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    • 专利摘要:
    The present invention relates to the compounds of the formula (I): Formula (I) in which Q is selected from O or S; R1 is an optionally substituted, saturated or unsaturated hydrocarbyl group, optionally including one or more N, O or S heteroatoms; and R2 is a cyclic group substituted in position a by a monovalent heterocyclic group 10 or a monovalent aromatic group, in which a ring atom of the heterocyclic or aromatic group is directly attached to the ring atom of the cyclic group, in which the heterocyclic or the aromatic group can optionally be substituted and in which the cyclic group can optionally be substituted further. 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:BR112020002948A2
    申请号:R112020002948-3
    申请日:2018-08-15
    公开日:2020-08-11
    发明作者:Matthew Cooper；Ian STRUTT；David Miller；Angus Macleod；Jimmy Van Wiltenburg；Stephen Thom；Stephen St-Gallay；Jonathan Shannon；Thomas Alanine；Stuart Onions
    申请人:Inflazome Limited；
    IPC主号:
    专利说明:

    [0001] [0001] The present invention relates to sulfonylureas and sulfonylthioureas comprising a cyclic group attached to the nitrogen atom of the urea group, wherein the cyclic group is substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group and salts, solvates, prodrugs and associated pharmaceutical compositions. The present invention also relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, mainly by inhibiting NLRP3. FUNDAMENTALS
    [0002] [0002] The NOD-like receptor family (NLR), the inflammasome of protein 3 containing the pyrin domain (NLRP3) is a component of the inflammatory process, and its aberrant activity is pathogenic in hereditary diseases such as periodic syndromes associated with crypirin (CAPS ) and complex diseases like multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.
    [0003] [0003] NLRP3 is an intracellular signaling molecule that detects many factors derived from pathogens, environmental and host derivatives. After activation, NLRP3 binds to the particle type protein associated with apoptosis, containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form a large aggregate known as an ASC particle. The polymerized ASC, in turn, interacts with the cysteine-protease caspase-1 to form a complex called inflammasome. This results in the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (called pro-IL-1 and pro-IL-18, respectively) to activate these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC particle can also recruit and activate caspase-8, which can process pro-IL-1 and pro-IL-18 and trigger apoptotic cell death.
    [0004] [0004] Caspase-1 cleaves pro-IL-1 and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. By controlling the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmine molecules, such as IL-33 and box 1 protein in the high mobility group (HMGB 1). 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 the production of IL-17 by CD4 Th17 cells with memory and by γδ T cells in the absence of involvement with T cell receptors. IL-18 and IL-12 they also synergize to induce IFN-γ production from memory T cells and NK cells that drive a Th1 response.
    [0007] [0007] Hereditary CAPS diseases, Muckle-Wells syndrome (MWS), familial autoinflammatory syndrome (FCAS) and neonatal onset multisystemic inflammatory disease (NOMID) are caused by NLRP3 function gain mutations, defining NLRP3 as a component critical of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of several complex diseases, including metabolic disorders, such as type 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 the signaling of
    [0009] [0009] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits the production of IL-1β at micromolar concentrations in response to NLRP3 activation, but not NLRC4 or NLRP1. Other weak NLRP3 inhibitors previously characterized include parthenolide, 3,4-methylenedioxy-β-nitrostyrene and dimethyl sulfoxide (DMSO), although these agents have limited potency and are non-specific.
    [0010] [0010] Current treatments for diseases related to NLRP3 include biological agents that target IL-1. These are the anakinra recombinant IL-1 receptor antagonist, the neutralizing IL-1β cannabinumab antibody and the soluble IL-1 receptor decoy rilonacept. These approaches have proven to be successful in the treatment of CAPS, and these biological agents have been used in clinical trials for other diseases associated with IL-1β.
    [0011] [0011] Some compounds containing diaylsulfonylureas have been identified as cytokine release inhibiting drugs (CRIDs) (Perregaux et al .; J. Pharmacol. Exp. Ther. 299, 187-197, 2001). CRIDs are a class of compounds containing diarylsulfonylurea that inhibit post-translational processing of IL-1β. Post-translational processing of IL-1β is accompanied by activation of caspase-1 and cell death. CRIDs arrest activated monocytes so that caspase-1 remains inactive and plasma membrane latency is preserved.
    [0012] [0012] Certain sulfonylurea-containing compounds are also disclosed as NLRP3 inhibitors (see, for example, Baldwin et al., J. Med. Chem., 59 (5), 1691-1710, 2016; and WO 2016/131098 A1, WO 2017/129897 A1, WO 2017/140778 A1, WO 2017/184604 A1, WO 2017/184623 A1, WO 2017/184624 A1, WO 2018/015445 A1 and WO 2018/136890 A1).
    [0013] [0013] There is a need to provide compounds with better pharmacological and / or physiological and / or physicochemical properties and / or those that provide a useful alternative to known compounds. SUMMARY OF THE INVENTION
    [0014] [0014] A first aspect of the invention provides a compound of formula (I):
    [0015] [0015] In one embodiment, the compound is not: O O O O O O S O N N N H H H
    [0016] [0016] In one embodiment, the compound is not: O O O O O O O O O O O O S S N N N N H H H H O O
    [0017] [0017] In one embodiment, the invention provides a compound of formula (I):
    [0018] [0018] In an additional embodiment, the invention provides a compound of formula (I):
    [0019] [0019] In an additional embodiment, the invention provides a compound of formula (I):
    [0020] [0020] In an additional embodiment, the invention provides a compound of formula (I):
    [0021] [0021] In an additional embodiment, the invention provides a compound of formula (I):
    [0022] [0022] In an additional embodiment, the invention provides a compound of formula (I):
    [0023] [0023] In an additional embodiment, the invention provides a compound of formula (I):
    [0024] [0024] In an additional embodiment, the invention provides a compound of formula (I):
    [0025] [0025] In an additional embodiment, the invention provides a compound of formula (I):
    [0026] [0026] In an additional embodiment, the invention provides a compound of formula (I):
    [0027] [0027] 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 heteroatoms, such as N, O or S, in your carbon skeleton. A hydrocarbyl group / fraction may be saturated or unsaturated (including aromatic) and may be straight or branched or be or include cyclic groups in which, unless otherwise indicated, the cyclic group does not include any heteroatom, such as N, O or S , in its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups / moieties / 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-C12 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 hydrocarbil group.
    [0028] [0028] 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 / fractions include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups / fractions. Unless otherwise indicated, the term "alkyl" does not include "cycloalkyl". Typically, an alkyl group is a C 1 -C 12 alkyl group. More typically, an alkyl group is a C1-C6 alkyl group. An "alkylene" group is similarly defined as a divalent alkyl group.
    [0029] [0029] An "alkenyl" substituent group or an alkenyl fraction in a substituent group refers to an unsaturated alkyl group or fraction with one or more carbon-carbon double bonds. Examples of alkenyl groups / fractions include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl groups and moieties 4-hexadienyl. Unless otherwise specified, the term "alkenyl" does not include "cycloalkenyl". Typically, an alkenyl group is a C2-C12 alkenyl group. More typically, an alkenyl group is a C2-C6 alkenyl group. An "alkenylene" group is similarly defined as a divalent alkenyl group.
    [0030] [0030] An "alkynyl" substituent group or an alkynyl fraction in a substituent group refers to an unsaturated alkyl group or fraction with one or more carbon-carbon triple bonds. Examples of alkynyl groups / fractions include ethynyl, propargyl, but-1-ynyl and but-2-ynyl. Typically, an alkynyl group is a C2-C12 alkynyl group. More typically, an alkynyl group is a C 2 -C 6 alkynyl group. An "alkynylene" group is similarly defined as a divalent alkynyl group.
    [0031] [0031] A "cyclic" substituent group or a cyclic fraction 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 heteroatoms, 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.
    [0032] [0032] A "heterocyclic" substituent group or a heterocyclic fraction in a substituent group refers to a cyclic group or fraction including one or more carbon atoms and one or more (such as one, two three or four) hetero atoms, for example , N, O or S, in the ring structure. Examples of heterocyclic groups include heteroaryl groups, as discussed below, and non-aromatic heterocyclic groups, such as azetidinyl, azetinyl, tetrahydrofuranyl,
    [0033] [0033] 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.
    [0034] [0034] 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.
    [0035] [0035] An "aryl" substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and fused ring polycyclic aromatic hydrocarbons, wherein all fused ring systems (excluding any ring systems that are part of or formed by optional substituents) are aromatic. Examples of aryl groups / fractions include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl".
    [0036] [0036] A "heteroaryl" substituent group or a heteroaryl fraction in a substituent group refers to an aromatic heterocyclic group or fraction. The term "heteroaryl" includes monocyclic aromatic heterocycles and fused ring polycyclic aromatic heterocycles, wherein all fused ring systems (excluding any ring systems that are part of or formed by optional substituents) are aromatic. Examples of heteroaryl groups / fractions include the following: N N N N N N N N N N G G G G G G N N N N N N N N N N N G G N N N N
    [0037] [0037] For the purposes of this specification, where a combination of fractions is referred to as a group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last fraction mentioned contains the atom by which the group is linked to the rest of the molecule. An example of an arylalkyl group is benzyl.
    [0038] [0038] For the purposes of this specification, in a group or fraction optionally substituted: (i) each hydrogen atom can 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-
    [0039] [0039] Typically, the compounds of the present invention comprise at most one quaternary ammonium group such as -N + (Rβ) 3 or -N + (Rβ) 2-.
    [0040] [0040] When reference is made to a group-Rα-C (N2) Rβ, the aim is:
    [0041] [0041] Typically, in a fraction or optionally substituted group: (i) each hydrogen atom can optionally be substituted by a group selected independently from halo; -CN; -NO2; -N3; -Rβ; - OH; -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; - Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; - Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; - CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα-COORβ; - Rα-OCORβ; -NH-CHO; -NRβ-CHO; -NH-CORβ; -NRβ-CORβ; -CONH2; -CONHRβ; - CON (Rβ) 2; -Rα-NH-CHO; -Rα-NRβ-CHO; -Rα-NH-CORβ; -Rα-NRβ-CORβ; -Rα- CONH2; -Rα-CONHRβ; -Rα-CON (Rβ) 2; -O-Rα-OH; -O-Rα-ORβ; -O-Rα-NH2; -O-Rα- NHRβ; -O-Rα-N (Rβ) 2; -NH-Rα-OH; -NH-Rα-ORβ; -NH-Rα-NH2; -NH-Rα-NHRβ; -NH- Rα-N (Rβ) 2; -NRβ-Rα-OH; -NRβ-Rα-ORβ; -NRβ-Rα-NH2; -NRβ-Rα-NHRβ; or -NRβ-Rα- N (Rβ) 2; and / or (ii) any two hydrogen atoms attached to the same carbon atom can optionally be replaced by a substituent attached to π independently selected from oxo (= O), = S, = NH or = NRβ; and / or (iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or fraction, can optionally be substituted by a bridged substituent independently selected from -O-, -S-, -NH -, -N (Rβ) - or -Rα-; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main 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 C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl or cyclic C2-C6 group, and any - Rβ can optionally be replaced by one or more C 1-C4alkyl, C1 -
    [0042] [0042] Typically, in a fraction or optionally substituted group: (i) each hydrogen atom can optionally be substituted by a group selected independently from halo; -CN; -NO2; -N3; -Rβ; -OH; - ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; -Rα- SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα-SO2NHRβ; -Rα- SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CHO; -CORβ; - COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα-COORβ; or -Rα- OCORβ; and / or (ii) any two hydrogen atoms attached to the same carbon atom can optionally be replaced by a substituent attached to π independently selected from oxo (= O), = S, = NH or = NRβ; and / or (iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or fraction (a), can optionally be substituted by a bridged substituent selected independently from -O-, -S- , -NH-, -N (Rβ) - or -Rα-; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more N, O or S heteroatoms, and wherein the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and wherein each -Rβ is independently selected from a C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl or cyclic C2-C6 group, and where any -Rβ can optionally be replaced by one or more C1-C4alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O (C1-C4 alkyl), -O (C1-C4 haloalkyl), -O (C3-C7 cycloalkyl), halo, - OH, -NH2, -CN, -C≡ CH or oxo groups (= O).
    [0043] [0043] Typically, in a fraction or optionally substituted group: (i) each hydrogen atom can optionally be substituted by a group selected independently from halo; -CN; -NO2; -N3; -Rβ; -OH; - ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N (Rβ) 2; -Rα-
    [0044] [0044] 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.
    [0045] [0045] Unless otherwise specified, any divalent bridge substituent (for example, O-, -S-, -NH-, -N (Rβ) -, -N (O) (Rβ) -, -N + (Rβ) 2- or -Rα-) of an optionally substituted group or portion (for example, R1) must be attached only to the specified group or fraction and cannot be attached to a second group or fraction (for example, R2), even if the second group or fraction can be optionally substituted.
    [0046] [0046] The term "halo" includes fluorine, chlorine, bromine and iodine.
    [0047] [0047] Unless otherwise specified, where a group is prefixed by the term "halo", such as a haloalkyl or halomethyl group, it should be understood that the group in question is replaced by one or more halo groups independently selected from fluorine, chlorine , bromine and iodine. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution in the corresponding group without the prefix halo. For example, a halomethyl group can contain one, two or three halo substituents. A haloethyl or halophenyl group can contain one, two, three, four or five halo substituents. Likewise, unless otherwise specified, where a group is prefixed by a specific halo group, it must be understood that the group in question is replaced by one or more specific halo groups. For example, the term "fluoromethyl" refers to a methyl group substituted by one, two or three fluoro groups.
    [0048] [0048] Unless otherwise specified, where it is said that a group is "substituted by halo", it should be understood that the group in question is replaced by one or more halo groups selected independently from fluoro, chloro, bromo e 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.
    [0049] [0049] 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.
    [0050] [0050] 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, if the cyclic group is a phenyl fraction, the positions α, β, α 'and β' are as follows:    ''
    [0051] [0051] For the avoidance of doubt, when it is stated that a cyclic group is substituted in positions α and / or α ', it should be understood that one or more hydrogen atoms in positions α and / or α' respectively are replaced by one or more substituents. 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.
    [0052] [0052] When reference is made to a hydrocarbyl or other group, including one or more N, O or S heteroatoms in its carbon skeleton, or when reference is made to a carbon atom of a hydrocarbyl or another group being replaced by a atom of N, O or S, what is intended is that: CH. N. . . is replaced by is replaced by; –CH2 – is replaced by – NH–, –O– or –S–; –CH3 is replaced by –NH2, –OH or –SH; –CH = is replaced by –N =; CH2 = is replaced by NH =, O = or S =; or CH≡ is replaced by N≡;
    [0053] [0053] provided that the resulting group comprises at least one carbon atom. For example, methoxy, dimethylamino and aminoethyl groups are considered hydrocarbyl groups including one or more N, O or S heteroatoms in their carbon backbone.
    [0054] [0054] When reference is made to a CH2- group in the main chain of a hydrocarbon or another group being replaced by a -N (O) (Rβ) - or - N + (Rβ) 2- group, what is intended is that : OR
    [0055] [0055] In the context of this specification, unless otherwise specified, a Cx-Cy group is defined as a group containing from x to y carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms. Optional substituents and fractions are not taken into account when calculating the total number of carbon atoms in the parent group replaced by the optional substituents and / or containing the optional fractions. For the avoidance of doubt, substitution heteroatoms, for example, N, O or S, should be counted as carbon atoms when calculating the number of carbon atoms in a Cx-Cy group. For example, a morpholinyl group should be considered a C6 heterocyclic group, not a C4 heterocyclic group.
    [0056] [0056] For the purposes of this specification, in which it is stated that a first atom or group is "directly linked" to a second atom or group, it must be understood that the first atom or group is covalently connected to the second atom or group with no atom or intervening groups present. So, for example, for the (C = O) N (CH3) 2 group, the carbon atom of each methyl group is directly attached to the nitrogen atom and the carbon atom of the carbonyl group is directly attached to the nitrogen atom, but the carbon atom of the carbonyl group is not directly linked to the carbon atom of the two methyl groups.
    [0057] [0057] R1 is a saturated or unsaturated (including aromatic) hydrocarbyl group, such as a C1-C30 or C2-C20 or C3-C17 hydrocarbyl group, wherein the hydrocarbyl group may be straight or branched or be or include cyclic groups , where the hydrocarbyl group can optionally be substituted and where the hydrocarbyl group can optionally include one or more N, O or S heteroatoms in its carbon backbone.
    [0058] [0058] In one embodiment, R1 is a cyclic group of 4 to 10 members, in which the cyclic group can optionally be substituted. Typically, the cyclic group is a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl group. In one embodiment, R1 is a phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tyrolyl, azidyl, cycloprotyl, triethyl, cyclone tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanil, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, 1,4-dioxatanil, thianyl, piperazinyl, morpholinyl, 2-thomorpholinyl oxo-1,2-dihydropyridinyl, 2-oxo-1,2-dihydropyrazinyl or 2-oxo-1,2-dihydropyrimidinyl, all of which can optionally be substituted. In one embodiment, R1 is a phenyl, naphthyl, pyridinyl group,
    [0059] [0059] In another embodiment, R1 is a C1-C15 alkyl, C2-C15 alkenyl or C2-C15 alkynyl group, all of which can be optionally substituted and all of which can optionally include one or more (such as one, two or three ) N, O or S heteroatoms in their carbon skeleton. R1 can be a C1- C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl group, all of which can be optionally substituted, and all of which can optionally include one or more (such as one, two or three) N, O heteroatoms or S in your carbon skeleton. In one embodiment, R1 is an optionally substituted C1-C5 alkyl or C2-C5 alkenyl group.
    [0060] [0060] In another embodiment, R1 is an optionally substituted phenyl or optionally substituted benzyl group.
    [0061] [0061] In another embodiment, R1 is a hydrocarbyl group, in which the hydrocarbyl group may be straight or branched, or be or include cyclic groups, in which the hydrocarbyl group may optionally be substituted and in which the hydrocarbyl group includes a or more N or O heteroatoms in its carbon backbone or is replaced by one or more N or O heteroatoms (that is, replaced by a substituent comprising one or more N or O heteroatoms). Typically, the hydrocarbon group contains 1-15 carbon atoms and 1-4 nitrogen or oxygen atoms.
    [0062] [0062] In the above modalities, R1 can be substituted by one or more substituents selected independently from halo; -CN; -NO2; -N3; -
    [0063] [0063] Alternatively, R1 can be substituted by one or more substituents selected independently from halo; -CN; -NO2; -N3; - Rβ; -OH; -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; - SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα- SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; - CHO; -CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα- COORβ; -Rα-OCORβ; -NH-CHO; -NRβ-CHO; -NH-CORβ; -NRβ-CORβ; -CONH2; - CONHRβ; -CON (Rβ) 2; -Rα-NH-CHO; -Rα-NRβ-CHO; -Rα-NH-CORβ; -Rα-NRβ-CORβ; -Rα-CONH2; -Rα-CONHRβ; -Rα-CON (Rβ) 2; -O-Rα-OH; -O-Rα-ORβ; -O-Rα-NH2; -O- Rα-NHRβ; -O-Rα-N (Rβ) 2; -NH-Rα-OH; -NH-Rα-ORβ; -NH-Rα-NH2; -NH-Rα-NHRβ; - NH-Rα-N (Rβ) 2; -NRβ-Rα-OH; -NRβ-Rα-ORβ; -NRβ-Rα-NH2; -NRβ-Rα-NHRβ; -NRβ-Rα- N (Rβ) 2; the C3-C7 cycloalkyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a C3-C7 cycloalkenyl group optionally substituted by one or more C1-C3 alkyl or C1-C3 haloalkyl groups; a 3- to 7-membered non-aromatic heterocyclic group optionally substituted by one or more C1-C6 alkyl or C1-C3 haloalkyl groups; oxo (= O); or a C1-C4 alkylene bridge; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main 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 the group C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or cyclic C2-C6 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, -
    [0064] [0064] Alternatively, R1 can be substituted by one or more substituents selected independently from halo; -CN; -NO2; -N3; - Rβ; -OH; -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; - SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα- SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; - CHO; -CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα- COORβ; -Rα-OCORβ; -NH-CHO; -NRβ-CHO; -NH-CORβ; -NRβ-CORβ; -CONH2; - CONHRβ; -CON (Rβ) 2; -Rα-NH-CHO; -Rα-NRβ-CHO; -Rα-NH-CORβ; -Rα-NRβ-CORβ; -Rα-CONH2; -Rα-CONHRβ; -Rα-CON (Rβ) 2; oxo (= O); or the C1-C4 alkylene bridge; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or more carbon atoms in the chain main 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group and where any -Rβ can optionally be substituted by one or more 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 or oxo groups (= O).
    [0065] [0065] Alternatively, R1 can be substituted by one or more substituents selected independently from halo; -CN; -NO2; -N3; - Rβ; -OH; -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; - SO2N (Rβ) 2; -Rα-SH; -Rα-SRβ; -Rα-SORβ; -Rα-SO2H; -Rα-SO2Rβ; -Rα-SO2NH2; -Rα- SO2NHRβ; -Rα-SO2N (Rβ) 2; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; - CHO; -CORβ; -COOH; -COORβ; -OCORβ; -Rα-CHO; -Rα-CORβ; -Rα-COOH; -Rα- COORβ; -Rα-OCORβ; -CONH2; -CONHRβ; -CON (Rβ) 2; oxo (= O); or a C1- C4 alkylene bridge; where each -Rα- is independently selected from an alkylene, alkenylene or alkynylene group, where the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its main chain, where one or two carbon atoms in the chain principal of the alkylene, alkenylene or alkynylene group can optionally be substituted by one or two N, O or S heteroatoms, and in which the alkylene, alkenylene or alkynylene group can optionally be substituted by one or more halo and / or -Rβ groups; and where each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group and where any -Rβ can optionally be 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 or oxo groups (= O).
    [0066] [0066] Alternatively, R1 can be substituted by one, two or three substituents independently selected from halo; -CN; -N3; -Rβ; - OH; -ORβ; -SO2Rβ; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; -Rα-N (Rβ) 2; -CORβ; - COORβ; -OCORβ; -Rα-CORβ; -Rα-COORβ; -Rα-OCORβ; -CONH2; -CONHRβ; - CON (Rβ) 2; or oxo (= O); where each -Rα-is independently selected from a C1-C6 alkylene group, where one or two carbon atoms in the main chain of the alkylene group can optionally be replaced by one or two N, O or S heteroatoms, and in that the alkylene group can optionally be substituted by one or two halo and / or -Rβ groups; and where 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, two or three 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 or oxo groups (= O).
    [0067] [0067] Alternatively, R1 can be substituted by one, two or three substituents independently selected from halo; C 1 -C5 alkyl; C1-C5 haloalkyl; -R5- (C3-C6 cycloalkyl); C2-C5 alkenyl; C2-C5 haloalkenyl; C2-C5 alkynyl; C2-C5 haloalkynyl; -R5-CN; -R5-N3; -R5-NO2; -R5-N (R6) 2; -R5-OR6; -R5-COR6; -R5- COOR6; -R5-CON (R6) 2; -R5-SO2R6; -R5- (C3-C6 cycloalkyl replaced by -R5- N (R6) 2); -R5-phenyl; -R5- (Het); oxo (= O); or -R51-; wherein R5 is independently selected from a bond or C1-C5 alkylene; each R6 is independently selected from hydrogen; C 1 -C5 alkyl; C1-C5 haloalkyl; C3-C6 cycloalkyl; benzyl; or C1-C5 alkyl substituted by C1-
    [0068] [0068] Typically, any divalent group -R51- forms a 4- to 6-membered fused ring.
    [0069] [0069] In one aspect of any of the previous modalities, R1 contains from 1 to 30 atoms other than hydrogen. More typically, R 1 contains 1 to 25 atoms other than hydrogen. More typically, R 1 contains 2 to 20 atoms other than hydrogen. More typically, R1 contains 4 to 17 atoms other than hydrogen.
    [0070] [0070] R2 is a cyclic group substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group, in which a ring atom of the heterocyclic or aromatic group is directly attached to an atom of the α ring 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. 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 optional substituent.
    [0071] [0071] In one embodiment, the 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 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 cyclic group substituted by α from R2 is a 5- or 6-membered phenyl or heteroaryl group, all of which can optionally be additionally substituted. In one embodiment, the α-substituted cyclic group of R2 is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazoli group, all of which can be substituted optionally posteriorly. In one embodiment, the cyclic group substituted by α from R 2 is a phenyl or pyrazolyl group, all of which can optionally be additionally substituted. In one embodiment, the cyclic group substituted by α from R2 is a phenyl group, which is optionally additionally substituted.
    [0072] [0072] R2 is a cyclic group substituted in position a by a monovalent heterocyclic group or a monovalent aromatic group, in which the heterocyclic or aromatic group can optionally be 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 in the α position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolil, isoxazolil, thiazolol, isothiazolyl, triazolyl, isothiazolyl, triazolyl, triazole, azetidinyl, oxetanil, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanil, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, 1,4-piperazinil, 1,4 thianyl, morpholinyl, thiomorpholinyl or 1-methyl-2-oxo-1,2-dihydropyridinyl, which can optionally be substituted. In one embodiment, the monovalent heterocyclic or aromatic group in the α position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolil, isoxazolil, thiazolil, isothiazolyl, triazolyl, isothiazolyl, triazolyl, triazolyl, isothiazolyl, triazole, azetidinyl, oxetanil, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanil, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, 1,4-piperazinil, 1,4 thianyl, morpholinyl or thiomorpholinyl, 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, oxazolil, isoxazolil, thiazolil, isothiazolyl, isothiazolyl, triazolyl, isothiazolyl, isothiazolyl, isothiazolyl, isothiazolyl, oxetanil, tietanil, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanil, 1,2-oxathiolanil, 1,3-
    [0073] [0073] 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 B4 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 hetero atoms, where any B 4 can optionally be substituted by halo and / or substituted by 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 heteroatoms O, and wherein the alkylene or alkenylene group can optionally be substituted by halo and / or substituted by 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;
    [0074] [0074] Typically, any divalent group -B44- forms a 4- to 6-membered fused ring.
    [0075] [0075] In one embodiment, the monovalent heterocyclic or aromatic group in position α 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, C1-C3 alkyl or -O (C1-C3 alkyl). 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, C1-C3 alkyl or -O (C1-C3 alkyl). In one embodiment, the monovalent heterocyclic group at the α position is an unsubstituted pyridin-3-yl group or a pyridin-4-yl group optionally substituted by one or two substituents independently selected from halo, -OH, -NH2, - CN, C1-C3 alkyl or -O (C1-C3 alkyl). Alternatively, any of these monovalent phenyl or heterocyclic groups in the α position can optionally be substituted by one or two substituents independently selected from halo, -OH, -NH2, -CN, -NO2, -B4, - OB4, -NHB4 or -N (B4) 2, where each B4 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group all of which can optionally be substituted by halo.
    [0076] [0076] R2 is a cyclic group substituted in position a by a monovalent heterocyclic group or a monovalent aromatic group, in which the cyclic group can optionally be additionally substituted. In one embodiment, the cyclic group substituted by α from R2 is substituted in positions α and α 'and can optionally be additionally substituted. For example, the cyclic group substituted by α from R2 may be a 6-membered phenyl or heterocyclic group substituted in positions 2 and 6, or substituted in positions 2, 4 and 6. In one embodiment, the cyclic group substituted by α from R2 it may be a phenyl group substituted at positions 2 and 6 or substituted at positions 2, 4 and 6.
    [0077] [0077] When the α-substituted cyclic group of R2 is a phenyl or a 6-membered heterocyclic group that is substituted in position 4 and is optionally substituted additionally, typically the substituent in position 4 is selected from a halo group, - CN, C1-C3 alkyl or C3-C6 cycloalkyl. In one embodiment, the substituent at position 4 is selected from a group of fluoro, chloro, -CN or cyclopropyl.
    [0078] [0078] R2 is a cyclic group substituted in position a by a monovalent heterocyclic group or a monovalent aromatic group, in which the cyclic group can optionally be additionally substituted. In one embodiment, these additional substituents are at the α 'position of the 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 independently selected from a 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 cyclic group of R2 are selected independently from halo, C1-C6 alkyl (in particular C3-C6 branched alkyl) or C3-C6 cycloalkyl groups, for example, fluorine, chlorine, isopropyl groups , cyclopropyl, cyclohexyl or t-butyl, wherein the alkyl and cycloalkyl groups are optionally substituted further by one or more fluoro and / or chloro groups.
    [0079] [0079] In one mode, -R2 has a formula selected from: R7
    [0080] [0080] Typically, any divalent group -B55- forms a 4- to 6-membered fused ring. Typically, R7 is C1-C4 alkyl or C3-C6 cycloalkyl, R8 is an optionally substituted 5- or 6-membered heterocyclic or aromatic group and X is hydrogen, halo, -CN, C1-C3 alkyl or C3-C6 cycloalkyl. More typically, R7 is C1-C4 alkyl, R8 is an optionally substituted 5- or 6-membered heterocyclic or aromatic group and X is hydrogen or halo. In one embodiment, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, -OH, -NH2, -CN, -NO2, -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, which can optionally be substituted by halo.
    [0081] [0081] Typically, -R2 has a formula selected from:
    [0082] [0082] Typically, any divalent group -B66- 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, -NO2, -B6, -OB6, -NHB6 or -N (B6) 2, where each B6 is independently selected from a C1-C4 alkyl group, C2-C4 alkenyl or C2-C4 alkynyl group, all of which can optionally be substituted by halo.
    [0083] [0083] Additional substituents on the α-substituted cyclic group of R2 also include cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings that are fused to the α-substituted cyclic group of R 2. Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl are ortho-fused to the cyclic group substituted by α from R2, that is, each cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or fused heteroaryl ring has only two atoms and a common bond with the cyclic group replaced by α from R2. Typically, the cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused to the cyclic group substituted by α from R2 through positions α ', β'.
    [0084] [0084] In one mode, -R2 has a formula selected from: X N X
    [0085] [0085] Typically, any divalent group -B77- forms a 4- to 6-membered fused ring. Typically, X is hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclocyclopropyl. Typically, X is hydrogen, halo, - CN, C1-C3 alkyl or C3-C6 cycloalkyl. More typically, X is hydrogen or halo. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, -OH, -NH2, -CN, -NO2, -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, which can optionally be substituted with halo.
    [0086] [0086] In one mode, -R2 has a formula selected from: N N
    [0087] [0087] Typically, any divalent group -B88- forms a 4- to 6-membered fused ring. Typically, the optional substituents on the heterocyclic or aromatic group are selected independently from halo, -OH, -NH2, - CN, -NO2, -B8, -OB8, -NHB8 or -N (B8) 2, where each B8 is independently selected from a C1-C4 alkyl group, C2-C4 alkenyl or C2-C4 alkynyl group, all of which can optionally be substituted by halo.
    [0088] [0088] Typically, -R2 has a formula selected from:
    [0089] [0089] Typically, any divalent group -B99- forms a 4- to 6-membered fused ring. Typically, X is hydrogen, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or halocyclocyclopropyl. Typically, X is hydrogen, halo, - CN, C1-C3 alkyl or C3-C6 cycloalkyl. More typically, X is hydrogen or halo. Typically, the optional substituents on the heterocyclic or aromatic group are independently selected from halo, -OH, -NH2, -CN, -NO2, -B9, - OB9, -NHB9 or -N (B9) 2, where each B9 is independently selected from a group C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, all of which can optionally be substituted by halo.
    [0090] [0090] In one aspect of any of the above modalities, R 2 contains 10 to 50 atoms other than hydrogen. More typically, R 2 contains 10 to 40 atoms other than hydrogen. More typically, R 2 contains 10 to 35 atoms other than hydrogen. More typically, R2 contains 12 to 30 atoms other than hydrogen.
    [0091] [0091] Q is selected from O or S. In an embodiment of the first aspect of the invention, Q is O.
    [0092] [0092] In a specific embodiment, the invention provides a compound of formula (I), where: Q is O; R1 is an optionally substituted 4, 5 or 6 membered saturated or unsaturated heterocycle; or R1 is an optionally substituted group selected from C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, phenyl or benzyl; or R1 is a hydrocarbyl group, where the hydrocarbyl group may be straight or branched, or be or include cyclic groups, where the hydrocarbyl group may optionally be substituted and where the hydrocarbyl group includes one or more N or O heteroatoms in its carbon skeleton it is either substituted by a substituent comprising one or more N or O heteroatoms (typically the hydrocarbyl group contains 1-15 carbon atoms and 1-4 nitrogen or oxygen atoms); and R2 is a 5- or 6-membered phenyl or heteroaryl group; wherein the 5- or 6-membered phenyl or heteroaryl group is substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group selected from a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl group , imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, azetinyl, azetidinyl, oxetanil, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, 1,3-imidazazyl, 1,3-imidazazyl -oxathiolanil, piperidinyl, tetrahydropyranyl, piperazinyl, 1,4-dioxanyl, thianyl, morpholinyl, thiomorpholinyl or 1-methyl-2-oxo-1,2-dihydropyridinyl, in which a ring atom of the heterocyclic or aromatic group it is directly attached to the ring atom α of the 5- or 6-membered phenyl or heteroaryl group and where the heterocyclic or aromatic group can optionally be substituted by one or two substituents independently selected from halo, -OH, -NH2, -CN , - N O2, -B4, -OB4, -NHB4, -N (B4) 2, -CONH2, -CONHB4, -CON (B4) 2, -NHCOB4, - NB4COB4, or -B44-; wherein the 5- or 6-membered phenyl or heteroaryl group is substituted in the α'position by a C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl or cyclic C2-C6 group (typically a pyridinyl) , or in positions α 'and β' with a divalent group -B44-; and wherein the 5- or 6-membered phenyl or heteroaryl group can optionally be further substituted (typically by one or two substituents independently selected from halo, -CN, C1-C3 alkyl or C3-C6 cycloalkyl); wherein each B4 is independently selected from a C1- C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl or phenyl group or a 4- to 6-membered heterocyclic group containing one or two N ring heteroatoms 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 replaced by a halo and / or substituted by 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 heteroatoms O, and wherein the alkylene or alkenylene group can optionally be substituted by halo and / or substituted by 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.
    [0093] [0093] Typically, any divalent group -B44- forms a 4- to 6-membered fused ring.
    [0094] [0094] Typically, in this specific embodiment, the invention provides a compound of formula (I), wherein: Q is O; R1 is an optionally substituted 4, 5 or 6 membered saturated or unsaturated heterocycle; or R1 is an optionally substituted group selected from C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, phenyl or benzyl; or R1 is a hydrocarbyl group, where the hydrocarbyl group may be straight or branched, or be or include cyclic groups, where the hydrocarbyl group may optionally be substituted and where the hydrocarbyl group includes one or more N or O heteroatoms in its carbon skeleton it is either substituted by a substituent comprising one or more N or O heteroatoms (typically the hydrocarbyl group contains 1-15 carbon atoms and 1-4 nitrogen or oxygen atoms); and R2 is a 5- or 6-membered phenyl or heteroaryl group; wherein the 5- or 6-membered phenyl group or heteroaryl group is substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group selected from a phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl group, wherein the heterocyclic group or aromatic group can optionally be substituted by one or two substituents independently selected from halo C1-C3 alkyl, C1-C3 haloalkyl, -
    [0095] [0095] In this specific embodiment, R1 may be an optionally substituted heterocycle selected from a group pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolil, thiazolyl, isothiazolyl, triazolyl, triazolyl, triazolyl, triazolyl, triazolyl, triazolyl, triazolyl, triazolyl, triazolyl, azetidinyl, oxetanil, tietanil, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, tianyl, 1,4 dioxanil, morpholinyl, thiomorpholinyl, 2-oxo-1,2-dihydropyridinyl, 2-oxo-1,2-dihydropyrazinyl or 2-oxo-1,2-dihydropyrimidinyl. Alternatively, R can be an optionally substituted heterocycle selected from a group pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazylil, azia, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl, azyl. , pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, 1,3-dioxolanil, 1,2-oxathiolanil, 1,3-oxathiolanil, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, 1,4-dioxanyl, morpholinyl or morpholinyl or . Alternatively, R 1 may be an optionally substituted heterocycle selected from a group pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-oxo-1,2-di-1,2 -hydropyridinyl, 2-oxo-1,2-dihydropyrazinyl or 2-oxo-1,2-dihydropyrimidinyl.
    [0096] [0096] Alternatively, in this specific embodiment, R1 can be a C1-C5 alkyl or C2-C5 alkenyl group optionally substituted by one or two substituents independently selected from a halo group, -CN, - N (R9) 2, - OR9, phenyl or heterocyclic; wherein each R9 is independently selected from hydrogen, C1-C5 alkyl or benzyl; and the heterocyclic group is independently selected from a group pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanil, tetrahydrofuranyl or tetrahydropyranyl, each of which can optionally be substituted by one or two substituents independently selected from halo or C 1 -C 3 alkyl.
    [0097] [0097] Alternatively, in this specific embodiment, R1 may be a phenyl group optionally substituted by one or two substituents independently selected from C1-C5 alkyl, C3-C6 cycloalkyl, -R10- N (R11) 2 or -R10-CON (R11) 2; wherein R10 is independently selected from a bond or C1-C3 alkylene; and each R11 is independently selected from hydrogen or C1-C3 alkyl.
    [0098] [0098] Alternatively, in this specific modality, R1 may be an unsubstituted benzyl group.
    [0099] Alternatively, in this specific embodiment, R1 can be a -OR12, -NHR12 or -N (R12) 2 group; wherein each R12 is independently selected from C1-C5 alkyl, C3-C6 cycloalkyl or -R13- (Het); R13 is independently selected from a bond or C 1 -C 3 alkylene; and Het is independently selected from the group azetidinyl, pyrrolidinyl, piperidinyl, oxetanil, tetrahydrofuranyl or tetrahydropyranyl, each of which can optionally be substituted by one or two substituents independently selected from halo or C1-C3 alkyl .
    [0100] [0100] In this specific modality, R1 can be optionally substituted by one, two or three substituents selected independently from halo; C1-C5 alkyl; C1-C5 haloalkyl; -R5- (C3-C6 cycloalkyl); C2-C5 alkenyl; C2-C5 haloalkenyl; C2-C5 alkynyl; C2-C5 haloalkynyl; -R5-CN; -R5-N3; -R5-NO2; -R5- N (R6) 2; -R5-OR6; -R5-COR6; -R5-COOR6; -R5-CON (R6) 2; -R5-SO2R6; -R5- (C3-C6 cycloalkyl replaced by -R5-N (R6) 2); -R5-phenyl; -R5- (Het); oxo (= O); or -R51-; wherein R5 is independently selected from a bond or C1-C5 alkylene; each R6 is independently selected from hydrogen; C1-C5 alkyl; C1-C5 haloalkyl; C3-C6 cycloalkyl; benzyl; or C1-C5 alkyl substituted by C1- C5 alkoxy; or two R6 together with the nitrogen atom to which they are attached can form a 4- to 6-membered saturated heterocyclic group; R51 is independently selected from a C 1 -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 by halo; and Het is independently selected from a group pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanil, tetrahydrofuranyl or hydropyranyl, each of which can optionally be substituted by one, two or three substituents independently selected from halo, C 1 -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C1-C3 alkoxy.
    [0101] [0101] Typically, any divalent group -R51- forms a 4- to 6-membered fused ring.
    [0102] [0102] Alternatively, in this specific embodiment, R1 can be optionally substituted by one, two or three substituents independently selected from halo, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2- C5 haloalkenyl, C2-C5 alkynyl, C2-C5 haloalkynyl, -R5-CN, -R5-N3, -R5-NO2, -R5-N (R6) 2, -R5-OR6, -R5-COR6, -R5- COOR6, -R5-CON (R6) 2, -R5-SO2R6, oxo (= O), (CH2) m (CH2) m ON R6 (CH2) n, or (CH2) n; wherein 5 R is independently selected from a bond or C 1 -C 3 alkylene; each R6 is independently selected from hydrogen, C 1 -C5 alkyl, C1-C5 haloalkyl or C3-C6 cycloalkyl; m is 1, 2 or 3; and n is 1, 2 or 3.
    [0103] [0103] In one aspect of any of the above embodiments, the compound of formula (I) has a molecular weight of 250 to 2,000 Da. Typically, the compound of formula (I) has a molecular weight of 300 to 1,000 Da. Typically , the compound of formula (I) has a molecular weight of 340 to 800 Da. More typically, the compound of formula (I) has a molecular weight of 380 to 600 Da.
    [0104] [0104] A second aspect of the invention provides a compound selected from the group consisting of:
    [0105] [0105] 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.
    [0106] [0106] The compounds of the present invention can be used both in their free base form and in their acid addition salt form. For the purposes of this invention, a "salt" of a compound of the present invention includes an acid addition salt. Acid addition salts are preferably non-toxic pharmaceutically acceptable addition salts with suitable acids, including, but not limited to, inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids ( for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids, such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxylic, mucic or galactic, gluconic, gluconic , pantothenic or pamoic), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-sulfonic acid, naphthalene-2-sulfonic or camphor sulfonic) or amino acids (for example, ornithinic, glutamic acid 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.
    [0107] [0107] When 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.
    [0108] [0108] 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.
    [0109] [0109] 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.
    [0110] [0110] 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.
    [0111] [0111] 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 into a compound of the invention. In most modalities, prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules 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 labile protecting groups in a functional fraction of the active compound. The prodrugs, but are not limited to compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated and / or dephosphorylated to produce the active compound. The present invention also encompasses salts and solvates of such prodrugs, as described above.
    [0112] [0112] The compounds, salts, solvates and prodrugs of the present invention can contain at least one chiral center. The compounds, salts, solvates and prodrugs can therefore exist in at least two isomeric forms. The present invention encompasses racemic mixtures of the compounds, salts, solvates and prodrugs of the present invention, as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of this invention, a "substantially enantiomerically pure" isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2% and more typically less than 0.5% by weight.
    [0113] [0113] The compounds, salts, solvates and prodrugs of the present invention 12 13 can contain any stable isotope, including, but not limited to C, C, 1 2 14 15 16 17 18 19 127 H, H (D), N, N, O, O, O, F and I, and any radioisotope including, but not limited to, 11C, 14C, 3H (T), 13N, 15O, 18F, 123I, 124I, 125I and 131I.
    [0114] [0114] The compounds, salts, solvates and prodrugs of the present invention can be in any polymorphic or amorphous form.
    [0115] [0115] 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.
    [0116] [0116] 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.
    [0117] [0117] 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 saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen sulfate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, carboxymethyl cellulose sodium, polyacrylates, waxes, polyoxypropylene-polyethylene-, polyethylene-glycol block polymers col and wool fat.
    [0118] [0118] In one embodiment, the pharmaceutical composition of the fourth aspect of the invention is a topical pharmaceutical composition. For example, the topical pharmaceutical composition can be a dermal pharmaceutical composition or an ocular pharmaceutical composition.
    [0119] [0119] In one embodiment, the pharmaceutical composition of the fourth aspect of the invention further comprises one or more additional active agents.
    [0120] [0120] 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.
    [0121] [0121] A fifth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine and / or for use in the treatment or prevention of a disease, disorder or condition. Typically, the use comprises administering the compound, salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the use comprises the co-administration of one or more additional active agents.
    [0122] [0122] The term "treatment", as used herein, also refers to curative and palliative or enhancing therapy. The term includes obtaining beneficial or desired physiological results, which may or may not be clinically established. Beneficial or desired clinical results include, but are not limited to, symptom relief, symptom prevention, decrease in disease extent, stabilization (ie, do not worsen) of a condition, delay or slowing of progression / worsening of a condition / symptoms, improvement or palliation of the condition / symptoms and remission (partial or total), whether detectable or undetectable. The term "palliation" and its variations, as used here, means that the extent and / or undesirable manifestations of a physiological condition or symptom are decreased and / or the progression of the progression is slower or longer, compared to not administering a composition, salt, solvate, prodrug or pharmaceutical composition of the present invention. The term "prevention", as used herein in connection with a disease, disorder or condition, refers to prophylactic or preventive therapy, as well as therapy to reduce the risk of developing the disease, disorder or condition. The term "prevention" includes both preventing the occurrence of the disease, disorder or condition, and delaying the onset of the disease, disorder or condition. Any statistically significant prevention (p ≤ 0.05) of the occurrence, delay in onset or risk reduction, as measured by a controlled clinical trial, can be considered a prevention of the disease, disorder or condition. Preventable subjects include those most at risk for a disease, disorder or condition identified by genetic or biochemical markers. Typically, genetic or biochemical markers are appropriate for the disease, disorder or condition under consideration and may include, for example, inflammatory biomarkers, such as C-reactive protein (CRP) and monocyte 1 chemoprotein protein 1 (MCP-1) in the case inflammation; total cholesterol, triglycerides, insulin resistance and C-peptide in the case of NAFLD and NASH; and more generally IL1β and IL18 in the case of a disease, disorder or condition responsive to NLRP3 inhibition.
    [0123] [0123] 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 the co-administration of one or more additional active agents.
    [0124] [0124] 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.
    [0125] [0125] An eighth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in the treatment or preventing an illness, disorder or condition in an individual, where the individual has a germline or a non-silent somatic mutation in NLRP3. The mutation can be, for example, a gain in function or another mutation resulting in increased NLRP3 activity. Typically, the use comprises administering the compound, salt, solvate, prodrug or pharmaceutical composition to an individual. In one embodiment, the use comprises the co-administration of one or more additional active agents. The use may also comprise the diagnosis of an individual with a non-silent somatic germline or somatic mutation in NLRP3, in which the compound, salt, solvate, prodrug or pharmaceutical composition is administered to an individual based on a positive diagnosis for the mutation . Typically, the identification of the mutation in the NLRP3 in the individual can be by any suitable genetic or biochemical means.
    [0126] [0126] 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 NLRP 3 activity. Typically, treatment or prevention comprises administering the compound, salt, solvate, prodrug or medication to the individual. In one embodiment, treatment or prevention comprises the co-administration of one or more additional active agents. Treatment or prevention may also comprise the diagnosis of an individual with a non-silent somatic germ or mutation in NLRP3, in which the compound, salt, solvate, prodrug or drug is administered to an individual based on a positive diagnosis for the mutation. Typically, the identification of the mutation in the NLRP3 in the individual can be by any suitable genetic or biochemical means.
    [0127] [0127] 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.
    [0128] [0128] In general terms, the disease, disorder or condition can be a disease, disorder or condition of the immune system, the cardiovascular system, the endocrine system, the gastrointestinal tract, the renal system, the hepatic system, the metabolic system, the respiratory system, the central nervous system, may be cancer or other malignancy and / or may be caused or associated with a pathogen.
    [0129] [0129] 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.
    [0130] [0130] 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.
    [0131] [0131] 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
    [0132] [0132] NLRP3 has been implicated in several autoinflammatory diseases, including Familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), pyogenic arthritis, pyoderma gangrenous and acne (PAPA), Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO) and acne vulgaris (Cook et al., Eur. J. Immunol., 40: 595–653, 2010). In particular, it has been found that mutations in NLRP3 are responsible for a set of rare autoinflammatory diseases known as CAPS (Ozaki et al., J. Inflammation Research, 8: 15-27, 2015; Schroder et al., Cell, 140: 821-832, 2010; and Menu et al., Clinical and Experimental Immunology, 166: 1–15, 2011). CAPS are inherited diseases characterized by recurrent fever and inflammation and are composed of three autoinflammatory diseases that form a clinical continuum. These diseases, in ascending order of severity, are the familial auto-inflammatory syndrome associated with cold (FCAS), the Muckle-Wells syndrome (MWS) and the chronic infantile cutaneous neurological joint syndrome (CINCA; also called neonatal multisystemic inflammatory disease) , NOMID) and all have been shown to result from function gain mutations in the NLRP3 gene, which leads to increased secretion of IL-1β.
    [0133] [0133] Several autoimmune diseases have been shown to involve NLRP 3, including, multiple sclerosis, type 1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler syndrome, macrophage activation syndrome (Masters Clin. Immunol. 2013; Braddock et al. Nat. Rev. Drug Disc. 2004 3: 1-10; Inoue et al., Immunology 139: 11-18, Coll et al. Nat. Med. 2015 21 (3): 248- 55; and Scott et al. Clin. Exp. Rheumatol 2016 34 (1): 88-93), systemic lupus erythematosus (Lu et al. J Immunol. 2017 198 (3): 1119-29), and systemic sclerosis (Artlett et al. Arthritis Rheum. 2011; 63 (11): 3563-74). NLRP3 has also been shown to play a role in several lung diseases, including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis and silicosis (De Nardo et al., Am. J. Pathol., 184 : 42-54, 2014 and Kim et al. Am J Respir Crit Care Med. 2017 196 (3): 283-97). It has also been suggested that NLRP3 plays a role in several conditions of the central nervous system, including Parkinson's disease (PD),
    [0134] [0134] The inflammasome, and NLRP3 specifically, has also been proposed as a target for modulation by various pathogens, including viruses such as DNA viruses (Amsler et al., Future Virol. (2013) 8 (4), 357–370).
    [0135] [0135] NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al., Clinical and Experimental Immunology 166: 1-15, 2011; and Masters Clin. Immunol. 2013). For example, several previous studies have suggested a role for IL-1β in cancer invasion, growth and metastasis, and inhibition of IL-1β with Canaquinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomized study, double-blind, placebo-controlled (Ridker et al. Lancet, S0140-6736 (17) 32247-X, 2017). Inhibition of NLRP3 or IL-1β inflammasome has also been shown to inhibit lung cancer cell proliferation and migration in vitro (Wang et al. Oncol Rep. 2016; 35 (4): 2053-64). A role for NLRP3 inflammasome has been suggested in myelodysplastic syndromes (Basiorka et al. Blood. December 22, 2016; 128 (25): 2960-2975) and also in the carcinogenesis of several other types of cancer, including glioma (Li et al Am J Cancer Res. 2015; 5 (1): 442-449), inflammation-induced tumors (Allen et al. J Exp Med. 2010; 207 (5): 1045-56 and Hu et al. PNAS. 2010; 107 (50): 21635-40), multiple myeloma (Li et al. Hematology 2016 21 (3): 144-51) and squamous cell carcinoma of the head and neck (Huang et al. J Exp Clin Câncer Res. 2017 2; 36 (1): 116). It has also been shown that the activation of the NLRP3 inflammasome mediates the chemoresistance of tumor cells to 5-fluorouracil (Feng et al. J Exp Clin Cancer Res. 2017 21; 36 (1): 81) and the activation of the NLRP3 inflammasome in the peripheral nerve contributes for neuropathic pain induced by chemotherapy (Jia et al. Mol Pain. 2017; 13: 1-11).
    [0136] [0136] NLRP3 has also been shown to be necessary for the efficient control of infections by viral, bacterial, fungal and helminth pathogens.
    [0137] [0137] Therefore, examples of diseases, disorders or conditions that can respond to NLRP3 inhibition and that can be treated or prevented according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention include: (i ) inflammation, including inflammation that occurs as a result of an inflammatory disorder, for example, an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs as a result of infection or inflammation secondary to trauma, injury or autoimmunity ; (ii) autoimmune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (PHC), anti-synthase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune insufficiency, autoimmune thyroiditis Celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, erythematous lupus including systemic lupus erythematosus ( SLE), multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), myasthenia gravis, myoclonus opsoclonus syndrome (WHO), optic neuritis, Ord thyroiditis , pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis l or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjogren's syndrome, systemic sclerosis to a systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, hot autoimmune hemolytic anemia, Wegener's granulomatosis, universal alopecia, Behçet's disease , Chagas' disease, dysautonomia, endometriosis, suppurative hidradenitis (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo or vulvodynia; (iii) cancer, including lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, including acute lymphocytic leukemia
    [0138] [0138] In one modality, the disease, disorder or condition is selected from: (i) cancer; (ii) an infection; (iii) a disease of the central nervous system; (iv) cardiovascular disease; (v) a liver disease; (vi) eye diseases; or (vii) a skin disease. 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.
    [0139] [0139] In one modality, the disease, disorder or condition is selected from: (i) acne conglobata; (ii) atopic dermatitis; (iii) Alzheimer's disease; (iv) amyotrophic lateral sclerosis; (v) age-related macular degeneration (AMD); (vi) anaplastic thyroid cancer;
    [0140] [0140] 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,
    [0141] [0141] 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), antibody deficiency and PLCG2-associated autoinflammatory immune dysregulation (APLA ID) or sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD).
    [0142] [0142] Examples of diseases, disorders or conditions that can respond to NLRP3 inhibition and that can be treated or prevented according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention are listed above. Some of these diseases, disorders or conditions are substantially or totally mediated by NLRP3 and IL-1β and / or IL-18 inflammasome activity. As a result, such diseases, disorders or conditions may be particularly responsive to inhibition of NLRP3 and may be particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention. Examples of such diseases, disorders or conditions include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), cold familial autoinflammatory syndrome (FCAS), neonatal onset multisystemic inflammatory disease (NOMID), familial Mediterranean fever (FMF) ), pyogenic arthritis, gangrenous pyoderma and acne syndrome (PAPA), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic juvenile idiopathic arthritis, Still's disease adult (AOSD), relapsing polychondritis, Schnitzler's syndrome, Sweet's syndrome, Behcet's disease, anti-synthase syndrome, interleukin 1 receptor antagonist (DIRA) deficiency and A20 haploinsufficiency (HA20) insufficiency.
    [0143] [0143] In addition, some of the diseases, disorders or conditions mentioned above arise due to mutations in NLRP 3, in particular, resulting in increased activity of NLRP3. As a result, such diseases, disorders or conditions may be particularly responsive to inhibition of NLRP3 and may be particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention. Examples of such diseases, disorders or conditions include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), cold-induced familial autoinflammatory syndrome (FCAS) and neonatal onset multisystemic inflammatory disease (NOMID).
    [0144] [0144] In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is not an NFκB-mediated disease or disorder. In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is not rheumatoid arthritis, osteoarthritis, an autoimmune disease, psoriasis, asthma, cardiovascular disease, coronary syndrome acute, atherosclerosis, myocardial infarction, unstable angina, congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type II diabetes, metabolic syndrome X, inflammatory bowel disease, systemic lupus erythematosus, Grave's disease, myasthenia gravis, insulin resistance , autoimmune hemolytic anemia, scleroderma with anti-collagen antibodies, pernicious anemia or diabetes mellitus. In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, the disease, disorder or condition is not an inflammatory bowel disease.
    [0145] [0145] In a fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention, treatment or prevention comprises topically administering 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 example, the disease, disorder or condition can be a skin disease or condition, where the treatment or prevention comprises topically administering 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 appearance on the skin. Alternatively, the disease, disorder or condition can be an eye disease or condition, where treatment or prevention comprises topically administering 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 in the eye.
    [0146] [0146] In an embodiment, where treatment or prevention comprises topical administration 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 of invention, one or more additional active agents can be co-administered. One or more additional active agents can also be administered topically, or can be administered via a non-topical route. Typically, one or more additional active agents are also administered topically. For example, when the pharmaceutical composition of the fourth aspect of the invention is a topical pharmaceutical composition, the pharmaceutical composition can further comprise one or more additional active agents.
    [0147] [0147] An eleventh aspect of the invention provides a method of inhibiting NLRP3, the method comprising the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to inhibit NLRP 3.
    [0148] [0148] In an eleventh aspect of the present invention, the method comprises the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention or a composition of the fourth aspect of the invention, in combination with one or more additional active agents.
    [0149] [0149] In an embodiment of the eleventh aspect of the present invention, the method is performed ex vivo or in vitro, for example, in order to analyze the effect on cells of NLRP3 inhibition.
    [0150] [0150] 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.
    [0151] [0151] 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.
    [0152] [0152] 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.
    [0153] [0153] 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 medication is co-administered with one or more additional active agents.
    [0154] [0154] 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.
    [0155] [0155] 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.
    [0156] [0156] In an embodiment of any one of the fifth to thirteenth aspects of the present invention comprising the use or co-administration of one or more additional active agents, one or more additional active agents are selected from: (i) chemotherapeutic agents ; (ii) antibodies; (iii) alkylating agents; (iv) anti-metabolites; (v) anti-angiogenic agents; (vi) plant alkaloids and / or terpenoids; (vii) topoisomerase inhibitors; (viii) mTOR inhibitors; (ix) stylbenoids; (x) STING agonists; (xi) cancer vaccines; (xii) immunomodulating agents; (xiii) antibiotics; (xiv) antifungal agents; (xv) anthelmintic agents; and / or (xvi) other active agents.
    [0157] [0157] 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.
    [0158] [0158] In some embodiments, one or more chemotherapeutic agents are selected from abiraterone acetate, altretamine, amsacrine, anhydrovinblastine, auristatin, azathioprine, adriamycin, bexarotene, bicalutamide, BMS 184476, bleomycin, N, N-dimethyl-L- valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, cisplatin, carboplatin, carboplatin cyclophosphamide, chlorambucil, cachectin, cemadotine, cyclophosphamide, carmustine, cryptophine, cytarabine, docetaxel, doxetaxel, doxorubicin, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine, dolastatin, etoposide, etoposide phosphate, enzalutamide (MDV3100), 5-fluorouracil, fludarabine, floamide, gencitabine, hydroxyane, hydroxyane, hydroxyane, hydroxyane lonidamine, lomustine (CCNU), larotaxel (RPR109881), meclorethamine, mercaptopurine, methotrexate, mitomycin C, mitoxantrone, melphalan, mivobulin, 3 ', 4'-didhydro-4'-deoxy-8'-norvin-kaleucoblastine, niluta mide, oxaliplatin, oxaliplatin, imustine, procarbazine, paclitaxel, anticancer agents containing platinum, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzene sulfonamide, prednimustine, procarbazine, rhizoxin, sertenefef , streptozocin, stramustine phosphate, tretinoin, tasonermin, taxol, topotecan, tamoxifen, teniposide, taxane, tegafur / uracil, vincristine, vinblastine, vinorelbine, vindesine, vindesine sulfate and / or vinflunine.
    [0159] [0159] Alternatively or in addition, one or more chemotherapeutic agents can be selected from the CD59 complement fragment, fibronectin fragment, gro-beta (CXCL2), heparinases, hexasaccharide heparin fragment, 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).
    [0160] [0160] 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.
    [0161] [0161] In some embodiments, one or more alkylating agents may comprise an agent capable of alkylating functional nucleophilic groups under conditions present in the cells, including, for example, cancer cells. In some embodiments, one or more alkylating agents are selected from cisplatin, carboplatin, mecloretamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin. In some embodiments, the alkylating agent may work by impairing cellular function, forming covalent connections with amino, carboxyl, sulfhydryl and / or phosphate groups in biologically important molecules. In some embodiments, the alkylating agent can work by modifying a cell's DNA.
    [0162] [0162] 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.
    [0163] [0163] In some embodiments, one or more antiangiogenic agents are selected from endostatin, angiogenin inhibitors, angiostatin, angioarrestin, angiostatin (plasminogen fragment), antiangiogenic factors derived from basement membrane collagen (tumstatin, canstatin or arrestin), antiantithrombin III angiogenic and / or cartilage-derived inhibitor (ICD).
    [0164] [0164] 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 the Madagascar periwinkle,
    [0165] [0165] 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
    [0166] [0166] 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.
    [0167] [0167] In some embodiments, one or more stylbenoids are selected from resveratrol, piceatanol, pinsilvin, pterostilbene, alpha-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, epsilon-vinferin, flexuosol A, gnetin H, hemsleyanol D, hopeafenol, transdiptoindonesin B, astringine, piceid and / or diptoindonesin A.
    [0168] [0168] 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).
    [0169] [0169] In some modalities, one or more cancer vaccines are selected from an HPV vaccine, a vaccine against hepatitis B, Oncophage and / or Provenge.
    [0170] [0170] In some embodiments, one or more immunomodulating agents may comprise an immune checkpoint inhibitor. The immune checkpoint inhibitor may target an immune checkpoint receptor or combination of receptors comprising, for example, CTLA-4, PD-1, PD-L1, PD-L2, T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9, phosphatidylserine, lymphocyte activation gene 3 protein (LAG3), MHC class I, MHC class II, 4-1BB, 4-1BBL, OX40, OX40L, GITR, GITRL, CD27, CD70 , TNFRSF25, TL1A, CD40, CD40L, HVEM, LIGHT, BTLA, CD160, CD80, CD244, CD48, ICOS, ICOSL, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2, TMIGD2, butyrophylline (including BTNL2), one member of the Siglec family, TIGIT, PVR, a killer cell immunoglobulin type receptor, an ILT, a leukocyte immunoglobulin type receptor, NKG2D, NKG2A, MICA, MICB, CD28, CD86, SIRPA, CD47, VEGF, neuropiline, CD30, CD39, CD73, CXCR4 and / or CXCL12.
    [0171] [0171] In some embodiments, the immune checkpoint inhibitor is selected from urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PD -L1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertibe, ulocuplumab, BKT140, bavituxima, and / or MNRP1685A.
    [0172] [0172] In some embodiments, one or more antibiotics are selected from amikacin, gentamicin, kanamycin, neomycin, netilmycin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenopen, meripenem, imipenopen, meripenem, , cefadroxil, cefazoline, cephalothin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditorene, cefoperazone, cefotaxime, cefphema, ceftaxine, ceftaxine, ceftaxine, ceftaxima, ceftaxine vancomycin, telavancin, dalbavancin, oritavancin, clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin,
    [0173] [0173] 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.
    [0174] [0174] In some embodiments, one or more antifungal agents are selected from bifonazole, butoconazole, clotrimazole, econazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, flaconazole, ezaconazole, flaconazol, , itraconazole, posaconazole, propiconazole, ravusconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naphthifine, terbinafine,
    [0175] [0175] 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, pirantelanamide, piramide, pyrantelanamide, pyrantelanamide niclosamide and oxyclozanide) and / or nitazoxanide.
    [0176] [0176] 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).
    [0177] [0177] Unless otherwise indicated, in any of the fifth to thirteenth aspects of the invention, the subject can be any human or other animal. Typically, 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.
    [0178] [0178] Any of the medications used in the present invention can be administered orally, parenterally (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), air (aerosol), rectal, vaginal, ocular or topical (including transdermal, buccal, mucous, sublingual and topical ocular).
    [0179] [0179] Typically, the mode of administration selected is 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.
    [0180] [0180] For oral administration, the compounds, salts, solvates or prodrugs of the present invention will generally be provided in the form of tablets, capsules, hard or soft gelatin capsules, pills, pills or tablets, as a powder or granules or as an aqueous solution, suspension or dispersion.
    [0181] [0181] 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.
    [0182] [0182] 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.
    [0183] [0183] Powders or granules for oral use can be supplied in sachets or containers. Aqueous solutions, suspensions or dispersions can be prepared by adding water to powders, granules or tablets.
    [0184] [0184] Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavoring agents, dyes and / or preservatives.
    [0185] [0185] Formulations for rectal administration can be presented as a suppository with a suitable base, which comprises, for example, cocoa butter or a salicylate.
    [0186] [0186] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, carriers known in the art as appropriate.
    [0187] [0187] 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 carriers 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 ethyl p-hydroxybenzoate and n-propyl. The compounds of the invention can also be presented as liposome formulations.
    [0188] [0188] 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.
    [0189] [0189] 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.
    [0190] [0190] Suitable suspensions and solutions can be used in inhalers for administration by air (aerosol).
    [0191] [0191] The dose of the compounds, salts, solvates or prodrugs of the present invention will, of course, vary 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.
    [0192] [0192] 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. Examples - synthesis of compounds
    [0193] [0193] 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-DME DMF dimethoxy N, N-dimethylformamide DMSO dimethyl sulfate eq or equivalent (ES +) Electrospray ionization, positive mode Et ethyl EtOAc ethyl acetate EtOH ethanol hour (s) HATU 1- [bis (dimethylamino) methylene hexafluorophosphate] -1H- 1,2,3-triazole [4,5-b] pyridinium HPLC high performance liquid chromatography LC liquid chromatography m multiplet m-CPBA 3-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MeOH methanol (M + H) + molecular ion protonated MHz mega-hertz min minute (s) MS spectrometry mass of Ms mesyl mass, also called methanesulfonyl MsCl mesyl chloride, also called methanesulfonyl chloride MTBE methyl tert-butyl ether, also called tert-butyl methyl ether m / z mass ratio for charge NaOtBu sodium tert-butoxide NBS 1-bromopyrrolidine- 2,5-dione, also called N-bromosuccinimide NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide NMP N-methylpyrrolidine NMR nuclear magnetic resonance (spectroscopy) Pd (dba) 3 tris (dibenzylidenacetone) dipaladium (0) Pd (dppf) Cl2 [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II)
    [0194] [0194] Nuclear magnetic resonance (NMR) spectra were recorded at 300, 400 or 500 MHz, unless otherwise specified; chemical shifts are reported in parts per million. The spectra were measured at 298 K, unless otherwise stated, and were referenced for solvent resonance. The spectra were recorded using one of the following machines: - A 400 MHz Bruker Avance III spectrometer equipped with a 5 mm BBO liquid probe. - A 400 MHz Bruker spectrometer using ICON-NMR, under the control of the TopSpin program. - A Bruker Avance III HD spectrometer at 500 MHz, equipped with a
    [0195] [0195] 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
    [0196] [0196] Methods 1a and 1b: Waters Xselect CSH C18 XP column, 2.5 µm (4.6 x 30 mm) at 40 ° C; flow rate of 2.5-4.5 mL min-1 eluted with a water-acetonitrile gradient containing 0.1% v / v formic acid (Method 1a) or 10 mM ammonium bicarbonate in water (Method 1b) for 4 minutes, using UV detection at 254 nm. Gradient information: 0-3.00 min, increased from 95% 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.
    [0197] [0197] 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
    [0198] [0198] Methods 2a and 2b: Waters BEH C18, 1.7 µm (2.1 x 30 mm) at 40 ° C; flow rate of 0.77 mL min-1 eluted with a water-acetonitrile gradient containing 0.1% v / v formic acid (Method 2a) or 10 mM ammonium bicarbonate in water (Method 2b) for 3 minutes , employing UV detection at 254 nm. Gradient information: 0-0.11 min, maintained at 95% water -5% acetonitrile, flow rate 0.77 mL min-1; 0.1-2.15 min, increased from 95% water -5% acetonitrile to 5% water -95% acetonitrile; 2.15-2.49 min, kept at 5% water -95% acetonitrile, flow rate 0.77 mL min -1; 2.49-2.56 min, returned to 95% water and -5% acetonitrile; 2.56-3.00 min, maintained at 95% water and 5% acetonitrile, flow rate reduced to 0.77 mL min -1. General Reverse Phase Preparative High Performance Liquid Chromatography Methods
    [0199] [0199] Method 1 (acid preparation): Waters X-Select CSH C18 column, 5 µm (19 x 50 mm), flow rate of 28 mL / min eluting with a water-acetonitrile gradient containing 0.1% v / v of formic acid for 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 20% acetonitrile; 0.2-5.5 minutes, increased from 20% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, increased from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, maintained at 95% acetonitrile.
    [0200] [0200] Method 2 (basic preparation): Waters X-Bridge Prep C18 column, 5 µm (19 x 50 mm), flow rate of 28 mL / min eluting with a gradient of 10 mM acetonitrile and ammonium bicarbonate over 6 , 5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 10% acetonitrile; 0.2-5.5 minutes, increased from 10% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, increased from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, maintained at 95% acetonitrile.
    [0201] [0201] 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.
    [0202] [0202] Method 4: Revelis C18 12g reverse phase cartridge [18% carbon charge; surface area 568 m2 / 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-methanol gradient for 35 minutes using UV detection at 215, 235, 254 and 280 nm. Gradient information: 0-5 minutes, maintained at 0% methanol; 5-30 minutes, increased from 0% to 70% methanol; 30 to 30.1 minutes, increased from 70% to 100% methanol; 30.1-35 minutes, maintained at 100% methanol. Synthesis of intermediaries
    [0203] [0203] Intermediate P1: 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0204] [0204] Step A: N, N-Bis- (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0205] [0205] A solution of 1-methyl-1H-pyrazol-3-sulfonyl chloride (13.0 g, 72.0 mmol) in dichloromethane (30 mL) was added slowly to a solution of bis- (4-methoxybenzyl) amine (20 g, 78 mmol) and triethylamine (20 mL, 143 mmol) in dichloromethane (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 methyl tert-butyl ether (250 ml), filtered and then purified by chromatography on silica gel (330 g column, 0-60% ethyl acetate / isohexane column) to generate the compound of title (27.66 g, 93%) as a white solid.
    [0206] [0206] 1H NMR (CDCl3) δ 7.42 (d, 1 H), 7.11-7.07 (m, 4 H), 6.81-6.77 (m, 4 H), 6.65 (d, 1 H), 4.33 (s, 4 H), 3.99 (s, 3 H) and 3.81 (s, 6 H).
    [0207] [0207] LCMS m / z 402 (M + H) + (ES +).
    [0208] [0208] Step B: 5 - ((Dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0209] [0209] A solution of n-BuLi (2.5 M in hexanes; 4.2 mL, 10.50 mmol) was added dropwise to a stirred solution of N, N-bis- (4-methoxybenzyl) -1 -methyl- 1H-pyrazol-3-sulfonamide (4 g, 9.96 mmol) in tetrahydrofuran (60 mL) at -78 ° C. The reaction was stirred for 1 hour, then N-methyl-N-methylene methanamine iodide (4 g, 21.62 mmol) was added. The reaction mixture was left at -78 ° C for 2 hours before the reaction was stopped with water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The organic layer was separated, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (Companion apparatus, 120 g column, 0-10% methanol / dichloromethane), then loaded onto an additional column (SCX, 13 g) in methanol. The column was washed with methanol and then the product was eluted with 0.7 M ammonia in methanol. The resulting mixture was further purified by chromatography on silica (80 g column, 0-5% methanol / dichloromethane) to generate the title compound (1.9 g, 38%) as a colorless oil.
    [0210] [0210] 1H NMR (DMSO-d6) δ 7.07 - 7.01 (m, 4 H), 6.84 - 6.78 (m, 4 H), 6.58 (s, 1 H), 4 , 21 (s, 4 H), 3.89 (s, 3 H), 3.72 (s, 6 H), 3.47 (s, 2 H) and 2.16 (s, 6 H).
    [0211] [0211] LCMS m / z 459.8 (M + H) + (ES +).
    [0212] [0212] Step C: 5 - ((Dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0213] [0213] 5 - ((Dimethylamino) methyl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (891 mg, 1.94 mmol) was dissolved in dichloromethane (3 mL ) and trifluoroacetic acid (3 ml) was added. The solution was stirred for 16 hours and then additional trifluoroacetic acid (2 ml) was added. The solution was stirred for an additional 16 hours before adding an additional aliquot of trifluoroacetic acid (2 mL) and 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 loaded onto a column (SCX; 4 g) in methanol and the column was washed with methanol and then the product was eluted with 0.7 M ammonia in methanol. The resulting mixture was concentrated in vacuo to generate the title compound (337 mg, 79%) as a white solid.
    [0214] [0214] 1H NMR (DMSO-d6) δ 7.36 (br s, 2 H), 6.51 (s, 1 H), 3.86 (s, 3 H),
    [0215] [0215] LCMS m / z 219.3 (M + H) + (ES +).
    [0216] [0216] Intermediate P2: 5 - ((Dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
    [0217] [0217] The title compound was prepared according to the procedure for 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P1) (339 mg, 73%).
    [0218] [0218] 1H NMR (DMSO-d6) δ 7.35 (s, 2 H), 6.45 (s, 1 H), 4.78 (sep, 1 H), 3.47 (s, 2 H) , 2.16 (s, 6 H) and 1.38 (d, 6 H).
    [0219] [0219] Intermediate P3: (4- (Dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide
    [0220] [0220] A solution of 1-isopropyl-1H-pyrazol-3-sulfonamide (712 mg, 3.76 mmol) in acetonitrile (4.4 mL) was treated with N, N-dimethylpyridin-4-amine (919 mg, 7.53 mmol) and the reaction mixture was stirred at room temperature until the sulfonamide dissolved. Diphenyl carbonate (887 mg, 4.14 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was filtered off, washed with methyl tert-butyl ether and dried to generate the title compound (776 mg, 61%) as a white solid, which was used without further purification.
    [0221] [0221] 1H NMR (CDCl3) δ 8.95 (d, J = 7.5 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H), 6.83 (d, J = 2 , 3 Hz, 1H), 6.62 (d, J = 7.5 Hz, 2H), 4.58 - 4.43 (m, 1H), 3.24 (s, 6H), 1.42 (d , J = 6.7 Hz, 6H).
    [0222] [0222] Intermediate P4: (4- (Dimethylamino) pyridin-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) amide
    [0223] [0223] Step A: 1-Methyl-3-sulfamoyl-1H-pyrazole-5 carboxylic acid, sodium salt
    [0224] [0224] 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 solution of sodium hydroxide (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.
    [0225] [0225] 1H NMR (D2O) δ 6.79 (s, 1 H) and 4.01 (s, 3 H).
    [0226] [0226] Step B: N, N, 1-Trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide
    [0227] [0227] To a mixture of 1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxylic acid, sodium salt (2.38 g, 10.48 mmol) T3P (50% in ethyl acetate, 12.47 ml, 20.95 mmol) and N, N-diisopropylethylamine (Hunig's Base, 3.66 ml, 20.95 mmol) in tetrahydrofuran (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 stopped with saturated aqueous ammonium chloride (10 ml) and extracted with acetate. ethyl (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 dichloromethane (20 ml) and filtered to obtain the title compound (900 mg) as a white solid. The mother layers were evaporated, dissolved in dichloromethane / methanol and purified by chromatography (Companion apparatus, 40 g column, 0-10% methanol / dichloromethane with the product eluted at ~ 5% methanol) 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%).
    [0228] [0228] 1H NMR (DMSO-d6) δ 7.50 (s, 2 H), 6.82 (s, 1 H), 3.90 (s, 3 H), 3.03 (s, 3 H) and 3.01 (s, 3 H).
    [0229] [0229] LCMS m / z 233.0 (M + H) + (ES +).
    [0230] [0230] Step C: ((4- (Dimethylamino) pyridin-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) amide
    [0231] [0231] A solution of N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (459 mg, 1.976 mmol) in acetonitrile (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 acetonitrile and dried to generate the title compound (578 mg, 77%) which was used in the next step without further purification.
    [0232] [0232] 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).
    [0233] [0233] Intermediate P5: (4- (Dimethylamino) pyridin-1-io-1-carbonyl) ((5- (2-methoxypropan-2-yl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) amide
    [0234] [0234] Step A: ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylate
    [0235] [0235] Ethyl 3- (chlorosulfonyl) -1-methyl-1H-pyrazol-5-carboxylate (9.2 g, 36.4 mmol) was added dropwise to a solution of bis (4-methoxybenzyl) amine ( 9.4 g, 36.5 mmol) and triethylamine (10 mL, 71.7 mmol) in dichloromethane (200 mL) cooled in an ice bath. The resulting mixture was stirred for 30 minutes, warmed to room temperature and stirred for 90 minutes before being washed with water (200 ml), aqueous hydrochloric acid (1 M, 200 ml), water (200 ml), dried (sulfate of magnesium), filtered and evaporated to produce a yellow oil. This was purified by chromatography on silica gel (220 g column, 0-60% ethyl acetate / isohexane) to generate the title compound (15.9 g, 91%) as a white solid.
    [0236] [0236] 1H NMR (DMSO-d6) δ 7.19 - 7.00 (m, 5 H), 6.85 - 6.77 (m, 4 H), 4.33 (q, 2 H), 4 , 25 (s, 4 H), 4.15 (s, 3 H), 3.71 (s, 6 H) and 1.33 (t, 3 H).
    [0237] [0237] LCMS m / z 496.4 (M + Na) + (ES +).
    [0238] [0238] Step B: 5- (2-Hydroxypropan-2-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0239] [0239] Ethyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxylate (1.4 g, 2.96 mmol) was dissolved in dry tetrahydrofuran (50 ml) and cooled to -78 ° C in a dry ice / acetone bath. Methylmagnesium chloride (3 M in tetrahydrofuran, 5 ml, 15.00 mmol) was added slowly via syringe over 15 minutes. The reaction mixture was warmed to room temperature and stirred overnight before being cooled in an ice bath and then slowly stopped with portions of aqueous ammonium chloride (20 ml). The mixture was extracted in ethyl acetate (3 x 50 ml) and the combined organic washes were washed with brine (10 ml), dried (sodium sulfate), filtered and concentrated in vacuo to generate a colorless oil. The crude product was purified by chromatography on silica (40 g column, 0-50% ethyl acetate / isohexane) to generate the title compound (1.11 g, 67%) as a thick colorless oil.
    [0240] [0240] 1H NMR (DMSO-d6) δ 7.09 - 7.03 (m, 4 H), 6.85 - 6.80 (m, 4 H), 6.41 (s, 1 H), 4 , 21 (s, 4 H), 4.04 (s, 3 H), 3.72 (s, 6 H) and 1.50 (s, 6 H).
    [0241] [0241] LCMS m / z 460 (M + H) + (ES +); 458 (M-H) - (ES-).
    [0242] [0242] Step C: N, N-Bis- (4-methoxybenzyl) -5- (2-methoxypropane-2-yl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0243] [0243] 5- (2-Hydroxypropane-2-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (2.5 g, 5.33 mmol) was dissolved in dry N, N-dimethylformamide (50 mL) under nitrogen atmosphere. After cooling in an ice bath, sodium hydride (60% in mineral oil, 0.25 g, 6.25 mmol) was added in a single portion and the cloudy yellow mixture was stirred for 30 minutes. Iodomethane (1.5 ml, 24.09 mmol) was added in a single portion and the mixture was stirred for an additional 2 hours while warming to room temperature. The reaction mixture was stopped by slowly adding saturated aqueous ammonium chloride (10 ml) and then partitioned between ethyl acetate (100 ml) and water (50 ml). The aqueous phase was extracted with ethyl acetate (4 x 50 ml) and the combined organic portions were washed with brine (20 ml), dried (sodium sulfate), filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by chromatography on silica (40 g column, 0-100% ethyl acetate / isohexane) to generate, after drying in vacuo, the title compound (2.41 g, 94%) as a colorless solid.
    [0244] [0244] 1H NMR (DMSO-d6) δ 7.10 - 7.04 (m, 4 H), 6.85 - 6.80 (m, 4 H), 6.48 (s, 1 H), 4 , 23 (s, 4 H), 3.97 (s, 3 H), 3.72 (s, 6 H), 2.97 (s, 3 H) and 1.50 (s, 6 H).
    [0245] [0245] LCMS m / z 474 (M + H) + (ES +); 472 (M-H) - (ES-).
    [0246] [0246] Step D: 5- (2-Methoxypropan-2-yl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0247] [0247] N, N-Bis- (4-methoxybenzyl) -5- (2-methoxypropan-2-yl) -1-methyl-1H-pyrazol-3-sulfonamide (2.4 g, 5.02 mmol) dissolved in acetonitrile (40 ml). A solution of cyclic ammonium nitrate (15 g, 27.4 mmol) in water (10 mL) was added in a single portion and the dark red reaction mixture was stirred at room temperature for 4 hours. Water (10 ml) and dichloromethane (250 ml) were added and the organic phase was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give an orange oil (~ 2.5 g). The crude product was purified by chromatography on silica (40 g column, 0-20% methanol / dichloromethane) to generate an orange oil. Trituration of this material in tert-butylmethylether (10 mL) and isohexanes (5 mL) gave a beige precipitate that was further purified by chromatography on silica (24 g, ethyl acetate 20-100% in hexanes) to generate the compound of the title (383 mg, 31%) as a yellow solid.
    [0248] [0248] 1H NMR (CDCl3) δ 6.57 (s, 1 H), 5.08 (s, 2 H), 4.06 (s, 3 H), 3.08 (s, 3 H) and 1 , 57 (s, 6 H).
    [0249] [0249] Step E: (4- (Dimethylamino) pyridin-1-io-1-carbonyl) ((5- (2-methoxypropan-2-yl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) amide
    [0250] [0250] A solution of 5- (2-methoxypropan-2-yl) -1-methyl-1H-pyrazol-3-sulfonamide (160 mg, 0.686 mmol) in acetonitrile (0.8 mL) was treated with N, N - dimethylpyridine-4-amine (168 mg, 1.372 mmol) and the reaction mixture was stirred at room temperature until the sulfonamide dissolved. Diphenyl carbonate (162 mg, 0.754 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was filtered, washed with dry methyl tert-butyl ether to generate the title compound (46 mg, 18%) as a white solid which was used without further purification.
    [0251] [0251] 1H NMR (CDCl3) δ 9.03 (d, J = 7.9 Hz, 2H), 6.77 (s, 1H), 6.74 (d, J = 7.8 Hz, 2H), 4.04 (s, 3H), 3.34 (s, 6H), 3.08 (s, 3H), 1.59 (s, 6H).
    [0252] [0252] Intermediate P6: (4- (Dimethylamino) pyridin-1-io-1-carbonyl) (1-isopropyl-1H-imidazol-4-yl) sulfonyl) amide
    [0253] [0253] A solution of 1-iso-propyl-1H-imidazol-4-sulfonamide (161 mg, 0.851 mmol) in acetonitrile (1 ml) was treated with N, N-dimethylpyridin-4-amine (208 mg, 1.702 mmol ) and the reaction mixture was stirred at room temperature until the sulfonamide dissolved. Then, diphenyl carbonate (200 mg, 0.936 mmol) was added and the reaction mixture was left at room temperature for 16 hours. The resulting precipitate was filtered off, washed with methyl tert-butyl ether and dried to generate the title compound (186 mg, 65%) as a white solid, which was used without further purification.
    [0254] [0254] Intermediate P7: 5 - ((Dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide
    [0255] [0255] The title compound was prepared according to the procedure for 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P1)
    [0256] [0256] 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).
    [0257] [0257] LCMS m / z 233.4 (M + H) + (ES +).
    [0258] [0258] Intermediate P8: 5- (3-Methoxyethoxy-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0259] [0259] Step A: 5- (3-Hydroxyoxetan-3-yl) -N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0260] [0260] 2.5 M n-Butyl lithium in hexanes (2.0 mL, 5.00 mmol) was added dropwise to the stirred solution of N, N-bis (4-methoxybenzyl) -1-methyl-1H -pyrazol-3-sulfonamide (2.0 g, 4.98 mmol) in THF (35 mL) cooled to -78 ° C and stirred for 1 hour. Then a solution of oxetan-3-one (0.292 mL, 4.98 mmol) in THF (16 mL) was added, warmed to room temperature with stirring for an additional 1 hour. The reaction was stopped with saturated aqueous NH4Cl solution (20 ml) and extracted with EtOAc (3 x 50 ml). The combined extracts were washed with brine (20 ml), dried (MgSO4), filtered and evaporated in vacuo to produce an orange oil. The crude product was purified by chromatography on silica gel (80 g column, 0-75% EtOAc / isohexane) to generate the title compound (1.44 g, 61%) as a colorless solid.
    [0261] [0261] 1H NMR (DMSO-d6) δ 7.10 - 7.00 (m, 4H), 6.90 (s, 1H), 6.85 - 6.78 (m, 4H), 6.75 ( s, 1H), 4.89 (d, J = 7.3 Hz, 2H), 4.76 (d, J = 7.2 Hz, 2H), 4.23 (s, 4H), 3.81 ( s, 3H), 3.71 (s, 6H).
    [0262] [0262] LCMS m / z 496.1 (M + Na) + (ES +).
    [0263] [0263] Step B: N, N-Bis (4-methoxybenzyl) -5- (3-methoxyethane-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0264] [0264] Sodium hydride (60% in mineral oil) (0.193 g, 4.81 mmol) was added in portions to 5- (3-hydroxyoxethane-3-yl) -N, N-bis (4-methoxybenzyl) - 1-methyl-
    [0265] [0265] 1H NMR (DMSO-d6) δ 7.12 - 7.03 (m, 4H), 7.00 (s, 1H), 6.87 - 6.78 (m, 4H), 4.87 ( d, J = 7.7 Hz, 2H), 4.78 (d, J = 7.7 Hz, 2H), 4.24 (s, 4H), 3.74 (s, 3H), 3.71 ( s, 6H), 2.96 (s, 3H).
    [0266] [0266] LCMS m / z 488.2 (M + H) + (ES +).
    [0267] [0267] Step C: 5- (3-Methoxyethoxy-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0268] [0268] N, N-Bis (4-methoxybenzyl) -5- (3-methoxyoxethane-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide (1.93 g, 3.60 mmol) was dissolved in acetonitrile (25 ml). A solution of cyclic ammonium nitrate (9.87 g, 18.01 mmol) in water (16 mL) was added in portions over 5 minutes. The orange mixture was stirred for 17 hours at room temperature, then concentrated to ~ 20 ml and poured over EtOAc (30 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 30 ml). The combined organic layers were dried (MgSO4), filtered and concentrated to dryness to produce an orange oil. The crude product was purified by C18 reverse phase flash column chromatography (130 g column, 0-20% acetonitrile / 10 mM ammonium bicarbonate, monitored at 215 nm), then further purified by silica gel chromatography (40 column g, 0-10% methanol / dichloromethane) to generate the title compound (357 mg, 40%) as a beige solid.
    [0269] [0269] 1H NMR (DMSO-d6) δ 7.46 (s, 2H), 6.92 (s, 1H), 4.94 - 4.82 (m, 2H),
    [0270] [0270] LCMS m / z 248.3 (M + H) + (ES +).
    [0271] [0271] Intermediate P9: 1- (2- (Dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide
    [0272] [0272] Step A: 1- (lithium-tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfinate
    [0273] [0273] To a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (100 g, 657.06 mmol, 1 eq) in THF (1380 mL) was added n-BuLi ( 2.5 M, 276 mL, 1.05 eq) slowly maintaining the temperature at -70 ° C. The reaction mixture was stirred for 1.5 hours, then SO2 was bubbled through the mixture for 15 minutes. After the reaction temperature was heated to 25 ° C, very solid was formed. The mixture was concentrated in vacuo. The residue was triturated with methyl tert-butyl ether (400 ml) and the mixture was filtered. The filter cake was washed with methyl tert-butyl ether, n-hexane and dried to generate the title compound (142 g, crude) as a white solid.
    [0274] [0274] 1H NMR (DMSO-d6) δ 7.28 (d, 1 H), 6.16 (d, 1 H), 5.97 (dd, 1 H), 3.92-3.87 (m , 1 H), 3.61-3.33 (m, 1 H), 2.25-2.18 (m, 1 H), 1.98-1.93 (m, 1 H), 1.78 -1.74 (m, 1 H) and 1.52-1.49 (m, 3 H).
    [0275] [0275] LCMS: m / z 215 (M-Li) - (ES-)
    [0276] [0276] Step B: 1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonyl chloride
    [0277] [0277] To a suspension of lithium 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfinate (20 g, 90.01 mmol, 1 eq) in dichloromethane (250 mL) NCS (12.02 g, 90.01 mmol, 1 eq) was added cooled in an ice bath. The mixture was stirred for 2 hours at 0 ° C. The solution was interrupted with water (100 ml), then partitioned between dichloromethane (300 ml) and water (200 ml). The organic layer was washed with water (200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. to produce the title compound (15.8 g, 63.02 mmol,
    [0278] [0278] Step C: N, N-Bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide bis (4-methoxybenzyl) amine
    [0279] [0279] A solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonyl chloride (15 g, 59.83 mmol, 1 eq) in dichloromethane (50 mL) added to a mixture of bis (4-methoxybenzyl) amine (16.01 g, 62.23 mmol, 1.04 eq) and triethylamine (19.33 g, 190.99 mmol, 26.58 ml, 3.19 eq ) in dichloromethane (300 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour and then stopped with water (250 ml). The organic layer was washed with water (250 ml), 1M aqueous HCl solution (2 x 250 ml), water (250 ml), dried over anhydrous MgSO4, filtered and concentrated in vacuo to generate the title product (25.5 g, 49.75 mmol, 83% yield, 92% purity) as a brown oil.
    [0280] [0280] LCMS: m / z 494 (M + Na) + (ES +).
    [0281] [0281] Step D: N, N-Bis (4-methoxybenzyl) -1H-pyrazol-5-sulfonamide
    [0282] [0282] To a solution of N, N-bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide (25 g, 53.01 mmol, 1 eq) in THF (183 ml) and MeOH (37 ml) 1M aqueous HCl solution (18.29 ml, 0.34 eq) was added and the mixture was stirred at 25 ° C for 1 hour. Then the solvent was evaporated and the residue was partitioned between dichloromethane (200 ml) and H2O (100 ml). The organic layer was washed with brine (100 ml), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was triturated with methyl tert-butyl ether, filtered and dried to generate the title compound (12.2 g, 30.61 mmol, 58% yield, 97% purity) as a white solid.
    [0283] [0283] 1H NMR (chloroform-d) δ 13.82-13.70 (br s, 1 H), 7.92 (d, 1 H),
    [0284] [0284] LCMS: m / z 410 (M + Na) + (ES +).
    [0285] [0285] Step E: 1- (2-Hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
    [0286] [0286] N, N-Bis (4-methoxybenzyl) -1H-pyrazol-5-sulfonamide (12 g, 30.97 mmol, 1 eq) and K2CO3 (8.39 g, 60.70 mmol, 1.96 eq ) were suspended in acetonitrile (150 mL) under a nitrogen atmosphere. 2-bromoethanol (5.03 g, 40.26 mmol, 2.86 ml, 1.3 eq) was added to this mixture and then the mixture was heated at 60 ° C for 17 hours. Water (500 ml) and dichloromethane (400 ml) were added to the reaction mixture. The organic layer was separated and washed with brine (300 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate = 30: 1 to 1: 1) to yield the title compound (8 g, 17.98 mmol, 58% yield, 97% yield). purity) as a yellow oil.
    [0287] [0287] 1H NMR (chloroform-d) δ 7.55 (d, 1 H), 7.04-7.02 (m, 4 H), 6.77-6.74 (d, 4 H), 6 , 06 (d, 1 H), 4.29 (s, 4 H), 4.26-4.23 (t, 2 H), 3.93-3.81 (m, 2 H) and 3.69 (s, 6 H).
    [0288] [0288] LCMS: m / z 454 (M + Na) + (ES +).
    [0289] [0289] Step F: 2- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) ethyl methanesulfonate
    [0290] [0290] To a solution of 1- (2-hydroxyethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (7 g, 16.22 mmol, 1 eq) and diisopropylethylamine (2, 94 g, 22.71 mmol, 3.96 mL, 1.4 eq) in anhydrous dichloromethane (116 mL) methanesulfonyl chloride (2.23 g, 19.47 mmol, 1.51 mL, 1.2 eq) was added ) under nitrogen. The reaction mixture was stirred at 25 ° C for 20 minutes. Then, the mixture was stopped with saturated aqueous NaHCO3 solution (50 ml) and water (30 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (8.3 g, crude) as a yellow oil which was used directly in the next step.
    [0291] [0291] Step G: 1- (2- (Dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
    [0292] [0292] To a solution of dimethylamine in THF (2M, 243 mL, 29.95 eq) was added 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) ethyl methanesulfonate (8.27 g, 16.23 mmol, 1 eq) and then the mixture was heated at 60 ° C for 17 hours. The reaction mixture was concentrated in vacuo. The residue was added to EtOAc (150 ml) and the mixture was stirred and filtered. The organic phase was concentrated in vacuo and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1 to 0: 1) to produce the title compound (6.5 g, 13.47 mmol, 83% yield, 95% purity) as a yellow oil.
    [0293] [0293] 1H NMR (chloroform-d) δ 7.55 (d, 1 H), 7.09-7.06 (m, 4 H), 6.81-6.78 (m, 4 H), 6 , 65 (d, 1 H), 4.31 (s, 4 H), 4.31 - 4.27 (m, 2 H), 3.80 (s, 6 H), 2.77 (t, 2 H) and 2.29 (m, 6 H),
    [0294] [0294] LCMS: m / z 459 (M + H) + (ES +).
    [0295] [0295] Step H: 1- (2- (Dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide
    [0296] [0296] To a solution of 1- (2- (dimethylamino) ethyl) -N, N-bis (4-methoxybenzyl) -
    [0297] [0297] 1H NMR (DMSO-d6) δ 7.86 (d, 1 H), 7.37 (br s, 2 H), 6.55 (d, 1 H), 4.24 (t, 2 H ), 2.65 (t, 1 H) and 2.16 (s, 6 H).
    [0298] [0298] LCMS: m / z 219 (M + H) + (ES +).
    [0299] [0299] Intermediate P10: 1- (Prop-2-in-1-yl) piperidine-4-sulfonamide
    [0300] [0300] To a mixture of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.), Potassium carbonate (4.0 equiv., 4.0 mmol, 552 mg) and acetonitrile (10 ml) propargyl bromide (0.1 ml, 1.0 mmol, 1.0 equiv.) was added. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and the crude material was suspended in methanol, coated with Agilent hydromatrix (a high purity inert diatomite sorbent) and then subjected to normal phase flash chromatography. using dichloromethane and a mixture of ammonia (3.5 M) in methanol to generate the title compound (115 mg, 56%).
    [0301] [0301] 1H NMR (CDCl3): δ 4.42 (br s, 1 H), 3.38 (s, 2 H), 3.05 (d, 2 H), 2.95 (m, 1 H) , 2.12 (m, 4 H) and 1.95 (m, 2 H).
    [0302] [0302] Intermediate P11: 1-Ethylpiperidine-4-sulfonamide
    [0303] [0303] Prepared as described for 1- (prop-2-in-1-yl) piperidine-4-sulfonamide (Intermediate P10) using ethyl iodide instead of propargyl bromide. The crude product was coated with Agilent hydromatrix (a high purity inert diatomite sorbent) and subjected to normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (1: 1 ratio) as the eluent to generate the compound of the title contaminated with triethylamine hydrochloride (50 mg, 26% yield). The crude product was used as such in the preparation of examples.
    [0304] [0304] 1H NMR (CDCl3): δ 5.05 (br s, 2 H), 3.10 (m, 2 H), 2.95 (m, 1 H), 2.45 (m, 2 H) , 2.20 (d, 2 H), 1.95 (m, 4 H) and 1.08 (t, 3 H).
    [0305] [0305] Intermediate P12: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide
    [0306] [0306] Step A: 6-Chlorine-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide
    [0307] [0307] Bis (4-methoxybenzyl) amine (3.71 g, 14.4 mmol) was added to a solution of 2-chloropyridine-5-sulfonyl chloride (3.00 g, 13.7 mmol) and triethylamine (2.49 mL, 17.8 mmol) in DCM (50 mL) at 0 ° C. The reaction was stirred at 0 ° C for 15 minutes and then allowed to warm to room temperature and stirred for 20 hours. Then, the reaction mixture was diluted with DCM (150 ml), washed with a saturated aqueous solution of NH4Cl (3x 40 ml) and brine (40 ml), dried over MgSO4, filtered and concentrated in vacuo to provide the crude product. like a cream solid. The crude product was triturated with TBME (70 ml), filtered and rinsed with TBME (2 x 40 ml) to provide the title compound (4.97 g, 83%) as an off-white solid.
    [0308] [0308] 1H NMR (DMSO-d6) δ 8.76 (dd, J = 2.6, 0.7 Hz, 1H), 8.19 (dd, J = 8.4, 2.6 Hz, 1H) , 7.69 (dd, J = 8.4, 0.7 Hz, 1H), 7.08 - 7.02 (m, 4H), 6.83 - 6.76 (m, 4H), 4.29 (s, 4H), 3.71 (s, 6H).
    [0309] [0309] LCMS: m / z 433.3 (M + H) + (ES +).
    [0310] [0310] Step B: 6-Hydroxy-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide
    [0311] [0311] A suspension of 6-chloro-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide (0.508 g, 1.17 mmol) in ethane-1,2-diol (10 mL) was treated with KOH 2 M (aq) (2.4 mL, 4.80 mmol). The resulting suspension was stirred at 140 ° C for 18 hours. Then, the reaction mixture was treated with additional 2 M KOH (aq) (0.6 mL, 1.2 mmol, 1 eq) and heated at 140 ° C for an additional 6 hours, and additional 2 M KOH (aq) (aq) (0.6 mL, 1.2 mmol, 1 eq) and heated to 140 ° C for an additional 18 hours. Then, the reaction mixture was diluted with water (40 ml) and DCM (30 ml). Brine (5 ml) was added and the organic layer was collected. The aqueous phase was extracted with DCM (5 x 30 ml). The combined organic extracts were washed with water (10 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue was dried under reduced pressure at 50 ° C overnight to provide the title compound (542 mg, 100%).
    [0312] [0312] 1H NMR (DMSO-d6) δ 12.17 (s, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.63 (dd, J = 9.6, 2, 9 Hz, 1H), 7.11 - 7.02 (m, 4H), 6.87 - 6.79 (m, 4H), 6.37 (d, J = 9.6 Hz, 1H), 21 (s, 4H), 3.72 (s, 6H).
    [0313] [0313] LCMS: m / z 415.4 (M + H) + (ES +), 413.4 (M-H) - (ES-).
    [0314] [0314] Step C: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide and 6-isopropoxy-N, N-bis (4-methoxybenzyl ) pyridine-3-sulfonamide
    [0315] [0315] Sodium hydride (60% by weight of dispersion in mineral oil) (36 mg, 0.91 mmol) was added to a mixture of 6-hydroxy-N, N-bis (4-methoxybenzyl) pyridine-3- sulfonamide (0.40 g, 0.869 mmol) and lithium bromide (0.154 g, 1.737 mmol) in DME: DMF (5 mL, 4: 1) at 0 ° C. The mixture was stirred at 0 ° C for
    [0316] [0316] 1-isopropyl-N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3-sulfonamide:
    [0317] [0317] 1H NMR (CDCl3) δ 7.91 (d, J = 2.7 Hz, 1H), 7.41 (dd, J = 9.6, 2.6 Hz, 1H), 7.09 - 7 , 04 (m, 4H), 6.84 - 6.79 (m, 4H), 6.54 (dd, J = 9.6, 0.5 Hz, 1H), 5.17 (sept, J = 6 , 8 Hz, 1H), 4.26 (s, 4H), 3.79 (s, 6H), 1.34 (d, J = 6.8 Hz, 6H).
    [0318] [0318] LCMS: m / z 457.4 (M + H) + (ES +).
    [0319] [0319] 6-Isopropoxy-N, N-bis (4-methoxybenzyl) pyridine-3-sulfonamide:
    [0320] [0320] 1H NMR (CDCl3) δ 8.60 - 8.55 (m, 1H), 7.84 - 7.79 (m, 1H), 7.06 - 6.99 (m, 4H), 6, 81 - 6.75 (m, 4H), 6.72 - 6.67 (m, 1H), 5.43 - 5.33 (m, 1H), 4.26 (s, 4H), 3.78 ( s, 6H), 1.37 (d, J = 6.2 Hz, 6H).
    [0321] [0321] LCMS: m / z 457.4 (M + H) + (ES +).
    [0322] [0322] Step D: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide
    [0323] [0323] TFA (0.43 ml, 5.64 mmol) was added to a solution of 1-isopropyl-N, N-bis (4-methoxybenzyl) -6-oxo-1,6-dihydropyridine-3- sulfonamide (0.26 g, 0.564 mmol) in DCM (3 mL) at room temperature and the mixture was stirred for 66 hours. Then, the reaction was concentrated in vacuo and the residue was redissolved in DCM (5 ml). The product was purified by chromatography on silica gel (12 g column, 0-10% MeOH / DCM) to provide the title compound (60 mg, 49%) as a white solid.
    [0324] [0324] LCMS: m / z 217.3 (M + H) + (ES +).
    [0325] [0325] Intermediate P13: 4-Isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide
    [0326] [0326] Step A: 2- (Benzylthio) -5-chloropyrazine
    [0327] [0327] To a solution of NaH (0.755 g, 18.88 mmol) in THF (55 mL) was added benzyl mercaptan (1.5 mL, 12.68 mmol) at 0 ° C. The reaction mixture was diluted with THF (20 ml) and stirred at 0 ° C for 10 minutes. Then, a solution of 2,5-dichloropyrazine (1.370 ml, 13.42 mmol) in THF (10 ml) was added dropwise. The reaction mixture was stirred at 0 ° C for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0 ° C, MeOH (1 ml) was added carefully and stirred for 5 minutes. Water (20 ml) was added, then DCM (150 ml) and the biphasic mixture was passed through a phase separator. The organic phase was concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-3% EtOAc / isohexane) to generate the title compound (2.373 g, 72%) as a light yellow oil.
    [0328] [0328] 1H NMR (DMSO-d6) δ 8.68 (d, J = 1.5 Hz, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.34 - 7.29 (m, 2H), 7.28 - 7.23 (m, 1H), 4.46 (s, 2H).
    [0329] [0329] Step B: 5-Chloro-N, N-bis (4-methoxybenzyl) pyrazine-2-sulfonamide Cl Cl N N N N PMB O S N s The PMB
    [0330] [0330] A solution of 2- (benzylthio) -5-chloropyrazine (0.916 g, 3.87 mmol) in DCM (15 mL, 233 mmol) was treated with water (1.5 mL) and the resulting suspension was cooled between -5 and 0 ° C. Sulfuryl chloride (2.2 mL, 26.2 mmol) was added and the reaction mixture was stirred for 2 hours, maintaining the temperature between -5 and 0 ° C. An ice / water paste (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (2 x 10 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to generate crude 5-chloropyrazine-2-sulfonyl intermediate chloride as a pale yellow liquid (1.198 g).
    [0331] [0331] A suspension of bis (4-methoxybenzyl) amine hydrochloride (1.198 g, 4.08 mmol) and TEA (1.2 mL, 8.61 mmol) in DCM (15 mL) at 0 ° C was treated with a solution of 5-chloropyrazine-2-sulfonyl chloride (0.824 g, 3.87 mmol) in DCM (5 mL) dropwise. The resulting solution was stirred at 0 ° C for 15 minutes and then allowed to warm to room temperature for 16 hours. A saturated aqueous solution of NH4Cl (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (2 x 10 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc / isohexane) to generate the title compound (1.312 g, 77%) as a white solid.
    [0332] [0332] 1H NMR (CDCl3) δ 8.78 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.11 - 7.07 (m , 4H), 6.79 - 6.75 (m, 4H), 4.43 (s, 4H), 3.79 (s, 6H).
    [0333] [0333] Step C: N, N-Bis (4-methoxybenzyl) -5-oxo-4,5-dihydropyrazine-2-sulfonamide
    [0334] [0334] A suspension of 5-chloro-N, N-bis (4-methoxybenzyl) pyrazine-2-sulfonamide (1.31 g, 2.99 mmol) in glycol (15 mL) was treated with 2 M KOH (aq. ) (7.5 mL, 15 mmol). The resulting suspension was stirred at 140 ° C for 18 hours. The reaction mixture was then allowed to cool to room temperature, diluted with water (100 ml) and neutralized with saturated aqueous NH 4Cl solution (30 ml). The white precipitate was collected by filtration, washed with water and dried at 60 ° C in vacuo to provide the title compound (1.094 g, 79%) as a pale yellow solid.
    [0335] [0335] 1H NMR (DMSO-d6) δ 7.94 (d, J = 1.2 Hz, 1H), 7.89 (br s, 1H), 7.10
    [0336] [0336] LCMS: m / z 438.2 (M + Na) + (ES +); 414.2 (M-H) - (ES-).
    [0337] [0337] Step D: 4-Isopropyl-N, N-bis (4-methoxybenzyl) -5-oxo-4,5-dihydropyrazine-2-sulfonamide
    [0338] [0338] A suspension of N, N-bis (4-methoxybenzyl) -5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.503 g, 1.090 mmol) and lithium bromide (0.192 g, 2.167 mmol) in DME: DMF (6 mL, 4: 1) at 0 ° C was treated with NaH (0.053 g, 1.325 mmol). The resulting suspension was stirred at 0 ° C for 10 minutes, treated with 2-iodopropane (0.218 ml, 2.136 mmol) and then stirred at 65 ° C for 64 hours. A saturated aqueous solution of NH4Cl (6mL) and EtOAc (10 mL) was added and the organic layer was collected. The aqueous layer was extracted with EtOAc (2 x 10 ml) and the combined organic extracts were washed with water (10 ml) and brine (2 x 10 ml), dried (MgSO 4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g column, 0-100% EtOAc / isohexane) to generate the title compound (0.293 g, 53%) as a light yellow oil.
    [0339] [0339] 1H NMR (DMSO-d6) δ 8.07 (d, J = 1.0 Hz, 1H), 7.96 (d, J = 0.9 Hz, 1H), 7.13 - 7.09 (m, 4H), 6.83 - 6.79 (m, 4H), 4.78 (sept, J = 6.5 Hz, 1H), 4.33 (s, 4H), 3.71 (s, 6H), 1.34 (d, J = 6.8 Hz, 6H).
    [0340] [0340] LCMS: m / z 480.3 (100, [M + Na] +), 458.5 (9, [M + H] +) (ES +).
    [0341] [0341] Step E: 4-Isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide
    [0342] [0342] A solution of 4-isopropyl-N, N-bis (4-methoxybenzyl) -5-oxo-4,5-di-
    [0343] [0343] 1H NMR (DMSO-d6) δ 8.14 (d, J = 1.0 Hz, 1H), 8.08 (d, J = 1.0 Hz, 1H), 7.40 (s, 2H ), 4.88 (sept, J = 6.7 Hz, 1H), 1.36 (d, J = 6.8 Hz, 6H).
    [0344] [0344] LCMS: 216.1 (M-H) - (ES-).
    [0345] [0345] Intermediate P14: 1-Isopropylazetidine-3-sulfonamide
    [0346] [0346] Step A: tert-Butyl 3-hydroxy-azetidine-1-carboxylate OH
    [0347] [0347] To a solution of azetidin-3-ol hydrochloride (45 g, 410.75 mmol, 1 eq) in MeOH (1.2 L) was added TEA (83.13 g, 821.51 mmol, 2 eq ) and di-tert-butyl dicarbonate (89.65 g, 410.75 mmol, 1 eq). The mixture was stirred at 25 ° C for 16 hours. Then, the reaction mixture was concentrated in vacuo. The residue was redissolved in EtOAc (1 L). The mixture was washed with H 2 O (3 x 500 ml) and brine (3 x 500 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to provide the title compound (65 g, 91% yield) as an oil. yellow, which was used directly in the next step.
    [0348] [0348] 1H NMR (CDCl3) δ 4.59 (s, 1 H), 4.19-4.12 (m, 2 H), 3.84-3.79 (m, 2 H), 1.45 (s, 9 H).
    [0349] [0349] Step B: tert-Butyl ((methylsulfonyl) oxy) azetidine-1-carboxylate O OH The S
    [0350] [0350] To a solution of tert-butyl 3-hydroxy-azetidine-1-carboxylate (65 g, 375.27 mmol, 1 eq) and TEA (113.92 g, 3 eq) in THF (650 ml) Methanesulfonyl chloride (51.58 g, 450.32 mmol, 1.2 eq) is added at 0 ° C. Then, the mixture was stirred at 25 ° C for 12 hours. The reaction mixture was diluted with EtOAc (2 L), washed with water (3 x 1.5 L) and brine (3 x 1.5 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to produce the compound title (90 g, 95%) as a yellow oil, which was used directly in the next step.
    [0351] [0351] 1H NMR (CDCl3) δ 5.25-5.20 (m, 1 H), 4.32-4.27 (m, 2 H), 4.14-4.10 (m, 2 H) , 3.08 (s, 3 H) and 1.46 (s, 9 H).
    [0352] [0352] Step C: tert-butyl 3- (acetylthio) azetidine-1-carboxylate The S The S
    [0353] [0353] To a solution of tert-butyl 3 - ((methylsulfonyl) oxy) azetidine-1-carboxylate (90 g, 358.14 mmol, 1 eq) in DMF (1.5 L) was added potassium ethanothioate ( 49.08 g, 429.77 mmol, 1.2 eq). The mixture was stirred at 80 ° C for 12 hours. Then, the reaction mixture was diluted with EtOAc (3 L), washed with saturated aqueous NH4Cl solution (3 x 2 L) and brine (3 x 2 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 100: 1 to 20: 1) to produce the title compound (54 g, 65%) as a yellow oil.
    [0354] [0354] 1H NMR (CDCl3) δ 4.37 (t, 2 H), 4.17-4.14 (m, 1 H), 3.82 (dd, 2 H), 2.34 (s, 3 H) and 1.44 (s, 9 H).
    [0355] [0355] Step D: tert-Butyl 3- (chlorosulfonyl) azetidine-1-carboxylate
    [0356] [0356] To a solution of tert-butyl 3- (acetylthio) azetidine-1-carboxylate (5 g, 21.62 mmol, 1 eq) in AcOH (200 mL) and H2O (20 mL) was added NCS (8 , 66 g, 64.85 mmol, 3 eq). The reaction mixture was stirred at 25 ° C for 1 hour. Then, the reaction mixture was diluted with DCM (300 mL), washed with water (3 x
    [0357] [0357] Step E: tert-Butyl 3-Sulfamoylazetidine-1-carboxylate
    [0358] [0358] Through a solution of tert-butyl 3- (chlorosulfonyl) azetidine-1-carboxylate (55.28 g, crude) in DCM (1.5 L), NH3 was bubbled through for 30 minutes at 0 ° C . Then, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and EtOAc (21 ml, 20: 1) to produce the title compound (27 g, 53%) as a white solid.
    [0359] [0359] 1H NMR (DMSO-d6) δ 7.16 (br s, 2 H), 4.18-4.03 (m, 2 H), 4.03-3.90 (m, 3 H) and 1.38 (s, 9 H).
    [0360] [0360] Step F: tert-Butyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) azetidine-1-carboxylate O
    [0361] [0361] To a solution of tert-butyl 3-sulfamoylazetidine-1-carboxylate (1 g, 4.23 mmol, 1 eq) in DMF (10 mL) was added NaH (507 mg, 12.69 mmol, 60% by weight of mineral oil, 3 eq) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes. Then, 1- (chloromethyl) -4-methoxybenzene (1.99 g, 12.69 mmol, 3 eq) was added. The mixture was stirred at 25 ° C for 14 hours. Then, the reaction mixture was diluted with EtOAc (50 ml), washed with a saturated aqueous solution of NH4Cl (3 x 30 ml) and brine (3 x 30 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with MeOH (10 ml) to give the title compound (1 g, 50%) as a white solid.
    [0362] [0362] 1H NMR (CDCl3) δ 7.17 (d, 4 H), 6.91-6.88 (m, 4 H), 4.30 (s, 4 H), 4.22 (dd, 2 H), 4.01 (t, 2 H), 3.83 (s, 6 H), 3.75-3.62 (m, 1 H) and 1.44 (s, 9 H).
    [0363] [0363] LCMS: m / z 499.2 (M + Na) + (ES +).
    [0364] [0364] Step G: N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide O O O N O N S S O O N HN O O O O
    [0365] [0365] To a solution of tert-butyl 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) azetidine-1-carboxylate (7 g, 14.69 mmol, 1 eq) and 2,6-lutidine ( 4.72 g, 44.06 mmol, 3 eq) in DCM (80 ml) trimethylsilyl trifluoromethanesulfonate (9.79 g, 44.06 mmol, 3 eq) was added at 0 ° C. Then, the reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was stopped with a saturated aqueous solution of NH4Cl (20 ml) and extracted with DCM (3 x 50 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (40 ml, 1: 1) to provide the title compound (4 g, 72%) as a white solid.
    [0366] [0366] 1H NMR (CD3OD) δ 7.21 (d, 4 H), 6.94-6.85 (m, 4 H), 4.35 (s, 4 H), 4.28-4.11 (m, 5 H) and 3.81 (s, 6 H).
    [0367] [0367] LCMS: m / z 377.2 (M + H) + (ES +).
    [0368] [0368] Step H: 1-isopropyl-N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide
    [0369] [0369] To a solution of N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (2.5 g, 6.64 mmol, 1 eq) and K2CO3 (1.38 g, 9.96 mmol, 1 , 5 eq) in MeCN (5 ml) 2-bromopropane (1.63 g, 13.28 mmol, 2 eq) was added. The mixture was stirred at 70 ° C for 12 hours. Then, H2O (10 ml) was added and the reaction mixture was extracted with EtOAc (3 x 30 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound (2.5 g, 90%).
    [0370] [0370] 1H NMR (CDCl3) δ 7.12-7.07 (m, 4 H), 6.83-6.76 (m, 4 H), 4.16 (s, 4 H), 3.74 (s, 6 H), 3.68-3.64 (m, 1 H), 3.43 (t, 2 H), 3.28 (t, 2 H), 2.38-2.29 (m , 1 H) and 0.82 (d, 6 H).
    [0371] [0371] LCMS: m / z 419.2 (M + H) + (ES +).
    [0372] [0372] Step I: 1-isopropylazetidine-3-sulfonamide
    [0373] [0373] A solution of 1-isopropyl-N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (1 g, 2.39 mmol, 1 eq) in TFA (7.70 g, 67.53 mmol, 28.27 eq) was stirred at 25 ° C for 12 hours. Then, the reaction mixture was concentrated in vacuo. The residue was treated with MeOH (10 ml), filtered and the filtrate was adjusted with NH3.H2O (30% NH3.H2O in water) until pH = 8-9. The resulting mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.1% NH3.H2O) -MeCN) to yield the title compound (220 mg, 52%) as a white solid.
    [0374] [0374] 1H NMR (CD3OD) δ 4.05-3.98 (m, 1 H), 3.67 (t, 2 H), 3.46 (t, 2 H), 2.59-2.48 (m, 1 H) and 0.97 (d, 6 H). Two interchangeable protons not observed.
    [0375] [0375] LCMS: m / z 179.1 (M + H) + (ES +).
    [0376] [0376] Intermediate P15: 1-Cyclobutylazetidine-3-sulfonamide
    [0377] [0377] Step A: Azetidine-3-sulfonamide
    [0378] [0378] A solution of tert-butyl 3-sulfamoylazetidine-1-carboxylate (3 g, 12.70 mmol, 1 eq, obtained according to Step E of the synthesis of intermediate P14) in DCM (10 ml) was HCl / EtOAc (12.70 mmol, 20 mL, 1 eq) is added. The mixture was stirred at 25 ° C for 1 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.05% NH3.H2O) -MeCN) to yield the title compound (0.8 g, 46%) as a white solid.
    [0379] [0379] 1H NMR (DMSO-d6) δ 6.92 (s, 1 H), 4.23-4.19 (m, 2 H) and 3.77-3.70 (m, 3 H). Two interchangeable protons not observed.
    [0380] [0380] LCMS: m / z 137.1 (M + H) + (ES +).
    [0381] [0381] Step B: 1-Cyclobutylazetidine-3-sulfonamide
    [0382] [0382] To a solution of azetidine-3-sulfonamide (50 mg, 367.18 μmol, 1 eq) in MeOH (1 ml) was added cyclobutanone (31 mg, 440.62 μmol, 1.2 eq) and NaBH ( OAc) 3 (97 mg, 458.98 μmol, 1.25 eq). The reaction mixture was stirred at 20 ° C for 2 hours. Then, the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.05% NH3.H2O) -MeCN) to yield the title compound (12.25 mg, 18%) as a white solid.
    [0383] [0383] 1H NMR (DMSO-d6) δ 6.92 (s, 2 H), 3.88-3.85 (m, 1 H), 3.41-3.33
    [0384] [0384] LCMS: m / z 191.1 (M + H) + (ES +).
    [0385] [0385] Intermediate P16: 1-Ethylazetidine-3-sulfonamide
    [0386] [0386] Step A: 1-Ethyl-N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide O O O O O O S I S N N HN N O O
    [0387] [0387] To a solution of N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (1 g, 2.66 mmol, 1 eq, obtained according to Step G of the synthesis of intermediate P14) and K2CO3 ( 367 mg, 2.66 mmol, 1 eq) in MeCN (2 ml) iodoethane (414 mg, 2.66 mmol, 1 eq) was added. The mixture was stirred at 70 ° C for 1 hour. The reaction mixture was stopped with water (30 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over anhydrous Na 2 SO4, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.1% NH3.H2O) -MeCN) to yield the title compound (0.7 g, 22% yield, 100% purity in LCMS) like a white solid.
    [0388] [0388] 1H NMR (CD3OD) δ 7.20 (d, 4 H), 6.90 (d, 4 H), 4.28 (s, 4 H), 4.00-3.93 (m, 1 H), 3.81 (s, 6 H), 3.51 (t, 2 H), 3.40 (t, 2 H), 2.53 (q, 2 H) and 0.96 (t, 3 H).
    [0389] [0389] LCMS: m / z 405.2 (M + H) + (ES +).
    [0390] [0390] Step B: 1-Ethylazetidine-3-sulfonamide O O O O O
    [0391] [0391] O
    [0392] [0392] A solution of 1-ethyl-N, N-bis (4-methoxybenzyl) azetidine-3-
    [0393] [0393] 1H NMR (DMSO-d6) δ 6.94 (s, 2 H), 3.95-3.86 (m, 1 H), 3.47 (t, 2 H), 3.31-3 , 25 (m, 2 H), 2.43 (q, 2 H) and 0.86 (t, 3 H).
    [0394] [0394] LCMS: m / z 165.1 (M + H) + (ES +).
    [0395] [0395] Intermediate P17: 1- (Pyridin-3-ylmethyl) azetidine-3-sulfonamide
    [0396] [0396] Step A: N, N-bis (4-methoxybenzyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide O O O O N N
    [0397] [0397] To a solution of N, N-bis (4-methoxybenzyl) azetidine-3-sulfonamide (1 g, 2.66 mmol, 1 eq, obtained according to Step G of the synthesis of intermediate P14) in MeCN ( 20 ml) nicotinaldehyde (341 mg, 3.19 mmol, 1.2 eq) and NaBH (OAc) 3 (1.13 g, 5.31 mmol, 2 eq) were added. The mixture was stirred at 15 ° C for 1 hour. Then, the reaction mixture was stopped with water (80 ml) and extracted with EtOAc (6 × 100 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 1: 1 to 0: 1) to produce the title compound (1.1 g, 89%) as a yellow oil.
    [0398] [0398] 1H NMR (DMSO-d6) δ 8.53 (s, 1 H), 8.46 (s, 1 H), 7.72 (d, 1 H), 7.37-7.33 (m , 1 H), 7.13 (d, 4 H), 6.88 (d, 4 H), 4.21 - 4.17 (m, 5 H), 3.73 (s, 6 H), 3 , 61 (s, 2 H), 3.47-3.41 (m, 2 H) and 3.33-3.31 (m, 2 H).
    [0399] [0399] Step B: 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide
    [0400] [0400] A solution of N, N-bis (4-methoxybenzyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (1 g, 2.14 mmol, 1 eq) in TFA (10 mL) was stirred at 10 ° C for 36 hours. Then, the reaction mixture was concentrated in vacuo. The residue was treated with MeOH (80 ml) and the mixture was stirred for an additional hour. Then, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (water (0.1% NH 3.H2O) - MeCN) to yield the title compound (240 mg, 49%) as a white solid.
    [0401] [0401] 1H NMR (DMSO-d6) δ 8.52-8.45 (m, 2 H), 7.67 (d, 1 H), 7.35 (dd, 1 H), 6.98 (s , 2 H), 3.99-3.94 (m, 1 H), 3.64 (s, 2 H), 3.54-3.49 (m, 2 H) and 3.44-3.35 (m, 2 H).
    [0402] [0402] LCMS: m / z 228.1 (M + H) + (ES +).
    [0403] [0403] Intermediate P18: 1-isopropylpiperidine-4-sulfonamide
    [0404] [0404] Step A: Benzyl 4-hydroxypiperidin-1-carboxylate H Cbz N N OH OH
    [0405] [0405] To a solution of piperidin-4-ol (100 g, 988.66 mmol, 1 eq) in DCM (1 L) was added TEA (100.04 g, 988.66 mmol, 1 eq) and chloroformate of benzyl (168.66 g, 988.66 mmol, 1 eq) at 0 ° C. The mixture was heated to 25 ° C and stirred for 12 hours. Then, the reaction mixture was diluted with DCM (500 ml), washed with brine (3 x 500 ml), dried over Na 2SO4, filtered and concentrated under reduced pressure to produce the title compound (220 g, 95%) as a yellow oil, which was used in the next step without further purification.
    [0406] [0406] 1H NMR (CDCl3) δ 7.36-7.29 (m, 5 H), 5.10 (s, 2 H), 3.90-3.81 (m, 3
    [0407] [0407] LCMS: m / z 258.1 (M + Na) + (ES +).
    [0408] [0408] Step B: Benzyl 4 ((methylsulfonyl) oxy) piperidine-1-carboxylate Cbz Cbz
    [0409] [0409] To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (220 g, 935.06 mmol, 1 eq) in DCM (1.7 L) was added TEA (189.24 g, 1.87 mol, 2 eq). Then, mesyl chloride (128.54 g, 1.12 mol, 1.2 eq) was added dropwise at 0 ° C. The solution was heated to 25 ° C and stirred for 1 hour. Then, the reaction mixture was stopped with saturated aqueous NaHCO3 solution (1.2 L) and the two layers were separated. The organic layer was washed with saturated aqueous NaHCO3 solution (1.2 L) and brine (2 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide the title compound (293 g, 100%), that was used directly in the next step.
    [0410] [0410] Step C: Benzyl 4- (acetylthio) piperidine-1-carboxylate
    [0411] [0411] To a solution of benzyl 4 - ((methylsulfonyl) oxy) piperidine-1-carboxylate (290 g, 925.43 mmol, 1 eq) in DMF (1.4 L) was added Cs 2CO3 (331.67 g, 1.02 mol, 1.1 eq) and thioethanic acid (77.49 g, 1.02 mol, 1.1 eq). The mixture was stirred at 80 ° C for 12 hours. Some solid was precipitated. The reaction mixture was filtered. The filtrate was concentrated in vacuo to remove most of the DMF. The residue was diluted with EtOAc (1.5 L), washed with H2O (3 x 1 L) and brine (2 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 50: 1 to 40: 1) to produce the title compound (146 g, crude) as a yellow oil.
    [0412] [0412] 1H NMR (CDCl3) δ 7.37-7.35 (m, 5 H), 5.13 (s, 2 H), 4.07-3.93 (m, 2 H), 3.66 -3.61 (m, 1 H), 3.19-3.12 (m, 2 H), 2.33 (s, 3 H), 1.94-1.91 (m, 2 H) and 1 , 59 - 1.56 (m, 2 H).
    [0413] [0413] LCMS: m / z 294.1 (M + H) + (ES +).
    [0414] [0414] Step D: Benzyl 4- (chlorosulfonyl) piperidine-1-carboxylate Cbz Cbz N N
    [0415] [0415] To a solution of benzyl 4- (acetylthio) piperidine-1-carboxylate (30.00 g, 102.26 mmol, 1 eq) in AcOH (1 L) and H2O (100 mL) was added NCS (40 , 96 g, 306.77 mmol, 3 eq). The reaction mixture was stirred at 25 ° C for 40 minutes. Then, the reaction mixture was poured into water (1 L) and extracted with DCM (1 L). The organic layer was washed with water (3 x 1 L) and brine (1 L), dried over Na2SO4 and filtered to produce the title compound in DCM solution (1 L) (theoretical amount: 32.4 g, crude) , which was used in the next step without further purification.
    [0416] [0416] Step E: Benzyl 4-sulfamoylpiperidine-1-carboxylate Cbz Cbz N N
    [0417] [0417] NH3 was bubbled into a solution of benzyl 4- (chlorosulfonyl) piperidine-1-carboxylate (theoretical amount: 30 g, crude) in DCM (1 L) at 0 ° C for 20 minutes. Then the reaction mixture was stirred at 25 ° C for 40 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of EtOAc (50 ml) and petroleum ether (40 ml) to produce the title compound (21 g, 75%) as a yellow solid.
    [0418] [0418] 1H NMR (DMSO-d6) δ 7.38-7.32 (m, 5 H), 6.79 (br s, 2 H), 5.10 (s, 2 H), 4.12- 4.01 (m, 2 H), 3.09-3.02 (m, 1 H), 3.01-2.75 (m, 2 H), 2.02-1.96 (m, 2 H ) and 1.51-1.41 (m, 2 H).
    [0419] [0419] Step F: Piperidine-4-sulfonamide Cbz H N N
    [0420] [0420] To a solution of benzyl 4-sulfamoylpiperidine-1-carboxylate (21 g, 70.39 mmol, 1 eq) in MeOH (200 mL) was added Pd / C (10% by weight of activated carbon charge, 4 g) under nitrogen. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 25 ° C for 30 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with EtOAc (200 ml) to produce the title compound (11.2 g, 97% yield, 100% LCMS purity) as a white solid.
    [0421] [0421] 1H NMR (DMSO-d6 + D2O) δ 3.06-2.90 (m, 2 H), 2.89-2.86 (m, 1 H), 2.50-2.46 (m , 2 H), 1.95-1.91 (m, 2 H) and 1.53-1.46 (m, 2 H). Three interchangeable protons not observed.
    [0422] [0422] LCMS: m / z 165.1 (M + H) + (ES +).
    [0423] [0423] Step G: 1-isopropylpiperidine-4-sulfonamide H
    [0424] [0424] To a solution of piperidine-4-sulfonamide (1.2 g, 7.31 mmol, 1 eq) in acetonitrile (20 ml) was added 2-bromopropane (3.59 g, 29.23 mmol, 4 eq ) and NaHCO3 (1.84 g, 21.92 mmol, 3 eq). Then, the reaction mixture was stirred at 70 ° C for 18 hours. The hot mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound (1.05 g, 69% yield, 98.5% LCMS purity) as a white solid.
    [0425] [0425] 1H NMR (DMSO-d6) δ 6.61 (s, 2 H), 2.81-2.77 (m, 2 H), 2.66-2.61 (m, 2 H), 2 , 05-1.99 (m, 2 H), 1.91-1.87 (m, 2 H), 1.50-1.45 (m, 2 H) and 0.89 (dd, 6 H) .
    [0426] [0426] LCMS: m / z 207.1 (M + H) + (ES +).
    [0427] [0427] Intermediate P19: (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl) sulfonyl) amide
    [0428] [0428] Step A: 5-bromo-1-isopropylpyrimidin-2 (1H) -one
    [0429] [0429] A suspension of 5-bromopyrimidin-2 (1H) -one (10.07 g, 57.5 mmol) and K2CO3 (8.35 g, 60.4 mmol) in DMF (200 mL) was treated with 2 - iodopropane (6.4 ml, 62.7 mmol) under nitrogen. The resulting suspension was stirred at room temperature for 40 hours, concentrated in vacuo and the residue was partitioned between EtOAc (100 ml) and water (50 ml). The organic layer was collected and the aqueous layer was extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with 20% v / v brine (3 x 50 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo to provide the crude product as a yellow oil (4.71 g) . The crude product was purified by chromatography on silica gel (dry charge) (40 g cartridge, 0-5% MeOH / DCM) to generate the title compound (1.34 g, 10%) as a light yellow oil which solidified at rest.
    [0430] [0430] 1H NMR (CDCl3) δ 8.52 (dd, J = 3.3, 1.6 Hz, 1H), 7.76 (d, J = 3.2 Hz, 1H), 4.99 (pd , J = 6.8, 1.6 Hz, 1H), 1.40 (dd, J = 6.8, 1.0 Hz, 6H).
    [0431] [0431] LCMS: m / z 217.0 (MBr79 + H) + (ES +).
    [0432] [0432] Step B: 5- (benzylthio) -1-isopropylpyrimidin-2 (1H) -one
    [0433] [0433] A solution of 5-bromo-1-isopropylpyrimidin-2 (1H) -one (1.217 g, 5.05 mmol), DIPEA (1.8 ml, 10.31 mmol) and benzyl mercaptane (0.6 ml , 5.07 mmol) in dioxane (25 ml) was sparged with nitrogen for 15 minutes before Pd 2 (dba) 3 (0.233 g, 0.254 mmol) and Xantphos (0.294 g, 0.508 mmol) were added. The reaction mixture was heated to 100 ° C for 22 hours and then concentrated in vacuo. The residue was partitioned between EtOAc (30 ml) and saturated aqueous NaHCO 3 (20 ml). The aqueous layer was extracted with EtOAc (3 x 30 ml) and the combined organic extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to generate the crude product as a brown oil (2.3 g) . The crude product was purified by chromatography on silica gel (dry charge) (40 g cartridge, 0-5% MeOH / DCM) to generate the title compound (1.49 g, 99%) as a brown oil.
    [0434] [0434] 1H NMR (CDCl3) δ 8.46 (d, J = 3.1 Hz, 1H), 7.30 - 7.22 (m, 3H), 7.15 (d, J = 3.2 Hz , 1H), 7.09 - 7.06 (m, 2H), 4.84 (sept, J = 6.8 Hz, 1H), 3.80 (s, 2H), 1.13 (d, J = 6.8 Hz, 6H).
    [0435] [0435] LCMS; m / z 261.1 (M + H) + (ES +).
    [0436] [0436] Step C: 1-isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyrimidine-5-sulfonamide
    [0437] [0437] A suspension of 5- (benzylthio) -1-isopropylpyrimidin-2 (1H) -one (1.012 g, 3.69 mmol) in DCM (15 mL) and water (1.5 mL) at 0 ° C was treated with SO2Cl2 (2 ml, 23.86 mmol) dropwise. The resulting yellow suspension was stirred at 0 ° C for 1 hour. An ice / water paste (20 mL) was added and the organic phase was collected and retained. The aqueous layer was extracted with DCM (2 x 10 mL) and the combined organic extracts were dried (MgSO 4) and concentrated in vacuo to generate intermediate crude sulfonyl chloride as a pale yellow liquid (1.024 g) which was used without further purification . A solution of bis (4-methoxybenzyl) amine (1.007 g, 3.91 mmol) and Et3N (0.6 ml, 4.30 mmol) in DCM (20 ml) at 0 ° C was treated with a solution of the intermediate crude sulfonyl chloride in DCM (10 mL). The resulting solution was allowed to warm to room temperature, stirred for 1 hour and then diluted with DCM (20 ml) and saturated aqueous NH 4Cl (20 ml). The organic layer was collected and washed with saturated aqueous NH4Cl (20 ml) and water (20 ml), dried (MgSO4) and concentrated in vacuo to generate the crude product as an orange oil (2.0 g). The crude product was triturated with TBME (30 ml), filtered, washed with TBME and dried in vacuo to generate the crude product which was purified by chromatography on silica gel (24 g cartridge, 0-5% MeOH / DCM) to generate the title compound (0.941 g, 44%) as a sticky orange oil.
    [0438] [0438] 1H NMR (CDCl3) δ 8.65 (d, J = 3.3 Hz, 1H), 7.96 (d, J = 3.3 Hz, 1H), 7.15 - 7.10 (m , 4H), 6.85 - 6.82 (m, 4H), 4.88 (sept, J = 6.8 Hz, 1H), 4.32 (s, 4H), 3.79 (s, 6H) , 1.34 (d, J = 6.8 Hz, 6H).
    [0439] [0439] LCMS: m / z 458.1 (M + H) + (ES +).
    [0440] [0440] Step D: 1-isopropyl-2-oxo-1,2-dihydropyrimidine-5-sulfonamide
    [0441] [0441] 1-Isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.941 g, 1.625 mmol) was treated with TFA (15 ml, 195 mmol) and the resulting solution was stirred at room temperature for 64 hours. Then the reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (dry charge) (12 g cartridge, 0-10% MeOH / DCM) to generate the title compound (0.350 g , 94%) as a beige solid.
    [0442] [0442] 1H NMR (DMSO-d6) δ 8.81 (d, J = 3.2 Hz, 1H), 8.51 (d, J = 3.3 Hz, 1H), 7.45 (s, 2H ), 4.77 (sept, J = 6.8 Hz, 1H), 1.37 (d, J = 6.8 Hz, 6H).
    [0443] [0443] LCMS; m / z 218.1 (M + H) + (ES +); 215.8 (M-H) - (ES-).
    [0444] [0444] Step E: ((4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-2-oxo- 1,2-dihydropyrimidin-5-yl) sulfonyl) amide
    [0445] [0445] A suspension of 1-isopropyl-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.150 g, 0.690 mmol) and DMAP (0.169 g, 1.383 mmol) in dry MeCN (2 mL) was stirred at room temperature for 10 minutes before adding diphenyl carbonate (0.163 g, 0.761 mmol) in one portion. The reaction was stirred for 18 hours, diluted with TBME (20 ml) and DCM (2 ml) and the precipitate was collected by filtration and used crude in the next step.
    [0446] [0446] Intermediate P20: 1-isopropyl-2-oxo-1,2-dihydropyridine-4-
    [0447] [0447] Step A: Lithium 2-chloropyridine-4-sulfinate
    [0448] [0448] A solution of 4-bromo-2-chloropyridine (5.8 ml, 52.3 mmol) in dry THF (100 ml) at -78 ° C was treated with 2.5 M BuLi (in hexanes) (22 ml, 55.0 mmol) dropwise under nitrogen. The resulting solution was stirred at -78 ° C for 10 minutes and then the SO2 gas was bubbled through the solution for 20 minutes. The reaction was allowed to warm to room temperature and then concentrated in vacuo. The residue was triturated with TBME (100 ml). The resulting solid was filtered, washed with TBME and dried in vacuo to generate the title compound (8.80 g, 92%) as a dark purple solid which was used crude in the next step.
    [0449] [0449] Step B: 2-chloro-N, N-bis (4-methoxybenzyl) pyridine-4-sulfonamide
    [0450] [0450] A suspension of lithium 2-chloropyridine-4-sulfinate (6.55 g, 35.7 mmol) in DCM (100 mL) at 0 ° C was treated with NCS (4.862 g, 35.7 mmol) in a portion. The resulting suspension was stirred at 0 ° C for 2 hours, interrupted with water (50 mL) and the organic layer was collected. The aqueous layer was extracted with DCM (2 x 50 ml) and the combined organic extracts were washed with water (50 ml), dried (MgSO4) and concentrated in vacuo to provide the crude sulfonyl chloride intermediate. A solution of the sulfonyl chloride intermediate in DCM (10 mL) was added dropwise to a suspension of bis (4-methoxybenzyl) amine (9.42 g, 36.6 mmol) and triethylamine (15.92 mL, 114 mmol ) in DCM (100 mL) at 0 ° C. The reaction mixture was allowed to warm to room temperature, stirred for 16 hours and then water (100 ml) was added. The organic layer was collected and the aqueous layer was extracted with DCM (2 x 50 ml). The combined organic extracts were washed with water (100 ml), 1 M HCl (aq) (2 x 100 ml), water (100 ml), dried (MgSO 4) and concentrated in vacuo to generate the crude product which was purified by chromatography on silica gel (dry charge) (80 g cartridge, 0-50% EtOAc / isohexane) to generate the title compound (0.677 g, 4% yield) as an orange solid.
    [0451] [0451] 1H NMR (CDCl3) δ 8.51 (dd, J = 4.8, 1.9 Hz, 1H), 8.30 (dd, J = 7.8, 1.9 Hz, 1H), 7 , 30 (dd, J = 7.8, 4.8 Hz, 1H), 7.04 - 6.99 (m, 4H), 6.81 - 6.75 (m, 4H), 4.38 (s , 4H), 3.78 (s, 6H).
    [0452] [0452] LCMS: m / z 433 (MCl35 + H) + (ES +).
    [0453] [0453] Step C: N, N-Bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-4-sulfonamide
    [0454] [0454] A suspension of 2-chloro-N, N-bis (4-methoxybenzyl) pyridine-4-sulfonamide (0.365 g, 0.759 mmol) in ethane-1,2-diol (5 ml, 0.759 mmol) was treated with 2 M KOH (aq) (1.9 ml, 3.80 mmol). The resulting suspension was stirred at 140 ° C for 72 hours, allowed to cool to room temperature and then diluted with saturated aqueous NH4Cl (30 ml) and EtOAc (20 ml). The organic layer was collected and the aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to generate the crude product as a yellow solid (510 mg). The crude product was purified by chromatography on silica gel (dry charge) (12 g cartridge, 0-100% EtOAc / isohexane) to generate the title compound (0.437 g, 68%) as a pale yellow solid.
    [0455] [0455] LCMS: m / z 437.3 (M + Na) + (ES +); 413.1 (MH) - (ES-).
    [0456] [0456] Step D: 1-Isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-4-sulfonamide
    [0457] [0457] A suspension of N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-4-sulfonamide (0.437 g, 0.949 mmol) and lithium bromide (0.171 g, 1.930 mmol) in DME: DMF (7.5 mL, 4: 1) at 0 ° C was treated with NaH in one portion. The resulting suspension was stirred at 0 ° C for 15 minutes, treated with 2-
    [0458] [0458] 1H NMR (DMSO-d6) δ 8.06 (dd, J = 6.8, 2.1 Hz, 1H), 7.99 (dd, J = 7.2, 2.0 Hz, 1H) , 7.07 - 7.03 (m, 4H), 6.82 - 6.78 (m, 4H), 6.39 (t, J = 7.0 Hz, 1H), 4.99 (sept, J = 6.8 Hz, 1H), 4.34 (s, 4H), 3.71 (s, 6H), 1.28 (d, J = 6.8 Hz, 6H).
    [0459] [0459] LCMS; m / z 479.3 (M + Na) + (ES +).
    [0460] [0460] Step E: 1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide
    [0461] [0461] 1-Isopropyl-N, N-bis (4-methoxybenzyl) -2-oxo-1,2-dihydropyridine-4-sulfonamide (0.375 g, 0.715 mmol) was treated with TFA (2 ml, 26 , 0 mmol) and the resulting red solution was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo, underwent azeotropic distillation with DCM (2 x 5 mL) and the crude product was purified by chromatography on silica gel (dry charge) (4 g cartridge, 0-10% MeOH / DCM ) to generate the title compound (0.160 g, 100%) as a white solid.
    [0462] [0462] 1H NMR (CDCl3) δ 8.09 (dd, J = 7.1, 2.1 Hz, 1H), 7.61 (dd, J = 6.9, 2.1 Hz, 1H), 6 , 42 (t, J = 7.0 Hz, 1H), 5.38 (br s, 2H), 5.32 (sept, J = 7.0 Hz, 1H), 1.41 (d, J = 6 , 8 Hz, 6H).
    [0463] [0463] LCMS: m / z 217.3 (M + H) + (ES +); 215.1 (M-H) - (ES-).
    [0464] [0464] Intermediate P21: 6- (dimethylamino) pyrazine-2-sulfonamide
    [0465] [0465] Step A: 2- (Benzylthio) -6-chloropyrazine Cl N Cl SNa Cl N S N N
    [0466] [0466] A solution of 2,6-dichloropyrazine (5 g, 33.56 mmol, 1.1 eq) and sodium phenylmethanethiolate (4.46 g, 30.51 mmol, 1 eq) in DMF (50 mL) stirred at 25 ° C for 16 hours. The reaction mixture was diluted with EtOAc (100 ml) and washed with saturated aqueous NH4Cl solution (3 x 50 ml) and brine (3 x 50 ml). The combined organic layers were 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 50: 1) to produce the title compound (2 g, 28%) as a colorless oil.
    [0467] [0467] 1H NMR (CDCl3): δ 8.33 (d, 1 H), 8.23 (s, 1 H), 7.46-7.42 (m, 2 H), 7.37-7, 29 (m, 3 H) and 4.43 (s, 2 H).
    [0468] [0468] LCMS: m / z 237.0 (M + H) + (ES +).
    [0469] [0469] Step B: 6-chloropyrazine-2-sulfonyl chloride
    [0470] [0470] A solution of 2- (benzylthio) -6-chloropyrazine (2 g, 8.45 mmol, 1eq) in CCl4 (80 mL) and H2O (20 mL) was bubbled with Cl2 at 0 ° C for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo to produce the title compound (1.8 g, crude), which was used directly in the next step.
    [0471] [0471] Step C: 6-chloropyrazine-2-sulfonamide
    [0472] [0472] A solution of 6-chloropyrazine-2-sulfonyl chloride (1.8 g, crude) in THF (50 mL) was bubbled with NH3 at 0 ° C for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (21 ml, v: v = 20: 1) to produce the title compound (1.2 g, 73%) as a yellow solid.
    [0473] [0473] 1H NMR (DMSO-d6): δ 9.09 (d, 2 H) and 7.96 (s, 2 H).
    [0474] [0474] Step D: 6- (Dimethylamino) pyrazine-2-sulfonamide
    [0475] [0475] To a solution of 6-chloropyrazine-2-sulfonamide (1 g, 5.16 mmol, 1 eq) in MeCN (10 ml) was added dimethylamine (2 M in THF, 3.23 ml, 1.25 eq ). The mixture was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 1: 1 to 1: 10) to yield the title compound (210 mg, 20%) as a yellow solid.
    [0476] [0476] 1H NMR (CD3OD): δ 8.26 (s, 1 H), 8.22 (s, 1 H) and 3.22 (s, 6 H).
    [0477] [0477] LCMS: m / z 203.1 (M + H) + (ES +).
    [0478] [0478] Intermediate P22: 5- (Dimethylamino) pyrazine-2-sulfonamide
    [0479] [0479] Step A: 2- (Benzylthio) -5-chloropyrazine N Cl N S Bn Cl N Cl N
    [0480] [0480] To a solution of 2,5-dichloropyrazine (3 g, 20.14 mmol, 1 eq) in MeCN (30 ml) was added phenylmethanethiol (2.25 g, 18.12 mmol, 0.9 eq) and K2CO3 (5.57 g, 40.27 mmol, 2 eq). The reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic layers were dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 10: 1 to 0: 1) to produce the title compound (4.5 g, 94%) as a yellow oil.
    [0481] [0481] 1H NMR (CDCl3): δ 8.43 (s, 1 H), 8.19 (s, 1 H), 7.42-7.38 (m, 2 H), 7.35-7, 28 (m, 3 H) and 4.42 (s, 2 H).
    [0482] [0482] Step B: 5-chloropyrazine-2-sulfonyl chloride
    [0483] [0483] Cl2 (15 psi) was bubbled into a solution of 2- (benzylthio) -5-
    [0484] [0484] Step C: 5-chloropyrazine-2-sulfonamide
    [0485] [0485] A saturated solution of NH3 in THF (20 mL) was added to a solution of 5-chloropyrazine-2-sulfonyl chloride (theoretical amount: 4 g, crude) in CCl4 (50 mL) and H2O (10 mL) at -10 ° C for 10 minutes. Then, the reaction mixture was heated to 25 ° C and stirred at 25 ° C for 50 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO 2, petroleum ether: ethyl acetate, 30: 1 to 1: 1) to produce the title compound (1.6 g, 44%) as a yellow oil .
    [0486] [0486] 1H NMR (CDCl3): δ 8.98 (dd, 1 H) r 7.88 (s, 1 H).
    [0487] [0487] Step D: 5- (Dimethylamino) pyrazine-2-sulfonamide O O O The N S
    [0488] [0488] 5-chloropyrazine-2-sulfonamide (800 mg, 4.13 mmol, 1 eq) was added to a solution of dimethylamine in water (2 M, 10.00 mL, 33% by weight in H2O, 4.84 eq). Then the mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was triturated with EtOAc (30 ml) to produce the title compound (800 mg, 96%) as a white solid.
    [0489] [0489] 1H NMR (DMSO-d6): δ 8.46 (s, 1 H), 8.20 (s, 1 H), 7.28 (s, 2 H) and 3.17 (s, 6 H ).
    [0490] [0490] Intermediate P23: 3- (Difluoromethyl) pyrazine-2-sulfonamide
    [0491] [0491] Step A: 3-Chloropyrazine-2-carbaldehyde N Cl N Cl O N N
    [0492] [0492] To a solution of 2,2,6,6-tetramethylpiperidine (27.13 g, 192.08 mmol, 2.2 eq) in THF (200 mL) was added n-BuLi (2.5 M, 73 , 34 mL, 2.1 eq) at -78 ° C. The reaction mixture was heated to 0 ° C and stirred for 15 minutes. Then, the reaction mixture was cooled to -78 ° C and 2-chloropyrazine (10 g, 87.31 mmol, 1 eq) was added. The resulting mixture was stirred at -78 ° C for 30 minutes. To the reaction mixture, DMF (12.76 g, 174.62 mmol, 2 eq) was added at - 78 ° C. The mixture was stirred at -78 ° C for 30 minutes and then stirred at 0 ° C for an additional 15 minutes. The reaction mixture was stopped with a solution of AcOH (50 ml) in THF (50 ml) at -78 ° C. Then, the reaction mixture was poured into water (300 ml) and extracted with EtOAc (3 × 300 ml). The combined organic layers were washed with brine, dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 10: 1 to 5: 1) to produce the title compound (2.4 g, 19%) as a yellow oil.
    [0493] [0493] 1H NMR (CDCl3): δ 10.35 (s, 1 H), 8.78-8.72 (m, 1 H) and 8.62-8.58 (m, 1 H).
    [0494] [0494] Step B: 2-Chloro-3- (difluoromethyl) pyrazine N Cl N Cl F The N N F
    [0495] [0495] To a solution of 3-chloropyrazine-2-carbaldehyde (1.2 g, 8.42 mmol, 1 eq) in DCM (50 mL) was added bis (2-methoxyethyl) aminosulfide trifluoride (2.79 g, 12.63 mmol, 1.5 eq) at -78 ° C. The mixture was heated to 25 ° C and stirred for 2 hours. The reaction mixture was stopped with water (50 ml) and extracted with DCM (3 × 80 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO 2, petroleum ether: ethyl acetate, 1: 0 to 10: 1) to produce the title compound (800 g, 58%) as a yellow oil.
    [0496] [0496] 1H NMR (CDCl3): δ 8.54 (d, 1 H), 8.47 (d, 1 H) and 6.85 (t, 1 H).
    [0497] [0497] Step C: 2- (Benzylthio) -3- (difluoromethyl) pyrazine
    [0498] [0498] To a solution of 2-chloro-3- (difluoromethyl) pyrazine (800 mg, 4.86 mmol, 1 eq) in MeCN (15 mL) was added phenylmethanethiol (664 mg, 5.35 mmol, 1.1 eq) and K2CO3 (874 mg, 6.32 mmol, 1.3 eq). The reaction mixture was stirred at 25 ° C for 12 hours. Then, the reaction mixture was poured into water (50 ml) and extracted with EtOAc (2 × 50 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO 2, petroleum ether: ethyl acetate, 1: 0 to 10: 1) to produce the title compound (1.1 g, 90%) as a colorless oil .
    [0499] [0499] 1H NMR (CDCl3): δ 8.56-8.52 (m, 1 H), 8.33 (d, 1 H), 7.45-7.42 (m, 2 H), 7, 36-7.30 (m, 3 H), 6.71 (t, 1 H) and 4.51 (s, 2 H).
    [0500] [0500] Step D: 3- (difluoromethyl) pyrazine-2-sulfonyl chloride N S O
    [0501] [0501] Cl2 (15 psi) was bubbled into a solution of 2- (benzylthio) -3- (difluoromethyl) pyrazine (500 mg, 1.98 mmol, 1 eq) in DCM (20 mL) and H 2 O (2 mL ) at -10 ° C for 5 minutes. The reaction mixture was used directly in the next step without purification.
    [0502] [0502] Step E: 3- (Difluoromethyl) pyrazine-2-sulfonamide
    [0503] [0503] To a solution of 3- (difluoromethyl) pyrazine-2-sulfonyl chloride (theoretical amount: 453 mg, crude) in DCM (20 mL) and H2O (2 mL) was added NH3.H2O (15 mL, 25 % by weight in water) at 0 ° C. The reaction mixture was stirred at 0 ° C for 5 minutes and then concentrated in vacuo. The residue was treated with water (50 ml) and the mixture was washed with EtOAc (3 × 80 ml). The aqueous layer was concentrated in vacuo. The residue was treated with EtOAc (100 ml) and the mixture was stirred for 10 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound (260 mg, 63%) as a yellow oil.
    [0504] [0504] 1H NMR (DMSO-d6): δ 9.08 (d, 1 H), 9.02 (s, 1 H), 8.10 (br s, 2 H) and 7.52 (t, 1 H).
    [0505] [0505] LCMS: m / z 210.1 (M + H) + (ES +).
    [0506] [0506] Intermediate P24: 4,6-Dimethylpyrimidine-2-sulfonamide
    [0507] [0507] Step A: 4,6-Dimethylpyrimidine-2-thiol and 1,2-bis (4,6-dimethylpyrimidine-2-yl) disulfane
    [0508] [0508] To a solution of pentane-2,4-dione (10.03 g, 100.17 mmol, 1.25 eq) in concentrated solution of HCl (12 M, 20 mL, 2.99 eq) and EtOH ( 100 ml) thiourea (6.1 g, 80.14 mmol, 1 eq) was added at 10 ° C. The reaction mixture was stirred at 70 ° C for 2 hours. The reaction mixture was cooled to 20 ° C and a large amount of solid was precipitated. The mixture was filtered and the filter cake was treated with saturated aqueous NaHCO3 solution (300 ml). The mixture was filtered again and the filter cake was ground with MeOH (200 ml) to produce the title compound (10.3 g, 44% yield, 97.2% purity in LCMS) as a yellow solid.
    [0509] [0509] 1H NMR (DMSO-d6): δ 6.39 (s, 2 H) and 2.13 (s, 12 H).
    [0510] [0510] LCMS: m / z 279.1 (M + H) + (ES +).
    [0511] [0511] Step B: 4,6-dimethylpyrimidine-2-sulfonyl chloride
    [0512] [0512] Cl2 (15 psi) was bubbled into a solution of 1,2-bis (4,6-dimethylpyrimidin-2-yl) disulfane (1 g, 3.59 mmol, 1 eq) in DCM (40 mL) and H2O (6 mL) at -10 ° C for 10 minutes. The reaction mixture was stopped with water (20 ml) and extracted with DCM (2 x 40 ml). The solution of the title compound (crude) in DCM (80 mL) was used directly in the next step without further purification.
    [0513] [0513] Step C: 4,6-Dimethylpyrimidine-2-sulfonamide
    [0514] [0514] NH3 (15 psi) was bubbled into a solution of 4,6-dimethylpyrimidine-2-sulfonyl chloride (theoretical amount: 0.74 g, crude) in DCM (80 mL) at 0 ° C for 10 minutes. The reaction mixture was stopped with water (20 ml) and washed with DCM (40 ml). Then the aqueous phase was concentrated in vacuo. The residue was triturated with EtOAc (300 ml) to produce the title compound (0.35 g, 52% yield, 100% purity in LCMS) as a yellow solid.
    [0515] [0515] 1H NMR (DMSO-d6): δ 7.49-7.47 (m, 3 H) and 2.52 (s, 6 H).
    [0516] [0516] LCMS: m / z 188.1 (M + H) + (ES +).
    [0517] [0517] Intermediate P25: 5- (Dimethylamino) pyridazine-3-sulfonamide
    [0518] [0518] Step A: 6-Chlorine-N, N-dimethylpyridazin-4-amine
    [0519] [0519] To a mixture of 3,5-dichloropyridazine (13.5 g, 90.62 mmol, 1 eq) in THF (100 mL) was added dimethylamine (270 mL, 543.70 mmol, in THF solution, 6 eq) in a portion at 25 ° C. Then, the reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (0.05% NH3.H2O in water / MeCN) to yield the title compound (7 g, 49% yield, 99.35% purity in LCMS) as a brown solid.
    [0520] [0520] 1H NMR (CDCl3): δ 8.63 (d, 1 H), 6.53 (d, 1 H) and 3.09 (s, 6 H).
    [0521] [0521] LCMS: m / z 158.1 (M + H) + (ES +).
    [0522] [0522] Step B: 6- (Benzylthio) -N, N-dimethylpyridazin-4-amine
    [0523] [0523] To a mixture of phenylmethanethiol (4.31 g, 34.70 mmol, 1.22 eq) in DMF (100 mL) was added NaH (1.37 g, 34.26 mmol, 60% by weight of oil mineral, 1.2 eq) at 0 ° C in a portion under N2. Then, the mixture was stirred at 0 ° C for 0.5 hour. Then, 6-chloro-N, N-dimethylpyridazin-4-amine (4.5 g, 28.55 mmol, 1 eq) was added. The reaction mixture was heated to 70 ° C and stirred for 1 hour. The reaction mixture was stopped with water (200 ml) and extracted with EtOAc (3 x 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, 1: 0 to 20: 1, then washed with EtOAc: EtOH, 50: 1 to 10: 1) to produce the compound of the title (5.2 g, 74%) as a brown solid.
    [0524] [0524] 1H NMR (CDCl3): δ 8.53 (d, 1 H), 7.45-7.43 (m, 2 H), 7.32-7.30 (m, 2 H), 7, 26-7.23 (m, 1 H), 6.34 (d, 1 H), 4.58 (s, 2 H) and 3.09 (s, 6 H).
    [0525] [0525] Step C: 5- (dimethylamino) pyridazine-3-sulfonyl chloride
    [0526] [0526] To a solution of 6- (benzylthio) -N, N-dimethylpyridazin-4-amine (1 g, 4.08 mmol, 1 eq) in DCM (50 mL) was added a solution of CaCl 2 (4, 52 g, 40.76 mmol, 10 eq) in HCl (1 M, 20.38 ml, 5 eq) at -30 ° C. Then, a solution of CaCl2 (14.70 g, 132.47 mmol, 32.5 eq) in aqueous NaClO solution (19.22 g, 15.49 mmol, 6 wt% in water, 3.8 eq ) was added dropwise at - 30 ° C. The resulting mixture was stirred at -30 ° C for 30 minutes. The reaction mixture was stopped with water (20 ml) and extracted with DCM (2 x 50 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to produce a solution of the title compound (theoretical amount: 0.9 g, crude) in DCM (100 mL), which was used directly in the next step without purification additional.
    [0527] [0527] Step D: 5- (Dimethylamino) pyridazine-3-sulfonamide
    [0528] [0528] NH3 (15 psi) was bubbled into a solution of 5- (dimethylamino) pyridazine-3-sulfonyl chloride (theoretical amount: 0.9 g, crude) in DCM (100 mL) at -20 ° C for 10 minutes. The mixture was stopped with water (50 ml) and washed with DCM (30 ml). Then the aqueous phase (50 ml) was concentrated in vacuo. The residue was purified by trituration with EtOAc (300 ml) to give the title compound (0.23 g, 28%) as a yellow solid.
    [0529] [0529] 1H NMR (DMSO-d6): δ 8.89 (d, 1 H), 7.55 (s, 2 H), 7.05 (d, 1 H) and 3.09 (s, 6 H ).
    [0530] [0530] LCMS: m / z 203.1 (M + H) + (ES +).
    [0531] [0531] Intermediate P26: 2-Methylpropane-1-sulfonamide O O
    [0532] [0532] A solution of 2-methylpropane-1-sulfonyl chloride (1.5 g, 9.58 mmol, 1 eq) in THF (20 mL) was cooled to 0 ° C. Then NH3 (15 psi) was bubbled into the mixture at 0 ° C for 10 minutes. The mixture was stirred at 0 ° C for an additional 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound (1 g, 76%) as a colorless oil.
    [0533] [0533] 1H NMR (DMSO-d6): δ 6.72 (s, 2 H), 2.86 (d, 2 H), 2.19-2.07 (m, 1 H) and 1.01 ( d, 6 H).
    [0534] [0534] Intermediate P27: 2-Phenylethanesulfonamide O O O O
    [0535] [0535] NH3 was bubbled into THF (10 mL) at -78 ° C for 5 minutes. Then, a solution of 2-phenylethanesulfonyl chloride (0.5 g, 2.44 mmol, 1 eq) in THF (10 mL) was added to the NH3 / THF solution at 25 ° C. The resulting mixture was stirred for 12 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound (0.38 g, 84%) as a white solid.
    [0536] [0536] 1H NMR (CDCl3): δ 7.38-7.33 (m, 2 H), 7.29-7.24 (m, 3 H), 4.42 (br s, 2 H), 3 , 45-3.40 (m, 2 H) and 3.22-3.17 (m, 2 H).
    [0537] [0537] LCMS: m / z 208.1 (M + Na) + (ES +).
    [0538] [0538] Intermediate P28: 1-Phenylethanesulfonamide
    [0539] [0539] Step A: N, N-Bis (4-methoxybenzyl) -1-phenylmethanesulfonamide
    [0540] [0540] To a solution of bis (4-methoxybenzyl) amine (4.05 g, 15.74 mmol, 1 eq) in DCM (40 mL) was added TEA (3.18 g, 31.47 mmol, 2 eq ) and phenylmethanesulfonyl chloride (3 g, 15.74 mmol, 1 eq). The mixture was stirred at 20 ° C for 12 hours. The reaction mixture was concentrated in vacuo. The residue was treated with water (50 ml) and extracted with EtOAc (2 x 50 ml). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 5: 1 to 3: 1) to produce the title compound (4 g, 62%) as a yellow solid.
    [0541] [0541] 1H NMR (CDCl3): δ 7.24-7.20 (m, 3 H), 7.11 (dd, 4 H), 7.00-6.95 (m, 2 H), 6, 80 (dd, 4 H), 4.03 (s, 2 H), 3.96 (s, 4 H) and 3.74 (s, 6 H).
    [0542] [0542] Step B: N, N-Bis (4-methoxybenzyl) -1-phenylethanesulfonamide
    [0543] [0543] To a solution of N, N-bis (4-methoxybenzyl) -1- phenylmethanesulfonamide (1 g, 2.43 mmol, 1 eq) in THF (10 mL) was added LDA (2 M, 1.34 mL , 1.1 eq) at -78 ° C under N2 atmosphere. The mixture was stirred at - 78 ° C for 1 hour. Iodomethane (379 mg, 2.67 mmol, 1.1 eq) was added and the resulting mixture was stirred at 20 ° C for 2 hours. The reaction mixture was stopped with saturated aqueous NH4Cl solution (20 mL) and then concentrated in vacuo to remove THF. The mixture was treated with water (10 ml) and extracted with EtOAc (3 × 15 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO 2, petroleum ether: ethyl acetate, 1: 0 to 5: 1) to produce the title compound (0.9 g, 87%) as a white solid .
    [0544] [0544] 1H NMR (CDCl3): δ 7.33-7.28 (m, 3 H), 7.14 (d, 4 H), 7.10-7.08 (m, 2 H), 6, 86 (dd, 4 H), 4.09 (d, 2 H), 4.03-4.01 (m, 1 H), 3.83 (s, 6 H), 3.76 (d, 2 H ) and 1.79 (d, 3 H).
    [0545] [0545] Step C: 1-Phenylethanesulfonamide
    [0546] [0546] To a solution of N, N-bis (4-methoxybenzyl) -1-phenylethanesulfonamide (900 mg, 2.11 mmol, 1 eq) in DCM (30 mL) was added TFA (46.20 g, 405, 19 mmol, 191.58 eq). The mixture was stirred at 20 ° C for 12 hours. The reaction mixture was concentrated in vacuo. The residue was treated with MeOH (15 ml). The suspension was filtered, and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (v: v = 20: 1, 10 ml) to produce the title compound (300 mg, 77%) as a white solid.
    [0547] [0547] 1H NMR (CDCl3): δ 7.47-7.39 (m, 5 H), 4.46 (br s, 2 H), 4.29 (q, 1 H) and 1.82 (d , 3 H).
    [0548] [0548] Intermediate P29: 1-Cyclopropyl-1H-pyrazol-3-sulfonamide
    [0549] [0549] Step A: 1-Cyclopropyl-3-nitro-1H-pyrazole N NO2 B (OH) 2 NO2 N HN N
    [0550] [0550] To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol, 1.1 eq) in DCE (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 0.5 hour. Then Cu (OAc) 2 (70.68 g, 389.12 mmol, 1 eq) was added and the resulting 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 with silica gel (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). Then 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, 30%) as a yellow oil.
    [0551] [0551] 1H NMR (CDCl3): δ 7.54 (d, 1 H), 6.84 (d, 1 H), 3.73-3.67 (m, 1 H),
    [0552] [0552] Step B: 1-Cyclopropyl-1H-pyrazol-3-amine N NO2 NH2 N N N
    [0553] [0553] 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 NH 4Cl (62.87 g, 1 , 18 mol, 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 in portions. The reaction mixture was stirred at 60 ° C for 16 hours and then concentrated under reduced pressure. The residue was diluted with H2O (500 ml) and extracted with EtOAc (3 × 500 ml). The combined organic layers were washed with brine (2 x 250 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 30: 1 to 1: 1) to produce the title compound (20 g, 69%) as a yellow oil.
    [0554] [0554] 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) and 0.90-0.87 (m, 2 H).
    [0555] [0555] LCMS: m / z 124.2 (M + H) + (ES +).
    [0556] [0556] Step C: 1-cyclopropyl-1H-pyrazol-3-sulfonyl chloride N NH2 O
    [0557] [0557] To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol, 1 eq) in MeCN (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), CuCl 2 (10.37 g, 77.14 mmol, 0.5 eq) and CuCl (763 mg, 7.71 mmol, 0.05 eq) were added. Then SO2 gas (15 psi) was bubbled into the resulting 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 H2O (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 with silica gel (SiO 2, petroleum ether: ethyl acetate, 100: 0 to 1: 1) to produce the title compound (14 g, 44%) as a yellow oil.
    [0558] [0558] 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) and 1.16-1.12 (m, 2 H).
    [0559] [0559] Step D: 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide MeO OMe PMB H O N O
    [0560] [0560] To a solution of 1-cyclopropyl-1H-pyrazol-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (300 mL) was added TEA (27.42 g, 270.99 mmol, 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. The reaction mixture was diluted with H 2 O (500 ml) and was extracted with EtOAc (3 x 500 ml). The combined organic layers were washed with brine (2 x 500 ml), dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (0.5% NH3.H2O-MeCN) to yield the title compound (30 g, 52% yield, 99.8% purity in LCMS).
    [0561] [0561] 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) and 1.09-1.06 (m, 2 H).
    [0562] [0562] LCMS: m / z 428.2 (M + H) + (ES +).
    [0563] [0563] Step E: 1-Cyclopropyl-1H-pyrazol-3-sulfonamide PMB O AT THE
    [0564] [0564] To a solution of 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (1 g, 2.34 mmol, 1 eq) in DCM (10 mL) was added TFA (15.40 g, 135.06 mmol, 57.74 eq). The reaction mixture was stirred at 25 ° C for 12 hours. Most of the solvent was evaporated and the residue was redissolved in MeOH (30 ml). Solids were formed and the mixture was filtered. The filtrate was concentrated in vacuo and then the crude product was triturated with a mixture of PE and EtOAc (30 ml, 20: 1) to produce the title compound (430 mg, 88% yield, 90% purity in LCMS) like a white solid.
    [0565] [0565] 1H NMR (DMSO-d6): δ 7.92 (s, 1 H), 7.38 (s, 2 H), 6.55 (s, 1 H), 3.84-3.78 ( m, 1 H) and 1.10-0.98 (m, 4 H).
    [0566] [0566] Intermediate P30: 1-Cyclopropyl-1H-pyrazol-4-sulfonamide
    [0567] [0567] Step A: 4-iodine-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole N O N HN N I O I
    [0568] [0568] To a mixture of 4-iodine-1H-pyrazole (50 g, 257.77 mmol, 1 eq) and pyridin-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 reaction mixture was stirred at 20 ° C for 12 hours and then concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO 2, petroleum ether: ethyl acetate, 1: 0 to 20: 1) to produce the title compound (65 g, 91%) as a colorless oil.
    [0569] [0569] 1H NMR (CDCl3): δ 7.67 (s, 1 H), 7.55 (s, 1 H), 3.84-3.82 (m, 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).
    [0570] [0570] Step B: S- (1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) benzothioate O SH N N
    [0571] [0571] 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.
    [0572] [0572] 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).
    [0573] [0573] Step C: 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-sulfonyl chloride N N NINTH
    [0574] [0574] 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 solution 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 (SiO 2, petroleum ether: ethyl acetate, 20: 1 to 5: 1) to produce the title compound (3.5 g, 27%) as a colorless oil .
    [0575] [0575] 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).
    [0576] [0576] Step D: N, N-Bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-sulfonamide MeO MeO OMe
    [0577] [0577] 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 ground with a mixture of PE and EtOAc (20 ml, v: v = 5: 1) to produce the title compound (3 g, 60% yield, 94.4% purity in LCMS) as a solid White.
    [0578] [0578] 1H NMR (CDCl3): δ 7.76 (s, 1 H), 7.65 (s, 1 H), 7.11 (d, 4 H), 6.81 (d, 4 H), 3.35 (q, 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).
    [0579] [0579] LCMS: m / z 472.1 (M + H) + (ES +).
    [0580] [0580] Step E: N, N-Bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide MeO MeO OMe OMe O O The N N S S N O HN O N N
    [0581] [0581] 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 20 ° C for 12 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (30 ml). The aqueous phase was extracted with ethyl acetate (3 × 20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound (2 g, crude) as a yellow oil, which was used in the next step without further purification.
    [0582] [0582] 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).
    [0583] [0583] LCMS: m / z 388.1 (M + H) + (ES +).
    [0584] [0584] Step F: 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide
    [0585] [0585] To a solution of cyclopropylboronic acid (109 mg, 1.28 mmol, 1.1 eq) in dioxane (5 mL) was added N, N-bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide ( 450 mg, 1.16 mmol, 1 eq), 2,2-bipyridine (181.39 mg, 1.16 mmol, 1 eq) and Na2CO3 (193 mg, 1.82 mmol, 1.57 eq). The reaction mixture was stirred at 25 ° C for 0.5 hour. Then, Cu (OAc) 2 (211 mg, 1.16 mmol, 1 eq) was added and the resulting mixture was heated to 70 ° C and stirred at 70 ° C for 11.5 hours. The reaction mixture was diluted with H2O (20 ml) and was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (2 × 20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography with silica gel (SiO2, petroleum ether: ethyl acetate, 20: 1 to 1: 1) to produce the title compound (210 mg, 42%) as a yellow solid.
    [0586] [0586] 1H NMR (DMSO-d6): δ 8.31 (s, 1 H), 7.78 (s, 1 H), 7.09-7.05 (m, 4 H), 6.83- 6.80 (m, 4 H), 4.14 (s, 4 H), 3.83-3.77 (m, 1 H), 3.72 (s, 6 H), 1.08-1, 03 (m, 2 H) and 1.02-1.00 (m, 2 H).
    [0587] [0587] LCMS: m / z 428.2 (M + H) + (ES +)
    [0588] [0588] Step G: 1-Cyclopropyl-1H-pyrazol-4-sulfonamide
    [0589] [0589] To a solution of 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-4-sulfonamide (170 mg, 397.65 µmol, 1 eq) in DCM (1 ml) was added TFA (5.24 g, 45.92 mmol, 115.48 eq). The mixture was stirred at 25 ° C for 2 hours. Most of the solvent was evaporated to produce the crude product. The crude product was added to MeOH (3 ml) and a solid was formed. The mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound (44 mg, 59%) as a red solid.
    [0590] [0590] 1H NMR (DMSO-d6): δ 8.29 (s, 1 H), 7.74 (s, 1 H), 7.23 (s, 2 H), 3.83-3.79 ( m, 1 H), 1.08-1.05 (m, 2 H) and 1.01-0.98 (m, 2 H).
    [0591] [0591] LCMS: m / z 188.1 (M + H) + (ES +).
    [0592] [0592] Intermediate P31: (1-Methylpyrrolidin-3-yl) methanesulfonamide
    [0593] [0593] Step A: tert-Butyl ((((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate
    [0594] [0594] To a mixture of tert-butyl 3- (hydroxymethyl) pyrrolidine-1-carboxylate (13 g, 64.59 mmol, 1 eq) and TEA (13.07 g, 129.18 mmol, 2.0 eq ) in DCM (200 mL) MsCl (8.23 g, 71.85 mmol, 1.1 eq) was added dropwise at 0 ° C. Then, the reaction mixture was heated to 25 ° C and stirred for 1 hour under N 2. The reaction mixture was stopped with water (100 ml) and extracted with DCM (3 x 100 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound (20 g, crude) as a brown oil, which was used directly in the next step without further purification .
    [0595] [0595] Step B: tert-butyl ((acetylthio) methyl) pyrrolidine-1-carboxylate
    [0596] [0596] To a mixture of tert-butyl 3 - (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate (20 g, 71.59 mmol, 1eq) in acetonitrile (300 mL) was added potassium ethanothioate ( 10 g, 87.56 mmol, 1.22 eq) in one portion. The reaction mixture was heated to 50 ° C and stirred for 12 hours. The mixture was concentrated in vacuo. The residue was treated with water (100 ml) and the mixture was extracted with EtOAc (3 x 100 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (SiO 2, petroleum ether: ethyl acetate, 50: 1 to 5: 1) to produce the title compound (14.2 g, 76%) as a yellow oil .
    [0597] [0597] 1H NMR (CDCl3): δ 3.61-3.41 (m, 2 H), 3.33-3.23 (m, 1 H), 3.05-2.87
    [0598] [0598] Step C: tert-butyl ((chlorosulfonyl) methyl) pyrrolidine-1-carboxylate
    [0599] [0599] To a mixture of tert-butyl 3 - ((acetylthio) methyl) pyrrolidine-1-carboxylate (4 g, 15.42 mmol, 1 eq) in AcOH (200 mL) and H2O (20 mL) was added NCS (6.18 g, 46.27 mmol, 3 eq) in one portion at 25 ° C. Then, the reaction mixture was stirred at 25 ° C for 1 hour. The mixture was stopped with water (200 ml) and extracted with DCM (2 x 100 ml). The combined organic phases were washed with brine (2 x 100 ml), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo to yield the title compound (4.38 g, crude) in DCM (200 ml), which was used directly to the next step without further purification.
    [0600] [0600] Step D: tert-Butyl 3- (sulfamoylmethyl) pyrrolidine-1-carboxylate
    [0601] [0601] NH3 (15 psi) was bubbled into a tert-butyl 3- ((chlorosulfonyl) methyl) pyrrolidine-1-carboxylate solution (4.38 g, crude) in DCM (200 mL) at -20 ° C for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound (2 g, crude) as a brown solid.
    [0602] [0602] 1H NMR (CDCl3): δ 3.78-3.73 (m, 1 H), 3.56-3.47 (m, 1 H), 3.37-3.31 (m, 1 H ), 3.25-3.15 (m, 2 H), 3.14-3.04 (m, 1 H), 2.78-2.72 (m, 1 H), 2.26-2, 20 (m, 1 H), 1.77-1.71 (m, 1 H) and 1.47 (s, 9 H).
    [0603] [0603] Step E: Pyrrolidin-3-ylmethanesulfonamide hydrochloride
    [0604] [0604] To a mixture of tert-3- (sulfamoylmethyl) pyrrolidine-1-carboxylate
    [0605] [0605] 1H NMR (DMSO-d6): δ 9.35-9.23 (m, 2 H), 6.99 (s, 2 H), 3.39-3.36 (m, 1 H), 3.22-3.19 (m, 2 H), 3.08-3.05 (m, 1 H), 2.93-2.85 (m, 1 H), 2.65-2.59 ( m, 2 H), 2.20-2.13 (m, 1 H) and 1.71-1.63 (m, 1 H).
    [0606] [0606] Step F: (1-Methylpyrrolidin-3-yl) methanesulfonamide
    [0607] [0607] To a solution of pyrrolidin-3-ylmethanesulfonamide hydrochloride (2 g, 9.97 mmol, 1 eq), TEA (1.21 g, 11.96 mmol, 1.2 eq) and HCHO (849 mg, 10.46 mmol, 1.05 eq) in MeCN (20 mL) NaBH (OAc) 3 (2.64 g, 12.46 mmol, 1.25 eq) was added in one portion. Then the reaction mixture was stirred at 25 ° C for 12 hours. The mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (0.05% NH3.H2O in water / MeCN) and then further purified by silica gel chromatography (0.1% NH3.H2O, EtOAc: EtOH, 1: 0 to 1: 1) to produce the title compound (1.5 g, 84%) as a yellow solid.
    [0608] [0608] 1H NMR (DMSO-d6): δ 5.60 (br s, 2 H), 3.04-3.01 (m, 2 H), 2.70-2.65 (m, 1 H) , 2.45-2.37 (m, 2 H), 2.30-2.21 (m, 5 H), 2.08-1.95 (m, 1 H) and 1.56-1.50 (m, 1 H).
    [0609] [0609] LCMS: m / z 179.1 (M + H) + (ES +).
    [0610] [0610] Intermediate P32: 3- (Diethylamino) propane-1-sulfonamide
    [0611] [0611] To a solution of 3-chloropropane-1-sulfonamide (203 mg, 1.29 mmol) in acetonitrile (10 mL) was added triethylamine (214 µL, 1.55 mmol, 1.2 equiv.), N, N-diethylamine (159 µL, 1.55 mmol 1.2 equiv.) And potassium iodide (43 mg, 0.26 mmol) and the reaction mixture was irradiated in the microwave at 100 ° C for 90 minutes. Additional potassium iodide (150 mg) was added and the resulting mixture was heated conventionally for an additional 2 hours at 100 ° C. After cooling to room temperature, the mixture was concentrated in vacuo to generate the crude title compound (> 100% yield); the material still contained salts and impurities, but was used without further purification.
    [0612] [0612] 1H NMR (CD3OD) δ 2.86 (m, 6 H), 2.47 (m, 2 H), 2.23 (m, 2 H) and 1.18 (t, 6 H).
    [0613] [0613] LCMS: m / z 195.1 (M + H) + (ES +).
    [0614] [0614] Intermediate P33: 3- (Benzyl (ethyl) amino) propane-1-sulfonamide
    [0615] [0615] Step A: 3- (benzyl (ethyl) amino) propane-1-sulfonic acid
    [0616] [0616] To a solution of 2,2-dioxide 1,2-oxathiolane (1 g, 8.19 mmol, 719.42 µL, 1 eq) in DCM (5 mL) was added N-benzylethanamine (3.94 g, 29.15 mmol, 3.56 eq) at 0 ° C. Then, the resulting mixture was stirred at 25 ° C for 2.5 hours. The mixture was concentrated in vacuo. The residue was triturated with EtOAc (40 ml) to produce the title compound (2.4 g, crude) as a white solid.
    [0617] [0617] 1H NMR (DMSO-d6): δ 7.37-7.23 (m, 5 H), 4.08 (s, 2 H), 2.91 (q, 2 H), 2.50- 2.40 (m, 4 H), 1.81 to 1.73 (m, 2 H) and 0.98 (t, 3 H).
    [0618] [0618] LCMS: m / z 258.1 (M + H) + (ES +).
    [0619] [0619] Step B: 3- (benzyl (ethyl) amino) propane-1-sulfonyl chloride O O O O
    [0620] [0620] A solution of 3- (benzyl (ethyl) amino) propane-1-sulfonic acid (2.1 g, 8.16 mmol, 1 eq) in SOCl2 (17.22 g, 144.74 mmol, 17, 74 eq) was stirred at 80 ° C for 6 hours. The filtrate was concentrated in vacuo to obtain the title compound (2 g, crude) as a yellow oil, which was used directly in the next step.
    [0621] [0621] Step C: 3- (Benzyl (ethyl) amino) propane-1-sulfonamide O O O O
    [0622] [0622] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonyl chloride (2 g, crude) in THF (3 mL) was added to a saturated solution of NH3 in THF (100 mL) at 0 ° C. Then the mixture was stirred at 20 ° C for 14 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% NH3.H2O) -MeCN) to obtain the title compound (1.15 g, 62% yield, 100% purity in LCMS) as a white solid.
    [0623] [0623] 1H NMR (CDCl3): δ 7.37-7.28 (m, 5 H), 4.98 (br s, 2 H), 3.57 (s, 2 H), 3.15 (t , 2 H), 2.61-2.52 (m, 4 H), 2.06-2.00 (m, 2H) and 1.07 (t, 3 H).
    [0624] [0624] Intermediate P34: 3-Methoxypropane-1-sulfonamide
    [0625] [0625] Step A: Sodium 3-Methoxypropane-1-sulfonate O
    [0626] [0626] A mixture of 1-bromo-3-methoxypropane (2 g, 13.07 mmol, 1 eq) and Na2SO3 (1.65 g, 13.07 mmol, 1 eq) in H2O (20 ml) was heated to 100 ° C and stirred for 16 hours. Then the reaction mixture was cooled and lyophilized to produce the title compound (2.25 g, 97% yield, Na salt) as a white solid.
    [0627] [0627] 1H NMR (D2O): δ 3.56 (t, 2 H), 3.34 (s, 3 H), 2.95-2.92 (m, 2 H) and 2.02-1, 94 (m, 2 H).
    [0628] [0628] LCMS: m / z 155.1 (M-Na + H) + (ES +).
    [0629] [0629] Step B: 3-methoxypropane-1-sulfonyl chloride O O O O
    [0630] [0630] A solution of sodium 3-methoxypropane-1-silphonate (0.7 g, 4.54 mmol, 1 eq) in POCl3 (8.25 g, 53.80 mmol, 11.85 eq) was stirred at 80 ° C for 5 hours. The mixture was stirred for 2 hours at 100 ° C. The mixture was diluted with DCM (80 ml) and filtered. The filtrate was concentrated in vacuo to produce the title compound (600 mg, crude) as a yellow oil, which was used directly in the next step.
    [0631] [0631] Step C: 3-methoxypropane-1-sulfonamide O O O O
    [0632] [0632] NH3 (15 psi) was bubbled into THF (20 mL) at 0 ° C for 5 minutes. A solution of 3-methoxypropane-1-sulfonyl chloride (600 mg, crude) in THF (2 ml) was added to the NH3 / THF solution (20 ml). The mixture was stirred at 20 ° C for 14 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield the crude compound (300 g, crude) as a yellow oil.
    [0633] [0633] 1H NMR (CDCl3): δ 4.94 (br s, 2 H), 3.53 (t, 2 H), 3.35 (s, 3 H), 3.25 (t, 2 H) and 2.17-2.10 (m, 2 H).
    [0634] [0634] Intermediate P35: N, N-Bis (2-methoxyethyl) -1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide
    [0635] [0635] Step A: 1-methyl-1H-pyrazol-3-sulfonyl chloride N N O
    [0636] [0636] A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (600 ml) at 0 ° C was treated with concentrated HCl (60 ml) and H 2O (60 mL). Then, an aqueous solution of NaNO2 (21.31 g, 308.90 mmol, 1.2 eq) in H2O (60 mL) was added slowly. The resulting mixture was stirred at 0 ° C for 40 minutes. AcOH (60 mL), CuCl2 (17.31 g, 128.71 mmol, 0.5 eq) and CuCl (1.27 g, 12.87 mmol, 307.78 µL, 0.05 eq) were added in Then, the SO 2 gas (15 psi) was bubbled into the mixture for 15 minutes at 0 ° C. The reaction mixture was concentrated in vacuo to remove most of the MeCN. Then, the reaction mixture was treated with H2O (2.5 L) and extracted with EtOAc (2 × 1.2 L). The combined organic layers were washed with brine (3 x 2 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography with silica gel (petroleum ether: ethyl acetate = 15: 1 to 5: 1) to produce the title compound (19 g, 41%) as a yellow oil.
    [0637] [0637] 1H NMR (CDCl3): δ 7.52 (d, 1 H), 6.89 (d, 1 H) and 4.07 (s, 3 H).
    [0638] [0638] Step B: N, N-Bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0639] [0639] To a solution of bis (4-methoxybenzyl) amine (99.83 g, 387.96 mmol, 0.91 eq) in THF (1 L) was added TEA (86.28 g, 852.65 mmol, 118.68 ml, 2 eq), followed by 1-methyl-1H-pyrazol-3-sulfonyl chloride (77 g, 426.33 mmol, 1 eq). Then the reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated in vacuo to remove most of the THF. The reaction mixture was stopped by adding aqueous HCl (1 M, 500 ml) and then extracted with EtOAc (2 x 500 ml). The combined organic layers were washed with brine (2 × 600 ml), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (70 ml, v: v = 5: 1) to produce the title compound (138 mg, 81%) as a white solid.
    [0640] [0640] 1H NMR (CDCl3): δ 7.40 (d, 1 H), 7.08 (d, 4 H), 6.78 (d, 4 H), 6.65- 6.63 (m, 1 H), 4.32 (s, 4 H), 3.98 (s, 3 H) and 3.79 (s, 6 H).
    [0641] [0641] LCMS: m / z 402.2 (M + H) + (ES +).
    [0642] [0642] Step C: carboxylic acid 3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1- methyl-1H-pyrazole-5 HOOC AT THE N S PMB N O N N S PMB O PMB N O PMB
    [0643] [0643] A solution of N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (100 g, 249.08 mmol, 1 eq) in THF (1.35 L) was cooled at -70 ° C. Then, n-BuLi (2.5 M, 104.61 mL, 1.05 eq) was added dropwise. The reaction mixture was stirred at -70 ° C for 1 hour, then CO2 (15 psi) was bubbled into the mixture for 15 minutes. The reaction mixture was stirred at -70 ° C for an additional 1 hour. The reaction mixture was stopped with H 2 O (1.2 L) and adjusted with aqueous HCl (1 M) to pH = 3. Then the mixture was extracted with EtOAc (2 x 1 L). The combined organic layers were washed with brine (2 × 1 L), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (300 ml, v: v = 1: 1) to produce the title compound (94 g, 84% yield, 99% purity in LCMS) as a white solid.
    [0644] [0644] 1H NMR (DMSO-d6): δ 6.98-7.16 (m, 5 H), 6.82 (d, 4 H), 4.25 (s, 4 H), 4.15 ( s, 3 H) and 3.72 (s, 6 H).
    [0645] [0645] LCMS: m / z 468.2 (M + Na) + (ES +).
    [0646] [0646] Step D: 3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -N, N-bis (2-methoxyethyl) - 1-methyl-1H-pyrazol-5-carboxamide MeO HOOC
    [0647] [0647] To a solution of 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazole-5 carboxylic acid (8 g, 17.96 mmol, 1 eq) in DMF (100 mL) HATU (10.24 g, 26.94 mmol, 1.5 eq), DIPEA (6.96 g, 53.87 mmol, 3 eq) and bis (2-methoxyethyl) amine (2.87 g , 21.55 mmol, 1.2 eq). The reaction mixture was stirred at 25 ° C for 1 hour. Then the reaction mixture was diluted with EtOAc (50 ml) and washed with saturated aqueous NH4Cl solution (3 x 50 ml) and brine (3 x 50 ml). The organic layer was dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (0.05% NH3.H2O-MeCN) to produce the title compound (8 g, 79%) as a red oil.
    [0648] [0648] 1H NMR (CD3OD): δ 7.05 (d, 4 H), 6.81-6.77 (m, 5 H), 4.29 (s, 4 H), 3.90 (s, 3 H), 3.79-3.72 (m, 8 H), 3.68-3.57 (m, 4 H), 3.48-3.46 (m, 2 H), 3.38 ( s, 3 H) and 3.27 (s, 3 H).
    [0649] [0649] LCMS: m / z 561.3 (M + H) + (ES +).
    [0650] [0650] Step E: N, N-Bis (2-methoxyethyl) -1-methyl-3-sulfamoyl-1H-pyrazol-5-carboxamide MeO MeO
    [0651] [0651] To a solution of 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -N, N-bis (2-methoxyethyl) -1-methyl-1H-pyrazol-5-carboxamide (8 g, 14 , 27 mmol, 1 eq) in DCM (50 ml) TFA (56 g, 491.13 mmol, 34.42 eq) was added. The reaction mixture was stirred at 25 ° C for 12 hours and then concentrated in vacuo. The residue was triturated with a mixture of EtOAc and PE (50 ml, v: v = 3: 2) to produce the title compound (4.0 g, 88%) as a white solid.
    [0652] [0652] 1H NMR (DMSO-d6): δ 7.50 (s, 2 H), 6.74 (s, 1 H), 3.84 (s, 3 H), 3.63 (t, 4 H ), 3.43-3.40 (m, 4 H), 3.28 (s, 3 H) and 3.18 (s, 3 H).
    [0653] [0653] Intermediate P36: N, N, 1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide
    [0654] [0654] Step A: 1-methyl-1H-pyrazol-3-sulfonyl chloride N N O
    [0655] [0655] A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (600 ml) at 0 ° C was treated with concentrated HCl (60 ml) and H 2O (60 mL). Then, an aqueous solution of NaNO2 (21.31 g, 308.90 mmol, 1.2 eq) in H2O (60 mL) was added slowly. The resulting mixture was stirred at 0 ° C for 40 minutes. AcOH (60 mL), CuCl2 (17.31 g, 128.71 mmol, 0.5 eq) and CuCl (1.27 g, 12.87 mmol, 307.78 µL, 0.05 eq) were added in Then, the SO 2 gas (15 psi) was bubbled into the mixture for 15 minutes at 0 ° C. The reaction mixture was concentrated in vacuo to remove most of the MeCN. Then, the reaction mixture was treated with H2O (2.5 L) and extracted with EtOAc (2 × 1.2 L). The combined organic layers were washed with brine (3 x 2 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography with silica gel (petroleum ether: ethyl acetate = 15: 1 to 5: 1) to produce the title compound (19 g, 41%) as a yellow oil.
    [0656] [0656] 1H NMR (CDCl3): δ 7.52 (d, 1 H), 6.89 (d, 1 H) and 4.07 (s, 3 H).
    [0657] [0657] Step B: N, N-Bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [0658] [0658] To a solution of bis (4-methoxybenzyl) amine (99.83 g, 387.96 mmol, 0.91 eq) in THF (1 L) was added TEA (86.28 g, 852.65 mmol, 118.68 ml, 2 eq), followed by 1-methyl-1H-pyrazol-3-sulfonyl chloride (77 g, 426.33 mmol, 1 eq). Then the reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated in vacuo to remove most of the THF. The reaction mixture was stopped by adding aqueous HCl (1 M, 500 ml) and then extracted with EtOAc (2 x 500 ml). The combined organic layers were washed with brine (2 × 600 ml), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (70 ml, v: v = 5: 1) to produce the title compound (138 mg, 81%) as a white solid.
    [0659] [0659] 1H NMR (CDCl3): δ 7.40 (d, 1 H), 7.08 (d, 4 H), 6.78 (d, 4 H), 6.65- 6.63 (m, 1 H), 4.32 (s, 4 H), 3.98 (s, 3 H) and 3.79 (s, 6 H).
    [0660] [0660] LCMS: m / z 402.2 (M + H) + (ES +).
    [0661] [0661] Step C: carboxylic acid 3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1- methyl-1H-pyrazole-5 HOOC AT THE N S PMB N O N N S PMB O PMB N O PMB
    [0662] [0662] A solution of N, N-bis (4-methoxybenzyl) -1-methyl-1H-pyrazol-3-sulfonamide (100 g, 249.08 mmol, 1 eq) in THF (1.35 L) at -70 ° C. Then, n-BuLi (2.5 M, 104.61 mL, 1.05 eq) was added dropwise. The reaction mixture was stirred at -70 ° C for 1 hour, then CO2 (15 psi) was bubbled into the mixture for 15 minutes. The reaction mixture was stirred at -70 ° C for an additional 1 hour. The reaction mixture was stopped with H 2 O (1.2 L) and adjusted with aqueous HCl (1 M) to pH = 3. Then the mixture was extracted with EtOAc (2 x 1 L). The combined organic layers were washed with brine (2 × 1 L), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (300 ml, v: v = 1: 1) to produce the title compound (94 g, 84% yield, 99% purity in LCMS) as a white solid.
    [0663] [0663] 1H NMR (DMSO-d6): δ 6.98-7.16 (m, 5 H), 6.82 (d, 4 H), 4.25 (s, 4
    [0664] [0664] LCMS: m / z 468.2 (M + Na) + (ES +).
    [0665] [0665] Step D: 3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazole-5-carboxamide HOOC N O AT THE N S PMB N O N N S PMB The N PMB O PMB
    [0666] [0666] To a solution of 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1-methyl-1H-pyrazole-5 carboxylic acid (100 g, 224.47 mmol, 1 eq), DIPEA (58 , 02 g, 448.95 mmol, 78.20 mL, 2 eq) and dimethylamine (2 M, 448.95 mL, 4 eq) in DMF (1 L) was added a solution of propylphosphonic anhydride in EtOAc (285.69 g, 448.95 mmol, 267.00 mL, 50% in EtOAc, 2 eq) at 25 ° C. Then, the reaction mixture was stirred for 30 minutes. The reaction mixture was stopped by adding H2O (2 L) and then extracted with EtOAc (2 x 1.1 L). The combined organic layers were washed with brine (2 × 1.2 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of EtOAc and petroleum ether (v: v = 5: 1, 150 ml) to produce the title compound (92.7 g, 87% yield, 100% purity in LCMS).
    [0667] [0667] 1H NMR (CDCl3): δ 7.09 (d, 4 H), 6.78 (d, 4 H), 6.63-6.70 (m, 1 H), 4.32 (s, 4 H), 4.02 (s, 3 H), 3.79 (s, 6 H) and 3.11 (d, 6 H).
    [0668] [0668] LCMS: m / z 473.3 (M + H) + (ES +).
    [0669] [0669] Step E: N, N, 1-Trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide N N O O N O O N
    [0670] [0670] To a solution of 3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazol-5-carboxamide (80 g, 169.29 mmol, 1 eq) in DCM (180 ml) TFA (381.33 g, 3.34 mol, 247.62 ml, 19.75 eq) was added. The reaction mixture was stirred at 15 ° C for 15 hours and then concentrated in vacuo. The residue was redissolved in dichloromethane (200 ml). The resulting solution was added to MeOH (1.2 L) and a solid precipitated. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was redissolved in dichloromethane (150 ml). Then, the resulting solution was added to methyl tert-butyl ether (700 ml) and a solid precipitated. The suspension was filtered and the filter cake was dried to produce the title compound (32 g, 81%) as a white solid.
    [0671] [0671] 1H NMR (DMSO-d6): δ 7.50 (s, 2 H), 6.81 (s, 1 H), 3.89 (s, 3 H) and 3.02 (d, 6 H ).
    [0672] [0672] LCMS: m / z 233.2 (M + H) + (ES +).
    [0673] [0673] Intermediate P37: ((1-cyclopropyl-1H-pyrazol-3-yl) sulfonyl) (4- (dimethylamino) pyridin-1-io-1-carbonyl) amide
    [0674] [0674] A mixture of 1-cyclopropyl-1H-pyrazol-3-sulfonamide (1.35 g, 7.21 mmol) and N, N-dimethylpyridin-4-amine (1.762 g, 14.42 mmol) in anhydrous MeCN (15 mL) was stirred at room temperature for 10 minutes. Then, diphenyl carbonate (1.70 g, 7.93 mmol) was added and the reaction was stirred for 16 hours. The obtained solid was collected by filtration and washed with MTBE (5 ml) to produce the title compound as a solid (1.57 g, 55%).
    [0675] [0675] 1H NMR (DMSO-d6) δ 8.82 - 8.63 (m, 2H), 7.81 (d, J = 2.3 Hz, 1H), 7.04 - 6.86 (m, 2H), 6.57 (d, J = 2.4 Hz, 1H), 3.76 (m, 1H), 3.25 (s, 6H), 1.07 - 1.01 (m, 2H), 1.00 - 0.95 (m, 2H).
    [0676] [0676] Intermediate P38: 1-Cyclobutyl-1H-pyrazol-3-sulfonamide
    [0677] [0677] Step A: 1- (lithium-tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfinate
    [0678] [0678] 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.
    [0679] [0679] 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).
    [0680] [0680] LCMS; m / z 215 (M-H) - (ES-).
    [0681] [0681] Step B: N, N-Bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-sulfonamide
    [0682] [0682] 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, interrupted 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.
    [0683] [0683] LCMS; m / z 494.2 (M + Na) + (ES +).
    [0684] [0684] Step C: N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
    [0685] [0685] A mixture of N, N-bis (4-methoxybenzyl) -1- (tetrahydro-2H-pyran-2-
    [0686] [0686] 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.
    [0687] [0687] LCMS: m / z 388 (M + H) + (ES +); 386 (M-H) - (ES-).
    [0688] [0688] Step D: 1-Cyclobutyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
    [0689] [0689] A solution of N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (5 g, 12.90 mmol) in DMF (60 mL) was cooled to 0 ° C, before the hydride sodium (0.671 g, 16.78 mmol) be added. The mixture was warmed to room temperature and stirred for 30 minutes, before the bromocyclobutane (1.3 ml, 13.81 mmol) was added slowly through a syringe. The resulting mixture was stirred at 50 ° C over the weekend. The mixture was diluted with EtOAc (100 ml). H2O (100 ml) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 100 ml) and the combined organic extracts were washed with brine (3 x 80 ml), passed through a phase separator and concentrated in vacuo. The residue was loaded onto silica and purified by chromatography (80 g column, 0-100% EtOAc / isohexane) to generate the title compound (4.72 g, 75%) as a pale yellow oil.
    [0690] [0690] 1H NMR (DMSO-d6) δ 8.03 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 4H), 6.81 (d, J = 8.6 Hz, 4H), 6.71 (d, J = 2.3 Hz, 1H), 4.94 (p, J = 8.4 Hz, 1H), 4.22 (s, 4H), 3.72 (s, 6H), 2.49 - 2.38 (m, 4H), 1.87 - 1.77 (m, 2H).
    [0691] [0691] LCMS; m / z 464.2 (M + Na) + (ES +).
    [0692] [0692] Step E: 1-Cyclobutyl-1H-pyrazol-3-sulfonamide
    [0693] [0693] 1-Cyclobutyl-N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (4.72 g, 10.69 mmol) was dissolved in TFA (5 mL) and DCM (5 mL) and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH / DCM) to generate the title compound (1.5 g, 66%) as a pale white solid.
    [0694] [0694] 1H NMR (DMSO-d6) δ 7.96 (d, J = 2.4 Hz, 1H), 7.39 (s, 2H), 6.59 (d, J = 2.4 Hz, 1H ), 4.96 - 4.86 (m, 1H), 2.50 - 2.44 (m, 2H), 2.44 - 2.36 (m, 2H), 1.85 - 1.77 (m , 2H).
    [0695] [0695] LCMS; m / z 202.0 (M + H) + (ES +).
    [0696] [0696] Intermediate P39: 1- (1- (Azetidin-1-yl) -2-methylpropan-2-yl) -1H-pyrazol-3-sulfonamide
    [0697] [0697] Step A: 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoate
    [0698] [0698] N, N-Bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (2.00 g, 5.16 mmol) (Intermediate P38, Step C) 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 brine (200 ml) and extracted with MTBE (2 x 50 ml). The combined organic layers were dried (MgSO 4), 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.
    [0699] [0699] 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).
    [0700] [0700] LCMS; m / z 511 (M + Na) + (ES +).
    [0701] [0701] Step B: 2- (3- (N, N-Bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoic acid
    [0702] [0702] 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 2 M 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.
    [0703] [0703] 1H NMR (CDCl3) δ 7.64 (d, J = 2.5 Hz, 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.
    [0704] [0704] LCMS; m / z 472 (M-H) - (ES-).
    [0705] [0705] Step C: 1- (1- (Azetidin-1-yl) -2-methyl-1-oxopropan-2-yl) -N, N-bis (4-methoxy benzyl) -1H-pyrazol-3- sulfonamide
    [0706] [0706]
    [0707] [0707] A mixture of 2- (3- (N, N-bis (4-methoxybenzyl) sulfamoyl) -1H-pyrazol-1-yl) -2-methylpropanoic acid (1.15 g, 2.234 mmol), base Hunig (1.557 ml, 8.91 mmol) and HATU (0.921 g, 2.422 mmol) in DMF (6.5 ml) was stirred at 0-5 ° C for 10 minutes. Then, azetidine HCl (0.272 g, 2.90 mmol) was added. The mixture was warmed to room temperature and stirred for 20 hours. Additional HATU (0.263 g, 1.117 mmol) was added, followed by Hunig's base (0.390 ml, 2.234 mmol). The mixture was cooled to 0-5 ° C for 10 minutes. Then, additional azetidine HCl (0.064 g, 1.117 mmol) was added. The mixture was allowed to warm to room temperature, stirred for another hour and then partitioned between TBME (75 ml) and water (40 ml). The organic layer was washed with 1M aq HCl (40 ml), water (25 ml), dried (MgSO4), filtered, evaporated and then purified by silica gel chromatography (120 g column, 0-100% TBME / isohexane column ) to generate the title compound (615 mg, 51%) as a clear gum.
    [0708] [0708] 1H NMR (CDCl3) δ 7.56 (d, J = 2.4 Hz, 1H), 7.13 - 7.09 (m, 4H), 6.80 - 6.76 (m, 5H) , 4.32 (s, 4H), 3.99 (t, J = 7.8 Hz, 2H), 3.79 (s, 6H), 3.23 (t, J = 7.7 Hz, 2H) , 2.08 - 2.01 (m, 2H), 1.78 (s, 6H).
    [0709] [0709] LCMS; m / z 513.1 (M + H) + (ES +).
    [0710] [0710] Step D: 1- (1- (Azetidin-1-yl) -2-methylpropan-2-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide
    [0711] [0711] BH3. THF (1 M in THF) (21.53 ml, 21.53 mmol) was added to a solution of 1- (1- (azetidin-1-yl) -2-methyl-1-oxopropan- 2-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (3.1537 g, 6.15 mmol) in THF (26.3 mL). The mixture was stirred for 3 minutes and then heated to reflux over the weekend. The reaction was allowed to cool to room temperature, before being placed in an ice bath. MeOH (50 ml) was added dropwise and the mixture was heated to 60 ° C for 3 hours and then allowed to cool to room temperature overnight. The mixture was concentrated under reduced pressure and loaded onto a SCX column (30 g) in MeOH (50 ml). The column was washed with MeOH (100 ml), 0.7 M ammonia in MeOH (100 ml) and then the product was eluted with 7 M ammonia in MeOH (100 ml). The resulting mixture was concentrated in vacuo to yield the title compound (2.89 g, 85%) as a colorless viscous oil.
    [0712] [0712] 1H NMR (DMSO-d6) δ = 7.98 (d, J = 2.5 Hz, 1H), 7.07 - 7.02 (m, 4H), 6.84 - 6.79 (m , 4H), 6.69 (d, J = 2.4 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 2.92 (t, J = 7.0 Hz , 4H), 2.68 (s, 2H), 1.84 (p, J = 7.0 Hz, 2H), 1.48 (s, 6H).
    [0713] [0713] LCMS; m / z 499.2 (M + H) + (ES +).
    [0714] [0714] Step E: 1- (1- (Azetidin-1-yl) -2-methylpropan-2-yl) -1H-pyrazol-3-sulfonamide
    [0715] [0715] 1- (1- (Azetidin-1-yl) -2-methylpropan-2-yl) -N, N-bis (4-methoxybenzyl) -1H-pyrazol-3-sulfonamide (2.89 g, 5 , 80 mmol) was dissolved in TFA (15 ml) and DCM (15 ml) and stirred overnight. Additional TFA (5 ml, 5.80 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, MeOH (50 ml) was added, the precipitate was removed by filtration and the filtrate was loaded onto an SCX column (30 g). The column was washed with MeOH (100 ml). The product was then eluted with 7N NH 3 in MeOH (100 ml) and concentrated in vacuo. The product was purified by silica gel chromatography (40 g column, 0-10% MeOH / DCM) to generate the title compound (1.06 mg, 69%) as a white solid.
    [0716] [0716] 1H NMR (DMSO-d6) δ 7.89 (d, J = 2.5 Hz, 1H), 7.34 (s, 2H), 6.54 (d, J = 2.4 Hz, 1H ), 2.94 (t, J = 7.0 Hz, 4H), 2.68 (s, 2H), 1.84 (p, J = 7.0 Hz, 2H), 1.47 (s, 6H ).
    [0717] [0717] LCMS; m / z 259.1 (M + H) + (ES +).
    [0718] [0718] Intermediate A1: 4-Fluoro-2-isopropyl-6- (pyridin-3-yl) aniline
    [0719] [0719] Step A: 2-Bromo-4-fluoro-6-iso-propylaniline
    [0720] [0720] N-Bromosuccinimide (5.64 g, 31.7 mmol) was added in portions to 4-fluoro-2-isopropylaniline (4.62 g, 30.2 mmol) in dichloromethane (72 mL) at 0 ° C . The resulting mixture was stirred at 0 ° C for 1 hour and then allowed to warm to room temperature for 21 hours. The reaction mixture was washed with an aqueous sodium hydroxide solution (2 M, 2 x 50 ml), dried (magnesium sulfate), 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% dichloromethane 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% dichloromethane / isohexane) to generate the title compound (4.99 g, 70% ) as a red oil.
    [0721] [0721] 1H NMR (CDCl3) δ 7.07 (dd, 1 H), 6.86 (dd, 1 H), 4.14 (s, 2 H), 2.93 (sep, 1 H) and 1 , 25 (d, 6 H).
    [0722] [0722] LCMS m / z 232.2 / 234.3 (M + H) + (ES +).
    [0723] [0723] Step B: 4-Fluoro-2-isopropyl-6- (pyridin-3-yl) aniline
    [0724] [0724] To a stirred degassed nitrogen mixture of 2-bromo-4-fluoro-6-iso-propylaniline (1.00 g, 4.27 mmol) was added pyridin-3-ylboronic acid (0.577 g, 4.69 mmol), [1,1′bis (di-phenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf) Cl2, 0.156 g, 0.213 mmol) and potassium carbonate (1.769 g, 12.80 mmol) in a mixture 10 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 Celite filter (10 g) and the filter cake was washed with ethyl acetate ( 2 x 30 mL). The filtrate was poured into water (50 mL) and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and 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% ethyl acetate / isohexane) to provide the title compound (273 mg, 27%) as a brown gum.
    [0725] [0725] 1H NMR (CDCl3) δ 8.70 (dd, 1 H), 8.63 (dd, 1 H), 7.82 (ddd, 1 H), 7.48 - 7.34 (m, 1 H), 6.94 (dd, 1 H), 6.70 (dd, 1 H), 2.93 (sept, 1 H), 3.98 - 2.44 (br s, 2 H) and 1, 29 (d, 6 H).
    [0726] [0726] LCMS m / z 231.1 (M + H) + (ES +).
    [0727] [0727] The following intermediates were synthesized following the general procedure for Intermediate A1: Intermediate Structure Analytical data io 1 H NMR (CDCl3) δ 7.68 (d, 1 H), 7.58 (d, 1 H), 6 , 86 (dd, 1 H), 6.78 (dd, 1 A2 H), 3.99 (s, 3 H), 3.74 (br s, 2 H), 4-Fluoro-2-isopropyl-6 - (1- 2.94 (sept, 1 H) and 1.29 (d, 6 H). Methyl-1H-pyrazol-4- (85 mg, 22%) yl) aniline 1 H NMR (CDCl3) δ 7 , 68 (s, 1 H), 7.20 (s, 1 H), 6.94 (dd, 1 H), 6.67 (dd, 1 H), 3.53 (s, 3 H), 2 , 94 - 2.82 (m, 1 H), A3 2.47 (s, 2 H) and 1.27 (d, 6 H). 4-Fluoro-2-isopropyl-6- (1- LCMS m / z 234.1 (M + H) + (ES +). Methyl-1H-imidazol-5- (56 mg, 13%) yl) aniline 1 H NMR (CDCl3) δ 7.50 - 7.32 (m, 5 H), 6.90 (dd, 1 H), 6.74 (dd, 1 H), 4.11 (br s, 2 H), 3.15 - 2.80 (m, 1 H) A4 and 1.29 (d, 6 H). 5-Fluoro-3-isopropyl- [1,1'-LCMS m / z 230.1 (M + H) + (ES +). biphenyl] -2-amine (161 mg, 82%)
    [0728] [0728] Intermediate A30: 4-Fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) aniline
    [0729] [0729] Step A: 2-Bromo-4-fluoro-6- (prop-1-en-2-yl) aniline
    [0730] [0730] The 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, then (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl methanesulfonate) [2- (2′-amino-1,1′-biphenyl)] palladium ( II)
    [0731] [0731] [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 provide the title compound ( 1.95 g, 43%) as an oil.
    [0732] [0732] 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).
    [0733] [0733] LCMS m / z 230.2 (M + H) + (ES +).
    [0734] [0734] Step B: 2- (3,6-Dihydro-2H-pyran-4-yl) -4-fluoro-6- (prop-1-en-2-yl) aniline
    [0735] [0735] 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 N, N-dimethylformamide (22 mL). The reaction mixture was heated under nitrogen at 100 ° C overnight and cooled before the residue was diluted with ethyl acetate (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% ethyl acetate / isohexanes)
    [0736] [0736] 1H NMR (CDCl3) δ 6.71 (dd, 1 H), 6.67 (dd, 1 H), 5.88 (m, 1 H), 5.35 - 5.31 (m, 1 H), 5.09 (m, 1 H), 4.32 (m, 2 H), 3.95 (t, 2 H), 3.82 (br s, 2 H), 2.42 (m, 2 H) and 2.09 - 2.07 (m, 3 H).
    [0737] [0737] Step C: 4-Fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) aniline
    [0738] [0738] 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 ethyl acetate (3.8 mL) was hydrogenated at 5 Bar for 1 hour. The mixture was filtered through Celite and evaporated to provide the title compound (340 mg, 91%).
    [0739] [0739] 1H NMR (CDCl3) δ 6.80 (dd, 1 H), 6.75 (dd, 1 H), 4.16 - 4.14 (m, 1 H), 4.13 - 4.10 (m, 1 H), 3.65 - 3.51 (m, 4 H), 3.01 - 2.89 (m, 1 H), 2.85 - 2.74 (m, 1 H), 1 , 86 - 1.78 (m, 4 H) and 1.28 (d, 6 H).
    [0740] [0740] LCMS m / z 238.1 (M + H) + (ES +).
    [0741] [0741] Intermediate A32: 4- (2-Amino-5-fluoro-3-isopropylphenyl) -N, N-dimethylpyridin-2-amine
    [0742] [0742] Step A: 4-Fluoro-2-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
    [0743] [0743] In an oven-dried, 2-bromo-4-fluoro-6-isopropylaniline round-bottom flask (3.0 g, 12.93 mmol), 4.4.4 ', 4', 5.5, 5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (8.21 g, 32.3 mmol), KOAc (4.44 g, 45.2 mmol) and Pd ( dppf) Cl 2. CH2Cl2 (2.11 g, 2.59 mmol) was added and the vessel was purged with nitrogen. Anhydrous 1,4-dioxane (86 mL) was added and the reaction was stirred at 110 ° C for 2 hours. Upon completion, the reaction mixture was diluted with water,
    [0744] [0744] 1H NMR (CDCl3) δ 7.21 (dd, J = 8.7, 3.1 Hz, 1H), 6.96 (dd, J = 10.0, 3.1 Hz, 1H), 4 , 72 (bs, 2H), 2.93 - 2.82 (m, 1H), 1.37 (s, 12H), 1.26 (d, J = 6.8 Hz, 6H).
    [0745] [0745]
    [0746] [0746] Step B: 4- (2-Amino-5-fluoro-3-isopropylphenyl) -N, N-dimethylpyridin-2-amine
    [0747] [0747] 4-Fluoro-2-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.379 g, 1.356 mmol), 4-bromo-N , N-dimethylpyridin-2-amine (0.3 g, 1.49 mmol) and potassium carbonate (0.6 g, 4.34 mmol) were suspended in a mixture of dioxane (10 mL) and water (1 mL ). After degassing with nitrogen for 15 minutes, Pd (dppf) Cl2. CH2Cl2 (0.055 g, 0.068 mmol) was added and the mixture was heated to 75 ° C for 1 hour. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 ml) and water (5 ml). The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo to provide a brown oil. The crude product was purified by chromatography on silica (24 g column, 0-60% EtOAc / isohexane) to provide the title compound (201 mg, 49%) as an orange oil.
    [0748] [0748] 1H NMR (CDCl3) δ 8.27 (d, J = 5.6 Hz, 1H), 6.96 (dd, J = 9.9, 3.0 Hz, 1H), 6.79 - 6 , 72 (m, 2H), 6.69 (s, 1H), 3.70 (s, 2H), 3.26 (s, 6H), 2.94 (sept, J = 7.0 Hz, 1H) , 1.31 (d, J = 6.8 Hz, 6H).
    [0749] [0749] LCMS m / z 274.4 (M + H) + (ES +); 272.8 (M-H) - (ES-).
    [0750] [0750] Intermediate A33: 4-Fluoro-2-isopropyl-6- (2- (prop-1-in-1-yl) pyridin-4-yl) aniline
    [0751] [0751] The title compound was prepared according to the procedure for 4- (2-amino-5-fluoro-3-isopropylphenyl) -N, N-dimethylpyridin-2-amine (Intermediate A32) (218 mg, 57% ).
    [0752] [0752] 1H NMR (CDCl3) δ 8.63 (d, J = 5.3 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 5.3 Hz, 1H), 6.97 (dd, J = 9.9, 2.9 Hz, 1H), 6.72 (dd, J = 8.5, 3.0 Hz, 1H), 4.30 - 2.50 (br s , 2H), 2.93 (sept, J = 6.6 Hz, 1H), 2.14 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H).
    [0753] [0753] LCMS m / z 269.3 (M + H) + (ES +); 267.2 (M-H) - (ES-).
    [0754] [0754] Intermediate A34: 7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
    [0755] [0755] Step A: N- (7-Fluoro-2,3-dihydro-1H-inden-4-yl) pivalamide
    [0756] [0756] To a solution of N- (2,3-dihydro-1H-inden-4-yl) pivalamide (2.5 g, 11.50 mmol) cooled on ice in dry dichloromethane (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 dichloromethane (10 mL) was then slowly added over 10 minutes to the mixture. 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 entire mixture was absorbed on silica gel and purified by silica gel chromatography (120 g column, 0-30% EtOAc / isohexane) to provide the title compound (0.635 g, 22%) as a yellow crystalline solid.
    [0757] [0757] 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).
    [0758] [0758] LCMS m / z 236.3 (M + H) + (ES +); 234.2 (M-H) - (ES-).
    [0759] [0759] Step B: 7-Fluoro-2,3-dihydro-1H-inden-4-amine
    [0760] [0760] 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% aq) (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 2M aq. The mixture was extracted with dichloromethane (3 x 100 ml). The combined organics were washed, dried by passing through a hydrophobic frit and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc / isohexane) to provide the title compound (350 mg, 82%) as a pale pink oil which solidified on standing.
    [0761] [0761] 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).
    [0762] [0762] LCMS m / z 152.3 (M + H) + (ES +).
    [0763] [0763] Step C: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine
    [0764] [0764] 7-Fluoro-2,3-dihydro-1H-inden-4-amine (345 mg, 2.282 mmol) was dissolved in dichloromethane (10 ml). NBS (450 mg, 2.53 mmol) was added at room temperature in a single portion. The mixture immediately turned dark brown and was stirred for 15 minutes at room temperature. The reaction mixture was partitioned between hydrochloride and 1M aq. (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 obtain a dark brown oil. The crude product was purified by chromatography on silica gel (24 g column, 0-20% EtOAc / isohexane) to provide the title compound (323 mg, 55%) as a dark purple oil.
    [0765] [0765] 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.
    [0766] [0766] Step D: 7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
    [0767] [0767] 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (320 mg, 1.391 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (600 mg, 4.34 mmol) in water (1 mL) and solid boronic acid (2-methoxypyridin-4-yl) (250 mg, 1.635 mmol) was added. The mixture was degassed with nitrogen for 15 minutes before Pd (dppf) Cl2. CH2Cl2 (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 ° C (bath temperature) for 24 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (30 ml) and water (20 ml). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to obtain a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc / isohexane) to provide the title compound (0.185 g, 49%) as a pale brown oil which crystallized on standing.
    [0768] [0768] 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,
    [0769] [0769] LCMS m / z 259.3 (M + H) + (ES +).
    [0770] [0770] Intermediate A35: 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
    [0771] [0771] Step A: N- (5-Bromo-2,3-dihydro-1H-inden-4-yl) pivalamide
    [0772] [0772] 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 aq. NaHCO3 (2 x 10 ml), water (2 x 10 ml) and brine (10 ml). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give a dark green amorphous solid. The crude product was purified by silica gel chromatography (40 g column, 0-30% EtOAc / isohexane) to provide the title compound (1.662 g, 100%) as a colorless crystalline solid that was contaminated with a small amount by-products of the reaction.
    [0773] [0773] LCMS m / z 296.3 / 298.3 (M + H) + (ES +).
    [0774] [0774] Step B: 5-Bromo-2,3-dihydro-1H-inden-4-amine
    [0775] [0775] 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. H 2SO4 (95% aq) (5 ml, 89 mmol) was added slowly to water (5 ml) and this mixture was then added to the reaction mixture. The paste was heated to 100 ° C (bath temperature), at which point the mixture became homogeneous and was stirred at this temperature throughout the week. The mixture was cooled to room temperature and then basified with 2M aq. NaOH. The mixture was extracted with dichloromethane (3 x 20 ml). The organic phase was dried by passing through a hydrophobic frit and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc / isohexane) to provide the title compound (0.138 g, 29%).
    [0776] [0776] 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).
    [0777] [0777] Step C: 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
    [0778] [0778] 5-Bromo-2,3-dihydro-1H-inden-4-amine (280 mg, 1.320 mmol) was dissolved in dioxane (5 ml). A solution of potassium carbonate (600 mg, 4.34 mmol) in water (1 mL) and boronic acid (2-methoxypyridin-4-yl) (250 mg, 1.635 mmol) was added. The mixture was degassed with nitrogen for 15 minutes before Pd (dppf) Cl2. CH2Cl2 (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 ° C (bath temperature) for 2 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (30 ml) and water (20 ml). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to obtain a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc / isohexane) to provide the title compound (0.289 g, 87%) as a pale yellow crystalline solid.
    [0779] [0779] 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.
    [0780] [0780] LCMS m / z 241.3 (M + H) + (ES +).
    [0781] [0781] Intermediate A36: 4- (4-Amino-2,3-dihydro-1H-inden-5-yl) picolinonitrile
    [0782] [0782] Prepared according to the general procedure of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35, Step C) from 5- bromo-2,3-dihydro-1H-inden-4-amine (Intermediate A35, Step B) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) picolinonitrile to provide the title compound (215 mg, 61%) as a pale yellow solid.
    [0783] [0783] 1H (DMSO-d6) δ 8.72 (dd, J = 5.1, 0.8 Hz, 1H), 8.03 (dd, J = 1.8, 0.8 Hz, 1H), 7.74 (dd, J = 5.1, 1.8 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H ), 4.94 (s, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H).
    [0784] [0784] LCMS: m / z 236.3 (M + H) + (ES +).
    [0785] [0785] Intermediate A37: 4- (5-fluoro-2-isocyanate-3 isopropylphenyl) picolinonitrile
    [0786] [0786] Step A: 4-Fluoro-2- (prop-1-en-2-yl) aniline NH2 NH2 Br
    [0787] [0787] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K2CO3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H2O (40 mL) Pd (dppf) Cl2 (7.51 g, 10.26 mmol, 0.05 eq) was added under a nitrogen atmosphere. Then the reaction mixture was stirred at 80 ° C for 5 hours. The reaction mixture was quenched by adding H 2O (600 ml) and extracted with EtOAc (2 × 500 ml). The combined organic layers were washed with brine (2 × 600 ml), dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate 1: 0 to 100: 1) to obtain the title compound (27 g, 77% yield, 89% purity in LCMS)
    [0788] [0788] 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).
    [0789] [0789] LCMS: m / z 152.2 (M + H) + (ES +).
    [0790] [0790] Step B: 4-Fluoro-2-isopropylaniline NH2 NH2 F F
    [0791] [0791] To a solution of 4-fluoro-2- (prop-1-en-2-yl) aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd / C (2 , 1 g, 178.59 mmol, 10% by weight of activated carbon charge) under a nitrogen atmosphere. The reaction mixture was degassed in vacuo and purged with hydrogen several times. The reaction mixture was stirred at 25 ° C for 12 hours under hydrogen (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the title compound (20 g, crude) as a yellow oil.
    [0792] [0792] 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).
    [0793] [0793] LCMS: m / z 154.2 (M + H) + (ES +).
    [0794] [0794] Step C: 2-Bromo-4-fluoro-6-isopropylaniline NH2 NH2 Br F F
    [0795] [0795] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 ml) was added NBS (23.24 g, 130.55 mmol, 1 eq) to 25 ° C. The reaction mixture was stirred at 25 ° C for 10 minutes. The reaction mixture was poured into H2O (300 ml) and extracted with EtOAc (2 x 250 ml). The combined organic phases were washed with brine (2 x 400 ml), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, eluting only using petroleum ether) to obtain the title compound (30 g, 99%) as a black brown oil.
    [0796] [0796] 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).
    [0797] [0797] LCMS: m / z 232.1 (M + H) + (ES +).
    [0798] [0798] Step D: 4- (2-Amino-5-fluoro-3-isopropylphenyl) picolinonitrile NH2 F Br O O + B H2N F NC N NC N
    [0799] [0799] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (3.6 g, 15.51 mmol, 1 eq) and 4- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) picolinonitrile (3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 ml) and H 2O (9 ml) Na2CO3 (4.11 g, 38, 78 mmol, 2.5 eq). Then, Pd (dppf) Cl2 (1.13 g, 1.55 mmol, 0.1 eq) was added to the mixture under an atmosphere of nitrogen. The resulting mixture was stirred at 80 ° C for 2 hours under nitrogen. Then the mixture was concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 20: 1 to 5: 1) and then triturated with petroleum ether (10 mL) to obtain the title compound (2 , 65 g, 65% yield, 97% purity in LCMS) as a yellow solid.
    [0800] [0800] 1HNMR (CDCl3) δ 8.79 (d, 1 H), 7.86 (d, 1 H), 7.65 (dd, 1 H), 6.99 (dd, 1 H), 6, 70 (dd, 1 H), 3.63 (br s, 2 H), 2.98-2.87 (m, 1 H) and 1.30 (d, 6 H).
    [0801] [0801] LCMS: m / z 256.2 (M + H) + (ES +).
    [0802] [0802] Step E: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) picolinonitrile
    [0803] [0803] To a solution of 4- (2-amino-5-fluoro-3-isopropylphenyl) picolinonitrile (1 g, 3.92 mmol, 1 eq) in THF (40 mL) was added TEA (793 mg, 7, 83 mmol, 2 eq). To the above mixture, triphosgene (465 mg, 1.57 mmol, 0.4 eq) was added in portions at 5 ° C. Then the mixture was stirred at 70 ° C for 1 hour. The mixture was diluted with EtOAc (200 ml) and then filtered through silica gel. The filtrate was concentrated in vacuo to obtain the title compound (1.2 g, crude) as a yellow solid, which was used directly in the next step.
    [0804] [0804] Intermediate A38: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) -2-methoxypyridine
    [0805] [0805] Step A: 4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) aniline NH2 F
    [0806] [0806] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (12 g, 51.70 mmol, 1 eq) in dioxane (240 ml) and H2O (48 ml) was added acid (2-methoxypyridin- 4-yl) boronic acid (9.49 g, 62.04 mmol, 1.2 eq) and Na2CO3 (13.70 g, 129.26 mmol, 2.5 eq). The reaction mixture was purged with nitrogen three times. Then, Pd (dppf) Cl2 (3.78 g, 5.17 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The mixing result was heated to 80 ºC for 2 hours. The reaction mixture was quenched with H2O (800 ml) and extracted with EtOAc (2 x 600 ml). The combined organic layers were washed with brine (2 × 800 ml), dried over filtered Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 70: 1 to 10: 1) and then triturated with hexane (100 mL) to obtain the title compound (10.05 72% yield, 96% purity in LCMS).
    [0807] [0807] 1H NMR (CDCl3) δ 8.24 (d, 1 H), 6.97 (d, 1 H), 6.93 (d, 1 H), 6.83 (s, 1 H), 6 , 73-6.70 (m, 1 H), 3.99 (s, 3 H), 3.66 (br s, 2 H), 2.97-2.89 (m, 1 H) and 1, 29 (dd, 6 H).
    [0808] [0808] LCMS: m / z 261.1 (M + H) + (ES +).
    [0809] [0809] Step B: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) -2-methoxypyridine
    [0810] [0810] To a solution of 4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) aniline (1 g, 3.84 mmol, 1 eq) in THF (40 mL) was added TEA (777 mg, 7.68 mmol, 2 eq). Then, triphosgene (456 mg, 1.54 mmol, 0.4 eq) was added in portions at 5 ° C. The mixture was stirred at 70 ° C for 1 hour. The mixture was diluted with EtOAc (200 ml) and filtered through silica gel. The filtrate was concentrated in vacuo to obtain the title compound (1.1 g, crude) as a yellow oil, which was used directly in the next step.
    [0811] [0811] Intermediate A39: 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine H2 N OCN O N O N
    [0812] [0812] To a solution of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL) was added in portions of bis (trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) at 0 ° C. Then the reaction mixture was stirred at 16 ° C for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to obtain the title compound (9.04 g, 74%) as a light yellow solid.
    [0813] [0813] 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).
    [0814] [0814] Intermediate A40: 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine
    [0815] [0815] Step A: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-one
    [0816] [0816] To a mixture of 7-fluoro-2,3-dihydro-1H-inden-1-one (9.5 g, 63.27 mmol, 1 eq) in concentrated H2SO4 (100 mL) was added dropwise drop a solution of HNO3 (5.37 mL, 82.25 mmol, 69% by weight of water, 1.3 eq) in
    [0817] [0817] 1H NMR (CDCl3) δ 8.51 (dd, 1 H), 7.22 (t, 1 H), 3.69-3.65 (m, 2 H) and 2.88-2.82 (m, 2 H).
    [0818] [0818] Step B: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol
    [0819] [0819] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one (30 g, 153.73 mmol, 1 eq) in EtOH (450 mL) was added NaBH4 (11.63 g, 307.46 mmol, 2 eq) in portions. The reaction mixture was stirred at 15 ° C for 1 hour. Then, the mixture was poured into water (500 ml) and extracted with DCM (2 x 200 ml). The combined organic phases were washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain the title compound (30 g, crude) as brown oil.
    [0820] [0820] 1H NMR (CDCl3) δ 8.21 (dd, 1 H), 7.08 (t, 1 H), 5.59-5.56 (m, 1 H), 3.66-3.59 (m, 1 H), 3.44-3.39 (m, 1 H), 2.56-2.51 (m, 1 H) and 2.22-2.17 (m, 2 H).
    [0821] [0821] Step C: 4-Fluoro-7-nitro-2,3-dihydro-1H-indene
    [0822] [0822] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol (4.5 g, 22.82 mmol, 1 eq) in TFA (20 mL) Et3SiH (7.96 g, 68.47 mmol, 3 eq) was added in one portion. The reaction mixture was stirred for 12 hours at 25 ° C. Then, the mixture was quenched with water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with saturated aqueous NaHCO3 solution (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain the title compound (5 g, crude) as brown oil.
    [0823] [0823] 1H NMR (CDCl3) δ 8.06 (dd, 1 H), 7.01 (t, 1 H), 3.46 (t, 2 H), 3.04 (t, 2 H) and 2 , 25-2.20 (m, 2 H).
    [0824] [0824] Step D: 7-Fluoro-2,3-dihydro-1H-inden-4-amine
    [0825] [0825] To a mixture of 4-fluoro-7-nitro-2,3-dihydro-1H-indene (5 g, 27.60 mmol, 1 eq) in MeOH (50 mL) was added Pd / C ( 0.5 g, 10 wt% loading on activated carbon) at 25 ° C under a nitrogen atmosphere. Then, the reaction mixture was stirred at 25 ° C for 12 hours under hydrogen (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate, 50: 1 to 10: 1) to obtain the title compound (1.8 g, 43%) as a brown solid .
    [0826] [0826] 1H NMR (CDCl3) δ 6.69 (t, 1 H), 6.44 (dd, 1 H), 3.47 (br s, 2 H), 2.95 (t, 2 H), 2.75 (t, 2 H) and 2.19-2.11 (m, 2 H).
    [0827] [0827] Step E: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine
    [0828] [0828] To a solution of 7-fluoro-2,3-dihydro-1H-inden-4-amine (8.3 g, 54.90 mmol, 1 eq) in toluene (100 mL) was added NBS ( 10.26 g, 57.65 mmol, 1.05 eq) in a portion at 25 ° C. The reaction mixture was immediately dark brown and then the mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was quenched with saturated aqueous Na2SO3 solution (200 ml) and extracted with EtOAc (2 x 100 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 1: 0 to 20: 1) to obtain the title compound (8.51 g, 67%) as a brown solid .
    [0829] [0829] 1H NMR (CDCl3) δ 6.99 (d, 1 H), 3.81 (br s, 2 H), 2.92 (t, 2 H), 2.78 (t, 2 H) and 2.21 - 2.13 (m, 2 H).
    [0830] [0830] Step F: 7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
    [0831] [0831] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (3.5 g, 15.21 mmol, 1 eq) and pyridin-4- acid ilboronic (1.96 g, 15.97 mmol, 1.05 eq) in dioxane (50 ml) and H2O (5 ml) was added K2CO3 (6.31 g, 45.64 mmol, 3 eq) and Pd (dppf ) Cl2 (1.11 g, 1.52 mmol, 0.1 eq) in one portion under a nitrogen atmosphere. The reaction mixture was heated to 80 ° C for 12 hours. The reaction mixture was filtered. The filtrate was diluted with water (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 10: 1 to 2: 1) to obtain the title compound (1.7 g, 45% yield, 90, 98% HPLC purity) as a brown solid.
    [0832] [0832] 1H NMR (CDCl3) δ 8.68 (dd, 2 H), 7.40 (dd, 2 H), 6.72 (d, 1 H), 3.76 (br s, 2 H), 3.01 (t, 2 H), 2.80 (t, 2 H) and 2.26-2.18 (m, 2 H).
    [0833] [0833] Step G: 4- (7-Fluoro-4-Isocyanato-2,3-dihydro-1H-inden-5-yl) pyridine
    [0834] [0834] To a solution of 7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (400 mg, 1.75 mmol, 1 eq) and TEA (355 mg, 3.50 mmol, 2eq) in THF (30 ml) bis (trichloromethyl) carbonate (208 mg, 700.94 μmol, 0.4 eq) was added at 0 ° C. The reaction mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was filtered through a silica gel filter and the filter cake was washed with THF (20 ml). The filtrate was concentrated in vacuo to reduce to
    [0835] [0835] Intermediate A41: 3- (5-Fluoro-2-isocyanato-3-isopropylphenyl) pyridine
    [0836] [0836] Step A: 4-Fluoro-2-isopropyl-6- (pyridin-3-yl) aniline NH2 F Br O O + B H2N F N N
    [0837] [0837] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (21 g, 90.48 mmol, 1 eq) in dioxane (450 ml) and H2O (90 ml) was added 3- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (22.26 g, 108.58 mmol, 1.2 eq) and Na2CO3 (23.98 g, 226.20 mmol, 2 , 5 eq). The reaction mixture was purged with nitrogen three times. Then, Pd (dppf) Cl2 (5.10 g, 6.97 mmol, 0.077 eq) was added under an atmosphere of nitrogen. The resulting mixture was heated to 80 ° C and stirred for 2 hours. The reaction mixture was quenched by adding H 2 O (800 ml) and extracted with EtOAc (2 × 600 ml). The combined organic layers were washed with brine (2 × 800 ml), dried over filtered Na 2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (SiO2, petroleum ether: ethyl acetate, 50: 1 to 1: 1) and then triturated with hexane (40 mL) to obtain the title compound (17 g, 82 %) as a gray solid.
    [0838] [0838] 1H NMR (CDCl3) δ 8.70 (d, 1 H), 8.63 (dd, 1 H), 7.79 (dd, 1 H), 7.41- 7.38 (m, 1 H), 6.94 (dd, 1 H), 6.71 (dd, 1 H), 3.57 (s, 2 H), 2.97-2.88 (m, 1 H) and 1.30 (d, 6 H).
    [0839] [0839] LCMS: m / z 231.2 (M + H) + (ES +).
    [0840] [0840] Step B: 3- (5-Fluoro-2-isocyanato-3-isopropylphenyl) pyridine
    [0841] [0841] To a solution of 4-fluoro-2-isopropyl-6- (pyridin-3-yl) aniline (0.5 g, 2.17 mmol, 1 eq) and TEA (439 mg, 4.34 mmol, 2 eq) in THF (10 mL) triphosgene (257 mg, 868.51 µmol, 0.4 eq) was added in portions at 5 ° C. Then the reaction mixture was heated to 70 ° C and stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was treated with EtOAc (100 ml) and filtered. The filtrate was concentrated in vacuo to obtain the title compound (0.2 g, crude) as a yellow oil, which was used directly in the next step.
    [0842] [0842] Intermediate A42: 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine
    [0843] [0843] Step A: 7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine HO OH F
    [0844] [0844] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (Intermediate A40, Step E) (8.5 g, 36.94 mmol, 1 eq ) and boronic acid (2-methoxypyridin-4-yl) (5.93 g, 38.79 mmol, 1.05 eq) in dioxane (150 ml) and water (15 ml) were added K2CO3 (15.32 g, 110.83 mmol, 3 eq) and Pd (dppf) Cl2 (2.70 g, 3.69 mmol, 0.1 eq) in one portion under nitrogen. The reaction mixture was heated to 80 ° C and stirred for 12 hours. The reaction mixture was quenched with water (300 ml) and extracted with EtOAc (3 x 300 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether: EtOAc, 1: 0 to 10: 1) and then purified by trituration with a mixture of TBME and n-hexane (50 ml, 1:20) to obtain the title compound (5.06 g, 52% yield, 97.44% LCMS purity) as an off-white solid.
    [0845] [0845] 1H NMR (CDCl3) δ 8.23 (d, 1 H), 6.99 (dd, 1 H), 6.86 (s, 1 H), 6.71 (d, 1 H), 3 , 99 (s, 3 H), 3.67 (br s, 2 H), 3.00 (t, 2 H), 2.79 (t, 2 H) and 2.25-2.17 (m, 2 H).
    [0846] [0846] Step B: 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine
    [0847] [0847] To a solution of phosgene (1.5 mL, 20 wt% toluene, 2.9 mmol) in toluene (40 mL) was added dropwise a solution of 7-fluoro-5- (2-methoxypyridine) -4-yl) -2,3-dihydro-1H-inden-4-amine (300 mg, 1.16 mmol) in toluene (20 mL) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, was concentrated in vacuo to provide the title compound as a brown oil (325 mg, 98%). The crude product was used directly in the next step without further purification.
    [0848] [0848] 1H NMR (CDCl3) δ 8.24 (d, 1H), 6.95 (dd, 1H), 6.88 (s, 1H), 6.85 - 6.75 (m, 1H), 4 .00 (s, 3H), 3.15 - 2.95 (m, 4H), 2.32 - 2.12 (m, 2H).
    [0849] [0849] Intermediate A43: 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) picolinonitrile
    [0850] [0850] To a solution of phosgene (1.7 ml, 20 wt% toluene, 3.2 mmol) in toluene (40 ml) was added dropwise a solution of 4- (4-amino-2,3 -dihydro-1H-inden-5-yl) picolinonitrile (Intermediate A36) (300 mg, 1.3 mmol) in toluene (20 mL) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling, was concentrated in vacuo to provide the title compound as a brown oil (333 mg, 100%). The crude product was used directly in the next step without further purification.
    [0851] [0851] 1H NMR (CDCl3) δ 8.75 (dd, 1H), 7.81 (dd, 1H), 7.63 (dd, 1H), 7.22 - 7.08 (m, 2H), 3 , 04 (m, 4H), 2.23 (m, 2H).
    [0852] [0852] Intermediate A44: 4- (4-Isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine
    [0853] [0853] Step A: 5- (Pyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
    [0854] [0854] The 5-bromo-2,3-dihydro-1H-inden-4-amine (1.2 g, 5.7 mmol) was dissolved in dioxane (25 ml). A solution of potassium carbonate (3.1 g, 23 mmol) in water (6 mL) and pyridin-4-ylboronic acid (0.83 g, 6.8 mmol) was added. The mixture was degassed with nitrogen for 20 minutes before Pd (dppf) Cl2. DCM (0.74 g, 0.91 mmol) was added. The reaction mixture was heated to 77 ° C for 2 hours. Then, the mixture was cooled to room temperature and filtered over Celite with DCM (100 ml) and water (25 ml). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to provide a brown oil (3.3g). The crude product was purified by silica gel chromatography (80 g column, 0-100% EtOAc / heptane) to provide the title compound (0.75 g, 63%) as a pale yellow crystalline solid.
    [0855] [0855] 1H NMR (CDCl3) δ 8.72 - 8.54 (m, 2H), 7.50 - 7.37 (m, 2H), 6.97 (d, 1H), 6.78 (d, 1H), 3.72 (s, 2H), 2.96 (t, 2H), 2.77 (t, 2H), 2.18 (m, 2H).
    [0856] [0856] Step B: 4- (4-Isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine
    [0857] [0857] To a solution of phosgene (1.1 mL, 20 wt% toluene, 2.06 mmol) in toluene (40 mL) was added dropwise a solution of 5- (pyridin-4-yl) - 2,3-dihydro-1H-inden-4-amine (175 mg, 0.83 mmol) in toluene (20 mL) at room temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and, after cooling to room temperature, a yellow precipitate formed. The solid was filtered and dried in vacuo to provide the title compound as a yellow solid (145 mg, 74%). The crude product was used directly in the next step without further purification.
    [0858] [0858] 1H NMR (CDCl3) δ 8.76 (d, 2H), 8.04 (d, 2H), 7.26 - 7.08 (m, 2H), 3.08 (t, 4H), 2 , 26 (m, 2H).
    [0859] [0859] Intermediate A45: 4- (6-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine
    [0860] [0860] Step A: 6-Bromo-2,3-dihydro-1H-inden-5-amine Br NH2 NH2
    [0861] [0861] To a solution of 2,3-dihydro-1H-inden-5-amine (10.6 g, 79.59 mmol, 1 eq) in toluene (150 mL) was added NBS (17.00 g , 95.50 mmol, 1.2 eq) in portions and then the mixture was stirred at 25 ° C for 12 hours. The reaction mixture was quenched with saturated aqueous Na 2SO3 solution (100 ml) and then extracted with EtOAc (3 x 150 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate, 1: 0 to 20: 1) to obtain the title compound (9.5 g, 56%) as a brown solid .
    [0862] [0862] 1H NMR (CDCl3): δ 7.15 (s, 1 H), 6.56 (s, 1 H), 3.72 (br s, 2 H), 2.70-2.61 (m , 4 H) and 1.95-1.85 (m, 2 H).
    [0863] [0863] Step B: 6- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-5-amine B (OH) 2
    [0864] [0864] To a solution of 6-bromo-2,3-dihydro-1H-inden-5-amine (1 g, 4.72 mmol, 1 eq) and boronic acid (2-methoxypyridin-4-yl) (793 mg, 5.19 mmol, 1.1 eq) in dioxane (15 ml) and H2O (2 ml) K2CO3 (1.95 g, 14.15 mmol, 3 eq) and Pd (dppf) Cl2 ( 345 mg, 471.51 µmol, 0.1 eq) in one portion under N2. The reaction mixture was heated to 80 ° C and stirred for 2 hours. The reaction mixture was washed with water (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (20 ml), dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO2, petroleum ether: ethyl acetate, 15: 1 to 10: 1) to obtain the title compound (556.4 mg, 49%) as a yellow solid .
    [0865] [0865] 1H NMR (CDCl3): δ 8.24 (d, 1 H), 7.05 (d, 1 H), 7.03 (s, 1 H), 6.85 (s, 1 H), 6.71 (s, 1 H), 3.96 (s, 3 H), 2.92-2.76 (m, 4 H) and 2.15-2.05 (m, 2 H).
    [0866] [0866] Step C: 4- (6-isocyanate-2,3-dihydro-1H-5-yl) -2-methoxypyridine NH2 NCO NINTH
    [0867] [0867] To a solution of 6- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-5-amine (200 mg, 832.29 µmol, 1 eq) and TEA (168 mg, 1.66 mmol, 2 eq) in THF (2 mL) triphosgene (99 g, 332.92 µmol, 0.4 eq) was added at 0 oC. Then, the reaction mixture was heated to 70 ° C for 1 hour. The reaction mixture was filtered through silica gel and washed with THF (50 ml). Then, the filtrate was concentrated in vacuo to obtain the title compound (246 mg, crude) as a light yellow solid, which was used directly in the next step.
    [0868] [0868] Intermediate A46: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) -2-isopropoxypyridine
    [0869] [0869] Step A: 4-Fluoro-2- (prop-1-en-2-yl) aniline NH2 NH2 Br
    [0870] [0870] 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
    [0871] [0871] 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).
    [0872] [0872] LCMS: m / z 152.2 (M + H) + (ES +).
    [0873] [0873] Step B: 4-Fluoro-2-isopropylaniline NH2 NH2 F F
    [0874] [0874] 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.
    [0875] [0875] 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).
    [0876] [0876] LCMS: m / z 154.2 (M + H) + (ES +).
    [0877] [0877] Step C: 2-Bromo-4-fluoro-6-isopropylaniline NH2 NH2 Br F F
    [0878] [0878] 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.
    [0879] [0879] 1H NMR (CDCl3): δ 6.99 (dd, 1 H), 6.78 (dd, 1 H), 3.91 (br s, 2 H),
    [0880] [0880] LCMS: m / z 232.1 (M + H) + (ES +).
    [0881] [0881] Step D: 4-Bromo-2-isopropoxypyridine Br Br Cl N O N
    [0882] [0882] 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2, petroleum ether: ethyl acetate = 50: 1 to 40: 1) to obtain the title compound (22 g, 98%) as a yellow oil.
    [0883] [0883] 1H NMR (CDCl3): δ 7.96 (d, 1 H), 6.98 (dd, 1 H), 6.89 (d, 1 H), 5.44 - 5.24 (m, 1 H) and 1.34 (d, 6 H).
    [0884] [0884] Step E: 2-Isopropoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine Br O O B The N The N
    [0885] [0885] 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 obtain the title compound (22 g, 95%) as a yellow oil.
    [0886] [0886] 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).
    [0887] [0887] LCMS: m / z 264.2 (M + H) + (ES +).
    [0888] [0888] Step F: 4-Fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropylaniline NH2 F Br O O H2N F O N N O
    [0889] [0889] 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.
    [0890] [0890] 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).
    [0891] [0891] LCMS: m / z 289.2 (M + H) + (ES +).
    [0892] [0892] Step G: 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) -2-isopropoxypyridine F
    [0893] [0893] 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.
    [0894] [0894] Intermediate A47: 7-Cyclopropyl-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
    [0895] [0895] Step A: 7-Bromo-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine
    [0896] [0896] NBS (389 mg, 2.185 mmol) was added to a mixture of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) (500 mg, 2.081 mmol) in CHCl3 (5 ml) with cooling in an ice bath. The resulting solution was stirred at room temperature for 16 hours, washed with 10% sodium thiosulfate solution (20 ml), brine (10 ml), dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-30% EtOAc / isohexane) to provide the title compound (400 mg, 57%) as a brownish solid.
    [0897] [0897] 1H NMR (DMSO-d6) δ 8.20 (d, J = 5.3 Hz, 1H), 7.04 - 6.97 (m, 2H), 6.80 (d, J = 1, 3 Hz, 1H), 4.84 (s, 2H), 3.89 (s, 3H), 2.83 (q, J = 7.1 Hz, 4H), 2.06 (p, J = 7, 6 Hz, 2H).
    [0898] [0898] LCMS; m / z 318.9 / 320.9 (M + H) + (ES +).
    [0899] [0899] Step B: 7-Cyclopropyl-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden- 4-amine
    [0900] [0900] A stirred mixture of 7-bromo-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (100 mg, 0.313 mmol), K2CO3 (87 mg , 0.627 mmol), tricyclohexylphosphine (11.42 mg, 0.041 mmol) and cyclopropylboronic acid (29.6 mg, 0.345 mmol) in toluene (10 ml) and water (2 ml) at room temperature was degassed with nitrogen for 15 minutes. minutes. After that time, palladium (II) acetate (7.03 mg, 0.031 mmol) was added and the reaction mixture was allowed to stir at 90 ° C for 24 hours. The reaction mixture was cooled and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-30% EtOAc / isohexane) to provide the title compound (56 mg, 54%) as a colorless solid on standing.
    [0901] [0901] 1H NMR (DMSO-d6) δ 8.17 (d, J = 5.2 Hz, 1H), 7.00 (dd, J = 5.3, 1.5 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 6.43 (s, 1H), 4.48 (s, 2H), 3.88 (s, 3H), 2.91 (t, J = 7, 5 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.04 (q, J = 7.3 Hz, 2H), 1.78 - 1.71 (m, 1H) , 0.81 - 0.75 (m, 2H), 0.55 - 0.48 (m, 2H).
    [0902] [0902] LCMS; m / z 281.5 (M + H) + (ES +).
    [0903] [0903] Intermediate A48: 4- (4-Isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine
    [0904] [0904] 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) (500 mg, 2.081 mmol) was dissolved in DCM (10 mL) and NaHCO3 (5 ml) was added. A solution of triphosgene (250 mg, 0.842 mmol) in DCM (5 mL) was added and the mixture was stirred at room temperature for 1 hour. The organic phase was separated, dried through a hydrophobic frit and concentrated in vacuo to provide the title compound (523 mg, 94%) as a pale yellow oil which was used without further purification.
    [0905] [0905] 1H NMR (CDCl3) δ 8.25 (d, J = 5.2 Hz, 1H), 7.18 - 7.13 (m, 2H), 7.01
    [0906] [0906] Intermediate A49: 4- (4-Isocyanate-2,3-dihydrobenzofuran-5-yl) -2-methoxypyridine
    [0907] [0907] Step A: N- (5-Bromo-2,3-dihydrobenzofuran-4-yl) acetamide
    [0908] [0908] N- (2,3-dihydrobenzofuran-4-yl) acetamide (13.1 g, 73.9 mmol), 4-methylbenzenesulfonic acid hydrate (7.73 g, 40.7 mmol) and diacetoxipaladium (0.830 g, 3.70 mmol) were suspended in toluene (250 mL) and stirred for 20 minutes. NBS (14.47 g, 81 mmol) was added and the mixture was stirred for 30 minutes, diluted with EtOAc (150 ml) and washed with NaHCO 3 aq (100 ml) and Na2S2O3 aq (10% by weight, 100 ml) . The aqueous phases were further extracted with DCM (150 ml). The organic phases were combined, dried (MgSO 4), filtered and concentrated under reduced pressure to provide the title compound (22.27 g, quant., 85% Purity by LCMS) which was used crude in the next step.
    [0909] [0909] LCMS; m / z 255.9, 257.9 (M + H) + (ES +).
    [0910] [0910] Step B: 5-Bromo-2,3-dihydrobenzofuran-4-amine
    [0911] [0911] A solution of N- (5-bromo-2,3-dihydrobenzofuran-4-yl) acetamide (22.27 g, 73.9 mmol) in MeOH (400 mL) and concentrated H2SO4 (40 mL) was stirred at reflux for 18 hours. The volatiles were removed under reduced pressure, the residue collected in DCM (300 ml) and basified with 1 M aq NaOH (100 ml). The organic phase was separated (Na 2SO4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-100% EtOAc / isohexane) to provide the title compound (9.17 g, 57%) as an off-white solid.
    [0912] [0912] 1H NMR (CDCl3) δ 7.16 (dt, J = 8.4, 0.9 Hz, 1H), 6.17 (d, J = 8.4 Hz, 1H), 4.61 (t , J = 8.7 Hz, 2H), 3.99 (br. S, 2H), 3.05 (t, J = 8.7 Hz, 2H).
    [0913] [0913] Step C: 5- (2-methoxypyridin-4-yl) -2,3-dihydrobenzofuran-4-amine
    [0914] [0914] Prepared according to the general procedure of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) from 5-bromo-2 , 3-dihydrobenzofuran-4-amine and (2-methoxypyridin-4-yl) boronic acid to provide the title compound (2.25 g, 79%) as an off-white solid.
    [0915] [0915] 1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 6.99 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.14 (d, J = 8.1 Hz, 1H), 4.91 (s, 2H), 4.54 (t, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.01 (t, J = 8.7 Hz, 2H).
    [0916] [0916] LCMS; m / z 243.1 (M + H) + (ES +).
    [0917] [0917] Step D: 4- (4-Isocyanate-2,3-dihydrobenzofuran-5-yl) -2-methoxypyridine
    [0918] [0918] Prepared according to the general procedure of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A48) of 5- (2-methoxypyridin- 4-yl) -2,3-dihydrobenzofuran-4-amine to provide the title compound (926 mg, 79%) as a pale yellow solid.
    [0919] [0919] 1H NMR (CDCl3) δ 8.23 (d, J = 5.3 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.98 (dd, J = 5 , 3, 1.4 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 4.72 (t, J = 8.7 Hz, 2H ), 4.02 (s, 3H), 3.33 (t, J = 8.7 Hz, 2H). Preparation of Examples Example 1: N - (((4-Fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
    [0920] [0920] 4-Fluoro-2-isopropyl-6- (pyridin-3-yl) aniline (Intermediate A1; 50 mg, 0.213 mmol) in acetonitrile (2 mL) was added to (4- (dimethylamino) pyridin-1- io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3; 71.8 mg, 0.213 mmol) and the mixture was stirred at 50 ° C for 10 minutes *, then at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC (basic method, 10-40% acetonitrile in 10 mM aqueous ammonium bicarbonate, 6.5 minutes of execution) to provide the title compound (41 mg, 42%) as a white solid.
    [0921] [0921] (* The reaction was usually carried out between 10 minutes and 1 hour of heating.)
    [0922] [0922] 1H NMR (DMSO-d6) δ 11.34 (s, 1 H), 8.96 (dd, 1 H), 8.93 (d, 1 H), 8.35 (d, 1 H) , 8.29 (s, 1 H), 8.14 (dt, 1 H), 7.78 (dd, 1 H), 7.62 (dd, 1 H), 7.48 (dd, 1 H) , 7.05 - 6.85 (m, 1 H), 5.02 (sept, 1 H), 3.48 - 3.34 (m, 1 H), 1.86 (d, 6 H) and 1 , 51 (d, 6 H).
    [0923] [0923] LCMS m / z 446.4 (M + H) + (ES +); 444.3 (M-H) - (ES-).
    [0924] [0924] The following examples 2-35 were synthesized following the general procedure for N - ((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1- iso-propyl- 1H-pyrazol-3-sulfonamide (Example 1) above. Sodium salts were synthesized using sodium tert-butoxide, where indicated. Example 2: N - (((4-Fluoro-2-iso-propyl-6- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0925] [0925] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (1-methyl-1H-pyrazol-4-yl) aniline (Intermediate A2) to provide the title compound (50 mg, 53%).
    [0926] [0926] 1H NMR (DMSO-d6) δ 11.07 (br s, 1 H), 7.95 (d, 1 H), 7.93 (s, 1 H), 7.89 (s, 1 H ), 7.64 (br s, 1 H), 7.14 (dd, 1 H), 6.99 (dd, 1 H), 6.65 (d, 1 H), 4.60 (sept, 1 H), 3.85 (s, 3 H), 3.02 - 2.88 (m, 1 H), 1.43 (d, 6 H) and 1.06 (d, 6 H).
    [0927] [0927] LCMS m / z 449.4 (M + H) + (ES +). Example 3: N - (((4-Fluoro-2-iso-propyl-6- (1-methyl-1H-imidazol-5-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0928] [0928] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (1-methyl-1H-imidazol-5-yl) aniline (Intermediate A3) to provide the title compound (20.1 mg, 42%) as an off-white solid.
    [0929] [0929] 1H NMR (DMSO-d6) δ 10.96 (s, 1 H), 7.92 (s, 1 H), 7.65 (s, 2 H), 7.18 (dd, 1 H) , 7.04 (dd, 1 H), 6.77 (s, 1 H), 6.53 (s, 1 H), 4.61 (sept, 1 H), 3.40 (s, 3 H) , 3.06 - 2.87 (m, 1 H), 1.45 (d, 6 H) and 1.08 (d, 6 H).
    [0930] [0930] LCMS m / z 449.4 (M + H) + (ES +); 447.1 (M-H) - (ES-). Example 4: N - (((5-Fluoro-3-iso-propyl- [1,1'-biphenyl] -2-yl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0931] [0931] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 5-fluoro-3 -isopropyl- [1,1'-biphenyl] -2-amine (Intermediate A4) to provide the title compound (26 mg, 38%) as a white solid.
    [0932] [0932] 1H NMR (DMSO-d6) δ 10.79 (br s, 1 H), 7.97 (d, 1 H), 7.68 (s, 1 H), 7.43 - 7.21 ( m, 5 H), 7.15 (dd, 1 H), 6.96 (dd, 1 H), 6.57 (d, 1 H), 4.60 (sept, 1 H), 3.02 - 2.87 (m, 1 H), 1.44 (d, 6 H) and 1.08 (d, 6 H).
    [0933] [0933] LCMS m / z 445.4 (M + H) + (ES +); 443.4 (M-H) - (ES-). Example 5: N - (((4-Fluoro-2-iso-propyl-6- (1-methyl-1H-pyrazol-5-yl) phenyl)
    [0934] [0934] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (1-methyl-1H-pyrazol-5-yl) aniline (Intermediate A5) to provide the title compound (44 mg, 64%) as a white solid.
    [0935] [0935] 1H NMR (DMSO-d6) δ 10.90 (s, 1 H), 7.96 (s, 1 H), 7.73 (s, 1 H), 7.38 (d, 1 H) , 7.25 (dd, 1 H), 7.09 (d, 1 H), 6.58 (s, 1 H), 6.11 (d, 1 H), 4.61 (sept, 1 H) , 3.55 (s, 3 H), 3.08 - 2.86 (m, 1 H), 1.45 (d, 6 H) and 1.09 (d, 6 H).
    [0936] [0936] LCMS m / z 449.5 (M + H) + (ES +); 447.4 (M-H) - (ES-). Example 6: N - (((4-Fluoro-2-iso-propyl-6- (thiazol-5-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0937] [0937] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (thiazol-5-yl) aniline (Intermediate A6) to provide the title compound (10 mg, 34%) as a white solid.
    [0938] [0938] 1H NMR (DMSO-d6) δ 11.20 (br s, 1 H), 9.08 (s, 1 H), 8.19 (s, 1 H), 7.86 (s, 2 H ), 7.40 (dd, 1 H), 7.21 - 7.08 (m, 1 H), 6.56 (s, 1 H), 4.77 - 4.29 (m, 1 H), 3.10 - 2.88 (m, 1 H), 1.42 (d, 6 H) and 1.06 (s, 6 H).
    [0939] [0939] LCMS m / z 452.4 (M + H) + (ES +); 450.2 (M-H) - (ES-). Example 7: N - (((4-Fluoro-2-iso-propyl-6- (isoxazol-4-yl) phenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
    [0940] [0940] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-
    [0941] [0941] 1H NMR (DMSO-d6) δ 11.26 (s, 1 H), 9.05 (s, 1 H), 8.83 (s, 1 H), 8.14 (s, 1 H) , 7.94 (d, 1 H), 7.32 (dd, 1 H), 7.15 (dd, 1 H), 6.64 (d, 1 H), 4.60 (sept, 1 H) , 3.06 - 2.95 (m, 1 H), 1.43 (d, 6 H) and 1.08 (br s, 6 H).
    [0942] [0942] LCMS 436.5 (M + H) + (ES +); 434.3 (M-H) - (ES-). Example 8: N - (((3'-Cyano-5-fluoro-3-iso-propyl- [1,1'-biphenyl] -2-yl) carbamoyl) -1- iso-propyl-1H-pyrazol-3- sulfonamide, sodium salt
    [0943] [0943] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 2'-amino- 5'-fluoro-3'- isopropyl- [1,1'-biphenyl] -3-carbonitrile (Intermediate A8) to provide the title compound (14.6 mg, 14%) as a colorless powder.
    [0944] [0944] 1H NMR (DMSO-d6) δ 7.78 (s, 1 H), 7.75 (d, 1 H), 7.66 (d, 1 H), 7.64 (s, 1 H) , 7.45 (s, 1 H), 7.42 (t, 1 H), 7.09 (dd, 1 H), 6.96 (dd, 1 H), 6.16 (d, 1 H) , 4.48 (sept, 1 H), 3.23 - 3.11 (m, 1 H), 1.40 (d, 6 H) and 1.08 (d, 6 H).
    [0945] [0945] LCMS m / z 470 (M + H) + (ES +); 468 (M-H) - (ES-). Example 9: N - (((4'-Cyano-5-fluoro-3-iso-propyl- [1,1'-biphenyl] -2-yl) carbamoyl) -1- iso-propyl-1H-pyrazol-3- sulfonamide, sodium salt
    [0946] [0946] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 2'-amino- 5'-fluoro-3'- isopropyl- [1,1'-biphenyl] -4-carbonitrile (Intermediate A9) to provide the title compound (47.4 mg, 48%) as a colorless powder.
    [0947] [0947] 1H NMR (DMSO-d6) δ 7.72 (s, 1 H), 7.67 (d, 2 H), 7.52 (d, 2 H), 7.39 (s, 1 H) , 7.11 (dd, 1 H), 6.93 (dd, 1 H), 6.24 (d, 1 H), 4.51 (sept, 1 H), 3.19 (br s, 1
    [0948] [0948] LCMS m / z 470 (M + H) + (ES +); 468 (M-H) - (ES-). Example 10: N - (((4-Fluoro-2-iso-propyl-6- (pyridin-4-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide, partial ammonium salt
    [0949] [0949] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (pyridin-4-yl) aniline (Intermediate A10) to provide the title compound (24 mg, 36%) as a white solid.
    [0950] [0950] 1H NMR (DMSO-d6) δ 8.55 - 8.34 (m, 2 H), 7.89 (s, 1 H), 7.79 (s, 1 H), 7.31 (d , 2 H), 7.21 (dd, 1 H), 7.03 (dd, 1 H), 6.49 (s, 1 H), 4.57 (sept, 1 H), 3.12 - 2 , 95 (m, 1 H), 1.43 (d, 6 H) and 1.09 (d, 6 H). An interchangeable signal as a very broad simplet at 11.25-10.00 ppm.
    [0951] [0951] LCMS m / z 446.4 (M + H) + (ES +); 444.1 (M-H) - (ES-). Example 11: N - ((2- (1,3 (Dimethyl-1H-pyrazol-5-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3- sulfonamide, partial ammonium salt
    [0952] [0952] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 2- (1, 3-dimethyl-1H-pyrazol-5-yl) -4-fluoro-6-isopropylaniline (Intermediate A11) to provide the title compound (41 mg, 57%) as a white solid.
    [0953] [0953] 1H NMR (DMSO-d6) δ 7.84 (s, 1 H), 7.53 (s, 1 H), 7.19 (dd, 1 H), 6.97 (dd, 1 H) , 6.45 (s, 1 H), 5.94 (s, 1 H), 4.55 (sept, 1 H), 3.45 (s, 3 H), 3.10 - 2.95 (m , 1 H), 2.13 (s, 3 H), 1.43 (d, 6 H) and 1.08 (d, J = 6.8 Hz, 6H); an unobserved interchangeable signal.
    [0954] [0954] LCMS m / z 463.4 (M + H) + (ES +); 461.3 (M-H) - (ES-). Example 12: N - (((4-Fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl)
    [0955] [0955] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (2-methoxypyridin-4-yl) aniline (Intermediate A12) to provide the title compound (32 mg, 44%) as a white solid.
    [0956] [0956] 1H NMR (DMSO-d6) δ 7.99 (d, 1 H), 7.78 (s, 1 H), 7.69 (s, 1 H), 7.11 (dd, 1 H) , 6.93 (dd, 1 H), 6.83 (d, 1 H), 6.70 (s, 1 H), 6.40 (s, 1 H), 4.48 (sept, 1 H) , 3.80 (s, 3 H), 3.02 - 2.82 (m, 1 H), 1.35 (d, 6 H) and 1.00 (d, 6 H); an unobserved interchangeable signal.
    [0957] [0957] LCMS m / z 476.4 (M + H) + (ES +); 474.3 (M-H) - (ES-). Example 13: N - (((4-Fluoro-2-iso-propyl-6- (2-methylpyridin-4-yl) phenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide, partial salt of ammonium
    [0958] [0958] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (2-methylpyridin-4-yl) aniline (Intermediate A13) to provide the title compound (37 mg, 53%) as a white solid.
    [0959] [0959] 1H NMR (DMSO-d6) δ 8.33 (d, 1 H), 7.83 (s, 1 H), 7.69 (s, 1 H), 7.21 (s, 1 H) , 7.17 (dd, 1 H), 7.11 (d, 1 H), 7.05 - 6.89 (m, 1 H), 6.44 (s, 1 H), 4.54 (sept , 1 H), 3.15 - 2.96 (m, 1 H), 2.45 (s, 3 H), 1.42 (d, 6 H) and 1.08 (d, 6 H); an unobserved interchangeable signal.
    [0960] [0960] LCMS m / z 460.5 (M + H) + (ES +); 458.4 (M-H) - (ES-). Example 14: N - (((4-Fluoro-2-iso-propyl-6- (2-methylpyridin-3-yl) phenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide, partial salt of ammonium
    [0961] [0961] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (2-methylpyridin-3-yl) aniline (Intermediate A14) to provide the title compound (8 mg, 11%) as a white solid.
    [0962] [0962] 1H NMR (DMSO-d6) δ 8.39 (dd, 1 H), 7.83 (s, 1 H), 7.54 (s, 1 H), 7.46 - 7.32 (m , 1 H), 7.21 - 7.03 (m, 2 H), 7.02 - 6.79 (m, 1 H), 6.34 (s, 1 H), 4.54 (sept, 1 H), 3.16 - 2.93 (m, 1 H), 2.19 (s, 3 H), 1.43 (d, 6 H) and 1.17 - 1.04 (m, 6 H) ; an unobserved interchangeable signal.
    [0963] [0963] LCMS m / z 460.5 (M + H) + (ES +); 458.4 (M-H) - (ES-). Example 15: N - (((4-Fluoro-2-iso-propyl-6- (6-methylpyridin-3-yl) phenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide, partial salt of ammonium
    [0964] [0964] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (6-methylpyridin-3-yl) aniline (Intermediate A15) to provide the title compound (21 mg, 30%) as a white solid.
    [0965] [0965] 1H NMR (DMSO-d6) δ 8.38 (s, 1 H), 7.84 (s, 1 H), 7.66 (s, 1 H), 7.61 (d, 1 H) , 7.19 (d, 1 H), 7.13 (dd, 1 H), 6.99 (dd, 1 H), 6.44 (s, 1 H), 4.56 (sept, 1 H) , 3.14 - 2.88 (m, 1 H), 2.50 (s, 3 H), 1.42 (d, 6 H) and 1.07 (d, 6 H); an unobserved interchangeable signal.
    [0966] [0966] LCMS m / z 460.5 (M + H) + (ES +); 458.3 (M-H) - (ES-). Example 16: N - ((2- (5-Chloropyridin-3-yl) -4-fluoro-6-iso-propylphenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide, partial ammonium salt
    [0967] [0967] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 2- (5- chloropyridin-3-yl) -4-fluoro-6-isopropylaniline (Intermediate A16) to provide the title compound (43.2 mg, 58%) as a white solid.
    [0968] [0968] 1H NMR (DMSO-d6) δ 8.57 (d, 1 H), 8.46 (s, 1 H), 7.98 - 7.79 (m, 3 H), 7.21 (dd , 1 H), 7.11 (dd, 1 H), 6.45 (d, 1 H), 4.56 (sept, 1 H), 3.07 - 2.92 (m, 1 H), 1 , 42 (d, 6 H) and 1.09 (d, 6 H).
    [0969] [0969] LCMS m / z 480.4 / 482.4 (M + H) + (ES +); 478.3 / 480.3 (M-H) - (ES-). Example 17: N - (((4-Fluoro-2-iso-propyl-6- (5-methoxypyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide, partial salt of ammonium
    [0970] [0970] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (5-methoxypyridin-3-yl) aniline (Intermediate A17) to provide the title compound (44.6 mg, 60%) as a white solid.
    [0971] [0971] 1H NMR (DMSO-d6) δ 8.24 (d, 1 H), 8.09 (d, 1 H), 7.93 - 7.75 (m, 2 H), 7.38 (s , 1 H), 7.18 (dd, 1 H), 7.06 (dd, 1 H), 6.50 (s, 1 H), 4.57 (sept, 1 H), 3.82 (s , 3 H), 3.06 - 2.89 (m, 1 H), 1.43 (d, 6 H) and 1.08 (d, 6 H).
    [0972] [0972] LCMS m / z 476.4 (M + H) + (ES +); 474.5 (M-H) - (ES-). Example 18: N - (((4-Fluoro-2-iso-propyl-6- (pyrimidin-5-yl) phenyl) carbamoyl) -1- iso-propyl-1H-pyrazol-3-sulfonamide
    [0973] [0973] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-
    [0974] [0974] 1H NMR (DMSO-d6) δ 11.06 (s, 1 H), 9.13 (s, 1 H), 8.75 (s, 2 H), 8.01 (s, 1 H) , 7.90 (s, 1 H), 7.25 (dd, 1 H), 7.18 (dd, 1 H), 6.49 (s, 1 H), 4.59 (sept, 1 H) , 3.04 (sept, 1 H), 1.44 (d, 6 H) and 1.10 (d, 6 H).
    [0975] [0975] LCMS m / z 447 (M + H) + (ES +); 445 (M-H) - (ES-). Example 19: N - (((4-Fluoro-2-iso-propyl-6- (6-methoxypyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0976] [0976] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (6-methoxypyridin-3-yl) aniline (Intermediate A19) to provide the title compound (29 mg, 53%) as a white solid.
    [0977] [0977] 1H NMR (DMSO-d6) δ 10.90 (s, 1 H), 8.10 (d, 1 H), 7.91 (s, 1 H), 7.80 (s, 1 H) , 7.63 (dd, 1 H), 7.15 (dd, 1 H), 7.01 (dd, 1 H), 6.74 (d, 1 H), 6.55 (s, 1 H) , 4.59 (sept, 1 H), 3.89 (s, 3 H), 3.07 - 2.86 (m, 1 H), 1.43 (d, 6 H) and 1.08 (d , 6 H).
    [0978] [0978] LCMS m / z 476.5 (M + H) + (ES +); 474.4 (M-H) - (ES-). Example 20: N - (((4-Fluoro-2-iso-propyl-6- (4-methylpyridin-3-yl) phenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide, partial salt of ammonium
    [0979] [0979] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (4-methylpyridin-3-yl) aniline (Intermediate A20) to provide the title compound (23 mg, 40%) as a white solid.
    [0980] [0980] 1H NMR (DMSO-d6) δ 8.40 - 8.34 (m, 1 H), 8.32 (s, 1 H), 7.85 (s, 1
    [0981] [0981] LCMS m / z 460.6 (M + H) + (ES +); 458.4 (M-H) - (ES-). Example 21: N - (((4-Fluoro-2- (5-fluoropyridin-3-yl) -6-isopropylphenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide, partial ammonium salt
    [0982] [0982] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 - (5-fluoropyridin-3-yl) -6-isopropylaniline (Intermediate A21) to provide the title compound (14.1 mg, 21%) as a colorless solid.
    [0983] [0983] 1H NMR (DMSO-d6) δ 8.51 (d, 1 H), 8.41 (s, 1 H), 7.81 - 7.63 (m, 3 H), 7.17 (dd , 1 H), 7.07 (dd, 1 H), 6.31 (s, 1 H), 4.51 (sept, 1 H), 3.21 - 3.04 (m, 1 H), 1 , 41 (d, 6 H) and 1.09 (d, 6 H); an unobserved interchangeable signal.
    [0984] [0984] LCMS m / z 464 (M + H) + (ES +); 462 (M-H) - (ES-). Example 22: N - (((4-Fluoro-2-iso-propyl-6- (3-methylpyridin-4-yl) phenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0985] [0985] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (3-methylpyridin-4-yl) aniline (Intermediate A22) to provide the title compound (27.9 mg, 41%) as a colorless powder.
    [0986] [0986] 1H NMR (DMSO-d6) δ 10.75 (s, 1 H), 8.42 (s, 1 H), 8.28 (d, 1 H), 7.96 (s, 1 H) , 7.70 (s, 1 H), 7.22 (dd, 1 H), 7.02 (s, 1 H), 6.93 (dd, 1 H), 6.49 (s, 1 H) , 4.60 (sept, 1 H), 2.98 (sept, 1 H), 2.00 (s, 3 H), 1.45 (d, 6 H) and 1.11 (d, 6 H) .
    [0987] [0987] LCMS m / z 460 (M + H) + (ES +); 458 (M-H) - (ES-). Example 23: N - (((2- (2-Aminopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -
    [0988] [0988] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4- (2- amino-5-fluoro-3-isopropylphenyl) pyridin-2-amine (Intermediate A23) to provide the title compound (19 mg, 27%) as a white solid.
    [0989] [0989] 1H NMR (DMSO-d6) δ 10.90 (br s, 1 H), 7.95 (d, 1 H), 7.78 (dd, 1 H), 7.70 (s, 1 H ), 7.18 (dd, 1 H), 6.93 (dd, 1 H), 6.58 (d, 1 H), 6.41 - 6.35 (m, 1 H), 6.32 ( s, 1 H), 5.95 (br s, 2 H), 4.60 (sept, 1 H), 3.06 - 2.83 (m, 1 H), 1.44 (d, 6 H) and 1.07 (d, 6 H).
    [0990] [0990] LCMS m / z 461.5 (M + H) + (ES +); 459.3 (M-H) - (ES-). Example 24: N - ((2- (2-Etoxypyridin-4-yl) -4-fluoro-6-iso-propylphenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0991] [0991] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 2- (2- ethoxypyridin-4-yl) -4-fluoro-6-isopropylaniline (Intermediate A24) to provide the title compound (20 mg, 27%) as a white solid.
    [0992] [0992] 1H NMR (DMSO-d6) δ 10.94 (s, 1 H), 8.06 (d, 1 H), 7.92 (s, 1 H), 7.85 (s, 1 H) , 7.20 (dd, 1 H), 7.02 (dd, 1 H), 6.93 - 6.79 (m, 1 H), 6.73 (d, 1 H), 6.55 (s , 1 H), 4.59 (sept, 1 H), 4.32 (q, 2 H), 3.07 - 2.88 (m, 1 H), 1.43 (d, 6 H), 1 , 34 (t, 3 H) and 1.20 - 0.88 (m, 6 H).
    [0993] [0993] LCMS m / z 490.5 (M + H) + (ES +); 488.3 (M-H) - (ES-). Example 25: N - (((4-Fluoro-2- (2-hydroxypyridin-4-yl) -6-iso-propylphenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0994] [0994] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4- (2- amino-5-fluoro-3-isopropylphenyl) pyridin-2-ol (Intermediate A25) to provide the title compound (10.5 mg, 15%) as a colorless powder.
    [0995] [0995] 1H NMR (DMSO-d6) δ 11.89 (s, 1 H), 7.75 (br s, 2 H), 7.23 (d, 1 H), 7.13 (dd, 1 H ), 6.92 (dd, 1 H), 6.45 (s, 1 H), 6.18 (s, 1 H), 6.07 (d, 1 H), 4.54 (sept, 1 H ), 3.21 - 3.02 (m, 1 H), 1.40 (d, 6 H) and 1.08 (d, 6 H); an unobserved interchangeable signal.
    [0996] [0996] LCMS m / z 462 (M + H) + (ES +); 460 (M-H) - (ES-). Example 26: N - (((4-Fluoro-2-iso-propyl-6- (2-methoxy-6-methylpyridin-4-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide
    [0997] [0997] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 -isopropyl-6- (2-methoxy-6-methylpyridin-4-yl) aniline (Intermediate A26) to provide the title compound (16.7 mg, 23%) as a colorless powder.
    [0998] [0998] 1H NMR (DMSO-d6) δ 7.74 (s, 1 H), 7.57 (s, 1 H), 7.13 (dd, 1 H), 6.94 (dd, 1 H) , 6.82 (s, 1 H), 6.60 (s, 1 H), 6.35 (s, 1 H), 4.51 (sept, 1 H), 3.85 (s, 3 H) , 3.19 - 3.02 (m, 1 H), 2.36 (s, 3 H), 1.41 (d, 6 H) and 1.08 (d, 6 H).
    [0999] [0999] LCMS m / z 490 (M + H) + (ES +); 488 (M-H) - (ES-). Example 27: N - (((4-Fluoro-2- (2-isopropoxypyridin-4-yl) -6-iso-propyl-phenyl) carbamoyl) -1-iso-propyl-1H-pyrazol-3-sulfonamide
    [1000] [1000] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro-2 - (2-isopropoxy-pyridin-4-yl) -6-isopropylaniline (Intermediate A27) to provide the title compound (31.6 mg, 42%) as a colorless powder.
    [1001] [1001] 1H NMR (DMSO-d6) δ 8.04 (d, 1 H), 7.87 (s, 1 H), 7.75 (s, 1 H), 7.18 (dd, 1 H) , 7.01 (dd, 1 H), 6.86 (d, 1 H), 6.70 (s, 1 H), 6.50 (s, 1 H), 5.27 (sept, 1 H) , 4.57 (sept, 1 H), 3.14 - 2.89 (m, 1 H), 1.43 (d, 6 H), 1.32 (d, 6 H) and 1.08 (d , 6 H).
    [1002] [1002] LCMS m / z 504 (M + H) + (ES +); 502 (M-H) - (ES-). Example 28: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-iso-propylphenyl) carbamoyl) - 1-iso-propyl-1H-pyrazol-3-sulfonamide
    [1003] [1003] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4- (2- amino-5-fluoro-3-isopropylphenyl) -picolinonitrile (Intermediate A28) to provide the title compound (18.5 mg, 26%) as a colorless powder.
    [1004] [1004] 1H NMR (DMSO-d6) δ 11.07 (s, 1 H), 8.67 (d, 1 H), 8.06 - 8.01 (m, 2 H), 7.85 (d , 1 H), 7.67 (dd, 1 H), 7.27 (dd, 1 H), 7.15 (dd, 1 H), 6.43 (s, 1 H), 4.56 (sept , 1 H), 3.18 - 2.96 (m, 1 H), 1.43 (d, 6 H) and 1.11 (d, 6 H).
    [1005] [1005] LCMS m / z 471 (M + H) + (ES +); 469 (M-H) - (ES-). Example 29: N - ((2- (2-Ethylpyridin-4-yl) -4-fluoro-6-iso-propylphenyl) carbamoyl) -1- iso-propyl-1H-pyrazol-3-sulfonamide
    [1006] [1006] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 2- (2- ethylpyridin-4-yl) -4-fluoro-6-isopropylaniline (Intermediate A29) to provide the title compound (27.8 mg, 39%) as a colorless powder.
    [1007] [1007] 1H NMR (DMSO-d6) δ 10.92 (s, 1 H), 8.41 (dd, 1 H), 7.95 (d, 1 H),
    [1008] [1008] LCMS m / z 474 (M + H) + (ES +); 472 (M-H) - (ES-). Example 30: 3- (N - (((4-Fluoro-2-iso-propyl-6- (tetrahydro-2H-pyran-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl- 1H-pyrazol-5-carboxamide, sodium salt
    [1009] [1009] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P4) and 4-fluoro-2-isopropyl-6- (tetrahydro-2H-pyran-4-yl) aniline (Intermediate A30) to provide the title compound (5 mg, 5%) as a solid.
    [1010] [1010] 1H NMR (DMSO-d6) δ 7.39 (s, 1 H), 6.81 (td, 2 H), 6.61 (s, 1 H), 3.90 - 3.81 (m , 5 H), 3.28 - 3.11 (m, 3 H), 3.04 - 2.97 (m, 7 H), 1.57 - 1.43 (m, 4 H) and 1.04 (d, 6 H).
    [1011] [1011] LCMS m / z 496.5 (M + H) + (ES +); 494.3 (M-H) - (ES-). Example 31: N - (((4-Fluoro-2-iso-propyl-6- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) -1-iso-propyl-1H-imidazole-4-sulfonamide
    [1012] [1012] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) (((1-isopropyl-1H-imidazol-4-yl) sulfonyl) amide (Intermediate P6) and 4-fluoro-2 -isopropyl-6- (1-methyl-1H-pyrazol-4-yl) aniline (Intermediate A2) to provide the title compound (24.9 mg, 37%) as a white solid.
    [1013] [1013] 1H NMR (DMSO-d6) δ 7.95 (s, 1 H), 7.90 (s, 1 H), 7.81 (s, 1 H), 7.68 (s, 1 H) , 7.68 - 7.64 (m, 1 H), 7.14 (dd, 1 H), 6.94 (dd, 1 H), 4.44 (sept, 1 H), 3.87 (s , 3 H), 3.14 - 2.87 (m, 1 H), 1.38 (d, 6 H) and 1.04 (d, 6 H); an unobserved interchangeable signal.
    [1014] [1014] LCMS m / z 449.4 (M + H) + (ES +); 447.2 (M-H) - (ES-). Example 32: 3- (N - (((4-Fluoro-2-iso-propyl-6- (pyrimidin-5-yl) phenyl)
    [1015] [1015] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5 (dimethylcarbamoyl) 1-methyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P4) and 4 -fluoro-2-isopropyl-6- (pyrimidin-5-yl) aniline (Intermediate A18) to provide the title compound (31 mg, 11%) as a white solid.
    [1016] [1016] 1H NMR (DMSO-d6) δ 9.03 (s, 1 H), 8.76 (s, 2 H), 7.30 (br s, 1 H), 7.11 (dd, 1 H ), 7.03 (dd, 1 H), 6.43 (s, 1 H), 3.85 (s, 3 H), 3.26 (sept, 1 H), 3.04 (s, 6 H ) and 1.14 (d, 6 H).
    [1017] [1017] LCMS m / z 490.4 (M + H) + (ES +). Example 33: 3- (N - (((4-Fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazole-5- carboxamide, sodium salt
    [1018] [1018] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5- (dimethylcarbamoyl) -1-methyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P4) and 4-fluoro-2-isopropyl-6- (pyridin-3-yl) aniline (Intermediate A1) to provide the title compound (23 mg, 9%) as a white solid.
    [1019] [1019] 1H NMR (DMSO-d6) δ 8.55 (m, 1 H), 8.45 (dd, 1 H), 7.77 (dt, 1 H), 7.25 (ddd, 1 H) , 7.06 (dd, 1 H), 6.91 (dd, 1 H), 6.44 (s, 1 H), 3.84 (s, 3 H), 3.26 (sept, 1 H) , 3.04 (s, 6 H) and 1.13 (d, 6 H).
    [1020] [1020] LCMS m / z 489.4 (M + H) + (ES +). Example 34: 3- (N - (((4-Fluoro-2-iso-propyl-6- (1-methyl-1Hpyrazol-4-yl) phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H- pyrazole-5-carboxamide, sodium salt
    [1021] [1021] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5-
    [1022] [1022] 1H NMR (DMSO-d6) δ 7.95 (s, 1 H), 7.76 (s, 1 H), 7.25 (s, 1 H), 7.10 (dd, 1 H) , 6.86 (dd, 1 H), 6.58 (s, 1 H), 3.82 (s, 3 H), 3.80 (s, 3 H), 3.20 (m, 1 H) , 2.99 (s, 6 H) and 1.06 (d, 6 H).
    [1023] [1023] LCMS m / z 492.4 (M + H) + (ES +); 490.3 (M-H) - (ES-). Example 35: N - (((4-Fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -5- (2-methoxypropan-2-yl) -1-methyl-1H-pyrazole -3-sulfonamide
    [1024] [1024] Prepared from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((5- (2-methoxypropan-2-yl) -1-methyl-1H-pyrazol-3-yl) sulfonyl ) amide (Intermediate P5) and 4-fluoro-2-isopropyl-6- (pyridin-3-yl) aniline (Intermediate A1) to provide the title compound (7 mg, 13%) as a white solid.
    [1025] [1025] 1H NMR (DMSO-d6) δ 10.93 (br s, 1 H), 8.55 (dd, 1 H), 8.49 (d, 1 H), 7.89 (s, 1 H ), 7.73 (dt, 1 H), 7.38 (ddd. 1 H), 7.22 (dd, 1 H), 7.07 (dd, 1 H), 6.56 (s, 1 H ), 4.00 (s, 3 H), 3.11 - 2.99 (m, 1 H), 2.99 (s, 3 H), 1.51 (s, 6 H) and 1.19 - 1.00 (br s, 6 H).
    [1026] [1026] LCMS m / z 490.4 (M + H) + (ES +). Example 36: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-methyl-1H-pyrazole- 3-sulfonamide
    [1027] [1027] 4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) aniline (Intermediate A12; 0.1 g, 0.384 mmol) was dissolved in dry tetrahydrofuran (2 ml). Triethylamine (0.06 ml, 0.430 mmol) and a solution of triphosgene (0.108 g, 0.365 mmol) in tetrahydrofuran (1 ml) were added. The thick, opaque mixture was stirred overnight and then filtered through a phase cartridge washing with toluene (30 ml). After concentration in vacuo, 4- (5-fluoro-2-isocyanate-3-
    [1028] [1028] 1H NMR (DMSO-d6) δ 10.87 (s, 1 H), 8.09 (dd, 1 H), 7.85 (s, 1 H), 7.22 (dd, 1 H) , 7.04 (dd, 1 H), 6.89 (dd, 1 H), 6.77 (s, 1 H), 6.51 (s, 1 H), 3.88 (s, 6 H) , 3.49 (s, 2 H), 3.02 (sept, 1 H), 2.17 (s, 6 H) and 1.09 (d, 6 H).
    [1029] [1029] LCMS m / z 505 (M + H) + (ES +); 503 (M-H) - (ES-). Example 37: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-iso-propyl-1H- pyrazol-3-sulfonamide
    [1030] [1030] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P2) and 4-fluoro-2-isopropyl -6- (2-methoxypyridin-4-yl) aniline (Intermediate A12) to provide the title compound (44.1 mg, 43%) as a colorless powder.
    [1031] [1031] 1H NMR (DMSO-d6) δ 10.92 (s, 1 H), 8.09 (dd, 1 H), 7.87 (s, 1 H), 7.22 (dd, 1 H) , 7.04 (dd, 1 H), 6.92 (dd, 1 H), 6.79 (s, 1 H), 6.48 (s, 1 H), 4.81 (sept, 1 H) , 3.88 (s, 3 H), 3.48 (s, 2 H), 2.98 (sept, 1 H), 2.15 (s, 6 H), 1.37 (d, 6 H) and 1.08 (d, 6 H).
    [1032] [1032] LCMS m / z 533 (M + H) + (ES +); 531 (M-H) - (ES-). Example 38: N - (((3'-Cyano-5-fluoro-3-isopropyl- [1,1'-biphenyl] -2-yl) carbamoyl) -5- ((dimethylamino) methyl) -1-methyl-1H -pyrazol-3-sulfonamide
    [1033] [1033] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediates P1) and 2'-amino-5 ' -fluoro-3'-isopropyl- [1,1'-biphenyl] -3-carbonitrile (Intermediate A8) to provide the title compound (37.3 mg, 34%) as a colorless powder.
    [1034] [1034] 1H NMR (DMSO-d6) δ 10.86 (s, 1 H), 7.90 (s, 1 H), 7.84 - 7.78 (m, 2 H), 7.65 - 7 , 60 (m, 1 H), 7.53 (t, 1 H), 7.21 (dd, 1 H), 7.06 (dd, 1 H), 6.45 (s, 1 H), 3 , 87 (s, 3 H), 3.49 (s, 2 H), 3.04 (sept, 1 H), 2.17 (s, 6 H) and 1.10 (br s, 6 H).
    [1035] [1035] LCMS m / z 499 (M + H) + (ES +); 497 (M-H) - (ES-). Example 39: N - (((3'-Cyano-5-fluoro-3-isopropyl- [1,1'-biphenyl] -2-yl) carbamoyl) -5- ((dimethylamino) methyl) -1-isopropyl-1H -pyrazol-3-sulfonamide
    [1036] [1036] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P2) and 2'-amino-5 ' -fluoro-3'-isopropyl- [1,1'-biphenyl] -3-carbonitrile (Intermediate A8) to provide the title compound (27.6 mg, 24%) as a colorless powder.
    [1037] [1037] 1H NMR (DMSO-d6) δ 10.92 (s, 1 H), 7.93 (s, 1 H), 7.82 (dt, 2 H), 7.66 (dt, 1 H) , 7.57 - 7.51 (m, 1 H), 7.21 (dd, 1 H), 7.07 (dd, 1 H), 6.42 (s, 1 H), 4.79 (sept , 1 H), 3.48 (s, 2 H), 3.00 (sept, 1 H), 2.15 (s, 6 H), 1.37 (d, 6 H) and 1.09 (s , 6 H).
    [1038] [1038] LCMS m / z 527 (M + H) + (ES +); 525 (M-H) - (ES-). Example 40: 5 - ((Dimethylamino) methyl) -N - ((5-fluoro-3-isopropyl- [1,1'-biphenyl] -2-yl) carbamoyl) -1-methyl-1H-pyrazol-3- sulfonamide
    [1039] [1039] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P1) and 5-fluoro-3-isopropyl - [1,1'-biphenyl] -2-amine (Intermediate A4) to provide the title compound (14.2 mg, 14%) as a colorless solid.
    [1040] [1040] 1H NMR (DMSO-d6) δ 10.73 (s, 1 H), 7.68 (s, 1 H), 7.42 - 7.30 (m, 3 H), 7.31 - 7 , 24 (m, 2 H), 7.16 (dd, 1 H), 6.96 (dd, 1 H), 6.54 (s, 1 H), 3.90 (s, 3 H), 3 , 50 (s, 2 H), 2.99 (sept, 1 H), 2.17 (s, 6 H) and 1.09 (d, 6 H).
    [1041] [1041] LCMS m / z 474 (M + H) + (ES +); 472 (M-H) - (ES-). Example 41: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazole- 3-sulfonamide
    [1042] [1042] 5 - ((Dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P2; 0.020 g, 0.081 mmol) and N, N-dimethylaminopyridine (0.030 g, 0.244 mmol) were dissolved in acetonitrile 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 A1; 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 ethyl acetate: dichloromethane (4 ml). The filtrate was then purified by preparative HPLC [Gilson apparatus, basic procedure (0.1% ammonium bicarbonate), basic Waters X-Bridge Prep-C18, 5 µm, 19 x 50 mm column, 5-95% acetonitrile in water with 10 mM ammonium bicarbonate) to provide the title compound (26 mg, 30%) as a white solid.
    [1043] [1043] 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).
    [1044] [1044] LCMS m / z 503.6 (M + H) + (ES +); 501.4 (M-H) - (ES-). Example 42: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-isopropyl-6- (pyrimidin-5-yl) phenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [1045] [1045] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P1) and 4-fluoro-2-isopropyl -6- (pyrimidin-5-yl) aniline (Intermediate A18) to provide the title compound (13.7 mg, 10%) as a colorless powder.
    [1046] [1046] 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 (hept, J = 6.9 Hz, 1H), 2.19 (s, 6H), 1.11 (d, J = 6.7 Hz, 6H).
    [1047] [1047] LCMS m / z 476 (M + H) + (ES +); 474 (M-H) - (ES-). Example 43: 5 - ((Dimethylamino) methyl) -N - ((4-fluoro-2-isopropyl-6- (pyrimidin-5-yl) phenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
    [1048] [1048] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P2) and 4-fluoro-2-isopropyl -6- (pyrimidin-5-yl) aniline (Intermediate A18) to provide the title compound (17.4 mg, 12%) as a colorless powder.
    [1049] [1049] 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).
    [1050] [1050] LCMS m / z 504 (M + H) + (ES +); 502 (M-H) - (ES-). Example 44: 5 - ((dimethylamino) methyl) -N - ((4-fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [1051] [1051] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P1) and 4-fluoro-2-isopropyl -6- (pyridin-3-yl) aniline (Intermediate A1) to provide the title compound (35.8 mg, 34%) as a colorless powder.
    [1052] [1052] 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).
    [1053] [1053] LCMS m / z 475 (M + H) + (ES +); 473 (M-H) - (ES-). Example 45: N - ((2- (1,3-Dimethyl-1H-pyrazol-5-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -5 - ((dimethylamino) methyl) -1-methyl-1H -pyrazol-3-sulfonamide
    [1054] [1054] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P1) and 2- (1,3- dimethyl-1H-pyrazol-5-yl) -4-fluoro-6-isopropylaniline (Intermediate A11) to provide the title compound (15.9 mg, 22%) as a colorless powder.
    [1055] [1055] 1H NMR (DMSO-d6) δ 10.84 (s, 1H), 7.68 (s, 1H), 7.24 (dd, J = 10.1,
    [1056] [1056] LCMS m / z 492 (M + H) + (ES +); 490 (M-H) - (ES-). Example 46: 5 - ((Dimethylamino) methyl) -N - ((5-fluoro-3-isopropyl- [1,1'-biphenyl] -2-yl) carbamoyl) -1-isopropyl-1H-pyrazol-3- sulfonamide
    [1057] [1057] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-isopropyl-1H-pyrazol-3-sulfonamide (Intermediate P2) and 5-fluoro-3-isopropyl - [1,1'-biphenyl] -2-amine (Intermediate A4) to provide the title compound (35.8 mg, 32%) as a colorless powder.
    [1058] [1058] 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 (hept, J = 6 , 6 Hz, 1H), 3.50 (s, 2H), 2.95 (hept, 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).
    [1059] [1059] LCMS m / z 502 (M + H) + (ES +); 500 (M-H) - (ES-). Example 47: N - (((4-Fluoro-2-isopropyl-6- (2- (trifluoromethyl) pyridin-4-yl) phenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
    [1060] [1060] Prepared according to the general procedure for N - ((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazole-3 -sulfonamide (Example 1) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro -2-isopropyl-6- (2- (trifluoromethyl) pyridin-4-yl) aniline (Intermediate A31) to provide the title compound (21.9 mg, 28%) as a colorless powder.
    [1061] [1061] 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 8.70 (d, J = 5.0 Hz, 1H), 8.04
    [1062] [1062] LCMS m / z 514 (M + H) + (ES +); 512 (M-H) - (ES-). Example 48: N - (((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 5 - ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide
    [1063] [1063] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P1) and 4- (2- amino- 5-fluoro-3-isopropylphenyl) picolin-nitrile (Intermediate A28) to provide the title compound (7.9 mg, 7%) as a colorless powder.
    [1064] [1064] 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).
    [1065] [1065] LCMS m / z 500.5 (M + H) + (ES +); 498.4 (M-H) - (ES-). Example 49: N - (((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 5 - ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide
    [1066] [1066] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P7) and 4- (2- amino- 5-fluoro-3-isopropylphenyl) picolin-nitrile (Intermediate A28) to provide the title compound (6.9 mg, 6%) as a colorless powder.
    [1067] [1067] 1H NMR (DMSO-d6) δ 8.65 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 1.7 Hz,
    [1068] [1068] LCMS m / z 514.6 (M + H) + (ES +); 512.4 (M-H) - (ES-). Example 50: N - ((2- (2- (Dimethylamino) pyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1-isopropyl-1H-pyrazol-3-sulfonamide
    [1069] [1069] Prepared according to the general procedure for N - ((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazole-3 -sulfonamide (Example 1) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4- ( 2-amino-5-fluoro-3-isopropylphenyl) - N, N-dimethylpyridin-2-amine (Intermediate A32) to provide the title compound (23.7 mg, 32%) as a colorless powder.
    [1070] [1070] 1H NMR (DMSO-d6) δ 8.01 (d, J = 5.1 Hz, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.15 (dd , J = 10.1, 3.0 Hz, 1H), 6.98 (dd, J = 9.0, 2.9 Hz, 1H), 6.58 (s, 1H), 6.54 - 6, 43 (m, 2H), 4.56 (sept, J = 6.7 Hz, 1H), 3.02 (s, 6H), 3.02 (m, 1H), 1.43 (d, J = 6 , 7 Hz, 6H), 1.07 (d, J = 6.8 Hz, 6H), an interchangeable proton not visible.
    [1071] [1071] LCMS m / z 489.6 (M + H) + (ES +); 487.5 (M-H) - (ES-). Example 51: N - (((4-Fluoro-2-isopropyl-6- (2- (prop-1-in-1-yl) pyridin-4-yl) phenyl) carbamoyl) -1-isopropyl-1H-pyrazole- 3-sulfonamide
    [1072] [1072] Prepared according to the general procedure for N - (((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazole-3 -sulfonamide (Example 1) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 4-fluoro -2-isopropyl-6- (2- (prop-1-in-1-yl) pyridin-4-yl) aniline (Intermediate A33) to provide the title compound
    [1073] [1073] 1H NMR (DMSO-d6) δ 10.94 (br s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 7.86 (s, 2H), 7.41 ( s, 1H), 7.28 - 7.23 (m, 1H), 7.21 (dd, J = 10.0, 3.0 Hz, 1H), 7.05 (dd, J = 8.8, 2.9 Hz, 1H), 6.46 (s, 1H), 4.56 (sept, J = 6.7 Hz, 1H), 3.12 - 2.95 (m, 1H), 2.09 ( s, 3H), 1.43 (d, J = 6.7 Hz, 6H), 1.09 (d, J = 6.8 Hz, 6H).
    [1074] [1074] LCMS m / z 484.4 (M + H) + (ES +); 482.3 (M-H) - (ES-). Example 52: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 5- (3-methoxyoxetan-3-yl) -1-methyl-1H-pyrazole -3-sulfonamide
    [1075] [1075] Prepared according to the general procedure of 5- ((dimethylamino) methyl) -N - ((4-fluoro-2-iso-propyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) - 1-methyl-1H-pyrazol-3-sulfonamide (Example 36) from 5- (3-methoxyethoxy-3-yl) -1-methyl-1H-pyrazol-3-sulfonamide (Intermediate P8) and 4-fluoro- 2-isopropyl-6- (2-methoxypyridin-4-yl) aniline (Intermediate A12) to provide the title compound (22.5 mg, 22%) as a colorless powder.
    [1076] [1076] 1H NMR (DMSO-d6) δ 11.08 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.89 (s, 1H), 7.23 (dd , J = 10.1, 2.9 Hz, 1H), 7.05 (dd, J = 8.8, 2.9 Hz, 1H), 6.99 (s, 1H), 6.92 (dd, J = 5.4, 1.5 Hz, 1H), 6.79 (s, 1H), 4.86 (d, J = 7.4 Hz, 2H), 4.79 (d, J = 7.3 Hz, 2H), 3.75 (s, 3H), 3.34 (s, 3H), 3.04 (sept, J = 7.0 Hz, 1H), 2.95 (s, 3H), 1, 09 (br s, 6H).
    [1077] [1077] LCMS m / z 534.4 (M + H) + (ES +); 532.2 (M-H) - (ES-). Example 53: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-isopropyl-1H-imidazole-4-sulfonamide
    [1078] [1078] Prepared according to the general procedure for N - ((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazole-3 -sulfonamide (Example 1) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-imidazol-4-yl) sulfonyl) amide (Intermediate P6) and 4-fluoro -2-isopropyl-6- (2-
    [1079] [1079] 1H NMR (DMSO-d6) δ 10.55 (bs, 1H), 8.09 (d, J = 5.3 Hz, 1H), 7.95 (s, 1H), 7.90 (s , 1H), 7.80 (s, 1H), 7.21 (dd, J = 10.0, 3.0 Hz, 1H), 7.03 (dd, J = 8.9, 3.0 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 6.74 (s, 1H), 4.48 (sept, J = 6.1 Hz, 1H), 3.88 (s, 3H), 3.02 - 2.93 (m, 1H), 1.41 (d, J = 6.7 Hz, 6H), 1.16 - 0.95 (m, 6H).
    [1080] [1080] LCMS m / z 476.6 (M + H) + (ES +). Example 54: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1- isopropyl-1H-imidazole-4-sulfonamide
    [1081] [1081] Prepared according to the general procedure for N - (((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazole-3 -sulfonamide (Example 1) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-imidazol-4-yl) sulfonyl) amide (Intermediate P6) and 4- ( 2-amino-5-fluoro-3-isopropylphenyl) picolin-nitrile (Intermediate A28) to provide the title compound (19 mg, 27%) as a white solid.
    [1082] [1082] 1H NMR (DMSO-d6) δ 10.78 (bs, 1H), 8.68 (d, J = 5.1 Hz, 1H), 8.02 (s, 2H), 7.89 (s , 1H), 7.82 (s, 1H), 7.63 (d, J = 5.0 Hz, 1H), 7.28 (dd, J = 10.1, 3.0 Hz, 1H), 7 , 16 (dd, J = 8.8, 3.0 Hz, 1H), 4.46 (sept, J = 6.9 Hz, 1H), 3.13 - 3.01 (m, 1H), 1, 41 (d, J = 6.7 Hz, 6H), 1.10 (d, J = 6.2 Hz, 6H).
    [1083] [1083] LCMS m / z 471.2 (M + H) + (ES +). Example 55: N - (((7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropyl-1H-pyrazole- 3-sulfonamide
    [1084] [1084] Prepared according to the general procedure for N - ((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazole-3 -sulfonamide (Example 1) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 7-fluoro -5- (2-methoxypyridin-4-yl) -2,3-
    [1085] [1085] 1H NMR (DMSO-d6) δ 10.92 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H ), 7.89 (s, 1H), 7.01 (d, J = 9.2 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (s, 1H), 6.61 (s, 1H), 4.60 (sept, J = 6.7 Hz, 1H), 3.89 (s, 3H), 2.94 (t, J = 7, 4 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H), 1.44 (d, J = 6.7 Hz , 6H).
    [1086] [1086] LCMS m / z 474.4 (M + H) + (ES +); 472.3 (M-H) - (ES-). Example 56: 1-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
    [1087] [1087] Prepared according to the general procedure for N - (((4-fluoro-2-iso-propyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1-iso-propyl-1H-pyrazole-3 -sulfonamide (Example 1) from (4- (dimethylamino) pyridin-1-io-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl) sulfonyl) amide (Intermediate P3) and 5- ( 2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) to provide the title compound (20.7 mg, 30%) as a colorless powder.
    [1088] [1088] 1H NMR (DMSO-d6) δ 10.86 (s, 1H), 8.12 (d, J = 5.4 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H ), 7.90 (s, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 5.3, 1.4 Hz, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 4.60 (sept, J = 6.3 Hz, 1H), 3.88 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 1.97 (p, J = 7.4 Hz , 2H), 1.44 (d, J = 6.7 Hz, 6H).
    [1089] [1089] LCMS m / z 456.4 (M + H) + (ES +); 454.3 (M-H) - (ES-). Example 57: 1- (2- (Dimethylamino) ethyl) -N - ((4-fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1H-pyrazol-3-sulfonamide N F F F O O O
    [1090] [1090] To a solution of 4-fluoro-2-isopropyl-6- (pyridin-3-yl) aniline
    [1091] [1091] 1H NMR (DMSO-d6) δ 8.51-8.48 (m, 2 H), 7.70 (s, 2 H), 7.49 (s, 1 H), 7.28-7 , 26 (m, 1 H), 7.10 (dd, 1 H), 6.97 (dd, 1 H), 6.28 (s, 1 H), 4.20 (t, 2 H), 3 , 14-3.12 (m, 1 H), 2.67-2.62 (m, 2 H), 2.18 (s, 6 H) and 1.08 (dd, 6 H).
    [1092] [1092] LCMS: m / z 475 (M + H) + (ES +). Example 58: 3- (Diethylamino) -N - ((4-fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) propane-1-sulfonamide F OCN
    [1093] [1093] To a solution of 3- (diethylamino) propane-1-sulfonamide (Intermediate P32) (200 mg, 1.03 mmol, 1 eq) in THF (5 mL) was added NaOMe (56 mg, 1.03 mmol , 1 eq) and 3- (5-fluoro-2-isocyanate-3-isopropylphenyl) iridine (Intermediate A41) (263.80 mg, 1.03 mmol, 1 eq). The reaction mixture was stirred at 70 ° C for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column:
    [1094] [1094] 1H NMR (DMSO-d6): δ 8.59 (br s, 1 H), 8.50 (dd, 1 H), 7.83-7.81 (m, 1 H), 7.38 (dd 2 H), 7.12 (dd, 1 H), 6.97 (d, 1 H), 3.29-3.25 (m, 1 H), 2.75-2.73 (m, 2 H), 2.49-2.43 (m, 6 H), 1.64-1.60 (m, 2 H), 1.16 (d, 6 H) and 0.97 (t, 6 H ).
    [1095] [1095] LCMS: m / z 451.2 (M + H) + (ES +). Example 61: 1- (2- (Dimethylamino) ethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H -pyrazol-3-sulfonamide
    [1096] [1096] 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) (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.
    [1097] [1097] 1- (2- (Dimethylamino) ethyl) -1H-pyrazol-3-sulfonamide (45 mg, 0.206 mmol) (Intermediate P9) 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 provide the title compound (16 mg, 16%) as a colorless powder.
    [1098] [1098] 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).
    [1099] [1099] LCMS; m / z 485.4 (M + H) + (ES +); 483.3 (M-H) - (ES-). Example 64: 5 - ((Dimethylamino) methyl) -1-ethyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide
    [1100] [1100] 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 61) from 5- ((dimethylamino) methyl) -1-ethyl-1H-pyrazol-3-sulfonamide (Intermediate P7) and 5- (2 - methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) to provide the title compound (29 mg, 28%) as a colorless powder.
    [1101] [1101] 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).
    [1102] [1102] LCMS; m / z 499.4 (M + H) + (ES +); 497.3 (M-H) - (ES-).
    [1103] [1103] The compounds of examples 59, 60, 62, 63 and 65-69 were synthesized by methods analogous to those described above and below.
    [1104] [1104] 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) (0.30 g, 1.25 mmol) was dissolved in THF ( 10 mL). TEA (0.20 ml, 1.43 mmol) was added, followed by a solution of bis (trichloromethyl) carbonate (0.35 g, 1.18 mmol) in THF (2 ml). The mixture was stirred at room temperature for 1 hour, then concentrated in vacuo and dried for 30 minutes to obtain intermediate 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2- methoxypyridine as a light yellow solid that was used without further purification.
    [1105] [1105] 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (45 mg, 0.21 mmol) was dissolved in dry THF (2 mL). NaO tBu (2 M in THF) (0.125 mL, 0.250 mmol) was added and the mixture was stirred at room temperature for 1 hour. A solution of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (prepared above) (55 mg) in THF (2 ml) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in DMSO (2 ml) and purified by basic preparative HPLC to obtain the title compound (41 mg, 40%) as a colorless powder.
    [1106] [1106] 1H NMR (DMSO-d6) δ 10.76 (s, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.03 (dd, J = 5.3, 0, 7 Hz, 1H), 7.91 (s, 1H), 7.60 (dd, J = 9.5, 2.6 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H) , 7.10 (d, J = 7.6 Hz, 1H), 6.83 (dd, J = 5.3, 1.5 Hz, 1H), 6.65 (s, 1H), 6.47 ( d, J = 9.6 Hz, 1H), 4.99 (sept, J = 6.8 Hz, 1H), 3.84 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.98 (p, J = 7.4 Hz, 2H), 1.29 (d, J = 6.8 Hz, 6H) .
    [1107] [1107] LCMS: m / z 483.3 (M + H) + (ES +); 481.5 (M-H) - (ES-). Example 71: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropyl-6-oxo-1,6- dihydropyridine-3-sulfonamide, sodium salt Step A: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1 - isopropyl-6-oxo-, 1,6-dihydropyridine-3-sulfonamide
    [1108] [1108] Prepared according to the general procedure of 1-isopropyl-N- ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) - 6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 70) of 4- (4-amino-2,3-dihydro-1H-inden-5-yl) picolinonitrile (Intermediate A36) (0 , 03g, 0.123mmol) and 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (0.027 g, 0.123 mmol) and purified by C18 reverse phase flash chromatography (12 g of column, 0-60% MeCN / 10 mM ammonium bicarbonate) to obtain the title compound (35 mg, 30%) as a white flocculent solid.
    [1109] [1109] 1H NMR (DMSO-d6) δ 8.56 (d, J = 5.1 Hz, 1H), 7.93 (d, J = 2.6 Hz,
    [1110] [1110] LCMS: m / z 478.3 (M + H) + (ES +); 476.2 (M-H) - (ES-). Step B: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- isopropi-6-oxo-1,6- dihydropyridine-3-sulfonamide, sodium salt Free acid Sodium salt
    [1111] [1111] N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- isopropyl-6-oxo-1,6- dihydropyridine-3-sulfonamide (0.025 g, 0.052 mmol) was treated with 0.1 M NaOH solution (520 μL) and the resulting solution lyophilized to obtain the title compound (26 mg, 99%) as a white solid.
    [1112] [1112] 1H NMR (DMSO-d6) δ 8.54 (dd, J = 5.1, 0.8 Hz, 1H), 7.91 - 7.89 (m, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.60 (dd, J = 5.1, 1.8 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.13 - 7.09 (m, 2H), 6.27 (d, J = 9.4 Hz, 1H), 4.97 (sept, J = 6.7 Hz, 1H), 2.89 (t, J = 7.5 Hz , 2H), 2.75 (t, J = 7.4 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.25 (d, J = 6.8 Hz, 6H ).
    [1113] [1113] LCMS: m / z 478.3 (M + H) + (ES +); 476.2 (M-H) - (ES-). Example 72: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4-isopropyl-5-oxo-4,5- dihydropyrazine-2-sulfonamide, sodium salt Step A: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4 - isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide
    [1114] [1114] Prepared according to the general procedure of 1-isopropyl-N- ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) - 6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 70) of 4- (4-amino-2,3-dihydro-1H-inden-5-yl) picolinonitrile (Intermediate A36) (0 , 03g, 0.123mmol) and 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P13) (0.027 g, 0.123 mmol) and purified by C18 reverse phase flash chromatography (12 g of column, 0-60% MeCN / 10 mM ammonium bicarbonate) to obtain the title compound (0.023 g, 19%) as a yellow flocculent solid.
    [1115] [1115] 1H NMR (DMSO-d6) δ 8.58 (d, J = 5.1 Hz, 1H), 7.93 (s, 2H), 7.89 (d, J = 1.7 Hz, 1H ), 7.76 (br s, 1H), 7.59 (dd, J = 5.2, 1.7 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.84 (p , J = 6.8 Hz, 1H), 2.91 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 1.99 (p, J = 7.5 Hz, 2H), 1.28 (d, J = 6.8 Hz, 6H).
    [1116] [1116] LCMS: m / z 479.3 (M + H) + (ES +); 477.2 (M-H) - (ES-). Step B: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4-isopropyl-5-oxo-4,5- dihydropyrazine-2-sulfonamide, sodium salt Free acid Sodium salt
    [1117] [1117] N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4-isopropyl-5-oxo-4,5- dihydropyrazine-2-sulfonamide (0.015 g, 0.031 mmol) was treated with 0.1 M NaOH solution (310 μL) and the resulting solution was lyophilized to obtain the title compound (16 mg, quantum yield) as a yellow solid.
    [1118] [1118] 1H NMR (DMSO-d6) δ 8.56 (d, J = 5.1 Hz, 1H), 7.89 (t, J = 1.6 Hz, 2H), 7.84 (d, J = 1.1 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.13 - 7.09 (m, 2H), 4.85 (sept, J = 6.8 Hz, 1H) , 2.90 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 1.98 (p, J = 7.5 Hz, 2H), 1 , 28 (d, J = 6.8 Hz, 6H).
    [1119] [1119] LCMS: m / z 479.3 (M + H) + (ES +); 477.1 (M-H) - (ES-).
    [1120] [1120] Prepared according to the general procedure of 1-isopropyl-N- ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) - 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide 6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 70) (Intermediate P13) (26 mg, 0.12 mmol) and 5- (2-methoxypyridin-4-yl) - 2,3-dihydro-1H-inden-4-amine (Intermediate A35) (50mg, 0.21mmol) to obtain the title compound (13, 2 mg, 23%).
    [1121] [1121] 1H NMR (DMSO-d6) δ 8.09 (s, 1H), 8.05 (d, J = 5.3 Hz, 1H), 7.98 (s, 1H), 7.71 (s , 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 5.3 Hz, 1H ), 6.65 (s, 1H), 4.86 (sept, J = 7.2, 6.7 Hz, 1H), 3.86 (s, 3H), 2.90 (t, J = 7, 4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 1.98 (p, J = 7.4 Hz, 2H), 1.30 (d, J = 6.7 Hz , 6H).
    [1122] [1122] LCMS: m / z 484.3 (M + H) + (ES +). Example 74: N - (((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 1-isopropylazetidine-3-sulfonamide
    [1123] [1123] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (70 mg, 392.70 μmol, 1 eq) in THF (2 ml) was added t-BuONa (37 mg, 392.70 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A37) (110 mg, 392.70 μmol, 1 eq) was added. The reaction mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN];
    [1124] [1124] 1H NMR (DMSO-d6) δ 8.75 (d, 1 H), 8.06 (s, 1 H), 7.77-7.66 (m, 2 H), 7.21 (dd , 1 H), 7.12 (dd, 1 H), 3.78-3.49 (m, 4 H), 3.26-3.22 (d, 2 H), 2.83-2.79 (m, 1 H), 1.15 (d, 6 H) and 0.95 (d, 6 H). An unobserved interchangeable proton.
    [1125] [1125] LCMS: m / z 460.2 (M + H) + (ES +). Example 75: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-isopropylazetidine-3-sulfonamide
    [1126] [1126] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (70 mg, 392.70 μmol, 1 eq) in THF (2 ml) was added t-BuONa (38 mg, 392.70 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (112 mg, 392.70 μmol, 1 eq) was added. The mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 12% -42% 11.5 min) to obtain the title compound (87.88 mg, 48% yield, 99% LCMS purity) as a white solid.
    [1127] [1127] 1H NMR (DMSO-d6) δ 8.11 (d, 1 H), 7.17 (br s, 1 H), 7.11 (d, 1 H), 7.01 (s, 1 H ), 6.93 (d, 1 H), 6.85 (s, 1 H), 3.86 (s, 3 H), 3.81-3.77 (m, 1 H), 3.26- 3.22 (m, 1 H), 3.18-3.15 (m, 2 H), 3.03-3.00 (m, 2 H), 2.22-1.98 (m, 1 H ), 1.16-1.12 (m, 6 H) and 0.80 (d, 6 H). An unobserved interchangeable proton.
    [1128] [1128] LCMS: m / z 465.2 (M + H) + (ES +). Example 76: 1-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide
    [1129] [1129] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (70 mg, 392.70 μmol, 1 eq) in THF (2 ml) was added t-BuONa (38 mg, 392.70 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (104 mg, 392.70 μmol, 1 eq) was added. The mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% - 38% 11.5 min) to obtain the title compound (56.2 mg, 32% yield, 100% LCMS purity) as a white solid.
    [1130] [1130] 1H NMR (DMSO-d6) δ 8.13 (d, 1 H), 7.49 (br s, 1 H), 7.12 (d, 1 H), 7.07 (d, 1 H ), 6.98 (d, 1 H), 6.79 (s, 1 H), 4.00-3.94 (m, 1 H), 3.87 (s, 3 H), 3.70- 3.64 (m, 2 H), 3.58-3.54 (m, 2 H), 2.91 (t, 2 H), 2.83 (t, 2 H), 2.76-2, 73 (m, 1 H), 2.04-1-97 (m, 2 H) and 0.94 (d, 6 H). An unobserved interchangeable proton.
    [1131] [1131] LCMS: m / z 445.2 (M + H) + (ES +). Example 77: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropylazetidine-3-sulfonamide O O O O O S S F F
    [1132] [1132] A mixture of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (50 mg, 280.50 μmol, 1 eq) and t-BuONa (27 mg, 280.50 μmol, 1 eq) in THF (2 ml ) was stirred at 25 ° C for 10 minutes. 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (71 mg, 280.50 μmol, 1 eq) was added and the resulting mixture it was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by
    [1133] [1133] 1H NMR (DMSO-d6) δ 8.55 (d, 2 H), 7.41-7.38 (m, 3 H), 6.95 (d, 1 H), 3.94-3 .88 (m, 1 H), 3.70-3.67 (m, 2 H), 3.61-3.58 (m, 2 H), 2.95 (t, 2 H), 2.86 (t, 2 H), 2.82-2.75 (m, 1 H), 2.10-2.02 (m, 2 H) and 0.96 (d, 6 H). An unobserved interchangeable proton.
    [1134] [1134] LCMS: m / z 433.2 (M + H) + (ES +). Example 78: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 1-cyclobutylazetidine-3-sulfonamide O
    [1135] [1135] A solution of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P15) (30 mg, 157.68 μmol, 1 eq) and t-BuONa (15 mg, 157.68 μmol, 1 eq) in THF (1 ml ) was stirred at 25 ° C for 10 minutes. 4- (5-Fluoro-2-isocyanato-3-isopropylphenyl) picolinonitrile (Intermediate A37) (44 mg, 157.68 μmol, 1 eq) was added and the resulting mixture was stirred at 25 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (6.35 mg, 8% yield, 97% purity in LCMS) as a white solid.
    [1136] [1136] 1H NMR (DMSO-d6) δ 8.75 (d, 1 H), 8.05 (s, 1 H), 7.77-7.75 (m, 1 H), 7.67-7 , 65 (m, 1 H), 7.23-7.18 (m, 1 H), 7.12 (d, 1 H), 3.95-3.68 (m, 2 H), 3.67 - 3.56 (m, 2 H), 3.55-3.42 (m, 2 H), 3.25-3.21 (m, 1 H), 1.99-1.97 (m, 2 H), 1.86-1.84 (m, 2 H), 1.71-1.62 (m, 2 H) and 1.16 (d, 6 H). An unobserved interchangeable proton.
    [1137] [1137] LCMS: m / z 472.2 (M + H) + (ES +). Example 79: 1-Cyclobutyl-N - ((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-
    [1138] [1138] To a solution of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P15) (25 mg, 131.40 μmol, 1 eq) in THF (1 ml) was added t-BuONa (13 mg, 131.40 μmol, 1 eq). The reaction mixture was stirred at 20 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (38 mg, 131.40 μmol, 1 eq) was added and the resulting mixture was stirred at 20 ° C for 20 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 15% -45%, 10 min ) to give the title compound (41.16 mg, 66% yield, 100% purity in LCMS) as a white solid.
    [1139] [1139] 1H NMR (DMSO-d6) δ 8.16 (d, 1 H), 7.61 (br s, 1 H), 7.16 (d, 1 H), 7.03-6.96 ( m, 2 H), 6.83 (s, 1 H), 4.02-3.92 (m, 1 H), 3.88 (s, 3 H), 3.75-3.48 (m, 4 H), 3.22-3.02 (m, 2 H), 2.15-1.95 (m, 2 H), 1.94-1.76 (m, 2 H), 1.74- 1.56 (m, 2 H) and 1.14 (d, 6 H). An unobserved interchangeable proton.
    [1140] [1140] LCMS: m / z 477.2 (M + H) + (ES +). Example 80: 1-Cyclobutyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide O O S O The HN The N
    [1141] [1141] A mixture of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P15) (40 mg, 210.24 μmol, 1 eq) and t-BuONa (20 mg, 210.24 μmol, 1 eq) in THF (2 ml ) was stirred at 25 ° C for 10 minutes. Then 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (56 mg, 210.24 μmol, 1 eq) was added and the mixture The resulting mixture was stirred at 70 ° C for 30 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 10% -40%, 10 min) to obtain the title compound (20.06 mg, 21% yield, 100% LCMS purity) as a white solid.
    [1142] [1142] 1H NMR (DMSO-d6) δ 8.13 (d, 1 H), 7.40 (br s, 1 H), 7.12 (d, 1 H), 7.06 (d, 1 H ), 6.96 (d, 1 H), 6.77 (s, 1 H), 4.06-3.98 (m, 1 H), 3.87 (s, 3 H), 3.49- 3.44 (m, 3 H), 3.38-3.35 (m, 2 H), 2.91 (t, 2 H), 2.82 (t, 2 H), 2.03-1, 99 (m, 2 H), 1.98-1.94 (m, 2 H), 1.85-1.81 (m, 2 H) and 1.71-1.62 (m, 2 H). An unobserved interchangeable proton.
    [1143] [1143] LCMS: m / z 457.3 (M + H) + (ES +). Example 81: 1-Cyclobutyl-N - (((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide O O O O O F S F s
    [1144] [1144] A mixture of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P15) (37 mg, 194.47 μmol, 1 eq) and t-BuONa (19 mg, 194.47 μmol, 1 eq) in THF (2 ml ) was stirred at 25 ° C for 10 minutes. Then 4- (7-Fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (49 mg, 194.47 μmol, 1 eq) was added and the The resulting mixture was stirred at 25 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18, 250mm * 50mm * 10μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B%: 0% -30%, 10 min) to obtain the title compound (18.09 mg, 20% yield, 97% purity in LCMS) as a yellow solid.
    [1145] [1145] 1H NMR (DMSO-d6) δ 8.57 (d, 2 H), 7.57 (br s, 1 H), 7.39 (d, 2 H), 6.97 (d, 1 H ), 4.02-3.95 (m, 1 H), 3.70-3.66 (m, 3 H), 3.57-3.54 (m, 1 H), 3.37-3, 27 (m, 1 H), 2.96 (t, 2 H), 2.86 (t, 2 H), 2.11 - 2.00 (m, 4 H), 1.92-1.87 ( m, 2 H) and 1.72 - 1.65 (m, 2 H). An unobserved interchangeable proton.
    [1146] [1146] LCMS: m / z 445.2 (M + H) + (ES +). Example 82: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1- ethylazetidine-3-sulfonamide F F O O O O
    [1147] [1147] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P16) (40 mg, 243.57 μmol, 1 eq) in THF (1 ml) was added t-BuONa (23 mg, 243.57 μmol, 1 eq). The mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -picolinonitrile (Intermediate A37) (68 mg, 243.57 μmol, 1 eq) was added and the mixture was stirred at 70 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% - 38%, 11.5 min) to obtain the title compound (48.97 mg, 45% yield, 100% LCMS purity) as a white solid.
    [1148] [1148] 1H NMR (DMSO-d6) δ 8.75 (d, 1 H), 8.05 (s, 1 H), 7.76 (s, 1 H), 7.66 (s, 1 H) , 7.22-7.18 (m, 1 H), 7.12-7.09 (m, 1 H), 3.83-3.76 (m, 5 H), 3.24-3.20 (m, 1 H), 2.93-2.88 (m, 2 H), 1.16 (d, 6 H) and 0.99 (t, 3 H). An unobserved interchangeable proton.
    [1149] [1149] LCMS: m / z 446.2 (M + H) + (ES +). Example 83: 1-Ethyl-N - (((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) azetidine-3-sulfonamide F F O O O O
    [1150] [1150] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P16) (40 mg, 243.57 μmol, 1 eq) in THF (1 ml) was added t-BuONa (23 mg, 243.57 μmol, 1 eq). The mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (69 mg,
    [1151] [1151] 1H NMR (DMSO-d6) δ 8.15 (d, 1 H), 7.48 (s, 1 H), 7.17-7.12 (m, 1 H), 7.03-6 , 94 (m, 2 H), 6.84 (s, 1 H), 3.99-3.77 (m, 8 H), 3.24-3.20 (m, 1 H), 2.95 - 2.92 (m, 2 H), 1.15 (d, 6 H) and 1.00 (t, 3 H). An unobserved interchangeable proton.
    [1152] [1152] LCMS: m / z 451.2 (M + H) + (ES +). Example 84: 1-Ethyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide O O O O
    [1153] [1153] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P16) (40 mg, 243.57 μmol, 1 eq) in THF (1 ml) was added t-BuONa (23 mg, 243.57 μmol, 1 eq). The mixture was stirred at 25 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (64 mg, 243.57 μmol, 1 eq) was added and the mixture it was stirred at 70 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% - 38%, 11.5 min) to obtain the title compound (52.99 mg, 51% yield, 100% LCMS purity) as a white solid.
    [1154] [1154] 1H NMR (DMSO-d6) δ 8.13 (d, 1 H), 7.43 (br s, 1 H), 7.12 (d, 1 H), 7.06 (d, 1 H ), 6.97 (dd, 1 H), 6.79 (s, 1 H), 4.08-4.00 (m, 1 H), 3.88 (s, 3 H), 3.85- 3.80 (m, 2 H), 3.77-3.72 (m, 2 H), 2.91 (t, 2 H), 2.87-2.80 (m, 4 H), 2, 04-1.96 (m, 2 H) and 0.98 (t, 3 H). An unobserved interchangeable proton.
    [1155] [1155] LCMS: m / z 431.2 (M + H) + (ES +).
    [1156] [1156] A solution of 1-ethylazetidine-3-sulfonamide (Intermediate P16) (50 mg, 304.46 μmol, 1 eq) and t-BuONa (29 mg, 304.46 μmol, 1 eq) in THF (1 ml ) was stirred at 25 ° C for 10 minutes. Then, a solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (77 mg, 304.46 μmol, 1 eq) in THF (2 ml) was added and the reaction mixture was stirred at 25 ° C for 10 minutes. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (9.59 mg, 8% yield, 100% LCMS purity) as a white solid.
    [1157] [1157] 1H NMR (DMSO-d6) δ 8.57 (d, 2 H), 7.43 (br s, 1 H), 7.40 (d, 2 H), 6.96 (d, 1 H ), 4.01-3.88 (m, 5 H), 2.98-2.93 (m, 4 H), 2.86 (t, 2 H), 2.11-2.03 (m, 2 H) and 1.01 (t, 3 H). An unobserved interchangeable proton.
    [1158] [1158] LCMS: m / z 419.2 (M + H) + (ES +). Example 86: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide
    [1159] [1159] A solution of 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (Intermediate P17) (50 mg, 219.99 μmol, 1 eq), 4- (5-fluoro-2-isocyanate-3- isopropylphenyl) picolinonitrile (Intermediate A37) (68 mg, 241.99 μmol, 1.1 eq) and t-BuONa (25 mg, 263.99 μmol, 1.2 eq) in THF (1.5 ml) was stirred at 16 ° C for
    [1160] [1160] 1H NMR (DMSO-d6) δ 8.74 (d, 1 H), 8.50-8.47 (m, 2 H), 8.05 (s, 1 H), 8.00 (br s, 1 H), 7.73 (d, 1 H), 7.68 (d, 1 H), 7.39-7.35 (m, 1 H), 7.29-7.25 (m, 1 H), 7.16 (d, 1 H), 4.03-3.97 (m, 1 H), 3.73-3.68 (m, 2 H), 3.45-3.38 ( m, 4 H), 3.19 - 3.15 (m, 1 H) and 1.14 (d, 6 H). An unobserved interchangeable proton.
    [1161] [1161] LCMS: m / z 509.3 (M + H) + (ES +). Example 87: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (pyridin-3-ylmethyl) azetidine-3 -sulfonamide
    [1162] [1162] A solution of 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (Intermediate P17) (50 mg, 219.99 μmol, 1 eq), 4- (4-isocyanate-2,3-di- hydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (64 mg, 241.99 μmol, 1.1 eq) and t-BuONa (25 mg, 263.99 μmol, 1.2 eq) in THF (1.5 ml) it was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3 v / v); B: MeCN]; B%: 15% -45 %, 12 min) to give the title compound (37 mg, 34%) as a white solid.
    [1163] [1163] 1H NMR (DMSO-d6) δ 8.49- 8.45 (m, 2 H), 8.12 (d, 1 H), 7.79 (br s, 1 H), 7.67 ( d, 1 H), 7.38-7.33 (m, 1 H), 7.18 (d, 1 H), 7.09 (d, 1 H), 6.92 (d, 1 H), 6.73 (s, 1 H), 4.19-4.15 (m, 1 H), 3.80 (s, 3 H), 3.66 (s, 2 H), 3.50-3, 43 (m, 2 H), 3.38-3.34 (m, 2 H), 2.91 (t, 2 H), 2.78 (t, 2 H) and 2.04-1.98 ( m, 2 H). An unobserved interchangeable proton.
    [1164] [1164] LCMS: m / z 494.2 (M + H) + (ES +).
    [1165] [1165] To a solution of 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (Intermediate P17) (54 mg, 235.98 μmol, 1 eq) in THF (5 ml) was added t-BuONa (27 mg, 283.18 μmol, 1.2 eq) and a solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (60 mg, 235.98 μmol, 1 eq) in THF (5 ml) and DCM (5 ml). The reaction mixture was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3 v / v); B: MeCN]; B%: 5% -50 %, 10 min) to give the title compound (35.53 mg, 31% yield, 99.4% LCMS purity) as a white solid.
    [1166] [1166] 1H NMR (DMSO-d6) δ 8.56-8.54 (m, 2 H), 8.49-8.47 (m, 2 H), 7.76 (br s, 1 H), 7.68 (d, 1 H), 7.36 (dd, 3 H), 7.00 (d, 1 H), 4.17-4.12 (m, 1 H), 3.68 (s, 2 H), 3.47 (t, 2 H), 3.40 (t, 2 H), 2.96 (t, 2 H), 2.84 (t, 2 H) and 2.11 - 2, 03 (m, 2 H). An unobserved interchangeable proton.
    [1167] [1167] LCMS: m / z 482.2 (M + H) + (ES +). Example 89: N - ((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) -1- isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide
    [1168] [1168] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (60 mg, 225.09 μmol, 1 eq), 4- (5-fluoro-2 -isocyanate-3-isopropylphenyl) -picolinonitrile (Intermediate A37) (70 mg, 247.60 μmol, 1.1 eq) and t- BuONa (26 mg, 270.11 μmol, 1.2 eq) in THF (1, 5 mL) was stirred at 16 ° C for
    [1169] [1169] 1H NMR (DMSO-d6) δ 8.57 (d, 1 H), 7.99-7.92 (m, 3 H), 7.64-7.62 (m, 1 H), 7 , 47-7.45 (m, 1 H), 7.25-7.22 (m, 1 H), 7.14-7.11 (m, 1 H), 6.36 (d, 1 H) , 4.99-4.91 (m, 1 H), 3.10-3.05 (m, 1 H), 1.25 (d, 6 H) and 1.09 (d, 6 H). An unobserved interchangeable proton.
    [1170] [1170] LCMS: m / z 498.3 (M + H) + (ES +). Example 90: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide
    [1171] [1171] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (60 mg, 225.09 μmol, 1 eq), 4- (5-fluoro-2 -isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (71 mg, 247.60 μmol, 1.1 eq) and t-BuONa (26 mg, 270.11 μmol, 1.2 eq) in THF ( 1.5 ml) was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18, 250mm * 50mm * 10μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B%: 2% -32%, 10 min) to give the title compound (61 mg, 54%) as a white solid.
    [1172] [1172] 1H NMR (DMSO-d6) δ 7.97 (d, 2 H), 7.51 (d, 2 H), 7.13 (dd, 1 H), 6.96-6.89 (m , 2 H), 6.73 (s, 1 H), 6.35 (d, 1 H), 5.00-4.95 (m, 1 H), 3.83 (s, 3 H), 3 , 09-3.04 (m, 1 H), 1.25 (d, 6 H) and 1.05 (d, 6 H). An unobserved interchangeable proton.
    [1173] [1173] LCMS: m / z 503.2 (M + H) + (ES +). Example 91: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-isopropyl-6-oxo-1, 6-dihydropyridine-3-sulfonamide
    [1174] [1174] Solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (50 mg, 187.58 μmol, 1 eq), 4- (7-fluoro-4- isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (52 mg, 206.34 μmol, 1.1 eq) and t-BuONa (22 mg, 225.10 μmol, 1.2 eq) in THF (1.5 ml) was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3 v / v); B: MeCN]; B%: 12% -42 %, 12 min) to give the title compound (6 mg, 7% yield, 99.17% LCMS purity) as a white solid.
    [1175] [1175] 1H NMR (DMSO-d6) δ 8.46 (d, 2 H), 8.08 (s, 1 H), 7.83 (br s, 1 H), 7.58 (dd, 1 H ), 7.26 (d, 2 H), 6.99 (d, 1 H), 6.45 (d, 1 H), 5.02-4.94 (m, 1 H), 2.94 ( t, 2 H), 2.71 (t, 2 H), 2.07-2.01 (m, 2 H) and 1.28 (d, 6 H). An unobserved interchangeable proton.
    [1176] [1176] LCMS: m / z 471.2 (M + H) + (ES +). Example 92: N - (((4-Fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1- isopropylazetidine-3-sulfonamide
    [1177] [1177] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (200 mg, 1.12 mmol, 1 eq) in THF (5 mL) was added MeONa (60 mg, 1.12 mmol, 1 eq ). The reaction mixture was stirred at 25 ° C for 30 minutes. Then 3- (5-fluoro-2-isocyanate-3-isopropylphenyl) pyridine (Intermediate A41) (431 mg, 1.68 mmol, 1.5 eq) was added and the resulting mixture was stirred at 70 ° C for 30 minutes . Then, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: Welch Ultimate XB_C18, 35mm * 235mm * 20 / 35μm, mobile phase: [A: water (0.05% ammonium hydroxide); B: MeCN]; B%: 0% -40%, 10 min) to give the title compound (33 mg, 7% yield, 100% LCMS purity) as a white solid.
    [1178] [1178] 1H NMR (DMSO-d6) δ 8.60-8.51 (m, 2 H), 7.92-7.77 (m, 1 H), 7.57 (s, 1 H), 7 , 44-7.40 (m, 1 H), 7.14 (d, 1 H), 7.00 (d, 1 H), 3.92-3.74 (m, 3 H), 3.29 - 2.95 (m, 4 H), 1.26-1.10 (m, 6 H) and 1.02 (d, 6 H). An unobserved interchangeable proton.
    [1179] [1179] LCMS: m / z 435.2 (M + H) + (ES +). Example 93: N - (((4-Fluoro-2-isopropyl-6- (pyridin-3-yl) phenyl) carbamoyl) -1- isopropylpiperidine-4-sulfonamide F N F
    [1180] [1180] To a solution of 1-isopropylpiperidine-4-sulfonamide (Intermediate P18) (720 mg, 3.49 mmol, 1 eq) in THF (10 mL) was added NaOMe (226 mg, 4.19 mmol, 1, 2 eq) and 3- (5-fluoro-2-isocyanate-3-isopropylphenyl) pyridine (Intermediate A41) (805 mg, 3.14 mmol, 0.9 eq). The reaction mixture was then stirred at 70 ° C for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 250mm * 50mm * 10μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 15% -45%, 10 min ) to give the title compound (69.36 mg, 4% yield, 100% purity in LCMS) as a white solid.
    [1181] [1181] 1H NMR (DMSO-d6) δ 8.57 (s, 1 H), 8.48 (d, 1 H), 7.87-7.80 (m, 1 H), 7.36-7 , 32 (m, 1 H), 7.25 (s, 1 H), 7.10 (d, 1 H), 6.95 (d, 1 H), 6.09 (s, 1 H), 2 , 95-2.85 (m, 1 H), 2.79-2.76 (m, 2 H), 2.70-2.63 (m, 2 H), 1.98-1.85 (m , 2 H), 1.65-1.61 (m, 2 H), 1.42-1.38 (m, 2 H), 1.14 (d, 6 H) and 0.94 (d, 6 H). An unobserved interchangeable proton.
    [1182] [1182] LCMS: m / z 463.4 (M + H) + (ES +). Example 94: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide
    [1183] [1183] A solution of 1- (pyridin-3-ylmethyl) azetidine-3-sulfonamide (Intermediate P17) (50 mg, 219.99 μmol, 1 eq), 4- (5-fluoro-2-isocyanate-3- isopropylphenyl) -2-methoxypyridine (Intermediate A38) (69 mg, 241.99 μmol, 1.1 eq) and t-BuONa (25 mg, 263.99 μmol, 1.2 eq) in THF (1.5 ml) it was stirred at 16 ° C for 0.5 hour. Then, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% -38%, 11.5 min) to give the title compound (44 mg, 38%) as a white solid.
    [1184] [1184] 1H NMR (DMSO-d6) δ 8.47 (s, 2 H), 8.12 (d, 1 H), 7.67 (d, 2 H), 7.35 (dd, 1 H) , 7.19 (d, 1 H), 7.01-6.95 (m, 2 H), 6.80 (s, 1 H), 4.04-3.98 (m, 1 H), 3 , 78 (s, 3 H), 3.64 (s, 2 H), 3.43-3.36 (m, 4 H), 3.16-3.12 (m, 1 H) and 1.12 (d, 6 H). An unobserved interchangeable proton.
    [1185] [1185] LCMS: m / z 514.3 (M + H) + (ES +). Example 95: 1-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-oxo-1,2- dihydropyrimidine-5-sulfonamide, sodium salt
    [1186] [1186] A suspension of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (0.033 g, 0.137 mmol) (Intermediate A35) and (4- (dimethylamino ) pyridin-1-io-1-carbonyl) ((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl) sulfonyl) amide (Intermediate P19) (0.069 g, 0.123 mmol) in dry MeCN (2 ml) was stirred at 50 ° C for 2 hours. Then, the reaction mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (column: Waters Xbridge C18, 19mm * 15mm * 5μm; mobile phase: [A: water (0.1% NH4HCO3); B: MeCN ]; B%: 10% -40%) to obtain 1-
    [1187] [1187] 1H NMR (DMSO-d6) δ 8.65 (d, J = 3.0 Hz, 1H), 8.35 (d, J = 3.1 Hz, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.24 (br s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H) , 6.88 (dd, J = 5.3, 1.4 Hz, 1H), 6.70 (t, J = 1.0 Hz, 1H), 4.76 (sept, J = 6.7 Hz, 1H), 3.82 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.30 (d, J = 6.8 Hz, 6H).
    [1188] [1188] LCMS: m / z 484.1 (M + H) + (ES +); 482.1 (M-H) - (ES-). Example 96: 1-Isopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-oxo-1,2- dihydropyridine-4-sulfonamide, sodium salt
    [1189] [1189] To a solution of 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A35) (0.156 g, 0.65 mmol) in DCM ( 5 ml) and saturated aqueous NaHCO3 (5 ml) a solution of bis (trichloromethyl) carbonate (0.079 g, 0.264 mmol) in toluene (1 ml) was added to the DCM layer without stirring. The reaction mixture was stirred for 1 hour, passed through a phase separator, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude isocyanate intermediate as an orange oil which was used without further purification. The crude isocyanate intermediate was dissolved in dry THF (11 ml).
    [1190] [1190] A solution of 1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Intermediate P20) (0.050 g, 0.224 mmol) in dry THF (3 mL) was treated with tert-butoxide sodium (2 M in THF) (0.120 ml, 0.24 mmol). The reaction mixture was stirred at room temperature for 1 hour, treated with a solution of the crude isocyanate intermediate in dry THF (4 ml) and then stirred at room temperature for 22 hours. The reaction mixture was concentrated in vacuo and the residue purified by C18 reverse phase flash chromatography (liquid charge) (12 g cartridge, 5-50% MeCN / 10 mM ammonium bicarbonate)
    [1191] [1191] 1H NMR (DMSO-d6) δ 8.06 (dd, J = 5.3, 0.7 Hz, 1H), 7.87 (dd, J = 6.9, 2.1 Hz, 1H) , 7.76 (dd, J = 7.0, 2.1 Hz, 1H), 7.30 (br s, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.76 (t, J = 1.0 Hz, 1H), 6 , 30 (t, J = 6.9 Hz, 1H), 5.14 (sept, J = 6.8 Hz, 1H), 3.85 (s, 3H), 2.85 (t, J = 7, 4 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 1.90 (p, J = 7.5 Hz, 2H), 1.30 (d, J = 6.8 Hz , 6H).
    [1192] [1192] LCMS: m / z 483.1 (M + H) + (ES +); 481.0 (M-H) - (ES-). Example 97: 1-Ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine-4-sulfonamide , potassium salt
    [1193] [1193] To a solution of 1-ethylpiperidine-4-sulfonamide (Intermediate P11; 90 mg, 0.37 mmol) in THF (5 mL) was added potassium tert-butoxide (49 mg, 0.44 mmol). The mixture was stirred at room temperature for 45 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A42; 90 mg, 0.32 mmol) was added and the mixture it was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and DMSO (0.5-1 ml) was added. The mixture (filtered over cotton when solids were present) was subjected to purification by reverse phase column chromatography (see "Experimental Methods", preparative reverse phase HPLC method 4) to obtain the title compound (18 mg, 10% ) as a white solid.
    [1194] [1194] 1H NMR (methanol-d4) δ 8.10 (d, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 6.84 (s, 1H), 3.92 (s, 3H), 3.23 (m, 2H), 3.07 (m, 1H), 3.00 (m, 4H), 2.68 (m, 2H), 2.32-
    [1195] [1195] LCMS: m / z 477 (M + H) + (ES +); 475 (M-H) - (ES-). Example 98: 1-Ethyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt
    [1196] [1196] Prepared as described for 1-ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 97) using 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) and 1-ethylpiperidine-4 -sulfonamide (Intermediate P11) to obtain the title compound (54 mg, 30%) as a white solid.
    [1197] [1197] 1H NMR (methanol-d4) δ 8.08 (d, 1H), 7.25 - 7.08 (m, 2H), 7.03 (dd, 1H), 6.86 (s, 1H) , 3.92 (s, 3H), 3.39 - 3.17 (m, 3H), 2.95 (m, 4H), 2.71 (q, 2H), 2.33 (t, 2H), 2.22 - 1.97 (m, 4H), 1.97 - 1.72 (m, 2H), 1.18 (t, 3H).
    [1198] [1198] LCMS: m / z 459 (M + H) + (ES +); 457 (M-H) - (ES-). Example 99: N - ((5- (2-Cyanopyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-ethylpiperidine-4-sulfonamide, potassium salt
    [1199] [1199] Prepared as described for 1-ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 97) using 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) picolinonitrile (Intermediate A43) and 1-ethylpiperidine-4-sulfonamide ( Intermediate P11) to obtain the title compound (18 mg, 18%) as a white solid.
    [1200] [1200] 1H NMR (methanol-d4) δ 8.66 (dd, 1H), 7.95 (d, 1H), 7.73 (dd, 1H),
    [1201] [1201] LCMS: m / z 454 (M + H) + (ES +); 452 (M-H) - (ES-). Example 100: 1-Ethyl-N - (((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) piperidine-4-sulfonamide, potassium salt
    [1202] [1202] Prepared as described for 1-ethyl-N - ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 97) using 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) and 1-ethylpiperidine-4-sulfonamide (Intermediate P11) to obtain the title compound (23 mg, 14%) as a white solid.
    [1203] [1203] 1H NMR (methanol-d4) δ 8.09 (d, 1H), 7.06 (dd, 2H), 6.88 (m, 2H), 3.92 (s, 3H), 3.72 (m, 1H), 3.19 (m, 1H), 3.08 (m, 2H), 2.49 (d, 2H), 1.87 (m, 6H), 1.23 (d, 6H) , 1.12 (t, 3H).
    [1204] [1204] LCMS: m / z 479 (M + H) + (ES +); 477 (M-H) - (ES-). Example 101: 1-Ethyl-N - ((5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine-4-sulfonamide, potassium salt
    [1205] [1205] Prepared as described for 1-ethyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) piperidine -4-sulfonamide, potassium salt (Example 97) using 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A44) and 1-ethylpiperidine-4-sulfonamide ( Intermediate P11) to obtain the title compound (11 mg, 13%) as a white solid.
    [1206] [1206] 1H NMR (methanol-d4) δ 8.55 - 8.42 (m, 2H), 7.58 - 7.44 (m, 2H), 7.24 - 7.05 (m, 2H), 3.22 (d, 2H), 3.07 (m, 1H), 2.97 (m, 4H), 2.65 (t, 2H), 2.23 (t, 2H), 2.10 (m , 2H), 2.04 - 1.67 (m, 4H), 1.18 (t, 3H).
    [1207] [1207] LCMS: m / z 429 (M + H) + (ES +); 427 (M-H) - (ES-). Example 102: N - (((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 6- (dimethylamino) pyrazine-2-sulfonamide The F F
    [1208] [1208] To a solution of 6- (dimethylamino) pyrazine-2-sulfonamide (intermediate P21) (65 mg, 321.41 μmol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321 , 41 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A37) (90 mg, 321.41 μmol, 1 eq) was added and the resulting mixture was stirred at 70 ° C for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 18% -48%, 11.5 min) to obtain the title compound (75.35 mg, 48% yield, 100% LCMS purity) as a white solid.
    [1209] [1209] 1H NMR (DMSO-d6): δ 8.57 (d, 1 H), 8.05 (s, 1 H), 7.96 (s, 1 H), 7.64 (br s, 1 H), 7.20-7.14 (m, 4 H), 3.19-3.15 (m, 1 H), 3.07 (s, 6 H) and 1.08 (d, 6 H) .
    [1210] [1210] LCMS: m / z 484.2 (M + H) + (ES +). Example 103: 6- (Dimethylamino) -N - ((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) pyrazine-2-sulfonamide O
    [1211] [1211] To a solution of 6- (dimethylamino) pyrazine-2-sulfonamide (intermediate P21) (65 mg, 321.41 μmol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321 , 41 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then, 4- (5-fluoro-2-isocyanato-3-isopropylphenyl) -2-methoxypyridine (intermediate A38) (92 mg, 321.41 μmol, 1 eq) was added. The mixture was stirred at 70 ° C for 10 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 20% -50%, 11.5 min) to obtain the title compound (41.48 mg, 26% yield, 100% LCMS purity) as a white solid.
    [1212] [1212] 1H NMR (DMSO-d6): δ 8.27 (s, 1 H), 8.10 (s, 1 H), 8.05 (d, 1 H), 7.74 (br s, 1 H), 7.14 (d, 1 H), 6.97 (d, 1 H), 6.91 (s, 1 H), 6.76 (s, 1 H), 3.87 (s, 3 H), 3.11 (s, 6 H), 3.04-2.95 (m, 1 H) and 1.25-1.02 (m, 6 H).
    [1213] [1213] LCMS: m / z 489.2 (M + H) + (ES +). Example 104: 6- (Dimethylamino) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) pyrazine-2-sulfonamide O
    [1214] [1214] To a solution of 6- (dimethylamino) pyrazine-2-sulfonamide (intermediate P21) (65 mg, 321.41 μmol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321 , 41 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (intermediate A39) (85 mg, 321.41 μmol, 1 eq) was added. The mixture was stirred at 70 ° C for 10 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 18% -48%, 11.5 min) to obtain the title compound (96.47 mg, 64% yield, 100% LCMS purity) as a white solid.
    [1215] [1215] 1H NMR (DMSO-d6): δ 8.23 (s, 1 H), 8.14 (s, 1 H), 8.06 (d, 1 H), 7.65 (br s, 1 H), 7.13 (d, 1 H), 7.06 (d, 1 H), 6.90 (d, 1 H), 6.74 (s, 1 H), 3.87 (s, 3 H), 3.09 (s, 6 H), 2.89 (t, 2 H), 2.71-2.67 (m, 2 H) and 2.00-1.91 (m, 2 H) .
    [1216] [1216] LCMS: m / z 469.2 (M + H) + (ES +). Example 105: 6- (Dimethylamino) -N - (((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) pyrazine-2-sulfonamide
    [1217] [1217] A mixture of 6- (dimethylamino) pyrazine-2-sulfonamide (intermediate P21) (60 mg, 296.69 μmol, 1 eq) and t-BuONa (29 mg, 296.69 μmol, 1 eq) in THF (2 mL) was stirred at 25 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (intermediate A40) (75 mg, 296.69 μmol, 1 eq) was added. The mixture was stirred at 25 ° C for 10 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (10 mg, 7% yield, 100% LCMS purity) as a white solid.
    [1218] [1218] 1H NMR (DMSO-d6): δ 11.13 (br s, 1 H), 8.50 (d, 2 H), 8.30 (s, 1 H), 8.15 (s, 1 H), 7.83 (br s, 1 H), 7.30 (d, 2 H), 6.98 (d, 1 H), 3.11 (s, 6 H), 2.94 (t, 2 H), 2.73-2.69 (m, 2 H) and 2.08-2.00 (m, 2 H).
    [1219] [1219] LCMS: m / z 457.2 (M + H) + (ES +). Example 106: N - ((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 5- (dimethylamino) pyrazine-2-sulfonamide O F O N S O O The HN N S F
    [1220] [1220] To a solution of 5- (dimethylamino) pyrazine-2-sulfonamide (intermediate P22) (60 mg, 296.69 μmol, 1 eq) in THF (4 mL) was added t-BuONa (29 mg, 296, 69 μmol, 1 eq) and 4- (5-fluoro-2-isocyanato-3 isopropylphenyl) picolinonitrile (intermediate A37) (83 mg, 296.69 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 5% -35%, 11.5 min) to obtain the title compound (49 mg, 34% yield, 100% LCMS purity) as a white solid.
    [1221] [1221] 1H NMR (DMSO-d6): δ 8.58 (d, 1 H), 8.24 (s, 1 H), 7.99 (s, 1 H), 7.92 (s, 1 H ), 7.78 (br s, 1 H), 7.60 (s, 1 H), 7.20 (dd, 1 H), 7.06 (dd, 1 H), 3.18 (s, 6 H), 3.14-1.09 (m, 1 H) and 1.10 (d, 6 H).
    [1222] [1222] LCMS: m / z 484.2 (M + H) + (ES +). Example 107: 5- (Dimethylamino) -N - ((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) pyrazine-2-sulfonamide O O F N S O O The HN N S
    [1223] [1223] To a solution of 5- (dimethylamino) pyrazine-2-sulfonamide (intermediate P22) (71 mg, 349.28 μmol, 1 eq) in THF (5 ml) was added t-BuONa (34 mg, 349, 28 μmol, 1 eq) and 4- (5-fluoro-2-isocyanato-3-isopropylphenyl) -2-methoxypyridine (intermediate A38) (100 mg, 349.28 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 0% -30%, 10 min) to obtain the title compound (30 mg, 18% yield, 100% LCMS purity) as a white solid.
    [1224] [1224] 1H NMR (DMSO-d6): δ 8.40 (s, 1 H), 8.12 (s, 1 H), 8.06 (d, 1 H), 7.73 (br s, 1 H), 7.16 (dd, 1 H), 6.99-6.96 (m, 1 H), 6.82 (d, 1 H), 6.72 (s, 1 H), 3.87 (s, 3 H), 3.18 (s, 6 H), 2.95-2.91 (m, 1 H) and 1.12-0.95 (m, 6 H).
    [1225] [1225] LCMS: m / z 489.3 (M + H) + (ES +). Example 108: 5- (Dimethylamino) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) pyrazine-2-sulfonamide O O N S O O The HN N S
    [1226] [1226] To a solution of 5- (dimethylamino) pyrazine-2-sulfonamide (intermediate P22) (70 mg, 346.13 μmol, 1 eq) in THF (5 ml) was added t-BuONa (33 mg, 346, 13 μmol, 1 eq) and 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (intermediate A39) (92 mg, 346.13 µmol, 1 eq) . The mixture was stirred at 25 ° C for 30 minutes and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 2% -32%, 11.5 min) to obtain the title compound (40 mg, 24% yield, 98.92% purity in LCMS) as a white solid.
    [1227] [1227] 1H NMR (DMSO-d6): δ 8.46-8.41 (m, 1 H), 8.09-8.07 (t, 2 H), 7.60 (br s, 1 H) , 7.13 (d, 1 H), 7.05 (d, 1 H), 6.82 (d, 1 H), 6.68 (s, 1 H), 3.86 (s, 3 H) , 3.16 (s, 6 H), 2.88 (t, 2 H), 2.65 (t, 2 H) and 1.99-1.91 (m, 2 H).
    [1228] [1228] LCMS: m / z 469.3 (M + H) + (ES +). Example 109: 5- (Dimethylamino) -N - (((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) pyrazine-2-sulfonamide O O F N S O
    [1229] [1229] To a mixture of 5- (dimethylamino) pyrazine-2-sulfonamide (intermediate P22) (80 mg, 393.30 μmol, 1 eq) in THF (5 ml) was added t-BuONa (41 mg, 432, 63 μmol, 1.1 eq) in one portion at 15 ° C. Then, the reaction mixture was stirred for 15 minutes. Then, a solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (intermediate A40) (100 mg, 393.30 μmol, 1 eq) in THF (2 ml) was added. The resulting mixture was stirred at 15 ° C for 30 minutes and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (72.57 mg, 40%) as an off-white solid.
    [1230] [1230] 1H NMR (DMSO-d6): δ 8.49 (d, 2 H), 8.40 (s, 1 H), 8.07 (s, 1 H), 7.54 (br s, 1 H), 7.28 (d, 2 H), 6.93 (d, 1 H), 3.16 (s, 6 H), 2.93 (t, 2 H), 2.74 (t, 2 H) and 2.07-1.99 (m, 2 H).
    [1231] [1231] LCMS: m / z 457.2 (M + H) + (ES +). Example 110: N - (((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 3- (difluoromethyl) pyrazine-2-sulfonamide
    [1232] [1232] To a solution of 3- (difluoromethyl) pyrazine-2-sulfonamide (intermediate P23) (74 mg, 355.51 μmol, 1 eq) in THF (4 mL) was added t-BuONa (34 mg, 355, 51 μmol, 1 eq) and 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (intermediate A37) (0.1 g, 355.51 µmol, 1 eq). The mixture was stirred at 25 ° C for 10 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3); B: MeCN]; B%: 20% -50%, 12 min) to give the title compound (13.20 mg, 7% yield, 98.3% LCMS purity) as a white solid.
    [1233] [1233] 1H NMR (DMSO-d6 + D2O): δ 8.75-8.61 (m, 2 H), 8.45 (d, 1 H), 7.95- 7.59 (m, 2 H ), 7.48 (d, 1H), 7.19-7.13 (m, 1 H), 7.12-6.95 (m, 1 H), 3.20-3.04 (m, 1 H) and 1.19-0.93 (m, 6 H).
    [1234] [1234] LCMS: m / z 491.2 (M + H) + (ES +). Example 111: 3- (Difluoromethyl) -N - (((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) pyrazine-2-sulfonamide O O
    [1235] [1235] To a solution of 3- (difluoromethyl) pyrazine-2-sulfonamide (intermediate P23) (73 mg, 349.28 μmol, 1 eq) in THF (4 mL) was added t-BuONa (34 mg, 349, 28 μmol, 1 eq) and 4- (5-fluoro-2-isocyanato-3-isopropylphenyl) -2-methoxypyridine (intermediate A38) (100 mg, 349.28 μmol, 1 eq). The mixture was stirred at 25 ° C for 10 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3); B: MeCN]; B%: 17% -47%, 12 min) to give the title compound (14.57 mg, 8% yield, 98.6% LCMS purity) as a white solid.
    [1236] [1236] 1H NMR (DMSO-d6 + D2O): δ 8.82-8.76 (m, 2 H), 7.98-7.65 (m, 2 H), 7.15-7.00 ( m, 1 H), 6.88-6.86 (m, 1 H), 6.79 (d, 1H), 6.61 (s, 1 H), 3.82-3.79 (m, 3 H), 3.19-2.93 (m, 1 H) and 1.21-0.97 (m, 6 H).
    [1237] [1237] LCMS: m / z 496.2 (M + H) + (ES +). Example 112: 3- (Difluoromethyl) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) pyrazine-2-sulfonamide O O O N S O The HN N S
    [1238] [1238] To a solution of 3- (difluoromethyl) pyrazine-2-sulfonamide (intermediate P23) (75 mg, 358.55 μmol, 1 eq) in THF (5 ml) was added t-BuONa (34 mg, 358, 55 μmol, 1 eq) and 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (intermediate A39) (95 mg, 358.55 µmol, 1 eq) . The mixture was stirred at 10 ° C for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 15% -45%, 12 min )
    [1239] [1239] 1H NMR (DMSO-d6): δ 8.78 (s, 2 H), 8.15-7.87 (m, 2 H), 7.07 (d, 1 H), 7.00 ( d, 1 H), 6.85-6.83 (m, 1 H), 6.67 (s, 1 H), 6.06 (br s, 1 H), 3.85 (s, 3 H) , 2.88-2.84 (m, 2 H), 2.68-2.63 (m, 2 H) and 1.96-1.90 (m, 2 H).
    [1240] [1240] LCMS: m / z 476.2 (M + H) + (ES +). Example 113: 3- (Difluoromethyl) -N - (((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) pyrazine-2-sulfonamide O O O F N S O The HN N S
    [1241] [1241] To a solution of 3- (difluoromethyl) pyrazine-2-sulfonamide (intermediate P23) (82.27 mg, 393.30 μmol, 1 eq) in THF (5 mL) was added t-BuONa (42 mg, 432.63 μmol, 1.1 eq) and a solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (intermediate A40) (100 mg, 393.30 μmol, 1 eq) in THF (5 ml) and DCM (5 ml). The reaction mixture was stirred at 16 ° C for 0.5 hour and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (0.05% NH4HCO3); B: MeCN]; B%: 15% -45%, 10 min) to give the title compound (25.31 mg, 14%) as a light yellow solid.
    [1242] [1242] 1H NMR (DMSO-d6 + D2O): δ 8.89 (s, 1 H), 8.85 (d, 1 H), 8.49 (d, 2 H), 7.76 (t, 1 H), 7.45-7.25 (m, 2 H), 6.96 (d, 1 H), 2.92 (t, 2 H), 2.72-2.67 (m, 2 H ) and 2.05-2.01 (m, 2 H).
    [1243] [1243] LCMS: m / z 464.1 (M + H) + (ES +). Example 114: N - (((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 4,6-dimethylpyrimidine-2-sulfonamide F OCN F O O O O O
    [1244] [1244] To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P24) (65 mg, 347.19 μmol, 1 eq) in THF (5 ml) was added t-BuONa (33 mg, 347.19 μmol, 1 eq) in one portion at 25 ° C under N2. The reaction mixture was stirred for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (intermediate A37) (98 mg, 347.19 μmol, 1 eq) was added. The resulting mixture was heated to 70 ° C and stirred for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 12% -42%, 10 min ) to give the title compound (19.94 mg, 12% yield, 100% LCMS purity) as a white solid.
    [1245] [1245] 1H NMR (DMSO-d6): δ 8.69-8.68 (m, 1 H), 8.02 (s, 1 H), 7.71-7.69 (m, 1 H), 7.35-7.33 (m, 1 H), 7.25-7.20 (m, 1 H), 7.13-7.09 (m, 2 H), 3.33-3.16 ( m, 1 H), 2.43 (s, 6 H) and 1.10 (d, 6 H).
    [1246] [1246] LCMS: m / z 469.2 (M + H) + (ES +). Example 115: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -4,6-dimethylpyrimidine-2-sulfonamide F OCN O O N S O O The NH
    [1247] [1247] To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P24) (65 mg, 349.28 μmol, 1 eq) in THF (5 ml) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) in one portion at 25 ° C under N2. The reaction mixture was stirred for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (intermediate A38) (100 mg, 349.28 μmol, 1 eq) was added. The resulting mixture was heated to 70 ° C and stirred for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 11.5 min) to obtain the title compound (60.47 mg, 37% yield, 100% LCMS purity) as a white solid.
    [1248] [1248] 1H NMR (DMSO-d6): δ 8.11-8.07 (m, 1 H), 7.85 (br s, 1 H), 7.42-7.39 (m, 1 H) , 7.18-7.12 (m, 1 H), 7.05-6.94 (m, 2 H), 6.76 (s, 1 H), 3.90 (s, 3 H), 3 , 12 - 3.08 (m, 1 H), 2.46 (s, 6 H) and 1.14-1.07 (m, 6 H).
    [1249] [1249] LCMS: m / z 474.2 (M + H) + (ES +). Example 116: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4,6-dimethylpyrimidine-2-sulfonamide OCN O O O The N S O N Y N The N
    [1250] [1250] To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P24) (70 mg, 375.52 μmol, 1 eq) in THF (5 ml) was added t-BuONa (36 mg, 375.52 μmol, 1 eq) in one portion at 25 ° C under N2. The reaction mixture was stirred for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (intermediate A39) (100 mg, 375.52 μmol, 1 eq) was added. The resulting mixture was heated to 70 ° C and stirred for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 2% -32%, 11.5 min) to obtain the title compound (41.33 mg, 24% yield, 98.29% LCMS purity) as a white solid.
    [1251] [1251] 1H NMR (DMSO-d6): δ 8.10 (d, 1 H), 7.32-7.30 (m, 1 H), 7.11 (d, 1
    [1252] [1252] LCMS: m / z 454.2 (M + H) + (ES +). Example 117: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -4,6-dimethylpyrimidine-2-sulfonamide F OCN O OO The N S The F
    [1253] [1253] To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P24) (50 mg, 267.07 μmol, 1 eq) in THF (3 ml) was added t-BuONa (26 mg, 267.07 μmol, 1 eq) in one portion at 25 ° C under N2. The reaction mixture was stirred for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-indent-5-yl) pyridine (intermediate A40) (68 mg, 267.07 μmol, 1 eq) was added. The reaction mixture was stirred at 25 ° C for 10 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (22.84 mg, 19% yield, 97.11% LCMS purity) as a white solid.
    [1254] [1254] 1H NMR (DMSO-d6): δ 8.56 (d, 2 H), 7.75 (br s, 1 H), 7.39-7.36 (m, 3 H), 6.98 (d, 1 H), 2.93 (t, 2 H), 2.85-2.75 (m, 2 H), 2.49 (s, 6 H) and 2.06-2.02 (m , 2 H).
    [1255] [1255] LCMS: m / z 442.1 (M + H) + (ES +). Example 118: N - (((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 5- (dimethylamino) pyridazine-3-sulfonamide F OCN F O O O NC N O
    [1256] [1256] To a mixture of 5- (dimethylamino) pyridazine-3-sulfonamide (intermediate P25) (70 mg, 346.13 μmol, 1 eq) in THF (2 ml) was added t-BuONa (33 mg, 346, 13 μmol, 1 eq) in one portion at 25 ° C under N2. The reaction mixture was stirred for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (intermediate A37) (97 mg, 346.13 μmol, 1 eq) was added. The reaction mixture was stirred at 25 ° C for 10 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (65.88 mg, 39% yield, 99.38% LCMS purity) as a white solid.
    [1257] [1257] 1H NMR (DMSO-d6): δ 8.77 (d, 1 H), 8.61-8.59 (m, 1 H), 7.94 (s, 1 H), 7.87- 7.84 (m, 1 H), 7.59-7.58 (m, 1 H), 7.20-7.17 (m, 1 H), 7.07 (dd, 1 H), 6, 96 (s, 1 H), 3.21-3.17 (m, 1 H), 3.09 (s, 6 H) and 1.15-1.08 (m, 6 H).
    [1258] [1258] LCMS: m / z 484.2 (M + H) + (ES +). Example 119: 5- (Dimethylamino) -N - (((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) pyridazine-3-sulfonamide F OCN O O N S O The HN O O N N Y N HN F
    [1259] [1259] To a mixture of 5- (dimethylamino) pyridazine-3-sulfonamide (intermediate P25) (40 mg, 197.79 μmol, 1 eq) in THF (5 ml) was added t-
    [1260] [1260] 1H NMR (DMSO-d6): δ 8.90-8.85 (m, 1 H), 8.09-8.05 (m, 1 H), 7.92- 7.87 (m, 1 H), 7.18-7.15 (m, 1 H), 7.07 (d, 1 H), 6.98 (d, 1 H), 6.84 (d, 1 H), 6, 73 (s, 1 H), 3.85 (s, 3 H), 3.07 (s, 6 H), 3.06-3.01 (m, 1 H) and 1.09-0.94 ( m, 6 H).
    [1261] [1261] LCMS: m / z 489.2 (M + H) + (ES +). Example 120: 5- (Dimethylamino) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) pyridazine-3-sulfonamide OCN O O N S O The HN O O N N Y N HN
    [1262] [1262] To a mixture of 5- (dimethylamino) pyridazine-3-sulfonamide (intermediate P25) (35 mg, 173.07 μmol, 1 eq) in THF (2 ml) was added t-BuONa (17 mg, 173, 07 μmol, 1 eq) in one portion at 25 ° C under N2. The reaction mixture was stirred for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (intermediate A39) (46 mg, 173.07 μmol, 1 eq) was added. The resulting mixture was heated to 25 ° C and stirred for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (21.73 mg, 27% yield, 99.14% LCMS purity) as a white solid.
    [1263] [1263] 1H NMR (DMSO-d6): δ 8.83 (d, 1 H), 8.06 (d, 1 H), 7.75-7.74 (m, 1 H), 7.13 ( d, 1 H), 7.07-7.05 (m, 2 H), 6.86 (d, 1 H), 6.71 (s, 1 H), 3.88 (s, 3 H), 3.06 (s, 6 H), 2.86 (t, 2 H), 2.68 (t, 2 H) and 1.99-1.93 (m, 2 H).
    [1264] [1264] LCMS: m / z 469.2 (M + H) + (ES +). Example 121: 5- (Dimethylamino) -N - (((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) pyridazine-3-sulfonamide F OCN O O O THE F The N
    [1265] [1265] To a mixture of 5- (dimethylamino) pyridazine-3-sulfonamide (intermediate P25) (50 mg, 247.24 μmol, 1 eq) in THF (3 ml) was added t-BuONa (24 mg, 247, 24 μmol, 1 eq) in one portion at 25 ° C under N2. The reaction mixture was stirred for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (intermediate A40) (63 mg, 247.24 μmol, 1 eq) was added. The reaction mixture was stirred at 25 ° C for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (22.81 mg, 20% yield, 98.41% LCMS purity) as a white solid.
    [1266] [1266] 1H NMR (DMSO-d6): δ 8.83 (d, 1 H), 8.51 (d, 2 H), 7.71 (br s, 1 H), 7.31-7.30 (m, 2 H), 7.04 (d, 1 H), 6.95 (d, 1 H), 3.06 (s, 6 H), 2.92 (t, 2 H), 2.78 - 2.75 (m, 2 H) and 2.05-2.00 (m, 2 H).
    [1267] [1267] LCMS: m / z 457.0 (M + H) + (ES +). Example 122: 3- (N-Methyl-N- (1-methylpyrrolidin-3-yl) sulfamoyl) -1- (5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden -4-il) urea
    [1268] [1268] To a cooled (0 ° C) solution of chlorosulfonyl isocyanate (59 mg, 0.41 mmol) in DCM (5 mL) was added 5- (2-methoxypyridin-4-yl) -2,3-di -hydro- 1H-inden-4-amine (Intermediate A35; 100 mg, 0.41 mmol). The mixture was stirred for 10 minutes at 0 ° C. N, 1-dimethylpyrrolidin-3-amine (95 mg, 0.83 mmol) in DCM (5 ml) was added and the reaction was allowed to reach room temperature for 30 minutes. The mixture was evaporated to dryness in vacuo and purified by reverse phase chromatography to provide the title compound (9 mg; 5%) as a white solid.
    [1269] [1269] 1H NMR (CD3OD) δ 8.12 (d, 1 H), 7.19 (d, 1 H), 7.13 (d, 1 H), 6.99 (d, 1 H), 6 , 83 (s, 1 H), 4.48 (m, 1 H), 3.92 (s, 3 H), 2.92 (m, 6 H), 2.82 (m, 2H), 2, 71 (s, 3 H), 2.50 (s, 3 H), 2.10 (m, 3 H) and 1.92 (m, 1 H).
    [1270] [1270] LCMS: m / z 460 (M + H) + (ES +); 458 (M-H) - (ES-). Example 123: 3- (N-Methyl-N - ((1-methylpyrrolidin-2-yl) methyl) sulfamoyl) -1- (5- (2-methoxypyridin-4-yl) -2,3-dihydro- 1H-inden-4-yl) urea
    [1271] [1271] Prepared as described for 3- (N-methyl-N- (1-methylpyrrolidin-3-yl) sulfamoyl) -1- (5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H -inden-4-yl) urea (Example 122), using chlorosulfonyl isocyanate (59 mg, 0.41 mmol), 5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden -4-amine (Intermediate A35; 100 mg, 0.41 mmol) and N-methyl-1- (1-methylpyrrolidin-2-yl) methanamine (107 mg, 0.83 mmol) to provide the title compound (2 mg; 1%) as a white solid.
    [1272] [1272] 1H NMR (CD3OD) δ 8.12 (d, 1 H), 7.19 (m, 2 H), 7.09 (d, 1 H), 6.93 (s, 1 H), 3 , 92 (s, 3 H), 3.88 (m, 1 H), 3.65 (m, 1 H), 3.09 (m, 1 H), 2.98 (m, 6 H), 2 , 79 (s, 3 H), 2.69 (s, 3 H), 2.10 (m, 3 H), 1.97 (m, 2 H) and 1.60 (m, 1 H).
    [1273] [1273] LCMS: m / z 474 (M + H) + (ES +). Example 124: 3- (N-Methyl-N - ((1-methylpyrrolidin-2-yl) methyl) sulfamoyl) -1- (7-fluoro-5- (2-methoxypyridin-4-yl) -2,3- dihydro-1H-inden-4-yl) urea
    [1274] [1274] Prepared as described for 3- (N-methyl-N- (1-methylpyrrolidin-3-yl) sulfamoyl) -1- (5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H -inden-4-yl) urea (Example 122), using chlorosulfonyl isocyanate (55 mg, 0.38 mmol), 7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro -1H-inden-4-amine (intermediate A34; 100 mg, 0.38 mmol) and N, 1-dimethylpyrrolidin-3-amine (95 mg, 0.83 mmol) to provide the title compound (12 mg; 10 %) as a white solid.
    [1275] [1275] 1H NMR (CD3OD) δ 8.14 (d, 1 H), 7.08 (d, 1 H), 6.98 (m, 2 H), 4.48 (m, 1 H), 3 , 92 (s, 3 H), 2.98 (m, 8 H), 2.71 (s, 3 H), 2.60 (s, 3 H), 2.10 (m, 3 H) and 1 , 92 (m, 1 H).
    [1276] [1276] LCMS: m / z 479 (M + H) + (ES +). Example 125: 3- (N-Methyl-N - ((1-methylpyrrolidin-2-yl) methyl) sulfamoyl) -1- (7-fluoro-5- (2-methoxypyridin-4-yl) -2,3- dihydro-1H-inden-4-yl) urea
    [1277] [1277] Prepared as described for 3- (N-methyl-N- (1-methylpyrrolidin-3-yl) sulfamoyl) -1- (5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H -inden-4-yl) urea (Example 122), using chlorosulfonyl isocyanate (55 mg, 0.38 mmol), 7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro -1H-inden-4-amine (Intermediate A34; 100 mg, 0.38 mmol) and N-methyl-1- (1-methylpyrrolidin-2-yl) methanamine (139 mg, 1.16 mmol) to provide the compound of the title (23 mg; 12%) as a white solid.
    [1278] [1278] 1H NMR (CD3OD) δ 8.12 (d, 1 H), 7.00 (d, 1 H), 6.90 (d, 1 H), 6.83 (s, 1 H), 3 , 92 (s, 3 H), 3.78 (m, 1 H), 3.55 (m, 1 H), 3.00 (m, 7 H), 2.79 (s, 3 H),
    [1279] [1279] LCMS: m / z 492 (M + H) + (ES +); 490 (M-H) - (ES-). Example 126: (1R, 4R) -N - ((7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -5- methyl-2,5-diazabicyclo [2,2,1] heptane-2-sulfonamide
    [1280] [1280] (1R, 4R) -2-methyl-2,5-diazabicyclo [2,2,1] heptane dihydrobromide (50 mg, 0.18 mmol) and sodium hydride (60%) (150 mg, 3 , 7 mmol) were refluxed for 1 hour in THF (10 mL). The mixture was cooled to room temperature and filtered over Celite. The filtrate was evaporated to dryness in vacuo and the residue was dissolved in DCM (10 ml), after which DABCO (20 mg, 0.18 mmol) was added.
    [1281] [1281] Meanwhile, to a cooled (0 ° C) solution of chlorosulfonyl isocyanate (35 mg, 0.25 mmol) in DCM (5 mL) was added 7-fluoro-5- (2-methoxypyridin-4-yl ) -2,3-dihydro-1H-inden-4-amine (Intermediate A34; 66 mg, 0.26 mmol). The mixture was stirred for 10 minutes at 0 ° C.
    [1282] [1282] Both DCM mixtures were combined and allowed to reach room temperature after 1 hour. The mixture was evaporated to dryness in vacuo and purified by reverse phase chromatography to provide the title compound (4 mg; 5%) as a white solid.
    [1283] [1283] 1H NMR (CD3OD) δ 8.12 (d, 1 H), 7.02 (d, 1 H), 6.90 (m, 2 H), 4.54 (m, 1 H), 4 , 24 (m, 1 H), 3.92 (s, 3 H), 3.39 (m, 2 H), 2.98 (m, 4H), 2.75 (s, 3 H), 2, 20 (m, 2 H), and 1.64 (m, 2 H).
    [1284] [1284] LCMS: m / z 476 (M + H) + (ES +); 474 (M-H) - (ES-). Example 127: N - (((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 1-phenylmethanesulfonamide F O F S O O
    [1285] [1285] To a solution of phenylmethanesulfonamide (61 mg, 355.51 μmol, 1 eq) in THF (2 ml) was added t-BuONa (34 mg, 355.51 μmol, 1 eq) and the mixture was stirred at 25 ° C for 0.5 hour. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (intermediate A37) (0.1 g, 355.51 µmol, 1 eq) was added and the resulting mixture was heated to 70 ° C and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% NH3.H2O); B: MeCN]; B%: 15 % -45%, 11.5 min) to obtain the title compound (0.038 g, 23% yield, 99% LCMS purity) as a white solid.
    [1286] [1286] 1H NMR (DMSO-d6): δ 10.59 (br s, 1 H), 8.77 (d, 1 H), 8.12 (s, 1 H), 7.80 (dd, 1 H), 7.30-7.10 (m, 7 H), 4.30 (s, 2 H), 3.24-3.20 (m, 1 H) and 1.20 (d, 6 H) .
    [1287] [1287] LCMS: m / z 453.3 (M + H) + (ES +). Example 128: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-phenylmethanesulfonamide O O F O S O O
    [1288] [1288] To a solution of phenylmethanesulfonamide (60 mg, 349.28 μmol, 1 eq) in THF (2 ml) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and the mixture was stirred at 25 ° C for 0.5 hour. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (intermediate A38) (0.1 g, 349.28 µmol, 1 eq) was added and the resulting mixture was heated to 70 ° C and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% NH3.H2O); B: MeCN]; B%: 10 % -40%, 11.5 min) to obtain the title compound
    [1289] [1289] 1H NMR (DMSO-d6): δ 8.15 (d, 1 H), 7.52 (br s, 1 H), 7.34-7.11 (m, 6 H), 7.10 -6.95 (m, 2 H), 6.87 (s, 1 H), 4.27 (s, 2 H), 3.85 (s, 3 H), 3.25-3.19 (m , 1 H) and 1.18 (d, 6 H).
    [1290] [1290] LCMS: m / z 458.3 (M + H) + (ES +). Example 129: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-phenylmethanesulfonamide O O O S O O
    [1291] [1291] To a solution of phenylmethanesulfonamide (64 mg, 375.52 μmol, 1 eq) in THF (2 ml) was added t-BuONa (36 mg, 375.52 μmol, 1 eq) and the mixture was stirred at 25 ° C for 0.5 hour. Then 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) - 2-methoxypyridine (intermediate A39) (0.1 g, 375.52 µmol, 1 eq) was added and the The resulting mixture was heated to 70 ° C and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% NH3.H2O); B: MeCN]; B%: 8 % -38%, 11.5 min) to obtain the title compound (90.80 mg, 55% yield, 99% LCMS purity) as a white solid.
    [1292] [1292] 1H NMR (DMSO-d6): δ 8.14 (d, 1 H), 7.50 (br s, 1 H), 7.32-7.30 (m, 3 H), 7.25 -7.24 (m, 2 H), 7.17 (d, 1 H), 7.09 (d, 1 H), 6.97 (dd, 1 H), 6.80 (s, 1 H) , 4.37 (s, 2 H), 3.87 (s, 3 H), 2.94 (t, 2 H), 2.85 (t, 2 H) and 2.09-1.97 (m , 2 H).
    [1293] [1293] LCMS: m / z 438.2 (M + H) + (ES +). Example 130: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-phenylmethanesulfonamide O O O S O The F
    [1294] [1294] A mixture of phenylmethanesulfonamide (70 mg, 408.84 μmol, 1 eq) and t-BuONa (39 mg, 408.84 μmol, 1 eq) in THF (2 ml) was stirred at 25 ° C for 10 minutes . Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (intermediate A40) (104 mg, 408.84 μmol, 1 eq) was added. The mixture was stirred at 70 ° C for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18, 250mm * 50mm * 10μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B%: 5% -35%, 10 min) to obtain the title compound (16.61 mg, 10% yield, 100% LCMS purity) as a white solid.
    [1295] [1295] 1H NMR (DMSO-d6): δ 8.54 (d, 2 H), 7.41 (d, 2 H), 7.26-7.22 (m, 4 H), 7.18- 7.02 (m, 2 H), 6.95 (d, 1 H), 4.21 (s, 2 H), 2.96 (t, 2 H), 2.89 (t, 2 H) and 2.12-2.03 (m, 2 H).
    [1296] [1296] LCMS: m / z 426.2 (M + H) + (ES +). Example 131: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 2-methylpropane-1-sulfonamide F F
    [1297] [1297] To a solution of 2-methylpropane-1-sulfonamide (49 mg, 355.51 μmol, 1 eq) (intermediate P26) in THF (2 ml) was added t-BuONa (34 mg, 355.51 μmol, 1 eq) and 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (intermediate A37) (100 mg, 355.51 µmol, 1 eq). The reaction mixture was stirred at 20 ° C for 20 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 3% -33%, 12.0 min) to obtain the title compound (48.16 mg, 32%) as a white solid.
    [1298] [1298] 1H NMR (DMSO-d6): δ 8.72 (d, 1 H), 8.07 (s, 1 H), 7.77 (s, 1 H), 7.67 (s, 1 H ), 7.21 (d, 1 H), 7.11 (d, 1 H), 3.26-3.23 (m, 1 H), 2.67-2.63 (m, 2 H), 1.77-1.66 (m, 1 H), 1.15 (d, 6 H) and 0.84 (d, 6 H).
    [1299] [1299] LCMS: m / z 419.2 (M + H) + (ES +). Example 132: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -2-methylpropane-1-sulfonamide F F O O
    [1300] [1300] To a solution of 2-methylpropane-1-sulfonamide (intermediate P26) (48 mg, 349.28 μmol, 1 eq) in THF (2 ml) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (intermediate A38) (100 mg, 349.28 μmol, 1 eq). The reaction mixture was stirred at 25 ° C for 10 minutes and was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 15% -45%, 11.5 min) to obtain the title compound (101.64 mg, 69% yield, 100% LCMS purity) as a white solid.
    [1301] [1301] 1H NMR (DMSO-d6): δ 8.17 (d, 1 H), 7.91 (s, 1 H), 7.27-7.24 (m, 1 H), 7.06 ( dd, 1 H), 6.99 (d, 1 H), 6.82 (s, 1 H), 3.87 (s, 3 H), 3.16-3.09 (m, 1 H), 3.00 (d, 2 H), 1.91 - 1.81 (m, 1 H), 1.16 (d, 6 H) and 0.91 (d, 6 H).
    [1302] [1302] LCMS: m / z 424.2 (M + H) + (ES +). Example 133: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-methylpropane-1-sulfonamide O O
    [1303] [1303] To a solution of 2-methylpropane-1-sulfonamide (intermediate P26) (55 mg, 401.36 μmol, 1 eq) in THF (2 mL) was added t-BuONa (39 mg,
    [1304] [1304] 1H NMR (DMSO-d6): δ 8.15 (d, 1 H), 7.93 (br s, 1 H), 7.22 (d, 1 H), 7.12 (d, 1 H), 6.94-6.91 (m, 1 H), 6.74 (s, 1 H), 3.86 (s, 3 H), 3.10 (d, 2 H), 2.93 (t, 2 H), 2.79 (t, 2 H), 2.05-1.95 (m, 3 H) and 0.95 (d, 6 H).
    [1305] [1305] LCMS: m / z 404.2 (M + H) + (ES +). Example 134: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-methylpropane-1-sulfonamide F F O O
    [1306] [1306] To a solution of 2-methylpropane-1-sulfonamide (intermediate P26) (54 mg, 393.30 μmol, 1 eq) in THF (2 ml) was added t-BuONa (38 mg, 393.30 μmol, 1 eq). Then the mixture was stirred at 25 ° C for 10 minutes. A solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (intermediate A40) (100 mg, 393.30 μmol, 1 eq) in THF ( 2.5 mL) was added. The resulting mixture was stirred at 25 ° C for 30 minutes and then concentrated in vacuo. The residue was purified by preparative HPLC (Column: Xtimate C18, 250mm * 50mm * 10μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN], B%: 1% -31%, 10.0 min) to obtain the title compound (45.33 mg, 29% yield, 100% LCMS purity) as a white solid.
    [1307] [1307] 1H NMR (DMSO-d6): δ 8.54 (d, 2 H), 7.40 (d, 2 H), 6.96 (d, 1 H), 2.95 (t, 2 H ), 2.89-2.83 (m, 4 H), 2.09-2.03 (m, 2 H), 1.96-1.91 (m, 1 H) and 0.93 (d, 6 H).
    [1308] [1308] LCMS: m / z 392.2 (M + H) + (ES +). Example 135: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 2-phenylethanesulfonamide F F O O O O O
    [1309] [1309] To a solution of 2-phenylethanesulfonamide (intermediate P27) (66 mg, 355.51 μmol, 1 eq) in THF (2 ml) was added t-BuONa (34 mg, 355.51 μmol, 1 eq) and the mixture was stirred at 25 ° C for 0.5 hour. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (intermediate A37) (0.1 g, 355.51 µmol, 1 eq) was added and the resulting mixture was heated to 70 ° C and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (0.05% NH3.H2O); B: MeCN]; B%: 12 % -42%, 11.5 min) to obtain the title compound (0.07 g, 42% yield, 99% LCMS purity) as a white solid.
    [1310] [1310] 1H NMR (DMSO-d6): δ 10.77 (br s, 1 H), 8.67 (d, 1 H), 8.11 (s, 1 H), 7.92 (br s, 1 H), 7.80 (d, 1 H), 7.31-7.18 (m, 5 H), 7.09 (d, 2 H), 3.25-3.19 (m, 3 H ), 2.70-2.51 (m, 2 H) and 1.17 (d, 6 H).
    [1311] [1311] LCMS: m / z 467.3 (M + H) + (ES +). Example 136: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -2-phenylethanesulfonamide O O F S O The HN O
    [1312] [1312] To a solution of 2-phenylethanesulfonamide (intermediate P27) (65 mg, 349.28 μmol, 1 eq) in THF (2 ml) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and the mixture was stirred at 25 ° C for 0.5 hour. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (intermediate A38) (0.1 g, 349.28 µmol, 1 eq) was added and the resulting mixture was heated to 70 ° C and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm;
    [1313] [1313] 1H NMR (DMSO-d6): δ 8.10 (d, 1 H), 8.00 (br s, 1 H), 7.34-7.22 (m, 4 H), 7.16 -6.99 (m, 4 H), 6.84 (s, 1 H), 3.73 (s, 3 H), 3.44-3.40 (m, 2 H), 3.18-3 , 13 (m, 1 H), 2.80-2.76 (m, 2 H) and 1.16 (d, 6 H).
    [1314] [1314] LCMS: m / z 472.2 (M + H) + (ES +). Example 137: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-phenylethanesulfonamide O O S O The HN O
    [1315] [1315] To a solution of 2-phenylethanesulfonamide (intermediate P27) (70 mg, 375.52 μmol, 1 eq) in THF (2 ml) was added t-BuONa (36 mg, 375.52 μmol, 1 eq) and the mixture was stirred at 25 ° C for 0.5 hour. Then 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (intermediate A39) (0.1 g, 375.52 µmol, 1 eq) was added and the The resulting mixture was heated to 70 ° C and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150mm * 25mm * 10μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 17% -47%, 11 min ) to give the title compound (0.021 g, 12% yield, 100% purity in LCMS) as a white solid.
    [1316] [1316] 1H NMR (DMSO-d6): δ 8.07 (d, 1 H), 7.50 (br s, 1 H), 7.33-7.26 (m, 2 H), 7.19 -7.13 (m, 4 H), 7.10-7.08 (m, 1 H), 6.99 (d, 1 H), 6.81 (s, 1 H), 3.77 (s , 3 H), 3.30-3.23 (m, 2 H), 2.92 (t, 2 H), 2.86-2.80 (m, 4 H) and 2.07-1.98 (m, 2 H).
    [1317] [1317] LCMS: m / z 452.2 (M + H) + (ES +). Example 138: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -2-phenylethanesulfonamide O O O O O F S F
    [1318] [1318] A mixture of 2-phenylethanesulfonamide (intermediate P27) (75 mg, 404.87 μmol, 1 eq) and t-BuONa (39 mg, 404.87 μmol, 1 eq) in THF (2 ml) was stirred at 25 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (intermediate A40) (103 mg, 404.87 μmol, 1 eq) was added. The resulting mixture was stirred at 25 ° C for 10 minutes, then heated to 70 ° C and stirred for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18, 250mm * 50mm * 10μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B%: 5% - 35%, 10 min) to obtain the title compound (15.1 mg, 8% yield, 100% LCMS purity) as a white solid.
    [1319] [1319] 1H NMR (DMSO-d6): δ 8.53 (d, 2 H), 7.63 (br s, 1 H), 7.42 (d, 2 H), 7.31 (t, 2 H), 7.23-7.16 (m, 3 H), 7.00 (d, 1 H), 3.39-3.35 (m, 2 H), 2.99 (t, 2 H) , 2.90-2.82 (m, 4 H) and 2.10-2.06 (m, 2 H).
    [1320] [1320] LCMS: m / z 440.2 (M + H) + (ES +). Example 139: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 1-phenylethanesulfonamide F F O O O
    [1321] [1321] To a solution of 1-phenylethanesulfonamide (intermediate P28) (50 mg, 269.92 μmol, 1 eq) in THF (2 ml) was added t-BuONa (26 mg, 269.92 μmol, 1 eq). After stirring at 20 ° C for 10 minutes, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (intermediate A37) (76 mg, 269.92 μmol, 1 eq) was added. The reaction mixture was stirred at 20 ° C for 20 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini c18, 150mm * 25mm * 10μm; mobile phase: [A: water (10mM of
    [1322] [1322] 1H NMR (DMSO-d6): δ 10.53 (br s, 1 H), 8.77 (d, 1 H), 8.10 (s, 1 H), 7.97-7.93 (m, 1 H), 7.77 (d, 1 H), 7.32-7.24 (m, 4 H), 7.23-7.19 (m, 3 H), 4.57-4 , 54 (m, 1 H), 3.15-3.12 (m, 1 H), 1.46-1.40 (m, 3 H) and 1.20-1.08 (m, 6 H) .
    [1323] [1323] LCMS: m / z 467.2 (M + H) + (ES +). Example 140: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1-phenylethanesulfonamide
    [1324] [1324] To a solution of 1-phenylethanesulfonamide (intermediate P28) (50 mg, 269.92 μmol, 1 eq) in THF (2 ml) was added t-BuONa (26 mg, 269.92 μmol, 1 eq). The mixture was stirred at 20 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (intermediate A38) (77 mg, 269.92 μmol, 1 eq) was added. The reaction mixture was stirred at 20 ° C for 20 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B% : 10% -40%, 12 min) to obtain the title compound (12.98 mg, 10% yield, 100% LCMS purity) as a white solid.
    [1325] [1325] 1H NMR (DMSO-d6): δ 10.40 (br s, 1 H), 8.15 (d, 1 H), 7.70 (br s, 1 H), 7.32-7, 20 (m, 6 H), 7.05-7.00 (m, 2 H), 6.85 (s, 1 H), 4.60-4.56 (m, 1 H), 3.86 ( s, 3 H), 3.16-3.11 (m, 1 H), 1.45 (d, 3 H) and 1.18 (dd, 6 H).
    [1326] [1326] LCMS: m / z 472.2 (M + H) + (ES +). Example 141: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-phenylethanesulfonamide
    [1327] [1327] To a solution of 1-phenylethanesulfonamide (intermediate P28) (50 mg, 269.92 μmol, 1 eq) in THF (2 ml) was added t-BuONa (26 mg, 269.92 μmol, 1 eq). The mixture was stirred at 20 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (72 mg, 269.92 μmol, 1 eq) was added and the mixture The resulting mixture was stirred at 20 ° C for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B% : 5% -35%, 12 min) to obtain the title compound (34.56 mg, 28% yield, 99.8% LCMS purity) as a white solid.
    [1328] [1328] 1H NMR (DMSO-d6): δ 8.12 (d, 1 H), 7.60 (br s, 1 H), 7.33-7.30 (m, 5 H), 7.19 (d, 1 H), 7.09 (d, 1 H), 6.94-6.92 (m, 1 H), 6.77 (s, 1 H), 4.69-4.66 (m , 1 H), 3.86 (s, 3 H), 2.93 (t, 2 H), 2.81 (t, 2 H), 2.07-2.01 (m, 2 H) and 1 , 54 (d, 3 H).
    [1329] [1329] LCMS: m / z 452.2 (M + H) + (ES +). Example 142: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1-phenylethanesulfonamide
    [1330] [1330] To a solution of 1-phenylethanesulfonamide (intermediate P28) (75 mg, 404.87 μmol, 1 eq) in THF (2 ml) was added t-BuONa (39 mg, 404.87 μmol, 1 eq). Then the reaction mixture was stirred at 20 ° C for 10 minutes. A solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (intermediate A40) (103 mg, 404.87 μmol, 1 eq) in THF ( 2 ml) was added. The resulting mixture was stirred at 20 ° C for 20 minutes and concentrated in vacuo.
    [1331] [1331] 1H NMR (DMSO-d6): δ 8.57 (d, 2 H), 7.69 (br s, 1 H), 7.37-7.30 (m, 7 H), 7.02 (d, 1 H), 4.75-4.67 (m, 1 H), 2.98 (t, 2 H), 2.84 (t, 2 H), 2.14-2.08 (m , 2 H) and 1.55 (d, 3 H).
    [1332] [1332] LCMS: m / z 440.2 (M + H) + (ES +). Example 143: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) methanesulfonamide
    [1333] [1333] 5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (326 mg, 1.36 mmol) (Intermediate A35) was dissolved in THF (5 mL ). Triethylamine (208 µl, 1.49 mmol) was added, followed by a solution of bis (trichloromethyl) carbonate (382 mg, 1.29 mmol) in THF (2 mL). The thick reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the solid formed was dried under high vacuum for 1 hour. The solid, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine, was suspended in THF (8 ml) of which 2 ml were used later.
    [1334] [1334] Methanesulfonamide (30 mg, 0.315 mmol) was suspended in THF (2 mL), sodium tert-butoxide (2 M in THF) (175 µl, 0.351 mmol) was added and the mixture was stirred for 30 minutes at room temperature. Then, a solution of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (78 mg, 0.292 mmol), prepared previously, in THF (2 ml) and the mixture was stirred overnight at room temperature. The THF was removed in vacuo and the residue was dissolved in DMSO (2 ml) and then purified by basic preparative HPLC to obtain the title compound (23.5 mg, 21%) as a colorless solid.
    [1335] [1335] 1H NMR (DMSO-d6): δ 8.17 (d, J = 5.3 Hz, 1H), 7.86 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.95 (dd, J = 5.3, 1.3 Hz, 1H), 6.77 (s,
    [1336] [1336] LCMS; m / z 362.2 (M + H) + (ES +); 360.0 (M-H) - (ES-). Example 144: 1-Cyclopropyl-N - ((6- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-5-yl) carbamoyl) -1H-pyrazol-3-sulfonamide OCN N N O O O N N The N
    [1337] [1337] To a solution of 1-cyclopropyl-1H-pyrazol-3-sulfonamide (Intermediate P29) (50 mg, 267.07 µmol, 0.7 eq) in THF (1.5 mL) was added t-BuONa ( 36 mg, 375.52 µmol, 1 eq) and 4- (6-isocyanate-2,3-dihydro-1H-inden-5-yl) - 2-methoxypyridine (Intermediate A45) (100 mg, 375.52 µmol, 1 eq). The mixture was stirred at 25 ° C for 0.5 hour. Most of the solvent was concentrated to produce the crude product. The residue was purified by preparative HPLC (column: Xtimate C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B% : 9% -39%, 8 min) to obtain the title compound (22.39 mg, 13% yield, 98% LCMS purity) as a white solid.
    [1338] [1338] 1H NMR (DMSO-d6): δ 8.19 (d, 1 H), 7.80-7.74 (m, 2 H), 7.24 (br s, 1 H), 7.01 (s, 1 H), 6.91 (d, 1 H), 6.72 (s, 1 H), 6.42 (s, 1 H), 3.89 (s, 3 H), 3.76 -3.73 (m, 1 H), 2.84-2.78 (m, 4 H), 2.04-1.98 (m, 2 H), and 1.03-0.95 (d, 4 H).
    [1339] [1339] LCMS: m / z 454.3 (M + H) + (ES +). Example 145: 1-Cyclopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-4-sulfonamide
    [1340] [1340] To a solution of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (intermediate A39) (71 mg, 267.07 µmol, 1 eq) in THF (1 mL) t-BuONa (26 mg, 267.07 µmol, 1 eq) and 1-cyclopropyl-1H-pyrazol-4-sulfonamide (intermediate P30) (50 mg, 267.07 µmol, 1 eq) were added ). The mixture was stirred at 25 ° C for 20 minutes. Most of the solvent was evaporated to produce the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B%: 12% -42%, 10 min) to obtain the title compound (12.82 mg, 11% yield, 100% LCMS purity) as a white solid.
    [1341] [1341] 1H NMR (DMSO-d6): δ 8.16 (s, 1 H), 8.04-8.03 (d, 1 H), 7.69 (s, 1 H), 7.63 ( s, 1 H), 7.18-7.16 (d, 1 H), 7.09-7.07 (d, 1 H), 6.82-6.80 (d, 1 H), 6, 68 (s, 1 H), 3.87 (s, 3 H), 3.85-3.78 (m, 1 H), 2.92-2.89 (m, 2 H), 2.68- 2.64 (m, 2 H), 2.01- 1.94 (m, 2 H), 1.06-1.03 (m, 2 H) and 1.01-0.96 (m, 2 H ).
    [1342] [1342] LCMS: m / z 454.4 (M + H) + (ES +). Example 146: N - (((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 3- (diethylamino) propane-1-sulfonamide F F
    [1343] [1343] To a solution of 3- (diethylamino) propane-1-sulfonamide (Intermediate P32) (80 mg, 411.75 μmol, 1 eq) in THF (1 ml) was added t-BuONa (40 mg, 411, 75 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A37) (116 mg, 411.75 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 12% -42%, 11.5 min) to obtain the title compound (105.29 mg, 55% yield, 100% LCMS purity) as a white solid.
    [1344] [1344] 1H NMR (DMSO-d6): δ 8.75 (d, 1 H), 8.08 (s, 1 H), 7.79-7.73 (m, 2 H), 7.23 ( d, 1 H), 7.13 (d, 1 H), 3.09-3.06 (m, 1 H), 3.03-2.88 (m, 8 H), 1.75-1, 72 (m, 2 H), 1.16 (d, 6 H) and 1.09 (t, 6 H).
    [1345] [1345] LCMS: m / z 476.3 (M + H) + (ES +). Example 147: 3- (Diethylamino) -N - ((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) propane-1-sulfonamide
    [1346] [1346] To a solution of 3- (diethylamino) propane-1-sulfonamide (Intermediate P32) (80 mg, 411.75 μmol, 1 eq) in THF (1 ml) was added t-BuONa (40 mg, 411, 75 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (118 mg, 411.75 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 18% -48%, 11.5 min) to obtain the title compound (59.65 mg, 30% yield, 100% LCMS purity) as a white solid.
    [1347] [1347] 1H NMR (DMSO-d6): δ 8.15 (d, 1 H), 7.64 (s, 1 H), 7.19 (d, 1 H), 7.09-6.95 ( m, 2 H), 6.85 (s, 1 H), 3.87 (s, 3 H), 3.23-3.20 (m, 1 H), 3.04-2.75 (m, 8 H), 1.77-1.72 (m, 2 H), 1.16 (d, 6 H) and 1.09-1.04 (m, 6 H).
    [1348] [1348] LCMS: m / z 481.3 (M + H) + (ES +). Example 148: 3- (Diethylamino) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) propane-1-sulfonamide
    [1349] [1349] To a solution of 3- (diethylamino) propane-1-sulfonamide (Intermediate P32) (80 mg, 411.75 μmol, 1 eq) in THF (1 ml) was added t-BuONa (40 mg, 411, 75 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (171 mg, 411.75 μmol, purity: 64% in LCMS, 1 eq ) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 15% -45%, 11.5 min) to obtain the title compound (53.15 mg, 28% yield, 100% LCMS purity) as a pink solid.
    [1350] [1350] 1H NMR (DMSO-d6): δ 8.13 (d, 1 H), 7.64 (br s, 1 H), 7.15 (d, 1 H), 7.09 (d, 1 H), 6.97 (dd, 1 H), 6.78 (s, 1 H), 3.86 (s, 3 H), 3.08 (t, 2 H), 2.91 (t, 2H ), 2.85-2.76 (m, 8 H), 2.03-2.00 (m, 2 H), 1.82-1.78 (m, 2 H) and 1.05 (t, 6 H).
    [1351] [1351] LCMS: m / z 461.3 (M + H) + (ES +). Example 149: 3- (Diethylamino) -N - ((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) propane-1-sulfonamide O O O
    [1352] [1352] A mixture of 3- (diethylamino) propane-1-sulfonamide (Intermediate P32) (60 mg, 308.81 μmol, 1 eq) and t-BuONa (30 mg, 308.81 μmol, 1 eq) in THF (2 mL) was stirred at 25 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (78 mg, 308.81 μmol, 1 eq) was added. The resulting mixture was stirred at 25 ° C for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A:
    [1353] [1353] 1H NMR (DMSO-d6): δ 8.58-8.56 (m, 2 H), 7.61 (br s, 1 H), 7.41 (d, 2 H), 6.99 (d, 1 H), 3.03 (t, 2 H), 2.96 (t, 2 H), 2.90-2.78 (m, 8 H), 2.11-2.04 (m , 2 H), 1.82– 1.75 (m, 2 H) and 1.07 (t, 6 H).
    [1354] [1354] LCMS: m / z 449.2 (M + H) + (ES +). Example 150: 3- (Benzyl (ethyl) amino) -N - (((4-fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) propane-1-sulfonamide
    [1355] [1355] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonamide (Intermediate P33) (90 mg, 351.06 μmol, 1 eq) in THF (1 mL) was added t-BuONa (34 mg, 351.06 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (101 mg, 351.06 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 20% -50%, 11.5 min) to obtain the title compound (66.21 mg, 35% yield, 100% LCMS purity) as a white solid.
    [1356] [1356] 1H NMR (DMSO-d6): δ 8.13 (d, 1 H), 7.72 (s, 1 H), 7.32-7.20 (m, 6 H), 7.06- 7.01 (m, 2 H), 6.83 (s, 1 H), 3.85 (s, 3 H), 3.53 (s, 2 H), 3.19-3.15 (m, 1 H), 3.04-3.01 (m, 2 H), 2.44-2.40 (m, 4 H), 1.68-1.64 (m, 2 H), 1.15 ( d, 6 H) and 0.96 (t, 3 H).
    [1357] [1357] LCMS: m / z 543.4 (M + H) + (ES +). Example 151: 3- (Benzyl (ethyl) amino) -N - ((2- (2-cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) propane-1-sulfonamide
    [1358] [1358] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonamide (Intermediate P33) (100 mg, 390.07 μmol, 1 eq) in THF (1 mL) was added t-BuONa (37 mg, 390.07 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A37) (110 mg, 390.07 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 28% -58%, 11.5 min) to obtain the title compound (37.69 mg, 18% yield, 100% LCMS purity) as a white solid.
    [1359] [1359] 1H NMR (DMSO-d6): δ 10.49 (br s, 1 H), 8.76 (d, 1 H), 8.14 (s, 1 H), 8.09 (s, 1 H), 7.76 (dd, 1 H), 7.34-7.20 (m, 7 H), 3.74 (s, 2 H), 3.18-3.09 (m, 3 H) , 2.47-2.42 (m, 4 H), 1.65-1.62 (m, 2 H), 1.17 (d, 6 H) and 0.96 (t, 3 H).
    [1360] [1360] LCMS: m / z 538.4 (M + H) + (ES +). Example 152: 3- (Benzyl (ethyl) amino) -N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) propane-1 -sulfonamide
    [1361] [1361] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonamide (Intermediate P33) (100 mg, 390.07 μmol, 1 eq) in THF (1 mL) was added t-BuONa (37 mg, 390.07 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (146 mg, 390.07 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 50 mm * 10 μm; mobile phase: [A: water (10 mM NH4HCO3); B: MeCN]; B%: 18% - 48%, 11.5 min) to obtain the title compound (35.98 mg, 17% yield, 98% purity in LCMS) as a white solid.
    [1362] [1362] 1H NMR (DMSO-d6): δ 10.31 (br s, 1 H), 8.16 (d, 1 H), 8.00 (s, 1H), 7.32-7.26 ( m, 4 H), 7.24 (d, 2 H), 7.14 (d, 1 H), 6.93 (d, 1 H), 6.75 (s, 1 H), 3.86 ( s, 3 H), 3.56 (s, 2 H), 3.26-3.22 (m, 2 H), 2.93 (t, 2 H), 2.79 (t, 2 H), 2.47-2.40 (m, 4 H), 2.02-1.97 (m, 2 H), 1.81-1.76 (m, 2 H) and 0.96 (t, 3 H ).
    [1363] [1363] LCMS: m / z 523.3 (M + H) + (ES +). Example 153: 3- (Benzyl (ethyl) amino) -N - (((7-fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) propane -1-sulfonamide
    [1364] [1364] To a solution of 3- (benzyl (ethyl) amino) propane-1-sulfonamide (Intermediate P33) (101 mg, 393.30 μmol, 1 eq) in THF (1 mL) was added t-BuONa (38 mg, 393.30 μmol, 1 eq). The reaction mixture was stirred at 15 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (100 mg, 393.30 μmol, 1 eq) was added. The resulting mixture was stirred at 15 ° C for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 5% -35%, 10 min) to obtain the title compound (67.23 mg, 33% yield, 100% LCMS purity) as a pink solid.
    [1365] [1365] 1H NMR (DMSO-d6): δ 8.57 (d, 2 H), 7.86 (br s, 1 H), 7.38 (d, 2 H), 7.31 (d, 4 H), 7.26-7.23 (m, 1 H), 7.03 (d, 1 H), 3.56 (s, 2 H), 3.18-3.15 (m, 2 H) , 2.96 (t, 2 H), 2.85 (t, 2 H), 2.47-2.42 (m, 4 H), 2.10-2.03 (m, 2 H), 1 , 76-1.70 (m, 2 H) and 0.96 (t, 3 H).
    [1366] [1366] LCMS: m / z 511.3 (M + H) + (ES +). Example 154: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 3-methoxypropane-1-sulfonamide O O F O S O The HN
    [1367] [1367] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P34) (65 mg, 426.62 μmol, 1.2 eq) in THF (1 ml) was added t-BuONa (34 mg, 355.51 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A37) (100 mg, 355.51 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 11.5 min) to obtain the title compound (113.93 mg, 74% yield, 100% LCMS purity) as a white solid.
    [1368] [1368] 1HNMR (DMSO-d6): δ 8.71 (d, 1 H), 8.06 (s, 1 H), 7.77 (s, 1 H), 7.58 (s, 1 H) , 7.23-7.18 (m, 1 H), 7.10 (d, 1 H), 3.29-3.24 (m, 3 H), 3.21 (s, 3 H), 2 , 76-2.73 (m, 2 H), 1.60-1.57 (m, 2 H) and 1.16 (d, 6 H).
    [1369] [1369] LCMS: m / z 435.2 (M + H) + (ES +). Example 155: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -3-methoxypropane-1-sulfonamide
    [1370] [1370] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P34) (64 mg, 419.14 μmol, 1.2 eq) in THF (1 ml) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (100 mg, 349.28 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 8% -38%, 11.5 min) to obtain the title compound (130.95 mg, 85% yield, 99.7% LCMS purity) as a white solid.
    [1371] [1371] 1H NMR (DMSO-d6): δ 8.11 (d, 1 H), 7.51 (s, 1 H), 7.16 (d, 1 H), 7.02-6.95 ( m, 2 H), 6.84 (s, 1 H), 3.86 (s, 3 H), 3.34-3.27 (m, 3 H), 3.21 (s, 3 H), 2.90-2.86 (m, 2 H), 1.72-1.61 (m, 2 H) and 1.15 (d, 6 H).
    [1372] [1372] LCMS: m / z 440.2 (M + H) + (ES +). Example 156: 3-Methoxy-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) propane-1-sulfonamide
    [1373] [1373] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P34) (72 mg, 469.98 μmol, 1.2 eq) in THF (1 ml) was added t-BuONa (38 mg, 391.65 μmol, 1 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (163 mg, 391.65 μmol, 1 eq) was added. The resulting mixture was stirred at 70 ° C for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm * 25 mm * 5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v / v); B: MeCN]; B %: 5% -35%, 11.5 min) to obtain the title compound (15.13 mg, 9% yield, 100% LCMS purity) as a white solid.
    [1374] [1374] 1H NMR (DMSO-d6): δ 10.34 (br s, 1 H), 8.17 (d, 1 H), 7.97 (br s, 1 H), 7.24 (d, 1 H), 7.14 (d, 1 H), 6.94 (d, 1 H), 6.76 (s, 1 H), 3.88 (s, 3 H), 3.37 (t, 2 H), 3.26-3.20 (m, 5 H), 2.95 (t, 2 H), 2.81 (t, 2 H), 2.06-2.02 (m, 2 H ) and 1.84-1.78 (m, 2 H).
    [1375] [1375] LCMS: m / z 420.2 (M + H) + (ES +). Example 157: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -3-methoxypropane-1-sulfonamide
    [1376] [1376] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P34) (60 mg, 393.30 μmol, 1 eq) in THF (1 ml) was added t-BuONa (38 mg, 393.30 μmol, 1 eq). The reaction mixture was stirred at 15 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (100 mg, 393.30 μmol, 1 eq) was added. The resulting mixture was stirred at 15 ° C for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 0% -30%, 10 min) to obtain the title compound (62.33 mg, 38% yield, 100% purity in LCMS) as a pink solid.
    [1377] [1377] 1H NMR (DMSO-d6): δ 8.57 (d, 2 H), 7.63 (br s, 1 H), 7.40 (d, 2 H), 7.00 (d, 1 H), 3.37-3.34 (m, 2 H), 3.23 (s, 3 H), 3.07-3.04 (m, 2 H), 2.97 (t, H), 2.87 (t, 2 H), 2.11-2.05 (m, 2 H) and 1.79-1.72 (m, 2 H).
    [1378] [1378] LCMS: m / z 408.2 (M + H) + (ES +). Example 158: N - ((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 1- (pyridin-3-yl) methanesulfonamide N F O N S O
    [1379] [1379] To a solution of pyridin-3-ylmethanesulfonamide (70 mg, 406.49 μmol, 1 eq) in THF (5 ml) was added t-BuONa (39 mg, 406.49 μmol, 1 eq) and 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A37) (114 mg, 406.49 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 5% -35%, 11.5 min) to obtain the title compound (68 mg, 37% yield, 100% LCMS purity) as a white solid.
    [1380] [1380] 1H NMR (DMSO-d6): δ 8.77 (d, 1 H), 8.50 (d, 1 H), 8.37 (s, 1 H), 8.10 (s, 1 H ), 7.86 (br s, 1 H), 7.79 (d, 1 H), 7.61-7.45 (m, 1 H), 7.33-7.27 (m, 2 H) , 7.19-7.02 (m, 1 H), 4.31 (s, 2 H), 3.24-3.18 (m, 1 H) and 1.20-1.06 (m, 6 H).
    [1381] [1381] LCMS: m / z 454.3 (M + H) + (ES +). Example 159: N - (((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -1- (pyridin-3-yl) methanesulfonamide N F O N S O
    [1382] [1382] To a solution of pyridin-3-ylmethanesulfonamide (60 mg, 348.42 μmol, 1 eq) in THF (5 ml) was added t-BuONa (33 mg, 348.42 μmol, 1 eq) and 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (100 mg, 348.42 µmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 8% -38%, 11.5 min) to obtain the title compound (70 mg, 44% yield, 100% LCMS purity) as a white solid.
    [1383] [1383] 1H NMR (DMSO-d6): δ 8.50 (d, 1 H), 8.41 (s, 1 H), 8.16 (d, 1 H), 7.61 (br s, 1 H), 7.50 (d, 1 H), 7.33-7.30 (m, 1 H), 7.21 (d, 1 H), 7.06-7.00 (m, 2 H) , 6.87 (s, 1 H), 4.33 (s, 2 H), 3.85 (s, 3 H), 3.22-3.17 (t, 1 H) and 1.20-1 , 04 (m, 6 H).
    [1384] [1384] LCMS: m / z 459.3 (M + H) + (ES +). Example 160: N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (pyridin-3-yl) methanesulfonamide N O N S O
    [1385] [1385] To a solution of pyridin-3-ylmethanesulfonamide (70 mg, 406.49 μmol, 1 eq) in THF (5 ml) was added t-BuONa (39 mg, 406.49 μmol, 1 eq) and 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (108 mg, 406.49 μmol, 1 eq). The mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 10 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN]; B %: 5% -35%, 11.5 min) to obtain the title compound (65 mg, 36% yield, 100% LCMS purity) as a white solid.
    [1386] [1386] 1H NMR (DMSO-d6): δ 8.52 (d, 1 H), 8.46 (d, 1 H), 8.16 (d, 1 H), 7.61 (d, 1 H ), 7.37-7.34 (m, 1 H), 7.17 (d, 1 H), 7.10 (d, 1 H), 6.97-6.95 (m, 1 H), 6.78 (s, 1 H), 4.45 (s, 2 H), 3.86 (s, 3 H), 2.93 (t, 2 H), 2.83 (t, 2 H) and 2.07-1.98 (m, 2 H).
    [1387] [1387] LCMS: m / z 439.3 (M + H) + (ES +). Example 161: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (pyridin-3-yl) methanesulfonamide N F N F O
    [1388] [1388] To a solution of pyridin-3-ylmethanesulfonamide (68 mg, 393.30 μmol, 1 eq) in THF (2 ml) was added t-BuONa (38 mg, 393.30 μmol, 1 eq). The reaction mixture was stirred at 25 ° C for 10 minutes. A solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (100 mg,
    [1389] [1389] 1H NMR (DMSO-d6): δ 8.57 (d, 2 H), 8.49- 8.45 (m, 2 H), 7.59 (d, 1 H), 7.39 ( d, 2 H), 7.34-7.30 (m, 1 H), 6.96 (d, 1 H), 4.34 (s, 2 H), 2.95 (t, 2 H), 2.87 (t, 2 H) and 210-2.05 (m, 2 H).
    [1390] [1390] LCMS: m / z 427.2 (M + H) + (ES +). Example 162: N - (((2- (2-Cyanopyridin-4-yl) -4-fluoro-6-isopropylphenyl) carbamoyl) - 1- (1-methylpyrrolidin-3-yl) methanesulfonamide F F O O O O O
    [1391] [1391] A solution of (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate P31) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) at 25 ° C for 10 minutes. Then, 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) picolinonitrile (Intermediate A37) (57 mg, 201.96 μmol, 0.2 eq) was added. The reaction mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 10% -40%, 10.0 min) to obtain the title compound (17.51 mg, 4% yield, 100% LCMS purity) as a white solid.
    [1392] [1392] 1H NMR (DMSO-d6 + D2O): δ 8.70 (d, 1 H), 8.00 (s, 1 H), 7.74 (s, 1 H), 7.17 (dd, 1 H), 7.06 (dd, 1 H), 3.26-3.15 (m, 2 H), 3.10-3.01 (m, 2 H), 2.95-2.80 ( m, 2 H), 2.77-2.72 (m, 1 H), 2.67 (s, 3 H), 2.45-2.40 (m, 1 H), 2.10-1, 98 (m, 1 H), 1.62-1.51 (m, 1 H) and 1.13 (d, 6 H).
    [1393] [1393] LCMS: m / z 460.2 (M + H) + (ES +). Example 163: N - ((4-Fluoro-2-isopropyl-6- (2-methoxypyridin-4-
    [1394] [1394] A solution of (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate P31) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 ml) was stirred at 25 ° C for 10 minutes. Then 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-methoxypyridine (Intermediate A38) (58 mg, 201.96 µmol, 0.2 eq) was added. The resulting mixture was stirred at 25 ° C for 30 minutes and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 12% -42%, 10.0 min) to obtain the title compound (4.92 mg, 1% yield, 100% LCMS purity) as a white solid.
    [1395] [1395] 1H NMR (DMSO-d6 + D2O): δ 8.12 (d, 1 H), 7.14-7.11 (m, 1 H), 7.04- 7.02 (m, 1 H ), 6.96-6.93 (m, 1 H), 6.85-6.83 (m, 1 H), 3.86 (s, 3 H), 3.30-3.14 (m, 2 H), 3.05-2.98 (m, 3 H), 2.92-2.83 (m, 2 H), 2.63 (s, 3 H), 2.60-2.57 ( m, 1 H), 2.04-2.00 (m, 1 H), 1.61-1.57 (m, 1 H) and 1.14 (d, 6 H).
    [1396] [1396] LCMS: m / z 465.2 (M + H) + (ES +). Example 164: N - ((5- (2-Methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (1-methylpyrrolidin-3-yl) methanesulfonamide NH2 OO O O
    [1397] [1397] A solution of (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate P31) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) at 25 ° C for 10 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (54 mg, 201.96 µmol, 0.2 eq) was added . The resulting mixture was stirred at 25 ° C for 30 minutes and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 10% -40%, 10.0 min) to obtain the title compound (5.47 mg, 1% yield, 100% LCMS purity) as a white solid.
    [1398] [1398] 1H NMR (DMSO-d6 + D2O): δ 8.09 (d, 1 H), 7.11 (d, 1 H), 7.04 (d, 1 H), 6.98 (d, 1 H), 6.78 (s, 1 H), 3.84 (s, 3 H), 3.28-3.21 (m, 1 H), 3.15-3.01 (m, 3 H ), 2.95-2.90 (m, 1 H), 2.89-2.86 (m, 3 H), 2.84-2.78 (m, 2 H), 2.64 (s, 3 H), 2.61 - 2.55 (m, 1 H), 2.11 - 1.96 (m, 3 H) and 1.66-1.55 (m, 1 H).
    [1399] [1399] LCMS: m / z 445.2 (M + H) + (ES +). Example 165: N - (((7-Fluoro-5- (pyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1- (1-methylpyrrolidin-3-yl ) methanesulfonamide F F O O O O
    [1400] [1400] To a solution of (1-methylpyrrolidin-3-yl) methanesulfonamide (Intermediate P31) (180 mg, 1.01 mmol, 5 eq) in THF (2 mL) was added t-BuONa (97 mg, 1, 01 mmol, 5 eq) and the mixture was stirred at 25 ° C for 10 minutes. Then 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (51 mg, 201.96 μmol, 1 eq) in THF (1, 5 mL) was added. The reaction mixture was stirred at 25 ° C for 30 minutes. Most of the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18, 150 mm * 25 mm * 5 μm, mobile phase: [A: water (0.05% v / v ammonium hydroxide); B: MeCN], B %: 8% -38%, 10 min) to obtain the title compound (5.52 mg, 6% yield, 100% LCMS purity) as a white solid.
    [1401] [1401] 1H NMR (DMSO-d6): δ 8.55 (d, 2 H), 7.41 (d, 2 H), 7.40 (br s, 1 H), 6.95 (d, 1 H), 3.12-3.08 (m, 2 H), 2.97-2.85 (m, 7 H), 2.75-2.71 (m, 1 H), 2.58 (s , 3 H), 2.53-2.50 (m, 1 H), 2.09-2.00 (m, 3 H) and 1.59-1.57 (m, 1 H).
    [1402] [1402] LCMS: m / z 433.2 (M + H) + (ES +). Example 166: 3- (N - (((4-Fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropyl-
    [1403] [1403] A solution of N, N-bis (2-methoxyethyl) -1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P35) (2.2 g, 6.87 mmol, 1 eq) , 4- (5-fluoro-2-isocyanate-3-isopropylphenyl) -2-isopropoxypyridine (Intermediate A46) (2.16 g, 6.87 mmol, 1 eq) and t-BuONa (659 mg, 6.87 mmol , 1 eq) in THF (100 mL) was stirred at 25 ° C for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: Welch Ultimate XB_C18, 41mm * 235mm * 20 / 40μm, mobile phase: [A: water (10 mM NH 4HCO3); B: MeCN]; B%: 0% - 30%, 35 min) to give the title compound (2.5 g, 56% yield, 98% purity in LCMS) as a white solid.
    [1404] [1404] 1H NMR (DMSO-d6): δ 11.10 (br s, 1 H), 8.06 (d, 1 H), 7.79 (br s, 1 H), 7.18 (d, 1 H), 7.02 (d, 1 H), 6.83-6.72 (m, 2 H), 6.70 (s, 1 H), 5.29-5.23 (m, 1 H ), 3.83 (s, 3 H), 3.64-3.61 (m, 2 H), 3.55-3.50 (m, 4 H), 3.45-3.40 (m, 2 H), 3.28 (s, 3 H), 3.14 (s, 3 H), 3.03-3.00 (m, 1 H), 1.30 (d, 6 H) and 1, 09-1.05 (m, 6 H).
    [1405] [1405] LCMS: m / z 635.4 (M + H) + (ES +). Step B: 3- (N - ((4-Fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropylphenyl) carbamoyl) sulfamoyl) -N, N-bis (2-methoxyethyl) -1-methyl- 1H-pyrazol-5-carboxamide, sodium salt F F
    [1406] [1406] To a solution of 3- (N - ((4-fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropylphenyl) carbamoyl) sulfamoyl) -N, N-bis (2-methoxyethyl) - 1-methyl-1H-pyrazol-5-carboxamide (2.5 g, 3.94 mmol, 1 eq, free form) in THF (100 mL) was added with t-BuONa (378 mg, 3.94 mmol, 1 eq). The reaction mixture was stirred at 25 ° C for 1 hour and then concentrated in vacuo. The residue was triturated with isopropyl ether (20 ml) to produce the title compound (2.2 g, 85% yield, 99% LCMS purity, sodium salt) as a white solid.
    [1407] [1407] 1H NMR (DMSO-d6): δ 7.99-7.88 (m, 1 H), 7.53-7.40 (m, 1 H), 7.15- 7.08 (m, 1 H), 6.94-6.82 (m, 2 H), 6.68 (s, 1 H), 6.51-6.44 (m, 1 H), 5.28-5.22 ( m, 1 H), 3.75 (s, 3 H), 3.74-3.56 (m, 6 H), 3.45-3.38 (m, 2 H), 3.29 (s, 3 H), 3.17 (s, 3 H), 3.12-3.07 (m, 1 H), 1.29 (d, 6 H) and 1.20-1.04 (m, 6 H ).
    [1408] [1408] LCMS: m / z 635.1 (M + H) + (ES +). Example 167: N, N-Bis (2-methoxyethyl) -3- (N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl ) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxamide, sodium salt Step A: N, N-Bis (2-methoxyethyl) -3- (N - (((5- (2-methoxypyridin-4-yl ) -2,3-dihydro-1H-inden-4-yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxamide OMe MeO N O O O
    [1409] [1409] A solution of N, N-bis (2-methoxyethyl) -1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P35) (2.56 g, 7.99 mmol, 1 eq) and t-BuONa (768 mg, 7.99 mmol, 1 eq) in THF (200 mL) was stirred at 25 ° C for 30 minutes. Then, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (3.34 g, 8.79 mmol, 1.1 eq) was added. The reaction mixture was stirred at 70 ° C for 2 hours and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: Welch Ultimate XB_C18, 41mm * 235mm * 20 / 40μm, mobile phase: [A: water (0.05% ammonium hydroxide); B: MeCN]; B%: 0% -30%, 35 min) to give the title compound (1.35 g, 29% yield, 99% LCMS purity) as a white solid.
    [1410] [1410] 1H NMR (DMSO-d6): δ 8.08 (d, 1 H), 7.14-7.11 (m, 1 H), 7.07-7.05
    [1411] [1411] LCMS: m / z 587.3 (M + H) + (ES +). Step B: N, N-Bis (2-methoxyethyl) -3- (N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl ) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxamide, sodium salt OMe OMe O O O O O O
    [1412] [1412] To a solution of N, N-bis (2-methoxyethyl) -3- (N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4 -yl) carbamoyl) sulfamoyl) -1-methyl-1H-pyrazol-5-carboxamide (1.35 g, 2.30 mmol, 1 eq, free form) in THF (20 mL) was added with t-BuONa (221 mg, 2.30 mmol, 1 eq). The reaction mixture was stirred at 25 ° C for 1 hour and then concentrated in vacuo. The residue was triturated with isopropyl ether (20 ml) to produce the title compound (1.2 g, 85% yield, 99% HPLC purity) as a white solid.
    [1413] [1413] 1H NMR (DMSO-d6): δ 8.05 (d, 1 H), 7.30 (br s, 1 H), 7.04 (dd, 2 H), 6.92 (d, 1 H), 6.76 (s, 1 H), 6.48 (d, 1 H), 3.85 (s, 3 H), 3.75 (s, 3 H), 3.64-3.62 (m, 2 H), 3.56-3.53 (m, 4 H), 3.39-3.37 (m, 2 H), 3.29 (s, 3 H), 3.15 (s , 3 H), 2.87 (t, 2 H), 2.73-2.70 (m, 2 H) and 1.98-1.91 (m, 2 H).
    [1414] [1414] LCMS: m / z 587.1 (M + H) + (ES +). Example 168: 3- (N - ((4-Fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropyl-phenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazole-5 -carboxamide, sodium salt Step A: 3- (N - ((4-Fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropylphenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H -pyrazol-5-carboxamide F The F O O AT THE s OCN N N N O H H
    [1415] [1415] To a solution of N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazole-5-
    [1416] [1416] 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) .
    [1417] [1417] 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
    [1418] [1418] To a solution of 3- (N - ((4-fluoro-2- (2-isopropoxypyridin-4-yl) -6-isopropylphenyl) carbamoyl) sulfamoyl) -N, N, 1-trimethyl-1H-pyrazole -5-carboxamide (1.71 g, 3.13 mmol, 1 eq, free form) in THF (40 mL) was added t-BuONa (300 mg, 3.13 mmol, 1 eq) at 25 ° C. Then the mixture was stirred for 1 hour. The mixture was concentrated in vacuo. The residue was triturated with MTBE (100 ml). The solid was dissolved in water (100 ml) and then lyophilized to obtain the title compound (1.60 g, 90% yield, 99.9% HPLC purity) as a white solid.
    [1419] [1419] 1H NMR (DMSO-d6): δ 7.95 (d, 1 H), 7.37 (br s, 1 H), 7.09 (d, 1 H), 6.93-6.90 (m, 2 H), 6.69 (s, 1 H), 6.53 (s, 1 H), 5.29-5.22 (m, 1 H), 3.83 (s, 3 H) , 3.15 - 3.09 (m, 1 H), 3.01 (d, 6 H), 1.29 (d, 6 H) and 1.05 (d, 6 H).
    [1420] [1420] LCMS: m / z 547.3 (M + H) + (ES +).
    [1421] [1421] A solution of N, N, 1-trimethyl-3-sulfamoyl-1H-pyrazol-5-carboxamide (Intermediate P36) (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 A39) (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 cake 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.
    [1422] [1422] 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).
    [1423] [1423] LCMS: m / z 499.3 (M + H) + (ES +). Example 170: 1-Cyclopropyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazole- 3-sulfonamide, sodium salt
    [1424] [1424] 7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A34) (60 mg, 0.232 mmol) and ((1- cyclopropyl-1H-pyrazol-3-yl) sulfonyl) (4- (dimethylamino) pyridin-1-io-1-carbonyl) amide (Intermediate P37) (80 mg, 0.239 mmol) were suspended in MeCN (2 mL) and mixture was heated to 50 ° C for 1 hour. The MeCN was removed in vacuo. The residue was dissolved in DMSO (2 ml) and purified by basic preparative HPLC. After concentrating the product containing fractions, the free acid (55 mg, 50%) was isolated as a colorless solid.
    [1425] [1425] 1H NMR (DMSO-d6) δ 8.09 - 8.03 (m, 1H), 7.70 (d, J = 9.9 Hz, 1H), 7.32 (s, 1H), 6 , 94 (s, 1H), 6.90 (d, J = 9.3 Hz, 1H), 6.79 (s, 1H), 6.31 - 6.24 (m, 1H), 3.87 ( s, 3H), 3.76 - 3.66 (m, 1H), 2.91 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.02 (p, J = 7.5 Hz, 2H), 1.08 - 1.00 (m, 2H), 0.99 - 0.90 (m, 2H).
    [1426] [1426] LCMS; m / z 472.2 (M + H) + (ES +); 470.0 (M-H) - (ES-). Example 171: 1-Cyclopropyl-N - (((7-cyclopropyl-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazole- 3-sulfonamide, sodium salt
    [1427] [1427] Prepared according to the general procedure of 1-cyclopropyl-N- ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl ) carbamoyl) -1H-pyrazol-3-sulfonamide, sodium salt (Example 170) from ((1-cyclopropyl-1H-pyrazol-3-yl) sulfonyl) (4- (dimethylamino) pyridin-1-yo- 1-carbonyl) amide (Intermediate P37) and 7-cyclopropyl-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A47) to provide the compound of title (36 mg, 39%) as a white solid.
    [1428] [1428] 1H NMR (DMSO-d6) δ 8.01 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.24 (s, 1H ), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.74 (d, J = 1.3 Hz, 1H), 6.54 (s, 1H), 6.28 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H), 3.76 - 3.67 (m, 1H), 2.95 (t, J = 7.5 Hz, 2H) , 2.73 (t, J = 7.5 Hz, 2H), 1.98 (p, J = 7.6 Hz, 2H), 1.90 - 1.80 (m, 1H), 1.08 - 1.01 (m, 2H), 0.98 - 0.92 (m, 2H), 0.90 - 0.84 (m, 2H), 0.67 - 0.59 (m, 2H).
    [1429] [1429] LCMS; m / z 494.1 (M + H) + (ES +). Example 172: 1-Cyclobutyl-N - (((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazole- 3-sulfonamide, sodium salt
    [1430] [1430] 7-Fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A34) (154 mg, 0.596 mmol) was dissolved in DCM ( 5 mL). Saturated aqueous NaHCO3 (3 ml) was added, followed by a solution of triphosgene (70 mg, 0.236 mmol) in DCM (1 ml). The biphasic mixture was stirred at room temperature for 1 hour. Then, the organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to provide 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2- crude methoxypyridine (85 mg, 50%) as a yellow solid that was used without further purification.
    [1431] [1431] 1-cyclobutyl-1H-pyrazol-3-sulfonamide (Intermediate P38) (60 mg, 0.298 mmol) was dissolved in dry THF (2 mL) and sodium tert-butoxide (2 M in THF) (160 µl, 0.320 mmol) was added. The mixture was stirred at room temperature for 1 hour, before a solution of 4- (7-fluoro-4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (85 mg , 0.298 mmol) in THF (1 mL) is added. The mixture was then stirred at room temperature overnight. Then the solvent was removed in vacuo, the residue was dissolved in DMSO (2 ml) and purified by basic preparative HPLC. The free acid was isolated as a colorless solid that was dissolved in 0.1 M aq NaOH (0.8 mL, 0.08 mmol, 1 eq) and the solution was lyophilized to provide the title compound (37 mg, 24% ) as a colorless solid.
    [1432] [1432] 1H NMR (DMSO-d6) δ 8.04 (d, J = 5.1 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.33 (s, 1H), 6 , 94 (d, J = 4.6 Hz, 1H), 6.90 (d, J = 9.3 Hz, 1H), 6.80 (s, 1H), 6.32 - 6.29 (m, 1H), 4.82 (p, J = 8.3 Hz, 1H), 3.86 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.7 Hz, 2H), 2.49 - 2.41 (m, 2H), 2.39 - 2.31 (m, 2H), 2.00 (p, J = 7.6 Hz, 2H ), 1.83 - 1.70 (m, 2H).
    [1433] [1433] LCMS; m / z 486.1 (M + H) + (ES +); 484.3 (M-H) - (ES-). Example 173: 1- (1- (Azetidin-1-yl) -2-methylpropan-2-yl) -N - ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-di -hydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide, sodium salt
    [1434] [1434] Prepared according to the general procedure of 1-cyclobutyl-N- ((7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl ) carbamoyl) -1H-pyrazol-3-sulfonamide, sodium salt (Example 172) from 1- (1- (azetidin-1-yl) -2-methylpropan-2-yl) -1H-pyrazol-3- sulfonamide (Intermediate P39) and 7-fluoro-5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-amine (Intermediate A34) to provide the title compound (60 mg , 37%) as a colorless solid.
    [1435] [1435] 1H NMR (DMSO-d6) δ 8.07 (d, J = 5.5 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.34 (s, 1H), 6 , 96 (d, J = 4.6 Hz, 1H), 6.90 (d, J = 9.3 Hz, 1H), 6.81 (s, 1H), 6.30 (q, J = 2, 1 Hz, 1H), 3.87 (s, 3H), 2.95 (t, J = 7.0 Hz, 4H), 2.91 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.64 (s, 2H), 1.99 (p, J = 7.6 Hz, 2H), 1.82 (p, J = 7.0 Hz , 2H), 1.44 (s, 6H).
    [1436] [1436] LCMS; m / z 543.1 (M + H) + (ES +); 541.0 (M-H) - (ES-). Example 174: 2-isopropoxy-N - (((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) ethanesulfonamide, sodium salt
    [1437] [1437] The 2-isopropoxyethanesulfonamide (50 mg, 0.299 mmol) was dissolved in dry THF (2 ml). Sodium tert-butoxide (2M in THF) (160 µL, 0.320 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A solution of 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A48) (80 mg, 0.299 mmol) in THF (1 mL) was added and the mixture was stirred for 2 hours at room temperature. THF was removed in vacuo. The residue was dissolved in DMSO (2 mL) and then purified by basic preparative HPLC to provide 2-isopropoxy-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden -4-yl) carbamoyl) ethanesulfonamide as a colorless solid. The solid was dissolved in aq NaOH (0.1 M, 0.74 ml, 1 eq) and the solution was lyophilized overnight to provide the title compound (30 mg, 22%) as a colorless solid.
    [1438] [1438] 1H NMR (DMSO-d6) δ 8.10 (d, J = 5.3 Hz, 1H), 7.13 - 7.02 (m, 3H),
    [1439] [1439] LCMS; m / z 434.2 (M + H) + (ES +); 432.1 (M-H) - (ES-). Example 175: 2-isopropoxy-N - (((5- (2-methoxypyridin-4-yl) -2,3-dihydrobenzofuran-4-yl) carbamoyl) ethanesulfonamide, sodium salt
    [1440] [1440] Prepared according to the general procedure of 2-isopropoxy-N- ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) ethanesulfonamide , Sodium (Example 174) from 2-isopropoxyethanesulfonamide and 4- (4-isocyanate-2,3-dihydrobenzofuran-5-yl) -2-methoxypyridine (Intermediate A49) and 2-isopropoxyethanesulfonamide to provide the title compound (22 mg, 16%) as a white solid.
    [1441] [1441] 1H NMR (DMSO-d6) δ 8.09 (d, J = 5.3 Hz, 1H), 7.20 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H ), 6.96 (dd, J = 5.3, 1.4 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 6.62 (d, J = 8.2 Hz , 1H), 4.54 (t, J = 8.7 Hz, 2H), 3.86 (s, 3H), 3.65 - 3.47 (m, 3H), 3.20 - 3.09 ( m, 4H), 1.07 (d, J = 6.1 Hz, 6H).
    [1442] [1442] LCMS; m / z 436.1 (M + H) + (ES +); 434.4 (M-H) - (ES-). Example 221: 1-Cyclopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide, sodium salt
    [1443] [1443] 1-Cyclopropyl-1H-pyrazol-3-sulfonamide (Intermediate P29) (516 mg, 2.76 mmol) was dissolved in THF (20 mL) and 2 M sodium tert-butoxide in THF (1 , 52 mL, 3.04 mmol). After 1 hour, 4- (4-isocyanate-2,3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Intermediate A39) (810 mg, 3.04 mmol) was added and the mixture of reaction was stirred at room temperature for 18 hours. Then, the reaction mixture was evaporated to dryness, redissolved in DMSO (5 mL) and purified by RP Flash C18 chromatography (40 g cartridge, 5-50% MeCN / 10 mM ammonium bicarbonate) to provide 1-cyclopropyl-N - ((5- (2-methoxypyridin-4-yl) -2,3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazol-3-sulfonamide (830 mg, 1.83 mmol). The solid was dissolved with 0.1 M aqueous sodium hydroxide (18.30 ml, 1.83 mmol) and the obtained solution was lyophilized to provide the title compound (837 mg, 63%) as a white solid.
    [1444] [1444] 1H NMR (DMSO-d6) δ 8.04 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.34 (s, 1H ), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.92 (dd, J = 5.2, 1.5 Hz , 1H), 6.75 (s, 1H), 6.28 (d, J = 2.3 Hz, 1H), 3.86 (s, 3H), 3.71 (tt, J = 7.6, 3.9 Hz, 1H), 2.88 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 1.95 (p, J = 7, 5 Hz, 2H), 1.08 - 0.91 (m, 4H).
    [1445] [1445] LCMS; m / z 454.3 (M + H) + (ES +); 452.1 (M-H) - (ES-).
    [1446] [1446] The compounds of examples 176-220 and 222-323 were synthesized by methods analogous to those described above. Spectrum of 1H Ex Structure and Name MS MW NMR
    [1447] [1447] It is well established that activation of NLRP3 leads to cellular 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
    [1448] [1448] 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 (~ 10 6 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 give a concentration of 625,000 cells / ml. To this diluted cell solution, LPS (Sigma # L4524) was added to give 1 µg / ml of Final Assay Concentration (FAC). 40µl of the final preparation was aliquoted in each well of a 96-well plate. The prepared plate was then used for screening compounds. Pyroptosis Assay with THP-1 Cells
    [1449] [1449] The following step-by-step assay method was followed for screening compounds.
    [1450] [1450] The results of the pyroptosis assay performed are summarized in Table 3 below as THP IC50. Human Blood IL1β Release Assay
    [1451] [1451] 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.
    [1452] [1452] Human whole blood in Li-heparin tubes was obtained from healthy donors from a panel of voluntary donors.
    [1453] [1453] The results of the human whole blood assay are summarized in Table 3 below as HWB IC50.
    [1454] [1454] 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.
    [1455] [1455] For intravenous administration, the compounds were formulated as a solution in water or DMSO: PBS [10:90] in a dosage volume of 2 mL / kg and administered through the tail vein. For oral administration, the compounds were formulated as a solution in DMSO: water [10:90] in a dosage volume of 5 ml / kg and administered orally.
    [1456] [1456] 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) for 3 minutes; or 5,696 rpm (3,000g) for 15 minutes) for plasma generation. The plasma was frozen on dry ice before bioanalysis. PK parameters were generated from LC-MS / MS data using Dotmatics or Phoenix WinNonlin 6.3 software. Example Dose AUC T½ Vdss Cl No. (mg / kg) (ng · hr / mL) (hr) (L / kg) (mL / min / kg) 1 1 340.9 3.3 4.49 49.1 10 1 , 98 806.3 3.8 7.14 40.9 25 1 411.5 0.4 0.41 41.9 28 1 385.5 1.2 1.07 43.3 30 1 182.5 2.3 2.72 91.3 33 1 274.4 6.3 3.95 60.7 34 1 661.2 12.1 3.03 25.2 36 1 356.0 0.5 0.8 47.6 37 1 247.8 0.3 1.32 67.2 38 1 375.4 1.2 1.14 51.5 44 1 259.0 0.5 0.75 64.9 45 1 259.1 0.5 0, 98 65.6 51 1 600.1 3.7 3.68 27.8 54 1 200 1.6 2.5 85.4 55 1 1862.5 6.9 3.25 9.8 58 1 591.0 0 , 9 0.55 28.2 60 1 300.2 1.0 1.22 56.3
    [1457] [1457] As is evident from the results shown in Table 3, surprisingly, despite structural differences from the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and, in particular, in the assay of human whole blood.
    [1458] [1458] As is evident from the results presented in Tables 4 and 5,
    [1459] [1459] 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 (18)
    [1]
    1. Compound of formula (I):
    O O Q S R2 1
    R N N
    H H Formula (I) characterized by the fact that: Q is selected from O or S; R1 is a saturated or unsaturated hydrocarbyl group, where the hydrocarbyl group may be straight or branched, or be or include cyclic groups, where the hydrocarbyl group may optionally be substituted, and where the hydrocarbyl group may optionally include one or more N, O or S heteroatoms in their carbon skeleton; and R2 is a cyclic group substituted in the α position by a monovalent heterocyclic group or a monovalent aromatic group, in which a ring atom of the heterocyclic or aromatic group is directly attached to a ring atom of the cyclic group, in which the heterocyclic or aromatic can optionally be substituted, and wherein the cyclic group can optionally be substituted further.
    [2]
    2. A compound according to claim 1, 1 characterized by the fact that R is a 4- to 10-membered cyclic group, in which the cyclic group can optionally be substituted.
    [3]
    3. A compound according to claim 1, characterized in that R1 is a C1-C15 alkyl, C2-C15 alkenyl or C2-C15 alkynyl group, all of which can be optionally substituted and all of which can optionally include a , two or three heteroatoms N, O or S in their carbon skeleton.
    [4]
    Compound according to any one of claims 1 to 3, characterized in that R1 is replaced with one,
    two or three substituents independently selected from halo; - CN; -N3; -Rβ; -OH; -ORβ; -SO2Rβ; -NH2; -NHRβ; -N (Rβ) 2; -Rα-NH2; -Rα-NHRβ; - Rα-N (Rβ) 2; -CORβ; -COORβ; -OCORβ; -Rα-CORβ; -Rα-COORβ; -Rα-OCORβ; - CONH2; -CONHRβ; -CON (Rβ) 2; or oxo (= O); where each -Rα- is independently selected from a C1-C6 alkylene group, where one or two carbon atoms in the main chain of the alkylene group can optionally be replaced by one or two N, O or S heteroatoms, and in that the alkylene group can optionally be substituted with one or two halo and / or -Rβ groups; and wherein each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and where any -Rβ can optionally be substituted by one, two or three C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O (C1-C4 alkyl), -O (C1- C4 haloalkyl), -O (C3-C7 cycloalkyl), halo, -OH, -NH2 groups , -CN, -C≡CH or oxo (= O).
    [5]
    Compound according to any one of claims 1 to 4, characterized in that the α-substituted cyclic group of R2 is a 5- or 6-membered cyclic group, wherein the cyclic group can optionally be additionally substituted.
    [6]
    A compound according to any one of claims 1 to 5, characterized by the fact that the monovalent heterocyclic or aromatic group at the α position of the cyclic group of R2 is phenyl or a 5- or 6-membered heterocyclic group, all of which can optionally be replaced.
    [7]
    Compound according to any one of claims 1 to 6, characterized in that the monovalent heterocyclic or aromatic group in the α position of the cyclic group of R2 is phenyl, pyridinyl, pyrimidinyl or pyrazolyl, all of which can optionally be substituted by one or two substituents independently selected from halo, -OH, -NH2, -CN, C1-C3 alkyl or -O (C1-C3 alkyl) groups.
    [8]
    A compound according to any one of claims 1 to 7, characterized in that the cyclic group of R2 is further substituted by one or two substituents independently selected from groups halo, -Rδ, -ORδ or -CORδ, wherein each Rδ is independently selected from a C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, and where each Rδ is optionally substituted further by one or more halo groups.
    [9]
    Compound according to any one of claims 1 to 8, characterized by the fact that Q is O.
    [10]
    10. Compound characterized by the fact that it is selected from the group consisting of:
    F F
    O O O O O O
    S S
    N N N N
    H H H H
    N N N N
    N N N
    F F
    O O O O O O
    S S
    N N N N
    H H H H
    N N N N N
    N
    F F
    O O O O O O
    S S
    N N N N
    H H H H
    N N N N N S
    N N
    F F
    O O O O O O
    S S
    N N N N
    H H H H
    N N N N
    The N
    CN
    F
    O O O F
    S O O O
    N N
    H H S
    N N N N
    H H
    N N
    CN N
    F F
    O O O O O O
    S S
    N N N N
    H H H H
    N N N N N
    N
    AT THE
    F F
    O O O O O O
    S S
    N N N N
    H H H H
    N N N N
    N
    N
    F
    O O O F
    S O O O
    N N S
    H H N N
    N N H H
    N N N
    N Cl
    F F
    O O O O O O
    S S
    N N N N
    H H H H
    N N N N
    N N N
    O
    F
    O O O
    F
    s
    N N O O O
    H H S
    N N N N
    H H
    N N N
    The N
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    [11]
    11. Pharmaceutically acceptable salt, solvate or prodrug characterized by the fact that it is of a compound as defined in any one of claims 1 to 10.
    [12]
    Pharmaceutical composition characterized by the fact that it comprises a compound as defined in any one of claims 1 to 10, or a salt, solvate or prodrug as defined in claim 11, and a pharmaceutically acceptable excipient.
    [13]
    Pharmaceutical composition according to claim 12, characterized in that the pharmaceutical composition is a topical pharmaceutical composition.
    [14]
    A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate or prodrug according to claim 11, or a pharmaceutical composition according to claim 12 or 13, characterized by fact that it is for medical use.
    [15]
    15. A compound, salt, solvate, prodrug or pharmaceutically acceptable pharmaceutical composition according to claim 14, 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.
    [16]
    16. Pharmaceutically acceptable compound, salt, solvate, prodrug or pharmaceutical composition according to claim 14 or 15, characterized by the fact that it is for use in the treatment or prevention of a disease, disorder or condition, in which the disease , disorder or condition is selected from: (i) inflammation; (ii) an autoimmune disease; (iii) cancer; (iv) an infection; (v) a disease of the central nervous system; (vi) a metabolic disease; (vii) a cardiovascular disease; (viii) a respiratory disease;
    (ix) a liver disease; (x) a kidney disease; (xi) an eye disease; (xii) a skin disease; (xiii) a lymphatic condition; (xiv) a psychological disorder; (xv) graft versus host disease; (xvi) allodynia; and (xvii) any disease in which an individual has been determined to have a germline or somatic non-silent mutation in NLRP3.
    [17]
    17. Compound, salt, solvate, prodrug or pharmaceutically acceptable pharmaceutical composition according to claim 14 or 15, 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).
    [18]
    18. Method of inhibiting NLRP3, characterized in that it comprises the use of a compound as defined in any of claims 1 to 10, or a pharmaceutically acceptable salt, solvate or prodrug as defined in claim 11, or a pharmaceutical composition as defined in claim 12 or 13, to inhibit NLRP3.
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    法律状态:
    2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|
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