1-cyclopropyl-5 - ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P22) (4.5 g, 18.42 mmol, 1 eq) in THF (50 mL ) t-BuONa (1.86 g, 19.34 mmol, 1.05 eq) was added. Then 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (3.67 g, 18.42 mmol, 1 eq) was added. The reaction mixture was stirred at 70 ° C for 10 minutes and then concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (column: Synergi Max-RP; 250mm * 50mm * 10µm; mobile phase: [water (10 mM NH4HCO3) -MeCN]; B%: 5% -35%, 20 minutes) to produce the title compound (5.1 g, 61.8% yield, 99% HPLC purity, free acid) as a white solid.
[1276] [1276] 1H NMR (DMSO-d6) δ 8.00 (s, 1 H), 6.93 (s, 1 H), 6.66 (s, 1 H), 3.82-3.78 (m , 1 H), 3.61 (s, 2 H), 2.80-2.76 (m, 4 H), 2.59-2.55 (m, 4 H), 2.21 (s, 6 H), 1.97-1.89 (m, 4 H) and 1.11-1.04 (m, 4 H).
[1277] [1277] LCMS: m / z 444.2 (M + H) + (ES +). Example 24B: 1-Cyclopropyl-5 - ((dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3 -sulfonamide, sodium salt O O O O N Y N Y N HN N HN HN HN
[1278] [1278] To a solution of 1-cyclopropyl-5 - ((dimethylamino) methyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 24) (3.7 g, 8.34 mmol, 1 eq) in THF (50 ml) t-BuONa (801 mg, 8.34 mmol, 1 eq) was added. The reaction mixture was stirred at 25 ° C for 1 hour and then concentrated in vacuo. The residue was triturated with TBME (25 ml). Then the mixture was filtered to yield the title compound. The title compound combined with another batch (3.7 g) obtained in parallel was redissolved in H 2O (300 ml) and lyophilized to produce the title compound (6.8 g, 87.36% yield, 100% yield). HPLC purity, sodium salt) as a white solid.
[1279] [1279] 1H NMR (DMSO-d6) δ 7.53 (s, 1 H), 6.76 (s, 1 H), 6.31 (s, 1 H), 3.65-3.61 (m , 1 H), 3.49 (s, 2 H), 2.76-2.72 (m, 4 H), 2.65-2.60 (m, 4 H), 2.18 (s, 6 H), 1.92-1.86 (m, 4 H), 1.08-1.05 (m, 2 H), 0.95-0.93 (m, 2 H).
[1280] [1280] LCMS: m / z 444.2 (M + H) + (ES +). Example 25: 1- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) -1H-1,2 , 3-triazole-4-sulfonamide, sodium salt
[1281] [1281] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N, N-dimethylacetamide, sodium salt (Example 1) of 1- (2- (dimethylamino) ethyl) -1H-1,2,3-triazole-4-sulfonamide (Intermediate 23) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (53 mg, 49%) as a white solid.
[1282] [1282] 1H NMR (DMSO-d6) δ 8.19 (s, 1H), 7.50 (s, 1H), 6.77 (s, 1H), 4.44 (t, J = 6.2 Hz , 2H), 2.75 (t, J = 7.4 Hz, 4H), 2.69 - 2.62 (m, 6H), 2.18 (s, 6H), 1.90 (p, J = 7.4 Hz, 4H). NH missing.
[1283] [1283] LCMS; m / z 419.5 (M + H) + (ES +). Example 26: 1- (2- (Dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H -pyrazol-3-sulfonamide
[1284] [1284] 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A3) (100 mg, 0.416 mmol) was dissolved in dry THF (5 mL) . Triethylamine (70 µL, 0.502 mmol) was added, followed by a solution of bis (trichloromethyl) carbonate (123 mg, 0.416 mmol) in THF (1 mL). The slurry was stirred at room temperature for two hours before being filtered. The solid was washed with THF (5 ml) and DCM (5 ml) and then the filtrate was concentrated in vacuo to yield 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) - 2-methoxypyridine as a pale yellow solid that was used without further purification.
[1285] [1285] 1- (2- (Dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide (45 mg, 0.206 mmol) (Intermediate P6) was dissolved in dry THF (2 mL). Sodium tert-butoxide (2M in THF) (104 µL, 0.208 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A solution of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (55 mg, 0.205 mmol) in DMF (2 mL) was added and the mixture was stirred during the night. THF was removed in vacuo. DMSO (1 ml) was added and the resulting solution was purified by preparative reverse phase HPLC (General Methods, basic preparation) to generate the title compound (16 mg, 16%) as a colorless powder.
[1286] [1286] 1H NMR (DMSO-d6) δ 10.70 (br s, 1H), 8.12 (dd, J = 5.3, 0.7 Hz, 1H), 7.88 (d, J = 2 , 4 Hz, 1H), 7.86 (s, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6, 87 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 - 6.71 (m, 1H), 6.58 (d, J = 2.4 Hz, 1H), 4.31 (t, J = 6.5 Hz, 2H), 3.89 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 6.7 Hz , 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.23 (s, 6H), 1.99 (p, J = 7.5 Hz, 2H).
[1287] [1287] LCMS; m / z 485.4 (M + H) + (ES +); 483.3 (M-H) - (ES-). Example 27: 1- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) -1H-1,2 , 4-triazole-3-sulfonamide
[1288] [1288] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N-
[1289] [1289] 1H NMR (DMSO-d6) δ 10.73 (s, 1H), 8.67 (s, 1H), 7.97 (s, 1H), 6.89 (s, 1H), 4.41 (t, J = 6.3 Hz, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.65 (t , J = 7.4 Hz, 4H), 2.31 (s, 6H), 1.94 (p, J = 7.4 Hz, 4H).
[1290] [1290] LCMS; m / z 419.4 (M + H) + (ES +). Example 28: 1- (2- (Dimethylamino) ethyl) -N - ((7-fluoro-5- (pyridin-3-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1291] [1291] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 26) from 1- (2- (dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P6) and 7-fluoro-5- (pyridin-3-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A4) to generate the title compound (3.1 mg, 4%) as a colorless powder.
[1292] [1292] 1H NMR (DMSO-d6) δ 8.55 (dd, J = 4.8, 1.7 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.83 (s, 1H), 7.73 - 7.68 (m, 1H), 7.40 (dd, J = 7.9, 4.9 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 4.33 (t, J = 6.5 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H) , 2.26 (s, 6H), 2.06 (p, J = 7.4 Hz, 2H). NH not observed.
[1293] [1293] LCMS; m / z 473.4 (M + H) + (ES +); 471.0 (M-H) - (ES-). Example 29: 1- (2- (Dimethylamino) ethyl) -N - ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1294] [1294] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 26) from 1- (2- (dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P6) and 7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A5) to generate the title compound (4.1 mg, 6%) as a colorless powder.
[1295] [1295] 1H NMR (DMSO-d6) δ 10.60 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H ), 7.85 (s, 1H), 7.00 (d, J = 9.2 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 4.32 (t, J = 6.5 Hz, 2H), 3.89 (s , 3H), 2.95 (t, J = 7.4 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H ), 2.26 (s, 6H), 2.05 (p, J = 7.6 Hz, 2H).
[1296] [1296] LCMS; m / z 503.5 (M + H) + (ES +); 501.2 (M-H) - (ES-). Example 30: 1- (2- (Dimethylamino) ethyl) -N - ((4-fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1297] [1297] To a solution of 4-fluoro-2-isopropyl-6- (pyridin-3-yl) aniline (Intermediate A6) (0.5 g, 2.17 mmol) and TEA (439 mg, 4.34 mmol ) in THF (10 mL) triphosgene (257 mg, 868.51 µmol) 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 dissolved in EtOAc (100 ml) and the resulting mixture was filtered. The filtrate was concentrated in vacuo to produce intermediate 3- (5-fluoro-2-isocyanate-3-isopropylphenyl) pyridine (0.2 g, crude) as a yellow oil.
[1298] [1298] To a solution of 1- (2- (dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P6) (100 mg, 458.14 µmol) in THF (10 mL) was added MeONa (29 mg , 549.76 µmol) and 3- (5-fluoro-2-isocyanate-3-isopropylphenyl) pyridine (129 mg, 503.95 µmol). Then the solution was stirred at 70 ° C for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative reversed-phase HPLC (General Methods, basic preparation) to generate the title compound (20 mg, 9%) as a yellow solid.
[1299] [1299] 1H NMR (DMSO-d6) δ 8.51 - 8.48 (m, 2H), 7.70 (s, 2H), 7.49 (s, 1H), 7.29 - 7.26 ( m, 1H), 7.11 (dd, J = 2.8, 10.0 Hz, 1H), 6.97 (dd, J = 2.8, 9.2 Hz, 1H), 6.28 (s, 1H ), 4.20 (t, J = 6.8 Hz, 2H), 3.16 - 3.10 (m, 1H), 2.65 (t, J = 6.8 Hz, 2H), 2.18 (s, 6H), 1.08 (d, J = 6.8 Hz, 6H).
[1300] [1300] LCMS; m / z 475.2 (M + H) + (ES +). Example 31: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (1-methylazetidin-4-yl) -1H-pyrazole- 3- sulfonamide
[1301] [1301] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-sulfonamide (Intermediate P25) and 4-isocyanate-1,2 , 3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (22 mg, 25%) as a white solid.
[1302] [1302] 1H NMR (DMSO-d6) δ 10.55 (bs, 1H), 7.91 (s, 2H), 6.89 (s, 1H), 6.66 (d, J = 2.4 Hz , 1H), 4.31 - 4.21 (m, 1H), 3.00 (d, J = 11.7 Hz, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2 , 60 (t, J = 7.4 Hz, 4H), 2.34 (s, 3H), 2.32 - 2.23 (m, 2H), 2.06 - 1.97 (m, 4H), 1.93 (t, J = 7.3 Hz, 4H).
[1303] [1303] LCMS; m / z 444.6 (M + H) + (ES +). Example 32: 1- (3- (Dimethylamino) propyl) -N - ((1,2,3,5,6,7-hexahydro-s-
[1304] [1304] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 1- (3- (dimethylamino) propyl) -1H-pyrazol-3-sulfonamide (Intermediate P26) and 4-isocyanate - 1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (52 mg, 55%) as a colorless solid.
[1305] [1305] 1H NMR (DMSO-d6) δ 7.86 - 7.75 (m, 2H), 6.86 (s, 1H), 6.59 (d, J = 2.3 Hz, 1H), 4 , 20 (t, J = 6.9 Hz, 2H), 2.77 (t, J = 7.4 Hz, 4H), 2.62 (t, J = 7.3 Hz, 4H), 2.35 (s, 6H), 2.13 - 1.83 (m, 6H). NH was not observed and a CH2 was under the water signal.
[1306] [1306] LCMS; m / z 432.3 (M + H) + (ES +). Example 33: 1- (2-Cyanopropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazole- 3-sulfonamide
[1307] [1307] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) of 1- (2-cyanopropan-2-yl) -1H-pyrazol-3-sulfonamide (Intermediate P27) and 4-isocyanate-1,2,3 , 5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (34 mg, 28%) as a colorless solid.
[1308] [1308] 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.94 (s, 1H), 6.90 (s , 1H), 6.82 (d, J = 2.6 Hz, 1H), 3.32 (s, 6H), 2.78 (t, J = 7.4 Hz, 4H),
[1309] [1309] LCMS; m / z 414.3 (M + H) + (ES +). Example 34: 1- (Cyanomethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1310] [1310] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) of 1- (cyanomethyl) -1H-pyrazol-3-sulfonamide (Intermediate P28) and 4-isocyanate-1,2,3,5,6,7 -hexa-hydro-s-indacene (Intermediate A1) to generate the title compound (33 mg, 33%) as a colorless powder.
[1311] [1311] 1H NMR (DMSO-d6) δ 7.94 (d, J = 2.4 Hz, 1H), 7.85 (s, 1H), 6.88 (s, 1H), 6.71 (d , J = 2.4 Hz, 1H), 5.58 (s, 2H), 2.77 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H ), 1.93 (p, J = 7.4 Hz, 4H). NH not observed.
[1312] [1312] LCMS; m / z 386 (M + H) + (ES +); 384 (M-H) - (ES-). Example 35: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (oxazol-2-ylmethyl) -1H-pyrazol-3- sulfonamide
[1313] [1313] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 1- (oxazol-2-ylmethyl) -1H-pyrazol-3-sulfonamide (Intermediate P29) and 4-isocyanate-1,2,3 , 5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (27 mg, 25%) as a white solid.
[1314] [1314] 1H NMR (DMSO-d6) δ 8.11 (d, J = 0.9 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.24 (d , J = 0.9 Hz, 1H), 6.89 (s, 1H), 6.70 (s, 1H), 5.62 (s, 2H), 2.78 (t, J = 7.4 Hz , 4H), 2.59 (t, J = 7.4 Hz, 4H), 1.93 (p, J = 7.4 Hz, 4H). NH not observed.
[1315] [1315] LCMS; m / z 428 (M + H) + (ES +); 426 (M-H) - (ES-). Example 36: N - (((5-Bromo-2,3-dihydro-1H-inden-4-yl) carbamoyl) -5- ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide
[1316] [1316] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P30) and 5-bromo- 2,3-dihydro-1H-inden-4-amine (Intermediate A3, Step B) to generate the title compound (24 mg, 24%) as a colorless powder.
[1317] [1317] 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 8.09 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.65 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.52 (s, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.18 (s, 6H), 1.92 (p, J = 7.6 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).
[1318] [1318] LCMS; m / z 470.3 / 472.3 (M + H) + (ES +); 468.4 / 470.2 (M-H) - (ES-). Example 37: 5 - ((Dimethylamino) methyl) -1-ethyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1319] [1319] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 26) from 5- ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P30) and 5- (2 -
[1320] [1320] 1H NMR (DMSO-d6) δ 10.81 (s, 1H), 8.13 (dd, J = 5.3, 0.7 Hz, 1H), 7.92 (s, 1H), 7 , 22 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 5.3, 1.5 Hz, 1H) , 6.73 - 6.71 (m, 1H), 6.56 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3, 50 (s, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.17 (s, 6H), 1, 96 (p, J = 7.5 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).
[1321] [1321] LCMS; m / z 499.4 (M + H) + (ES +); 497.3 (M-H) - (ES-). Example 38: ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) ((1-isopropyl- 5- (1- (trimethylammonium) ethyl) -1H- pyrazol-3-yl) sulfonyl) amide
[1322] [1322] Sodium tert-butoxide (2 M in THF) (0.24 mL, 0.480 mmol) was added to a solution of 1- (1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) -N , N, N-trimethylethanamine trifluoroacetate (Intermediate P31) (90 mg, 0.233 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (51.1 mg, 0.256 mmol) was added and stirred at room temperature overnight. 4-Isocyanate-1,2,3,5,6,7-hexahydro-s-indacene- (Intermediate A1) (51.1 mg, 0.256 mmol) was added and the mixture was stirred for 24 hours. The volatiles were evaporated and the residue was dissolved in DMSO (2 ml), filtered and purified by preparative reversed-phase HPLC (General Methods, basic preparation) to generate the title compound (35 mg, 31%) as a white solid.
[1323] [1323] 1H NMR (DMSO-d6) δ 7.44 (s, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 5.07 (q, J = 6.8 Hz , 1H), 4.97 - 4.85 (m, 1H), 3.01 (s, 9H), 2.75 (t, J = 7.4 Hz, 4H), 2.67 - 2.57 ( m, 4H), 1.96 - 1.81 (m, 4H), 1.69 (d, J = 6.8 Hz, 3H), 1.50 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.3 Hz, 3H).
[1324] [1324] LCMS; m / z 474.5 (M + H) + (ES +). Example 39: ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) ((1-methyl-5-
[1325] [1325] Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) ((1-isopropyl-5- (1- (trimethylammonium) ethyl) -1H-pyrazol-3-yl) sulfonyl) amide (Example 38) from N, N, N-trimethyl-1- (1-methyl-3-sulfamoyl-1H-pyrazol-5-yl ) ethan-1-aminium-2,2,2-trifluoroacetate (Intermediate P32) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the compound of the title (27 mg, 37%) as a white solid.
[1326] [1326] 1H NMR (DMSO-d6) δ 7.45 (s, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 4.99 (q, J = 6.8 Hz , 1H), 3.93 (s, 3H), 3.01 (s, 9H), 2.75 (t, J = 7.4 Hz, 4H), 2.72 - 2.57 (m, 4H) , 1.98 - 1.80 (m, 4H), 1.68 (d, J = 6.8 Hz, 3H).
[1327] [1327] LCMS; m / z 446.5 (M + H) + (ES +). Example 40: 5 - ((Dimethylamino) methyl) -1-ethyl-N - (((7-fluoro-5- (pyridin-3-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1328] [1328] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P30) and 7-fluoro- 5- (pyridin-3-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A4) to generate the title compound (5 mg, 6%) as a colorless powder.
[1329] [1329] 1H NMR (DMSO-d6) δ 10.83 (s, 1H), 8.56 (dd, J = 4.8, 1.6 Hz, 1H), 8.50 (d, J = 2, 2 Hz, 1H), 7.90 (s, 1H), 7.72 - 7.68 (m, 1H), 7.43 - 7.39 (m, 1H), 7.03 (d, J = 9 , 2 Hz, 1H), 6.54 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 2.95 (t, J = 7 , 4 Hz, 2H), 2.68 (t, J = 7.3 Hz, 2H), 2.18 (s, 6H), 2.03 (p, J = 7.6 Hz, 2H), 1, 36 (t, J = 7.2 Hz, 3H).
[1330] [1330] LCMS; m / z 487.5 (M + H) + (ES +); 485.3 (M-H) - (ES-). Example 41: 5 - ((Dimethylamino) methyl) -1-ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4- il) carbamoyl) -1H-pyrazol-3-sulfonamide
[1331] [1331] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 26) from 5- ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P30) and 7-fluoro- 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A5) to generate the title compound (5 mg, 7%) as a colorless powder.
[1332] [1332] 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.90 (s, 1H), 7.02 (d , J = 9.2 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (s, 1H), 6.56 (s, 1H), 4 , 22 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3.51 (s, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2 , 66 (t, J = 7.1 Hz, 2H), 2.18 (s, 6H), 2.02 (p, J = 7.6 Hz, 2H), 1.35 (t, J = 7, 2 Hz, 3H).
[1333] [1333] LCMS; m / z 517.4 (M + H) + (ES +); 515.3 (M-H) - (ES-). Example 42: 1-Cyclopropyl-5- (1- (dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H -pyrazol-3-sulfonamide
[1334] [1334] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 1-cyclopropyl-5- (1- (dimethylamino) ethyl) - 1Hpyrazol-3-sulfonamide (Intermediate P33) and 4-isocyanate-1 , 2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (83 mg, 52%)
[1335] [1335] 1H NMR (DMSO-d6) δ 10.76 (s, 1H), 8.00 (s, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 4.09 (q, J = 6.8 Hz, 1H), 3.92 - 3.84 (m, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.56 (t, J = 7.4 Hz, 4H), 2.17 (s, 6H), 1.93 (p, J = 7.4 Hz, 4H), 1.29 (d, J = 6.8 Hz, 3H), 1 , 22 - 1.14 (m, 1H), 1.08 - 0.97 (m, 3H).
[1336] [1336] LCMS; m / z 458.5 (M + H) + (ES +). Example 43: 5- (1- (Azetidin-1-yl) propyl) -1-cyclopropyl-N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1337] [1337] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 5- (1- (azetidin-1-yl) propyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide (Intermediate P34) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (42 mg, 36%) as a white solid.
[1338] [1338] 1H NMR (DMSO-d6) δ 10.77 (s, 1H), 7.98 (s, 1H), 6.91 (s, 1H), 6.58 (s, 1H), 3.96 - 3.87 (m, 1H), 3.81 - 3.73 (m, 1H), 3.16 (q, J = 6.9 Hz, 2H), 3.09 (q, J = 6.9 Hz, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.56 (t, J = 7.4 Hz, 4H), 2.00 - 1.87 (m, 6H), 1.77 - 1.63 (m, 1H), 1.63 - 1.49 (m, 1H), 1.20 - 1.12 (m, 1H), 1.12 - 1.01 (m, 3H ), 0.69 (t, J = 7.4 Hz, 3H).
[1339] [1339] LCMS; m / z 484.5 (M + H) + (ES +). Example 44: 1-Cyclopropyl-5- (1- (dimethylamino) propyl) - N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide
[1340] [1340] Prepared according to the general procedure of 2- (3- (N-
[1341] [1341] 1H NMR (DMSO-d6) δ 10.77 (s, 1H), 7.99 (s, 1H), 6.92 (s, 1H), 6.66 (s, 1H), 3.90 (dd, J = 9.3, 5.3 Hz, 1H), 3.87 - 3.79 (m, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.55 ( t, J = 7.4 Hz, 4H), 2.16 (s, 6H), 1.92 (p, J = 7.4 Hz, 4H), 1.88 - 1.78 (m, 1H), 1.77 - 1.63 (m, 1H), 1.20 - 0.98 (m, 4H), 0.78 (t, J = 7.3 Hz, 3H).
[1342] [1342] LCMS; m / z 472.4 (M + H) + (ES +). Example 45: 5- (1- (Azetidin-1-yl) ethyl) -1-cyclopropyl-N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1343] [1343] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 5- (1- (azetidin-1-yl) ethyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide (Intermediate P36) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (11 mg, 12%) as a white solid.
[1344] [1344] 1H NMR (DMSO-d6) δ 10.80 (s, 1H), 7.96 (s, 1H), 6.91 (s, 1H), 6.55 (s, 1H), 3.92 - 3.79 (m, 2H), 3.24 - 3.05 (m, 4H), 2.78 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 2.01 - 1.87 (m, 6H), 1.19 (d, J = 6.5 Hz, 3H), 1.15 - 1.02 (m, 4H).
[1345] [1345] LCMS; m / z 470.4 (M + H) + (ES +). Example 46: 5- (1- (Azetidin-1-yl) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -methyl-1H-pyrazol-3-sulfonamide, sodium salt (Enantiomer 1)
[1346] [1346] To a solution of 5- (1- (azetidin-1-yl) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide, enantiomer B (Intermediate P38) (3.4 g, 13.92 mmol , 1 eq.) In THF (100 ml) and DMF (13 ml) was added t-BuONa (2 M, 6.96 ml, 1 eq) and the reaction mixture was stirred for 20 minutes. Then, a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (2.77 g, 13.92 mmol, 1 eq) was added in THF (20 mL). The mixture was stirred at 25 ° C for 20 minutes. LCMS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated in vacuo. The residue was triturated with MTBE (150 ml) and a solid was formed. The mixture was filtered. The filter residue was purified by preparative reverse phase HPLC (General Methods, basic preparation) to generate the title compound (2.77 g, 43%) as a white solid.
[1347] [1347] 1H NMR (DMSO-d6) δ 8.03 (s, 1H), 6.93 (s, 1 H), 6.61 (s, 1 H), 3.93 (s, 3 H), 3.78-3.74 (m, 1 H), 3.23-3.13 (m, 4 H), 2.81-2.77 (t, 4 H), 2.61-2.57 ( m, 4 H), 1.98-1.92 (m, 6 H), 1.16 (d, 3 H).
[1348] [1348] LCMS m / z 444.2 (M + H) + (ES +). Step B: 5- (1- (Azetidin-1-yl) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -methyl-1H-pyrazol-3-sulfonamide, sodium salt (Enantiomer 1)
[1349] [1349] To a solution of 5- (1- (azetidin-1-yl) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide (Enantiomer 1) (3.5 g, 7.89 mmol, 1 eq, free acid) in THF (20 mL) was added a solution of t-BuONa in THF (2M, 3.95 mL, 1 eq). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was triturated with MBTE (100 ml). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was combined with another batch of product (350 mg, crude) and redissolved in H 2 O and lyophilized to produce the title compound (2.96 g, 69%) as a light yellow solid.
[1350] [1350] 1H NMR (DMSO-d6) δ 7.58 (s, 1H), 6.77 (s, 1H), 6.24 (s, 1H), 3.80 (s, 3H), 3.56 - 3.50 (m, 1H), 3.09 - 3.00 (m, 4H), 2.75 - 2.71 (m, 4H), 2.63 - 2.60 (m, 4H), 1 , 91 - 1.86 (m, 6H), 1.09 (d, J = 6.0 Hz, 3H).
[1351] [1351] LCMS; m / z 444.2 (M + H) + (ES +). Example 47: 5- (1- (Azetidin-1-yl) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -methyl-1H-pyrazol-3-sulfonamide, sodium salt (Enantiomer 2) Enantiomer 2, sodium salt Step A: 5- (1- (Azetidin-1-yl) ethyl) -N - ((1,2,3, 5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide (Enantiomer 2) enantiomer A enantiomer 2, free acid
[1352] [1352] A solution of sodium tert-butoxide in THF (2 M, 3.27 mL) was added to a solution of 5- (1- (azetidin-1-yl) ethyl) -1-methyl-1H-pyrazole Sulfonamide, enantiomer A (Intermediate P37) (1.6 g, 6.55 mmol) in THF (20 ml) and DMF (20 ml) at 20 ° C. The reaction was stirred for 10 minutes at 20 ° C, before a solution of 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (913 mg, 4, 58 mmol, 0.7 eq) in THF (12 mL) was added dropwise. The resulting mixture was stirred at 20 ° C for 1 hour. The reaction mixture was diluted with MTBE (96 ml) and the solid was filtered and purified by preparative reversed-phase HPLC (General Methods, basic preparation) to generate the title compound (581 mg, 20%) as a white solid.
[1353] [1353] 1H NMR (DMSO-d6) δ 8.03 (s, 1H), 6.93 (s, 1 H), 6.61 (s, 1 H), 3.93 (s, 3 H), 3.78-3.74 (m, 1 H), 3.23-3.13 (m, 4 H), 2.81-2.77 (t, 4 H), 2.61-2.57 ( m, 4 H), 1.98-1.92 (m, 6 H), 1.16 (d, 3 H).
[1354] [1354] LCMS: m / z 444.2 (M + H) + (ES +). Step B: 5- (1- (Azetidin-1-yl) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -methyl-1H-pyrazol-3-sulfonamide, sodium salt (Enantiomer 2) enantiomer 2, free acid enantiomer 2, sodium salt
[1355] [1355] To a solution of 5- (1- (azetidin-1-yl) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide (Enantiomer 2) (950 mg, 2.10 mmol) in THF (20 mL) a solution of t-BuONa in THF (2 M, 1.05) was added mL). The mixture was stirred at 20 ° C for 1 hour and then concentrated in vacuo. The residue was triturated with MTBE (30 ml) and the solid was filtered. The filter residue was redissolved in THF (20 ml) and the resulting solution was added dropwise to 60 ml MTBE. Some precipitate formed at the same time. The suspension was filtered to yield the title compound (760 mg) as an off-white solid. The product combined with another batch of product (200 mg) was redissolved in deionized water (40 ml) and then lyophilized to produce the title compound (841 mg, 78%).
[1356] [1356] 1H NMR (DMSO-d6) δ 7.57 (s, 1 H), 6.77 (s, 1 H), 6.25 (s, 1 H), 3.81 (s, 3 H) , 3.55 - 3.52 (m, 1), 3.11 3.01 (m, 4 H), 2.76 - 2.73 (m, 4 H), 2.64 - 2.61 ( m, 4 H), 1.93 -1.86 (m, 6 H), 1.10 (d, J = 6.4 Hz, 3H).
[1357] [1357] LCMS m / z 444.2 (M + H) + (ES +). Example 48: 4- (2- (3 - ((5 - ((Dimethylamino) methyl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) ureido) -5-fluoro-3-isopropylphenyl) picolinamide
[1358] [1358] 4- (2-Amino-5-fluoro-3-isopropylphenyl) picolinonitrile (Intermediate A12) (0.05 g, 0.196 mmol) was dissolved in dry THF (2 mL). Triethylamine (0.030 ml, 0.215 mmol) and a solution of bis (trichloromethyl) carbonate (0.058 g, 0.196 mmol) in THF (1 ml) was added. The thick, opaque mixture was stirred for two hours. The THF was removed in vacuo and the mixture was suspended in toluene (10 ml) and filtered through a phase separator cartridge washing with toluene (10 ml). After concentration in vacuo, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile was isolated as a yellow oil which was used without further purification. The isocyanate was dissolved in dry THF (2 ml).
[1359] [1359] A suspension of 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) (0.043 g, 0.196 mmol) in dry THF (2 mL) was treated with sodium hydride (10 mg, 0.250 mmol), which had previously been washed with isohexanes (5 mL) to remove the silicone oil. The suspension was stirred at room temperature for 30 minutes, before the previously prepared solution of 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile was added in a single portion. The reaction mixture was stirred at room temperature overnight. The THF was removed in vacuo and the residue was dissolved in DMSO (2 ml) and then purified by preparative reversed-phase HPLC (General Methods, basic preparation). After concentration of the product containing fractions, the title compound (16 mg, 15%) was isolated as a colorless powder. Hydrolysis of nitrile occurred during the reaction.
[1360] [1360] 1H NMR (DMSO-d6) δ 10.86 (s, 1H), 8.53 (d, J = 5.0 Hz, 1H), 8.16 (d, J = 2.7 Hz, 1H), 7.96 (s, 2H), 7.69 (s, 1H), 7.49 (dd, J = 5.1, 1.8 Hz, 1H), 7.25 (dd, J = 10.1, 3.0 Hz, 1H), 7.10 (dd, J = 8.8, 2.9 Hz, 1H), 6.41 (s, 1H), 3.86 (s, 3H), 3.47 (s, 2H), 3.17 - 2.96 (m, 1H), 2.16 (s, 6H), 1.11 (br s, 6H).
[1361] [1361] LCMS; m / z 518.4 (M + H) + (ES +); 516.3 (M-H) - (ES-). Example 49: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-5- (1- (3-methylazetidin-1- il)) ethyl) -1H-pyrazol-3-sulfonamide
[1362] [1362] To a solution of 1-methyl-5- (1- (3-methylazetidin-1-yl) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P40) (75 mg, 0.290 mmol) in THF (2 ml), sodium tert-butoxide (2M in THF) (0.15 ml, 0.300 mmol) was added and the mixture was stirred at room temperature for 1 hour. 4-isocyanate- 1,2,3,5,6,7-hexahydrosindacene (Intermediate A1) (58 mg, 0.291 mmol) in THF (2 mL) was added and stirring was continued overnight. The mixture was diluted with EtOAc (6 ml) and extracted twice with H 2 O (2 ml) containing a few drops of 2 M NaOH. The combined aqueous extracts were loaded onto a reverse phase column and purified by chromatography on RP Flash C18 (13 g column, 5-75% MeCN / 10 mM ammonium bicarbonate) to generate a light colorless solid. The product was further purified by preparative HPLC to generate the title compound (72 mg, 54%) as a clear colorless solid.
[1363] [1363] 1H NMR (DMSO-d6) δ 10.71 (s, 1H), 7.98 (s, 1H), 6.92 (s, 1H), 6.56 (s, 1H), 3.91 (s, 3H), 3.75 - 3.62 (m, 1H), 3.39 (d, J = 6.0 Hz, 1H), 3.24 (t, J = 6.9 Hz, 1H), 2 , 78 (t, J = 7.5 Hz, 4H), 2.75 - 2.64 (m, 2H), 2.58 (t, J = 7.5 Hz, 4H), 2.47 - 2, 33 (m, 1H), 1.93 (p, J = 7.5 Hz, 4H), 1.14 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H).
[1364] [1364] LCMS; m / z 458.5 (M + H) + (ES +). Example 50: 5- (Azetidin-1-ylmethyl) -1-cyclopropyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H- pyrazol-3-sulfonamide
[1365] [1365] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (azetidin-1-ylmethyl) -1-cyclopropyl-1H-pyrazol-3-sulfonamide (Intermediate P41) and 4-isocyanate- 1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (72 mg, 49%) as a clear colorless solid.
[1366] [1366] 1H NMR (DMSO-d6) δ 10.78 (s, 1H), 7.98 (s, 1H), 6.92 (s, 1H), 6.59 (s, 1H), 3.79 (s, 2H), 3.76 - 3.68 (m, 1H), 3.28 (t, J = 7.1 Hz, 4H), 2.78 (t, J = 7.4 Hz, 4H) , 2.58 (t, J = 7.4 Hz, 4H), 2.03 (p, J = 7.1 Hz, 2H), 1.93 (p, J = 7.4 Hz, 4H), 1 , 10 - 0.98 (m, 4H).
[1367] [1367] LCMS; m / z 456.4 (M + H) + (ES +). Example 51: 5 - ((Dimethylamino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s - indacen- 4-yl) carbamoyl) -1-neopentyl-1H- pyrazol-3-sulfonamide
[1368] [1368] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 5 - ((dimethylamino) methyl) -1-neopentyl-1H-pyrazol-3-sulfonamide (Intermediate P42) and 4-isocyanate-1, 2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (16 mg, 28%) as a colorless powder.
[1369] [1369] 1H NMR (DMSO-d6) δ 10.81 (s, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 4.03 (s, 2H), 3.51 (s, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.3 Hz, 4H), 2.17 (s, 6H), 1.92 (p, J = 7.4 Hz, 4H), 0.92 (s, 9H).
[1370] [1370] LCMS; m / z 474.2 (M + H) + (ES +); 472.4 (M-H) - (ES-).
[1371] [1371] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 5- (1- (dimethylamino) cyclopropyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P43) and 4-isocyanate -1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (22 mg, 25%) as a white solid.
[1372] [1372] 1H NMR (DMSO-d6) δ 10.84 (s, 1H), 8.03 (s, 1H), 6.93 (s, 1H), 6.62 (s, 1H), 4.96 (sept, J = 6.5 Hz, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.58 - 2.52 (m, 4H), 2.16 (s, 6H) , 1.91 (p, J = 7.5 Hz, 4H), 1.40 (d, J = 6.5 Hz, 6H), 1.07 - 1.00 (m, 2H), 0.85 - 0.78 (m, 2H).
[1373] [1373] LCMS; m / z 472.5 (M + H) + (ES +); 470.3 (M-H) - (ES-). Example 53: 5- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-isopropyl-1H -pyrazol-3-sulfonamide, sodium salt
[1374] [1374] Sodium tert-butoxide (2 M in THF) (0.103 mL, 0.206 mmol) was added to a solution of 5- (2- (dimethylamino) ethyl) -1-isopropyl-1H-pyrazol-3-sulfonamide ( Intermediate P44) (51 mg, 0.196 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (43 mg, 0.216 mmol) was added and stirred at room temperature overnight. The suspension was filtered and the collected solid was washed with THF (2 ml) and MTBE (4 ml). The solid was dissolved in MeCN and evaporated in vacuo to generate the title compound (63 mg, 64%).
[1375] [1375] 1H NMR (DMSO-d6) δ 7.58 (s, 1H), 6.77 (s, 1H), 6.23 (s, 1H), 4.51
[1376] [1376] LCMS; m / z 460.6 (M + H) + (ES +). Example 54: 5- (2- (Dimethylamino) propan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -methyl-1H-pyrazol-3-sulfonamide
[1377] [1377] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (2- (dimethylamino) propan-2-yl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P45) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (4.8 mg, 4%) as a solid colorless clear.
[1378] [1378] 1H NMR (DMSO-d6) δ 7.60 (s, 1H), 6.78 (s, 1H), 6.27 (s, 1H), 3.98 (s, 3H), 2.75 (t, J = 7.4 Hz, 4H), 2.61 (t, J = 7.4 Hz, 4H), 2.10 (s, 6H), 1.89 (p, J = 7.4 Hz , 4H), 1.32 (s, 6H). NH not resolved.
[1379] [1379] LCMS; m / z 446.5 (M + H) + (ES +). Example 55: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 5 - ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide
[1380] [1380] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) of 5 - ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P30) and 4- (2-amino -5-fluoro-3 - isopropylphenyl) picolinonitrile (Intermediate A12) to generate the title compound (7 mg, 6%) as a colorless powder.
[1381] [1381] 1H NMR (DMSO-d6) δ 11.02 (br s, 1H), 8.65 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H) , 7.97 (s, 1H), 7.73 - 7.65 (m, 1H), 7.26 (dd, J = 10.0, 3.0 Hz, 1H), 7.15 (dd, J = 8.8 , 3.0 Hz, 1H), 6.29 (s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.46 (s, 2H), 3.21 - 3.02 (m , 1H), 2.16 (s, 6H), 1.33 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 6.8 Hz, 6H).
[1382] [1382] LCMS; m / z 514.6 (M + H) + (ES +); 512.4 (M-H) - (ES-). Example 56: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1383] [1383] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) of 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 4- (2-amino -5-fluoro-3-isopropylphenyl) picolinonitrile (Intermediate A12) to generate the title compound (8 mg, 7%) as a colorless powder.
[1384] [1384] 1H NMR (DMSO-d6) δ 10.91 (s, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.07 - 7.97 (m, 2H), 7 , 73 - 7.61 (m, 1H), 7.27 (dd, J = 9.9, 3.0 Hz, 1H), 7.15 (dd, J = 8.8, 2.9 Hz, 1H), 6.33 (s, 1H), 3.86 (s, 3H), 3.48 (s, 2H), 3.12 (sept, J = 6.5 Hz, 1H), 2.17 (s, 6H ), 1.12 (d, J = 6.8 Hz, 6H).
[1385] [1385] LCMS; m / z 500.5 (M + H) + (ES +); 498.4 (M-H) - (ES-). Example 57: 1- (tert-Butyl) -5 - ((dimethylamino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1386] [1386] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-
[1387] [1387] 1H NMR (DMSO-d6) δ 10.78 (bs, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.68 (s, 1H), 3.53 (s, 2H), 2.79 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 2.17 (s, 6H), 1.93 (p, J = 7.4 Hz, 4H), 1.62 (s, 9H).
[1388] [1388] LCMS; m / z 460.5 (M + H) + (ES +). Example 58: 5- (Azetidin-1-ylmethyl) -1- (tert-butyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl ) -1H-pyrazol-3-sulfonamide
[1389] [1389] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (azetidin-1-ylmethyl) -1- (tert-butyl) -1H-pyrazol-3-sulfonamide
[1390] [1390] (Intermediate P47) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (45 mg, 31%) as a white solid.
[1391] [1391] 1H NMR (DMSO-d6) δ 10.78 (bs, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 3.76 (s, 2H), 3.22 (t, J = 7.0 Hz, 4H), 2.79 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7.4 Hz, 4H ), 2.02 (p, J = 7.1 Hz, 2H), 1.93 (p, J = 7.4 Hz, 4H), 1.60 (s, 9H).
[1392] [1392] LCMS; m / z 472.8 (M + H) + (ES +). Example 59: 5 - ((Dimethylamino) methyl) -N - ((5-fluoro-3-isopropyl- [1,1'-biphenyl] -2-yl) carbamoyl) -1-isopropyl-1H-pyrazol-3- sulfonamide
[1393] [1393] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1- isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P48) and 5-fluoro- 3-isopropyl- [1,1'-biphenyl] -2-amine (Intermediate A7) to generate the title compound (36 mg, 32%) as a colorless powder.
[1394] [1394] 1H NMR (DMSO-d6) δ 10.77 (s, 1H), 7.70 (s, 1H), 7.39 - 7.27 (m, 5H), 7.16 (dd, J = 10.1, 3.0 Hz, 1H), 6.97 (dd, J = 8.9, 3.0 Hz, 1H), 6.51 (s, 1H), 4.83 (sept, J = 6.6 Hz, 1H), 3.50 (s, 2H), 2.95 (sept, J = 7.9 Hz, 1H), 2.17 (s, 6H), 1.39 (d, J = 6.5 Hz, 6H), 1.09 (d, J = 6.8 Hz, 6H).
[1395] [1395] LCMS; m / z 502 (M + H) + (ES +); 500 (M-H) - (ES-). Example 60: N - ((2- (1,3-dimethyl-1H-pyrazol-5-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -5 - ((dimethylamino) methyl) -1-methyl-1H -pyrazol-3-sulfonamide
[1396] [1396] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 2- (1 , 3-dimethyl-1H-pyrazol-5-yl) -4-fluoro-6-isopropylaniline (Intermediate A9) to generate the title compound (16 mg, 22%) as a colorless powder.
[1397] [1397] 1H NMR (DMSO-d6) δ 10.84 (s, 1H), 7.68 (s, 1H), 7.24 (dd, J = 10.1,
[1398] [1398] LCMS; m / z 492 (M + H) + (ES +); 490 (M-H) - (ES-). Example 61: 5 - ((dimethylamino) methyl) -N - ((4-fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1399] [1399] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 4- (2 -amino-6-fluoro-3-isopropylphenyl) picolinonitrile (Intermediate A6) to generate the title compound (36 mg, 34%) as a colorless powder.
[1400] [1400] 1H NMR (DMSO-d6) δ 10.84 (s, 1H), 8.57 - 8.52 (m, 1H), 8.49 (s, 1H), 7.83 (s, 1H) , 7.73 - 7.67 (m, 1H), 7.35 (dd, J = 8.0, 4.9 Hz, 1H), 7.21 (dd, J = 10.1, 3.0 Hz, 1H), 7.06 (dd, J = 8.9, 3.0 Hz, 1H), 6.47 (s, 1H), 3.89 (s, 3H), 3.49 (s, 2H), 3.04 (sept , J = 6.4 Hz, 1H), 2.17 (s, 6H), 1.10 (d, J = 6.6 Hz, 6H).
[1401] [1401] LCMS; m / z 475 (M + H) + (ES +); 473 (M-H) - (ES-). Example 62: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-isopropyl-6- (pyrimidin-5-yl) phenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[1402] [1402] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1- isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P48) and 4-fluoro- 2-isopropyl-6- (pyrimidine-5-yl) aniline (Intermediate A11) to generate the title compound (17 mg, 12%) as a colorless powder.
[1403] [1403] 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 9.13 (s, 1H), 8.76 (s, 2H), 8.04 (s, 1H), 7.26 (dd, J = 10.0, 3.0 Hz, 1H), 7.20 (dd, J = 8.8, 3.0 Hz, 1H), 6.44 (s, 1H), 4.81 (sept, J = 6, 6 Hz, 1H), 3.51 (s, 2H), 3.03 (sept, J = 7.0 Hz, 1H), 2.17 (s, 6H), 1.38 (d, J = 6.6 Hz , 6H), 1.10 (d, J = 6.8 Hz, 6H).
[1404] [1404] LCMS; m / z 504 (M + H) + (ES +); 502 (M-H) - (ES-). Example 63: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-isopropyl-6- (pyrimidin-5-yl) phenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1405] [1405] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 4-fluoro- 2-isopropyl-6- (pyrimidin-5-yl) aniline (Intermediate A11) to generate the title compound (14 mg, 10%) as a colorless powder.
[1406] [1406] 1H NMR (DMSO-d6) δ 10.93 (s, 1H), 9.15 (s, 1H), 8.73 (s, 2H), 8.02 (s, 1H), 7.27 (dd, J = 10.0, 3.0 Hz, 1H), 7.19 (dd, J = 8.8, 3.0 Hz, 1H), 6.48 (s, 1H), 3.90 (s, 3H), 3 , 53 (s, 2H), 3.06 (sept, J = 6.9 Hz, 1H), 2.19 (s, 6H), 1.11 (d, J = 6.7 Hz, 6H).
[1407] [1407] LCMS; m / z 476 (M + H) + (ES +); 474 (M-H) - (ES-). Example 64: ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) ((1-methyl-5- ((trimethylammonium) methyl) -1H-pyrazole- 3-yl) sulfonyl) amide
[1408] [1408] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from N, N, N-trimethyl-1- (1-methyl-3-sulfamoyl-1H-pyrazol-5-yl) 2,2, Methanamine 2-trifluoroacetate (Intermediate P49) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (22 mg, 25%) like a white powder.
[1409] [1409] 1H NMR (DMSO-d6) δ 7.45 (s, 1H), 6.78 (s, 1H), 6.76 (s, 1H), 4.66
[1410] [1410] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1- isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P48) and 2'-amino -5'-fluoro-3'- isopropyl- [1,1'-biphenyl] -3-carbonitrile (Intermediate A8) to generate the title compound (28 mg, 24%) as a colorless powder.
[1411] [1411] 1H NMR (DMSO-d6) δ 10.92 (s, 1H), 7.93 (s, 1H), 7.85 - 7.79 (m, 2H), 7.68 - 7.63 ( m, 1H), 7.57 - 7.51 (m, 1H), 7.21 (dd, J = 10.0, 3.0 Hz, 1H), 7.07 (dd, J = 8.9, 3.0 Hz, 1H ), 6.42 (s, 1H), 4.79 (sept, J = 6.6 Hz, 1H), 3.48 (s, 2H), 3.00 (sept, J = 6.9 Hz, 1H ), 2.15 (s, 6H), 1.37 (d, J = 6.6 Hz, 6H), 1.09 (s, 6H).
[1412] [1412] LCMS; m / z 527 (M + H) + (ES +); 525 (M-H) - (ES-). Example 66: N - (((3'-Cyano-5-fluoro-3-isopropyl- [1,1'-biphenyl] -2-yl) carbamoyl) -5- ((dimethylamino) methyl) -1-methyl-1H -pyrazol-3-sulfonamide
[1413] [1413] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 2'-amino -5'-fluoro-3'-isopropyl- [1,1'-biphenyl] -3-carbonitrile (Intermediate A8) to generate the title compound (37 mg, 34%) as a colorless powder.
[1414] [1414] 1H NMR (DMSO-d6) δ 10.86 (s, 1H), 7.90 (s, 1H), 7.84 - 7.78 (m, 2H), 7.65 - 7.60 ( m, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.21 (dd, J = 10.0, 3.0 Hz, 1H), 7.06 (dd, J = 8.9, 3.0 Hz, 1H), 6.45 (s, 1H), 3.87 (s, 3H), 3.49 (s, 2H), 3.04 (sept, J = 7.0 Hz, 1H), 2.17 ( s, 6H), 1.10 (br s, 6H).
[1415] [1415] LCMS; m / z 499 (M + H) + (ES +); 497 (M-H) - (ES-). Example 67: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3- sulfonamide
[1416] [1416] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1- isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P48) and 4-fluoro- 2-isopropyl-6- (2-methoxypyridine-4-yl) aniline (Intermediate A10) to generate the title compound (44 mg, 43%) as a colorless powder.
[1417] [1417] 1H NMR (DMSO-d6) δ 10.92 (s, 1H), 8.09 (dd, J = 5.3, 0.7 Hz, 1H), 7.87 (s, 1H), 7 , 22 (dd, J = 10.0, 3.0 Hz, 1H), 7.04 (dd, J = 8.9, 3.0 Hz, 1H), 6.92 (dd, J = 5.2, 1.5 Hz, 1H), 6.79 (s, 1H), 6.48 (s, 1H), 4.81 (sept, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.48 ( s, 2H), 2.98 (sept, J = 6.9 Hz, 1H), 2.15 (s, 6H), 1.37 (d, J = 6.6 Hz, 6H), 1.08 ( d, J = 6.8 Hz, 6H).
[1418] [1418] LCMS; m / z 533 (M + H) + (ES +); 531 (M-H) - (ES-). Example 68: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-methyl-1H-pyrazol-3- sulfonamide
[1419] [1419] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) -
[1420] [1420] 1H NMR (DMSO-d6) δ 10.87 (s, 1H), 8.09 (dd, J = 5.3, 0.7 Hz, 1H), 7.85 (s, 1H), 7 , 22 (dd, J = 10.0, 3.0 Hz, 1H), 7.04 (dd, J = 8.8, 3.0 Hz, 1H), 6.89 (dd, J = 5.3, 1.4 Hz, 1H), 6.77 (s, 1H), 6.51 (s, 1H), 3.88 (s, 6H), 3.49 (s, 2H), 3.02 (sept, J = 7.2 Hz, 1H), 2.17 (s, 6H), 1.09 (d, J = 6.8 Hz, 6H).
[1421] [1421] LCMS; m / z 505 (M + H) + (ES +); 503 (M-H) - (ES-). Example 69: 5- (Azetidin-1-ylmethyl) -1-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1H- pyrazol-3-sulfonamide
[1422] [1422] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (azetidin-1-ylmethyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P50) and 4-isocyanate- 1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (52 mg, 40%) as a white solid.
[1423] [1423] 1H NMR (DMSO-d6) δ 10.85 (br s, 1H), 7.99 (s, 1H), 6.92 (s, 1H), 6.61 (s, 1H), 4, 18 (q, J = 7.2 Hz, 2H), 3.68 (s, 2H), 3.22 (t, J = 7.1 Hz, 4H), 2.79 (t, J = 7.4 Hz, 4H), 2.59 (t, J = 7.4 Hz, 4H), 2.01 (p, J = 7.1 Hz, 2H), 1.94 (p, J = 7.4 Hz, 4H), 1.35 (t, J = 7.2 Hz, 3H).
[1424] [1424] LCMS; m / z 444.4 (M + H) + (ES +). Example 70: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1- isopropyl-5 - ((methylamino) methyl) -1H-pyrazole -3-sulfonamide
[1425] [1425] Sodium tert-butoxide (2 M in THF) (0.152 mL, 0.305 mmol) was added to a solution of 2,2,2-trifluoro-N - ((1-isopropyl-3-sulfamoyl-1H-pyrazole -5-yl) methyl) -N-methylacetamide (Intermediate P51) (100 mg, 0.305 mmol) in THF (6 mL) and stirred at room temperature for 1 hour. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (67 mg, 0.336 mmol) was added and stirred at room temperature overnight. The volatiles were evaporated. MeOH (0.3 mL) and K2CO3 (44 mg, 0.318 mmol) were added and stirred for 16 hours. Another K2CO3 equivalent (44 mg, 0.318 mmol) was added and stirred for another 16 hours. The volatiles were evaporated and the crude product was purified by preparative reverse phase HPLC (General Methods, basic preparation) to generate the title compound (23 mg, 17%) as a white solid.
[1426] [1426] 1H NMR (DMSO-d6) δ 7.83 (s, 1H), 6.86 (s, 1H), 6.59 (s, 1H), 4.70 (sept, J = 6.4 Hz , 1H), 3.96 (s, 2H), 3.33 (bs, 1H), 2.77 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz , 4H), 2.42 (s, 3H), 1.92 (p, J = 7.5 Hz, 4H), 1.35 (d, J = 6.5 Hz, 6H). An exchangeable proton is missing.
[1427] [1427] LCMS; m / z 432.5 (M + H) + (ES +). Example 71: 5 - ((Dimethylamino) methyl) -1-ethyl-N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1H-pyrazol-3-sulfonamide
[1428] [1428] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N- methylacetamide (Example 2) from 1- (2- (dimethylamino) ethyl) -5- ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P30 ) and 5-fluoro-2-isocyanate-1,3-diisopopylbenzene (Intermediate A2) to generate the title compound (53 mg, 45%).
[1429] [1429] 1H NMR (DMSO-d6) δ 10.96 (br s, 1H), 7.76 (s, 1H), 6.91 (d, J = 9.9 Hz, 2H), 6.58 ( s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.46 (s, 2H), 3.04 - 2.91 (m, 2H), 2.14 (s, 6H ), 1.36 (t, J = 7.2 Hz, 3H), 1.14 - 0.93 (m, 12H).
[1430] [1430] LCMS; m / z 454.5 (M + H) + (ES +). Example 72: 5 - ((Dimethylamino) methyl) -1-ethyl-N - (((1,2,3,5,6,7-hexahydro-s-- indacen-4-yl) carbamoyl) -1H- pyrazol-3-sulfonamide
[1431] [1431] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 1- (2 - ((dimethylamino) ethyl) -5- ((dimethylamino) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P30 ) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (44 mg, 39%).
[1432] [1432] 1H NMR (DMSO-d6) δ 10.79 (br s, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.62 (s, 1H), 4, 21 (q, J = 7.2 Hz, 2H), 3.48 (s, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7.4 Hz, 4H), 2.16 (s, 6H), 1.93 (p, J = 7.4 Hz, 4H), 1.35 (t, J = 7.2 Hz, 3H).
[1433] [1433] LCMS; m / z 432.4 (M + H) + (ES +). Example 73: 5- (Azetidin-1-ylmethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl-1H- pyrazol-3-sulfonamide
[1434] [1434] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 5- (azetidin-1-ylmethyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P52) and 4-isocyanate 1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (88 mg, 54%) as a white solid.
[1435] [1435] 1H NMR (DMSO-d6) δ 10.78 (br s, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.60 (s, 1H), 4, 74 (sept, J = 6.5 Hz, 1H), 3.66 (s, 2H), 3.18 (t, J = 7.1 Hz, 4H), 2.79 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7.3 Hz, 4H), 2.03 - 1.97 (m, 2H), 1.96 - 1.90 (m,
[1436] [1436] 5 - ((Dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P48; 0.020 g, 0.081 mmol) and N, N-dimethylaminopyridine (0.030 g, 0.244 mmol) were dissolved in MeCN dried (1 mL) at room temperature and stirred for 10 minutes, making the mixture homogeneous. Diphenyl carbonate (0.019 g, 0.089 mmol) was added as a solid and the slightly cloudy reaction mixture was stirred at room temperature overnight. This was repeated 4 times at different temperatures. The crude reaction mixtures were combined and added to 4-fluoro-2-isopropyl-6- (pyridin-3-yl) aniline (Intermediate A6) (36.4 mg, 0.158 mmol). The mixture was then heated to 70 ° C for 2 hours, evaporated to dryness in vacuo and the obtained brown residue triturated with 1: 4 EtOAc: DCM (4 ml). The filtrate was then purified by preparative reverse phase HPLC (General Methods, basic preparation) to generate the title compound (26 mg, 30%) as a white solid.
[1437] [1437] 1H NMR (DMSO-d6) δ 10.91 (br s, 1 H), 8.60 - 8.39 (m, 2 H), 7.86 (s, 1 H), 7.73 ( dt, 1 H), 7.36 (ddd, 1 H), 7.21 (dd, 1 H), 7.07 (dd, 1 H), 6.44 (s, 1 H), 4.80 ( sept, 1 H), 3.48 (s, 2 H), 3.04 - 2.93 (m, 1 H), 2.15 (s, 6 H), 1.38 (d, 6 H) and 1.09 (d, 6 H).
[1438] [1438] LCMS; m / z 503.6 (M + H) + (ES +); 501.4 (M-H) - (ES-). Example 75: N - (((4-Chloro-2,6-diisopropylphenyl) carbamoyl) -5- ((dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[1439] [1439] Prepared according to the general procedure of 1- (1-
[1440] [1440] 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 7.87 (s, 1H), 7.13 (s, 2H), 6.59 (s, 1H), 4.82 (sept, J = 6.6 Hz, 1H), 3.48 (s, 2H), 2.95 (sept, J = 6.9 Hz, 2H), 2.14 (s, 6H), 1.39 (d, J = 6.6 Hz, 6H), 1.05 (br s, 12H).
[1441] [1441] LCMS; m / z 484/486 (M + H) + (ES +); 482/484 (M-H) - (ES-). Example 76: 5 - ((((2,2-Difluoroethyl) (methyl) amino) methyl) -N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl ) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide, sodium salt
[1442] [1442] Prepared according to the general procedure of 5- (2- (dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl -1H-pyrazol-3-sulfonamide, sodium salt (Example 53) from 5 - (((2,2-difluoroethyl) (methyl) amino) methyl) -1-isopropyl-1H-pyrazole -3-sulfonamide (Intermediate P53) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (70 mg, 55%).
[1443] [1443] 1H NMR (DMSO-d6) δ 7.55 (s, 1H), 6.76 (s, 1H), 6.32 (s, 1H), 6.12 (tt, J = 55.7, 4.3 Hz, 1H), 4.67 (sept, J = 6.7 Hz, 1H), 3.63 (s, 2H), 2.84 - 2.72 (m, 6H), 2.63 ( t, J = 7.3 Hz, 4H), 2.25 (s, 3H), 1.88 (p, J = 7.4 Hz, 4H), 1.36 (d, J = 6.6 Hz, 6H).
[1444] [1444] LCMS; m / z 496.5 (M + H) + (ES +). Example 77: 5 - (((((2-Fluoroethyl) (methyl) amino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl ) -1-isopropyl-1H-pyrazol-3-sulfonamide, sodium salt
[1445] [1445] Prepared according to the general procedure of 5- (2- (dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl -1H-pyrazol-3-sulfonamide, sodium salt (Example 53) from 5 - (((2-fluoroethyl) (methyl) amino) methyl) -1-isopropyl-1H-pyrazole-3 -sulfonamide (Intermediate P54) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (42 mg, 33%).
[1446] [1446] 1H NMR (DMSO-d6) δ 7.57 (s, 1H), 6.77 (s, 1H), 6.31 (s, 1H), 4.74 - 4.65 (m, 1H) , 4.52 (dt, J = 47.8, 4.8 Hz, 2H), 3.55 (s, 2H), 2.75 (t, J = 7.5 Hz, 4H), 2.71 - 2.60 (m, 6H), 2.19 (s, 3H), 1.89 (p, J = 7.4 Hz, 4H), 1.35 (d, J = 6.6 Hz, 6H).
[1447] [1447] LCMS; m / z 478.5 (M + H) + (ES +). Example 78: 5- (1- (Dimethylamino) cyclopropyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H -pyrazol-3-sulfonamide, sodium salt
[1448] [1448] Prepared according to the general procedure of 5- (2- (dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 53) from 5- (1- (dimethylamino) cyclopropyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P55) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (64 mg, 65%) as a white solid.
[1449] [1449] 1H NMR (DMSO-d6) δ 7.55 (s, 1H), 6.76 (s, 1H), 6.29 (s, 1H), 3.84 (s, 3H), 2.74 (t, J = 7.5 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 2.16 (s, 6H), 1.88 (p, J = 7.4 Hz , 4H), 1.01 - 0.92 (m, 2H), 0.88 - 0.71 (m, 2H). LCMS; m / z 444.5 (M + H) + (ES +); 442.1 (M-H) - (ES-). Example 79: 5- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) -1-methyl-1H -pyrazol-3-sulfonamide
[1450] [1450] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (2- (dimethylamino) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P56) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (70 mg, 57%) as a clear glass, which generated a solid white after being scratched.
[1451] [1451] 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 6.90 (s, 1H), 6.51 (s, 1H), 3.79 (s, 3H), 2.85 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.4 Hz, 4H), 2.71 (t, J = 7.5 Hz, 2H), 2.63 (t , J = 7.4 Hz, 4H), 2.36 (s, 6H), 1.95 (p, J = 7.4 Hz, 4H). NH not observed.
[1452] [1452] LCMS; m / z 432.5 (M + H) + (ES +). Example 80: 4- (Dimethylamino) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -4,5,6,7-tetra- hydropyrazole [1,5-a] pyridine-2-sulfonamide
[1453] [1453] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 4- (dimethylamino) - 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine- 2-sulfonamide (Intermediate P57) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (57 mg, 64%) as a light brown solid.
[1454] [1454] 1H NMR (DMSO-d6) δ 10.75 (s, 1H), 8.03 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 4.20 - 4.12 (m, 1H), 4.08 - 3.98 (m, 1H), 3.93 (dd, J = 9.9, 5.3 Hz, 1H), 2.79 (t, J = 7.5 Hz, 4H), 2.59 (t, J = 7.5, 4H), 2.24 (s, 6H), 2.20 - 2.11 (m, 1H), 2.02 - 1.82 (m, 6H), 1.74 - 1.61 (m, 1H).
[1455] [1455] LCMS; m / z 444.5 (M + H) + (ES +). Example 81: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[1456] [1456] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)) sulfamoyl) -1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 5 - ((dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P48) and 5-fluoro-2 -isocyanate-1,3-diisopopylbenzene (Intermediate A2) to generate the title compound (35 mg, 36%) as a colorless powder.
[1457] [1457] 1H NMR (DMSO-d6) δ 11.01 (s, 1H), 7.79 (s, 1H), 6.92 (d, J = 9.9 Hz, 2H), 6.60 (s , 1H), 4.83 (sept, J = 6.5 Hz, 1H), 3.48 (s, 2H), 2.95 (sept, J = 7.1 Hz, 2H), 2.14 (s , 6H), 1.39 (d, J = 6.5 Hz, 6H), 1.05 (br s, 12H).
[1458] [1458] LCMS; m / z 468 (M + H) + (ES +); 466 (M-H) - (ES-). Example 82: 5- (1- (Dimethylamino) propyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
[1459] [1459] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (1- (dimethylamino) propyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P58) and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (17 mg, 19%) as a crystalline solid.
[1460] [1460] 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 7.77 (s, 1H), 6.91 (d, J = 9.9 Hz, 2H), 6.57 (s , 1H), 4.91 - 4.80 (m, 1H), 3.68 (dd, J = 10.0, 4.7 Hz, 1H), 3.03 - 2.91 (m, 2H), 2, 11 (s, 6H), 1.86 - 1.77 (m, 1H), 1.68 - 1.59 (m, 1H), 1.41 (d, J = 6.5 Hz, 3H), 1 , 35 (d, J = 6.5 Hz, 3H), 1.04 (br s, 12H), 0.75 (t, J = 7.3 Hz, 3H).
[1461] [1461] LCMS; m / z 496.6 (M + H) + (ES +).
[1462] [1462] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (1- (dimethylamino) propyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P58) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (11 mg, 13%) as a colorless crystalline solid.
[1463] [1463] 1H NMR (DMSO-d6) δ 10.84 (s, 1H), 7.86 (s, 1H), 6.86 (s, 1H), 6.49 (s, 1H), 4.87 - 4.76 (m, 1H), 3.64 (dd, J = 9.8, 4.7 Hz, 1H), 2.76 (t, J = 7.4 Hz, 4H), 2.57 ( t, J = 7.4 Hz, 4H), 2.11 (s, 6H), 1.94 - 1.78 (m, 5H), 1.71 - 1.56 (m, 1H), 1.39 (d, J = 6.5 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H).
[1464] [1464] LCMS; m / z 474.5 (M + H) + (ES +). Example 84: N- (((4-Chloro-2,6-diisopropylphenyl) carbamoyl) -5- (1- (dimethylamino) propyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1465] [1465] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (1- (dimethylamino) propyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P59) and 5-chloro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A22) to generate the title compound (15 mg, 25%) as a colorless glass, which produced a white solid after being scratched.
[1466] [1466] 1H NMR (DMSO-d6) δ 10.99 (br s, 1H), 7.85 (s, 1H), 7.12 (s, 2H), 6.58 (s, 1H), 3, 88 (s, 3H), 3.65 (dd, J = 9.5, 5.1 Hz, 1H), 3.05 - 2.94 (m, 2H), 2.10
[1467] [1467] LCMS; m / z 484.5 / 486.5 (M + H) + (ES +). Example 85: 5- (1- (Dimethylamino) propyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1468] [1468] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (1- (dimethylamino) propyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P59) and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (18 mg, 32%) as a colorless glass, which produced a white solid after being scratched.
[1469] [1469] 1H NMR (DMSO-d6) δ 10.95 (br s, 1H), 7.80 (s, 1H), 6.91 (d, J = 9.9 Hz, 2H), 6.59 ( s, 1H), 3.89 (s, 3H), 3.65 (dd, J = 9.5, 5.1 Hz, 1H), 3.03 - 2.94 (m, 2H), 2.10 (s, 6H), 1.87 - 1.75 (m, 1H), 1.69 - 1.56 (m, 1H), 1.04 (app. br s, 12H), 0.77 (t, J = 7.3 Hz, 3H).
[1470] [1470] LCMS; m / z 468.5 (M + H) + (ES +). Example 86: 5 - ((Dimethylamino) methyl) -N - ((5-fluoro-3-isopropyl- [1,1'-biphenyl] -2-yl) carbamoyl) -1-methyl-1H-pyrazol-3- sulfonamide
[1471] [1471] Prepared according to the general procedure of 1- (2- (dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-indent 4-yl) carbamoyl) - 1H-pyrazol-3-sulfonamide (Example 26) from 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 4- (2 -amino-6-fluoro-3-isopropylphenyl) picolinonitrile (Intermediate A7) to generate the title compound (14 mg, 14%) as a colorless solid.
[1472] [1472] 1H NMR (DMSO-d6) δ 10.73 (s, 1H), 7.68 (s, 1H), 7.42 - 7.30 (m, 3H), 7.31 - 7.24 ( m, 2H), 7.16 (dd, J = 10.0, 3.0 Hz, 1H), 6.96 (dd, J = 9.0, 3.0 Hz, 1H), 6.54 (s, 1H), 3.90 ( s, 3H), 3.50 (s, 2H), 2.99 (sept, J = 7.6 Hz, 1H), 2.17 (s, 6H), 1.09 (d, J = 6.8 Hz, 6H).
[1473] [1473] LCMS; m / z 474 (M + H) + (ES +); 472 (M-H) - (ES-). Example 87: N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-5 - ((methylamino) methyl) -1H-pyrazole -3-sulfonamide
[1474] [1474] 2 M sodium tert-butoxide in THF (47.2 µL, 0.094 mmol) was added to a solution of 2,2,2-trifluoro-N-methyl-N - ((1-methyl-3-sulfamoyl -1H-pyrazol-5-yl) methyl) acetamide (Intermediate P60) (27 mg, 0.090 mmol) in THF (2 mL) and 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 stirred at room temperature overnight. The volatiles were evaporated. MeOH (0.1 mL) and K2CO3 (13 mg, 0.094 mmol) were added and stirred for 16 hours. The volatiles were evaporated and the crude product was purified by RP Flash C18 chromatography (12 g column, 5-50% MeCN / 10 mM ammonium bicarbonate) to generate the title compound (15 mg, 39%) as a white solid.
[1475] [1475] 1H NMR (DMSO-d6) δ 7.74 (s, 1H), 6.84 (s, 1H), 6.57 (s, 1H), 3.94 (s, 2H), 3.82 (s, 3H), 2.77 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 2.41 (s, 3H), 1.92 (p, J = 7.3 Hz, 4H). Two interchangeable protons not observed.
[1476] [1476] LCMS; m / z 404.5 (M + H) + (ES +). Example 88: 5 - ((Dimethylamino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen 4-yl) carbamoyl) -1-isopropyl-1H-pyrazole -3-sulfonamide
[1477] [1477] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- ((dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P48) and 4 - isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (5 mg, 7%) as a white solid.
[1478] [1478] 1H NMR (DMSO-d6) δ 10.90 (s, 1H), 7.96 (s, 1H), 6.91 (s, 1H), 6.59 (s, 1H), 4.85 - 4.75 (m, 1H), 3.48 (s, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7.4 Hz, 4H) , 2.15 (s, 6H), 1.92 (p, J = 7.5 Hz, 4H), 1.38 (d, J = 6.5 Hz, 6H).
[1479] [1479] LCMS; m / z 446.4 (M + H) + (ES +). Example 89: 5- (1- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-methyl-1H -pyrazol-3-sulfonamide, Enantiomer 1 O O O O O O N Y N Y N N N N H H H H
[1480] [1480] Prepared by chiral separation of 5- (1- (dimethylamino) ethyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 97) (142.3 mg, 0.330 mmol) per SFC column (AmyC (20 mm x 250 mm, 5 µm), 40 ° C, flow rate 50 ml / min at 100 BarG isocratic 20: 80 MeOH: CO2 with 90.2 v / v NH3, monitoring at 210 nm) to produce the title compound (35 mg, 24%).
[1481] [1481] 1H NMR (DMSO-d6) δ 10.77 (br s, 1H), δ 8.00 (s, 1H), 6.92 (s, 1H), 6.64 (s, 1H), 3 , 94 (q, J = 6.8 Hz, 1H), 3.89 (s, 3H), 2.78 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7, 4 Hz, 4H), 2.13 (s, 6H), 2.01 - 1.85 (m, 4H), 1.24 (d, J = 6.8 Hz, 3H).
[1482] [1482] LCMS; m / z 432.5 (M + H) + (ES +); 430.4 (M-H) - (ES-).
[1483] [1483] Prepared by chiral separation of 5- (1- (dimethylamino) ethyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 97) (142.3 mg, 0.330 mmol) per SFC column (AmyC (20 mm x 250 mm, 5 µm), 40 ° C, flow rate 50 ml / min at 100 BarG isocratic 20: 80 MeOH: CO2 with 90.2 v / v NH3, monitoring at 210 nm) to produce the title compound (29 mg, 20%).
[1484] [1484] 1H NMR (DMSO-d6) δ 10.73 (br s, 1H), 8.01 (s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 3, 95 (q, J = 6.8 Hz, 1H), 3.89 (s, 3H), 2.78 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7.4 Hz, 4H), 2.13 (s, 6H), 2.05 - 1.83 (m, 4H), 1.25 (d, J = 6.8 Hz, 3H).
[1485] [1485] LCMS; m / z 432.4 (M + H) + (ES +); 430.4 (M-H) - (ES-). Example 91: 5- (1- (Dimethylamino) propyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H -pyrazol-3-sulfonamide, Enantiomer 1 O O O O O O N Y N Y N N N N H H H H
[1486] [1486] Prepared by chiral separation of 5- (1- (dimethylamino) propyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 94) (68.8 mg, 0.330 mmol) per SFC column (AmyC (20 mm x 250 mm, 5 µm), 40 ° C, flow rate 50 ml / min at 100 BarG isocratic 20: 80 MeOH: CO2 with 90.2 v / v NH3, monitoring at 210 nm) to produce the title compound (20 mg, 29%).
[1487] [1487] 1H NMR (DMSO-d6) δ 10.73 (br s, 1H), 8.02 (s, 1H), 6.92 (s, 1H),
[1488] [1488] LCMS; m / z 446.4 (M + H) + (ES +); 444.4 (M-H) - (ES-). Example 92: 5- (1- (Dimethylamino) propyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H -pyrazol-3-sulfonamide, Enantiomer 2 O O O O O O N Y N Y N N N N H H H H
[1489] [1489] Prepared by chiral separation of 5- (1- (dimethylamino) propyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 94) (68.8 mg, 0.330 mmol) per SFC column (AmyC (20 mm x 250 mm, 5 µm), 40 ° C, flow rate 50 ml / min at 100 BarG isocratic 20: 80 MeOH: CO2 with 90.2 v / v NH3, monitoring at 210 nm) to produce the title compound (20 mg, 29%).
[1490] [1490] 1H NMR (DMSO-d6) δ 10.73 (br s, 1H), 8.00 (s, 1H), 6.92 (s, 1H), 6.64 (s, 1H), 3, 89 (s, 3H), 3.68 (dd, J = 9.4, 5.1 Hz, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 2.12 (s, 6H), 1.99 - 1.87 (m, 4H), 1.87 - 1.76 (m, 1H), 1.73 - 1, 58 (m, 1H), 0.78 (t, J = 7.3 Hz, 3H).
[1491] [1491] LCMS; m / z 446.4 (M + H) + (ES +); 444.4 (M-H) - (ES-). Example 93: 5- (1- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-isopropyl-1H -pyrazol-3-sulfonamide
[1492] [1492] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (1-
[1493] [1493] 1H NMR (DMSO-d6) δ 10.79 (s, 1H), 8.01 (s, 1H), 6.93 (s, 1H), 6.62 (s, 1H), 4.97 - 4.82 (m, 1H), 3.99 (q, J = 6.7 Hz, 1H), 2.79 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 2.14 (s, 6H), 1.98 - 1.85 (m, 4H), 1.43 - 1.33 (m, 6H), 1.26 (d, J = 6.7 Hz, 3H).
[1494] [1494] LCMS; m / z 460.5 (M + H) + (ES +). Example 94: 5- (1- (Dimethylamino) propyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H -pyrazol-3-sulfonamide
[1495] [1495] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (1- (dimethylamino) propyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P59) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (77 mg, 62%) as a white solid.
[1496] [1496] 1H NMR (DMSO-d6) δ 10.73 (br s, 1H), 8.01 (s, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 3, 90 (s, 3H), 3.69 (dd, J = 9.5, 5.1 Hz, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 2.13 (s, 6H), 1.98 - 1.88 (m, 4H), 1.88 - 1.78 (m, 1H), 1.72 - 1, 59 (m, 1H), 0.78 (t, J = 7.3 Hz, 3H).
[1497] [1497] LCMS; m / z 446.5 (M + H) + (ES +). Example 95: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -5- (3-hydroxy-1-methylazetidin-3-yl) - 1-methyl-1H-pyrazol-3-sulfonamide
[1498] [1498] Prepared according to the general procedure of 1- (1-
[1499] [1499] 1H NMR (DMSO-d6) δ 10.75 (br s, 1H), 7.93 (s, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 6, 43 (s, 1H), 3.87 (d, J = 8.1 Hz, 2H), 3.81 (s, 3H), 3.39 (d, J = 8.1 Hz, 2H), 2, 78 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.3 Hz, 4H), 2.38 (s, 3H), 1.99 - 1.90 (m, 4H ).
[1500] [1500] LCMS; m / z 446.4 (M + H) + (ES +). Example 96: 5- (1- (Azetidin-1-yl) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -methyl-1H-pyrazol-3-sulfonamide
[1501] [1501] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (1- (azetidin-1-yl) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P63) and 4-isocyanate- 1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (40 mg, 10%) as a white solid.
[1502] [1502] 1H NMR (DMSO-d6) δ 10.76 (br s, 1H), 8.00 (s, 1H), 6.92 (s, 1H), 6.58 (s, 1H), 3, 92 (s, 3H), 3.73 - 3.66 (m, 1H), 3.22 - 3.05 (m, 6H), 2.78 (t, J = 7.5 Hz, 4H), 2 , 58 (t, J = 7.4 Hz, 4H), 1.98 - 1.89 (m, 4H), 1.14 (d, J = 6.5 Hz, 3H).
[1503] [1503] LCMS; m / z 444.5 (M + H) + (ES +). Example 97: 5- (1- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-methyl-1H -pyrazol-3-sulfonamide
[1504] [1504] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (1- (dimethylamino) ethyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P64) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (222 mg, 77%) as a white solid.
[1505] [1505] 1H NMR (DMSO-d6) δ 10.73 (br s, 1H), 8.01 (s, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 3, 96 (q, J = 6.7 Hz, 1H), 3.90 (s, 3H), 2.78 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7.4 Hz, 4H), 2.14 (s, 6H), 1.93 (p, J = 7.4 Hz, 4H), 1.25 (d, J = 6.8 Hz, 3H).
[1506] [1506] LCMS; m / z 432.5 (M + H) + (ES +). Example 98: N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-5- (pyrrolidin-1-ylmethyl) -1H- pyrazol-3-sulfonamide, sodium salt
[1507] [1507] 1-Methyl-5- (pyrrolidin-1-ylmethyl) -1H-pyrazol-3-sulfonamide (Intermediate P65) (35 mg, 0.143 mmol) was dissolved in 2-MetF (0.5 mL) and DMF ( 0.5 ml), and 2 M sodium tert-butoxide in THF (0.079 ml, 0.158 mmol) was added. After 1 hour, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (31.4 mg, 0.158 mmol) followed by 2-MetF (1 mL) was added and the mixture was stirred at room temperature for 2 days. EtOAc (3 ml) was added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue obtained was purified by chromatography on RP Flash C18 (13 g column, 5-50% MeCN / 10 mM ammonium bicarbonate) to generate a white solid (30 mg). The white solid obtained was suspended in EtOAc (1 ml) and 1 molar equivalent of 2 M sodium tert-butoxide in THF was added. The solvent was removed under reduced pressure to produce a pale yellow glass. A 1: 1 mixture of MTBE: MeCN (2 mL) was added and the reaction mixture was left to stand for 2 hours. The soluble portion was decanted and concentrated to dryness to yield the title compound (23 mg, 32%) as a white solid.
[1508] [1508] 1H NMR (DMSO-d6) δ 7.50 (s, 1H), 6.75 (s, 1H), 6.27 (s, 1H), 3.75 (s, 3H), 3.57 (s, 2H), 2.74 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 2.44 - 2.37 (m, 4H) , 2.02 - 1.76 (m, 4H), 1.76 - 1.58 (m, 4H).
[1509] [1509] LCMS; m / z 444.5 (M + H) + (ES +); 442.3 (M-H) - (ES-). Example 99: N- (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) -5 - ((3-fluoroazetidin-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1510] [1510] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5 - (((3-fluoroazetidin-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P66) and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (28 mg, 40%) as a white solid.
[1511] [1511] 1H NMR (DMSO-d6) δ 10.96 (br s, 1H), 7.82 (s, 1H), 6.92 (d, J = 9.9 Hz, 2H), 6.63 ( s, 1H), 5.16 (sd, J = 5.0, 57.6 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 2H), 3.55 (m, 2H), 3.19 (m, 2H), 2.96 (m, 2H), 1.06 (d, J = 12.0 Hz, 12H).
[1512] [1512] LCMS; m / z 470.5 (M + H) + (ES +); 468.4 (M-H) - (ES-). Example 100: 5 - (((3-Fluoroazetidin-1-yl) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -methyl-1H-pyrazol-3-sulfonamide
[1513] [1513] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5 - (((3-fluoroazetidin-1-yl) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P66) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (25 mg, 38%) as a white solid.
[1514] [1514] 1H NMR (DMSO-d6) δ 10.77 (br s, 1H), 8.02 (s, 1H), 6.94 (s, 1H), 6.66 (s, 1H), 5, 17 (sd, J = 5.0, 57.6 Hz, 1H), 3.85 (s, 3H), 3.72 (s, 2H), 3.55 (m, 2H), 3.20 (m, 2H ), 2.79 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7.3 Hz, 4H), 1.95 (p, J = 7.4 Hz, 4H).
[1515] [1515] LCMS; m / z 448.5 (M + H) + (ES +); 446.3 (M-H) - (ES-). Example 101: N- (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-5- (pyrrolidin-1-ylmethyl) -1H-pyrazol-3-sulfonamide
[1516] [1516] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 1-methyl-5- (pyrrolidin-1-ylmethyl) -1H-pyrazol-3-sulfonamide (Intermediate P65) and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (18 mg, 26%) as a white solid.
[1517] [1517] 1H NMR (DMSO-d6) δ 10.93 (s, 1H), 7.78 (s, 1H), 6.91 (d, J = 9.9 Hz, 2H), 6.60 (s , 1H), 3.87 (s, 3H), 3.66 (s, 2H), 3.00 - 2.92 (m, 2H), 2.44 (br s, 4H), 1.68 (br s, 4H), 1.04 (br s, 12H).
[1518] [1518] LCMS; m / z 466.5 (M + H) + (ES +); 464.4 (M-H) - (ES-). Example 102: 5 - ((Diethylamino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H-pyrazole -3-sulfonamide, sodium salt
[1519] [1519] Sodium tert-butoxide, 2 M in THF (78 µL, 0.156 mmol) was added to a solution of 5 - ((diethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P67) (35 mg, 0.142 mmol) in 2-MetF (2 mL) and stirred for 30 minutes. Then 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (31 mg, 0.156 mmol) was added and the reaction was stirred for another 2 days. The resulting solid was filtered off, washed with EtOAc and dried to generate the title compound (26 mg, 38%) as a white solid.
[1520] [1520] 1H NMR (DMSO-d6) δ 7.52 (s, 1H), 6.77 (s, 1H), 6.29 (s, 1H), 3.77 (s, 3H), 3.52 (s, 2H), 2.75 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 2.45 (q, J = 7.1 Hz , 4H), 1.89 (p, J = 7.3 Hz, 4H), 0.97 (t, J = 7.1 Hz, 6H).
[1521] [1521] LCMS; m / z 446.5 (M + H) + (ES +); 444.4 (M-H) - (ES-). Example 103: 5 - ((Diethylamino) methyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1522] [1522] Prepared according to the general procedure of 5- ((diethylamino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 102) from 5- ((diethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P67) and 5-fluoro -2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (53 mg, 75%) as a white solid.
[1523] [1523] 1H NMR (DMSO-d6) δ 7.39 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.28 (s, 1H), 3.76 (s , 3H), 3.51 (s, 2H), 3.13 (m, 2H), 2.45 (q, J = 7.1 Hz, 4H), 1.03 (d, J = 6.8 Hz , 12H), 0.97 (t, J = 7.1 Hz, 6H).
[1524] [1524] LCMS; m / z m / z 468.5 (M + H) + (ES +); 466.3 (M-H) - (ES-). Example 104: 5 - ((Ethyl (methyl) amino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl -1H-pyrazol-3-sulfonamide
[1525] [1525] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 5 - ((ethyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P68) and 4- isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (32 mg, 48%) as a white powder.
[1526] [1526] 1H NMR (DMSO-d6) δ 10.75 (s, 1H), 8.01 (s, 1H), 6.94 (s, 1H), 6.66 (s, 1H), 3.88 (s, 3H), 3.56 (s, 2H), 2.79 (t, J = 7.4 Hz, 4H), 2.59 (t, J = 7.4 Hz, 4H), 2.42 (q, J = 7.1 Hz, 2H), 2.13 (s, 3H), 1.94 (p, J = 7.5 Hz, 4H), 1.02 (t, J = 7.1 Hz , 3H).
[1527] [1527] LCMS; m / z 432.5 (M + H) + (ES +); 430.4 (M-H) - (ES-). Example 105: 5 - ((Cyclopropyl (methyl) amino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl -1H-pyrazol-3-sulfonamide, sodium salt
[1528] [1528] Sodium tert-butoxide, 2 M in THF (79 µL, 0.158 mmol) was added to a solution of 5 - ((cyclopropyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P69) (35 mg, 0.143 mmol) in THF (2 mL) and stirred for 30 minutes. Then 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (32 mg, 0.161 mmol) was added and the reaction was stirred for another 2 days. The THF was evaporated in vacuo, the residue dissolved in a mixture of DMF / water / THF and purified by RP Flash C18 chromatography (12 g column, 5-50% MeCN / 10 mM ammonium bicarbonate) to produce a solid White. This solid (32 mg) was dissolved in THF (1 ml), treated with sodium tert-butoxide, 2 M in THF (38 µL, 0.076 mmol) and stirred for 1 hour. The resulting solid was filtered off, washed with EtOAc and dried to generate the title compound (17 mg, 25%) as a white solid.
[1529] [1529] 1H NMR (DMSO-d6) δ 7.52 (s, 1H), 6.76 (s, 1H), 6.30 (s, 1H), 3.72 (s, 3H), 3.63 (s, 2H), 2.75 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 2.18 (s, 3H), 1.89 (p, J = 7.5 Hz, 4H), 1.74-1.68 (m, 1H), 0.44 (m, 2H), 0.32 (m, 2H).
[1530] [1530] LCMS; m / z 444.4 (M + H) + (ES +); 442.1 (M-H) - (ES-). Example 106: 5- (Azetidin-1-ylmethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H- pyrazol-3-sulfonamide, sodium salt
[1531] [1531] Prepared according to the general procedure of 5- ((cyclopropyl (methyl) amino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4- il) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 105) from 5- (azetidin-1-ylmethyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P70 ) and 4-isocyanate-1, 2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (15 mg, 21%) as a white powder.
[1532] [1532] 1H NMR (DMSO-d6) δ 7.52 (s, 1H), 6.77 (s, 1H), 6.26 (s, 1H), 3.73 (s, 3H), 3.50 (s, 2H), 3.12 (t, J = 7.0 Hz, 4H), 2.75 (t, J = 7.3 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H ), 1.97 (m, 2H), 1.90 (p, J = 7.4 Hz, 4H).
[1533] [1533] LCMS; m / z 430.5 (M + H) + (ES +); 428.0 (M-H) - (ES-). Example 107: 5 - ((Cyclopropyl (methyl) amino) methyl) -N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1534] [1534] 2 M sodium tert-butoxide in THF (79 µL, 0.158 mmol) was added to a solution of 5 - ((cyclopropyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P69) (35 mg, 0.143 mmol) in THF (2 mL) and stirred for 30 minutes. Then, 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) (35 mg, 0.158 mmol) was added and the reaction was stirred for another 2 days. The resulting solid was filtered off, washed with EtOAc and dried to generate the title compound (47 mg, 67%) as a white solid.
[1535] [1535] 1H NMR (DMSO-d6) δ 7.38 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.28 (s, 1H), 3.70 (s , 3H), 3.63 (s, 2H), 3.13 (m, 2H), 2.18 (s, 3H), 1.74-1.69 (m, 1H), 1.03 (d, J = 6.8 Hz, 12H), 0.45 (m, 2H), 0.33 (m, 2H).
[1536] [1536] LCMS; m / z m / z 466.5 (M + H) + (ES +); 464.4 (M-H) - (ES-). Example 108: 5- (Azetidin-1-ylmethyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1537] [1537] Prepared according to the general procedure of 5- ((cyclopropyl (methyl) amino) methyl) -N- ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazole-3 -sulfonamide, sodium salt (Example 107) from 5- (azetidin-1-ylmethyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P70) and 5-fluoro-2-isocyanate-1,3- diisopropylbenzene (Intermediate A2) to generate the title compound (46 mg, 63%) as a white solid.
[1538] [1538] 1H NMR (DMSO-d6) δ 7.38 (s, 1H), 6.79 (d, J = 10.2 Hz, 2H), 6.25 (s, 1H), 3.72 (s , 3H), 3.50 (s, 2H), 3.14 (m, 2H), 3.12 (t, J = 7.0 Hz, 4H), 2.03 - 1.91 (m, 2H), 1 , 03 (d, J = 6.8 Hz, 12H).
[1539] [1539] LCMS; m / z 452.5 (M + H) + (ES +); 450.4 (M-H) - (ES-). Example 109: 5 - ((Ethyl (methyl) amino) methyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1540] [1540] Prepared according to the general procedure of 5- ((cyclopropyl (methyl) amino) methyl) -N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazole-3 -sulfonamide, sodium salt (Example 107) from 5- ((ethyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P68) and 5-fluoro-2-isocyanate-1 , 3-diisopropylbenzene (Intermediate A2) to generate the title compound (39 mg, 54%) as a white solid.
[1541] [1541] 1H NMR (DMSO-d6) δ 7.39 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.27 (s, 1H), 3.75 (s , 3H), 3.44 (s, 2H), 3.13 (m, 2H), 2.38 (q, J = 7.2 Hz, 2H), 2.11 (s, 3H), 1.11 - 0.95 (m, 15H).
[1542] [1542] LCMS; m / z 454.5 (M + H) + (ES +); 452.4 (M-H) - (ES-). Example 110: N- (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) -5- ((isopropyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1543] [1543] Prepared according to the general procedure of 5- ((cyclopropyl (methyl) amino) methyl) -N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazole-3 -sulfonamide, sodium salt (Example 107) from 5- ((isopropyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P71) and 5-fluoro-2-isocyanate-1 , 3-diisopropylbenzene (Intermediate A2) to generate the title compound (45 mg, 64%) as a white solid.
[1544] [1544] 1H NMR (DMSO-d6) δ 7.39 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.27 (s, 1H), 3.75 (s , 3H), 3.48 (s, 2H), 3.13 (m, 2H), 2.83 (sept, J = 6.6 Hz, 1H), 2.05 (s, 3H), 1.03 (d, J = 6.8 Hz, 12H), 1.00 (d, J = 6.6 Hz, 6H).
[1545] [1545] LCMS; m / z 468.5 (M + H) + (ES +); 466.4 (M-H) - (ES-). Example 111: N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -5- ((isopropyl (methyl) amino) methyl) -1-methyl -1H-pyrazol-3-sulfonamide
[1546] [1546] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 5 - ((propyl (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P71) and 4- isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (33 mg, 51%) as a white solid.
[1547] [1547] 1H NMR (DMSO-d6) δ 10.65 (bs, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.62 (s, 1H), 3.86 (s, 3H), 3.58 (s, 2H), 2.85 (m, 1H), 2.79 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7, 4 Hz, 4H), 2.06 (s, 3H), 1.94 (p, J = 7.5 Hz, 4H), 1.01 (d, J = 6.6 Hz, 6H).
[1548] [1548] LCMS; m / z 446.5 (M + H) + (ES +); 444.4 (M-H) - (ES-). Example 112: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2,6-diisopropyl-phenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1549] [1549] Prepared according to the general procedure of 5- ((cyclopropyl (methyl) amino) methyl) -N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazole-3 -sulfonamide, sodium salt (Example 107) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (41 mg, 55%) as a white solid.
[1550] [1550] 1H NMR (DMSO-d6) δ 7.37 (s, 1H), 6.78 (d, J = 10.1 Hz, 2H), 6.26 (s, 1H), 3.74 (s , 3H), 3.37 (s, 2H), 3.12 (m, 2H), 2.13 (s, 6H), 1.01 (d, J = 6.9 Hz, 12H).
[1551] [1551] LCMS; m / z 440.4 (M + H) + (ES +); 438.4 (M-H) - (ES-). Example 113: N - (((4-Chloro-2,6-diisopropylphenyl) carbamoyl) -5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1552] [1552] Prepared according to the general procedure of 5- ((cyclopropyl (methyl) amino) methyl) -N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazole-3 -sulfonamide, sodium salt (Example 107) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 5-chloro-2-isocyanate-1,3-diisopropyl -benzene (Intermediate A22) to generate the title compound (43 mg, 64%) as a white solid.
[1553] [1553] 1H NMR (DMSO-d6) δ 7.46 (s, 1H), 7.01 (s, 2H), 6.27 (s, 1H), 3.75 (s, 3H), 3.38 (s, 2H), 3.13 (m, 2H), 2.14 (s, 6H), 1.03 (d, J = 6.8 Hz, 12H).
[1554] [1554] LCMS; m / z 456.4 / 458.4 (M + H) + (ES +); 454.3 / 456.3 (M-H) - (ES-). Example 114: 5 - ((Dimethylamino) methyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-methyl-1H-pyrazole -3-sulfonamide
[1555] [1555] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P39) and 4 - isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (38 mg, 66%) as a white solid.
[1556] [1556] 1H NMR (DMSO-d6) δ 10.74 (br s, 1H), 7.99 (s, 1H), 6.93 (s, 1H), 6.65 (s, 1H), 3, 88 (s, 3H), 3.49 (s, 2H), 2.79 (t, J = 7.4 Hz, 4H), 2.59 (t, J = 7.4 Hz, 4H), 2, 17 (s, 6H), 1.94 (quin, J = 7.4 Hz, 4H).
[1557] [1557] LCMS; m / z 418.45 (M + H) + (ES +); 416.36 (M-H) - (ES-). Example 115: 5- (1- (Dimethylamino) -2,2,2-trifluoroethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl ) -1-methyl-1H-pyrazol-3-sulfonamide
[1558] [1558] 2 M sodium tert-butoxide in THF (0.147 ml, 0.293 mmol) was added to a solution of 5- (1- (dimethylamino) -2,2,2-trifluoroethyl) -1-methyl-1H- pyrazole-3-sulfonamide (Intermediate P72) (80 mg, 0.279 mmol) in THF (1 mL) and stirred at room temperature for 1 hour. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (61.2 mg, 0.307 mmol) in THF (1mL) was added and stirred at temperature environment at night. The reaction mixture was concentrated and the crude product was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN / 10 mM ammonium bicarbonate), followed by preparative reverse phase HPLC (General Methods, preparation basic) to generate the title compound (9 mg, 7%) as a colorless solid.
[1559] [1559] 1H NMR (DMSO-d6) δ 10.87 (s, 1H), 8.02 (s, 1H), 6.89 (s, 1H), 6.70 (s, 1H), 5.14 (q, J = 8.4 Hz, 1H), 3.92 (s, 3H), 2.75 (t, J = 7.4 Hz, 4H), 2.55 (t, J =
[1560] [1560] LCMS; m / z 486.3 (M + H) + (ES +). Example 116: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- isopropyl-5 - ((methyl (2,2,2- trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide
[1561] [1561] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 1-isopropyl-5- (((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazole -3-sulfonamide (Intermediate P73) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (17 mg, 76%) as a white solid.
[1562] [1562] 1H NMR (DMSO-d6) δ 10.86 (s, 1H), 8.00 (s, 1H), 6.93 (s, 1H), 6.70 (s, 1H), 4.81 - 4.75 (m, 1H), 3.82 (s, 2H), 3.31 - 3.26 (m, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2, 57 (t, J = 7.4 Hz, 4H), 2.30 (s, 3H), 1.92 (p, J = 7.5 Hz, 4H), 1.39 (d, J = 6.5 Hz, 6H).
[1563] [1563] LCMS; m / z 514.4 (M + H) + (ES +). Example 117: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-5 - ((methyl (2,2,2- trifluoroethyl) amino) methyl) -1H-pyrazol-3-sulfonamide, sodium salt
[1564] [1564] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N, N-dimethylacetamide, sodium salt (Example 1) from 1-methyl-5 - ((methyl (2,2,2-trifluoroethyl) amino) methyl) -1H-pyrazole -3-sulfonamide (Intermediate P74) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (110 mg, 83%).
[1565] [1565] 1H NMR (DMSO-d6) δ 7.54 (s, 1H), 6.77 (s, 1H), 6.36 (s, 1H), 3.77
[1566] [1566] LCMS; m / z 486.5 (M + H) + (ES +). Example 118: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1 - ((1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-3-sulfonamide
[1567] [1567] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 1 - ((1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-3-sulfonamide (Intermediate P75) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (34 mg, 21%) as a white solid.
[1568] [1568] 1H NMR (DMSO-d6) δ 10.85 (br s, 1H), 7.97 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.14 ( d, J = 1.1 Hz, 1H), 6.93 (s, 1H), 6.85 (d, J = 1.2 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.53 (s, 2H), 3.63 (s, 3H), 2.79 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 1.95 (p, J = 7.5 Hz, 4H).
[1569] [1569] LCMS; m / z 441.4 (M + H) + (ES +). Example119: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (pyridin-2-yl) -1H-pyrazol-3-sulfonamide sodium salt
[1570] [1570] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N, N-
[1571] [1571] 1H NMR (DMSO-d6) δ 8.52 (d, J = 2.6 Hz, 1H), 8.47 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H) , 8.05 - 7.98 (m, 1H), 7.92 - 7.86 (m, 1H), 7.48 (s, 1H), 7.37 (ddd, J = 7.3, 4, 9, 1.0 Hz, 1H), 6.75 (s, 1H), 6.67 (d, J = 2.6 Hz, 1H), 2.73 (t, J = 7.4 Hz, 4H), 2 , 67 (t, J = 7.3 Hz, 4H), 1.87 (p, J = 7.5 Hz, 4H).
[1572] [1572] LCMS; m / z 424 (M + H) + (ES +). Example 120:: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (thiazol-2-yl) -1H-pyrazol-3 -sulfonamide, sodium salt
[1573] [1573] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N, N-dimethylacetamide, sodium salt (Example 1) from 1- (thiazol-2-yl) -1H-pyrazol-3-sulfonamide (Intermediate P77) and 4-isocyanate- 1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (16 mg, 24%) as a white solid.
[1574] [1574] 1H NMR (DMSO-d6) δ 8.40 (d, J = 2.6 Hz, 1H), 7.64 (d, J = 3.5 Hz, 1H), 7.57 (d, J = 3.5 Hz, 1H), 7.48 (s, 1H), 6.77 (s, 1H), 6.70 (d, J = 2.6 Hz, 1H), 2.81 - 2.70 (m, 8H), 1.93 - 1.87 (m, 4H).
[1575] [1575] LCMS; m / z 430 (M + H) + (ES +). Example 121: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1- (pyridin-3-yl) -1H-pyrazol-3- sulfonamide
[1576] [1576] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from 1- (pyrimidin-3-yl) -1H-pyrazol-3-sulfonamide (Intermediate P78) and 4-isocyanate-1,2,3 , 5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (16 mg, 17%) as a white solid.
[1577] [1577] 1H NMR (DMSO-d6) δ 11.12 (br s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.6 Hz, 1H) , 8.62 (dd, J = 4.7, 1.4 Hz, 1H), 8.25 (ddd, J = 8.4, 2.7, 1.5 Hz, 1H), 7.95 (s , 1H), 7.62 (ddd, J = 8.3, 4.7, 0.7 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 6.88 (s, 1H), 2.76 (t, J = 7.4 Hz, 4H), 2.61 (t, J = 7.4 Hz, 4H), 1.88 (p, J = 7.4 Hz, 4H) .
[1578] [1578] LCMS; m / z 424 (M + H) + (ES +); 422 (M-H) - (ES-). Example 122: 5- (3- (Dimethylamino) oxetan-3-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -methyl-1H-pyrazol-3-sulfonamide
[1579] [1579] 5- (3- (Dimethylamino) oxetan-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P79) (65 mg, 0.21 mmol) was dissolved in 4: 1 THF: DMF (2.5 ml) and sodium tert-butoxide (2 M in THF; 0.117 ml, 0.233 mmol) was added. After 1 hour, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (46.5 mg, 0.233 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by C18 reverse phase flash chromatography chromatography (12 g column, 10-40% MeCN / 10 mM ammonium bicarbonate) to generate the title compound ( 20 mg, 20%) as a white solid.
[1580] [1580] 1H NMR (DMSO-d6) δ 10.82 (br s, 1H), 7.98 (s, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 4, 95 (d, J = 7.2 Hz, 2H), 4.76 (d, J = 7.2 Hz, 2H), 3.76 (s, 3H), 2.78 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7.4 Hz, 4H), 2.21 (s, 6H), 1.93 (p, J = 7.4 Hz, 4H).
[1581] [1581] LCMS; m / z 460.3 (M + H) + (ES +); 458.2 (M-H) - (ES-). Example 123: N - (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) -5 - (((2-hydroxy) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1582] [1582] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5 - ((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3- sulfonamide (Intermediate P80) and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (28 mg, 32%) as a white solid.
[1583] [1583] 1H NMR (DMSO-d6) δ 10.97 (br s, 1H), 7.82 (s, 1H), 6.93 (d, J = 9.9 Hz, 2H), 6.64 ( s, 1H), 4.48 (t, J = 5.3 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 2H), 3.52 (q, J = 5.9 Hz, 2H), 2.97 (m, 2H), 2.46 (t, J = 6.1 Hz, 2H), 2.15 (s, 3H), 1.06 (br s, 12H).
[1584] [1584] LCMS; m / z 470.5 (M + H) + (ES +); 468.2 (M-H) - (ES-). Example 124: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -5 - (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
[1585] [1585] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5 - (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3 -sulfonamide (Intermediate P80) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (22 mg, 27%) as a solid White.
[1586] [1586] 1H NMR (DMSO-d6) δ 10.71 (br s, 1H), 7.94 (s, 1H), 6.91 (s, 1H), 6.61 (s, 1H), 4, 47 (t, J = 5.3 Hz, 1H), 3.88 (s, 3H), 3.59 (s, 2H), 3.52 (q, J = 5.9 Hz, 2H), 2, 79 (t, J = 7.4 Hz, 4H), 2.61 (t, J = 7.4 Hz, 4H), 2.46 (t, J = 6.1 Hz, 2H), 2.15 ( s, 3H), 1.94 (p, J = 7.5 Hz, 4H).
[1587] [1587] LCMS; m / z 448.5 (M + H) + (ES +); 446.1 (M-H) - (ES-). Example 125: N - (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) -5 - (((2-methoxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide, salt sodic
[1588] [1588] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N, N-dimethylacetamide, sodium salt (Example 1) from 5 - (((2-methoxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3 -sulfonamide (Intermediate P81) and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (22 mg, 39%) as a white solid.
[1589] [1589] 1H NMR (DMSO-d6) δ 7.37 (s, 1H), 6.79 (d, J = 10.0 Hz, 2H), 6.27 (s, 1H), 3.76 (s, 3H ), 3.50 (s, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.23 (s, 3H), 3.14 (m, 2H), 2.51 (t , J = 5.8 Hz, 2H), 2.15 (s, 3H), 1.03 (d, J = 6.8 Hz, 12H).
[1590] [1590] LCMS; m / z 484.5 (M + H) + (ES +); 482.3 (M-H) - (ES-). Example 126: N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -5 - (((2-methoxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1591] [1591] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N, N-dimethylacetamide, sodium salt (Example 1) from 5 - (((2-methoxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrazol-3 -sulfonamide (Intermediate P81) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (32 mg, 47%) as a solid White.
[1592] [1592] 1H NMR (DMSO-d6) δ 7.59 (m, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.79 (s, 3H), 3.52 (s, 2H), 3.44 (t, J = 5.8 Hz, 2H), 3.23 (s, 3H), 2.75 (t, J = 7.3 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 2.51 (t, J = 5.8 Hz, 2H), 2.16 (s, 3H), 1.90 (p, J = 7.5 Hz , 4H).
[1593] [1593] LCMS; m / z 462.4 (M + H) + (ES +); 460.4 (M-H) - (ES-). Example 127: N - (((4-Chloro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-5- (morpholinomethyl) -1H-pyrazol-3-sulfonamide, sodium salt
[1594] [1594] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N, N-dimethylacetamide, sodium salt (Example 1) from 1-methyl-5 (morpholinomethyl) -1H-pyrazol-3-sulfonamide (Intermediate P82) and 5-chloro-2 -isocyanate-1,3-diisopropylbenzene (Intermediate A22) to generate the title compound (38 mg, 53%) as a white solid.
[1595] [1595] 1H NMR (DMSO-d6) δ 7.45 (s, 1H), 7.01 (s, 2H), 6.28 (s, 1H), 3.77 (s, 3H), 3.56 (t, J = 4.6 Hz, 4H), 3.48 (s, 2H), 3.13 (m, 2H), 2.36 (t, J = 4.6 Hz, 4H), 1.03 (d, J = 6.8 Hz, 12H).
[1596] [1596] LCMS; m / z 498.4 / 500.5 (M + H) + (ES +); 496.3 / 498.4 (M-H) - (ES-). Example 128: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-5- (morpholinomethyl) -1H-pyrazol-3- sulfonamide
[1597] [1597] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 1-methyl-5- (morpholinomethyl) -1H-pyrazol-3-sulfonamide (Intermediate P82) and 4-isocyanate-
[1598] [1598] 1H NMR (DMSO-d6) δ 10.81 (br s, 1H), 7.96 (s, 1H), 6.91 (s, 1H), 6.62 (s, 1H), 3, 88 (s, 3H), 3.56 (s, 2H), 3.56 (m, 4H), 2.78 (t, J = 7.4 Hz, 4H), 2.59 (t, J = 7 , 4 Hz, 4H), 2.36 (m, 4H), 1.93 (p, J = 7.5 Hz, 4H).
[1599] [1599] LCMS; m / z 460.4 (M + H) + (ES +); 458.4 (M-H) - (ES-). Example 129: N - ((3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-isopropyl-1H-pyrazole -5-yl) methyl) -N-methylacetamide
[1600] [1600] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N-methylacetamide (Example 2) from N - (((1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl) methyl) -N-methylacetamide (Intermediate P83) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (20 mg, 38%) as a white solid.
[1601] [1601] 1H NMR (DMSO-d6) δ 10.77 (br s, 1H), 7.93 (s, 1H), 6.88 (s, 1H), 6.62 (s, 1H), 4, 75 - 4.61 (m, 1H), 4.59 (s, 2H), 2.90 (s, 3H), 2.75 (t, J = 7.4 Hz, 4H), 2.56 (t , J = 7.3 Hz, 4H), 2.02 (s, 3H), 1.90 (p, J = 7.6 Hz, 4H), 1.31 (d, J = 6.5 Hz, 6H ).
[1602] [1602] LCMS; m / z 474.5 (M + H) + (ES +) Example 130: 5- (Azetidine-1-carbonyl) -N - (((4-fluoro-2,6-diisopropiphenyl) carbamoyl) -1-isopropyl-1H -pyrazol-3-sulfonamide, sodium salt
[1603] [1603] Prepared according to the general procedure of 2- (3- (N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) - 1H-pyrazol-1-yl) -N, N-
[1604] [1604] 1H NMR (DMSO-d6) δ 7.33 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.65 (s, 1H), 5.26 (sept , J = 6.7 Hz, 1H), 4.25 (t, J = 7.7 Hz, 2H), 4.02 (t, J = 7.8 Hz, 2H), 3.22 - 2.93 (m, 2H), 2.26 (app. pent, J = 7.7 Hz, 2H), 1.37 (d, J = 6.6 Hz, 6H), 1.03 (d, J = 6, 8 Hz, 12H).
[1605] [1605] LCMS; m / z 494.4 (M + H) + (ES +); 492.3 (MH) - (ES-) Example 131: 5- (Azetidine-1-carbonyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4- il) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide, partial ammonium salt
[1606] [1606] Prepared according to the general procedure of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (Example 17) from 5- (azetidine-1-carbonyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P91) and 4-isocyanate- 1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to generate the title compound (47 mg, 53%) as a white solid.
[1607] [1607] 1H NMR (DMSO-d6) δ 7.77 (s, 1H), 6.92 - 6.68 (m, 2H), 5.28 (sept, J = 6.5 Hz, 1H), 4 , 27 (t, J = 7.7 Hz, 2H), 4.03 (t, J = 7.7 Hz, 2H), 2.76 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7.3 Hz, 4H), 2.31 - 2.19 (m, 2H), 1.90 (p, J = 7.4 Hz, 4H), 1.38 (d, J = 6.6 Hz, 6H).
[1608] [1608] LCMS; m / z 472.5 (M + H) + (ES +); 470.3 (M-H) - (ES-). Example 132: 3- (N - (((4-Chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1609] [1609] HATU (68.8 mg, 0.181 mmol) was added to a solution of 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazole- 5- carboxylic, disodium salt (Intermediate P90) (73.4 mg, 0.151 mmol) and methylamine (83 µL, 0.166 mmol) in DMF (1 mL). TEA (21 µL, 0.151 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (1 ml) was added slowly and the mixture was stirred for 1 hour, filtered and the collected solid triturated in water (3 ml) for 0.5 hour. The suspension was filtered, the solid washed with water (0.5 ml) and MTBE (1 ml) and then purified by RP Flash C18 chromatography (13 g column, 0-50% MeCN / 10 mM ammonium bicarbonate ). The product was triturated with MTBE (2 ml) for 1 hour, filtered and vacuum dried for 15 hours to generate the title compound (7 mg, 10%) as a white solid.
[1610] [1610] 1H NMR (DMSO-d6) δ 11.21 (s, 1H), 8.64 (s, 1H), 7.89 (s, 1H), 7.31 (s, 1H), 7.12 (s, 2H), 4.13 (s, 3H), 3.00 - 2.90 (m, 2H), 2.74 (d, J = 4.5 Hz, 3H), 1.05 - 1, 01 (m, 12H).
[1611] [1611] LCMS; m / z 456.4 and 458.4 (M + H) + (ES +). Example 133: 3- (N - (((4-Fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H- pyrazol-5-carboxamide, sodium salt
[1612] [1612] A mixture of (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P92) ( 70 mg, 0.184 mmol) and 4-fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) aniline (Intermediate A14) (40 mg, 0.167 mmol) in MeCN (1 mL) was stirred at 50 ° C for 1 hour. The crude product was purified by preparative reverse phase HPLC (General Methods, basic preparation) to generate the desired carboxamide as a white solid (21 mg). To a solution of the carboxamide (21 mg) in THF (0.5 ml), a solution of 2.0 M NaOtBu in THF (1.0 eq) was added. The mixture was stirred for 1 hour, the solvent was evaporated and the solid triturated with THF / MTBE. The precipitate was collected by filtration, washed with ether and dried in vacuo to generate the title compound (5 mg, 6%) as a white solid.
[1613] [1613] 1H NMR (DMSO-d6), rotamers; δ 7.39 (s, 1H), 6.81 (td, J = 10.6, 2.9 Hz, 2H), 6.61 (s, 1H), 3.90 - 3.81 (m, 5H ), 3.28 - 3.11 (m, 3H), 3.04 - 2.97 (m, 7H), 1.57 - 1.43 (m, 4H), 1.04 (d, J = 6 , 8 Hz, 6H).
[1614] [1614] LCMS; m / z 496.5 (M + H) + (ES +); 494.3 (M-H) - (ES-). Example 134: 3- (N - ((2-isopropyl-5- (pyrimidin-5-yl) phenyl) carbamoyl) sulfamoyl) - N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt
[1615] [1615] Prepared according to the general procedure for 3- (N - (((4-fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt (Example 133) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl -1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P92) and 2-isopropyl-5- (pyrimidin-5-yl) aniline (Intermediate A16) to generate the title compound (27 mg, 23%) as a white solid.
[1616] [1616] 1H NMR (DMSO-d6), rotamers; δ 9.15 (s, 1H), 9.01 (s, 2H), 8.14 (s, 1H), 7.77 (s, 1H), 7.31 (s, 2H), 6.63 ( s, 1H), 3.82 (s, 3H), 3.19 (sept, J = 6.8 Hz, 1H), 3.03 (s, 3H), 2.98 (s, 3H), 1, 17 (d, J = 6.8 Hz, 6H).
[1617] [1617] LCMS; m / z 472.4 (M + H) + (ES +); 470.4 (M-H) - (ES-). Example 135: 3- (N - ((4-Fluoro-2-isopropyl-6- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H- pyrazol-5-carboxamide, sodium salt
[1618] [1618] Prepared according to the general procedure for 3- (N - ((4-fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt (Example 133) from (4- (dimethylamino) pyridin-1-ium-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl -1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P92) and 4-fluoro-2-isopropyl-6- (1-methyl-1H-pyrazol-4-yl) aniline (Intermediate A13) to provide the compound of title (40 mg, 20%) as a white solid.
[1619] [1619] 1H NMR (DMSO-d6), rotamers; δ 7.95 (s, 1H), 7.76 (s, 1H), 7.25 (s, 1H), 7.10 (dd, J = 9.9, 3.0 Hz, 1H), 6.86 ( dd, J = 9.8, 2.9 Hz, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.20 (m, 1H ), 2.99 (s, 6H), 1.06 (d, J = 6.8 Hz, 6H).
[1620] [1620] LCMS; m / z 492.4 (M + H) + (ES +); 490.3 (MH) - (ES-) Example 136: 3- (N - ((2-isopropyl-5- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N , 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt
[1621] [1621] Prepared according to the general procedure for 3- (N - ((4-fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt (Example 133) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl -1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P92) and 2-isopropyl-5- (1-methyl-1H-pyrazol-4-yl) aniline (Intermediate A15) to generate the title compound (6 mg , 5%) as a white solid.
[1622] [1622] 1H NMR (DMSO-d6), rotamers; δ 7.94 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.10 - 7.05 (m, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.09 (sept, J = 6.8 Hz, 1H), 3.03 (s, 3H), 2.98 (s, 3H), 1.14 (d, J = 6.8 Hz, 6H).
[1623] [1623] LCMS; m / z 474.5 (M + H) + (ES +); 472.3 (M-H) - (ES-). Example 137: 3- (N - ((4-Chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N- (cyanomethyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1624] [1624] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P90) and 2- ( methylamino) acetonitrile, HCl to generate the title compound (26 mg, 42%).
[1625] [1625] 1H NMR (DMSO-d6), rotamers; δ 11.25 (s, 1H), 7.99 (s, 1H), 7.14 (s, 3H), 4.58 (s, 2H), 3.97 (s, 3H), 3.12 ( s, 3H), 2.98 - 2.85 (m, 2H), 1.05 (br s, 12H),
[1626] [1626] LCMS; m / z 495.5 and 497.5 (M + H) + (ES +). Example 138: 3- (N - ((2,6-Diisopropylphenyl) carbamoyl) sulfamoyl) -N-isopropyl-1-methyl-1H-pyrazol-5-carboxamide
[1627] [1627] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P88) and isopropylamine to generate the title compound (28 mg, 45%) as a white solid.
[1628] [1628] 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.47 (s , 1H), 7.27 - 7.20 (m, 1H), 7.11 (d, J = 7.6 Hz, 2H), 4.15 (s, 3H), 4.09 - 3.99 ( m, 1H), 2.90 - 2.86 (m, 2H), 1.13 (d, J = 6.6 Hz, 6H), 1.05 - 1.03 (m, 12H).
[1629] [1629] LCMS; m / z 450 (M + H) + (ES +). Example 139: N - ((2,6-Diisopropylphenyl) carbamoyl) -5- (3-fluoroazetidine-1-
[1630] [1630] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P88) and 3-fluoroazetidine, HCl. The sodium salt was generated by dissolving the free acid (19 mg, 0.041 mmol) in THF (1 mL) and adding a 2 M solution of sodium tert-butoxide (20.50 µL, 0.041 mmol) in THF. The suspension was stirred for 2 hours and filtered. The collected solid was washed with EtOAc (2 ml) and dried under reduced pressure for 6 hours to generate the title compound (6 mg, 8%) as a white solid.
[1631] [1631] 1H NMR (DMSO-d6), rotamers; δ 7.32 (s, 1H), 7.11 - 7.10 (m, 1H), 7.01 (d, J = 7.3 Hz, 2H), 6.71 (s, 1H), 5, 51 - 5.33 (m, 1H), 4.63 - 4.59 (m, 1H), 4.40 - 4.32 (m, 2H), 4.11 - 4.01 (m, 1H), 3.98 (s, 3H), 3.16 - 3.12 (m, 2H), 1.04 (d, J = 6.8 Hz, 12H).
[1632] [1632] LCMS; m / z 466 (M + H) + (ES +) Example 140: N- (Cyanomethyl) -3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazole- 5-carboxamide
[1633] [1633] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P88) and 2- (methylamino) acetonitrile, HCL for generate the title compound (25 mg, 33%) as a white solid.
[1634] [1634] 1H NMR (DMSO-d6) δ 7.59 (s, 1H), 7.20 - 7.12 (m, 1H), 7.06 (d, J = 7.6 Hz, 2H), 6 , 91 (s, 1H), 4.57 (s, 2H), 3.91 (s, 3H), 3.13 (s, 3H), 3.08 - 3.05 (m, 2H), 1, 05 (d, J = 6.9 Hz, 12H). No acidic NH was observed.
[1635] [1635] LCMS; m / z 461 (M + H) + (ES +). Example 141: 3- (N - (((4-Fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt
[1636] [1636] Prepared according to the general procedure for 3- (N - ((4-fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt (Example 133) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl -1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P92) and 4-fluoro-2-isopropyl-6- (pyridin-3-yl) aniline (Intermediate A6) to generate the title compound (23 mg, 9 %) as a white solid.
[1637] [1637] 1H NMR (DMSO-d6, 70 ° C) δ 8.55 (m, 1H), 8.45 (dd, J = 4.8, 1.7 Hz, 1H), 7.77 (dt, J = 7.8, 2.0 Hz, 1H), 7.25 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.06 (dd, J = 10.2, 3.0 Hz, 1H), 6.91 (dd, J = 9.1, 3.0 Hz, 1H), 6.44 (s, 1H), 3.84 (s, 3H), 3.26 (sept, J = 6.9 Hz, 1H), 3.04 (s, 6H), 1.13 (d, J = 6.9 Hz, 6H). NH not observed.
[1638] [1638] LCMS; m / z 489.4 (M + H) + (ES +). Example 142: 3- (N - (((4-Fluoro-2-isopropyl-6- (pyrimidin-5-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt
[1639] [1639] Prepared according to the general procedure for 3- (N - ((4-fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-
[1640] [1640] 1H NMR (DMSO-d6, 70 ° C) δ 9.03 (s, 1H), 8.76 (s, 2H), 7.30 (bs, 1H), 7.11 (dd, J = 10 , 2, 3.0 Hz, 1H), 7.03 (dd, J = 9.0, 3.0 Hz, 1H), 6.43 (s, 1H), 3.85 (s, 3H), 3.26 (sept, J = 6.8 Hz, 1H), 3.04 (s, 6H), 1.14 (d, J = 6.8 Hz, 6H).
[1641] [1641] LCMS; m / z 490.4 (M + H) + (ES +). Example 143: N-Cyanopropyl-3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1642] [1642] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P88) and N-methylcyclopropanamine, HCL to generate the compound of the title (45 mg, 55%) as a white solid.
[1643] [1643] 1H NMR (DMSO-d6), rotamers; δ 11.04 (s, 1H), 7.96 - 7.86 (2 xs, 1H), 7.26 - 7.23 (m, 1H), 7.16 - 7.11 (m, 3H), 3.95 (s, 3H), 3.09 - 2.84 (m, 6H), 1.18 - 1.14 (m, 12H), 0.55 - 0.52 (m, 4H). LCMS; m / z 462 (M + H) + (ES +). Example 144: 3- (N - ((2,5-Diisopropylphenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt
[1644] [1644] Prepared according to the general procedure for 3- (N - ((4-
[1645] [1645] 1H NMR (DMSO-d6), rotamers; δ 7.51 - 7.47 (m, 2H), 7.05 (d, J =
[1646] [1646] LCMS; m / z 436.5 (M + H) + (ES +). Example 145: 5- (Azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropiphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt
[1647] [1647] Azetidine hydrochloride (17 mg, 0.182 mmol), NaHCO3 (30 mg, 0.357 mmol) and HATU (68 mg, 0.179 mmol) were added successively to a solution of 3- (N - ((4-fluoro- 2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P89) (70 mg, 0.149 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (1 mL) and purified by RP Flash C18 chromatography (12 g column, 5-50% MeCN / 10 mM ammonium bicarbonate) to generate the free acid (59 mg, 84%) as a white solid. The sodium salt was generated by dissolving the free acid (55 mg, 0.12 mmol) in THF (3 mL) and adding a 2 M solution of sodium tert-butoxide (63 µL, 0.126 mmol) in THF. The suspension was stirred for 30 minutes and filtered. The collected solid was washed with EtOAc (2 ml), mixed with MeCN (3 ml), filtered and dried in vacuo to generate the title compound (29 mg, 40%) as a white solid.
[1648] [1648] 1H NMR (DMSO-d6) δ 7.33 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.67 (s, 1H), 4.29 (t , J = 7.7 Hz, 2H), 4.03 (t, J = 7.7 Hz, 2H), 3.98 (s, 3H), 3.11 (m, 2H), 2.27 (p , J = 7.7 Hz, 2H), 1.02 (d, J = 7.7 Hz, 12H).
[1649] [1649] LCMS; m / z 466.4 (M + H) + (ES +); 464.3 (M-H) - (ES-). Example 146: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N-isopropyl-1-methyl-1H-pyrazole -5 -carboxamide
[1650] [1650] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5- carboxylic, disodium salt (Intermediate P87) and isopropylamine to generate the title compound (14 mg, 24%) as a white solid.
[1651] [1651] 1H NMR (DMSO-d6) δ 10.94 (s, 1H), 8.50 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.46 (s , 1H), 6.94 (s, 1H), 4.13 (s, 3H), 4.09 - 3.98 (m, 1H), 2.79 (t, J = 7.4 Hz, 4H) , 2.60 (t, J = 7.4 Hz, 4H), 1.98 - 1.91 (m, 4H), 1.14 (d, J = 6.6 Hz, 6H).
[1652] [1652] LCMS; m / z 446 (M + H) + (ES +). Example 147: 3- (N - (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N-isopropyl-N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1653] [1653] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 145) from 3- (N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P89) and N-methylpropane-2-amine to generate the title compound (33 mg, 45%) as a white solid.
[1654] [1654] 1H NMR (DMSO-d6), rotamers; δ 11.18 (bs, 1H), 7.82 (s, 1H), 6.92 & 6.80 (2 xs, 1H), 6.90 (d, J = 10.0 Hz, 2H), 4.67 & 3.96 (2 xm, 1H), 3.89 & 3.87
[1655] [1655] LCMS; m / z 482.4 (M + H) + (ES +); 480.3 (M-H) - (ES-). Example 148: N, N-Diethyl-3- (N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxamide, sodium salt
[1656] [1656] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 145) from 3- (N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P89) and diethylamine to generate the title compound (26 mg, 34%) as a white solid.
[1657] [1657] 1H NMR (DMSO-d6), rotamers; δ 7.35 (s, 1H), 6.79 (d, J = 10.0 Hz, 2H), 6.51 (s, 1H), 3.77 (s, 3H), 3.50 - 3.28 ( m, 4H), 3.14 (m, 2H), 1.12 (bs, 6H), 1.03 (d, J = 6.8 Hz, 12H).
[1658] [1658] LCMS; m / z 482.4 (M + H) + (ES +); 480.4 (M-H) - (ES-). Example 149: N-Ethyl-3- (N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide, sodium salt
[1659] [1659] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 145) from 3- (N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P89) and N-methylethhanamine to generate the title compound (24 mg, 33%) as a white solid.
[1660] [1660] 1H NMR (DMSO-d6), rotamers; δ 7.34 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.58 & 6.52 (2 xs, 1H), 3.80 (s, 3H), 3 , 52 - 3.35 (m, 2H), 3.14 (m, 2H), 3.0 & 2.96 (2 xs, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1 , 03 (d, J = 6.9 Hz, 12H).
[1661] [1661] LCMS; m / z 468.4 (M + H) + (ES +); 466.3 (M-H) - (ES-). Example 150: 3- (N - (((4-Fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1662] [1662] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 145) from 3- (N - (((4-fluoro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P89) and methylamine to generate the title compound (26 mg, 39%) as a white solid.
[1663] [1663] 1H NMR (DMSO-d6) δ 11.16 (bs, 1H), 8.62 (q, J = 4.6 Hz, 1H), 7.76 (s, 1H), 7.28 (s , 1H), 6.89 (d, J = 10.0 Hz, 2H), 4.12 (s, 3H), 2.95 (sept, J = 6.4 Hz, 2H), 2.74 (d, J = 4.6 Hz, 3H), 1.02 (bs, 12H).
[1664] [1664] LCMS; m / z 440.4 (M + H) + (ES +); 438.4 (M-H) - (ES-). Example 151: 5- (Azetidine-1-carbonyl) -N - ((2,6-diisopropiphenyl) carbamoyl) -1- methyl-1H-pyrazol-3-sulfonamide
[1665] [1665] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P88) and azetidine, HCL to generate the title compound (6 mg, 8%) as a white solid.
[1666] [1666] 1H NMR (DMSO-d6) δ 7.38 (s, 1H), 7.11 (dd, J = 8.4, 6.8 Hz, 1H), 7.06 - 6.99 (m, 2H), 6.71 (s, 1H), 4.29 (t, J = 7.7 Hz, 2H), 4.07 - 3.97 (m, 5H), 3.12 - 3.08 (m , 2H), 2.31 - 2.22 (m, 2H), 1.04 (d, J = 6.8 Hz, 12H). Acidic NH not observed.
[1667] [1667] LCMS; m / z 448 (M + H) + (ES +). Example 152: N-Cyclopropyl-3- (N - (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H -pyrazol-5-carboxamide
[1668] [1668] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5- carboxylic, disodium salt (Intermediate P87) and N-methylcyclopropanamine, HCL to generate the title compound (28 mg, 34%) as a white solid.
[1669] [1669] 1H NMR (DMSO-d6) δ 10.90 (br s, 1H), 8.06 (s, 1H), 7.16 (br s, 1H), 6.95 (s, 1H), 3 , 94 (s, 3H), 2.99 (s, 3H), 2.79 (t, J = 7.4 Hz, 4H), 2.59 (t, J = 7.4 Hz, 4H), 1 , 99 - 1.91 (m, 4H), 0.60 - 0.50 (m, 4H). An unobserved interchangeable proton.
[1670] [1670] LCMS; m / z 458 (M + H) + (ES +). Example 153: N- (Cyanomethyl) -3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N, 1-dimethyl -1H-pyrazol-5-carboxamide, partial ammonium salt
[1671] [1671] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-
[1672] [1672] 1H NMR (DMSO-d6) δ 7.75 (s, 1H), 6.91 (s, 1H), 6.84 (s, 1H), 4.58 (s, 2H), 3.90 (s, 3H), 3.14 (s, 3H), 2.77 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 1.92 (quin, J = 7.4 Hz, 4H).
[1673] [1673] LCMS; m / z 457.4 (M + H) + (ES +); 455.3 (M-H) - (ES-). Example 154: 5- (Azetidine-1-carbonyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1-methyl-1H- pyrazol-3-sulfonamide
[1674] [1674] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 145) from 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl- 1H-pyrazol-5-carboxylic, disodium salt (Intermediate P87) and azetidine, HCL to generate the title compound (40 mg, 55%) as a white solid.
[1675] [1675] 1H NMR (DMSO-d6) δ 10.93 (bs, 1H), 8.09 (s, 1H), 7.06 (s, 1H), 6.95 (s, 1H), 4.34 (t, J = 7.7 Hz, 2H), 4.08 (s, 3H), 4.05 (t, J = 7.7 Hz, 2H), 2.79 (t, J = 7.4 Hz , 4H), 2.60 (t, J = 7.3 Hz, 4H), 2.33 - 2.20 (m, 2H), 1.95 (quin, J = 7.4 Hz, 4H).
[1676] [1676] LCMS; m / z 444.5 (M + H) + (ES +); 442.3 (M-H) - (ES-). Example 155: 3- (N - ((2,6-Diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1677] [1677] Methylamine in THF (108 µL, 0.217 mmol) and HATU (82 mg, 0.217 mmol) were added successively to a solution of 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic, disodium salt (Intermediate P88) (70 mg, 0.155 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 ml) and purified by preparative reverse phase HPLC (General Methods, basic preparation) to generate the title compound (26 mg, 40%) as a white solid.
[1678] [1678] 1H NMR (DMSO-d6) δ 11.07 (bs, 1H), 8.62 (d, J = 5.1 Hz, 1H), 7.74 (s, 1H), 7.28 (s , 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 7.7 Hz, 2H), 4.13 (s, 3H), 2.96 (m , 2H), 2.73 (d, J = 4.5 Hz, 3H), 1.06 - 1.00 (m, 12H).
[1679] [1679] LCMS; m / z 422.4 (M + H) + (ES +); 420.4 (M-H) - (ES-). Example 156: 3- (N - ((2,6-Diisopropylphenyl) carbamoyl) sulfamoyl) -N-ethyl-N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1680] [1680] Prepared according to the general procedure for 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 155) from acid 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P88) and N-methylethhanamine to generate the title compound (10 mg, 14%) as a white solid.
[1681] [1681] 1H NMR (DMSO-d6), rotamers; δ 11.09 (bs, 1H), 7.81 (s, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.6 Hz, 2H) , 6.96 & 6.87 (2 xs, 1H), 3.92 & 3.90 (2 xs, 3H), 3.46 & 3.31 (2 xq, J = 7.1 Hz, 2H), 2.98 (br s, 5H), 1.16 - 1.0 (m, 15H).
[1682] [1682] LCMS; m / z 450.5 (M + H) + (ES +); 448.4 (M-H) - (ES-). Example 157: 3- (N - ((2,6-Diisopropylphenyl) carbamoyl) sulfamoyl) -N, N-diethyl-1-methyl-1H-pyrazol-5-carboxamide
[1683] [1683] Prepared according to the general procedure for 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 155) from acid 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic, disodium salt (Intermediate P88) and diethylamine to generate the title compound (33 mg, 45% ) as a white solid.
[1684] [1684] 1H NMR (DMSO-d6), rotamers; δ 11.09 (bs, 1H), 7.83 (s, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H) , 6.87 (s, 1H), 3.88 (s, 3H), 3.45 (m, 2H), 3.31 (m, 2H), 2.98 (sept, J = 6.8 Hz, 2H), 1.20 - 0.95 (m, 18H).
[1685] [1685] LCMS; m / z 464.5 (M + H) + (ES +); 462.4 (M-H) - (ES-). Example 158: 3- (N - ((2,6-Diisopropylphenyl) carbamoyl) sulfamoyl) -N-isopropyl- N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1686] [1686] Prepared according to the general procedure for 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 155) from acid 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic, disodium salt (Intermediate P88) and N-methylpropan-2-amine to generate the title compound (47 mg, 58%) as a white solid.
[1687] [1687] 1H NMR (DMSO-d6), rotamers; δ 11.13 (br s, 1H), 7.91 (s, 1H), 7.30 - 7.19 (m, 1H), 7.12 (d, J = 7.7 Hz, 2H), 7 , 02 (s, 0.5H), 6.90 (s, 0.5H), 4.74 - 4.57 (m, 1H), 3.92 -3.78 (m, 3H), 2.95 -2.93 (m, 2H), 2.85 -2.82 (m, 3H), 1.11 - 1.08 (m, 18H).
[1688] [1688] LCMS; m / z 464 (M + H) + (ES +). Example 159: N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-5- (pyrrolidine-1-carbonyl) -1H- pyrazol-3-sulfonamide
[1689] [1689] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide ( Example 130) from 1-methyl-5- (pyrrolidine-1-carbonyl) -1H-pyrazol-3-sulfonamide (Intermediate P86) and 4-isocyanate-1,2,3,5,6,7-hexa- hydro-s-indacene (intermediate A1). The crude product was purified by RP Flash C18 chromatography (13 g column, 0-50% MeCN / 10 mM ammonium bicarbonate) to generate the title compound (25 mg, 28%) as a white solid.
[1690] [1690] 1H NMR (DMSO-d6), rotamers; δ 10.9 (br s, 1H), 7.99 (s, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 3.98 (s, 3H), 3.52 and 3.47 (2 xt, J = 6.2 Hz, 4H), 2.78 (t, J = 7.4 Hz, 4H), 2.61 (t, J = 7.4 Hz, 4H), 2.02 - 1.75 (m, 8H).
[1691] [1691] LCMS; m / z 458 (M + H) + (ES +). Example 160: 3- (N - (((4-Fluor-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt
[1692] [1692] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide ( Example 130) from N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (Intermediate P84) and 5-fluoro-2-isocyanate-1,3-diisopropylbenzene (Intermediate A2) to generate the title compound (55 mg, 67%) as a white solid.
[1693] [1693] 1H NMR (DMSO-d6), rotamers; δ 7.35 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.59 (s, 1H), 3.81 (s, 3H), 3.18 - 3, 07 (m, 2H), 3.03 (s, 3H), 2.98 (s, 3H), 1.02 (d, J = 6.9 Hz, 12H).
[1694] [1694] LCMS; m / z 454 (M + H) + (ES +).
[1695] [1695] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 145) from acid 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H -pyrazol-5-carboxylic, disodium salt (Intermediate P87) and 3-fluoroazetidine, HCL to generate the title compound (36 mg, 50%) as a white solid.
[1696] [1696] 1H NMR (DMSO-d6), rotamers; δ 7.74 (s, 1H), 6.87 (s, 1H), 6.78 (s, 1H), 5.45-5.26 (m, 1H), 4.61 - 4.47 (m , 1H), 4.44 - 4.22 (m, 2H), 4.08 - 3.95 (m, 1H), 3.95 (s, 3H), 2.70 (t, J = 7.4 Hz, 4H), 2.55 (t, J = 7.4 Hz, 4H), 1.85 (quin, J = 7.5 Hz, 4H).
[1697] [1697] LCMS; m / z 462.4 (M + H) + (ES +); 460.4 (M-H) - (ES-). Example 162: N-Ethyl-3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H -pyrazol-5-carboxamide
[1698] [1698] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide, sodium salt (Example 145) from 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl- 1H-pyrazol-5-carboxylic, disodium salt (Intermediate P87) and N-methylethhanamine to generate the title compound (31 mg, 44%) as a white solid.
[1699] [1699] 1H NMR (DMSO-d6), rotamers; δ 10.98 (s, 1H), 8.00 (s, 1H), 6.96 - 6.87 (m, 2H), 3.90 & 3.88 (2 xs, 3H), 3.47 and 3.33 (2 xq, J = 7.0 Hz, 2H), 3.00 and
[1700] [1700] LCMS; m / z 446.4 (M + H) + (ES +); 444.4 (M-H) - (ES-). Example 163: N - ((2,6-Diisopropylphenyl) carbamoyl) -1-methyl-5- (pyrrolidine-1-carbonyl) -1H-pyrazol-3-sulfonamide
[1701] [1701] Prepared according to the general procedure for 5- (azetidine-1-carbonyl) -N - ((4-fluoro-2,6-diisopropylphenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide ( Example 130) from 1-methyl-5- (pyrrolidine-1-carbonyl) -1H-pyrazol-3-sulfonamide (Intermediate P86) and 2-isocyanate-1,3-diisopropylbenzene (intermediate A18). The crude product was purified by RP Flash C18 chromatography (12 g column, 5-50% MeCN / 10 mM ammonium bicarbonate) to generate the title compound (40 mg, 43%) as a colorless solid.
[1702] [1702] 1H NMR (DMSO-d6), rotamers; δ 11.11 (s, 1H), 7.89 (s, 1H), 7.30 - 7.18 (m, 1H), 7.16 - 7.07 (m, 3H), 4.01 (s , 3H), 3.57 - 3.40 (m, 4H), 3.03 - 2.85 (m, 2H), 1.91 - 1.78 (m, 4H), 1.04 (br s, 12H).
[1703] [1703] LCMS; m / z 462.5 (M + H) + (ES +). Example 164: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N-isopropyl-N, 1-dimethyl-1H -pyrazol-5-carboxamide
[1704] [1704] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5- carboxylic (Intermediate P85) and N-methylpropan-2-amine to generate the title compound (25 mg, 42%) as a white solid.
[1705] [1705] 1H NMR (DMSO-d6), rotamers; δ 7.74 (s, 1H), 6.85 (s, 1H), 6.78 & 6.67 (2 xs, 1H), 4.68 & 4.03 (s, 1H), 3.83 ( s, 3H), 2.85 (s, 3H), 2.77 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 1.92 ( quin, J = 7.4 Hz, 4H), 1.15 (d, J = 6.7 Hz, 6H). Acidic proton not observed.
[1706] [1706] LCMS; m / z 460.5 (M + H) + (ES +); 458.3 (M-H) - (ES-). Example 165: N, N-dimethyl-3- (N - (((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H -pyrazol-5-carboxamide
[1707] [1707] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5- carboxylic (Intermediate P85) and diethylamine to generate the title compound (35 mg, 58%) as a white solid.
[1708] [1708] 1H NMR (DMSO-d6), rotamers; δ 10.96 (s, 1H), 7.92 (s, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 3.86 (s, 3H), 3.45 & 3.30 (2 xm, 4H), 2.78 (t, J = 7.3 Hz, 4H), 2.61 (t, J = 7.4 Hz, 4H), 1.94 (quin, J = 7.4 Hz, 4H), 1.18 - 1.05 (m, 6H).
[1709] [1709] LCMS; m / z 460.5 (M + H) + (ES +); 458.4 (M-H) - (ES-). Example 166: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazole-5 -carboxamide
[1710] [1710] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5- carboxylic (Intermediate P85) and methylamine to generate the title compound (18 mg, 35%) as a white solid.
[1711] [1711] 1H NMR (DMSO-d6) δ 10.88 (s, 1H), 8.61 (q, J = 4.6 Hz, 1H), 7.97 (s, 1H), 7.28 (s , 1H), 6.87 (s, 1H), 4.07 (s, 3H), 2.71 (t, J = 7.4 Hz, 4H), 2.67 (d, J = 4.6 Hz , 3H), 2.52 (t, J = 7.4 Hz, 4H), 1.87 (quin, J = 7.5 Hz, 4H).
[1712] [1712] LCMS; m / z 418.4 (M + H) + (ES +); 416.3 (M-H) - (ES-). Example 167: 3- (N - ((2,6-Diisopropylphenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt
[1713] [1713] N, N, 1-Trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (Intermediate P84) (105 mg, 0.452 mmol) was dissolved in THF (5 mL) and 2 M sodium tert-butoxide in THF (0.237 ml, 0.475 mmol) was added. After 1 hour, 2-isocyanate-1,3-diisopropylbenzene (Intermediate A18) (92 mg, 0.452 mmol) was added and the mixture was stirred at room temperature for 15 hours. The suspension was filtered and washed with THF (1 ml). The collected solid was triturated with EtOAc (5 ml) for 1 hour, filtered and dried in vacuo to generate the title compound (137 mg, 64%) as a white solid.
[1714] [1714] 1H NMR (DMSO-d6), rotamers; δ 7.37 (br s, 1H), 7.14 - 7.05 (m, 1H), 7.01 (d, J = 7.5 Hz, 2H), 6.61 (s, 1H), 3 , 81 (s, 3H), 3.15 - 3.13 (m, 2H), 3.03 (s, 3H), 2.99 (s, 3H), 1.03 (d, J = 6.8 Hz, 12H).
[1715] [1715] LCMS; m / z 436 (M + H) + (ES +). Example 168: 3- (N - (((4-Chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) - N, N, 1-trimethyl-1H-pyrazol-5-carboxamide
[1716] [1716] 4-Chloro-2,6-diisopropylaniline, HCl (51.9 mg, 0.209 mmol) and triethylamine (0.064 ml, 0.460 mmol) were dissolved in dry THF (5 ml).
[1717] [1717] 1H NMR (DMSO-d6), rotamers; δ 11.24 (s, 1H), 7.98 (s, 1H), 7.14 (s, 2H), 7.01 (s, 1H), 3.93 (s, 3H), 3.00 ( s, 3H), 2.99 (s, 3H), 2.98 - 2.91 (m, 2H), 1.17 - 0.93 (br d, 12H).
[1718] [1718] LCMS; m / z 469 and 471 (M + H) + (ES +). Example 169: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazole -5-carboxamide, sodium salt
[1719] [1719] Prepared according to the general procedure for 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide, sodium salt (Example 167 ) from N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (Intermediate P84) and 4-isocyanate-1,2,3,5,6,7-hexahydro-s- indacene (Intermediate A1) to generate the title compound (235 mg, 64%) as a white solid.
[1720] [1720] 1H NMR (DMSO-d6), rotamers; δ 7.51 (s, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 3.82 (s, 3H), 3.04 (s, 3H), 2.99 ( s, 3H), 2.75 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.93 - 1.86 (m, 4H).
[1721] [1721] LCMS; m / z 432 (M + H) + (ES +).
[1722] [1722] 2 M sodium tert-butoxide in THF (0.120 mL, 0.241 mmol) was added to a solution of a mixture of 2 - ((dimethylamino) methyl) -1-methyl-1H-imidazole-4-sulfonamide and 5 - ((dimethylamino) methyl) -1-methyl-1H-imidazole-4-sulfonamide (Intermediates P93 and P94) (50 mg, 0.229 mmol) in THF (1 mL) and stirred at room temperature for 1 hour. Then, 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (47.9 mg, 0.241 mmol) in THF (1 mL) was added and the reaction it was stirred at room temperature over the weekend. The reaction mixture was concentrated and the crude product was purified by chromatography (Complementary apparatus, RP Flash C18, 12 g column, 5-50% MeCN / 10 mM ammonium bicarbonate) to generate 2 - ((dimethylamino) methyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H-imidazol-4-sulfonamide (Example 170) (44 mg , 46%) and 5 - ((dimethylamino) methyl) -N- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1-methyl-1H -imidazole-4-sulfonamide (Example 171) (3 mg, 3%), both as colorless solids. Example 170: 1H NMR (DMSO-d6) δ 7.91 (s, 1H), 7.77 (s, 1H), 6.83 (s, 1H), 4.26 (s, 2H), 3.67 (s, 3H), 2.76 (t, J = 7.4 Hz, 4H), 2.66 - 2.53 (m, 10H), 1.96 - 1.84 (m, 4H) (1 NH not observed interchangeable).
[1723] [1723] LCMS; m / z 418.3 (M + H) + (ES +). Example 171: 1H NMR (DMSO-d6) δ 10.70 (br s, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 6.90 (s, 1H), 3, 68 (s, 3H), 3.46 (s, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.58 (t, J = 7.4 Hz, 4H), 2, 14 (s, 6H), 1.99 - 1.86 (m, 4H).
[1724] [1724] LCMS; m / z 418.3 (M + H) + (ES +). Example 172:: 3- (N - ((4-Chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N- (2-hydroxyethyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1725] [1725] Prepared according to the general procedure for 3- (N - ((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 132) from 3- (N - (((4-chloro-2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P90) and 2- (methylamino) ethanol to generate the title compound (10 mg, 18%) as a white solid.
[1726] [1726] 1H NMR (DMSO-d6), rotamers; δ 11.18 (s, 1H), 7.95 (s, 1H), 7.14 (s, 2H), 6.98 (s, 1H), 4.96 - 4.79 (m, 1H), 3.93 - 3.86 (m, 3H), 3.64 - 3.41 (m, 4H), 3.06 - 2.88 (m, 5H), 1.08 (br s, 12H).
[1727] [1727] LCMS; m / z 500.4 / 502.4 (M + H) + (ES +). Example 173: 3- (N - ((2,6-Diisopropylphenyl) carbamoyl) sulfamoyl) -N- (2-hydroxyethyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide
[1728] [1728] Prepared according to the general procedure for 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 155) from acid 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -1- methyl-1H-pyrazol-5-carboxylic acid, disodium salt (Intermediate P88) and 2- (methylamino) ethanol to generate the title compound ( 8 mg, 11%) as a white solid.
[1729] [1729] 1H NMR (DMSO-d6), rotamers; δ 11.07 (s, 1H), 7.88 (s, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 7.7 Hz, 2H) , 7.02 & 7.0 (2 xs, 1H), 4.96 & 4.81 (t, J = 5.0 & 5.7 Hz, 1H), 3.94 & 3.89 (2 xs, 3H), 3 , 59 & 3.40 (2 xt, J = 5.6 & 5.1 Hz,
[1730] [1730] LCMS; m / z 466.5 (M + H) + (ES +); 464.4 (M-H) - (ES-). Example 174: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N- (2-hydroxy-ethyl) -1 -methyl-1H-pyrazol-5-carboxamide, partial ammonium salt
[1731] [1731] Prepared according to the general procedure for 3- (N - ((2,6-diisopropylphenyl) carbamoyl) sulfamoyl) -N, 1-dimethyl-1H-pyrazol-5-carboxamide (Example 155) from acid 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic, disodium salt (Intermediate P87) and ethanolamine to generate the title compound (18 mg, 25%) as a white solid.
[1732] [1732] 1H NMR (DMSO-d6) δ 8.61 (t, J = 5.7 Hz, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 6.88 (s , 1H), 4.73 (t, J = 5.7 Hz, 1H), 4.10 (s, 3H), 3.48 (app q, J = 6.0 Hz, 2H), 3.27 (app q , J = 6.0 Hz, 2H), 2.78 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7.4 Hz, 4H), 1.93 (p, J = 7 , 4 Hz, 4H). An unobserved interchangeable proton.
[1733] [1733] LCMS; m / z 448.4 (M + H) + (ES +); 446.4 (M-H) - (ES-). Example 175: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N- (2-methoxyethyl) -1-methyl -1H-pyrazol-5-carboxamide, partial ammonium salt
[1734] [1734] Prepared according to the general procedure for 3- (N - ((2,6-
[1735] [1735] 1H NMR (DMSO-d6) δ 10.93 (br s, 1H), 8.74 (t, J = 5.5 Hz, 1H), 7.90 (s, 1H), 7.36 ( s, 1H), 6.90 (s, 1H), 4.11 (s, 3H), 3.44 (t, J = 5.5 Hz, 2H), 3.39 (t, J = 5.5 Hz, 2H), 3.26 (s, 3H), 2.78 (t, J = 7.4 Hz, 4H), 2.61 (t, J = 7.3 Hz, 4H), 1.94 ( p, J = 7.5 Hz, 4H).
[1736] [1736] LCMS; m / z 462.4 (M + H) + (ES +); 460.3 (M-H) - (ES-). Example 176: 3- (N - ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -N- (2-hydroxy-ethyl) -N , 1-dimethyl-1H-pyrazol-5-carboxamide, partial ammonium salt
[1737] [1737] Prepared according to the general procedure for N - ((2,6-diisopropylphenyl) carbamoyl) -1-methyl-5- (pyrrolidine-1-carbonyl) -1H-pyrazol-3-sulfonamide (Example 163) a from 3- (N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylic acid , disodium salt (Intermediate P87) and 2- (methylamino) ethanol to generate the title compound (39 mg, 54%) as a white solid.
[1738] [1738] 1H NMR (DMSO-d6), rotamers; δ 7.69 (s, 1H), 7.10 (s, 1H), 7.10 & 6.74 (2 xs, 1H), 6.82 (s, 1H), 4.96 & 4.84 ( 2 xt, J = 5.5 Hz, 1H), 3.84 & 3.80 (2 xs, 3H), 3.59 (m, 1H), 3.55 - 3.41 (m, 3H), 3 , 06 & 2.97 (2 xs, 3H), 2.76 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.5 Hz, 4H), 1.92 (p , J = 7.5 Hz, 4H).
[1739] [1739] LCMS; m / z 462.42 (M + H) + (ES +); 460.30 (M-H) - (ES-).
[1740] [1740] The compounds of examples 177-178 were synthesized by methods analogous to those described above and below.
[1741] [1741] To a solution of N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (Intermediate P84) (1.7 g, 7.32 mmol, 1 eq) in THF (20 mL) t-BuONa (703 mg 7.32 mmol, 1 eq) was added at 25 ° C and stirred for 0.5 hour. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-isopropoxypyridine (Intermediate A19) (2.30 g, 7.32 mmol, 1 eq) was added and the resulting mixture was stirred for 0.5 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Ultimate XB_C18, 41 mm * 235 mm * 20/40 µm; mobile phase: [water (10 mM NH4HCO3) -ACN]; B%: 0% -30%, 35 min ) to obtain the title compound (2.34 g, 59% yield, 98% HPLC purity) as a white solid.
[1742] [1742] 1H NMR (DMSO-d6): δ 8.03 (d, 1 H), 7.65 (br s, 1 H), 7.16 (d, 1 H), 6.98 (d, 1 H), 6.85 (d, 1 H), 6.74 (s, 1 H), 6.70 (s, 1 H), 5.30-5.21 (m, 1 H), 3.89 (s, 3 H), 3.09-3.03 (m, 1 H), 3.00 (s, 6 H), 1.30 (d, 6 H) and 1.07 (d, 6 H) .
[1743] [1743] LCMS: m / z 547.4 (M + H) + (ES +). Step B: 3- (N - ((4-Fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropylphenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide sodium salt F F O O O O O O S S N N N N H H H H N N N N N N
[1744] [1744] A solution of N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (Intermediate P84) (6.59 g, 28.39 mmol, 0.9 eq) and t-BuONa ( 3.33 g, 34.70 mmol, 1.1 eq) in THF (200 mL) was stirred at 16 ° C for 0.5 hour. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A20) (8.4 g, 31.54 mmol, 1 eq) was added. The reaction mixture was stirred at 16 ° C for 0.5 hour and then filtered. The filter residue was washed with MeCN (125 ml). Then, the solid was dissolved in H2O (100 ml) and filtered. The filtrate was lyophilized to obtain the title compound (8.02 g, 49% yield, 99.54% LCMS purity, Na salt) as a white solid.
[1745] [1745] 1H NMR (DMSO-d6): δ 8.02 (d, 1 H), 7.42 (br s, 1 H), 7.10-7.02 (m, 2 H), 6.89 (dd, 1 H), 6.74 (s, 1 H), 6.59 (s, 1 H), 3.84 (d, 6 H), 3.02 (d, 6 H), 2.87 (t, 2 H), 2.72 (t, 2 H) and 1.97-1.90 (m, 2 H).
[1746] [1746] LCMS: m / z 499.3 (M + H) + (ES +). Example 181: 1- (2- (Dimethylamino) ethyl) -N - ((1,2,3,7-tetrahydro-s-indacen-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide, salt potassium
[1747] [1747] To a solution of 1- (2- (dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide (Intermediate P6) (130 mg, 0.52 mmol) in THF (5 mL) was added tert-butoxide potassium (68 mg, 0.6 mmol). The mixture was stirred at room temperature for 45 minutes. 8-Isocyanate-1,2,3,5-tetrahydro-s-indacene (Intermediate A21) (110 mg, 0.52 mmol) was added and the mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and DMSO (0.75 ml) was added. The mixture (filtered over cotton when solids were present) was purified by preparative reverse phase HPLC (General Methods, water-methanol preparation) to generate the title compound (65 mg, 27%) as a white solid.
[1748] [1748] 1H NMR (methanol-d4): mixture of δ 7.67 (d, 1H) isomers, 7.11, 7.04 (s, 1H), 6.81, 6.75 (d, 1H), 6.66, 6.43 (d, 1H), 6.37 (dt, 1H), 4.32 (td, 2H), 3.34 (m, 2H), 2.97 - 2.85 (m, 4H), 2.80 (td, 2H), 2.31 (d, 6H), 2.13 - 1.92 (m, 2H).
[1749] [1749] LCMS: m / z 416 (M + H) + (ES +); 414 (M-H) - (ES-). Example 182: 1- (2- (Dimethylamino) ethyl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl) carbamoyl) -1H-pyrazol-4 -sulfonamide H The N
[1750] [1750] To a solution of 1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-sulfonamide (Intermediate P95) (103 mg, 471.88 µmol, 1 eq) and 4-isocyanate-1,2, 3,5,6,7-hexahydro-s-indacene (Intermediate A1) (94 mg, 471.88 µmol, 1 eq) in THF (1 ml) MeONa (25 mg, 471.88 µmol, 1 was added eq). The mixture was stirred at 70 ° C for 0.5 hour and then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (column: Fenomenex Gemini C18, 150 mm * 25 mm * 10µm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN] ; B%: 10% -40%, 11.5 min) to obtain the title compound (71.14 mg, 34% yield, 100% LCMS purity) as a white solid.
[1751] [1751] 1H NMR (DMSO-d6): δ 8.16 (s, 1 H), 7.69 (s, 1 H), 6.85 (s, 1 H), 4.20 (t, 2 H ), 2.77 (t, 4 H), 2.65-2.60 (m, 6 H), 2.16 (s, 6 H), 1.96-1.88 (m, 4 H).
[1752] [1752] LCMS: m / z 418.2 (M + H) + (ES +). Example 183: 1- (1- (Dimethylamino) -2-methylpropan-2-yl) -N - ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl ) -1H-pyrazol-4-sulfonamide
[1753] [1753] To a solution of 1- (1- (dimethylamino) -2-methylpropan-2-yl) -1H-pyrazol-4-sulfonamide (Intermediate P96) (50 mg, 202.98 µmol, 1 eq) in THF (2 ml) t-BuONa (19.51 mg, 202.98 µmol, 1 eq) was added. The mixture was stirred at 20 ° C for 10 minutes. Then 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (40.44 mg, 202.98 µmol, 1 eq) was added. The reaction mixture was stirred for 20 minutes at 20 ° C and then concentrated in vacuo. The residue was purified by preparative reverse phase 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 obtain the title compound (32.72 mg, 35% yield, 98% LCMS purity) as a white solid.
[1754] [1754] 1H NMR (DMSO-d6): δ 8.14 (s, 1 H), 7.85 (br s, 1 H), 7.77 (s, 1 H), 6.87 (s, 1 H), 2.77 (t, 4 H), 2.61-2.56 (m, 6 H), 1.94-1.89 (m, 10 H) and 1.49 (s, 6 H) .
[1755] [1755] LCMS: m / z 446.3 (M + H) + (ES +).
[1756] [1756] The compounds of examples 184-210 were synthesized by methods analogous to those described above.
[1757] [1757] 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. THP-1 Cells: Culture and Preparation
[1758] [1758] THP-1 cells (ATCC # TIB-202) were cultured in RPMI containing L-glutamine (Gibco # 11835) supplemented with 1 mM sodium pyruvate (Sigma # S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma # P4333) in 10% Bovine Fetal Serum (FBS) (Sigma # F0804). The cells were routinely passed and cultured until confluence (~ 106 cells / ml). On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted and the viability (> 90%) was checked for trypan blue (Sigma # T8154). Appropriate dilutions were made to produce a concentration of 625,000 cells / ml. To this diluted cell solution, LPS (Sigma # L4524) was added to produce 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. Pyroptosis Assay with THP-1 Cells
[1759] [1759] The following step-by-step assay method was followed for screening compounds.
[1760] [1760] The results of the pyroptosis assay performed are summarized in Table 3 below as THP IC50. IL1β Release Assay in Human Whole Blood
[1761] [1761] 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.
[1762] [1762] Human whole blood in Li-heparin tubes was obtained from healthy donors from a panel of voluntary donors.
[1763] [1763] The results of the human whole blood assay are summarized in Table 3 below as HWB IC50. Example No. THP IC50 HWB IC50 Example No. THP IC50 HWB IC50 1 +++ * 106 +++ *** 2 +++ ** 107 ++ ND 3 +++ *** 108 +++ ***** 4 ++ ND 109 +++ ***** 5 + ND 110 +++ ***** 6 + ND 111 +++ **** 7 +++ ***** 112 +++ * ****
[1764] [1764] Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-350g; 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 some animals administered orally were deprived of food during the night before the study.
[1765] [1765] 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.
[1766] [1766] 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) or at each of the 12 post-dose moments (0.03, 0.1, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h) or pre -dose and at each of the 9 post-dose moments (0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h). The samples were kept on ice for no more than 30 minutes before centrifugation (10,000 rpm (8,385g)
[1767] [1767] As is evident from the results shown in Table 3, surprisingly, despite structural differences from prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in the human whole blood assay .
[1768] [1768] As is evident from the results presented in Tables 4 and 5, 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.
[1769] [1769] 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 (29)
[1]
1. Compound of formula (I):
O O Q 1 R S R2
W
N N
X A H H 3 Z (R) m Y Formula (I) characterized by the fact that: Q is selected from O or S; W, X, Y and Z are each independently N, O, S, NH or CH, where at least one of W, X, Y and Z is N or NH; R1 is a monovalent group comprising at least one nitrogen atom, where -R1 contains from 1 to 7 atoms other than hydrogen or halogen; or R1 is a divalent group comprising at least one nitrogen atom, where -R1- contains 1 to 7 atoms other than hydrogen or halogen, and where -R1- is directly linked to any two W, X, Y or Adjacent Z; R2 is a cyclic group substituted at the α position, where R2 can optionally be additionally substituted; m is 0, 1, 2 or 3; each R3 is independently a halo, -OH, -NO2, -NH2, -N3, -SH, or a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight or branched or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted and where the hydrocarbyl group may include one or more N, O or S heteroatoms in its carbon backbone; and where optionally any R3, and any two adjacent W, X, Y or Z can together form a saturated or unsaturated cyclic group of 3 to 12 members fused to ring A, where the cyclic group fused to ring A can optionally be substituted .
[2]
2. Compound according to claim 1, characterized by the fact that ring A is monocyclic.
[3]
3. A compound according to claim 1 or claim 2, characterized by the fact that W, X, Y and Z are each independently N, NH or CH.
[4]
Compound according to any one of claims 1 to 3, characterized by the fact that at least two of W, X, Y and Z are N or NH.
[5]
Compound according to any one of claims 1 to 4, characterized in that R1 is directly linked to a nitrogen atom in ring A.
[6]
A compound according to any one of claims 1 to 5, characterized in that R1 is a monovalent group comprising at least one nitrogen atom, where -R1 contains from 1 to 7 atoms other than hydrogen or halogen.
[7]
Compound according to claim 6, characterized in that -R1 is a straight or branched chain group.
[8]
8. Compound according to claim 6 or claim 7, characterized by the fact that -R1 has the formula: R13 R14 R15 10
R
N C C C R11 R13 R14 R15 p q r where: p is 0 or 1; q is 0 or 1; r is 0 or 1; R10 and R11 are each independently selected from hydrogen or a saturated heterocyclic, alkyl or cycloalkyl group, or R10 and R11, together with the nitrogen atom to which they are attached, form a saturated heterocyclic group; each R13, R14 and R15 is independently selected from hydrogen or a halo group, -CN, -OH, alkyl, -O-alkyl, cycloalkyl, -O-cycloalkyl, saturated heterocyclic or -O- (saturated heterocyclic) and / or any two R13, two R14 or two R15 may, together with the carbon atom to which they are attached, form a group C = O and / or any two R 13, R14 or R15 may, together with the carbon atom or atoms carbon to which they are attached, form a saturated cycloalkyl or heterocyclic group; wherein optionally R11 together with any R13, R14 or R15 may, together with the carbon and nitrogen atoms to which they are attached, form a saturated heterocyclic group; wherein any saturated heterocyclic, alkyl or cycloalkyl group can optionally be substituted with one or more halo, -CN, -OH, oxo (= O), alkyl, haloalkyl, -O-alkyl and / or -O-haloalkyl groups.
[9]
Compound according to claim 6 or claim 7, characterized in that -R1 has the formula: R10 R13 R14 R15 R11 N C C C R12 R13 R14 R15 p q r where: p is 0 or 1; q is 0 or 1; r is 0 or 1; R10, R11 and R12 are each independently selected from a saturated heterocyclic, alkyl or cycloalkyl group, or R10 and R11, together with the nitrogen atom to which they are attached,
they form a saturated heterocyclic group, or R10, R11 and R12, together with the nitrogen atom to which they are attached, form a saturated heterocyclic group; each R13, R14 and R15 is independently selected from hydrogen or a halo group, -CN, -OH, alkyl, -O-alkyl, cycloalkyl, -O-cycloalkyl, saturated heterocyclic or -O- (saturated heterocyclic) and / or any two R13, two R14 or two R15 may, together with the carbon atom to which they are attached, form a group C = O and / or any two R 13, R14 or R15 may, together with the carbon atom or atoms carbon to which they are attached, form a saturated cycloalkyl or heterocyclic group; wherein optionally R11 together with any R13, R14 or R15 may, together with the carbon and nitrogen atoms to which they are attached, form a saturated heterocyclic group; wherein any saturated heterocyclic, alkyl or cycloalkyl group can optionally be substituted with one or more halo, -CN, -OH, oxo (= O), alkyl, haloalkyl, -O-alkyl and / or -O-haloalkyl groups.
[10]
10. A compound according to claim 1, characterized by the fact that R1 is a divalent group comprising at least one nitrogen atom, where -R1- is a saturated or unsaturated hydrocarbilene group, in which the hydrocarbilene group can be straight or branched chain or be or include cyclic groups, where the hydrocarbilene group can optionally be substituted, where the hydrocarbilene group includes at least one heteroatom N in its carbon backbone and where the hydrocarbilene group can optionally include one or more others heteroatoms N, O or S in their carbon skeleton.
[11]
A compound according to any one of claims 1 to 10, characterized by the fact that R1 contains only atoms selected from the group consisting of carbon, hydrogen, nitrogen and halogen atoms.
[12]
A compound according to any one of claims 1 to 11, characterized in that R1 comprises at least one nitrogen atom that is not directly linked to a sp2 hybridized atom.
[13]
13. A compound according to any one of claims 1 to 12, characterized by the fact that each R3 is independently selected from halo; -CN; -NO2; -N3; -Rβ; -OH; - ORβ; -Rα-halo; -Rα-CN; -Rα-NO2; -Rα-N3; -Rα-Rβ; -Rα-OH; -Rα-ORβ; -SH; -SRβ; - SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα- SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; -CORβ; -COOH; - COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα-COORβ; or -Rα- OCORβ; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and wherein each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or cyclic C2-C6 group, and where any -Rβ can optionally be substituted by one or more C1 -C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O (C1-C4 alkyl), -O (C1-C4 haloalkyl), -O (C3-C7 cycloalkyl), halo, -OH, -NH2, - CN, -C≡CH, oxo (= O) or 4- to 6-membered heterocyclic group.
[14]
Compound according to any one of claims 1 to 13, 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.
[15]
15. A compound according to claim 14, 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 R 2 can optionally be substituted .
[16]
16. A compound according to claim 15, 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 positions α, β and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group through the α ', β' positions, and where R2 can optionally be additionally substituted.
[17]
17. A compound according to any one of claims 1 to 13, characterized in that R2 is a cyclic group substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the heterocyclic group or The aromatic is directly attached to the ring atom α of the cyclic group, in which the heterocyclic or aromatic group can optionally be substituted and in which the cyclic group can optionally be substituted.
[18]
18. A compound according to any one of claims 1 to 13, characterized in that R2 is a cyclic group substituted at positions α and α ', in which R2 can optionally be additionally substituted.
[19]
19. A compound according to claim 18, characterized by the fact that each substituent at positions α and α 'comprises a carbon atom.
[20]
20. A compound according to any one of claims 1 to 19, characterized by the fact that Q is O.
[21]
21. A compound characterized by the fact that it is selected from the group consisting of:
THE
THE
O O O
O O S N
N H
O O
Y N Y N H
N H N H
H H N
N
N N
N N
O O
N
N HN
THE
THE
THE
Y N
N H
H
THE
AT THE
AT THE
Y N
N H
The H
N N
N
N
THE
O O
O O
O O
Y N Y N
N H N H
The H H
N N
N N
HO
HN N
O O
O O
O O
Y N Y N
N H N H
N H H
N HO N
N N
N N
O O
O O
O O
N Y N
Y N H
N H
The H H
THE
The N N
Y N N
N N
H
H
N
N N
N N
O O O
O O O
O O O
Y N Y N Y
N H N H N H
H H H
N N N
N N N
HN N N
H
O F O O
O O O
O O O
Y N Y N Y
N H N H N H
H H H
N N N
N N N
N N N
O O O
O O O
O O O
N Y N N
Y N Y
N H H N H
H H H
N N N
N N N
N N N
O O
O O
O O
Y N Y N
N H N N H O
H O
H S O
N
N
N N N HN
HN
N
N N
N
O O O
N S
N N
H H
N N
O O O
N S
N N
H H
N N
O O O
N S
N N
H H
N N
O O O O O O
N Y N Y
N N N N
H H H H
N N N N
O O O
N S
N N
H H
N N
O O O
s
N N
H H
N N N
CN
O O O F
S O O
N N O
H H S
N N
N N H H
N N N N OMe N
O O N
N
H
The N
N
N O NH
O O O O S
N S S O O
The N
N N HN
H H N
O N N HN
N
The N
H
THE
HN N
s
O O N
N N e.
[22]
22. Pharmaceutically acceptable salt, solvate or prodrug of a compound characterized by the fact that it is of a compound as defined in any one of claims 1 to 21.
[23]
23. Pharmaceutical composition characterized by the fact that it comprises a compound as defined in any one of claims 1 to 21, or a salt, solvate or prodrug according to claim 22, and a pharmaceutically acceptable excipient.
[24]
24. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate or prodrug according to claim 22, or a pharmaceutical composition according to claim 23, characterized in that which is for medical use.
[25]
25. A pharmaceutically acceptable compound, salt, solvate, prodrug or pharmaceutical composition according to claim 24, characterized by the fact that it is for use in the treatment or prevention of a disease, disorder or condition, in which the disease, disorder or condition is responsive to inhibition of NLRP3.
[26]
26. A pharmaceutically acceptable compound, salt, solvate, prodrug or pharmaceutical composition according to claim 24 or 25, characterized by the fact that it is for use in the treatment or prevention of a disease, disorder or condition, 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.
[27]
27. A pharmaceutically acceptable compound, salt, solvate, prodrug or pharmaceutical composition according to claim 26, characterized by the fact that the disease, disorder or condition is selected from: (i) inflammation; (ii) an infection; (iii) cardiovascular disease; (iv) a respiratory disease; (v) a liver disease; (vi) a kidney disease; (vii) an eye disease; (viii) a skin disease; (ix) a psychological disorder; (x) a lymphatic condition; and / or (xi) any disease, disorder or condition in which an individual has been determined to have a germline or non-silent somatic mutation in NLRP3.
[28]
28. A pharmaceutically acceptable compound, salt, solvate, prodrug or pharmaceutical composition according to claim 24 or 25, characterized by the fact that it is for use in the treatment or prevention of a disease, disorder or condition, in which the disease , disorder or condition is selected from: (i) cryopyrin-associated periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii) 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).
[29]
29. Method of inhibiting NLRP3, characterized in that it comprises the use of a compound as defined in any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate or prodrug as defined in claim 22, or a pharmaceutical composition as defined in claim 23, to inhibit NLRP3.

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法律状态:
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