EA047011B1 - Sulfonylurea derivatives as modulators of the NLRP3 inflammasome - Google Patents

Description

Related Application

This application claims benefit from United Kingdom Application No. 1721185.5, filed December 18, 2017, the entire contents of which are incorporated herein by reference.

Field of technology to which the invention relates

The present invention relates to sulfonylurea derivatives, their prodrugs and pharmaceutically acceptable salts, which may have inflammasome inhibitory activity and are accordingly useful in methods of treating a human or animal body. The present invention also relates to methods for preparing these compounds, to pharmaceutical compositions containing them and to their use for the treatment of disorders involving inflammasome activity, such as inflammatory, autoinflammatory and autoimmune diseases and cancer.

State of the art

Autoimmune diseases are associated with the overproduction of proinflammatory factors. One of these is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts and other components of the innate immune system such as dendritic cells. IL-1 is involved in various cell activities, including cell proliferation, differentiation and apoptosis (Seth L. et al. Rev. Immunol. 2009. 27:621-68).

In humans, the 22 NLR proteins are divided into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple members of the NLR family are associated with inflammasome formation.

Although inflammasome activation appears to be involved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability to be activated in response to endogenous sterile danger signals. Many such sterile signals have been studied and their formation is associated with specific pathological conditions. For example, uric acid crystals found in patients with gout are effective triggers for NLRP3 activation. Likewise, cholesterol crystals found in patients with atherosclerosis may also promote NLRP3 activation. The identification of the role of sterile danger signals as activators of NLRP3 has led to the conclusion that IL-1 and IL-18 are involved in a wide variety of pathophysiological manifestations, including metabolic, physiological, inflammatory, hematological and immunological disorders.

The present invention is driven by the need for additional compounds to specifically modulate NLRP3-dependent cellular processes. In particular, specific compounds with improved physicochemical, pharmacological and pharmaceutical characteristics compared to known compounds are desirable.

The essence of the invention

In some aspects, the present invention relates in particular to a compound of formula (I)

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein Ri is C ₃ -C _{1 6} cycloalkyl or C ₆ -C ₁₀ aryl, wherein C ₃ -C ₈ monocyclic cycloalkyl, polycyclic cycloalkyl or C ₆ -C ₁₀ aryl is optionally substituted with one or more amount of R _1S ; wherein each R _1S is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or halogen;

R2 is -(CX ₂ X ₂ ) _n -R _2S where n is 0, 1 or 2, and each X ₂ is independently H, C1-C6 alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, wherein C1-C6 alkyl, _C2 - _C6 alkenyl or _C2 - _C6 alkynyl is optionally substituted by one or more of the following: halogen, -CN, -OH, -O(C1- _C6 alkyl), -NH2, -NH (C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group;

R _2S means 4-8 membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group; And

_R3 is 7-12 membered heterocycloalkyl or 5- or 6-membered heteroaryl, optionally substituted by one or more _R3S , wherein each _R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen or C3-C8 heterocycloalkyl, wherein C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted by -O(C1- _C6 alkyl), N(C1- _C6 alkyl) ₂ , halogen or -CN.

In some aspects, the present invention relates to a compound obtained or obtained by a method for preparing a compound described in the present invention (for example, a method

- 1 047011 including one or more stages described in diagrams 1-2).

In some aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

In some aspects, the present invention relates to an intermediate described in the present invention suitable for use in a method for preparing a compound described in the present invention (eg, the intermediate is selected from among the intermediates described in Examples 1-166).

In some aspects, the present invention provides a method of inhibiting the activity of an inflammasome (eg, NLRP3 inflammasome) (eg, in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

In some aspects, the present invention provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention. in the present invention.

In some aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in inhibiting the activity of an inflammasome (eg, the NLRP3 inflammasome) (eg, in vitro or in vivo).

In some aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

In some aspects, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting the activity of an inflammasome (eg, the NLRP3 inflammasome) (eg, in vitro or in vivo).

In some aspects, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

In some aspects, the present invention relates to a method for preparing a compound of the present invention.

In some aspects, the present invention relates to a method for preparing a compound, comprising one or more of the steps described in the present invention.

Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention relates. In the description, singular forms also include plural forms unless the context clearly indicates otherwise. Although any methods and materials similar or equivalent to those described in the present invention can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other literature references cited in the present invention are incorporated herein by reference. Publications cited in the present invention are not considered prior art to the claimed invention. In the event of any conflict, this specification, including definitions, governs. Moreover, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the event of a conflict between the chemical structures and the names of the compounds disclosed herein, the chemical structures govern.

Other features and advantages of the present invention will be apparent from the following detailed description and claims.

Detailed Description of the Invention

Autoimmune diseases are associated with the overproduction of proinflammatory factors. One of these is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts and other components of the innate immune system such as dendritic cells. IL-1 is involved in various cell activities, including cell proliferation, differentiation and apoptosis (Seth L. et al. Rev. Immunol. 2009. 27:621-68).

Autoimmune diseases are associated with the overproduction of proinflammatory factors. One of these is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts and other components of the innate immune system such as dendritic cells. IL-1 is involved in various cell activities, including cell proliferation, differentiation and apoptosis (Seth L. et al. Rev. Immunol. 2009. 27:621-68).

- 2 047011

IL-1 family cytokines are highly active and, as important mediators of inflammation, are mainly associated with acute and chronic inflammation (Sims J. et al. Nature Reviews Immunology 10, 89102 (February 2010)). Overproduction of IL-1 is considered a mediator of several autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and unprovoked inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.

Proinflammatory cytokines of the IL-1 superfamily include IL-1a, IL-1e, IL-18 and IL-36a, β, λ and are produced in response to pathogens and other cellular stressors as part of the host innate immune response. Unlike many other cytokine-secreting systems, which are processed and released by the cell's standard secretory apparatus of the endoplasmic reticulum and Golgi apparatus, members of the IL-1 family lack the leader sequences required for endoplasmic reticulum entry and thus post-translation they are stored intracellularly. In addition, IL-1e, IL-18 and IL-36a, β, λ are synthesized as procytokines, which require proteolytic activation in order for them to become optimal ligands for binding to their cognate target cell receptors.

In the case of IL-1a, ΓΒ-1β and IL-18, it is now accepted that a multimeric protein complex known as the inflammasome is responsible for the activation of the protoforms of ΓΒ-1β and IL-18 and for the extracellular release of these cytokines. The inflammasome complex typically consists of a sensor molecule such as NLR (nucleotide oligomerization domain (NOD)-type receptor), adapter molecule ASC (apoptosis-associated Speck-like protein containing CARD (caspase recruitment domain)), and procaspase-1. In response to a variety of danger signals, including pathogen-associated molecular patterns (PAMPS) and danger-associated molecular patterns (DAMPS), inflammasome subunits oligomerize to form a supramolecular structure in the cell. PAMPS include molecules such as peptidoglycan, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPS are composed of a wide variety of endogenous or exogenous sterile triggers, including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and beta-amyloid peptide aggregates. Assembly of the inflammasome platform facilitates autocatalysis of procaspase-1 to produce a highly active cysteine protease responsible for the activation and release of pro-IL-1e and pro-IL-18. Thus, the release of these highly inflammatory cytokines is achieved only in response to detection by inflammasome sensors and in response to specific molecular danger signals.

In humans, the 22 NLR proteins are divided into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple members of the NLR family are associated with inflammasome formation, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF).

Two other structurally distinct inflammasome structures containing a PYHIN domain (pyrin domain and HIN containing protein) are absent in melanoma 2 (AIM2) and IFN/.-inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol. 2013 13 (6) 397-311) act as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) is another type of inflammasome platform associated with proIL-1e activation (Chae et al., Immunity 34, 755-768, 2011).

The requirement for assembly of the inflammasome platform to mediate the activation and release of IL-1β and IL-18 from monocytes and macrophages to enable their production is carefully regulated through a 2-step process. First, the cell must encounter a priming ligand (such as the TLR4 receptor LPS ligand or an inflammatory cytokine such as TNFa), which leads to NFkB-dependent transcription of NLRP3, pro-IL-1e, and pro-IL-18. These newly translated protocytokines remain intracellular and inactive unless the producing cells receive a second signal leading to activation of the inflammasome structure and maturation of protocaspase-1.

In addition to the proteolytic activation of pro-IL-1e and pro-IL-18, active caspase-1 also triggers a form of inflammatory cell death known as pyroptosis by cleaving gasdermin-D. Pyroptosis allows the release of mature forms of IL-1e and IL-18 along with the release of alarmin molecules (a compound that promotes inflammation and activates innate and adaptive immunity), such as high mobility protein box 1 (HMGB1), IL-33, and IL-1a .

Although inflammasome activation appears to be involved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability to be activated in response to endogenous and exogenous sterile danger signals. Many such sterile signals have been studied and their formation is associated with specific pathological conditions. For example, uric acid crystals found in patients with gout are effective triggers for NLRP3 activation. Likewise, cholesterol crystals found in patients with atherosclerosis may also promote NLRP3 activation. Defining the role of sterile signals is dangerous

- 3 047011 activators of NLRP3 has led to the conclusion that IL-1 and IL-18 are involved in a wide variety of pathophysiological manifestations, including metabolic, physiological, inflammatory, hematological and immunological disorders.

The best example of a link to human disease is the discovery that mutations in the NLRP3 gene, which lead to gain-of-function, span a range of autoinflammatory pathological conditions collectively referred to as cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), McLawels disease (MWS) and infantile multisystem inflammatory disease (NOMID) (Hoffman et al., Nat Genet. 29(3) (2001) 301-305). Likewise, sterile neurotransmitter-induced activation of NLRP3 has been implicated in a wide range of disorders including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic disease (type 2 diabetes, atherosclerosis, hypertension), central nervous system disease (Alzheimer's disease, Parkinson's disease, multiple sclerosis). ), gastrointestinal (Crohn's disease, ulcerative colitis), pulmonary (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis) and liver (fibrosis, non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH)). NLRP3 activation has also been suggested to promote renal inflammation and thereby contribute to chronic kidney disease (CKD).

Current treatments for diseases in which IL-1 is implicated as a contributing factor include the IL-1 receptor antagonist anakinra, an Fc-containing fusion construct of the extracellular domains of the IL-1 receptor and the IL-1 receptor accessory protein (rilonacept), and monoclonal antibodies to ΓΕ-1β canakinumab. For example, canakinumab has been licensed for the treatment of CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D syndrome (HIDS)/mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

Several small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glyburide is a specific inhibitor of NLRP3 activation, albeit at micromolar concentrations that are unlikely to be possible in vivo. Nonspecific agents such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-b-nitrostyrene have been reported to reduce NLRP3 activation but are thought to have limited therapeutic utility due to the similarity to the general structural system containing an olefin activated by substitution of an electron-withdrawing group ; this can lead to undesirable formation of covalent adducts with protein-containing thiol groups. A number of natural products, such as βhydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to inhibit NLRP3 activation. Likewise, numerous effectors/modulators of other molecular targets have been reported to impair NLRP3 activation, including the G protein-coupled receptor agonist TGR5, the sodium-glucose cotransport inhibitor epigliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, fenamate non-steroidal anti-inflammatory drugs, and the β-adrenergic receptor blocker nebivolol. The utility of these molecules as therapeutic agents for the long-term treatment of NLRP3-dependent inflammatory disorders remains unestablished. A group of sulfonylurea-containing molecules have previously been identified as active and selective inhibitors of post-translational processing of pro-IL-1e (Perregaux et al., J Pharmacol. Exp. Ther. 299, 187-197, 2001). The representative molecule CP-456.773 shown in this publication was recently characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nat Med 21, 3 (2015): 248-255.).

The present invention provides compounds useful for specifically modulating NLRP3-dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological and pharmaceutical characteristics compared to known NLRP3 modulating compounds are desirable.

Definitions

Unless otherwise specified, the following terms used in the specification and claims have the meanings indicated below.

It should be understood that an indication of treatment includes an indication of alleviation of established symptoms of a pathological condition. Treatment of a condition, disorder, or condition therefore involves: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition developing in a person who may be affected by or susceptible to the condition, disorder, or condition, but who does not experience or no clinical or subclinical symptoms of the condition, disorder or pathological condition are manifested, (2) suppression of the condition, disorder or pathological condition, i.e. stopping, weakening or delaying the development of the disease or its relapse (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms, or (3) facilitating the course or weakening of the disease, i.e. ensuring regression of a condition, disorder or pathological

- 4 047011 condition or at least one of its clinical or subclinical symptoms.

A therapeutically effective amount means an amount of a compound that, when administered to a mammal to treat a disease, is sufficient to provide effective treatment of the disease. The therapeutically effective amount varies depending on the compound, the disease and its severity, and age, body weight, and the like. mammal being treated.

When used in the present invention, alkyl, C1, _C2 , C3, _C4 , C5 or _C6 alkyl or _C1 - _C6 alkyl includes C1, C2, C3, _C4 , C5 or _C6 linear chain (linear) saturated aliphatic hydrocarbon groups and C ₃ , C ₄ , C ₅ or C ₆ branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl includes C1, C2, C3, _C4 , C5 and _C6 alkyl groups. Examples of alkyl include moieties containing from 1 to 6 carbon atoms such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sim-butyl, t-butyl, n-pentyl, isopentyl or n-hexyl. In some embodiments, the linear or branched alkyl contains 6 or fewer carbon atoms (eg, C1-C6 in the case of a straight chain, C3-C6 in the case of a branched chain), and in another embodiment, the linear or branched alkyl contains 4 or fewer carbon atoms.

As used in the present invention, the term optionally substituted alkyl means unsubstituted alkyl or alkyl containing the specified substituents replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate group, phosphonate group, phosphinate group, amino group (including alkylamino group, dialkylamino group, arylamino group, diarylamino group and alkylaryl amino group), acylamino group (including alkylcarbonylamino group, arylcarbonylamino group, carbamoyl and ureide group), amidine group, imino group, sulfhydryl group, alkylthio group, , thiocarboxylate group, sulfates, alkylsulfinyl, sulfonate group, sulfamoyl group, sulfonamide group, nitro group, trifluoromethyl group, cyano group, azide group, heterocyclyl group, alkylaryl group, or an aromatic or heteroaromatic moiety.

As used herein, the term alkenyl includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but which contain at least one double bond. For example, the term alkenyl includes linear alkenyl groups (eg, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, a linear or branched alkenyl group contains 6 or fewer carbon atoms in its backbone (eg, C2- _C6 for a straight chain, C3- _C6 for a branched chain). The term C2- _C6 includes alkenyl groups containing from 2 to 6 carbon atoms. The term C3- _C6 includes alkenyl groups containing from 3 to 6 carbon atoms.

As used in the present invention, the term optionally substituted alkenyl means unsubstituted alkenyl or alkenyl containing the specified substituents replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate group, phosphonate group, phosphinate group, amino group (including alkylamino group, dialkylamino group, arylamino group, diarylamino group and alkylaryl amino group), acylamino group (including alkylcarbonylamino group, arylcarbonylamino group, carbamoyl and ureide group), amidine group, imino group, sulfhydryl group, alkylthio group, , thiocarboxylate group, sulfates, alkylsulfinyl, sulfonate group, sulfamoyl group, sulfonamide group, nitro group, trifluoromethyl group, cyano group, heterocyclyl group, alkylaryl group, or an aromatic or heteroaromatic moiety.

As used herein, the term alkynyl includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, alkynyl includes linear alkynyl groups (eg, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, nonynyl, decynyl) and branched alkynyl groups. In some embodiments, the linear or branched alkynyl group contains 6 or fewer carbon atoms in its backbone (eg, C ₂ -C ₆ in the case of a linear chain, C ₃ -C ₆ in the case of a branched chain). The term C ₂ -C ₆ includes alkynyl groups containing from 2 to 6 carbon atoms. The term C ₃ -C ₆ includes alkynyl groups containing from 3 to 6 carbon atoms. When used in the present invention, the C ₂ -C ₆ alkenylene bridge or C ₂ -C ₆ alkynylene bridge includes C ₂ , C ₃ , C ₄ , C5 or C ₆ chain (linear

- 5 047011 or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene bridge includes C2, C3, _C4 , C5 and _C6 alkenylene bridge groups.

As used in the present invention, the term optionally substituted alkynyl means unsubstituted alkynyl or alkynyl containing the specified substituents replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate group, phosphonate group, phosphinate group, amino group (including alkylamino group, dialkylamino group, arylamino group, diarylamino group and alkylaryl amino group), acylamino group (including alkylcarbonylamino group, arylcarbonylamino group, carbamoyl and ureide group), amidine group, imino group, sulfhydryl group, alkylthio group, , thiocarboxylate group, sulfates, alkylsulfinyl, sulfonate group, sulfamoyl group, sulfonamide group, nitro group, trifluoromethyl group, cyano group, azide group, heterocyclyl group, alkylaryl group, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl) include unsubstituted moieties and moieties containing one or more of these substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6tetramethylpiperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

As used herein, the term cycloalkyl means a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (for example, fused, bridged or spiro-linked) system containing from 3 to 30 carbon atoms (for example, C ₃ -C ₁₂ , C ₃ -Cu or C3- C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl and adamantyl. In the case of a polycyclic cycloalkyl, only one of the cycloalkyl rings must be non-aromatic. In some embodiments, the cycloalkyl is hexahydroindacenyl. In some embodiments, cycloalkyl is

As used herein, the term heterocycloalkyl means a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro-linked) or 11-14 membered tricyclic ring system (fused, bridged or spiro-linked) containing one or more heteroatoms (such as O, N, S, P or Se), for example 1 or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or for example , 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, unless otherwise indicated. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, tietanyl, 6 -tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2 -oxa-6-azaspiro[3.3]heptanyl, 2,6diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1oxaspiro[4.5]decanyl, 1 -azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7Ήspiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3Ή- spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5 ,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3^]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c]pyridinyl,

5,6,7,8-tetrahydropyrido[4,3^]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2 -azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, etc. .P. In the case of polycyclic heterocycloalkyl, only one of the heterocycloalkyl rings must be non-aromatic (for example, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

As used herein, the term aryl includes groups having aromaticity, including conjugated or polycyclic systems with one or more aromatic rings and not containing any heteroatom in the ring structure. The term aryl is inclusive

- 6 047011 no monovalent systems and divalent systems. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Preferably, the aryl is phenyl.

As used herein, the term heteroaryl includes a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocyclic ring that consists of carbon atoms and one or more heteroatoms, for example 1 or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or, for example, 1, 2, 3, 4, 5 or 6 heteroatoms , independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (ie N or NR, where R is H or other substituents as defined). Nitrogen and sulfur heteroatoms may optionally be oxidized (ie N^O and S(O)p, where p=1 or 2). It should be noted that the total number of S and O atoms in an aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine and so on. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are non-aromatic to form a polycyclic system (eg, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

In addition, the terms aryl and heteroaryl include polycyclic aryl and heteroaryl groups, e.g. tricyclic, bicyclic, e.g. naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolysine

A cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted at one or more positions on the ring (e.g., at a ring-forming carbon atom or a heteroatom such as N) with substituents described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, carboxylate group, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, alkylthiocarbonyl, phosphate, phosphonate group, phosphinate group, amino group (including alkylamino group, dialkylamino group, arylamino group, diarylamino group and alkylaryl amino group), acylamino group (including alkylcarbonylamino group, arylcarbonylamino group, carbamoyl and ureide group), amidine group, imino group, sulfhydryl, alkylthio group, arylthio group, thiocarboxylate group, sulfates, alkylsulfinyl, sulfonate group, oil, sulfonamide group, nitro group, trifluoromethyl, a cyano group, an azide group, a heterocyclyl, an alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are non-aromatic to form a polycyclic system (eg, tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

As used in the present invention, the term substituted means that any one or more hydrogen atoms of a given atom are replaced by a selection from the specified groups, provided that the normal valency of the specified atom is not exceeded and that the substitution produces a stable compound. If the substituent is an oxo group or a keto group (i.e. =O), then 2 hydrogen atoms are replaced at this atom. Keto substituents are not found in aromatic moieties. Ring double bonds as used in the present invention are double bonds that are formed between two adjacent ring atoms (eg, C=C, C=N or N=N). A stable compound and a stable structure indicate a compound that is strong enough to withstand isolation to a significant degree of purity from the reaction mixture and processing into an effective therapeutic agent.

If a bond to a substituent is shown to cross a bond connecting two atoms in the ring, then that substituent can be bonded to any atom on the ring. If a substituent is specified without specifying the atom through which such substituent is linked to the rest of the compound of a given formula, then such substituent may be linked through any atom in such formula. Combinations of substituents and/or variables are acceptable, but only if such combinations produce stable compounds.

If any variable (such as R) appears more than once in any component or formula of a compound, its definition in each occurrence is independent of its definition in each other occurrence. Thus, for example, if a group is specified to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties, and R in each case is selected regardless of the definition of R. In addition, combinations of substituents and/or variables are permitted , but only if such combinations produce stable compounds.

As used herein, the term hydroxy or hydroxyl includes groups containing -OH or -O'.

As used in the present invention, the term halogen or halogen means fluorine, chlorine, bromine and iodine.

The term haloalkyl or haloalkoxy means an alkyl or alkoxy substituted with one

- 7 047011 or more halogen atoms.

As used herein, the term optionally substituted haloalkyl means an unsubstituted haloalkyl containing said substituents replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate group, phosphonate group, phosphinate group, amino group (including alkylamino group, dialkylamino group, arylamino group, diarylamino group and alkylaryl amino group), acylamino group (including alkylcarbonylamino group, arylcarbonylamino group, carbamoyl and ureide group), amidine group, imino group, sulfhydryl group, alkylthio group, , thiocarboxylate group, sulfates, alkylsulfinyl, sulfonate group, sulfamoyl group, sulfonamide group, nitro group, trifluoromethyl group, cyano group, azide group, heterocyclyl group, alkylaryl group, or an aromatic or heteroaromatic moiety.

As used herein, the term alkoxy or alkoxy includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxy radicals include, but are not limited to, methoxy group, ethoxy group, isopropyloxy group, propoxy group, butoxy group and pentoxy group. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups may be substituted with groups including the following: alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carbonyl, alkoxy, phosphate group, phosphonate group, phosphinate group, amino group (including alkylamino group, dialkylamino group, arylamino group, diarylamino group and alkylaryl amino group), acylamino group (including alkylcarbonylamino group, arylcarbonylamino group, carbamoyl and ureide group), amidine group, imino group, sulfhydryl group, alkylthio group, , thiocarboxylate group, sulfates, alkylsulfinyl, sulfonate group, sulfamoyl group, sulfonamide group, nitro group, trifluoromethyl group, cyano group, azide group, heterocyclyl, alkylaryl or aromatic or heteroaromatic moieties. Examples of halogenated alkoxy groups include, but are not limited to, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, chloromethoxy group, dichloromethoxy group and trichloromethoxy group.

When used in the present invention, the expression one or more of A, B or C, one or more of A, B or C, one or more of A, B and C, one or more of A, B and C selected from the group consisting of A, B and C selected from the group consisting of A, B and C, etc. are used interchangeably and all mean a choice from the group consisting of A, B and/or C, i.e. one or more A, one or more B, one or more C, or any combination thereof unless otherwise specified.

It should be understood that the present invention relates to methods for synthesizing compounds of any of the formulas described in the present invention. The present invention also relates to detailed methods for the synthesis of various disclosed compounds proposed in the present invention, according to the following schemes, as well as those given in the examples.

It should be understood that, as used herein, when compositions are described as having, including, or containing specific components, it is intended that the compositions also essentially consist of or consist of said components. Likewise, when methods or processes are described as having, including, or containing specific method steps, the methods also generally consist of or consist of said method steps. In addition, it should be understood that the order of steps or the order in which certain actions are carried out is immaterial if the present invention is to continue to operate. In addition, two or more stages or actions can be carried out simultaneously.

It should be understood that the synthetic methods proposed in the present invention can be carried out for a large number of functional groups, so different substituted starting materials can be used. The methods generally yield the desired final compound at or near completion of the entire procedure, although in some cases it may be desirable to subsequently convert the compound to its pharmaceutically acceptable salt.

It should be understood that the compounds of the present invention can be prepared in a variety of ways using commercially available starting materials, compounds known from the literature, or from readily prepared intermediates using standard synthetic techniques and procedures known to those skilled in the art. or which are obvious to one skilled in the art based on the data provided in the present invention. Standard methods and synthetic procedures for the preparation of organic molecules and functional transformations

- 8 047011 national groups and operations with them are given in the relevant scientific literature or in standard manuals for this field of technology. Without being limited to any one or more sources, classic publications such as Smith, M. W., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5 ^th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, ^3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated herein by reference, are applicable and known reference texts for organic synthesis known to those skilled in the art.

One of ordinary skill in the art will appreciate that in the reaction sequences and synthesis schemes described in the present invention, the order of certain steps, such as the introduction and removal of protecting groups, may be altered. One of ordinary skill in the art will understand that some groups may require protection with protecting groups under reaction conditions. Protecting groups can also be used to distinguish between similar functional groups in molecules. A list of protecting groups and procedures for introducing and removing these groups are given in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, ^3rd edition, John Wiley & Sons: New York, 1999.

It should be understood that, unless otherwise indicated, any description of a method of treatment includes the use of the compounds and the provision of such treatment or prevention as described in the present invention, as well as the use of the compounds for the preparation of a medicament for the treatment or prevention of such pathological condition. Treatments include treatment of human or non-human animals, including rodents, and other disease models.

As used in the present invention, the term subject is used interchangeably with the term subject in need, both meaning a subject who has a disease or is at increased risk of developing a disease. Subject includes a mammal. The mammal may be, for example, a human or a suitable non-human mammal such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. The subject may also be a bird or poultry. In one embodiment, the mammal is a human. The subject in need thereof may be one who has previously been diagnosed or found to have a disease or disorder disclosed in the present invention. The subject in need thereof may also be one who has a disease or disorder (eg, suffers from a disease or disorder disclosed in the present invention). Alternatively, the subject in need may also be one who has an increased risk of developing such a disease or disorder compared to the population as a whole (ie, a subject who is predisposed to developing such a disorder compared to the population as a whole). The subject in need thereof may have a stable or refractory disease or disorder disclosed in the present invention (ie, a disease or disorder disclosed in the present invention that does not or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof has taken and failed all known effective treatments for the disease or disorder disclosed herein. In some embodiments, the subject in need thereof has taken at least one prior treatment.

As used herein, the term treat or treat describes the treatment and care of a patient to combat a disease, condition or disorder and includes the administration of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to relieve symptoms or complications of the disease , disorder or pathological condition or to eliminate a disease, pathological condition or disorder. The term treatment may also include treating a cell in vitro or in an animal model.

It should be understood that a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, may also be used for the prevention of a corresponding disease, condition or disorder, or used to identify suitable candidates for such purposes.

As used herein, the term prevent, prevent, or protect against describes the attenuation or avoidance of the onset of symptoms or complications of such a disease, condition, or disorder.

It should be understood that one skilled in the art may refer to general publications for detailed descriptions of known techniques discussed in the present invention or equivalent techniques. These publications include Ausubel et al, Current Protocols in Molecular Biology; John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual ( ^3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology,

- 9 047011

John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, ^18th edition (1990). These publications, of course, can be referred to when implementing or using the subject matter of the present invention.

It should be understood that the present invention also relates to pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

As used herein, the term pharmaceutical composition means a preparation containing the compounds of the present invention in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an intravenous (IV) bag, a tablet, a unit pump in an aerosol inhaler, or a container. The amount of active ingredient (eg, in a preparation of the disclosed compound or a salt, hydrate, solvate or isomer thereof) in a single dose of the composition is an effective amount and varies depending on the particular treatment being administered. One skilled in the art will understand that it is sometimes necessary to make standard dosage adjustments depending on the age and condition of the patient. The dose also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of a compound of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that are required.

As used herein, the term pharmaceutically acceptable means those compounds, anions, cations, materials, compositions, carriers and/or dosage forms which, based on careful medical clinical evaluation, are suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic reaction or other difficulties or complications with a reasonable benefit/risk ratio.

As used in the present invention, the term pharmaceutically acceptable excipient means an excipient that is useful for the preparation of a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable and includes an excipient that is acceptable for use in veterinary medicine as well as in medicine. A pharmaceutically acceptable excipient as used in the specification and claims includes one or more than one such excipient.

It should be understood that the pharmaceutical composition provided by the present invention is formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral, eg, intravenous, intradermal, subcutaneous, oral (eg, ingestion), inhalation, transdermal (topical), and transmucosal. Solutions or suspensions used for parenteral, intradermal or subcutaneous use may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; bactericidal agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents to adjust tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. The parenteral drug may be placed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

It should be understood that the compound or pharmaceutical composition of the present invention can be administered to a subject by many well known techniques currently used for chemotherapy treatment. For example, the compound of the present invention can be injected into the bloodstream or body cavities, or taken orally or administered through the skin using patches. The dose chosen should be sufficient to provide effective treatment, but not so large as to cause unacceptable side effects. The disease state, pathological condition (eg, the disease or disorder disclosed in the present invention) and the health of the patient preferably need to be closely monitored during and for a reasonable period after treatment.

As used herein, the term therapeutically effective amount means an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to provide a detectable therapy.

- 10 047011 petic or inhibitory effects. The effect can be detected by any analytical technique known in the art. The exact effective amount for a subject depends on the subject's body weight, size, and health status; the nature and severity of the pathological condition; and a therapeutic agent or combination of therapeutic agents selected for administration. Therapeutically effective amounts for a given situation can be determined by standard experiments that are within the skill and judgment of the clinician.

It should be understood that for any compound, a therapeutically effective amount can be estimated in advance using assays using cell cultures, such as tumor cells, or animal models, typically rats, mice, rabbits, dogs or pigs. An animal model can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine applicable doses and routes of administration to humans. Therapeutic/prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures using cell cultures or experimental animals, for example, ED50 (dose therapeutic for 50% of the population) and LD50 (dose lethal for 50% of the population). The ratio of doses providing toxic and therapeutic effects is the therapeutic index and can be represented as the ratio LD ₅₀ /ED ₅₀ . Pharmaceutical compositions that have large therapeutic indices are preferred. The dose may vary within this range depending on the dosage form used, the sensitivity of the patient and the route of administration.

The dose and administration are adjusted to ensure sufficient levels of active agent(s) or to maintain the desired effect. Factors that may be considered include the severity of the pathological condition, the general health of the subject, the age, body weight and sex of the subject, diet, timing, frequency of administration, drug combination(s), sensitivity response and tolerability/response to therapy. Long-acting pharmaceutical compositions can be administered every 3-4 days, once a week or every 2 weeks depending on the half-life and elimination rate of the particular drug.

Pharmaceutical compositions containing the active compounds of the present invention can be prepared in a manner generally known, for example, by conventional mixing, dissolution, granulation, panning, trituration, emulsification, encapsulation, encapsulation or lyophilization techniques. Pharmaceutical compositions can be prepared in conventional manner using one or more pharmaceutically acceptable carriers, including excipients and/or excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate drug depends on the route of administration chosen.

Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if the substance is soluble in water) or dispersions and sterile powders to prepare sterile injectable solutions or dispersions for immediate use. For intravenous administration, suitable vehicles include saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and liquid to the extent that it can be easily syringed. It must be stable under the conditions of preparation and storage and must be protected from the contaminating effects of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerin, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof. Proper flowability can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion by using surfactants. Prevention of the contaminating effects of microorganisms can be achieved by using various antibacterial and fungicidal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, for example, sugars, polyhydric alcohols such as mannitol and sorbitol, and sodium chloride. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

Sterile solutions for injection can be prepared by incorporating the active compound in the required amount in a suitable solvent, if necessary, with one or a combination of the ingredients listed above, followed by sterilization by filtration. Typically, dispersions are prepared by incorporating the active compound into a sterile diluent that contains a basic dispersing medium and other necessary ingredients from those listed above. In the case of sterile powders for preparing sterile solutions for injection, the preparation techniques are vacuum drying and freeze drying, which produces a powder of the active ingredient with the addition of any additional desired ingredient from the previously obtained filter sterilization solution.

Oral compositions typically include an inert diluent or food grade pharmaceutical

- 11 047011 acceptable medium. They can be included in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be included in excipients and used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, wherein the compound in the liquid carrier is administered orally and rinsed and spit or swallowed. Pharmaceutically compatible binding agents and/or excipients can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant agent such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint flavor, methyl salicylate, or orange flavor.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser that contains a suitable propellant, for example a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be done by transmucosal or transdermal means. For transmucosal or percutaneous administration, the drug uses permeability agents appropriate to the barrier to be passed through. Such permeation agents are generally known in the art and include, for example, for transmucosal administration, disinfectants, bile salts and fusidic acid derivatives. Transmucosal administration can be done using nasal sprays or suppositories. For transdermal administration, the active compounds are formulated as ointments, balms, gels or creams, as is generally known in the art.

The active compounds can be formulated with pharmaceutically acceptable carriers that protect the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Techniques for preparing such preparations should be obvious to those skilled in the art. Materials are also available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes directed to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. They can be prepared by methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4522811.

It is particularly preferable to formulate oral or parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used in the present invention means a single portion suitable for use as unit doses for a subject being treated; each portion contains a predetermined amount of active compound calculated to provide the desired therapeutic effect together with the required pharmaceutical carrier. The characteristics of the unit dosage forms provided by the present invention are determined by and are directly dependent on the unique characteristics of the active compound and the particular therapeutic effect desired.

For therapeutic use, the dosages of the pharmaceutical compositions used in accordance with the present invention, along with other factors influencing the selected dosages, will vary depending on the agent, age, body weight and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner. doctor prescribing treatment. Typically, the dosage will be sufficient to slow and preferably suppress the symptoms of the disease or disorder disclosed herein and will also preferably be sufficient to completely suppress the disease or disorder. Doses may range from about 0.01 mg/kg/day to about 5000 mg/kg/day. In preferred embodiments, dosages may range from about 1 mg/kg/day to about 1000 mg/kg/day. In one subject, the dose ranges from about 0.1 mg/day to about 50 g/day; from about 0.1 mg/day to about 25 g/day; from about 0.1 mg/day to about 10 g/day; from about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day in single, divided, or continuous doses (this dose may be adjusted depending on the patient's body weight in kilograms, body surface area in m ² and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively detectable improvement that is detectable by a clinician or other qualified observer. Increased survival and growth indicate suppression. As used herein, the term effective in a dose-dependent manner means the amount of active compound to provide the desired biological effect on a subject or cell.

It should be understood that pharmaceutical compositions can be placed in a container, package or

- 12 047011 dispenser with instructions for administration.

It should be understood that for compounds of the present invention that are capable of further forming salts, all of these forms are also included within the scope of the claimed invention.

As used herein, the term pharmaceutically acceptable salts means derivatives of the compounds of the present invention wherein the parent compound is modified by forming salts thereof with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids with basic moieties such as amines, alkalis, or organic salts of acidic moieties such as carboxylic acids and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such common non-toxic salts include, but are not limited to, those formed from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarboxylic, carbonic, citric, ethylenediaminetetraacetic, ethanedisulfonic, 1,2-ethanesulfonic, fumaric, glucoheptonic, gluonic, glutamic, glycolic, glycolylarsanyl, hexylresorcinol, hydrabamine, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, inova, apple, almond, methanesulfonic, naphthalene sulfonic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, peracetic, succinic, sulfamyl, sulfanilic, sulfate, tannic, tartaric, toluene sulfonic and common amino acids, for example glycine, alanine, phenylalanine, in and so on.

In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonium salt, an arginine salt, or a lysine salt. .

Other examples of pharmaceutically acceptable acids include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4 -methylbicyclo-[2.2.2]-oct-2-ene1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid and the like. The present invention also includes salts formed when the parent compound has an acidic proton that is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be understood that in salt form, the ratio of the amount of compound to the amount of cation or anion of the salt may be 1:1 or a ratio other than 1:1, for example, 3:1, 2:1, 1:2 or 1:3 .

It should be understood that all references to pharmaceutically acceptable salts include references to solvent addition forms (solvates) or crystalline forms (polymorphs), as defined herein, of the same salts.

The compounds or a pharmaceutically acceptable salt thereof are administered orally, nasally, transdermally, pulmonaryly, inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will understand the advantages of certain routes of administration.

The mode of administration using the compounds is selected taking into account various factors, including the type, species, age, body weight, sex and pathological condition of the patient; the severity of the pathological condition being treated; routes of administration; the patient's kidney and liver function; and the specific compounds or salts thereof used. A physician or veterinarian with general training can easily determine and prescribe the effective amount of drug needed to prevent, control, or stop the progression of the condition.

Methods for preparation and administration of the disclosed compounds of the present invention are given in Remington: the Science and Practice of Pharmacy, ^19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described in the present invention and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid excipients or diluents and sterile aqueous or organic solutions. The compounds are contained in such pharmaceutical compositions in quantities sufficient to provide the desired dosage level within the range described in the present invention.

All contents, expressed as percentages and ratios, used in the present invention, unless otherwise indicated, are by weight. Other features and benefits of this

- 13 047011 inventions are obvious from various examples. The following examples illustrate the various components and methodologies useful in practicing the present invention. The examples do not limit the claimed invention. Based on the present invention, one skilled in the art can identify and use other components and methodologies useful in practicing the present invention.

In the synthesis schemes described in the present invention, compounds may be depicted in one specific configuration for simplicity. Such specific configurations should not be construed as limiting the present invention to one or the other isomer, tautomer, regioisomer or stereoisomer, and does not exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it should be understood that a given isomer, tautomer, regioisomer or stereoisomer may have greater activity than another isomer, and a tautomer, regioisomer or stereoisomer may have greater activity than another isomer, tautomer, regioisomer or stereoisomer.

All publications and patent documents cited in the present invention are incorporated herein by reference as if each publication or document were specifically and individually stated to be incorporated herein by reference. Citation of publications and patent documents does not imply that any of them is prior art and does not constitute any assumption as to their contents or date. The present invention has been described by written description, it will be understood by those skilled in the art that the present invention may be practiced in a variety of embodiments, and that the above description and the following examples are provided by way of illustration and not limitation of the following claims.

When used in the present invention, the expression compound proposed in the present invention means those compounds that are disclosed in the present invention, generally and specifically.

Compounds of the invention

In some aspects, the present invention provides a compound of formula (I):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R1 is C3-C16 cycloalkyl or Ce- _C10 aryl, wherein C3-C8 monocyclic cycloalkyl, polycyclic cycloalkyl or _C6 - _C10 aryl is optionally substituted with one or more _R1S ; where each R1S independently represents a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group or halogen;

R2 is -(CX2X2) _n -R _2S where n is 0, 1 or 2, and each X ₂ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally substituted by one or more of the following: halogen, -CN, -OH, -O(C ₁ -C ₆ alkyl), -NH2, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ or oxo group;

R2S means 4-8 membered heterocycloalkyl, optionally substituted by one or more of the following: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ or oxo group; And

R3 is a 7- to 12-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, optionally substituted by one or more R3S, wherein each R3S is independently _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, C3-C8 cycloalkyl, halogen or C3-C8 heterocycloalkyl, wherein C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), N( _C1 - _C6 alkyl) ₂ , halogen or -CN.

It should be understood that in a compound of formula (I), each R1, _R1S , _R2 , _R2S , R3 and R3S may, if applicable, be selected from the groups described in the present invention, and any group described in the present invention for any of R1, _R1S , _R2 , _R2S , R3 and R3S may be combined, if applicable, with any group described in the present invention for one or more of the remaining _R1 , _R1S , _R2 , _R2S , R ₃ and R _3S .

In some embodiments, R1 is C3-C16 cycloalkyl or _C6 - _C10 aryl, wherein C3-C8 monocyclic cycloalkyl or _C8 - _C16 polycyclic cycloalkyl is optionally substituted with one or more R1S.

In some embodiments, R ₁ is C3-C ₇ monocyclic cycloalkyl, C ₈ -C ₁₆ polycyclic cycloalkyl, or C ₆ -C ₁₀ aryl, wherein C3-C8 monocyclic cycloalkyl or C ₈ -C ₁₆ polycyclic cycloalkyl is optionally substituted with one or more R1S .

In some embodiments, R ₁ is C3-C7 monocyclic cycloalkyl, C ₉ -C ₁₀ bicyclic cycloalkyl, C ₁₂ -C ₁₆ tricyclic cycloalkyl, or C ₆ -C ₁₀ aryl, wherein C3-C7 monocyclic

- 14 047011 cycloalkyl, C ₉ -C ₁₀ bicyclic cycloalkyl or C ₁₂ -C ₁₆ tricyclic cycloalkyl is optionally substituted with one or more R1 S.

In some embodiments, R1 is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, or C ₆ -C ₁₀ aryl, wherein C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, or C ₆ -C ₆ aryl is optionally substituted with one or more R _1S .

In some embodiments, R1 is C3-C7 monocyclic cycloalkyl, C8- _C16 polycyclic cycloalkyl, or _C6 - _C10 aryl, wherein C3-C7 monocyclic cycloalkyl, C8- _C16 polycyclic cycloalkyl, or _C6 - _C6 aryl is optionally substituted with one or a large amount of R _1S .

In some embodiments, R1 is C3-C7 monocyclic cycloalkyl, C ₉ -C ₁₀ bicyclic cycloalkyl, C ₁₂ -C ₁₆ tricyclic cycloalkyl, or C ₆ -C ₁₀ aryl, wherein C3-C7 monocyclic cycloalkyl, C ₉ -C ₁₀ bicyclic cycloalkyl, C ₁₂ -C ₁₆ tricyclic cycloalkyl or C ₆ -C ₁₀ aryl is optionally substituted with one or more R1S.

In some embodiments, R1 is a C3-C7 monocyclic cycloalkyl, optionally substituted with one or more _R1S .

In some embodiments, R ₁ is a C ₃ -C ₇ monocyclic saturated cycloalkyl, optionally substituted with one or more R _1S .

In some embodiments, R ₁ is a C ₃ -C ₇ monocyclic partially saturated cycloalkyl, optionally substituted with one or more R _1S .

In some embodiments, R1 is a C ₉ -C ₁₀ bicyclic cycloalkyl, optionally substituted with one or more R _1S .

In some embodiments, R1 is a C ₉ -C ₁₀ bicyclic saturated cycloalkyl, optionally substituted with one or more R _1S .

In some embodiments, R1 is a C ₉ -C ₁₀ bicyclic partially saturated cycloalkyl, optionally substituted with one or more R _1S .

In some embodiments, R1 is a C ₁₂ -C ₁₆ tricyclic cycloalkyl, optionally substituted with one or more R _1S .

In some embodiments, R ₁ is a C ₁₂ -C ₁₆ tricyclic saturated cycloalkyl, optionally substituted with one or more R _1S .

In some embodiments, R ₁ is a C ₁₂ -C ₁₆ tricyclic partially unsaturated cycloalkyl, optionally substituted with one or more R _1S .

In some embodiments, R1 is a C8- _C16 polycyclic cycloalkyl substituted with one or more _R1S .

In some embodiments, R1 is 2,3-dihydro-1H-indenyl, optionally substituted with one or more R1 S.

In some embodiments, R1 is 2,3-dihydro-1H-indenyl. In some embodiments, R1 is

where n is 0, 1 or 2.

In some embodiments, R1 is

where n is 0, 1 or 2.

In some embodiments, R1 is

where n is 0, 1 or 2.

- 15 047011

In some embodiments, R ₁ means

where n is 0, 1 or 2.

In some embodiments, R1 is

where n is 0, 1 or 2, and where R _1S is C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C1-C ₆ haloalkoxy or halogen.

In some embodiments, R1 is

where n is 0, 1 or 2, and where R _1S is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ C ₆ haloalkoxy or halogen.

In some embodiments, R1 is

In some embodiments, R ₁ means

where R _1S means C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group or halogen.

In some embodiments, R1 is

where R _1S is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or halogen.

In some embodiments, R1 is 2,3-dihydro-N-indenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group or halogen.

In some embodiments, Rj is unsubstituted 2,3-dihydro-N-indenyl.

In some embodiments, R1 is

or

- 16 047011

In some embodiments, R ₁ is hexahydroindacenyl, optionally substituted with one or more R _1S .

In some embodiments, R1 is hexahydroindacenyl.

In some embodiments, R1 is

or

where n and na are all independently equal to 0, 1, 2 or 3.

In some embodiments, R1 is

where n and na are all independently equal to 0, 1, 2 or 3.

In some embodiments, R1 is

where n and na are all independently equal to 0, 1, 2 or 3.

In some embodiments, R1 is

where n and na are all independently equal to 0, 1, 2 or 3, and where R _1S is C1- _C6 alkyl, C1- _C6 haloalkyl, C1-C6 alkoxy, _C1 - _C6 haloalkoxy or halogen.

In some embodiments, Rj is

- 17 047011 or

In some embodiments, R1 is

where R1S is C1-C6 alkyl, C1-C6 haloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy or halogen.

In some embodiments, R1 is hexahydroindacenyl, optionally substituted with one, two, three or four substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy group or halogen.

In some embodiments, R1 is unsubstituted hexahydroindacenyl.

In some embodiments, R1 is

In some embodiments, R1 is C ₆ -C ₁₀ aryl, optionally substituted with one or more R1S.

In some embodiments, R1 is C ₆ -C ₁₀ aryl substituted with one or more R _1S .

In some embodiments, R1 is _C6 monocyclic aryl, optionally substituted with one or more _R1S .

In some embodiments, R1 is _C6 monocyclic aryl substituted with one or more _R1S .

In some embodiments, R1 is phenyl, optionally substituted with one or more _R1S .

In some embodiments, R1 is phenyl substituted with one or more R1S.

In some embodiments, R1 is phenyl substituted with one R1S.

In some embodiments, R1 is

or

In some embodiments, R1 is phenyl substituted with two R1S.

In some embodiments, R1 is

In some embodiments, R1 is phenyl substituted with three R1S.

- 18 047011

In some embodiments, R1 is

In some embodiments, R1 is

In some embodiments, R1 is

In some embodiments, R1 is phenyl substituted with one or more substituents independently selected from the group consisting of _C1 - _C4 alkyl, _C1 - _C2 alkoxy, C1-C2 haloalkoxy, halogen, and -CF3.

In some embodiments, R ₁ is phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of C1-C4 alkyl (eg, linear or branched).

In some embodiments, R ₁ is phenyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of Cl and F.

In some embodiments, R ₁ is phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of a C1-C2 alkoxy group.

In some embodiments, R ₁ is phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of a C1-C2 haloalkoxy group.

In some embodiments, R1 is

In some embodiments, R1 is

- 19 047011

In some embodiments, R1 is

- 20 047011

In some embodiments, R1 is

In some embodiments, R1 is

- 21 047011

In some embodiments, R1 is

In some embodiments, R1 is

In some embodiments, R1 is cyclopentyl, cyclohexyl, or cycloheptyl, wherein the cyclopentyl, cyclohexyl, or cycloheptyl is optionally substituted with one or more R1S. In some embodiments, R1 is cyclopentyl, cyclohexyl, or cycloheptyl.

In some embodiments, R1 is

In some embodiments, R1 is

In some embodiments, R1 is

In some embodiments, R1 is

In some embodiments, at least one R _1S is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halogen.

In some embodiments, at least one R _1S is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or halogen.

In some embodiments, at least one R _1S is C1-C6 alkyl, C1-C6 halo-alkyl, or halogen.

- 22 047011

In some embodiments, at least one R _1S is C1-C6 alkyl or halogen.

In some embodiments, at least one R _1S is C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, at least one R _1S is C1-C6 alkyl (eg, straight or branched).

In some embodiments, at least one R1 S is methyl. In some embodiments, at least one R1 S is ethyl. In some embodiments, at least one R _1S is a cut. In some embodiments, at least one R _1S is butyl. In some embodiments, at least one R _1S is pentyl. In some embodiments, at least one R1 S is hexyl. In some embodiments, at least one R _1S is isopropyl. In some embodiments, at least one R1 S is isobutyl. In some embodiments, at least one R _1S is isopentyl. In some embodiments, at least one R _1S is isohexyl. In some embodiments, at least one R _1S is sec-butyl. In some embodiments, at least one R _1S is sec-pentyl. In some embodiments, at least one R1 S is sec-hexyl.

In some embodiments, at least one R1 S is a C ₁ -C ₆ haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl substituted with one or more halogens).

In some embodiments, at least one R _1S is -CH2F, -CHF2, -CF3.

In some embodiments, at least one R _1S is -CH2F. In some embodiments, at least one R _1S is -CHF2. In some embodiments, at least one R _1S is -CF3.

In some embodiments, at least one R _1S is a C1-C6 alkoxy group or a C1-C6 haloalkoxy group.

In some embodiments, at least one R _1S is a C1-C6 alkoxy group.

In some embodiments, at least one R _1S is a methoxy group. In some embodiments, at least one R _1S is an ethoxy group. In some embodiments, at least one R _1S is a propoxy group. In some embodiments, at least one R _1S is butoxy. In some embodiments, at least one R _1S is a pentoxy group. In some embodiments, at least one R _1S is hexoxy.

In some embodiments, at least one R _1S is a C1-C6 haloalkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, pentoxy group or hexoxy group substituted with one or more halogens).

In some embodiments, at least one R _1S is a halogen methoxy group. In some embodiments, at least one R _1S is a haloethoxy group. In some embodiments, at least one R _1S is a halopropoxy group. In some embodiments, at least one R _1S is a halobutoxy group. In some embodiments, at least one R _1S is a halopentoxy group. In some embodiments, at least one R _1S is a halohexoxy group.

In some embodiments, at least one R _1S is -OCF3.

In some embodiments, at least one R _1S is -OCH2CF3.

In some embodiments, at least one R1 S is halogen.

In some embodiments, at least one R _1S is F, Cl, Br, or I.

In some embodiments, at least one R _1S is F or Cl.

In some embodiments, at least one R _1S is F.

In some embodiments, at least one R1 S is Cl.

In some embodiments, at least one R1 S is methyl, ethyl, isopropyl, isobutyl, sec-butyl, methoxy, ethoxy, -CF ₃ , -OCF ₃ , -OCH ₂ CF ₃ , F or Cl.

In some embodiments, R2 is R2S.

In some embodiments, R2 is -(CX2X ₂ )nR _2S , where n is 1 or 2.

In some embodiments, R2 is -(CX ₂ X ₂ )-R _2S .

In some embodiments, R2 is -(CX ₂ X ₂ ) ₂ -R _2S .

In some embodiments, R2 is -( _CH2 ) _n - _R2S , where n is 1. In some embodiments, R2 is -(CH2)n-R2S, where n is 2.

In some embodiments, at least one X ₂ is H.

In some embodiments, each X ₂ is an H.

In some embodiments, at least one X ₂ is C1-C6 alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein C1-C6 alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optional substituted with one or more of the following: halogen, -CN, -OH, -O(C1- _C6alkyl ), -NH2, -NH( _C1 - _C6alkyl ), -N(C1- _C6alkyl ) ₂ , or oxo group.

- 23 047011

In some embodiments, at least one X2 is a C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl), optionally substituted by one or more of the following: halogen, -CN, -OH, -O(C1 -C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C ₁ -C ₆ alkyl)2 or oxo group.

In some embodiments, at least one X2 is C1- _C6 alkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl).

In some embodiments, at least one X ₂ is C ₂ -C ₆ alkenyl (e.g., ethenyl, propenyl, butenyl, pentenyl, or hexenyl), optionally substituted with one or more of the following: halogen, -CN, -OH, -O( C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl)2 or oxo group.

In some embodiments, at least one X2 is C2-C6 alkenyl (eg, ethenyl, propenyl, butenyl, pentenyl, or hexenyl).

In some embodiments, at least one X2 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl), optionally substituted with one or more of the following: halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group.

In some embodiments, at least one X ₂ is C ₂ -C ₆ alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

In some embodiments, R2 _S is a 4-8 membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C2- _C6 alkenyl, C2- _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN,

-OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl)2 or oxo group.

In some embodiments, R2 _S is a 4-8 membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C2- _C6 alkenyl, C2- _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, - OH, -NH2 or oxo group.

In some embodiments, R2 _S is a 4-8 membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C2- _C6 alkenyl, C2- _C6 alkynyl, _C1 - _C6 haloalkyl, halogen or oxo.

In some embodiments, R2 _S is a 4-8 membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 _S is 4-8 membered heterocycloalkyl.

In some embodiments, R2 _S is a 5-8 membered heterocycloalkyl.

In some embodiments, R2 _S is a 5-7 membered heterocycloalkyl.

In some embodiments, R2 _S is a 5-6 membered heterocycloalkyl.

In some embodiments, R2 _S is a 5- or 6-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O.

In some embodiments, R2 _S is a 5- or 6-membered heterocycloalkyl containing one heteroatom selected from the group consisting of N and O.

In some embodiments, R2 _S is a 5- or 6-membered heterocycloalkyl containing two heteroatoms selected from the group consisting of N or O.

In some embodiments, R2 _S is a 6-membered heterocycloalkyl.

In some embodiments, R2 _S is a 6-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C2- _C6 alkenyl, C2- _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl)2 or oxo group.

In some embodiments, R2 _S is a 6-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 _S is a 6-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R2 _S is a 6-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R2 _S is a 6-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl.

In some embodiments, R2 _S is tetrahydropyranyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1- _C6 haloalkyl, or oxo.

In some embodiments, R2 _S is tetrahydropyranyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R2 _S is tetrahydropyranyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R2 _S is tetrahydropyranyl, optionally substituted

- 24 047011 ny one or more of the following: C ₁ -C ₆ alkyl.

In some embodiments, R2S is tetrahydropyranyl, optionally substituted with one or more methyls. In some embodiments, R2S is tetrahydropyranyl, optionally substituted with one or more ethyls. In some embodiments, R _2S is tetrahydropyranyl, optionally substituted with one or more propyls. In some embodiments, R _2S is tetrahydropyranyl, optionally substituted with one or more butyls. In some embodiments, R _2S is tetrahydropyranyl, optionally substituted with one or more pentyls. In some embodiments, R _2S is tetrahydropyranyl, optionally substituted with one or more hexyls.

In some embodiments, R _2S is tetrahydropyranyl, optionally substituted with one or more oxo groups.

In some embodiments, R _2S is tetrahydropyranyl, optionally substituted with one or more of the following: C1-C ₆ haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl, optionally substituted with one or more halogens).

In some embodiments, R2S means

In some embodiments, R2s means

In some embodiments, R2S is piperidinyl, optionally substituted with one or more of the following: C1- _C6 alkyl, _C1 - _C6 haloalkyl, or oxo.

In some embodiments, R2S piperidinyl is optionally substituted with one or more of the following: C1- _C6 alkyl or oxo.

In some embodiments, R _2S is piperidinyl, optionally substituted with one or more of the following: C1-C ₆ alkyl or C1-C ₆ haloalkyl.

In some embodiments, R _2S is piperidinyl, optionally substituted with one or more of the following: C1-C ₆ alkyl.

In some embodiments, R _2S is piperidinyl, optionally substituted with one or more methyls. In some embodiments, R _2S is piperidinyl, optionally substituted with one or more ethyls. In some embodiments, R _2S is piperidinyl, optionally substituted with one or more propyls. In some embodiments, R _2S is piperidinyl, optionally substituted with one or more butyls. In some embodiments, R _2S is piperidinyl, optionally substituted with one or more pentyls. In some embodiments, R _2S is piperidinyl, optionally substituted with one or more hexyls.

In some embodiments, R _2S is piperidinyl, optionally substituted with one or more oxo groups.

In some embodiments, R _2S is piperidinyl, optionally substituted with one or more of the following: C1-C ₆ haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl, optionally substituted with one or more halogens).

In some embodiments, R _2S is piperidinyl, optionally substituted with one or more of the following: -CH2F, -CHF2, -CF3, -(CH)2CH2F, -(CH)2CHF2 or -(CH)2CF3.

In some embodiments, R2S means

ί -ΐ A* 5

- 25 047011

In some embodiments, R2S means

In some embodiments, R2S is morpholinyl.

In some embodiments, R2S is morpholinyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C1 - _C6 haloalkyl, or oxo.

In some embodiments, R2S is morpholinyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R ₂ S is morpholinyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R _2S is morpholinyl, optionally substituted with one or more of the following: C1-C6 alkyl.

In some embodiments, R2S is morpholinyl, optionally substituted with one or more methyls. In some embodiments, R2S is morpholinyl, optionally substituted with one or more ethyls. In some embodiments, R _2S is morpholinyl, optionally substituted with one or more propyls. In some embodiments, R _2S is morpholinyl, optionally substituted with one or more butyls. In some embodiments, R _2S is morpholinyl, optionally substituted with one or more pentyls. In some embodiments, R _2S is morpholinyl, optionally substituted with one or more hexyls.

In some embodiments, R2S is morpholinyl, optionally substituted with one or more oxo groups.

In some embodiments, R ₂ S is morpholinyl, optionally substituted with one or more of the following: C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl, optionally substituted with one or more halogens).

In some embodiments, R2S means

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 0 and R2S is 6-membered heterocycloalkyl.

In some embodiments, R2 is -(CH2) _n -R2 _S , wherein n is 0 and R2S is a 6-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S , where n is 0 and R _2S is tetrahydropyranyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 0 and R2S is piperidinyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , wherein n is 0 and R2S is morpholinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 1 and R2S is 6-membered heterocycloalkyl.

In some embodiments, R2 is -(CH2)n-R2S, where n is 1 and R2S is a 6-membered heterocycloalkyl, optionally substituted by one or more of the following:

- 26 047011

C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or oxo group.

In some embodiments, R2 is -(CH2) _n -R2 _S , wherein n is 1 and R2S is tetrahydropyranyl, optionally substituted with one or more of the following: C1- _C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S , where n is 1 and R _2S is piperidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 1 and R2S is morpholinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 2 and R2S is 6-membered heterocycloalkyl.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , where n is 2 and R2S is a 6-membered heterocycloalkyl, optionally substituted by one or more of the following: _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, or oxo.

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S , where n is 2 and R _2S is tetrahydropyranyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or oxo group .

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S , where n is 2 and R _2S is piperidinyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or oxo group .

In some embodiments, R2 is -(CH2)n-R2S, wherein n is 2 and R2S is morpholinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S is a 5-membered heterocycloalkyl.

In some embodiments, R _2S is a 5-membered heterocycloalkyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, halogen, -CN, -OH, -O(C ₁ -C ₆ alkyl), -NH2, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ or oxo group.

In some embodiments, R _2S is a 5-membered heterocycloalkyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or oxo.

In some embodiments, R2S is a 5-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R2S is a 5-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R2S is a 5-membered heterocycloalkyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl.

In some embodiments, R _2S is tetrahydrofuranyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or oxo.

In some embodiments, R _2S is tetrahydrofuranyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl or oxo group.

In some embodiments, R2S is tetrahydrofuranyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R2S is tetrahydrofuranyl, optionally substituted with one or more of the following: C1-C6 alkyl.

In some embodiments, R2S is tetrahydrofuranyl, optionally substituted with one or more methyls. In some embodiments, R2S is tetrahydrofuranyl, optionally substituted with one or more ethyls. In some embodiments, R _2S is tetrahydrofuranyl, optionally substituted with one or more propyls. In some embodiments, R _2S is tetrahydrofuranyl, optionally substituted with one or more butyls. In some embodiments, R _2S is tetrahydrofuranyl, optionally substituted with one or more pentyls. In some embodiments, R _2S is tetrahydrofuranyl, optionally substituted with one or more hexyls.

In some embodiments, R2S is tetrahydrofuranyl, optionally substituted with one or more oxo groups.

In some embodiments, R2S is tetrahydrofuranyl, optionally substituted with one or more of the following: C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl, optionally substituted with one or more halogens).

- 27 047011

In some embodiments, R2S means

In some embodiments, R2S is pyrrolidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C1 - _C6 haloalkyl, or oxo.

In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl or oxo group.

In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl.

In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more methyls. In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more ethyls. In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more propyls. In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more butyls. In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more pentyls. In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more hexyls.

In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more oxo groups.

In some embodiments, R _2S is pyrrolidinyl, optionally substituted with one or more of the following: C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl, optionally substituted with one or more halogens).

In some embodiments, R2S means

In some embodiments, R2 is -(CH2) _n -R _2S , where n is 0 and R2S is 5-membered heterocycloalkyl.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 0 and R2S is a 5-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 0 and R2S is tetrahydrofuranyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C1 - _C6 haloalkyl, or oxo.

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S , where n is 0 and R _2S is pyrrolidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 1 and R2S is 5-membered heterocycloalkyl.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 1 and R2S is a 5-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S , where n is 1 and R _2S is tetrahydrofuranyl, optionally substituted by one or more of the following: C 1 -C 6 alkyl, C ₁ -C ₆ haloalkyl, or oxo.

- 28 047011

In some embodiments, R2 is -(CH ₂ )nR _2S , where n is 1 and R2S is pyrrolidinyl, optionally substituted with one or more of the following: Ci-Ce alkyl, Ci-Ce haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 2 and R2S is 5-membered heterocycloalkyl.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 2 and R2S is a 5-membered heterocycloalkyl, optionally substituted by one or more of the following: C1- _C6 alkyl, C1- _C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2)n-R2S, wherein n is 2 and R2S is tetrahydrofuranyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1- _C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2)n-R2S, where n is 2 and R2S is pyrrolidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S is a 4-membered heterocycloalkyl.

In some embodiments, R _2S is a 4-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, - OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group.

In some embodiments, R _2S is a 4-membered heterocycloalkyl, optionally substituted with one or more of the following: Ci-C6 alkyl, Ci-C6 haloalkyl, or oxo.

In some embodiments, R2S is a 4-membered heterocycloalkyl, optionally substituted with one or more of the following: Ci-C6 alkyl or oxo.

In some embodiments, R2S is a 4-membered heterocycloalkyl, optionally substituted with one or more of the following: Ci _{-C 6} alkyl or _Ci -C ₆ haloalkyl.

In some embodiments, R _2S is a 4-membered heterocycloalkyl, optionally substituted with one or more of the following: C _i -C ₆ alkyl.

In some embodiments, R _2S is oxetanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R _2S is oxetanyl, optionally substituted with one or more of the following: Ci-C6 alkyl or oxo.

In some embodiments, R2S is oxetanyl, optionally substituted with one or more of the following: Ci-C6 alkyl or Ci-C6 haloalkyl.

In some embodiments, R2S is oxetanyl, optionally substituted with one or more of the following: Ci-C6 alkyl.

In some embodiments, R2S is oxetanyl, optionally substituted with one or more methyls. In some embodiments, R _2S is oxetanyl, optionally substituted with one or more ethyls. In some embodiments, R _2S is oxetanyl, optionally substituted with one or more propyls. In some embodiments, R _2S is oxetanyl, optionally substituted with one or more butyls. In some embodiments, R _2S is oxetanyl, optionally substituted with one or more pentyls. In some embodiments, R2S is oxetanyl, optionally substituted with one or more hexyls.

In some embodiments, R2S is oxetanyl, optionally substituted with one or more oxo groups.

In some embodiments, R2S is oxetanyl, optionally substituted with one or more of the following: C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl, optionally substituted with one or more halogens).

In some embodiments, R2S means

In some embodiments, R2S is azetidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S is azetidinyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R _2S is azetidinyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R _2S is azetidinyl, optionally substituted with one or more of the following: C1-C6 alkyl.

- 29 047011

In some embodiments, R2S is azetidinyl, optionally substituted with one or more methyls. In some embodiments, R2S is azetidinyl, optionally substituted with one or more ethyls. In some embodiments, R2S is azetidinyl, optionally substituted with one or more propyls. In some embodiments, R _2S is azetidinyl, optionally substituted with one or more butyls. In some embodiments, R _2S is azetidinyl, optionally substituted with one or more pentyls. In some embodiments, R2S is azetidinyl, optionally substituted with one or more hexyls.

In some embodiments, R2S is azetidinyl, optionally substituted with one or more oxo groups.

In some embodiments, R2S is azetidinyl, optionally substituted with one or more of the following: C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl, optionally substituted with one or more halogens).

In some embodiments, R2S means

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 0 and R2S is 4-membered heterocycloalkyl.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 0 and R2S is a 4-membered heterocycloalkyl, optionally substituted by one or more of the following: _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S where n is 0 and R2S is oxetanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 0 and R2S is azetidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 1 and R2S is 4-membered heterocycloalkyl.

In some embodiments, R2 is -(CH2)n-R2S, wherein n is 1 and R2S is a 4-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 1 and R2S is oxetanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 1 and R2S is azetidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 2 and R2S is 4-membered heterocycloalkyl.

In some embodiments, R2 is -(CH2)n-R2S, where n is 2 and R2S is a 4-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , where n is 2 and _R2s is oxetanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 2 and R2S is azetidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S is a 7-membered heterocycloalkyl.

In some embodiments, _R2S is a 7-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, - OH, -O(Ci-C ₆ alkyl), -NH2, -NH(Ci-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group.

In some embodiments, R2S is a 7-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

- 30 047011

In some embodiments, R2S is a 7-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R _2S is a 7-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R _2S is a 7-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl.

In some embodiments, R _2S is oxepanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1- _C6 haloalkyl, or oxo.

In some embodiments, R2S is oxepanyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R2S is oxepanyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R2S is oxepanyl, optionally substituted with one or more of the following: C1-C6 alkyl.

In some embodiments, R _2S is oxepanyl, optionally substituted with one or more methyls. In some embodiments, R _2S is oxepanyl, optionally substituted with one or more ethyls. In some embodiments, R _2S is oxepanyl, optionally substituted with one or more propyls. In some embodiments, R _2S is oxepanyl, optionally substituted with one or more butyls. In some embodiments, R _2S is oxepanyl, optionally substituted with one or more pentyls. In some embodiments, R2S is oxepanyl, optionally substituted with one or more hexyls.

In some embodiments, R2S is oxepanyl, optionally substituted with one or more oxo groups.

In some embodiments, R2S is oxepanyl, optionally substituted with one or more of the following: C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl, optionally substituted with one or more halogens).

In some embodiments, R _2S is azepanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R _2S is azepanyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R2S is azepanyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R2S is azepanyl, optionally substituted with one or more of the following: C1-C6 alkyl.

In some embodiments, R2S is azepanil, optionally substituted with one or more methyls. In some embodiments, R2S is azepanil, optionally substituted with one or more ethyls. In some embodiments, R _2S is azepanil, optionally substituted with one or more propyls. In some embodiments, R _2S is azepanyl, optionally substituted with one or more butyls. In some embodiments, R _2S is azepanyl, optionally substituted with one or more pentyls. In some embodiments, R2S is azepanyl, optionally substituted with one or more hexyls.

In some embodiments, R2S is azepanil, optionally substituted with one or more oxo groups.

In some embodiments, R2S is azepanyl, optionally substituted with one or more of the following: C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl, optionally substituted with one or more halogens).

In some embodiments, R2S means

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 0 and R2S is 7-membered heterocycloalkyl.

In some embodiments, R2 is -(CH2)n-R2S, wherein n is 0 and R2S is a 7-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S , where n is 0 and R _2S is oxepanyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 halo

- 31 047011 genalkyl or oxo group.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 0 and R2S is azepanyl, optionally substituted with one or more of the following: _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 1 and R2S is 7-membered heterocycloalkyl.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 1 and R2S is a 7-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1- _C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2)n-R2S, where n is 1 and R2S is oxepanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2)n-R2S, wherein n is 1 and R2S is azepanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 2 and R2S is 7-membered heterocycloalkyl.

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S , where n is 2 and R _2S is a 7-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2)n-R2S, wherein n is 2 and R2S is oxepanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2)n-R2S, wherein n is 2 and R2S is azepanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S is an 8-membered heterocycloalkyl.

In some embodiments, R _2S is an 8-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, - OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group.

In some embodiments, R2S is an 8-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S is an 8-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R2S is an 8-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R _2S is an 8-membered heterocycloalkyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl.

In some embodiments, R _2S is oxocanyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or oxo.

In some embodiments, R _2S is oxocanyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R2S is oxocanyl, optionally substituted with one or more of the following: C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R2S is oxocanyl, optionally substituted with one or more of the following: C1-C6 alkyl.

In some embodiments, R2S is oxocanyl, optionally substituted with one or more methyls. In some embodiments, R _2S is oxocanyl, optionally substituted with one or more ethyls. In some embodiments, R _2S is oxocanyl, optionally substituted with one or more propyls. In some embodiments, R _2S is oxocanyl, optionally substituted with one or more butyls. In some embodiments, R _2S is oxocanyl, optionally substituted with one or more pentyls. In some embodiments, R2S is oxocanyl, optionally substituted with one or more hexyls.

In some embodiments, R2S is oxocanyl, optionally substituted with one or more oxo groups.

In some embodiments, R2S is oxocanyl, optionally substituted with one or more of the following: C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl, optionally substituted with one or more halogens).

In some embodiments, R _2S is azocanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

- 32 047011

In some embodiments, R2S is azocanyl, optionally substituted with one or more of the following: C1-C6 alkyl or oxo.

In some embodiments, R _2S is azocanyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, R _2S is azocanyl, optionally substituted with one or more of the following: C1-C ₆ alkyl.

In some embodiments, R _2S is azocanyl, optionally substituted with one or more methyls. In some embodiments, R _2S is azocanyl, optionally substituted with one or more ethyls. In some embodiments, R2S is azocanyl, optionally substituted with one or more propyls. In some embodiments, R2S is azocanyl, optionally substituted with one or more butyls. In some embodiments, R2S is azocanyl, optionally substituted with one or more pentyls. In some embodiments, R2S is azocanyl, optionally substituted with one or more hexyls.

In some embodiments, R _2S is azocanyl, optionally substituted with one or more oxo groups.

In some embodiments, R _2S is azocanyl, optionally substituted with one or more of the following: C1-C ₆ haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl, optionally substituted with one or more halogens).

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 0 and R2S is 8-membered heterocycloalkyl.

In some embodiments, R2 is -(CH2) _n -R2 _S , wherein n is 0 and R2S is an 8-membered heterocycloalkyl, optionally substituted by one or more of the following: C1- _C6 alkyl, C1- _C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 0 and R2S is oxocanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 0 and R2S is azocanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 1 and R2S is 8-membered heterocycloalkyl.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 1 and R2S is an 8-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1- _C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 1 and R2S is oxocanyl, optionally substituted with one or more of the following: Ci-C ₆ alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 1 and R2S is azocanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2) _n -R2 _S , where n is 2 and R2S is 8-membered heterocycloalkyl.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 2 and R2S is an 8-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 2 and R2S is oxocanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S where n is 2 and R2S is azocanyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R _2S is a spiro-linked heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group.

In some embodiments, R2S is a spiro-linked heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2)n-R2S, wherein n is 0 and R2S is a spiro-linked heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

- 33 047011

In some embodiments, R2 is -( _CH2 ) _nR2S , where n is 1 and R2S is a spiro-linked heterocycloalkyl, optionally substituted by one or more of the following: _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH ₂ ) _n -R _2S , where n is 2 and R2S is a spiro-linked heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S is a spiro-linked 7-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S is a spiro-linked 7-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl.

In some embodiments, R2S is a spiro-linked 7-membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 haloalkyl.

In some embodiments, R2S is 2-azaspiro[3.3]heptane, optionally substituted with one or more of the following: C1-C6 alkyl, _C1 - _C6 haloalkyl, or oxo. In some embodiments, R2S is 2-oxaspiro[3.3]heptane, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or oxo.

In some embodiments, R2S means

In some embodiments, R2S is a bridged heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, - O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group.

In some embodiments, R _2S is a bridged heterocycloalkyl, optionally substituted with one or more of the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or oxo.

In some embodiments, R2 is -( _CH2 ) _n - _R2S , wherein n is 0 and R2S is bridged heterocycloalkyl, optionally substituted by one or more of the following: _C1C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2 is -(CH2)n-R2S, where n is 1 and R2S is bridged heterocycloalkyl, optionally substituted by one or more of the following: _C1C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R ₂ is -(CH ₂ ) _n -R _2S where n is 2 and R _2S is bridged heterocycloalkyl, optionally substituted by one or more of the following: C ₁ C ₆ alkyl, C 1 -C 6 haloalkyl, or oxo.

In some embodiments, R2S is a bridged 8-membered heterocycloalkyl, optionally substituted with one or more of the following: C1 -C ₆ alkyl, C1 -C ₆ haloalkyl, or oxo.

In some embodiments, R2S is a bridged quinuclidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, or oxo.

In some embodiments, R2S means

In some embodiments, R2 is

- 34 047011

In some embodiments, R3 is a 7-12 membered heterocycloalkyl, optionally substituted with one or more R3S.

In some embodiments, R3 is 7-12 membered heterocycloalkyl.

In some embodiments, R3 is an 8- to 11-membered heterocycloalkyl, optionally substituted with one or more R3S.

In some embodiments, R ₃ is 8-11 membered heterocycloalkyl.

In some embodiments, R3 is a 9- or 10-membered heterocycloalkyl, optionally substituted with one or more _R3S .

In some embodiments, R3 is a 9- or 10-membered heterocycloalkyl.

In some embodiments, R ₃ is a 9-membered heterocycloalkyl, optionally substituted with one or more R _3S .

In some embodiments, R3 is a 9-membered heterocycloalkyl.

In some embodiments, R3 is

ABOUT'

^.^Z”^.(R _3S ) ₀ -4

In some embodiments, R3 means jZ-·;·./'\

In some embodiments, R3 is a 5- or 6-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, _C3 - _C8 cycloalkyl, halogen, or _C3 -C ₈ heterocycloalkyl, wherein C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1- _C6 alkyl), N( _C1 - _C6 alkyl) ₂ or -CN.

- 35 047011

In some embodiments, R3 is a 5- or 6-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or C3-C8 heterocycloalkyl, wherein C ₁ -C ₆ alkyl is optionally substituted with -O(C1-C ₆ alkyl), -N(C1-C ₆ alkyl)2, halogen or -CN.

In some embodiments, _R3 is a 5- or 6-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or C3-C8 heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with -O(C1- _C6 alkyl) or -N(C1- _C6 alkyl)2.

In some embodiments, R3 is a 5- or 6-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or C3-C8 heterocycloalkyl.

In some embodiments, R3 is a 5- or 6-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R ₃ is a 5- or 6-membered heteroaryl containing one, two, or three heteroatoms.

In some embodiments, R ₃ is a 5- or 6-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of N and O.

In some embodiments, R3 is a 5- or 6-membered heteroaryl containing one heteroatom selected from the group consisting of N and O.

In some embodiments, R3 is a 5- or 6-membered heteroaryl containing two heteroatoms selected from the group consisting of N and O.

In some embodiments, R3 is a 5-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or C3-C8 heterocycloalkyl, wherein C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1- _C6 alkyl), -N(C1- _C6 alkyl) ₂ , halogen or -CN.

In some embodiments, _R3 is a 5-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or C3-C8 heterocycloalkyl, wherein C1- C6 alkyl is optionally substituted with -O(C1- _C6 alkyl), -N( _C1 - _C6 alkyl)2, halogen or -CN.

In some embodiments, R3 is a 5-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or C3-C8 heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with -O(C1-C ₆ alkyl) or -N(C1-C ₆ alkyl)2.

In some embodiments, R3 is a 5-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, _C3 - _C8 cycloalkyl, halogen, or _C3 - _C8 heterocycloalkyl.

In some embodiments, R ₃ is a 5-membered heteroaryl, optionally substituted with one or more R 3 S, wherein each R 3 S is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C ₃ -C ₈ cycloalkyl.

In some embodiments, _R3 is a 5-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, R3 is a 5-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl.

In some embodiments, R3 is a 6-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or C3-C8 heterocycloalkyl, wherein C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1- _C6 alkyl), -N(C1- _C6 alkyl) ₂ , halogen or -CN.

In some embodiments, R ₃ is a 6-membered heteroaryl, optionally substituted with one or more R 3 S, wherein each R 3 S is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C ₃ -C ₈ cycloalkyl, halogen, or C ₃ -C ₈ heterocycloalkyl .

In some embodiments, R3 is a 6-membered heteroaryl, optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl.

In some embodiments, R3 is a 5- or 6-membered heteroaryl, optionally substituted with one or more R3S.

In some embodiments, R3 is a 5-membered heteroaryl, optionally substituted with one or more R3S.

In some embodiments, R ₃ is pyrrolyl, optionally substituted with one or more R _3S .

- 36 047011

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is pyrazolyl, optionally substituted with one or more R3S.

In some embodiments, R3 is

In some embodiments, R3 is

- 37 047011

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is imidazolyl, optionally substituted with one or more R3S.

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is triazolyl, optionally substituted with one or more R3S.

In some embodiments, R3 is

In some embodiments, R3 is

- 38 047011 or

In some embodiments, R ₃ is or

In some embodiments, R ₃ is tetrazolyl, optionally substituted with one or more R _3S .

In some embodiments, R ₃ is

In some embodiments, R ₃ is

In some embodiments, _R3 is isoxazolyl, optionally substituted with one or more R3S.

In some embodiments, R ₃ is

In some embodiments, _R3 is furanyl, optionally substituted with one or more R3S.

In some embodiments, R ₃ is

In some embodiments, R ₃ is

- 39 047011

In some embodiments, R3 is or

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is oxazolyl, optionally substituted with one or more R3S.

In some embodiments, R3 is or

In some embodiments, R3 is

- 40 047011

In some embodiments, R3 is

or

In some embodiments, R3 is 4,5,6,7-tetrahydrobenzo[c]isoxazole, optionally substituted with one or more R3S.

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is isothiazolyl, optionally substituted with one or more R3S.

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is thiazolyl, optionally substituted with one or more _R3S .

In some embodiments, R3 is or

In some embodiments, R3 is

In some embodiments, _R3 is thiadiazolyl, optionally substituted with one R3S ^.

In some embodiments, R3 is

- 41 047011

In some embodiments, R3 is

In some embodiments, R3 is a 6-membered heteroaryl, optionally substituted with one or more R3S.

In some embodiments, R3 is pyridinyl, optionally substituted with one or more R3S. In some embodiments, R3 is diazinyl, optionally substituted with one or more _R3S . In some embodiments, R ₃ is pyridazinyl, optionally substituted with one or more R _3S . In some embodiments, R3 is pyrimidinyl, optionally substituted with one or more _R3S . In some embodiments, R ₃ is pyrazinyl, optionally substituted with one or more R _3S . In some embodiments, R ₃ is triazinyl, optionally substituted with one or more R _3S . In some embodiments, R ₃ is tetrazinyl, optionally substituted with one R _3S . In some embodiments, R3 is pentazinyl.

In some embodiments, R3 is or

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is

In some embodiments, R3 is

or

- 42 047011

In some embodiments, R3 is

or

In some embodiments, at least one R3S is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C8 cycloalkyl, halogen, or C3-C8 heterocycloalkyl.

In some embodiments, at least one R3S is C1-C6 alkyl, C1-C6 haloalkyl, or _C3 - _C8 cycloalkyl.

In some embodiments, at least one R3S is C1-C6 alkyl or C1-C6 haloalkyl.

In some embodiments, at least one R3S is C1-C6 alkyl (eg, straight or branched).

In some embodiments, at least one R3S is methyl. In some embodiments, at least one R3S is ethyl. In some embodiments, at least one R _3S is a cut. In some embodiments, at least one R3S is butyl. In some embodiments, at least one R3S is pentyl. In some embodiments, at least one R _3S is hexyl. In some embodiments, at least one R _3S is isopropyl. In some embodiments, at least one R _3S is isobutyl. In some embodiments, at least one R _3S is isopentyl. In some embodiments, at least one R3S is isohexyl. In some embodiments, at least one R3S is sec-butyl. In some embodiments, at least one R3S is sec-pentyl. In some embodiments, at least one R3S is sec-hexyl.

In some embodiments, at least one R3S is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl, wherein C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl optionally substituted with -O(C1-C ₆ alkyl), -N(C1-C ₆ alkyl)2, halogen or -CN.

In some embodiments, at least one R3S is C1-C6 alkyl, optionally substituted with -O(C1- _C6 alkyl), -N(C1- _C6 alkyl)2, halogen, or -CN.

In some embodiments, at least one R3S is C1-C6 alkyl, optionally substituted with -O(C1- _C6 alkyl) or -N(C1- _C6 alkyl)2.

In some embodiments, at least one R3S is C1-C6 alkyl, optionally substituted with an -O(C1- _C6 alkyl) group (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl).

In some embodiments, at least one R3S is methyl, optionally substituted with an -O(C1-C ₆ alkyl) group. In some embodiments, at least one R3S is ethyl, optionally substituted with an -O(C1-C6 alkyl) group. In some embodiments, at least one R3S is propyl, optionally substituted with an -O(C1-C6 alkyl) group. In some embodiments, at least one R _3S is butyl, optionally substituted with an -O(C1-C ₆ alkyl) group. In some embodiments, at least one R3S is pentyl, optionally substituted with an -O(C1-C ₆ alkyl) group. In some embodiments, at least one R3S is hexyl, optionally substituted with an -O(C1-C ₆ alkyl) group.

In some embodiments, at least one R3S is C1-C6 alkyl, optionally substituted with a -N(C1- _C6 alkyl)2 group (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl).

In some embodiments, at least one R3S is methyl, optionally substituted with a -N(C1-C ₆ alkyl)2 group. In some embodiments, at least one R3S is ethyl, optionally substituted with a -N(C1-C ₆ alkyl)2 group. In some embodiments, at least one R3S is propyl, optionally substituted with a -N(C1-C6 alkyl)2 group. In some embodiments, at least one R3S is butyl, optionally substituted with a -N(C ₁ -C ₆ alkyl) ₂ group. In some embodiments, at least one R _3S is pentyl, optionally substituted with a -N(C ₁ -C ₆ alkyl) ₂ group. In some embodiments, at least one R3S is hexyl, optionally substituted with a -N(C1-C ₆ alkyl)2 group.

In some embodiments, at least one R3S is C1-C6 alkyl, optionally substituted with a -CN group.

In some embodiments, at least one R _3S is methyl, optionally substituted with a -CN group. In some embodiments, at least one R3S is ethyl, optionally substituted with a -CN group. In some embodiments, at least one R3S is propyl, optionally substituted with a -CN group. In some embodiments,

- 43 047011 at least one R3S is butyl, optionally substituted with a -CN group. In some embodiments, at least one R3S is pentyl, optionally substituted with a -CN group. In some embodiments, at least one R _3S is hexyl, optionally substituted with a -CN group.

In some embodiments, at least one R3S is a C1-C6 haloalkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl substituted with one or more halogens).

In some embodiments, at least one R3S is a C1-C6 haloalkyl, optionally substituted with -O(C1- _C6 alkyl), -N(C1- _C6 alkyl)2, halogen or -CN.

In some embodiments, at least one R3S is -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, or -CH2CF3.

In some embodiments, at least one R3S is -CHF2. In some embodiments, at least one R3S is -CH2CHF2. In some embodiments, at least one R3S is -CH2CF3.

In some embodiments, at least one R3S is C3-C8 cycloalkyl.

In some embodiments, at least one R3S is C3-C8 cycloalkyl, optionally substituted with -O(C1- _C6 alkyl), -N(C1- _C6 alkyl)2, halogen, or -CN.

In some embodiments, at least one R3S is C3-C7 cycloalkyl. In some embodiments, at least one R _3S is C ₃ -C ₆ cycloalkyl. In some embodiments, at least one R3S is C3-C5 cycloalkyl. In some embodiments, at least one R3S is C3- _C4 cycloalkyl.

In some embodiments, at least one R3S is cyclopropyl.

In some embodiments, at least one R3S is cyclobutyl.

In some embodiments, at least one R3S is C3-C8 heterocycloalkyl.

In some embodiments, at least one R _3S is C ₃ -C ₈ heterocycloalkyl, optionally substituted with -O(C1-C ₆ alkyl), -N(C1-C ₆ alkyl)2, halogen or -CN.

In some embodiments, at least one R _3S is C ₃ -C ₇ heterocycloalkyl. In some embodiments, at least one R _3S is C ₃ -C ₆ heterocycloalkyl. In some embodiments, at least one R _3S is C ₃ -C ₅ heterocycloalkyl. In some embodiments, at least one R3S is C3- _C4 heterocycloalkyl. In some embodiments, at least one R3S is _C4 -C5 heterocycloalkyl.

In some embodiments, at least one R3S is oxetanyl.

In some embodiments, the at least one R3S is

In some embodiments, at least one R3S is methyl, ethyl, isopropyl, -CH2OCH3, -CH2CF3, -CH2CH2OCH3, -CH2CN, CH2CF2, or -CH2CH2N(CH3)2.

In some embodiments, at least one R3S is halogen.

In some embodiments, at least one R3S is F, Cl, Br, or I.

In some embodiments, at least one R _3S is F or Cl.

In some embodiments, at least one R _3S is F.

In some embodiments, at least one R _3S is Cl.

In some embodiments, the compound is described by formula (Ia-1):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R2 and R3 are as described in the present invention.

- 44 047011

In some embodiments, the compound is described by formula (Ia-2):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R _1S , R ₂ and R 3 are the same as described in the present invention.

In some embodiments, the compound is described by formula (Ib-1):

are the

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R1, R2S and R3 are the same as described in the present invention.

In some embodiments, the compound is described by formula (Ib-2):

are the

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R1, R2S and R3 are the same as described in the present invention.

In some embodiments, the compound is described by formula (Ib-3):

are the

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R1, R2S and R3 are the same as described in the present invention.

are tha- 45 047011

In some embodiments, the compound is described by any of formulas (Ib-1a), (Ib-1b), or (Ib-1c):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R ₁ and R 3 are as described in the present invention.

In some embodiments, a compound of formula (Ib-1a) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R ₁ and R ₃ are as described herein.

In some embodiments, a compound of formula (Ib-1b) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1 and R3 are as described herein.

In some embodiments, a compound of formula (Ib-1c) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1 and R3 are as described herein.

- 46 047011

In some embodiments, the compound is described by formula (Ic-1), (Ic-2), (Ic-3), or (Ic-4):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R1, _R2 and _R3S are as described in the present invention.

In some embodiments, a compound of formula (Ic-1) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1, R2, and _R3S are as described herein.

In some embodiments, a compound of formula (Ic-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R ₁ , R ₂ and R _3S are as described herein.

In some embodiments, a compound of formula (Ic-3) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1, R2, and _R3S are as described herein.

In some embodiments, a compound of formula (Ic-4) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1, R2, and _R3S are as described herein.

- 47 047011

In some embodiments, the compound is described by formula (Ic-5), (Ic-6, (Ic-7) or (Ic-8):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R1, R2 and R3S are as described in the present invention.

In some embodiments, a compound of formula (Ic-5) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1, R2, and R3S are as described herein.

In some embodiments, a compound of formula (Ic-6) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1, R2, and R3S are as described herein.

In some embodiments, a compound of formula (Ic-7) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1, R2, and R3S are as described herein.

In some embodiments, a compound of formula (Ic-8) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1, R2, and R3S are as described herein.

In some embodiments, the compound is described by formula (Iab-1):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R2S and R3 are as described in the present invention.

In some embodiments, the compound is described by formula (Iab-2):

- 48 047011 or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein _R1S , R2S and R3 are as described in the present invention.

In some embodiments, the compound is described by formula (Iac-1):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R2 and R3S are as described in the present invention.

In some embodiments, the compound is described by formula (Iac-2):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein _R1S , R2 and R3S are as described in the present invention.

In some embodiments, the compound is described by formula (Iac-3):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R2 and R3S are as described in the present invention.

In some embodiments, the compound is described by formula (Iac-4):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein _R1S , R2 and R3S are as described in the present invention.

In some embodiments, the compound is described by formula (Ibc-1):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R _b R2S and R3S are as described in the present invention.

In some embodiments, the compound is described by formula (Ibc-2):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R1, R2S and R3S are as described in the present invention.

- 49 047011

In some embodiments, the compound is described by formula (Iabc-1):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R _2S and R _3S are as described in the present invention.

In some embodiments, the compound is described by formula (Iabc-1), where R _2S is a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, optionally selected from the group consisting of N or O.

In some embodiments, the compound is described by formula (Iabc-1), wherein at least one R _3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or _C3- C8 heterocycloalkyl.

In some embodiments, the compound is described by formula (Iabc-1), wherein at least one R _3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, or _C3C8 heterocycloalkyl, wherein R _3S is optionally substituted with a group -O(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ , halogen or -CN.

In some embodiments, the compound is described by the formula (Iabc-1n):

(Iabc-1 a) or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R _3S is as described in the present invention.

In some embodiments, the compound is described by formula (Iabc-1b):

or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein R _3S is as described in the present invention.

It should be understood that in a compound of any of the formulas described in the present invention, each R1, R _1S , R2, R2 _S , R3 and R _3S , if applicable, can, if applicable, be selected from the groups described in the present invention, and any group described in the present invention for any of R1, R _1S , R2, R2s, R3 and R _3S can be combined, if applicable, with any group described in the present invention for one or more of the remaining R1, R _1S , R2, R2 _S , R3 and R _3S .

In some embodiments, the compound is selected from among the compounds described in Tables 1 and 2, and their prodrugs and pharmaceutically acceptable salts.

In some embodiments, the compound is selected from among the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

In some embodiments, the compound is selected from among the compounds described in Tables 1 and 2.

In some embodiments, the compound is selected from among the compounds described in table. 1, and their prodrugs and pharmaceutically acceptable salts.

In some embodiments, the compound is selected from among the compounds described in table. 1, and pharmaceutically acceptable salts thereof.

- 50 047011

In some embodiments, the compound is selected from among the compounds described in table. 1.

In some embodiments, the compound is selected from among the compounds described in table. 2, and their prodrugs and pharmaceutically acceptable salts.

In some embodiments, the compound is selected from among the compounds described in table. 2, and their pharmaceutically acceptable salts.

In some embodiments, the compound is selected from among the compounds described in table. 2.

Table 1

Connection No. Structure 1 AL ΑθΧ A/ ⁿ ~ ^ch 3 Z Ν Ν Ν '0 2 ο 0 0 JL 1 ΑθΧ А/ ^ы ~ ^сНз / Ν Ν Ν у Ν CH ₃ 3 A/ o oo g=^Ч L II ΰ jL _z n-ch ₃ /Χχ Ух 7 ^ύ Z γ Ν Ν Ν X- ^{7 Η} Ν® L Na 0Η ₃

- 51 047011

4 Χγ 0 0 0 сн ₃ 1 11 11 e LN—/ / 7^ NNN gn \ J Н I ^СНз “0 5 X\G o OO g==\ sn _e 1 II th LN—/ ZNNN _РН ^'Ф СНз 6 Χγ o o O Г=Л СНз 1 II И o ^Z/ LN—/ Х\ ©-и-S^ Х ⁴ ^/ ZNNN '0 7 Xy o OO g=\ cn ₃ 1 II c L n— / Ν Ν Ν ' -φ СНз 8 ХфС О О 0 r= ^N \ XJL X/ ^N ~ ^CH2 VJ H _N ..^ '—о

- 52 047011

- 53 047011

14 r^iJ ⁰ 0 0 Γ=Α JL X ΑθΧ AL ^CH ^ VJ ^Η ϊ sn ₃ ^Νί Ο Ν CH ₃ 15 7 U n ₃ with γΛι i? ° ° JL 1 ΑθΧ >L/ ⁿ ~ch ₃ V7 η 1 U ^Na 'O Ν I CH ₃ 16 f ⁱ |l η ^{0 0} JL JL ΑθΧ >L/ ⁿ - ^ch 3 Ζ 'ν ν ν \____1 η 1 .. ® Na \ ^ν LO 17 \ Ύ g [Γ ό 0 18 rii I <λ,° 9'^ lis. JL^ ₈ ^sC, ^СНе Ζ Ν Ν Ν ^Ν, '0 0

- 54 047011

- 55 047011

24 ° ο ο to 1 ΑθΛί >^/ ^Ν ~θΗ ₃ Ζ γ-^ Ν Ν Ν 'сн ₃ 25 r ⁱⁱⁱ |f 0 0 0 f=4 F to L 11 =A to n—/ / γ Ν Ν N _F -0 26 ° o o g=Ч L 1 11 e to ^N —\ / Ν Ν NV _p v/ ^H n/D Λ CHU 27 γ'γ ooo g=Ч to 1 11 e to Ν—. Ν Ν 0—- -And 28 ooo g=Ч k £ Ie's /y ^K 'N' ^A 'N''''N ^z47 0_ “ό N 1 29 o oo g=H k 1 11 's k N—l / y^ NNN V_ _n “ύ ' thirty Αιί 0 oo f=4 to Η 11 _ο % to Ν— _Ύ / ^γ Ν Ν Ν V VJ ^Η _Na . 1 ^hour

- 56 047011

31 А/ ^{0 0} 0 Г=Ч L II Ц 'c L ν—у / Ν Ν Ν \. \___ Η » 1 ^λ -- Na* Ζ\ Ν 1 32 Αγ ο οο ρ= ^Ν 4 JL 1 11 _Α ν A y ^N ~~ /γ ^Λ 'Ν' ^Λ4 Ν ^/ sg. Ν 33 УАу 0 ΟΟ f=4 L JI les jL/— cr. ,,^N 34 Yiu LLC f=4 F L II ]i 'U' L n—< NNN _F ” ““ό N 1 35 [ \ F LLC f=4 U-f L II X e's Zy^^N'^'N''''N' ^X ^ ^/ - 36 / \ F LLC G=CH U-f L JI ji-L k/J- ⁷ Z^V^N^ r<'N''' ⁴ ^ 6 N 1 37 ΛΛ FF r^lf ⁰ О 0 f=4 /—F XA Αθχ Z Ν Ν N 6 N 1

- 57 047011

38 fAA o oo Г=Ч /~~® 1 и с 1 N—/ As. θ .3. t ¹ ^/ 7 NNN ^ ⁷ OV ,..^ Ν 1 39 [Αγ ⁷ ° oo g=Ч L JI Ie's A.yN'-O ό Ν 1 40 LLC Γ==4 AL ΑθΑ Λ/ ^{ΝΗ α} 'ό Ν 1 41 [Αγ ο οο g=H l ΛΑ Α®Α Λ</ ^Ν ~ν)ο 7 Ν Ν Ν ^ ⁷ \ζ 42 ⁰ οο g=H l Λ.Λ, ΑθΑ Ai/ ^N ~v)° CO. ,, _ό Ν 1 43 (Αγ ° ° о g=Ч ΑΛα _θ χΑ/ ^ν ' ^{/ χ} 7 7^ _{Ν Ν} Ν ^ ⁷ ” “ό 44 (Αγ ⁷ LLC Γ=4 /. 1 1 11 s 1 ν—7 \ Α^ ΑΑ ΑΑ ^: ^-3- ΑΑ>/ \ / 7 Ν Ν Ν^ ⁷ ν CO. 1 Ν 1

- 58 047011

45 A|[ ° 0 O (=4 1 11 U s to ν— / γ NNN ^ ⁷ 7 N F 46 Aif o oo g=CH AL ay A/~~ / Ν Ν Ν ^ ⁷ \ / Η „ 1 '-- Na® < 0 ο 47 ΑιΓ ο ο ο [=*4 to II ιι to ν— Y>ts. >k Jk. θ>S _V / / NNN ^ ⁷ \__ _H 1 '— ΝεΓ^Ά. ^:Ύο 1 48 ° o o g = H L II D ' = L nh /4. jYA. ft -, S 4. jY**5s / NNN ^ ⁷ 0 0 49 ιίη o o o f=4 . 11 AeX A/ ^N - NNN ^ ^{7 Ν} 'ό N 1 50 All ° ο ο Π==Ν A Α Α θχ A/ ⁿ ~~ / Ν Ν N ^ ^{7 n n} A N^__

- 59 047011

51 ⁰ 0 0 fA L II U _{Q s} jL·,/ ¹ '/у ⁴ N'^'NN ^H AN 52 r^if ⁰ О 0 [A 11 ΑθΧ A/ ^N - NNN ' -0 _Y 53 A ⁰ o o fA 1 II P _c L n— < NNN 0 N 1 54 lii? ° ° AA a®x A/- / XNNN \ JH _s | '---' Na® 4x ^N 55 o 0 or=4 / L II A ®'s Α/ ^ν ~λ / ^Z Y^ ^X N'^ ^X N'' \ \/ ^H Na® \x ^N \ 56 lii i? ° ⁰ Г* ¹⁴ ' / 1 II II _{Q s} ji n—/ /V^'N'^N'' ^V N'^ ^/ \ ^H a >— N 57 ril i? 0 ⁰ i^ ^N ' AA a®x A/ ⁿ ~~ / NNN \ JH ® I '— Na® Ax-\ TN—

- 60 047011

58 νΎ ° о 0 А АчХ, ΛΖ / NNN \ JH ® I Na® A. x ^z 1 59 YY o o 0 G=H 1 II D _a * _s L N- VJ H _Na .^ N 1 60 GP 0 0 0 (=4 A Λ Λζκ A/~ / γ^ Ν Ν ^X N \ JH ® I '---' Na® to al ? ^F 61 rn ° o o Z AA AeX A/ ⁿ A f 1— N , ^F \—Zf F 62 Ay o o o [==4 AL Αθχ A/ ⁿ / NNN 63 Ay o o o g=l A-Λ A®A ,A/ ⁿ ~/ NNN \ JH _e | '—' Na® <

- 61 047011

64 PT 9 ο ο Γ* ^Ν ' L 1 Η VL ν— / Ν Ν Ν “Ί 65 Γΐΐ ί? ° ⁰ Γ* ^Ν ' 1 II ιι _e '' _s /. ν—SG. ,, _ή Ν kx-F T^FF 66 AA OOO G^CH LA ΑθΧ X/ ^N ~ Ζ Ν Ν Ν \ J Η a 1 '---' Na® /k ο ^ζ 67 GT o _o 0 G^CH HA Atk A/ ⁿ Ν Ν Ν ^”“ό Ν \ 68 Tif 0 ο 0 ί=4 ΑΛ Αθχ Α/- Ζ γ Ν Ν Ν \ Ηal '—'Na® /N-U 69 A, JL, AT ^s s Ah/ ^m ~ A y NNN \ JH ® | '--' Na® yk ^X N ^Z At GT F

- 62 047011

70 A ° ° ° X X1 AeX X/ ^N g NNN ^ ⁷ '0 71 Ail 0 o 0 r«4\JLX A«X AX ^H ό 72 Cl f't 2 ^{0 0} Z XX ΑθΧ X/~ Cl NNN ^ ^{7 H} ® 1 Na A ^cy 73 fll 9 o ⁰ A ₄ 11 AA AL NNN ^ ⁷ “ '-'6 0 74 [Ύ 9, ^{0 0} A XX AA ΛΑ' NNN ^ ⁷ \ 1 H ® I ¹ Na® < Ϋ 75 Γιΐ 9 ⁰ ° A s to 1 UA jL n— >f NNN ^ ^{7 FH Na} 'A ^{h sg}

- 63 047011

76 Al 0 0 0 f=4 Al A ©AA/ ^N - Y 77 o IZ _z i° “® ^z \®,o /---->. “4 / \ / Ό o >— zz 1 78 rii ° o ⁰ g^H 11 JU's* A/- / Ύ' ^X NZ 'N Ύ 79 Ay o o o g=*h L II and 'VL n— zASs. YA. ©-Ο,. / T^ NNN \ / H _m I '---' Na* ⁴ 'o'\ 80 ^F'Yii ? ⁰ ° Al Αθχ A</ ⁿ - NNN 81 Γιΐ n ⁰ ° Г ⁵ * ¹ ' AAU A ©a A</ ⁿ ~~' g NNN “'0 82 Ay o o o g^h A A a ©a A/Z T^ N N N γ,0

- 64 047011

83 GA ° 0 o J DD JhM. χΧ/ ^Ν SG Η _Na . ι h 0 ^λ 84 GP? ^{0 0} 1 11 π ⁴ VL n— / Ν NN ^ ⁷ -0.. 85 Γ*Π π ^{0 0} A ^N ' L 1 1 _{a s} AA ZZ^ NNZ ^ ⁷ \ JH « I '—' Na® Zx 86 J/ A'K S \Ύ ? °-° ί v АжАх Ax^n / Y Ν Ν Ν 87 Γ^ιΙ ° 0 0 L 1 and /V 11 ν A^h. .Ach aS. хАж _Λ ^ζ Ν Ν Ν ο </. . _Ό 88 ADA ° ο ο ρ=Λ L JL Aes Αχζ ^Ν Ν Ν' ^{5 4} Ν ζ 89 ίίΊ? ° ⁰ J-J JL®Js'x Χγ/ ^Ν Cl Ν Ν Ν ^ ⁷ z ο

- 65 047011

90 '''''о ιΓί ii ° ° Г=^ DD A«;< A/ ⁿ 0 NNN ^ ⁷ > . ₀ 0 91 Cl ιΑ ° ο ο DA ΑθΧ А/Cl NNN ^ ^{7 H} ® 1 Na* -A. ^A'N \ 92 Cl Al o o o nA YES AeХ D/j ⁿ D o 93 CI A O o O G=H AA Ae's A-A O N N'' N ^ ⁷ ' -ό o 94 Cl fS ϊθνχ ^Ν ' ^Ν - Cl NNN ' -ό O 95 ГП ° о О 7=^ L Н и 'А L Ν— NNN ^ ^{7 Η} -ό 96 Air ° ⁰ O G=*H D.D. A «'A -D ^/Ν / Ν Ν Ν Ν -'ό

- 66 047011

97 °ΟΟ ^F '^x ^x AA' ΑθΑ AA'''>Ц NNN 98 ril ° ⁰ o f* ^N λΐ ΑθΧ A/ ^N ~ Cl NNN 'ό 99 A/ ° o _o y L 1 AAA/- NNN 'ό 100 r Ύ ° o _s/ o γ c As AA ®Α A.^ ^r ' ^J / NNN '0 101 rn ° ° o A·· Il A®X AA~ ^H A ^Na * |Ί \X ^N -x 102 zS] О о О g=Ч αζζ 2< NNN ^F F ^H I, Na® 103 Ay o oach AJL Αθχ X/ ^N / NNN \___1 H | Na* \x ^N X

- 67 047011

104 X./^N. A. ZΎ ? ° z° || J XX LH X-.N Z T Ν Ν N ” 0 105 ril? ⁰ o JL, χθχ Cl NNN X 106 Cl A 0 0 o fX F JL 1 AeS' jL/ ^N - >Z^ 0 'XZ'· NN' ^b N '' - ό o 107 Z|f O O O / Ν Ν Ν VJ ^Η ι. Na® ΤΧ yi-U 108 X. X X θχ .X / Ζ Ν Ν Ν Ν '0 109 ΓιΤ ° ο ο ηΧ 1 χ ιι _η y II ,ν Ζυ^Ν'^'Ν'·''Ν'-χ)'0 110 ΓΪΙ ί? ⁰ ο Ζ ^Ν ' XsJk Дч®Хх >χ/ ^Ν ~~ Ζ Ν Ν Ν \ 1 η ι Na® ΐΧ N-У

- 68 047011

111 LLC g^4 DD Αθχ D/- \___/ Η 1 Na* Ρ / 112 CI [А ο ο 0 Γ=4 L II II V / _Ν _ Cl NNN H 1 Na® 1Ά FROM V-/ ^H N# JL ⁴ o^ 114 F F^F rA O O 0 [=4 LI Ass ^{1 H} /N-U 115 Cl [As ο ο o ,=4 \DA АяХ Д/~ ⁿ nJ ⁸ JL 116 [Αγ 0 op O-N_ ΑΑδχ X^Z / Y^ NNN \ VJ ^H Nil ' \X ^N \ 117 rY π °° rVzyA _N A^ ^s ^ _N A _s VJ ^H Nf 1 ⁴ cr

- 69 047011

118 LLC f=^N' JL JL He's jL/N— / yNN N \—' ^H NiP L X[\-^f _ZN—/ 119 ZZZ o o o g^CH / LX iss X/X Z\ ZX. fe?L· About h. Z^^ z \ X^ NN n \ 1 ^H n<F 1 120 С|[ ooo ГЧ -Aw-JA χΧ/ ^Ν Ζ γ^ Ν Ν Ν \-Ζ ^Η Nf L γ^ο / ^Ν \Ζ 121 Φγ o o o g==Ч JL X Ah's AZ Ζ Ν Ν Ν \—1 ^Η Νί k \> ^,,F /N-U 122 φ|[ 0 0 0 f= ^N ' L JI K _s s AZ ZX Z\ Their O h. 7 Z Ν Ν N \—1 ^N N# X[ XnuF /N-U 123 φγ ooo g=Х JL A Ab's AZ Z^4 ΖΧ". ZX. “./Οχ. z ⁴ ^·/ Ζ γ^ Ν Ν N ^H NiP k \ \- ^F /N-U 124 LLC [=4 LX Ab's AZ ZX ZX Their O Z^*^» 7 γΝΝ N 1 ^H NiP JL XT

- 70 047011

125 Verse ooo 11 Aa's A/' I ^H N<PA 126 YlT Ooo f=4 F^ll AaA xl/ ^N ~~ >ZNNN ^F F ^H NeP JL 127 r*|[ ooo r=4 11 Ah's A/ ¹ ' Cl NN ^x Z ^H N# 1 128 Cl p ί ril ° o o /=4 A 11 As's 1/' ^H Nf 1 ⁴ o^ 129 Ay 0 OO O-N_/ As. A xAz ' NN N D \—1 ^H NiP JL ' 130 AY °oo on 11 Α _Η χ a>^ ⁿ / NNN D VJ ^H Ni JL ' ⁴ o^ 131 Ay ° °° °ί^ Av^ n1 A ^ν ^\Ί VJ ^H n# JL ^v — ⁱ h o^ 132 Ay ° °„° °a_/ As. As YshAs A/ \ NNN D \ VJ ^H n# JL ' ⁴ o^

- 71 047011

133 0 op O'N__ zT zZz's's А/ 'xj ZN 14 N \ \_j ^H №P JL ' ⁴ cr 134 Ζγ o op °\ _ζ °— ζΑτΑA r'ss _N A%/ ' \—1 ^H n# JL ' ⁴ cr 135 Al ⁰ o o ,==4 ΑΛ a kA A/~ Z Ν Ν N p VJ ^H Ni L/ 136 [Αγ ° 0 0 f=4 kl Ah's Az ^N ~ VJ ^H NiP 137 ^A/ / Г II ? ° ° il 3 AsJk A kA zAzs-n Ν NN \_J ^H №P JL 138 ΓΥ 0 0 0 r= ^N x kl Ah's Az ^N ~ \—1 ^H nI® _N. A. 139 TiZ o o o g=H kl As s zk/ ^N - Z Ν Ν N V-/ ^H \— ^F /N-U

- 72 047011

140 ΓιΤ? 4/° /TV JL JL U and ν JI z-ci /γ ⁴ Ν ^Λ 'Ν ^Ζ4 Ν ^Α 'Ο \_j ^H NeP JL 141 Cl ^F AS| ⁰ o o g=H JL 1 1's Al- ^H 142 ^F Y|1 ⁰ o o f=4 . L JI Ab's A/ ⁿ — —NN 'N ^ ^{7 H} N<P^ 143 ^F >A ⁰ o o r=4 Abs A/ ⁿ ' NN ^X N ^ ^{7 H Na} * /NA 144 Cl Ooo Г^Ч \AJl AeJsL A/ ^N 'isr'' ^{7 H} L^v _z nA 145 А/ ooo № ^N _X AL АчХ X/ ^N ~ Ζγ N^IT N ^ ⁷ \—I ^H n# JL XT 146 Αγ ooo n®4 JLA AoA AA7γ^ NN NN \' ^H Na® J. 147 [*li Ooo r=\ AV^A- vj ^H _N f JL ⁴ o^

- 73 047011

148 lk IZ _n “ta ^H co cQ-z''° 1 149 GY o o o r==\ LX la's X/ ^N ' VJ ^H Nil ' ⁴ cr 150 Ylf O O O G=H kl Ab's A/ ⁿ - ' ^H NiP k-. z ^N λ 151 Υγ ooo g=Х /klx Α.θΑ'- xk/ ^N ζγ Ν Ν Ν ^ ⁷ V-/ ^Η ν# ζ ^Ν \ '~F 152 Αιί 0 0 0 Γ=4 kl Ab'S Α/ ^ν - \—I ^Η N# JL 1 153 ζ “® ^Ζ \® , ο /—4 ^ω ί Ο^Λ-ζ' ° 7 154 ζ t---< Wi sGL-z' '°

- 74 047011

155 rTg ° o o AXL Λζ == ^ν Ν Ν Ν 0 VJ ^Η Νί JL ΊΧ 156 Ζιϊ οοο f=\ JL II A as Az° VJ ^H Νί JL 157 Ml Ϊ ° ⁰ rV /γΧ'χ ³ ''^ ₀ \—/ ^H Ni A 158 ν' o :5ο ;ω '—' °=( ^zx 159 Ml h °° H LAAgAM o VJ ^H No.? JL ⁴ cr 160 [Ay o o o nA AsJk JLhXL Αϊ/° Z y^ NNN \-JH _Nif ⁴ cr 161 z ,, O Oy.”

- 75 047011

162 AA o op gA_ Vj ^h nJ ⁸ 1 ⁴ cr 163 Ajf 0 op N'N_ ΑΑ'Ψ'Λ VJ h Nl 1 164 k. Z χΝ, cY 0 0 0 ^N Ay^N^lf' ^S ''N'X^ vJ H NJ® 1 v 165 AA xX / ZY ⁰ 4 "/° ^N AsxA χΆθΑχ .JI AZY^ NNN \-J ^H Ni 1 XT 166 xA/ χ ^Ν , ZY ? θ, „° π ZXsA, ΧΧθχΑ xAz^k Z^A nn ^n vj ⁿ _N fa \r

table 2

Connection No. Structure 1A O<. Vz iz ^4.0 2A NN ^Z d x AD J o o rS z^a ⁿ A A Λ A i T n^nAA x ^N A ⁰ HH \ _/

- 76 047011

BEHIND NN ^Z k 1 'Χ-θ' z -f NN' y \ 1 N H ⁰ 4A Ν-Ν'^ /ζ a a P <i A i 'O 5A , ^O= ^ i ^o — x- --l Qs '° Q \ 6A 1 °A ί Οί ' u. 0 7A NN ⁷ ^ // d /A X 0 o \|% ii JI JJ T Α'Ν-^Ν-^Αν ⁰ N N \_y 8A °=< ο, , ^ζχ X 'W Ό 0 9A b <χ Xvb A 1D LJ <I Y'H)

- 77 047011

10A X-Y XX/ A JO IA A U 12A сх А1/а Уд £J <л «А> 13A ON V <Х ^•А/ l XX О » ^? X'"X 14A Xl-N Αχ X AL Jo o Υί r ^x '' ^z s and L A ⁰ Η Η \ ] 15A \-Ν Αχ A- ΑΛ JI JI J ί Τ ζ/ ⁰ η η \ ] 16A УО' 'J3 ΛΠ 17A Ν^Ν l Jj ау ααΧ ^ρ a JO Г Τ α ^νΛν tS °χΑ ⁰ n n Ly

- 78 047011

18A ο- F ^x 0 19A Ο ^Ν 'ν' ^Ν ( 1 A JO £j <л ηΆ 20A b <χ t o 0 Υ% -'-A - _s ii II J ί T V\ v\ ,.,ν,Ο ⁰ η η \ ] 21A A -. Ο Μ ( 1 A JO o ^r j ό' ή in '0 22A NN ^Z Y <A o YQ lad 1 N nA\ O ⁰ HH \ J 23A NN ^Z Д \ n ° 9 aS '-n'-'v'S'', and Λ A AY ⁰ HH \ J 24A ί ' ^Z SS IZ '° xZ° 25A F L+ N-N Y <A /yv A JO oQ oYYA)

- 79 047011

26A F ,-Yf N-N V V <x А/ l XJ Cr /rrt 27A N-N a JO o^J o' H H 12? 28A A O=( ? c, Sy-A Q \ 29A 0 — N-N Y <X 2 T.J. <U °Y ΥΎ) 30A №—\ NN Λ JO XT c\ 'N 0^> ⁰ HH Yy 31A ό Cl A JO Λ ^Ν > T Αν'ή^Υυ // lA ⁰ HH LJ N 32A Q (T x JO ⁰ Η H \__/

- 80 047011

ZZA Q l XL 1 ⁰ Η Η \__/ 34A 4^. X / ^g— *CD _S ⁴ ---- ^f Τ.-Z. ^Q 35A F NN ⁷ p V <X ζΑ A '0. oQ άΥό 36A Qo. /hD/ l Td f-^ ⁿ A L iD F 37A ό φ. /hD/ l χι <n d5 F F 38A 0— N-N V Ck A XX J J 3' ή rA

- 81 047011

39A Q 9 τ 0 0 γΑ ⁰ Η Η \_/ 40A ό 9-, *? J 1 1 Ν ^Ζ ([ Ζ' Ν ^Λ Ν ^Λ γ\ ΗΝ^ ⁰ Η Η DD 41A D Ν-Ν JSC a ha Μ <Π η L7 42A Q 9. ⁷ -L/ A ΛΑ °\АЧ Τ X''Ν' Α· γ \ ⁰ Η Η \__/ 43A \ Ν — Ν-Ν V Οχ <V ^N 'S° A YES Μ ό ^? ΌπΎ) 44A ό Α /ν a ΛΑ \ζ \ Τ D Ν- Ή- γ χ γΥ ⁰ Η Η \__/

- 82 047011

45A NN ^Z V <A f zv-/ A XX A1J ° 'th yD> 46A °=< o. F ^x A Q 47A Ao. A? A ° o ⁴ 48A HN-N VA Х-Д/ A II o ^r J ό''and th η 49A X N-N X /l 1 xLq I jTI XJJ o and yaG 50A <A /aA/ a π ⁰ Η H \_y 51A II V# A \ Az ' ⁴ <X z ^Z \ J czx IZ '° A°

- 83 047011

52A ^N'X id θ 9 111 Ts JJ ~Ν Τ ? Ν' Ν 'Ύ > X ⁰ Η Η \_/ 53A X Ν-Ν .- Λ 5 [ <^гХ' ^? l JUL Ζ J ° 4 X' 54A Ν-Ν ^Ζ V <χ γ-Χ A JO y ό' Hoch 55A NN^ d l Ha χΑ' _ν α _ν ΛΧ SU ⁰ η η \_/ 56A Ν-Ν^” ί l lu />Х' ^Р l jQ. 57A \lN x\ Cl s. °Д4о~ Χ ν ν '> \ 1 η η ⁰ 58A 1 Ν /OS? ι VS ⁰ Η Η У/

- 84 047011

59A ο.? ¹ Λ ^and '. —ζ0>—ζ '° Μ χ ζ ! 60A \ У~^ ζ—( \ /^ζ ο. Μα 'Οχ χ τζ ^4.0 61A Ν-Ν ^Ζ Λ λ у—ϊ ΧΟ s η m yo FF 62A °h ο.. , ^ZI f--\ «- <θ'°' l 1 63A NN ^Z /? λ /Υ _Γ ν - Μ Α ΤΙ LS Α Ν Ν Α > ⁰ Η \ ] 64A Ή Ο.. ^ΖΙ \ >.. ϋΑ / ^-г \/— ^г> ° Μ χ ,^· ζ 1 65A Λ°χο. Μα τζ' ^4.0 66A Ν-Ν ^Ζ W Λ /^ι Τ 0 0 ΪΙΊ ill r^LJ λΝΝΑ\ JO ⁰ Η Η V/

- 85 047011

67A N-I Λ\Z—1 AC? ? jn -\_J ή I o 68A Χ-Ν d χγ X °AQ <J th 'δ ¹ 69A F ζ^ λ /^ζ θί- ^ζ Αζ 'SL _H V ΙΣ '° I ⁰ ιζ AM' 70A \ Ν-Ν VX AC ^P JL JQ. Μ°''th 71A \ Ν-Ν / γγΧ/1 Γχ Μ °''й ίΓ^Τ 72A ο °=<' ^rx -g <χ Aw ° 0 73A \ Ν-Ν s V X <·γ'/ JL Χ1 V /'йХА^ 74A \-Ν Ζ ft 4—1 _Γ Ν-^< A AD L 1 Ζ Ν Ν γ > ⁰ Η Η Yy

- 86 047011

75A \F N-N FjT V X ✓A A XX 76A \NN VA <xA/ A XX XJ /'n ^A nA>^ 77A v ^Cl xxX/ A xX □ O ⁰ HH 78A Very good -S'..to,. \___ 79A Q O* ' ^Z Vz ω. x TZ ^4.0 80A 'c/\IZ '° xZ° 81A \ NN mХ/ A XI Г J vN ^A N^ZY □O ⁰ HH 82A °/o A ^“Vz to. X IZ°

- 87 047011

83A NN ^Z Y a. A Xjl Al /nYY σ 84A AD n Η L c=N AT I ο'Ά ⁰ th 85A °ts ' ^ΖΙ J . 'bOch. A g' 1 86A N^N |lj £ Ii o ^r jr L1L) 87A °=( o. A_,^o A 88A Ν-N У-Ϋ/αΑ XT Ω' ^νΛ ' ^Ν Ί ^ζ oA θ η h | 89A V ^Cl <xX' ^p a bi Г J Υίμ'Α'^> α ^χ 'Α □A ⁰ HH

- 88 047011

90A v XC? s Δ Г Т Λ Ν Ν ^ Ό^ суН o _{n n} 91A / Ν-Ν V А zj-'vM A XjL 1 1 <G L'A-a ⁰ n n 92A And ZZ O., ? ^x A 93A V ^C| <хА'Р JL itl ij ,, 94A L1_ ΖΖ °Α ' ^rx Αν =rw Ό Q 95A °=( ο. F ^x - Q 96A °=( ο. F ^x -τΐίΧ ° ⁷ -? X- ^Ο '7> 97A \ F Ν-Ν R |Τ l 1 Α' Ν Ν Ο ⁰ Η Η

- 89 047011

98A V ^Cl XX? x Xi 1 0-^J ⁰ HH 99A N-l/ \ /~L a jo ij θ' 'th and L) 100 A °4 / O- ^ ^x z-ί °λ5. U A ° A -o 101A A? ^cl -n-X' ^? _{n a n} Xv A' Ν N kA ⁰ HH 102 A \-N fJLf GL V X v\A/ A Xjl 'o 'Y 4 103A NN ^Z n ⁰ 9 Υί 'ή'ύ ^ν 5' a L 2 1 Annas ⁰ HH \ J 104 A °4 o, F ^{x z} 6 -o

- 90 047011

105A N-N V A О/ a JUL θ' /fjAAp 106 A TZ°IZA 107 A \-N FROM / £Y 1AQ O and ¹ 108A nT) /~L ΖυΎ a O. o ^r J θΑ Y O 109 A °=< o, F ^x ^.Ό ω, A 110A \lN or Λ oa °Όο CO й fa ¹ 111A \-N С а °Хь zVnna \ / HH ⁰ 112A α H XjL a %- ^Ν Άί^ And fa '

- 91 047011

IZA a LA Ajr about 1 VL) 114A \-Ν ..,- 0 Ϋο 0 Λ V—·Ν „ D Γ II _F / ΤΝ ^ί7 4 ⁰ Η Η jL F 115A ChL ^Cl a-Х/ l ΐΧ to J '/ Ν νΆ ⁰ Η Η 116A Ν=< ο. Ja λλ ν ⁰ 9 Υί '-Ν'-γΎ l ΛΑ 1 /Ν Ν Υ\ ⁰ Η Η \ ] 117A °ts ο. F ^x ry _z % b 118A _r \lN 'AY OX? x jS / ZNN 'Y _? ^0HH \] 119A 0 bA A ^{Z 0} Η H | 120 A \-N OA _s A L -—A X JI J ⁰ HH \ J

- 92 047011

121A _F XN DH? a A / NNV\ ⁰ HH \ ] 122 A _c \-N b-X a xx / NNV\ ⁰ HH \ ] 123A °=( o. F ¹ '(L J 124 A XN/X? l D G ] ^'νΛι^υ o,A ⁰ n n 1 125A \ Ν-Ν V CX a Χχ 126 A Χ-Ν V <χ ,Дч ^р аХХ f oQr ό' ή h' ⁴ A ^c f 127 A \-Ν V <χ ν '? IΥ1 XX 0''И ϋ ^α 128A 4 °C “Vz 'C/λ, 1Ζ° □ζς: ο

- 93 047011

129 A M AL· 2 Xi A ά' ή χ 130A 0=. O. On TZ°' 131A .0 η OO/ l XX χϊ δ- ιΥΥ 132A Ν =/ όΑ·^ ΛΧ x-D / X JO £ Τ η' ^ν '' ^Ν ' Ύ ^χ > οΑ ⁰ η η ou 133A ζ~λ / g jo o^D θ' Η n ' y) 134A Υ °=( ο ί / F ^x χ^-0 ^3* TVz ^ο ^0 135A \|-Ν V ο. JL· χ χ4ι f /'ν ^λ νΑΑ F-^y. Η Η V

- 94 047011

136A F \-N 0X s Al A x ji j 1 Λ ΝΝύΑ' ⁰ HH \ J 137A I o o Tn jOf /-On XX A' ^{J 0} HH VJ 138A \lN χχΧ° ί I AAAA ⁰ HH \ J 139A _r \-N ' ΑΧ r\ O-ji/ l dd / nn X\ ¹ ° η h va 140 A X <A A JO, o ^r J ^'th nA) 141A v ^Cl aoAXXJC A- ⁰ HH 142 A \ NN Λ Λ I do'АХуС A- ⁰ HH 143A \|-N <dХ° l j6c ' ⁰ HH

- 95 047011

144 A \|-N L V „ L/ 00/ A AT 145A \-N On O\ A JO T O'yn'O °n H\/ 146 A \-N iOn O\ A JO A J <Л βΎ) 147 A o=< O. ABOUT -с-, °Ъ rw ° 0 148A I A? 0, ^z ZZ>'GCL X----/ ΙΞ '° □2^ 149 A O. .= ¹ /—\ 150A \-N V <x AA- ⁿ '$° a JlX ⁰ HH \ J 151A \lN / Λ ^f OAX₽ j? yS ' ° and «Ύ>

- 96 047011

152A 1 g A ^f TO s iS ~N Τ A-Nn 'fX ⁰ Η H DD 153A °=< Ox F ^x \,о ωχ z 0 154A Ox f- yj ω ₄ С/ iz ^4.0 >o 155A .N Φ A <Q /ID) 156A y n /vO A IJ oU <n βΎ> 157A Ον Ο ' ^Ζ \ζ ω„ τζ ^4.0 158A νΓ^ λλ υυΛ/ J Тд Ο °' 'And «and

- 97 047011

In some aspects, the present invention provides a compound that is an isotopic derivative (eg, an isotopically labeled compound) of any of the compounds of the formulas disclosed herein.

In some embodiments, the compound is an isotopically substituted form of any of the compounds described in Table. 1, and their prodrugs and pharmaceutically acceptable salts.

In some embodiments, the compound is an isotopically substituted form of any of the compounds described in Table. 1, and pharmaceutically acceptable salts thereof.

In some embodiments, the compound is an isotopically substituted form of any of the compounds described in Table. 1.

- 98 047011

In some embodiments, the compound is an isotopically substituted form of any of the compounds described in Table. 2, and their prodrugs and pharmaceutically acceptable salts.

In some embodiments, the compound is an isotopically substituted form of any of the compounds described in Table. 2, and their pharmaceutically acceptable salts.

In some embodiments, the compound is an isotopically substituted form of any of the compounds described in Table. 2.

It should be understood that the isotope-containing derivative can be prepared by many techniques known in the art. For example, an isotope-containing derivative can generally be prepared by the procedures disclosed in the diagrams and/or examples described in the present invention by replacing the non-isotopically labeled reagent with the isotope-labeled reagent.

In some embodiments, the isotope-containing derivative is a deuterium-labeled compound.

In some embodiments, the isotope-containing derivative is a deuterium-labeled compound of any of the compounds of the formulas disclosed herein.

In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in table. 1, and their prodrugs and pharmaceutically acceptable salts.

In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in table. 1, and pharmaceutically acceptable salts thereof.

In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in table. 1.

In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in table. 2, and their prodrugs and pharmaceutically acceptable salts.

In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in table. 2, and their pharmaceutically acceptable salts.

In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in table. 2.

It should be understood that the deuterium-labeled compound includes a deuterium atom having a deuterium content that is greater than the natural content of 0.015%.

In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of not less than 3500 (52.5% deuterium inclusion for each deuterium atom), not less than 4000 (60% deuterium inclusion), not less than 4500 (67.5 % inclusion of deuterium), not less than 5000 (75% deuterium), not less than 5500 (82.5% inclusion of deuterium), not less than 6000 (90% inclusion of deuterium), not less than 6333.3 (95% inclusion of deuterium), not less 6466.7 (97% deuterium inclusion), not less than 6600 (99% deuterium inclusion) or not less than 6633.3 (99.5% deuterium inclusion). As used in the present invention, the term deuterium enrichment factor means the ratio of deuterium content to natural deuterium content.

It should be understood that the deuterium-labeled compound can be prepared by many techniques known in the art. For example, a deuterium-labeled compound can generally be prepared by the procedures disclosed in the Schemes and/or Examples described herein by replacing a non-deuterium-labeled reagent with a deuterium-labeled reagent.

The compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, which contains the above deuterium atom(s) is within the scope of the present invention. In addition, deuterium (ie ^2H ) substitution may provide some therapeutic benefits due to their higher metabolic stability, such as increased in vivo half-life or the ability to use lower doses.

For the avoidance of doubt, it should be understood that when in the present invention a group is specified as described in the present invention, the specified group includes the first occurrence and the broadest definition, as well as each and all specific definitions of that group.

Specific compounds provided by the present invention include, for example, compounds of any of the formulas disclosed in the present invention, or a pharmaceutically acceptable salt thereof, wherein, unless otherwise indicated, all R1, _R3 , _R4 any substituent groups associated therewith have any of the meanings defined above in the present invention.

The various functional groups and substituents forming the compounds of formula (I) are usually chosen so that the molecular weight of the compound does not exceed 1000 Da. More often, the molecular weight of the compound is less than 900, for example less than 800 or less than 750, or less than 700, or less than 650 Da. More preferably, the molecular weight is less than 600 and, for example, 550 Da or less.

A suitable pharmaceutically acceptable salt of a compound of the present invention is, for example, an acid addition salt of a compound of the present invention that is sufficiently basic, for example, an acid addition salt of, for example, an inorganic or organic acid, for example, hydrochloric, hydrobromic , sulfuric, phosphoric, trifluoroacetic, formic, citric, methanesulfonic or maleic acid. In addition, a suitable pharmaceutically acceptable salt of the compound provided herein

- 99 047011 invention, which is sufficiently acidic, is an alkali metal salt, for example a sodium salt or a potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base, which contains a pharmaceutically acceptable cation, for example, salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

It should be understood that the compounds of any of the formulas disclosed in the present invention, and any pharmaceutically acceptable salt thereof, include stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of these compounds.

As used herein, the term isomerism means compounds that have the same molecular formulas but differ in the binding sequence of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of each other are called diastereoisomers, and stereoisomers that are not superimposed mirror images of each other are called enantiomers or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a racemic mixture.

As used herein, the term chiral center means a carbon atom bonded to four unequal substituents.

As used herein, the term chiral isomer means a compound containing at least one chiral center. Compounds containing more than one chiral center can exist as individual diastereoisomers or as a mixture of diastereoisomers, called a diastereoisomeric mixture. If a single chiral center is contained, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration means the arrangement in space of substituents attached to the chiral center. Substituents attached to the chiral center in question are ranked according to the Cahn, Ingold and Prelog sequence rule (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. 1951, 612; Cahn et al., 1956, 12, 81; .

As used herein, the term geometric isomer refers to diastereoisomers that exist due to inhibited rotation around double bonds or a cycloalkyl bridge (eg, 1,3-cyclobutyl). These configurations have different names, distinguished by the prefixes cis and trans or Z and E, which indicate that the groups are on the same or different sides of the double bond in the molecule, in accordance with the rules of Kahn, Ingold and Prelog.

It should be understood that the compounds of the present invention can be represented as different chiral isomers or geometric isomers. It should also be understood that while compounds have different isomeric or geometric isomeric forms, all isomeric forms are included within the scope of the present invention and the names of the compounds do not exclude any isomeric forms, it should be understood that not all isomers may have the same degree of activity.

It should be understood that the structures and other compounds contemplated in the present invention include all of their atopic isomers. It should also be understood that not all atopic isomers may have the same degree of activity.

As used herein, the term atopic isomers is a type of stereoisomer where the atoms of the two isomers are arranged differently in space. Atopic isomers exist due to limited rotation caused by the inhibited rotation of large groups around the central bond. These atopic isomers usually exist as a mixture, but recent advances in chromatographic techniques have made it possible in some cases to separate mixtures of two atopic isomers.

As used herein, the term tautomer means one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This transformation results in a formal displacement of the hydrogen atom, accompanied by rearrangement of adjacent conjugated double bonds. Tautomers in solution exist as a mixture of tautomeric sets. In solutions, where tautomerization occurs, a chemical equilibrium of tautomers is established. The exact number of tautomers depends on various factors, including temperature, solvent, and pH. The property of tautomers that transform into each other through tautomerization is called tautomerism. Of the different possible types of tautomerism, two types are usually observed. In keto-enol tautomerism, a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism occurs when the aldehyde groups (-CHO) on a chain sugar molecule react with one of the hydroxy groups (-OH) on the same molecule to form a cyclic (ring-shaped) form, an example of which is glucose.

It should be understood that the compounds of the present invention can be represented as different tautomers. It should also be understood that if compounds have different tautomeric

- 100 047011 m forms, all tautomeric forms are included within the scope of the present invention, and the names of the compounds do not exclude any tautomeric form. It should be understood that some tautomers may have a greater degree of activity than others.

Compounds that have the same molecular formulas but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space are called isomers. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not superimposed mirror images of each other are called diastereomers, and stereoisomers that are not superimposed mirror images of each other are called enantiomers. If a compound contains an asymmetric center, for example it is bound to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described using the rules of the R- and S-sequences of Cahn and Prelog, or so when the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e. as (+) or (- )-isomers, respectively). A chiral compound can exist as a single enantiomer or as a mixture of both. A mixture containing equal amounts of individual enantiomers is called a racemic mixture.

The compounds of the present invention may have one or more asymmetric centers; Therefore, such compounds can be obtained in the form of individual (R)- or ^-stereoisomers or in the form of mixtures thereof. Unless otherwise indicated, the description or name of a particular compound in the specification and claims includes the individual enantiomers and mixtures thereof, racemic or otherwise. Techniques for determining the stereochemical configuration and separating stereoisomers are well known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 4th edition J. March, John Wiley and Sons, New York, 2001), for example, carried out by synthesis from optically active starting materials or by resolution of the racemic form. Some of the compounds proposed in the present invention may contain geometric isomeric centers (E- and Z-isomers). It should be understood that the present invention includes all optical isomers, diastereoisomers and geometric isomers and mixtures thereof that have inflammasome inhibitory activity.

The present invention also includes compounds of the present invention, as defined herein, that contain one or more isotopic substitutions.

It should be understood that the compounds of any formula described in the present invention include the compounds themselves, as well as their salts and their solvates, if possible. A salt, for example, can be formed from an anion and a positively charged group (eg, an amino group) in the substituted compounds disclosed in the present invention. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalene sulfonate and acetate (eg trifluoroacetate).

As used herein, the term pharmaceutically acceptable anion means an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed from a cation and a negatively charged group (eg, carboxylate) in the substituted compounds disclosed in the present invention. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion and ammonium cation such as tetramethylammonium ion or diethylamine ion. Substituted compounds disclosed in the present invention also include their salts containing quaternary nitrogen atoms.

It should be understood that the compounds of the present invention, eg, salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

As used herein, the term solvate refers to solvent-added forms that contain stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar amount of solvent molecules in a crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alkoxide. Hydrates are formed by combining one or more molecules of water with one molecule of a substance in which the water remains in its molecular state as _H2O .

As used herein, the term analog means a chemical compound that is structurally similar to another but slightly different in composition (as in the replacement of one atom with an atom of another element or in the presence of a particular functional group or in the replacement of one functional group with another functional group). Thus, the analogue is

- 101 047011 a compound that is similar or comparable in function and appearance, but not in structure or origin, to the comparable compound.

As used in the present invention, the term derivative means compounds that share a common core structure and are substituted with different groups as described in the present invention.

As used herein, the term bioisostere means a compound formed by the exchange of an atom or group of atoms for another, broadly similar, atom or group of atoms. The goal of bioisosteric substitution is to form a new compound with biological characteristics similar to those of the original compound. Bioisosteric substitution may be physicochemical or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates; see, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

It should also be understood that some compounds of any of the formulas disclosed in the present invention may exist in solvated as well as non-solvated forms, such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate, such as a hemihydrate, monohydrate, dihydrate or trihydrate. It should be understood that the present invention includes all such solvated forms that have inflammasome inhibitory activity.

It should also be understood that some compounds of any of the formulas disclosed in the present invention may exhibit polymorphism and that the present invention includes all such forms or mixtures thereof that have inflammasome inhibitory activity. It is generally known that crystalline materials can be analyzed by conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis, diffuse infrared reflectance Fourier spectroscopy (DRIFT), near-infrared spectroscopy (NIR), nuclear magnetic resonance spectroscopy in solution and/or solid state. The water content of such crystalline materials can be determined using Karl Fischer analysis.

The compounds of any of the formulas disclosed in the present invention may exist in a number of different tautomeric forms and reference to compounds of formula (I) includes all such forms. To eliminate doubt, it should be noted that if a compound can exist in one of several tautomeric forms and only one is specifically described or cited, all others are nevertheless included in formula (I). Examples of tautomeric forms include keto, enol, and enolate forms, as in the following tautomeric pairs: ketone/enol (presented below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso form/oxime, thioketone/ethiol, and nitro group/acid nitro group.

^H _Z O \ ,ΟΗ Η* _χ 0' —“E—C/ === C=C'C—c' ] X / \Ι-G / X keto form enol form enolate form Compounds of any of the formulas disclosed in the present invention, the content of an amino group can also form N-oxides. Reference in the present invention to a compound of formula (I) which contains an amino group also includes reference to an N-oxide. If a compound contains multiple amino groups, one or more than one nitrogen atom may be oxidized to form Noxide. Specific examples of N-oxides are N-oxides of a tertiary amine or the nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be prepared by treating the corresponding amine with an oxidizing reagent such as hydrogen peroxide or a peracid (eg, peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More preferably, the N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which the amine is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

The compounds of any of the formulas disclosed in the present invention can be administered in the form of a prodrug, which is destroyed in the human or animal body and releases the compound proposed in the present invention. A prodrug can be used to change the physical characteristics and/or pharmacokinetic characteristics of a compound of the present invention. A prodrug can be prepared if the compound of the present invention contains a suitable group or substituent to which a characteristic-altering group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents on a sulfonylurea group in a compound of any of the formulas disclosed in the present invention.

Accordingly, the present invention includes those compounds of any of the formulas disclosed in the present invention, as defined above in the present invention, which may be available by organic synthesis and may be available in the human or animal body by

- 102 047011 cleavage of its prodrug. Accordingly, the present invention includes those compounds of any of the formulas disclosed in the present invention that are formed by organic synthesis, and also those compounds that are formed in the human or animal body by metabolism of the precursor compound, i.e. a compound of any of the formulas disclosed in the present invention may be a synthetically produced compound or a metabolically produced compound.

A suitable pharmaceutically acceptable prodrug of a compound of any of the formulas disclosed herein is one that, based on reasonable medical judgment, is found suitable for administration to a human or animal body without undesirable pharmacological activity and without undue toxicity. Various forms of the prodrug are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 Design and Application of Prodrugs, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull. 32, 692 (1984); g) T. Higuchi and V. Stella, Pro-Drugs as Novel Delivery Systems, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), Bioreversible Carriers in Drug Design, Pergamon Press, 1987.

A suitable pharmaceutically acceptable prodrug of a compound of any of the formulas disclosed in the present invention that contains a hydroxy group is, for example, its in vivo-cleavable ester or ether. An in vivo degradable ester or ether of a compound of any of the formulas disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is degraded in the human or animal body to form the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphates (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include Ο ₁ -Ο ₁₀ alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ο ₁ -Ο ₁₀ alkoxycarbonyl groups such as ethoxycarbonyl, N, N-( C1-C ₆ alkyl) ₂ -carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1ylmethyl and 4-(C1- _C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically acceptable prodrug of a compound of any of the formulas disclosed herein which contains a carboxy group is, for example, its in vivo degradable amide, for example an amide formed from an amine such as ammonia, a _C1-4 alkylamine such as methylamine (C1-C4 alkyl) ₂ -amine such as dimethylamine, N-3τπλ-Nmethylamine or diethylamine, C1-C4 alkoxy- _C2 - _C4 alkylamine such as 2-methoxyethylamine, phenyl- _C1C4 alkylamine such as benzylamine and amino acids such as glycine or its ester.

A suitable pharmaceutically acceptable prodrug of a compound of any of the formulas disclosed herein which contains an amino group is, for example, an in vivo cleaving amide derivative thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, those derived from C ₁ -C ₁₀ alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, Nalkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(Cj-C ₄ alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of any of the formulas disclosed in the present invention may be caused by one or more metabolites that are formed in the human or animal body after administration of a compound of any of the formulas disclosed in the present invention. As noted above in the present invention, the in vivo effects of a compound of any of the formulas disclosed in the present invention may also occur through metabolism of the precursor (prodrug) compound.

Accordingly, the present invention excludes any individual compounds that do not have the biological activity defined in the present invention.

Methods of synthesis.

In some aspects, the present invention relates to a method for preparing a compound of the present invention.

In some aspects, the present invention relates to a method for preparing a compound, including one or more steps, described in the present invention.

- 103 047011

In some aspects, the present invention relates to a compound obtained or obtained, or directly obtained by the method for preparing the compound described in the present invention.

In some aspects, the present invention relates to an intermediate described in the present invention suitable for use in a method for preparing a compound described in the present invention.

The compounds of the present invention can be prepared by any suitable procedure known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

In describing the synthetic procedures described in the present invention and any reference synthetic procedures that are used to prepare the starting materials, it should be understood that the reaction conditions given, including the choice of solvent, the atmosphere in which the reaction is carried out, the reaction temperature, the duration of the experiment and the operating procedures may be selected by one skilled in the art.

It is obvious to one skilled in the field of organic synthesis that the functional groups contained in different parts of the molecule must be compatible with the reagents used and the reaction conditions.

It should be understood that during the synthesis of the compounds proposed in the present invention, according to the methods defined in the present invention, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesirable reaction. The skilled chemist must understand when such protection is required and how such protecting groups can be introduced and subsequently removed.

Examples of protecting groups are given in one of the many general publications on the subject, see, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any conventional technique described in the literature or known to the skilled chemist as suitable for removing the protecting group in question, such techniques being selected so that the effect of removal of the protecting group on other groups of the molecule is minimal. Thus, if the reactants include, for example, groups such as an amino group, a carboxy group, or a hydroxy group, it may be desirable to protect the groups in some of the reactions described in the present invention.

For example, a suitable protecting group for an amino group or alkylamino group is, for example, an acyl group, for example, an alkanoyl group, such as an acetyl, an alkoxycarbonyl group, for example, a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example, a benzyloxycarbonyl or aroyl group, for example , benzoyl. The conditions for removing the above protecting groups inevitably vary depending on the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, can be removed, for example, by hydrogenation over a catalyst, such as palladium on carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate). A suitable alternative protecting group for the primary amino group is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine or hydrazine.

A suitable protecting group for the hydroxy group is, for example, an acyl group, eg an alkanoyl group, such as acetyl, an aroyl group, eg benzoyl, or an arylmethyl group, eg benzyl. The conditions for removing the above protecting groups inevitably vary depending on the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium or ammonium hydroxide. Alternatively, an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

A suitable protecting group for the carboxy group is, for example, an esterifying group, for example a methyl or ethyl group, which can be removed, for example, by hydrolysis with a suitable base such as sodium hydroxide, or, for example, a tert-butyl group, which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or, for example, a benzyl group, which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

Once a compound of formula (I) has been synthesized by one of the procedures defined in the present invention, the procedures may further include the additional steps of: (i) removing any protecting groups contained; (ii) converting a compound of formula (I) into another compound

- 104 047011 formula (I); (iii) obtaining a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) preparing a prodrug thereof.

The resulting compounds of formula (I) can be isolated and purified by methods well known in the art.

Typically, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under appropriate reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of these solvents, or mixtures with water.

The reaction temperature is preferably from about -100°C to 300°C depending on the reaction stage and conditions used.

Reaction times typically range from a fraction of a minute to several days, depending on the reactivity of the compounds involved and the respective reaction conditions. The appropriate duration of the reaction can be easily determined by techniques known in the art, for example, by monitoring the reaction. Based on the reaction temperatures given above, suitable reaction times are generally in the range of 10 minutes to 48 hours.

In addition, by using the procedures described in the present invention, taking into account general training in the art, additional compounds proposed in the present invention can be easily prepared. It will be readily apparent to those skilled in the art that slight variations in the conditions of the following preparation procedures can be used to prepare these compounds.

As will be appreciated by one skilled in the art of organic synthesis, the compounds of the present invention are readily prepared by a variety of synthetic routes, some of which are illustrated in the accompanying examples. One skilled in the art will readily understand what type of reagents and reaction conditions should be used and how to use them and adapt them to any particular case, if necessary or useful, to prepare the compounds of the present invention. In addition, some of the compounds of the present invention can be easily synthesized by the reaction of other compounds of the present invention under suitable conditions, for example, by converting one particular functional group contained in the compound of the present invention, or a suitable one one precursor molecule into another using standard synthetic techniques such as reduction, oxidation, addition or substitution reactions; these techniques are well known to one skilled in the art. Likewise, one skilled in the art will use synthetic protecting (or protecting) groups if necessary or useful; suitable protecting groups, as well as procedures for their introduction and removal, are well known to one skilled in the art of chemical synthesis and are described in more detail, for example, in P.G.M. Wuts, T.W. Greene, Greene's Protective Groups in Organic Synthesis, 4th edition (2006) (John Wiley & Sons).

General routes for preparing the compound of the present invention are described in Schemes 12 in the present invention.

Scheme 1

In Scheme 1, L ₁ represents a suitable leaving group (eg Cl or other halide). Reaction (i) can be carried out by reacting amine 1 with isocyanate 2 in a suitable solvent (eg diisopropyl ether or dichloromethane) and optionally at low temperature (eg 0°C or -15°C) to give intermediate 3 In some embodiments, intermediate 3 may be used directly as a solution and not isolated.

Reaction (ii) can be carried out by reacting amine 4 with carbonyl 5 in a suitable solvent (eg methanol or dichloromethane) in the presence of a reducing reagent (eg sodium cyanoborohydride or sodium triacetoxyborohydride) and optionally in the presence of an acid catalyst (eg acetic acid) to obtain intermediate 6. Intermediate 6 can be isolated by purification (eg, flash column chromatography or preparative HPLC). In some embodiments, intermediate 6 is isolated as the free amine or as a salt (eg, trifluoroacetate).

Reaction (iii) can be carried out by reacting intermediate 3 with intermediate 6 in a suitable solvent (eg tetrahydrofuran), in the presence of a base (eg sodium hydride or sodium methoxide) and optionally in the presence of a catalyst (eg 4-(dimethylamino)- pyridine) to obtain compounds of formula (I). The compound of formula (I) can be isolated by purification (eg, flash column chromatography or preparative HPLC). In some embodiments, the compounds of formula (I) are isolated as a neutral compound or as a salt (eg, sodium salt).

Scheme 2 ^R3 'mu ^- ^R2

NHj θ' 3 4

° O

A A R3

NNN ^HH R2

Formula I

In Scheme 2, L1 represents a suitable leaving group (eg Cl or other halide).

Reaction (i) can be carried out by reacting isocyanate 1 with tert-butanol in a suitable solvent (e.g., tetrahydrofuran) and optionally at low temperature (e.g., 0°C) to produce intermediate 2. In some embodiments, intermediate 2 is then used directly in the form of a solution and is not directly isolated.

Reaction (ii) can be carried out by reacting amine 3 with carbonyl 4 in a suitable solvent (eg methanol or dichloromethane) in the presence of a reducing reagent (eg sodium cyanoborohydride or sodium triacetoxyborohydride) and optionally in the presence of an acid catalyst (eg acetic acid) to obtain intermediate 5. Intermediate 5 can be isolated by purification (eg, flash column chromatography or preparative HPLC). In some embodiments, intermediate 5 is isolated as the free amine or as a salt (eg, trifluoroacetate).

Reaction (iii) can be carried out by reacting intermediate 5 with intermediate 2 in a suitable solvent (e.g. tetrahydrofuran) and in the presence of a base (e.g. diisopropylethylamine) to give intermediate 6. Intermediate 6 can be isolated by purification (e.g. flash column chromatography or preparative HPLC).

Reaction (iv) can be carried out by reacting intermediate 6 with a suitable acid

- 106 047011 solution (for example, hydrochloric acid or trifluoroacetic acid) in a suitable solvent (for example, 1,4-dioxane or dichloromethane) and optionally at low temperature (for example, 0°C) to obtain intermediate 7. Intermediate 7 can be isolated by purification (eg, flash column chromatography or preparative HPLC). In some embodiments, intermediate 7 is isolated as the free amine or as a salt (eg, trifluoroacetate).

Reaction (v) can be carried out by reacting primary amine 8 with a suitable reagent (eg triphosgene) in the presence of a suitable base (eg diisopropylethylamine or triethylamine) and in the presence of a suitable solvent (eg 1,4-dioxane) and optionally at elevated temperature ( for example, 40°C) and obtain intermediate product 9.

Reaction (vi) can be carried out by reacting intermediate 7 with intermediate 9 in a suitable solvent (e.g. tetrahydrofuran) in the presence of a base (e.g. sodium hydride or sodium methoxide) and optionally in the presence of a catalyst (e.g. 4-(dimethylamino)pyridine) and obtain compounds of formula (I). In some embodiments, reaction (iv) can be carried out at a low temperature (eg, 0°C). The compound of formula (I) can be isolated by purification (eg, flash column chromatography or preparative HPLC). In some embodiments, the compound of formula (I) is isolated as a neutral compound or as a salt (eg, sodium salt).

It should be understood that in the description and formulas above, the different groups are as defined in the present invention unless otherwise indicated. Moreover, for the purposes of synthesis, the compounds in the diagrams are merely representative and are given with preferred substituents to illustrate the general methodology for the synthesis of the compounds disclosed in the present invention.

It should be understood that the neutral compound of formula (I) can be converted to a salt (eg, sodium salt) by standard techniques known in the art (eg, pH adjustment and optional extraction (eg, into an organic phase)). In addition, a salt (eg, sodium salt) of a compound of formula (I) can be converted to the neutral compound by standard techniques known in the art (eg, pH adjustment and optional extraction (eg, into an aqueous phase)).

Biological analyses.

Compounds designed, selected and/or optimized according to the procedures described above, once prepared, can be characterized using various assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized using conventional assays, including, but not limited to, the assays described below, to determine whether they have predicted activity, binding activity, and/or binding specificity.

Additionally, high-throughput screening can be used to speed up such analyses. As a result, it may be possible to rapidly screen the molecules described in the present invention for activity determination using techniques known in the art. General methodologies for conducting high throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and in the U.S. patent. No. 5763263. High-throughput screening may use one or more different assay techniques, including, but not limited to, those described below.

Various in vitro or in vivo biological assays may be suitable to determine the effects of the compounds of the present invention. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described in the present invention.

Pharmaceutical compositions.

In some aspects, the present invention relates to a pharmaceutical composition comprising a compound of the present invention as an active ingredient. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound selected from those listed in Tables 1 and 2.

As used herein, the term composition includes a product containing specified ingredients in specified amounts, as well as any product that is directly or indirectly obtained from a combination of specified ingredients in specified amounts.

The compounds of the present invention can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release formulations).

- 107 047011 release or time-delayed release), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of the present invention may also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (eg, patch) administration, all forms being well known to one of ordinary skill in the pharmaceutical field.

The drug proposed in the present invention may be in the form of an aqueous solution including an aqueous diluent. The aqueous diluent may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, a chelating agent, a preservative, a tonicity adjusting agent, a viscosity adjusting/suspending agent, a buffer and a pH adjusting agent, and mixtures thereof.

Any suitable solubility enhancing agent may be used. Examples of the solubility enhancing agent include a cyclodextrin such as selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin , hydroxyethyl-β-cyclodextrin, 2-hydroxy-3(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfonated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin and trimethyl-γ-cyclodextrin and mixtures thereof.

Any suitable chelating agent may be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate and tetrasodium ethylenediaminetetraacetate, and mixtures thereof.

Any suitable preservative may be used. Examples of the preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenyl mercuric nitrate, phenyl mercuric acetate, phenyl mercuric neodecanoate, methiolate, methyl paraben, paraben, sorbic acid, potassium sorbate, sodium benzoate, propionate sodium, ethyl p-hydroxybenzoate, propylaminopropyl biguanide and butyl p-hydroxybenzoate and sorbic acid and mixtures thereof.

The aqueous diluent may also include a tonicity adjusting agent to regulate tonicity (osmotic pressure). The tonicity adjusting agent may be selected from the group consisting of glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerin, dextrose, glycerin, mannitol, potassium chloride and sodium chloride, and mixtures thereof.

The aqueous diluent may also contain a viscosity adjusting/suspending agent. Suitable viscosity control/suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose and cross-linked acrylic acid polymers (carbomers) such as acrylic acid polymers. acids cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P) and mixtures thereof.

To establish an acceptable pH of the formulation (typically a pH in the range of about 5.0 to about 9.0, more preferably from about 5.5 to about 8.5, especially preferably from about 6.0 to about 8.5, from about 7 .0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjusting agent. The pH adjusting agent is typically an inorganic acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or alkaline pH adjusting agents are added to adjust the pH of the formulation within the target acceptable range. Therefore, it may not be necessary to use both an acid and a base; depending on the preparation, adding only an acid or only a base may be sufficient to bring the pH of the mixture into the desired range.

The aqueous diluent may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid or its salts, including disodium tetraborate), a citrate buffer (such as citric acid or its salts, including sodium citrate), and aminocaproic acid and mixtures thereof.

The preparation may also contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of oxypropylene-oxyethylene block copolymers (poloxamers), polyethoxylated castor oil esters, polyethoxylated sorbitan ethers (lysorbates), ethoxylated octylphenol polymers (Tyloxapol), polyoxyl 40 stearate, fatty glycol ethers acids, glyceryl fatty acid esters, sucrose fatty acid esters and polyoxyethylene fatty acid esters, and mixtures thereof.

Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be included in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be included in excipients and used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, wherein the compound in the liquid carrier is administered orally and rinsed and spit or swallowed. Pharmaceutically compatible binding agents and/or excipients can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant agent such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint flavor, methyl salicylate, or orange flavor.

Another aspect of the present invention is a pharmaceutical composition that includes a compound of the present invention as defined above in the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.

The compositions of the present invention may be in a form suitable for oral administration (for example, such as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical administration (for example, such as creams, ointments, gels or aqueous or oily solutions or suspensions), for administration by inhalation (for example, such as a fine powder or liquid aerosol), for administration by insufflation (for example, such as a fine powder) or for parenteral administration (eg, such as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

The compositions of the present invention can be prepared by conventional techniques using conventional pharmaceutical excipients well known in the art. Thus, compositions for oral administration may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent the inflammasome-associated pathological condition described in the present invention, slow its progression and/or alleviate symptoms associated with the pathological condition.

The dosage level of a compound of formula (I) for therapeutic or prophylactic purposes will, of course, vary depending on the nature and severity of the pathological conditions, the age and sex of the animal or patient and the route of administration in accordance with well known principles of medicine.

Methods of application.

In some aspects, the present invention provides a method of inhibiting the activity of an inflammasome (eg, NLRP3 inflammasome) (eg, in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

In some aspects, the present invention provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention. in the present invention.

In some embodiments, the disease or disorder involves inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder that involves inflammasome activity.

In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and/or an autoimmune disorder.

In some embodiments, the disease or disorder is selected from the group consisting of cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold

- 109 047011 autoinflammatory syndrome (FCAS), Muckle-Wales syndrome (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome/infantile multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD) ), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin disease (eg, acne ) and neuroinflammation that occurs in diseases caused by protein misfolding (eg, prion diseases).

In some embodiments, the disease or disorder is a neurodegenerative disease.

In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

In some embodiments, the disease or disorder is a skin disease.

In some embodiments, the dermatological condition is acne.

In some embodiments, the disease or disorder is cancer.

In some embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung carcinoma, brain cancer (eg, glioblastoma), or colorectal adenocarcinoma.

In some aspects, the present invention provides a method of treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, proposed in the present invention.

In some aspects, the present invention relates to a method of treating or preventing an inflammatory disorder, an autoinflammatory disorder, and/or an autoimmune disorder selected from the group consisting of cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Mackle syndrome, Wales (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome/infantile multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis , osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin disease (eg, acne), and neuroinflammation occurring in protein misfolding diseases ( for example, prion diseases) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

In some aspects, the present invention provides a method of treating or preventing a neurodegenerative disease (eg, Parkinson's disease or Alzheimer's disease) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition proposed in the present invention.

In some aspects, the present invention provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

In some aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in inhibiting the activity of an inflammasome (eg, the NLRP3 inflammasome) (eg, in vitro or in vivo).

In some aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

In some aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject in need thereof.

In some aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an inflammatory disorder, an autoinflammatory disorder, and/or an autoimmune disorder selected from the group consisting of cryopyrine-associated autoinflammatory syndrome (CAPS; eg familial cold autoinflammatory syndrome (FCAS), Muckle-Wales syndrome

- 110 047011 (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome/infantile multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammation occurring in diseases caused by protein misfolding (eg, prion diseases) in subject in need of it.

In some aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a neurodegenerative disease (eg, Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

In some aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject in need thereof.

In some aspects, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting the activity of an inflammasome (eg, the NLRP3 inflammasome) (eg, in vitro or in vivo).

In some aspects, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

In some aspects, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject in need thereof.

In some aspects, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of an inflammatory disorder, an autoinflammatory disorder, and/or an autoimmune disorder selected from the group consisting of cryopyrin-associated autoinflammatory syndrome (CAPS) ; e.g. familial cold autoinflammatory syndrome (FCAS), Muckle-Wales syndrome (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome/infantile multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty infiltration liver (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin disorders ( eg, acne) and neuroinflammation occurring in protein misfolding diseases (eg, prion diseases) in the subject in need.

In some aspects, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a neurodegenerative disease (eg, Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

In some aspects, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of cancer in a subject in need thereof.

The present invention relates to compounds that function as inhibitors of inflammasome activity. Therefore, the present invention relates to a method of inhibiting inflammasome activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

The effectiveness of the compounds of the present invention can be determined using industry-accepted disease assays/models consistent with standard detection practices described in the art and available in the prior art.

The present invention also provides a method of treating a disease or disorder involving inflammasome activity in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, as defined herein.

In general, the compounds of the present invention that inhibit the maturation of IL-1 family cytokines are effective in all therapeutic disorders that are mediated by or

- 111 047011 are associated with increased levels of active forms of cytokines belonging to the IL-1 family of cytokines (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010).

Typical diseases and relevant literature references are given below: inflammatory, autoinflammatory and autoimmune diseases such as CAPS (Dinarello C.A. Immunity. 2004 Mar; 20(3):243-4; Hoffman H.M. al. Reumatologia 2005; 21(3), gout , rheumatoid arthritis (Gabay S. et al. Arthritis Research & Therapy 2009, 11:230; Schett G. et al. Nat Rev Rheumatol. 2016 Jan; 12(1): 14-24.), Crohn's disease (Jung Mogg Kim Korean J Gastroenterol Vol. 58 No. 6, 300-310), COPD (Mortaz E. et al. Tanaffos. 2011; 10(2): 9-14.), fibrosis (Gasse P. et al. Am J Respir Crit Care Med. 2009 May 15; 179(10):903-13), obesity, type 2 diabetes (Dinarello C.A. et al. Curr Opin Endocrinol Diabetes Obes. 2010 Aug; 17(4):314-21) multiple sclerosis (see EAE model in Coll R.C. et al. Nat Med. 21(3):248-55) and many others (Martinon F. et al. Immunol. 27:229-65). Alzheimer's disease (Michael T. et al. Nature 493, 674-678 (31 January 2013); Halle A. et al., Nat Immunol. 2008 Aug; 9(8):857-65; Saresella M. et al. Mol Neurodegener. 2016 Mar 3; 11:23) and some cancer disorders.

Advantageously, the compounds of the present invention can be used to treat a disease selected from the group consisting of an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a neurodegenerative disease and cancer. Said inflammatory, autoinflammatory and autoimmune disease is preferably selected from the group consisting of cryopyrin-associated autoinflammatory syndrome (CAPS, such as, for example, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous articular syndrome (CINCA) ) syndrome/infantile multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (eg acne) and neuroinflammation occurring in protein misfolding diseases such as prion diseases. Said neurodegenerative disease includes, but is not limited to, Parkinson's disease and Alzheimer's disease.

Accordingly, the compounds of the present invention can be used to treat a disease selected from the group consisting of cryopyrin-associated autoinflammatory syndrome (CAPS, such as, for example, familial cold autoinflammatory syndrome (FCAS), Muckle-Wales syndrome (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome/infantile multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g. acne) neuroinflammation occurring in protein misfolding diseases such as prion diseases, neurodegenerative diseases (e.g. Parkinson's disease, Alzheimer's disease) and cancer disorders.

Cancer treatment; connections with the inflammasome.

Chronic inflammatory responses associated with different types of cancer have long been observed. During malignant transformation or cancer treatment, inflammasomes can be activated in response to danger signals, and this activation in cancer can be beneficial or detrimental.

Ρ-1β expression is elevated in a variety of cancers (including breast, prostate, colon, lung, head and neck, and melanoma) and patients with Ρ-1β-producing tumors generally have a poor prognosis (Lewis, Anne M ., et al. Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. Journal of translational medicine 4.1 (2006): 48).

Cancers arising from epithelial cells (carcinoma) or glandular epithelium (adenocarcinoma) are heterogeneous; consisting of many different types of cells. These may include, but are not limited to, fibroblasts, immune cells, adipocytes, endothelial cells, and pericytes, all of which can secrete cytokine/chemokine (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. Immunity, inflammation, and cancer. Cell 140.6 (2010): 883-899). This may lead to cancer-related inflammation through the infiltration of immune cells. The presence of leukocytes in tumors is known, but only recently has it become apparent that the inflammatory microenvironment is an important component of all tumors. Most tumors (>90%) are the result of somatic mutations or environmental factors rather than germline mutations, and many environmental causes of cancer are associated with chronic inflammation (20% of cancers are associated with chronic infection, 30% with smoking/inhalation-induced pollution, and 35% with dietary factors (20% of all cancers are associated with obesity) (Aggarwal, Bharat V., R.V. Vijayalekshmi, and Bokyung Sung. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clinical Cancer Research 15.2 (2009): 425-430).

- 112 047011

GI cancer.

Gastrointestinal (GI) cancers are often associated with chronic inflammation. For example, H. pylori infection is associated with gastric cancer (Amieva, Manuel, and Richard M. Peek. Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology 150.1 (2016): 64-78). Colorectal cancer is associated with inflammatory bowel disease (Bernstein, Charles N., et al. Cancer risk in patients with inflammatory bowel disease. Cancer 91.4 (2001): 854-862). Chronic gastric inflammation leads to upregulation of IL-1 and other cytokines (Basso D., et al., (1996) Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res 26:207-210) and IL-1[i gene polymorphisms may increase the risk of gastric cancer (Wang P., et al., (2007) Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int J Cancer 120:552–562).

In 19% of gastric cancers, caspase-1 expression is reduced, which correlates with stage, lymph node metastasis, and survival (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric cancer, and its activation of the NLRP3 inflammasome may be associated with its promotion of gastric cancer metastasis (Xu et al., 2013).

Skin cancers.

Ultraviolet radiation is the most important environmental hazard for skin cancer, which is promoted by DNA damage, immunosuppression, and inflammation. The most malignant skin cancer, melanoma, is characterized by up-regulation of inflammatory cytokines, all of which can be regulated by IL-1[i (Lazar-Molnar, Eszter, et al. Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 12.6 (2000 ): 547-554). Systemic inflammation induces melanoma cell metastasis and growth through IL-1-dependent mechanisms in vivo. When using thymoquinone inhibition of metastasis in a mouse model of B16F10 melanoma, it was shown to depend on inhibition of the NLRP3 inflammasome (Ahmad, Israr, et al. Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome. Toxicology and applied pharmacology 270.1 (2013): 70-76).

Glioblastoma.

NLRP3 promotes glioma resistance to radiotherapy. Ionizing radiation can induce NLRP3 expression, and inhibition of NLRP3 reduces tumor growth and increases survival in mice after radiation therapy. Therefore, inhibition of the NLRP3 inflammasome represents a therapeutic strategy for the treatment of radiation-resistant glioma (Li, Lianling, and Yuguang Liu. Aging-related gene signature regulated by Nlrp3 predicts glioma progression. American journal of cancer research 5.1 (2015): 442).

Metastasis.

More broadly, applicants believe that NLRP3 is involved in promoting metastasis and therefore modulation of NLRP3 is likely to block it. IL-1 is involved in tumor genesis, tumor invasiveness, tumor metastasis, tumor-host interactions (Apte, Ron N., et al. The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer and Metastasis Reviews 25.3 (2006): 387-408) and angiogenesis (Voronov, Elena, et al. IL-1 is required for tumor invasiveness and angiogenesis. Proceedings of the National Academy of Sciences 100.5 (2003): 2645-2650).

The IL-1 gene is frequently expressed in metastases from patients with certain types of human cancers. For example, IL-1mRNA was highly expressed in more than half of all human metastatic tumor samples examined, including, but not limited to, non-small cell lung carcinoma, colorectal adenocarcinoma, and melanoma samples (Elaraj, Dina M., et al. The role of interleukin 1 in growth and metastasis of human cancer xenografts. Clinical Cancer Research 12.4 (2006): 1088-1096) and IL1RA suppresses xenograft growth in IL-1-producing tumors but without antiproliferative effects in vitro.

Additionally, IL-1 signaling is a biomarker for predicting breast cancer in patients at increased risk of developing bone metastases. In a mouse model, !Γ-1β and its receptor are up-regulated in breast cancer cells that metastasize to bone compared with cells that do not metastasize. In a mouse model, the IL-1 receptor antagonist anakinra reduced proliferation and angiogenesis, and also had a significant effect on the tumor environment by reducing the turnover of bone markers, IL-1 β and TNF alpha (Holen, Ingunn, et al. IL-1 drives breast cancer growth and bone metastasis in vivo. Oncotarget (2016).

IL-18 induces MMP-9 production in the human leukemia cell line HL-60, which favors extracellular matrix destruction and migration and invasiveness of cancer cells (Zhang, Bin, et al. IL-18 increases invasiveness of HL-60 myeloid leukemia cells: up -regulation of matrix metalloproteinases-9 (MMP-9) expression. Leukemia research 28.1 (2004): 91-95). In addition, IL-18 may support the development of tumor metastasis in the liver by inducing VCAM-1 expression in the sinusoidal endothelium of the liver (Carrascal, Maria Teresa, et al. Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium. Cancer Research 63.2 (2003): 491-497).

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CD36.

The fatty acid uptake receptor CD36 plays a dual role in priming pro-IL-1e gene transcription and inducing assembly of the NLRP3 inflammasome complex. CD36 and the TLR4-TLR6 heterodimer recognize oxLDL, which initiates a signaling pathway leading to transcriptional up-regulation of NLRP3 and pro-IL-1e (signal 1). CD36 also mediates clearance of oxLDL into the lysosomal compartment, where crystals are formed that induce lysosomal destruction and activation of the NLRP3 inflammasome (signal 2) (Kagan, J. and Horng T., NLRP3 inflammasome activation: CD36 serves double duty. Nature immunology 14.8 (2013) : 772-774).

A subpopulation of human oral carcinoma cells express large amounts of the fatty acid uptake receptor CD36 and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet increases the metastatic potential of CD36+ cells. Neutralization of anti-CD36 antibodies blocks metastasis in orthotopic mouse models of human oral cancer. The presence of metastasis-initiating CD36+ cells correlates with poor prognosis for numerous types of carcinoma. It has been suggested that dietary lipids may promote metastasis (Pasqual, G., Avgustinova, A., Mejetta, S., Martin, M., Castellanos, A., Attolini, C.S.-O., Berenguer, A., Prats, N. , Toll, A., Hueto, J.A., Bescos, C., Di Croce, L., and Benitah, S.A. 2017 Targeting metastasis-initiating cells through the fatty acid receptor CD36 Nature 541:41-45).

In hepatocellular carcinoma, endogenous palmitic acid activates an endothelial-mesenchymal transition (EMT)-type program and induces migration that was reduced by the CD36 inhibitor, sulfo-H-succinimidyl oleate (Nath, Aritro, et al. Elevated free fatty acid uptake via CD36 promotes epithelial -mesenchymal transition in hepatocellular carcinoma. Scientific reports 5 (2015). Body mass index was not associated with the degree of EMT, and this showed that it was indeed CD36 and free fatty acids that were important.

Cancer stem cells (CSCS) use CD36 to promote their action. Oxidized phospholipids, ligands of CD36, were present in glioblastoma and proliferation of CSCS, but not CSCS, increased with increasing exposure to oxidized LDL. CD36 also correlates with patient prognosis.

Chemotherapy resistance.

In addition to direct cytotoxic effects, chemotherapeutic agents enhance the host immune system, which promotes antitumor activity. However, gemcitabine and 5-FU have been shown to activate NLRP3 in myeloid cell-derived suppressor cells, leading to the production of IL-1e, which reduces antitumor efficacy. Mechanistically, these agents destabilize the lysosome to release cathepsin B to activate NLRP3. IL1β mediates the production of IL-17 from CD4+ T cells, which in turn reduces the effectiveness of chemotherapy. Greater antitumor effects of gemcitabine and 5-FU were observed when tumors formed in NLRP3 −/− or Caps1 −/− mice or WT mice were treated with IL-1RA. Therefore, activation of myeloid-derived suppressor cells limits the antitumor efficacy of gemcitabine and 5-FU (Bruchard, Melanie, et al. Chemotherapy triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nature medicine 19.1 (2013): 57-64.). Therefore, the compounds proposed in the present invention may be useful in chemotherapy for the treatment of various cancers.

The compounds of the present invention, or a pharmaceutically acceptable salt thereof, may be administered alone as a single drug or may be administered in addition to one or more other substances and/or treatments. Such co-treatment can be achieved by simultaneous, sequential or separate administration of the individual treatment components.

For example, therapeutic efficacy may be increased by administration of an excipient (ie, the excipient itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be enhanced by administering a compound of formula (I) together with another therapeutic agent (which also includes a therapeutic regimen) that also has a therapeutic benefit.

In cases where the compound of the present invention is administered in combination with other therapeutic agents, the compound of the present invention should not be administered by the same route as other therapeutic agents, but may be administered by a different route due to different physical and chemical characteristics . For example, a compound of the present invention may be administered orally to establish and maintain proper blood levels, and another therapeutic agent may be administered intravenously. Initial administration can be carried out in accordance with established regimens known in the art, and then, taking into account the observed effects, the dose, route of administration and times of administration can be modified by a qualified

- 114 047011 clinician.

The specific choice of other therapeutic agent depends on the diagnosis of the treating physicians and their judgment of the individual's condition and the appropriate treatment regimen. This object of the present invention is a combination for use in the treatment of a disease in which inflammasome activity is involved, comprising a compound of the present invention as defined above in the present invention, or a pharmaceutically acceptable salt thereof, and another suitable agent.

Another aspect of the present invention is a pharmaceutical composition that includes a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a suitable pharmaceutically acceptable diluent or carrier.

In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmaceutical agents for the development and standardization of in vitro and in vivo test systems for studying the effect of inflammasome inhibitors on laboratory animals such as dogs, rabbits , monkeys, rats and mice, as part of the search for new therapeutic agents.

For any of the above pharmaceutical compositions, the process, method, use, drug and preparation features described in the present invention are also applicable to any of the alternative embodiments of the macromolecules proposed in the present invention described in the present invention.

Routes of administration.

The compounds of the present invention, or pharmaceutical compositions comprising these compounds, can be administered to a subject by any suitable route of administration, systemic/peripheral or local (ie, at the site of desired effect).

Routes of administration include, but are not limited to, oral (eg, ingestion); buccal; sublingual; transdermal (including, for example, patch, adhesive tape, etc.); transmucosal (including, for example, adhesive tape, adhesive tape, etc.); intranasal (for example, using a nasal spray); ophthalmic (for example, using eye drops); pulmonary (eg, by inhalation therapy or by insufflation using, for example, an aerosol, for example, through the mouth or nose); rectal (for example, using a suppository or enema); vaginal (for example, using a pessary); parenteral, for example by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid and epigastric; by implanting a depot or reservoir, for example, subcutaneously or intramuscularly.

Additional objects of the invention

The first object of the present invention is a compound of formula (I) or a prodrug or pharmaceutically acceptable salt thereof:

where R1 means a monocyclic (C3-C8) alkyl ring or a polycyclic alkyl ring or a monocyclic (C ₆ ) aryl ring or a 9- or 10-membered bicyclic partially unsaturated carbocyclic ring system or a 12-, 13-, 14-, 15- or 16 -membered tricyclic partially unsaturated carbocyclic ring system, R ₂ means the group:

R4 where X is (CH ₂ ) ₀ d _or 2 and R ₄ is a saturated 4-7 membered heterocyclic ring containing at least one or more N and O; And

R3 is selected from the group consisting of a 5- or 6-membered heterocyclic aromatic ring containing two or three different atoms independently selected from the group consisting of C, N, O and S, wherein R3 is bonded to an adjacent N of formula I through a C atom.

In some embodiments, R1 is a phenyl group or a substituted phenyl group.

- 115 047011

In some embodiments, R ₁ has the structure:

R6

R9 where each of R5, _R6 , R7, R8 and _R9 is independently selected from the group consisting of H, C1- _C6 alkyl, C2- _C6 alkenyl, C2- _C6 alkynyl, halogen, haloalkyl, cyano, C1-C6 alkoxy group and amino group.

In some embodiments, the first set of two adjacent groups selected from the group consisting of R5, Rg, R7, Rs and _R9 defines a 4-7 membered alkyl or aryl ring A.

In some embodiments, a second, different set of two adjacent groups selected from the group consisting of R5, _R6 , R7, _R8 and _R9 defines a 4-7 membered alkyl or aryl ring B.

In some embodiments, R ₅ and R ₆ form the first set.

In some embodiments, R ₈ and R ₉ form a second set.

Optionally, in some embodiments described above, ring A and/or ring B may be substituted with one or more groups independently selected from the group consisting of C1-C6 alkyl, C2- _C6 alkenyl, C2- _C6 alkynyl, halogen, hydroxy group, haloalkyl, cyano group, C1-C6 alkoxy group and amino group.

In some embodiments, R1 is hexahydroindacene.

In some embodiments, R4 is an optionally substituted oxa-, aza-, or thiacyclopentane, or an optionally substituted oxa-, aza, or thiacyclohexane.

In some embodiments, R ₄ is substituted with one or more groups independently selected from the group consisting of C1-C6 alkyl, C2- _C6 alkenyl, C2- _C6 alkynyl, halogen, haloalkyl, cyano, alkoxy, hydroxy, keto, amino, and amide group.

In other embodiments, at least one substituent group is bonded to the N atom of the R ₄ ring.

In preferred embodiments, the at least one substituent group is a methyl group bonded to the N atom of the R4 ring.

In some embodiments, R4 is morpholine.

In some embodiments, the 5- or 6-membered heterocycle at R3 contains 1, 2, or 3 N atoms.

In some embodiments, the 5- or 6-membered heterocycle in R3 includes one N atom and one O atom.

In some embodiments, the 5- or 6-membered heterocycle at R3 is selected from the group consisting of pyrazole, isoxazole, imidazole, triazole, pyrimidine, and pyrazine, where the heterocycle is optionally substituted.

In some embodiments, the 5- or 6-membered heterocyclic aromatic ring in R ₃ is substituted with at least one group independently selected from the group consisting of linear, branched or cyclic (C1-C6) alkyl, alkenyl, alkynyl, halogen, hydroxy, haloalkyl , cyano group, alkoxy group, amino group and amide group.

The substituent group is preferably a methyl, ethyl or propyl group.

In some embodiments, at least one substituent group is bonded to the N atom of the heterocycle in R3. In other embodiments, at least one substituent group is bonded to the C atom of the heterocycle in R3. If there are two or more substituent groups, in some embodiments they may be bonded to both the N and C atoms of the heterocycle in R ₃ .

- 116 047011

In preferred embodiments, the compound of the present invention is selected from the group consisting of 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 - methyl-1 H-pyrazol4-yl)(oxan-4-yl)sulfamoyl]urea;

sodium salt 3-(1,2,3,5, 6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol4-yl)( 1 -methylpiperidin-4- yl)sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol4-yl)[(1-methylpiperidin-4 -yl)methyl]sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-ind acen-4-yl)-1 -[(oxan-4-yl) [ 1 (propan-2-yl)-1H -pyrazol-4-yl]sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1-methylpiperidin-4yl) [ 1 -(propan-2-yl)-1 N-pyrazol-4-yl]sulfamoyl]urea;

sodium salt 1-[(1-ethyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydro-8-indacen-4-yl )urea;

sodium salt 1 -[(1 -ethyl-1 H-pyrazol-4-yl)( 1 -methylpiperide in-4-yl)sulfamoyl]3-(1,2,3,5,6,7-hexahydro-8- indacen-4-yl)urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol4-yl)(oxolan-3-yl) sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol3-yl)(oxan-4-yl) sulfamoyl]urea;

sodium salt 1 - [(1,5 -dimethyl-1 H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl] -3 (1,2,3,5,6,7-hexahydro-8-ind acen-4-yl)urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1-[(oxan-4-yl)(1,3,5trimethyl-1H-pyrazol-4 -yl)sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1-[(5-methyl-1,2-oxazol3-yl)(oxan-4-yl )sulfamoyl]urea;

sodium salt of 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1-[(oxan-4-yl)(1,2oxazol-4-yl)sulfamoyl]urea ;

sodium salt 1 -[(1,5 -dimethyl-1 H-pyrazol-4-yl)( 1 -methylpiperidin-4yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro-8- indacen-4-yl)urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1-methylpiperidin-4yl)( 1,3,5-trimethyl-1 H- pyrazol-4-yl)sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol- 117 047011

4-yl)[(oxetan-3-yl)methyl]sulfamoyl]urea;

sodium salt of 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 - [(oxan-4yl)(pyrimidin-5-yl)sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1-[(3-methyl-1,2-oxazol5-yl)(oxan-4-yl )sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-ind acen-4-yl)-1 - [(1-methyl-1 Η-1,2,4triazol-3-yl) (oxan-4-yl)sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol3 -yl)( 1 -methylpiperidin-4- yl)sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-imidazol4-yl)(oxan-4-yl) sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol4-yl)(oxan-3-yl) sulfamoyl]urea;

sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol4-yl)( 1 -methylpiperidin-3- yl)sulfamoyl]urea; and sodium salt 3-(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)-1 -[(1 -methyl-1 H-pyrazol4-yl)( 1 -methylpyrrolidin-3 -yl)sulfamoyl]urea.

(2-6C)Alkenylene means a linear divalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched divalent hydrocarbon radical containing from 3 to 6 carbon atoms containing at least one double bond, for example, as in ethenylene, 2. 4pentadienylene, etc.

(2-6C)Alkynylene means a linear divalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched divalent hydrocarbon radical containing from 3 to 6 carbon atoms containing at least one triple bond, for example, as in ethynylene, propynylene and butynylene, etc.

(3-8C)Cycloalkyl means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

Suitable meanings of the term (1-6C)alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group and butoxy group.

Suitable meanings of the term (1-3C)alkylamino group include methylamino group, ethylamino group, propylamino group, isopropylamino group and butylamino group.

Suitable meanings of the term di-[(1-3C)alkyl]amino group include dimethylamino group, diethylamino group, Nethyl-N-methylamino group and diisopropylamino group.

The term 5-membered monocyclic heteroaryl ring system is used to define a ring system where the ring system optionally includes 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Suitable examples include furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.

The term 8-, 9-, or 10-membered bicyclic heteroaryl ring system is used to define the ring system formed and optionally includes 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Suitable examples include indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, 1H-pyrrolo[3,2-b]pyridinyl, 1Hpyrrolo[2,3-c ]pyridinyl, pyrido[3,2^]pyrimidyl and pyrimidoimidazolyl. The term 8, 9 or 10 membered bicyclic heteroaryl ring system also includes partially aromatic bicyclic ring systems where the first ring is aromatic and the other second ring is non-aromatic, saturated or partially saturated. Suitable examples of partially aromatic bicyclic ring systems include, for example, 4,5,6,7-tetrahydroindolyl, 4,5,6,7tetrahydroisoindolyl and 2H,4H,5H,6H-cyclopenta[c]pyrrolyl.

The term 5- or 6-membered monocyclic heteroaryl ring system means a 5- or 6-membered aromatic ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Suitable examples include furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.

The term 3-, 4-, 5- or 6-membered monocyclic heterocyclyl ring system means a 3-, 4-, 5- or 6-membered non-aromatic saturated or partially saturated heterocyclic ring system, where the ring system optionally contains 1 or 2 heteroatoms, regardless selected

- 118 047011 from the group consisting of oxygen, nitrogen and sulfur, wherein the ring sulfur atom is optionally oxidized to form S-oxide(s). Suitable examples include oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydropyran and 1,4-thiazinyl.

The term 12-, 13-, 14-, 15-, or 16-membered tricyclic partially unsaturated heterocyclic ring system, when used to define a ring system, means a 12-, 13-, 14-, 15-, or 16-membered partially unsaturated heterocyclic ring system, which includes 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring sulfur atom is optionally oxidized to form S-oxide(s). Suitable examples include rings such as 2-azatricyclo[7.3.0.0 ³ ' ⁷ ]dodeca-1,3(7),8-trienyl,1,2,3,4,5,6,7,8octahydroacridinyl-1,7 -azatricyclo[7.3.0.0 ^2,7 ]dodeca-1,6,8-trienyl, 1,2,3,4,7,8,9,10octahydrophenanthridenyl, W,2H,3H,6H,7H,8H,9H- cyclopenta[c]isoquinolinyl, 1H,2H,3H,6H,7H,8H,9Hcyclopenta[c]quinolonyl, 1H,2H,3H,5H,6H,7H,8H-cyclopenta[b]quinolonyl, 1H,2H,3H, 5H,6H,7Hcyclopenta[b]pyrrolizinyl, 1H,2H,3H,5H,6H,7H,8H-cyclohexa[b]pyrrolizinyl, 1H,2H,3H,5H,6H,7Hcyclopenta[b]pyrrolizinyl and 1H,2H, 3H,5H,6H,7H,8H-cyclopenta[b]indolizinyl.

A 12-, 13-, 14-, 15-, or 16-membered tricyclic partially unsaturated carbocyclic ring system contains only carbon atoms. Suitable examples include rings such as 1,2,3,5,6,7-hexahydro-indacenyl, 1,2H,3H,6H,7H,8H,9H-cyclopenta[a]naphthalenyl, 1,2,3, 6,7,8hexahydro-indacenyl, 1,2,3,4,5,6,7,8-octahydroanthracenyl, 1,2,3,4,5,6,7,8-octahydrophenanthrenyl and 1H,2H,3H ,5H,6H,7H,8H-cyclopenta[b]naphthalenyl.

The term 3-, 4-, 5- or 6-membered saturated or partially unsaturated carbocyclic ring system means a monocyclic ring system containing only carbon atoms. Suitable examples include cyclopropanyl, cyclopentanyl, cyclohexanyl and cyclohexenyl.

Another object of the present invention is a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

Another object of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof as defined herein for use as a drug.

Another object of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein or a pharmaceutical composition as defined herein for use in treating a disorder involving inflammasome activity.

In some embodiments, the composition is for use in treating cancer. In particularly preferred embodiments, the cancer is selected from the group consisting of metastatic cancer, brain cancer, squamous cell carcinoma of the head and neck, gastrointestinal cancer, skin cancer, non-small cell lung carcinoma, and colorectal adenocarcinoma.

Another object of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an inflammatory, autoinflammatory or autoimmune disorder, neurodegenerative disease or cancer. In a preferred embodiment, the inflammatory, autoinflammatory or autoimmune disorder is a cryopyrin-associated autoinflammatory syndrome (CAPS, such as, for example, familial cold autoinflammatory syndrome (FCAS), Muckle-Wales syndrome (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome/ infantile multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, calcium pyrophosphate deposition disease (CPPD), pyrophosphate deposition disease calcium (CPPD), rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin disease (eg acne) or neuroinflammation occurring in diseases caused by protein misfolding such as prion diseases. In another embodiment, the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.

Another object of the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for the preparation of a medicament for the treatment of an inflammatory, autoinflammatory or autoimmune disorder, neurodegenerative disease or cancer. Preferably, the inflammatory, autoinflammatory or autoimmune disorder is a cryopyrin-associated autoinflammatory syndrome (CAPS, such as, for example, familial cold autoinflammatory syndrome (FCAS), Mackie-Wells syndrome (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome /infantile multisystem inflammatory disease (NOMID)), familial Mediterranean

- 119 047011 sea fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, calcium pyrophosphate deposition disease (CPPD), rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (eg acne) or neuroinflammation occurring in protein misfolding diseases such as prion diseases. Preferably, the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.

Another object of the present invention is a method of inhibiting the activity of an inflammasome (such as the NLRP3 inflammasome) in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein.

Another aspect of the present invention is a method of treating a disease or disorder involving inflammasome activity in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition , as defined in the present invention.

Another aspect of the present invention is a method of treating an inflammatory, autoinflammatory or autoimmune disorder, neurodegenerative disease or cancer in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I) a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined in the present invention.

Another object of the present invention is a method of treating an inflammatory, autoinflammatory or autoimmune disorder and/or an autoimmune disorder selected from the group consisting of cryopyrin-associated autoinflammatory syndromes (CAPS, including familial cold autoinflammatory syndrome (FCAS), Mackie-Wells syndrome (MWS), chronic infantile neurological cutaneous articular (CINCA) syndrome/infantile multisystem inflammatory disease (NOMID), familial Mediterranean fever and nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, calcium pyrophosphate deposition disease (CPPD), rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (eg acne) and neuroinflammation occurring in diseases caused by protein misfolding such as prion diseases in needing such treatment of a patient, said method comprises administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein.

Another aspect of the present invention is a method of treating a neurodegenerative disease such as Parkinson's disease or Alzheimer's disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined in the present invention.

Another object of the present invention is a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein.

Another object of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, obtained or obtained, or directly obtained by the method for preparing the compound as defined in the present invention.

Another object of the present invention is new intermediates defined in the present invention, which are suitable for use in any of the synthetic procedures described in the present invention.

The present invention has been described above, the following examples are provided for illustration and not limitation.

Examples

Representative salts of the compounds of formula (I) were synthesized and studied in the examples. It should be understood that neutral compounds of formula (I) can be similarly synthesized and studied using typical procedures described in the examples. In addition, it should be understood that salts (e.g., sodium salt) of the compounds of formula (I) can be converted into the corresponding neutral compounds by standard techniques used in the art, for example, (by adjusting the pH and optionally extraction (e.g., into the aqueous phase )).

Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as indicated and at 300.3 K unless otherwise indicated; chemical shifts (δ) are given in parts per million (ppm). Spectra were recorded on a Bruker or Varian instrument with 8, 16 or 32 scans.

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Chromatograms and LC-MS spectra were recorded using Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instruments using a C-18 column such as Luna-C18 2.0x30 mm or Xbridge Shield RPC18 2.1x50 mm. Injected volumes were 0.7–8.0 μL and flow rates were typically 0.8 or 1.2 mL/min. Detection was performed using a diode array detector (DAD) or evaporative light scattering (ELSD) and positive ion electrospray ionization. MS range was 100-1000 Da. Solvents were used in a gradient mode using water and acetonitrile, both containing a modifier (usually 0.01-0.04%) such as trifluoroacetic acid or ammonium carbonate.

Abbreviations.

ACN Acetonitrile AcOH Acetic acid AR Atmosphere pressure Ag argon BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DMF N,N-dimethylformamide DMSO-Y Hexadeuterodimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene eq. equivalents MS ES ⁺ electrospray ionization mass spectroscopy producing positive ions ESI electrospray ionization EtOAc ethyl acetate

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FCC flash column chromatography h watch) HATU N-oxide N-[(dimethylamino)-1 Η-1,2,3-triazolo-[4,5-b]pyridine-1 - ylmethylene]-M-methylmethanamminium hexafluorophosphate HPLC high performance liquid chromatography LC-MS liquid chromatography-mass spectrometry MeOD Methanol-s/c MeOH Methanol Min Minute(s) MTBE methyl tert-butyl ether NaHMDS sodium hexamethyldisilylazide R.M. reaction mixture Rt room temperature S.M. starting material TBAF ammonium tetra-n-butyl fluoride TEA Triethylamine T.F.A. trifluoroacetic acid THF Tetrahydrofuran TLC thin layer chromatography Y exit

General technique A

AcOH, NaBHoCN, O

NH ₂ ⁺ o, ^RSM „ R2„ R3 ² R3 ► 'ν

N; or

AcOH, NaBHnCN, O

NH, ⁺ □, ^РСМ „ R2 R3 ² R2 --------------►'

Η

Sodium cyanoborohydride (1.5 equiv) was added to a solution of amine (1 eq.), ketone or aldehyde (1 eq.), and acetic acid (0.5 eq.) in DCM (1.0 M). The reaction mixture was stirred at RT for 3 hours. The mixture was concentrated in vacuo, diluted with water and extracted three times with EtOAc. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel eluting with ethyl acetate/petroleum ether or MeOH/dichloromethane) to give the desired product.

General technique B

To a solution of sulfamoyl chloride (1 eq., sometimes prepared from a solution in isopropyl ether) and amine (1 eq.) in THF (0.2 M) was added NaH (60% in mineral oil, 4 eq.) at 0°C in an atmosphere N2. The mixture was stirred at 0°C for 2 hours. The reaction mixture was evaporated under a stream of N2.

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General technique C

Triphosgene (1.1 equiv) and base were added to a solution of amine (1 eq.) in dioxane (0.1 M). The RM was stirred at 40°C for 1 hour or until the reaction was complete. The solvent was removed in vacuo to obtain the desired product.

General procedure D

To a solution of Na(oxomethylene)sulfamoyl chloride (1 eq.) in isopropyl ether (0.4 M), cooled to -30°C, the amine (1 eq.) in isopropyl ether (0.4 M) was added under a nitrogen atmosphere. The RM was stirred at -30°C for 0.5 to 2 hours and the reaction was monitored using LC-MS (the appearance of methyl sulfonate was recorded). The product was used without treatment as a solution in isopropyl ether (0.2 M).

Synthesis of intermediate products.

{[(1,2,3,5,6,7-Hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride

For the synthesis of 1.2.3.5.6.7-hexahydroch-indacene-4-amine, WO 9832733 A1 can be used as a direct reference.

To a solution of Na(oxomethylene)sulfamoyl chloride (185 μl, 2.13 mmol) in isopropyl ether (20 ml) was added 1.2.3.5.6.7-hexahydroch-indacene-4-amine (369 mg, 2.13 mmol) at -15° WITH. The mixture was stirred at -15°C for 0.5 hours. The reaction product was used without treatment in the next step. LC-MS in MeOH (ESI): m/z: [MH] ⁺ = 311.

4-Isocyanato-1,2,3,5,6,7-hexahydro^-indacene

For the synthesis of 1,2,3,5,6,7-hexahydro^-indacene-4-amine, see patent WO 9832733 A1.

To a mixture of triphosgene (1.71 g, 5.77 mmol) with DCM (5 ml), cooled to 0°C, 1,2,3,5,6,7-hexahydro-indacene-4 was added in portions under a nitrogen atmosphere -amine (1.00 g, 5.77 mmol) and triethylamine (1.69 ml, 12.12 mmol). The mixture was stirred at RT for 5 hours. The mixture was concentrated under reduced pressure to obtain the title compound as a white solid. LC-MS in MeOH (ESI): m/z: [M+MeOH+H] ⁺ = 232 tert-Butyl-H-(chlorosulfonyl)carbamate

To a solution of Na(oxomethylene)sulfamoyl chloride (307 µl, 3.53 mmol) in DCM (6 ml), cooled to 0°C, was added a solution of tert-butanol (338 µl, 3.53 mmol) in DCM ( 6 ml). The mixture was stirred at 0°C for 2 hours. The solution was used without treatment in the next step.

Example 1. Sodium salt of 3-(1.2.3.5.6.7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(oxan-4-yl)sulfamoyl]urea

ABOUT

Step 1: 1-methyl-Ntetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1-methylpyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a red oil. ^1H NMR (400 MHz, CDCl ₃ ) δ = 7.13 (s, 1H), 6.94 (s, 1H), 4.00-3.97 (m, 3H), 3.80 (s, 3H ), 3.473.41 (m, 2H), 3.07-3.04 (m, 1H), 2.01-1.93 (m, 2H), 1.51-1.38 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(oxan-4-yl) )sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-Ntetrahydropyran-4-ylpyrazol-3-amine were used. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 5 µm, 100x30 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B%: 20-40%, 12 min) to obtain the desired compound as a white solid. ^1H NMR (400 MHz, MeOD) δ = 7.71 (s, 1H), 7.42 (s, 1H), 6.98 (s, 1H), 4.33 (t, J=12 Hz, 1H ), 3.96-3.86 (m, 5H), 3.47 (t, J=12 Hz, 2H), 2.88 (t, J=7 Hz, 4H), 2.79 (t, J =7 Hz, 4H), 2.11-2.04 (m, 4H), 1.87 (d, J=10 Hz, 2H), 1.47-1.43 (m, 2H). LC-MS (ESI): m/z: [MH] ^- = 458.0.

Example 2. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-III-pyrazol-4yl) (1-methylpiperidin-4 -yl)sulfamoyl]urea

N I

CH ₃

Step 1: 1-methyl-N(1-methylpyrazol-4-yl)piperidin-4-amine. General Procedure A was followed and 1-methylpyrazol-4-amine and 1-methylpiperidin-4-one were used to obtain the title compound as a red oil.

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)(1methylpiperidin-4 -yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N(1-methylpyrazol-4-yl) were used. piperidine-4-amine. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 5 µm 100x30 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 20-40%, 12 min) and obtained the desired compound in the form of a white solid. ^1H NMR (400 MHz, MeOD) δ = 7.67 (s, 1H), 7.43 (s, 1H), 6.94 (s, 1H), 4.28-4.20 (m, 1H) , 3.86 (s, 3H), 3.14 (d, J=12 Hz, 2H), 2.87 (t, J=8 Hz, 4H), 2.79 (t, J=7 Hz, 4H ), 2.62 (t, J=13 Hz, 2H), 2.48 (s, 3H), 2.13-1.99 (m, 6H), 1.59-1.48 (m, 2H) . LC-MS (ESI): m/z: [MH] ^- = 471.1.

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Example 3. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl) [(1-methylpiperidin- 4-yl)methyl]sulfamoyl]urea

Step 1: 1-methyl-H-(1-methylpyrazol-4-yl)piperidine-4-carboxamide. To a mixture of 1-methylpyrazol-4amine (0.30 g, 3.09 mmol, 1 eq.) and 1-methylpiperidine-4-carboxylic acid (442 mg, 3.09 mmol, 1 eq.) in pyridine (10 ml) 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (888 mg, 4.64 mmol, 1.5 eq.) was added in one portion at 0°C under N2. The mixture was stirred at RT for 2 hours. The mixture was concentrated in vacuo, then diluted with water (10 ml). The aqueous phase was extracted with ethyl acetate (3x10 ml). The combined organic phase was washed with saturated brine (3x8 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% MeOH in ethyl acetate) to give 1-methyl-N-(1methylpyrazol-4-yl)piperidin-4-carboxamide as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.83 (s, 1H), 7.90-7.78 (m, 1H), 7.82 (s, 1H), 7.44-7 .29 (m, 1H), 5.89-5.70 (m, 1H), 3.75 (s, 2H), 3.02-2.93 (m, 1H), 3.02-2.93 (m, 1H), 2.78 (d, J=12 Hz, 2H), 2.10 (s, 3H), 1.90-1.78 (m, 2H), 1.49-1.45 ( m, 1H).

Step 2: 1-methyl-N-((1-methylpiperidin-4-yl)methyl)-N-pyrazol-4-amine. Lithium aluminum hydride (51 mg, 1.35 mmol, 1.5 eq.). The mixture was stirred at 70°C for 2 hours. The reaction was stopped by adding H2O (1 ml) at 0°C, then the reaction mixture was diluted with 10% NaOH (1 ml), filtered and concentrated in vacuo to give 1-methyl- N-((1methylpiperidin-4-yl)methyl)-N-pyrazol-4-amine in the form of red oil. LC-MS (ESI): m/z: [M+H]+ = 209.

Step 3: 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[(1-methylpiperidine) sodium salt -4-yl)methyl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-((1methylpiperidin-4-yl) methyl)-1H-pyrazol-4-amine. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 5 µm 100x30 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B%: 20-40%, 12 min) to obtain the title compound as a white solid. ¹ H NMR (400 MHz, MeOD) δ ppm 7.68 (s, 1H) 7.51 (s, 1H) 6.92 (s, 1H) 3.85 (s, 3H) 3.62 (br. d, J=7.28 Hz, 2H) 2 .91-2.66 (m, 14H) 2.22-1.87 (m, 7H) 1.72 (br.s, 1H) 1.49 (br.s, 2H). LC-MS (ESI): m/z: [MH] ^- = 485.2.

Example 4. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)[1-(propan-2yl)-1H -pyrazol-4-yl]sulfamoyl]urea

ABOUT

Step 1: 1-Isopronyl-Ntetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1-isopropylpyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a red oil. ^1H NMR (400 MHz, CDCl ₃ ) δ = 7.15 (s, 1H), 7.01 (d, J=1 Hz, 1H), 4.41-4.38 (m, 1H), 4, 01-3.97 (m, 2H), 3.48-3.41 (m, 2H), 3.13-3.03 (m, 1H), 2.51 (s, 1H), 2.02- 1.93 (m, 2H), 1.49-1.42 (m, 8H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)[1-(propan-2-yl) 1H-pyrazol-4-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-isopropyl-Ntetrahydropyran-4ylpyrazol-4-amine were used. The reaction mixture was poured into MTBE and the mixture was filtered. The filter cake was collected and washed with acetonitrile and the acetonitrile containing phase was collected by filtration and concentrated to give the crude product. It was purified using preparative HPLC (colon

- 125 047011 ka: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 1242%, 21 min) and the title compound was obtained as a white solid. 1H NMR (400 MHz, MeOD) δ = 7.73 (s, 1H), 7.45 (s, 1H), 6.95 (s, 1H), 4.50 (td, J=7, 13.2 Hz, 1H), 4.31 (t, J=12 Hz, 1H), 3.91 (dd, J=4, 12 Hz, 2H), 3.47 (t, J=12 Hz, 2H), 2 .87 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.10-2.03 (m, 4H), 1.89 (d, J=13 Hz , 2H), 1.48 (d, J=7 Hz, 6H), 1.46-1.38 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 488.3.

Example 5. Sodium salt of 3-(1.2.3.5.6.7-hexahydro^-indacen-4-yl)-1-|(1-methylpiperidin-4-yl)|1(propan-2-yl)-1I-p-irazole -4-il| sulfamoyl]urea

N

CH ₃

Step 1: Na(1-isopropylpyrazol-4-yl)-1-methylpiperidin-4-amine. General Procedure A was followed and 1-isopropylpyrazol-4-amine and 1-methylpiperidin-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 0-20%, 21 min) to obtain the title compound in in the form of red oil. 1H NMR (400 MHz, CDCl ₃ ) δ = 7.13 (s, 1H), 6.98 (s, 1H), 4.42-4.31 (m, 1H), 2.93-2.77 ( m, 3H), 2.29 (s, 3H), 2.13-1.93 (m, 4H), 1.52-1.40 (m, 8H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4-yl)[1(propan-2-yl) )-1H-pyrazol-4-yl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and N-(1-isopropylpyrazol4-yl)-1-methylpiperidin- 4-amine The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 535%, 21 min) to obtain the title compound as a white solid . 1H NMR (400 MHz, MeOD) δ = 7.73 (s, 1H), 7.45 (s, 1H), 6.94 (s, 1H), 4.52-4.45 (m, J=7 Hz, 1H), 4.30-4.15 (m, 1H), 3.11 (d, J=19 Hz, 2H), 3.00 (s, 1H), 2.91-2.84 (m , 5H), 2.81 (t, J=8 Hz, 4H), 2.55 (s, 2H), 2.44 (s, 2H), 2.14-1.99 (m, 6H), 1 .58-1.49 (m, 2H), 1.47 (d, J=7 Hz, 6H), 1.22 (s, 2H), 1.20-1.11 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 501.2.

Example 6. Sodium salt of 1-[(1-ethyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydro^-indacene-4 -yl)urea

ABOUT

Step 1: 1-ethyl-N-tetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1-ethylpyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a red oil. 1H NMR (400 MHz, CDC13) δ = 7.16 (s, 1H), 7.00 (s, 1H), 4.15-4.04 (m, 2H), 4.04-3.96 (m , 2H), 3.493.35 (m, 2H), 3.13-3.04 (m, 1H), 2.03-1.94 (m, 2H), 1.52-1.40 (m, 5H ).

Step 2: sodium salt 1-[(1-ethyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydro^-indacene-4 -yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-ethyl-N-tetrahydropyran-4-ylpyrazol-4-amine were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mMNH ₄ HCO ₃ )-ACN]; B: 3-33%, 21 min) to obtain the title compound as white solid. 1H NMR (400 MHz, MeOD) δ = 7.75 (s, 1H), 7.44 (s, 1H), 6.98 (s, 1H), 4.40-4.28 (m, 1H), 4.21-4.15 (m, 2H), 3.90-3.93 (m, 2H), 3.47 (t, J=11 Hz, ZN), 2.922.84 (m, 4H), 2 .80 (t, J=7 Hz, 4H), 2.11-2.04 (m, 4H), 1.88 (d, J=10 Hz, 2H), 1.48-1.42 (m, 4H). LC-MS (ESI): m/z: [M+H]+ = 474.2.

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Example 7. Sodium salt of 1-[(1-ethyl-1H-pyrazol-4-yl)(1-methylpiperidin-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea

Step 1: Na(1-ethylpyrazol-4-yl)-1-methylpiperidin-4-amine. General Procedure A was followed and 1-ethylpyrazol-4-amine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250γ50 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 0-20%, 21 min) to obtain the title compound as a red oil .

Step 2: 1-[(1-ethyl-1H-pyrazol-4-yl)(1-methylpiperidin-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro-8) sodium salt -indacen-4-yl)urea. General procedure B was used and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and Na(1-ethylpyrazol-4-yl)1-methylpiperidin- 4-amine The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 6-36%, 21 min) to obtain the title compound as a white solid substances. 1H NMR (400 MHz, MeOH) δ = 7.72 (s, 1H), 7.45 (s, 1H), 6.95 (s, 1H), 4.29-4.20 (m, 1H), 4.18-4.12 (m, 2H), 3.13 (d, J=11 Hz, 2H), 2.87 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.60 (t, J=12 Hz, 2H), 2.47 (s, 3H), 2.12-2.02 (m, 6H), 1.60-1.47 (m , 2H), 1.44 (t, J=7 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 487.2.

Example 8. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(oxolan-3-yl) )sulfamoyl]urea

Step 1: 1-methyl-N-tetrahydrofuran-3-ylpyrazol-4-amine. General Procedure A was followed and 1-ethylpyrazol-4-amine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Agela Venusil XBP Phenyl 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 1-17%, 20 min) to obtain the title compound as a white solid.

Step 2: 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(oxolan-3-) sodium salt yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-tetrahydrofuran-3-ylpyrazol-4-amine were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 7-37%, 21 min) to obtain the title compound in as a white solid. ^1H NMR (400 MHz, MeOD) δ = 7.77 (s, 1H),

7.50 (s, 1H), 6.99 (s, 1H), 5.04-4.94 (m, 1H), 3.91 (d, J=3 Hz, 1H), 3.89 (s , 3H), 3.79-3.77 (m, 1H), 3.65-3.47 (m,

2H), 2.88 (t, J=8 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.28-2.22 (m, 1H), 2.10-2, 07 (m, 4H), 1.97-1.86 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 446.1.

Example 9. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-3 yl)(oxan-4- yl)sulfamoyl]urea

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Step 1: 1-methyl-N-tetrahydropyran-4-ylpyrazol-3-amine. General Procedure A was followed and 1-methylpyrazol-N-amine and tetrahydropyran-4-one were used to obtain the title compound as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.11 (s, 1H), 5.53 (s, 1H), 3.99 (d, J=11 Hz, 2H), 3.623.38 (m, 3H ), 2.37 (s, 1H), 2.05 (d, J=12 Hz, 2H), 1.58-1.39 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-3yl)(oxan-4-yl) )sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro-N-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-tetrahydropyran-4ylpyrazol-3-amine were used. The reaction mixture was poured into MTBE, filtered and the resulting solid was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 10-40% , 21 min) and obtained the desired compound in the form of a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 7.35 (d, J=2 Hz, 1H), 7.03 (s, 1H), 6.21 (d, J =2 Hz, 1H), 4.23 (s, 1H), 4.00-3.96 (m, 2H), 3.83 (s, 3H), 3.46 (t, J=12 Hz, 2H ), 2.95-2.78 (m, 8H), 2.142.04 (m, 4H), 1.98-1.95 (m, 2H), 1.75-1.64 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 460.2.

Example 10. Sodium salt of 1-[(1,5-dimethyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea

Step 1: 1,5-dimethyl-N-tetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1,5-dimethylpyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a white solid. LC-MS (ESI): m/z: [M+H]+= 196.2.

Step 2: sodium salt 1-[(1,5-dimethyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydro^-indacene -4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1,5-dimethyl-N-tetrahydropyran-4ylpyrazol-4-amine were used. The crude product was purified by preparative HPLC (column: YMCActus Triart C18 5 µm 100x30 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 18-38%, 55 min) to obtain the title compound as white solid matter. ^1H NMR (400 MHz, MeOD) δ 7.35 (s, 1H), 6.98 (s, 1H), 4.42 (t, J=12 Hz, 1H), 3.91 (d, J= 11 Hz, 2H), 3.80 (s, 3H), 3.50-3.43 (m, 2H), 2.88 (t, J=7 Hz, 4H), 2.79 (t, J= 7 Hz, 4H), 2.27 (s, 3H), 2.12-2.03 (m, 4H), 1.98-1.80 (m, 2H), 1.40 (s, 2H). LC-MS (ESI): m/z: [M+H]+ = 474.2.

Example 11. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)(1,3,5trimethyl-1H-pyrazole -4-yl)sulfamoyl]urea

Step 1: 1,3,5-trimethyl-N-tetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1,3,5-trimethylpyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a yellow oil. ¹ H NMR (400 MHz, DMSC46) δ ppm 4.17-4.10 (m, 1H), 3.83-3.79 (m, 2H), 3.55 (s, 3H), 3.25-3.18 (m, 2H), 2. 07 (s, 3H), 1.99 (s, 3H), 1.67-1.64 (m, 2H), 1.36-1.25 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)(1,3,5-trimethyl1H-pyrazole -4-yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1,3,5-trimethylpyrazol-4-amine were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 5-35%, 21 min) to obtain the title compound in as a white solid. ^1H NMR (400 MHz, MeOD) δ 6.98 (s, 1H), 4.58-4.49 (m, 1H), 3.92-3.88 (m, 2H), 3.72 (s , 3H), 3.46 (t, J=11 Hz, 2H), 2.88 (t, J=7 Hz, 4H), 2.77 (t, J=7 Hz, 4H), 2.25 ( s, 3H), 2.20 (s, 3H), 2.10-2.01 (m, 4H), 1.98-1.89 (m, 2H), 1.48-1.35 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 488.2.

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Example 12. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(5-methyl-1,2-oxazol-3yl)(oxan-4 -yl)sulfamoyl]urea

Step 1: 5-methyl-M-tetrahydropyran-4-ylisoxazol-3-amine. General Procedure A was followed and 5-methylisoxazol-N-amine and tetrahydropyran-4-one were used to obtain the title compound as a yellow oil. ¹ H NMR (400 MHz, CDCis) δ ppm 5.47 (s, 1H), 3.69 (d, J=7 Hz, 1H), 3.42-3.31 (m, 1H), 2.83 (d, J=11 Hz, 2H), 2.30 (s, 3H), 2.18-2.07 (m, 4H), 1.59-1.47 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(5-methyl-1,2-oxazol-3yl)(oxan-4 -yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 5-methyl-M-tetrahydropyran-4-ylisoxazol-3-amine were used. The crude product was purified by preparative HPLC (column: YMCActus Triart C18 5 µm 100x30 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 25-45%, 55 min) to obtain the title compound as white solid matter. 1H NMR (400 MHz, MeOD) δ 6.95 (s, 1H), 6.35 (s, 1H), 4.47-4.36 (m, 1H), 3.96-3.92 (m, 2H), 3.49-3.43 (m, 2H), 2.86 (t, J=8 Hz, 4H), 2.78 (t, J=7 Hz, 4H), 2.40 (s, 3H), 2.10-2.01 (m, 4H), 1.96-1.84 (m, 4H). LC-MS (ESI): m/z: [M+H]+ = 461.1.

Example 13. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)(1,2-oxazol-4yl)sulfamoyl ] urea

Step 1: n-tetrahydropyran-4-ylisoxazol-4-amine. General Procedure A was followed and isoxazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.05 (s, 1H), 7.96 (s, 1H), 4.02-3.97 (m, 2H), 3.49-3.43 (m, 2H), 3.14-3, 06 (m, 1H), 1.98 (d, J=14 Hz, 2H), 1.51-1.42 (m, 2H), 1.25 (s, 1H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)(1,2-oxazol-4yl)sulfamoyl ]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and n-tetrahydropyran-4-ylisoxazol-4-amine were used. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 5 µm 100x30 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 25-45%, 12 min) to obtain the desired compound as a white solid. 1H NMR (400 MHz, MeOD) δ 8.88 (s, 1H), 8.48 (s, 1H), 6.51 (s, 1H), 4.28-4.26 (m, 1H), 3 .98-3.91 (m, 2H), 3.48 (t, J=12 Hz, 2H), 2.80 (t, J=7 Hz, 4H), 2.70 (t, J=7 Hz , 4H), 2.10-2.01 (m, 4H), 1.87 (d, J=13 Hz, 2H), 1.47-1.42 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 447.1.

Example 14. Sodium salt of 1-[(1,5-dimethyl-III-pyrazol-4-yl)(1-methylpiperidin-4yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro) -indacen-4-yl)urea

Step 1: Na(1,5-dimethylpyrazol-4-yl)-1-methylpiperidin-4-amine. General Procedure A was followed and 1,5-dimethylpyrazol-4-amine and 1-methylpiperidin-4-one were used to obtain the title compound as a white solid. LC-MS (ESI): m/z: [M+H]+ = 209.3.

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Step 2: 1-[(1,5-dimethyl-1H-pyrazol-4-yl)(1-methylpiperidin-4-yl)sulfamoyl]-3(1.2.3.5.6.7-hexahydro^-indacene-4-) sodium salt silt)urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and Y(1.5-dimethylpyrazol4-yl)-1-methylpiperidin-4 were used -amine. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 5 µm 100x30 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 2040%, 55 min) to obtain the title compound in as a white solid.

1H NMR (400 MHz, MeOD) δ 7.36 (s, 1H), 6.95 (s, 1H), 4.37-4.27 (m, 1H), 3.76 (s, 3H), 3 .10 (d, J=12 Hz, 2H), 2.87 (t, J=8 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.65-2.50 (m , 2H), 2.45 (s, 3H), 2.26 (s, 3H), 2.10-2.03 (m, 6H), 1.47 (s, 2H). LC-MS (ESI): m/z: [M+H]+ = 487.2.

Example 15. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4yl) (1,3,5-trimethyl-1H -pyrazol-4-yl)sulfamoyl]urea

Step 1: 1-methyl-N(1,3,5-trimethylpyrazol-4-yl)piperidin-4-amine. General Procedure A was followed and 1,3,5-trimethylpyrazol-4-amine and 1-methylpiperidin-4-one were used to obtain the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.55 (s, 3H), 3.17 (s, 3H), 3.10 (d, J=12 Hz, 2H), 2.70-2.61 (m, 1H), 2.59-2 .52 (m, 2H), 2.07 (s, 3H), 1.99 (s, 2H), 2.01-1.99 (m, 1H), 1.80-1.74 (m, 2H ), 1.51-1.38 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4-yl) (1,3,5-trimethyl - 1H-pyrazol-4-yl)sulfamoyl]urea.

General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N(1,3,5-trimethylpyrazol-4- yl)piperidin-4-amine. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 6-36%, 21 min) to obtain the title compound as white solid matter. ^1H NMR (400 MHz, MeOD) δ 6.95 (s, 1H), 4.43 (t, J=12 Hz, 1H), 3.66 (s, 3H), 3.03 (d, J= 13 Hz, 2H), 2.87 (t, J=7 Hz, 4H), 2.79 (t, J=7 Hz, 4H), 2.44 (t, J=13 Hz, 2H), 2, 38 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.14-2.02 (m, 6H), 1.60-1.35 (m, 2H) . LC-MS (ESI): m/z: [M+H]+ = 501.2.

Example 16. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl) [(oxetan-3 - yl)methyl]sulfamoyl]urea

Step 1: 1-methyl-N(oxetan-3-ylmethyl)pyrazol-4-amine. General Procedure A was followed and 1-methylpyrazol-4-amine and oxetane-3-carbaldehyde were used to obtain the title compound as a red oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.12 (d, J=1 Hz, 1H), 6.93 (d, J=1 Hz, 1H), 4.86-4.83 (m, 2H), 4.45 (t, J=6 Hz, 2H), 3.82 (s, 3H), 3.32-3.27 (m, 2H), 3.26-3.14 (m, 1H ).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[(oxetan-3- yl)methyl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N(oxetan-3ylmethyl)pyrazol-4- amine. The crude product was purified by preparative HPLC (column: Phenomenex Luna. (2) C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 7-37%, 20 min) to obtain the desired compound as a white solid. ^1H NMR (400 MHz, MeOD) δ = 7.71 (s, 1H), 7.49 (s, 1H), 6.98 (s, 1H), 4.71-4.67 (m, 2H) , 4.39 (t, J=6 Hz, 2H), 4.06 (d, J=8 Hz, 2H), 3.86 (s, 3H), 3.22-3.10 (m, 1H) , 2.87 (t, J=7 Hz, 4H), 2.76 (t, J=7 Hz, 4H), 2.11-2.04 (m, 4H). LC-MS (ESI): m/z: [M+H]+ = 446.1.

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Example 17. Sodium salt of 3-(1.2.3.5.6.7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)(pyrimidin-5yl)sulfamoyl]urea

Step 1: n-tetrahydropyran-4-ylpyrimidin-5-amine. General Procedure A was followed and 1-methylpyrazol-4-amine and oxetane-3-carbaldehyde were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 5-35%, 21 min) to obtain the title compound in as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ = 8.58 (s, 1H), 8.12 (s, 2H), 4.07-3.98 (m, 3H), 3.86-3.64 (m, 2H), 3.58-3.46 (m, 4H), 2.04 (d, J=13 Hz, 2H), 1.81 (s, 3H), 1.59-1.46 ( m, 3H).

Step 2: sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)(pyrimidin-5yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and n-tetrahydropyran-4-ylpyrimidin-5-amine were used. The reaction mixture was poured into MTBE and filtered. The filter cake was collected and washed with acetonitrile, and then the acetonitrile-containing phase was concentrated to give the crude product. It was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 15-40%, 21 min) to obtain the title compound as white solid. ^1H NMR (400 MHz, MeOD) δ = 9.15 (s, 1H), 8.77 (s, 2H), 6.97 (s, 1H), 4.44 (t, J=12 Hz, 1H ), 3.95-3.91 (m, 2H), 3.48 (t, J=12 Hz, 2H), 2.94-2.75 (m, 8H), 2.13-1.94 ( m, 6H), 1.45-1.28 (m, 2H). LC-MS (ESI): m/z: [M+H]+ 458.2.

Example 18. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(3-methyl-1,2-oxazol-5yl)(oxan-4 -yl)sulfamoyl]urea

Step 1: 3-methyl-H-tetrahydropyran-4-ylisoxazol-5-amine. General Procedure A was followed and 1-methylpyrazol-4-amine and oxetane-3-carbaldehyde were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1%TFA) - ACN]; B: 0-30%, 20 min) to obtain the title compound as yellow oil. LC-MS (ESI): m/z: [M+H]+ = 183.2.

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(3-methyl-1,2-oxazol-5yl)(oxan-4 -yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 3-methyl-N-tetrahydropyran-4-ylisoxazol-5-amine were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 10-40%, 20 min) to obtain the title compound in as a white solid. ¹ H NMR (400 MHz, MeOD) δ ppm 6.90 (s, 1H), 6.15 (s, 1H), 4.42-4.32 (m, 1H), 3.96-3.92 (m, 2H), 3.51-3, 46 (m, 2H), 2.85 (t, J=7 Hz, 4H), 2.79 (t, J=7 Hz, 4H), 2.24 (s, 3H), 2.07-1, 93 (m, 6H), 1.79-1.67 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 461.1.

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Example 19. Sodium salt of 3-(1,2,3,5,6,7-hexahydrooindacen-4-yl)-1-|(1-methyl-1H-1,2,4-triazol3-yl)(oxan- 4-yl)sulfamoyl]urea

Step 1: 1-methylA-tetrahydropyran-4-yl-1.2.4-triazol-3-amine. General Procedure A was followed and 1-methyl-1.2.4-triazoloamine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.l%TFA) - ACN]; B: 0-15%, 20 min) to obtain the title compound as white solid. 1H NMR (400 MHz, MeOD) δ = 8.62 (s, 1H), 3.97-3.94 (m, 2H), 3.81 (s, 3H), 3.63-3.60 (m , 1H), 3.52-3.47 (m, 2H), 2.02-1.97 (m, 2H), 1.60-1.55 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 183.3.

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-1,2,4-triazol-3yl) (oxan-4-yl)sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-tetrahydropyran-4-yl1,2,4- triazol-3-amine. The crude product was diluted with ACN (20 ml), then the solvent was filtered under reduced pressure and the filtrate was collected. The mixture was diluted with ACN (20 ml), then the solvent was filtered under reduced pressure and the filtrate was evaporated to obtain the title compound as a white solid. 'H NMR (400 MHz, MeOD) δ = 7.89 (s, 1H), 7.03-6.81 (m, 1H), 4.31 (s, 1H), 3.95 (d, J= 10 Hz, 2H), 3.74 (s, 2H), 3.48 (s, 3H), 2.85-2.67 (m, 10H), 2.05-1.80 (m, 4H), 1.90 (s, 2H). LC-MS (ESI): m/z: [M+H]+ = 461.2.

Example 20. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-3yl)(1-methylpiperidin-4 -yl)sulfamoyl]urea

CH ₃

Step 1: 1-methyl-N-(1-methylpyrazol-3-yl) piperidin-4-amine. General Procedure A was followed and 1-methylpyrazol-N-amine and 1-methylpiperidin-4-one were used to obtain the title compound as a yellow oil. Ί1 NMR (400 MHz, CDCl ₃ ) δ = 7.10 (d, J=2 Hz, 1H), 5.52 (d, J=2 Hz, 1H), 3.71-3.58 (m, 3H ), 3.36 (s, 1H), 2.98 (d, J=12 Hz, 2H), 2.44 (s, 3H), 2.17-2.12 (m, 6H), 1.69 -1.60 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 195.4.

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-3-yl)(1methylpiperidin-4 -yl)sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-(1-methylpyrazol-3-yl) were used ) piperidine-4-amine. The mixture was diluted with acetonitrile, filtered under reduced pressure and the filtrate was concentrated to give the crude product. It was purified by preparative HPLC (column: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) ACN]; B: 5-35%, 20 min) and the title compound was obtained as white solid matter. ¹ H NMR (400 MHz, MeOD) δ = 7.51 (d, J=2 Hz, 1H), 6.90 (s, 1H), 6.25 (d, J=2 Hz, 1H), 4, 20-4.10 (m, 1H), 3.81 (s, 3H), 3.68 (s, 1H), 3.02-2.88 (m, 2H), 2.86-2.80 ( m, 8H), 2.39-2.35 (m, 5H), 2.09-2.03 (m, 6H), 1.68-1.66 (m, 2H).

LC-MS (ESI): m/z: [M+H]+ = 473.3.

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Example 21. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-ivdacen-4-yl)-1-[(1-methyl-III-imvdazol-4yl)(oxan-4-yl) )sulfamoyl]urea

Step 1: 1-methyl-4-nitroimidazole. To a solution of 4-nitro-1H-imidazole (5.0 g, 44 mmol, 1 eq.) in ACN (50 ml) was added K ₂ CO ₃ (9.17 g, 66 mmol). Methyl iodide (7.53 g, 53 mmol, 3.30 ml) was slowly added to the mixture at RT, then the mixture was heated at 60°C for 14 hours. The solvent was removed under reduced pressure, then the residue was diluted with water (30 ml), extracted with DCM (5x30 ml) and the combined organic layers were dried over Na ₂ SO ₄ . The organic phase was concentrated in vacuo to give the title compound as a yellow solid. 1H NMR (400 MHz, _DMSOd6 ) δ = 8.35 (s, 1H), 7.80 (s, 1H), 3.75 (s, 3H).

Step 2: 1-methylimidazol-4-amine. To a solution of 1-methyl-4-nitroimidazole (2 g, 15.7 mmol, 1 eq.) in MeOH (100 ml) was added 10% Pd/C (1 g, 15.7 mmol) under H ₂ atmosphere. The mixture was stirred under H ₂ ( ¹⁵ psi) at 25°C for 1 hour. The mixture was diluted with MeOH (50 ml) and filtered under reduced pressure. The filtrate was evaporated to obtain the title compound as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ = 7.03 (s, 1H), 6.17 (s, 1H), 3.60-3.10 (m, 5H).

Step 3: 1-methyl-N-tetrahydropyran-4-ylimidazol-4-amine. General Procedure A was followed and 1-methylimidazol-4-amine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1%TFA) - ACN]; B: 0-10%, 20 min) to obtain the title compound as yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ = 7.82-7.76 (m, 1H), 6.03 (s, 1H), 4.01-3.96 (m, 2H), 3.76 ( s, 3H), 3.50-3.47 (m, 2H), 3.453.13 (m, 1H), 1.96 (d, J = 13 Hz, 2H), 1.69-1.61 (m , 2H). LC-MS (ESI): m/z: [M+H]+ = 182.4.

Step 4: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-III-imidazol-4yl)(oxan-4-yl) )sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-tetrahydropyran-4-ylimidazol-4-amine were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 15-40%, 21 min) to obtain the title compound as a white solid substances. LC-MS (ESI): m/z: [M+H]+ = 460.2.

Example 22. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-III-pyrazol-4yl)(oxan-3-yl) )sulfamoyl]urea

Step 1: 1-Methyl-H-tetrahydropyran-3-ylpyrazol-4-amine General Procedure A was followed and 1-methylpyrazol-4-amine and tetrahydropyran-3-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 0-30%, 21 min) to obtain the title compound as a red oil . 1H NMR (400 MHz, chloroform-d) δ = 7.12 (s, 1H), 6.93 (s, 1H), 3.92 (d, J=11 Hz, 1H), 3.81 (s, 3H), 3.77-3.68 (m, 1H), 3.59-3.48 (m, 1H), 3.38-3.30 (m, 1H), 3.12-3.01 ( br. s, 1H), 2.04-1.92 (m, 1H), 1.80-1.68 (m, 1H), 1.671.48 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(oxan-3- yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-tetrahydropyran-3 ylpyrazol-4-amine were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 7-37%, 21 min) to obtain the title compound as a white solid substances. 1H NMR (400 MHz, MeOD) δ = 7.68 (s, 1H), 7.40 (s, 1H), 6.98 (s, 1H), 4.26-4.13 (m, 1H), 4.12-4.06 m, 1H), 3.88 (s, 3H), 3.79-3.71 (m, 1H),

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3.13-3.04 (m, 2H), 2.88 (t, J=8 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.12-2.04 (m , 5H), 1.79-1.60 (m, 2H), 1.39-1.26 (m, 1H).

LC-MS (ESI): m/z: [M+H]+ = 460.1.

Example 23. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-|(1-methyl-1H-pyrazol-4yl)(1-methylpiperidin-3 -yl)sulfamoyl]urea

Step 1: 1-methyl^-(1-methylpyrazol-4-yl)piperidin-3-amine. General Procedure A was followed and 1-methylpyrazol-4-amine and 1-methylpiperidin-3-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 0-25%, 20 min) to obtain the title compound in in the form of red oil. 1H NMR (400 MHz, CDC13) δ = 7.10 (s, 1H), 6.91 (s, 1H), 3.79 (s, 3H), 3.19-3.09 (m, 1H), 2.81-2.70 (br.s, 1H), 2.56-2.40 (br.s, 1H), 2.26 (s, 3H), 1.87-1.66 (m, 2H ), 1.64-1.48 (m, 1H), 1.41-1.22 (m, 1H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)(1methylpiperidin- 3-yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1 -methyl-N-i 1 methylpyrazol-4-yl)piperidin- 3-amine The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) ACN]; B: 15-40%, 21 min) to obtain the title compound as a white solid . 1H NMR (400 MHz, MeOD) δ = 7.66 (s, 1H), 7.43 (s, 1H), 6.94 (s, 1H), 4.36-4.28 (m, 1H), 3.87 (s, 3H), 3.52-3.41 (m, 1H), 3.05-3.00 (m, 1H), 2.87 (t, J=7.3 Hz, 4H) , 2.81 (t, J=7 Hz, 4H), 2.55 (s, 3H), 2.40-2.16 (m, 2H), 2.11-1.99 (m, 5H), 1.92-1.81 (m, 1H), 1.80-1.66 (m, 1H), 1.28-1.12 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 473.2.

Example 24. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(1-methylpyrrolidin-3 -yl)sulfamoyl]urea

dn ₃

Step 1: tert-butyl 3-[(1-methylpyrazol-4-yl)amino]pyrrolidine-1-carboxylate. To a solution of 1methylpyrazol-4-amine (1.0 g, 10.3 mmol, 1 eq.) and tert-butyl-3-oxopyrrolidine-1-carboxylate (1.91 g, 10.3 mmol, 1 eq.) in DCM (10 ml) and CH3COOH (1 ml) NaBH ₃ CN (0.97 g, 15.5 mmol, 1.5 eq.) was added. The mixture was stirred at RT for 3 hours and then concentrated in vacuo. Water (10 ml) was added and the aqueous phase was extracted with ethyl acetate (3x30 ml). The combined organic phases were washed with brine (3x10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc in petroleum ether) to give the title compound as a red oil. 1H NMR (400 MHz, CDCl ₃ ) δ = 7.12 (s, 1H), 6.93 (s, 1H), 3.81 (s, 3H), 3.73-3.68 (br.s, 1H), 3.65-3.14 (m, 5H), 2.14-2.06 (m, 1H), 1.87-1.80 (br. s, 1H), 1.45 (s, 9H).

Step 2: 1-methyl-N(1-methylpyrrolidin-3-yl)pyrazol-4-amine. To a solution of tert-butyl-3-[(1methylpyrazol-4-yl)amino]pyrrolidine-1-carboxylate (810 mg, 3.04 mmol, 1 eq.) in THF (20 mL) was added lithium aluminum hydride (0.58 g , 15.2 mmol, 5 equiv.). The mixture was stirred at 70°C for 2 hours then the reaction was stopped by adding H ₂ O (3 ml) at 0°C. The reaction mixture was diluted with 10% NaOH (3 ml), filtered and the filtrate was concentrated under reduced pressure to give the title compound as a red oil, which was used without treatment.

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)(1methylpyrrolidin- 3-yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N(1-methylpyrrolidin-3-yl) were used. pyrazol-4-amine. The crude product was purified by preparative HPLC (column: Agela Durashell C18 5 µm 150x25 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; V: 14

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44%, 10 min) and obtained the desired compound in the form of a white solid. 1H NMR (400 MHz, MeOD) δ = 7.71 (s, 1H), 7.49 (s, 1H), 6.92 (s, 1H), 4.98-4.90 (m, 1H), 3.87 (s, 3H), 3.42-3.34 (m, 2H), 3.05-2.98 (m, 2H), 2.86 (t, J=7 Hz, 4H), 2 .79 (t, J=7 Hz, 4H), 2.67 (s, 3H), 2.40-2.25 (m, 1H), 2.11-1.96 (m, 5H). LC-MS (ESI): m/z: [M+H]+ = 459.1.

Example 25. 1-{[1-(Difluoromethyl)-1H-pyrazol-4-yl](oxan-4-yl)sulfamoyl}-3(1.2.3.5.6.7-hexahydroch-indacen-4-yl)urea sodium salt

Step 1: 1-(difluoromethyl)-4-nitropyrazole. To a solution of 4-nitro-1H-pyrazole (2.0 g, 17.7 mmol) in DMF (20 ml) was added Cs ₂ CO ₃ (5.76 g, 17.7 mmol), then the mixture was stirred at 120°C within 5 min. (2-Chloro-2,2-difluoroacetyl)oxysodium (5.39 g, 35.4 mmol) was added to the mixture portionwise over 20 minutes. The mixture was stirred at 120°C for 10 minutes. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were combined and washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to leave a residue. The residue was purified with FCC (5-20% petroleum ether in ethyl acetate) to give the title compound as a light yellow oil (Y=17%). 1H NMR (400 MHz, chloroform-d) δ ppm 8.58 (s, 1H), 8.22 (s, 1H), 7.22 (t, J=60 Hz, 1H).

Step 2: 1-(difluoromethyl)pyrazol-4-amine. To a solution of 1-(difluoromethyl)-4-nitropyrazole (0.5 g, 3.07 mmol) in MeOH (10 ml) was added 10% Pd/C (100 mg) under N ₂ atmosphere. The suspension was degassed and purged several times with H ₂ . The mixture was stirred under H ₂ (15 psi) at ²⁵ ° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a light brown oil, which was used without further treatment. purification (Y=98%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.31 (s, 2H), 7.05 (t, J=60 Hz, 1H), 3.30-2.94 (br s., 2H).

Step 3: 1-(difluoromethyl)-H-tetrahydropyran-4-ylpyrazol-4-amine trifluoroacetate. To a solution of 1(difluoromethyl)pyrazol-4-amine (400 mg, 3.01 mmol) in DCM (6 mL) was added tetrahydropyran-4-one (276 μL, 3.01 mmol) and AcOH (0.70 mL, 12 .24 mmol). The mixture was stirred at RT for 1 hour. NaBH ₃ CN (378 mg, 6.02 mmol) was added and the mixture was stirred at RT for 12 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Acchrom C18ME 7 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-15%, 23 min) to obtain the title compound as a white solid substances (Y=40%). 1H NMR (400 MHz, CD3OD) δ ppm 8.37 (s, 1H), 7.89 (s, 1H), 7.54 (t, J=59 Hz, 1H), 4.03 (dd, J=4, 12 Hz, 2H), 3, 65-3.59 (m, 1H), 3.48-3.38 (m, 2H), 2.02-1.92 (m, 2H), 1.72-1.66 (m, 2H).

Step 4: sodium salt 1-{[1-(difluoromethyl)-1H-pyrazol-4-yl](oxan-4-yl)sulfamoyl}-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-(difluoromethyl)-Ntetrahydropyran-4-ylpyrazol-4- amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 2-35%, 20 min) to obtain the title compound in as a white solid (Y=4%). 1H NMR (400 MHz, methanol^) δ ppm 8.08 (s, 1H), 7.68 (s, 1H), 7.58-7.29 (m, 1H), 6.91 (s, 1H), 4.28-4.25 (m, 1H), 3.95-3.87 (m, 2H), 3.51-3.45 (m, 2H), 2.90-2.72 (m, 8H), 2.10-1.98 ( m, 4H), 1.96-1.89 (m, 2H), 1.44-1.36 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 496.2.

Example 26. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)[1-(2,2,2trifluoroethyl) -1H-pyrazol-4-yl]sulfamoyl]urea

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Step 1: 4-nitro-1-(2,2,2-trifluoroethyl)pyrazole. To a solution of 4-nitro-N-pyrazole (5.0 g, 44.2 mmol) in DMF (50 ml) was added 1,1,1-trifluoro-2-iodoethane (6.51 ml, 66.3 mmol) and Cs ₂ CO ₃ (17.3 g, 53.1 mmol), then the mixture was stirred at 60°C for 18 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3x30 ml). The organic layers were combined and washed with brine (10 ml), dried over Na ₂ SO ₄ and evaporated. The residue was purified with FCC (9-20% EtOAc in petroleum ether) to give the title compound as a light yellow solid (Y=30%). ¹ H NMR (400 MHz, chloroform-d) δ = 8.30 (s, 1H), 8.16 (s, 1H), 4.77 (sq, J=8 Hz, 2H).

Step 2: 1-(2,2,2-trifluoroethyl)pyrazol-4-amine. To a solution of 4-nitro-1-(2,2,2-trifluoroethyl)pyrazole (2.0 g, 10.25 mmol) in MeOH (30 ml) was added 10% Pd/C (200 mg) under N2 atmosphere. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ atmosphere at RT for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a red-brown oil (Y=100%). ¹ H NMR (400 MHz, chloroform-d) δ = 7.21 (s, 1H), 7.07 (s, 1H), 4.54 (sq, J=9 Hz, 2H), 3.41 (s , 2H).

Step 3: n-tetrahydropyran-4-yl-1-(2,2,2-trifluoroethyl)pyrazole-4-amine trifluoroacetate. General Procedure A was followed and 1-(2,2,2-trifluoroethyl)pyrazol-4-amine and tetrahydropyran-4-one were used. The crude material was purified by preparative HPLC (column: C18, mobile phase: [water (0.1% TFA) - ACN]) to obtain the title compound as a white solid (Y=27%). 1H NMR (400 MHz, meganol-f) δ = 8.15 (s, 1H), 7.78 (s, 1H), 5.02 (q, J=9 Hz, 2H), 4.03 (dd, J=4, 12 Hz, 2H), 3.663.58 (m, 1H), 3.45-3.39 (m, 2H), 1.97-1.93 (m, 2H), 1.73-1 .63 (m, 2H).

Step 4: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)[1-(2,2,2trifluoroethyl) -SH-pyrazol-4-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and n-tetrahydropyran-4-yl1-(2,2,2 -trifluoroethyl)pyrazole-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM ammonium carbonate) - ACN]; B: 5-35%, 20 min) to obtain the title compound as a white solid substances (Y=5%). 1H NMR (400 MHz, methanol^) δ = 7.88 (s, 1H), 7.55 (s, 1H), 6.96 (s, 1H), 4.95 (sq, J=9 Hz, 2H ), 4.38-4.26 (m, 1H), 3.94-3.89 (m, 2H), 3.51-3.45 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.11-2.03 (m, 4H), 1.95-1.85 (m, 2H), 1.49-1 .39 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 528.1.

Example 27. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-{[1-(methoxymethyl)-1Hpyrazol-4-yl](oxan-4 -yl)sulfamoyl}urea

Step 1: 1-(methoxymethyl)-4-nitropyrazole. To a solution of 4-nitro-N-pyrazole (5.0 g, 44.2 mmol) in THF (50 mL) was added sodium methoxide (2.87 g, 53.1 mmol) in portions. The RM was stirred at RT for 30 min, then chloro(methoxy)methane (4.03 mL, 53.1 mmol) was added dropwise. The RM was stirred at RT for 15 hours. The mixture was diluted with EtOAc (100 ml) and water (50 ml). The aqueous layer was separated and extracted with EtOAc (2x30 ml) and the combined organic layers were washed with brine (20 ml) and dried over Na ₂ SO ₄ The residue was purified with FCC (9-20% EtOAc in petroleum ether) to give the title compound as white solid (Y=76%). 1H NMR (400 MHz, chloroform-d) δ = 8.32 (s, 1H), 8.13 (s, 1H), 5.43 (s, 2H), 3.42 (s, 3H).

Step 2: 1-(methoxymethyl)pyrazol-4-amine. To a solution of 1-(methoxymethyl)-4-nitropyrazole (3.0 g, 19.1 mmol) in MeOH (50 ml) was added 10% Pd/C (300 mg) under N2. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ (15 ^psi ) at RT for 3 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound as a red-brown oil (Y=99%). 1H NMR (400 MHz, chloroform-d) δ = 7.20 (s, 1H), 7.13 (s, 1H), 5.23 (s, 2H), 3.27 (s, 3H), 2. 98 (s, 2H).

Step 3: 1-(methoxymethyl)-H-tetrahydropyran-4-ylpyrazol-4-amine acetate. General Procedure A was followed and 1-(methoxymethyl)pyrazol-4-amine and tetrahydropyran-4-one were used. The crude material was purified by preparative HPLC (column: Acchrom C18ME 7 µm 250x50 mm, mobile phase: [water (0.1% TFA) - ACN]; B: 1-30%, 23 min) to obtain the title compound as white solid (Y=47%). 1H NMR (400 MHz, meganol-f) δ = 8.18 (s, 1H), 7.77 (s, 1H), 5.44 (s, 2H), 4.03 (dd, J=5, 12 Hz, 2H), 3.68-3.60 (m, 1H), 3.45-3.33 (m, 2H), 3.33 (s, 3H), 1.96 (dd, J=2, 12 Hz, 2H), 1.75-1.64 (m, 2H).

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Step 4: 3-(1.2.3.5.6.7-hexahydro^-indacen-4-yl)-1-{[1-(methoxymethyl)-1Hpyrazol-4-yl](oxan-4-yl)sulfamoyl}urea sodium salt . General procedure B was used and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl|amino;sul(|unyl chloride and 1-(methoxymethyl)-Ntetrahydropyran-4-ylpyrazole -4-Aminacetate The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM ammonium carbonate) ACN]; B: 2-35%, 20 min) to obtain the title compound. as a white solid (Y=7%). 1H NMR (400 MHz, methanol^) δ =7.91 (s, 1H), 7.54 (s, 1H), 6.97 (s, 1H), 5.38 (s, 2H), 4.38-4.28 (m, 1H), 3.92 (dd, J=4, 11 Hz, 2H), 3.48 (t, J=11 Hz, 2H ), 3.36-3.31 (m, 3H), 2.88 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.092.04 (m, 4H ), 1.95-1.85 (m, 2H), 1.50-1.40 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 490.1.

Example 28. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-{[1-(methoxymethyl)-1Hpyrazol-4-yl] (1-methylpiperidine -4-yl)sulfamoyl}urea

Step 1: N[1-(methoxymethyl)pyrazol-4-yl]-1-methylpiperidin-4-amine trifluoroacetate. General Procedure A was followed and 1-(methoxymethyl)pyrazol-4-amine (synthesis described in Example 27) and 1-methylpiperidin-4-one were used. The crude material was purified by preparative HPLC (column: Acchrom C18ME 7 µm 250x50 mm, mobile phase: [water (0.1% TFA) - ACN]; B: 1-20%, 23 min) to obtain the title compound as white solid (Y=38%). ^1H NMR (400 MHz, methanol- _f4 ) δ = 7.68 (s, 1H), 7.45 (s, 1H), 5.33 (s, 2H), 3.64-3.56 (m , 2H), 3.35-3.26 (m, 3H), 3.09 (t, J=13 Hz, 2H), 2.88 (s, 3H), 2.34-2.24 (m, 2H), 2.12-2.00 (br. s, 1H), 1.80-1.71 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-{[1-(methoxymethyl)-1Hpyrazol-4-yl](1-methylpiperidine -4-yl)sulfamoyl}urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and Na[1-(methoxymethyl)pyrazol-4-yl]- 1-Methylpiperidine-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM ammonium carbonate) - ACN]; B: 2-35%, 20 min) to obtain the title compound as a white solid substances (Y=13%). ^! H NMR (400 MHz, methanol-f) δ = 7.89 (s, 1H), 7.54 (s, 1H), 6.95 (s, 1H), 5.36 (s, 2H), 4, 32-4.25 (m, 1H), 3.33 (s, 3H), 3.18 (d, J=12 Hz, 2H), 2.87 (t, J=7 Hz, 4H), 2, 80 (t, J=7 Hz, 4H), 2.72-2.64 (m, 2H), 2.51 (s, 3H), 2.14-2.03 (m, 6H), 1.61 -1.51 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 503.2.

Example 29. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-{[1-(2-methoxyethyl)-1Hpyrazol-4-yl](oxane -4-yl)sulfamoyl}urea

Step 1: 1-(2-methoxyethyl)-4-nitropyrazole. To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in CH ₃ CN (100 ml) was added 1-bromo-2-methoxyethane (4.15 ml, 44.2 mmol, 4.15 ml) and K ₂ CO ₃ (12.22 g, 88.4 mmol). The mixture was stirred at 80°C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3x50 ml), the organic layers were combined and washed with brine (20 ml), dried over Na ₂ SO ₄ , and concentrated. The resulting residue was purified using FCC (10-25% petroleum ether in ethyl acetate) to give the title compound as a colorless oil (Y=79%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.24 (s, 1H), 8.08 (s, 1H), 4.32 (t, J=5 Hz, 2H), 3.75 (t, J=5 Hz, 2H), 3.36 ( s, 3H).

Step 2: 1-(2-methoxyethyl)pyrazol-4-amine. To a solution of 1-(2-methoxyethyl)-4-nitropyrazole (3.0 g, 17.53 mmol) in MeOH (50 ml) was added 10% Pd/C (300 mg) under N2 atmosphere. The suspension was degassed and purged several times with H ₂ . The mixture was stirred under H ₂ atmosphere at 25°C for 3 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give

- 137 047011 the desired compound in the form of red oil (Y=97%). 'H NMR (400 MHz, chloroform-d) δ ppm 7.16 (s, 1H), 7.09 (s, 1H), 4.16 (t, J=5 Hz, 2H), 3.69 (t, J=5 Hz, 2H), 3.32 ( s, 3H), 2.93-2.83 (br. s, 2H).

Step 3: 1-(2-methoxyethyl)-H-tetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1-(2-methoxyethyl)pyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a pale brown oil. (Y=50%). 1H NMR (400 MHz, methanol-dp δ ppm 8.00 (s, 1H), 7.68 (s, 1H), 4.34 (t, J=5 Hz, 2H), 4.03 ( dd, J=4, 12 Hz, 2H), 3.74 (t, J=5 Hz, 2H), 3.68-3.55 (m, 1H), 3.42 (t, J=12 Hz, 2H), 3.31 (s, 3H), 2.00-1.90 (m, 2H), 1.75-1.61 (m, 2H).

Step 4: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-{[1-(2-methoxyethyl)-1Hpyrazol-4-yl](oxane -4-yl)sulfamoyl}urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-(2-methoxyethyl)-Ntetrahydropyran-4-ylpyrazol- 4-amine The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ ) - ACN]; B: 333%, 20 min) to obtain the title compound as a white solid (Y=10%). 1H NMR (400 MHz, methanol-dp δ ppm 7.67 (s, 1H), 7.45 (s, 1H), 6.90 (s, 1H), 4.33-4.19 (m , 3H), 3.90 (dd, J=4, 11 Hz, 2H), 3.71 (t, J=5 Hz, 2H), 3.47 (t, J=11 Hz, 2H), 3, 29 (s, 3H), 2.92-2.75 (m, 8H), 2.11-2.00 (m, 4H), 1.91 (d, J=11 Hz, 2H), 1.44 -1.41 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 504.2.

Example 30. Sodium salt 1-{[1-(cyanomethyl)-1H-pyrazol-4-yl](oxan-4-yl)sulfamoyl}-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea

Step 1: 2-(4-nitropyrazol-1-yl)acetonitrile. To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in DMF (50 ml) was added 2-bromoacetonitrile (5.89 ml, 88.4 mmol) and K ₂ CO ₃ (18.3 g, 133 mmol), then the mixture was stirred at 80°C for 5 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified with FCC (9-25% EtOAc in petroleum ether) to give the title compound as a light brown solid (Y=89%). 1H NMR (400 MHz, chloroform-d) δ ppm 8.36 (s, 1H), 8.17 (s, 1H), 5.15 (s, 2H).

Step 2: 2-(4-aminopyrazol-1-yl)acetonitrile. A mixture of 2-(4-nitropyrazol-1-yl)acetonitrile (6.0 g, 39.4 mmol), Fe (8.8 g, 158 mmol) and NH ₄ Cl (8.4 g, 158 mmol) in MeOH (120 ml) and H ₂ O (20 ml) were stirred at 80°C for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified with FCC (5-17% MeOH in DCM) to give the title compound as a brown solid (Y=87%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.24 (s, 1H), 7.10 (s, 1H), 4.95 (s, 2H), 3.02 (s, 2H).

Step 3: 2-[4-(tetrahydropyran-4-ylamino)pyrazol-1-yl]acetonitrile. General Procedure A was followed and 2-(4-aminopyrazol-1-yl)acetonitrile and tetrahydropyran-4-one were used to obtain the title compound as a colorless oil (Y=59%). 1H NMR (400 MHz, methanol-dp δ ppm 7.31 (s, 1H), 7.27 (s, 1H), 5.16 (s, 2H), 3.99-3.92 (m , 2H), 3.52-3.42 (m, 2H), 3.15-3.06 (m, 1H), 1.98-1.91 (m, 2H), 1.50-1.37 (m, 2H).

Step 4: sodium salt 1-{[1-(cyanomethyl)-1H-pyrazol-4-yl](oxan-4-yl)sulfamoyl}-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 2-[4-(tetrahydropyran-4ylamino)pyrazol-1- yl]acetonitrile. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 333%, 20 min) to obtain the title compound as a white solid ( Y=13%). 1H NMR (400 MHz, methanol-dp δ ppm 7.90 (s, 1H), 7.56 (s, 1H), 6.99 (s, 1H), 5.34 (s, 2H), 4.42-4.27 (m, 1H), 3.96-3.88 (m, 2H), 3.48 (t, J=12 Hz, 2H), 2.88 (t, J=7 Hz , 4H), 2.80 (t, J=7 Hz, 4H), 2.13-2.04 (m, 4H), 1.92-1.85 (m, 2H), 1.53-1, 38 (m, 2H). LC-MS (ESI): m/z: [M+H]+= 485.2.

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Example 31. Sodium salt of CN^cyanomethylHS-pyrazol^-ylKSmethylpiperidin^yl)sulfamoyl}-3 -(1,2,3,5,6,7-hexahydro^-indacen-4-yl)urea

Step 1: 2-[4-[(1-methyl-4-piperidyl)amino]pyrazol-1-yl]acetonitrile trifluoroacetate. General Procedure A was followed and 2-(4-aminopyrazol-1-yl)acetonitrile (synthesis described in Example 30) and 1-methylpiperidin-4-one were used to obtain the title compound as a white solid (Y=48%). 'H NMR (400 MHz, methanol^) δ ppm 7.77 (s, 1H), 7.56 (s, 1H), 5.29 (s, 2H), 3.65-3.57 (m, 2H), 3.53-3.42 (m, 1H), 3.14-3.04 (m, 2H), 2.87 (s, 3H), 2.34-2.24 (m, 2H), 1.92-1.75 (m, 2H) .

Stage 2: sodium salt of HSH^cyanomethyl^III-pyrazol^-ylKSmethylpiperidin^yl)sulfamoyl}-3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 2-[4-[(1methyl-4-piperidyl)amino were used ]pyrazol-1-yl]acetonitrile trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 5-35%, 20 min) to obtain the title compound in as a white solid (Y=8%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.87 (s, 1H), 7.56 (s, 1H), 6.96 (s, 1H), 5.31 (s, 2H), 4.39-4.26 (m, 1H), 3 .29-3.20 (m, 2H), 2.95-2.75 (m, 10H), 2.59 (s, 3H), 2.20-1.95 (m, 6H), 1.65 -1.50 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 498.2.

Example 32. Sodium salt of 1-[(1-ethylpiperidin-4-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea

Step 1: 1-ethylA-(1-methylpyrazol-4-yl)piperidin-4-amine trifluoroacetate. To a solution of 1methylpyrazol-4-amine (1 g, 10.3 mmol) in DCM (10 ml) was added 1-ethylpiperidin-4-one (1.63 ml, 12.4 mmol) and AcOH (2.0 ml, 35 mmol). The mixture was stirred at RT for 1 hour, then NaBH ₃ CN (1.29 g, 20.6 mmol) was added. The mixture was stirred at RT for another 12 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Acchrom C18ME 7µm, 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-30%, 23 min) to obtain the title compound as a yellow oil (Y=69%). 'H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.87 (s, 1H), 7.59 (s, 1H), 3.91 (s, 3H), 3.72-3.59 (m, 3H), 3.22-3.16 (m, 2H), 3.08-2.98 (m, 2H), 2.35-2.27 (m, 2H), 2.01-1.90 (m, 2H), 1.34 (t, J= 7 Hz, 3H).

Step 2: 1-[(1-ethylpiperidin-4-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1.2.3.5.6.7-hexahydroch-indacen-4-yl)urea sodium salt . General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-ethyl-N-(1-methylpyrazol-4-yl ) piperidine-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150γ40 10 µm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 5-35%, 11 min) to obtain the title compound as white solid (Y=3%). '11 NMR (400 MHz, methanol^) δ ppm 7.67 (s, 1H), 7.43 (s, 1H), 6.93 (s, 1H), 4.32-4.26 (m, 1H), 3.85 (s, 3H), 2 .88-2.83 (m, 6H), 2.82-2.78 (m, 6H), 2.77-2.66 (m, 2H), 2.22-2.03 (m, 6H) , 1.62-1.51 (m, 2H), 1.17 (t, J=7 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 487.2.

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Example 33. Sodium salt of 3-(1.2.3.5.6.7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[1-(propan-2-yl)piperidin- 4-yl]sulfamoyl]urea

Step 1: 1-isopropyl-N-(1-methylpyrazol-4-yl) piperidin-4-amine trifluoroacetate. General Procedure A was followed and 1-methylpyrazol-4-amine and 1-isopropylpiperidin-4-one were used. The crude material was purified by preparative HPLC (column: Acchrom C18ME 7 µm 250x50 mm, mobile phase: [water (0.1% TFA) - ACN]; B: 1-20%, 23 min) to obtain the title compound as a pale brown oils (Y=36%). ^1H NMR (400 MHz, methanol-ph) δ =7.93 (s, 1H), 7.63 (s, 1H), 3.92 (s, 3H), 3.70-3.53 (m, 4H), 3.17-3.09 (m, 2H), 2.37-2.29 (m, 2H), 2.06-1.96 (m, 2H), 1.35 (d, J = 7 Hz, 6H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)[1(propane -2-yl)piperidin-4-yl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-isopropyl-N-(1-methylpyrazol-4-yl) were used )piperidine-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM ammonium carbonate) - ACN]; B: 2-35%, 20 min) to obtain the title compound as a white solid substances (Y=8%). ^1H NMR (400 MHz, methanol^) δ =7.66 (s, 1H), 7.43 (s, 1H), 6.92 (s, 1H), 4.34-4.27 (m, 1H ), 3.83 (s, 3H), 3.26-3.23 (m, 3H), 2.98-2.92 (m, 2H), 2.86 (t, J=7 Hz, 4H) , 2.79 (t, J=7 Hz, 4H), 2.24-2.14 (m, 2H), 2.102.02 (m, 4H), 1.65-1.54 (m, 2H), 1.22 (d, J=7 Hz, 6H). LC-MS (ESI): m/z: [M+H]+ = 501.2.

Example 34. Sodium salt of 1-{[1-(difluoromethyl)-1H-pyrazol-4-yl](1-methylpiperidin-4yl)sulfamoyl}-3-(1,2,3,5,6,7-hexahydro^ -indacen-4-yl)urea

Step 1: 1-(difluoromethyl)-4-nitropyrazole. Cs ₂ CO ₃ (25.9 g, 79.6 mmol) was added to a solution of 4-nitro-N-pyrazole (9.0 g, 79.6 mmol) in DMF (90 mL). The mixture was stirred at 120°C for 5 minutes, then (2-chloro-2,2-difluoroacetyl)oxysodium (24.3 g, 159.2 mmol) was added to the mixture in portions over 20 minutes. The mixture was stirred at 120°C for 10 minutes. The solvent was removed under reduced pressure. The residue was diluted with water (50 ml) and extracted with EtOAc (3x60 ml). The combined organic layers were washed with brine (30 ml) and dried over Na ₂ SO ₄ . The residue was purified with FCC (5-20% petroleum ether in ethyl acetate) to give the title compound as a light yellow oil (Y=77%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.59 (s, 1H), 8.21 (s, 1H), 7.27 (t, J=60 Hz, 1H).

Step 2: 1-(difluoromethyl)pyrazol-4-amine. To a solution of 1-(difluoromethyl)-4-nitropyrazole (3.0 g, 18.4 mmol) in MeOH (30 ml) was added 10% Pd/C (300 mg) under nitrogen atmosphere. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ (15 ^psi ) at RT for 3 hours. The mixture was filtered under reduced pressure and the filtrate was distilled to give the title compound as a yellow oil (Y=88%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.33 (s, 2H), 7.05 (t, J=60 Hz, 1H), 3.32-2.80 (br. s, 2H).

Step 3: N[1-(difluoromethyl)pyrazol-4-yl]-1-methylpiperidin-4-amine trifluoroacetate. General Procedure A was followed and 1-(difluoromethyl)pyrazol-4-amine and 1-methylpiperidin-4-one were used. The residue was purified by preparative HPLC (column: Acchrom C18ME 7 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-20%, 23 min) to obtain the title compound as a white solid substances (Y=66%). ¹ H NMR (400 MHz, methanol-f ₄ ) δ ppm 7.56-7.13 (m, 3H), 3.60-3.52 (m, 2H), 3.27-3.22 (m,

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1H), 3.14-3.04 (m, 2H), 2.88 (s, 3H), 2.32-2.24 (m, 2H), 1.69-1.59 (m, 2H) .

Step 4: sodium salt 1-{[1-(difluoromethyl)-1H-pyrazol-4-yl](1-methylpiperidin-4yl)sul(|)amoyl;-3-(1,2,3,5,6, 7-hexahydroch-indacen-4-yl)urea. General procedure B was used and {|(1.2,3.5.6.7-hexahydro-indacen-4-yl)carbamoyl|amino;sul((unyl chloride and N-[1(difluoromethyl)pyrazol-4-yl]-1-methylpiperidin- 4-Amintrifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (0.05% ammonium hydroxide v/v) - ACN]; B: 2-35%, 20 min) and obtained the desired compound as a white solid (Y=4%). ¹ H NMR (400 MHz, D2O) δ ppm 8.12 (s, 1H), 7.71 (s, 1H) , 7.40 (t, J=60 Hz, 1H), 7.05 (s, 1H), 4.27-4.18 (m, 1H), 3.51-3.44 (m, 2H), 3.17-3.07 (m, 2H), 2.87-2.80 (m, 4H), 2.77 (s, 3H), 2.70-2.62 (m, 4H), 2. 20-2.12 (m, 2H), 2.05-1.91 (m, 4H), 1.61-1.52 (m, 2H) LC-MS (ESI): m/z: [M]. +H]+ = 509.2.

Example 35. Sodium salt 1-{[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl](oxan-4-yl)sulfamoyl}-3(1,2,3,5,6,7 -hexahydro^-indacen-4-yl)urea

Step 1: 1-(2,2-difluoroethyl)-4-nitropyrazole. To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in THF (100 ml) was added 2,2-difluoroethanol (4.35 g, 53.1 mmol) and triphenylphosphine (17.40 g , 66.3 mmol) at RT in an N ₂ atmosphere. RM cooled to 0°C and diisopropyl azodicarboxylate (10.3 mL, 53.1 mmol) were added. The RM was allowed to warm to rt and then stirred for 12 hours. The solvent was removed under reduced pressure. The residue was purified with FCC (5-20% EtOAc in petroleum ether) to give the title compound as a white solid (Y=83%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.25 (s, 1H), 8.14 (s, 1H), 6.31-5.99 (m, 1H), 4.57-4.49 (m, 2H).

Step 2: 1-(2,2-difluoroethyl)pyrazol-4-amine. To a solution of 1-(2,2-difluoroethyl)-4-nitropyrazole (2.0 g, 11.3 mmol) in MeOH (50 ml) was added 10% Pd/C (200 mg) under N2 atmosphere. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was then stirred under _H2 (15 ^psi ) at RT for 3 hours. The mixture was stirred under H2 (15 ^psi ) at RT for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and obtained the desired compound in the form of a brown oil (Y=96%). ¹ H NMR (400 MHz, methanol-f ₄ ) δ ppm 7.25 (s, 1H), 7.21 (s, 1H), 6.25-5.90 (m, 1H), 4.44-4.35 (m, 2H).

Step 3: 1-(2,2-difluoroethyl)-H-tetrahydropyran-4-ylpyrazol-4-amine trifluoroacetate. To a solution of 1(2,2-difluoroethyl)pyrazol-4-amine (900 mg, 6.12 mmol) in AcOH (2 mL) and DCM (10 mL) was added tetrahydropyran-4-one (562 μL, 6.12 mmol ). The RM was stirred at RT for 30 min. NaBH ₃ CN (769 mg, 12.2 mmol) was added and the RM was stirred at RT for an additional 1.5 hours. The mixture was evaporated under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm 10 μm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-20%, 20 min) to obtain the title compound as yellow oils (Y=24%). ¹ H NMR (400 MHz, methanol-f ₄ ) δ ppm 8.10 (s, 1H), 7.77 (d, J=1 Hz, 1H), 6.36-6.07 (m, 1H), 4.68-4.60 (m, 2H), 4 .07-3.99 (m, 2H), 3.68-3.58 (m, 1H), 3.493.40 (m, 2H), 1.98-1.93 (m, 2H), 1.74 -1.64 (m, 2H).

Step 4: sodium salt 1-{[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl](oxan-4-yl)sulfamoyl}-3(1,2,3,5,6,7 -hexahydro^-indacen-4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-(2,2-difluoroethyl)-Ntetrahydropyran-4- Ilpyrazole-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell C18 250x50 mm 10 µm; mobile phase: [water (0.05% ammonium hydroxide v/v) - ACN]; B: 5-35%, 20 min) and the title compound was obtained as a white solid (Y=5%). ¹ H NMR (400 MHz, methanol-ph) δ ppm 7.83 (s, 1H), 7.52 (s, 1H), 6.99 (s, 1H), 6.33-6.06 (m, 1H), 4.61-4.54 (m, 2H), 4.39-4.32 (m, 1H), 3.94-3.90 (m, 2H), 3.47 (t, J=12 Hz, 2H), 2.88 (t, J =7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.10-2.05 (m, 4H), 1.90-1.86 (m, 2H), 1.49 -1.40 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 510.2.

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Example 36. Sodium salt of 1-{[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl](1-methylpiperidin-4yl)sulfamoyl;-3-(1.2.3.5.6.7-hexahydro^-indacene -4-yl)urea

Step 1: H-|1-(2,2-di((((((()torethyl))pyrazol-4-yl]-1-methylpiperidin-4-aminetrifluoroacetate. General procedure A was used and 1-(2,2-difluoroethyl)pyrazole was used -4-amine (synthesis described in Example 35) and 1-methylpiperidin-4-one. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm 10 μm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-20%, 20 min) and obtained the desired compound as a yellow oil (Y=68%). ¹ H NMR (400 MHz, methanol^ ₄ ) δ ppm , 1H), 7.66 (s, 1H), 6.18 (t, J=55 Hz, 1H), 4.62-4.58 (m, 2H), 3.65-3.57 (m, 3H), 3.15-3.05 (m, 2H), 2.88 (s, 3H), 2.36-2.25 (m, 2H), 1.99-1.90 (m, 2H) .

Step 2: sodium salt 1-{[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl](1-methylpiperidin-4yl)sulfamoyl}-3-(1,2,3,5,6, 7-hexahydro^-indacen-4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and N-[1-(2,2di(torethyl)pyrazol- 4-yl]-1-methylpiperidin-4-aminetri(thoracetate. The crude product was purified using preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ ) - ACN]; B: 2 -35%, 20 min) and obtained the desired compound as a white solid (Y = 12%). ¹ H NMR (400 MHz, methanol^ ₄ ) δ ppm. , 1H), 7.52 (s, 1H), 6.95 (s, 1H), 6.32-6.02 (m, 1H), 4.58-4.50 (m, 2H), 4. 30-4.24 (m, 1H), 3.20-3.14 (m, 2H), 2.90-2.76 (m, 8H), 2.71-2.63 (m, 2H), 2.50 (s, 3H), 2.12-2.03 (m, 6H), 1.59-1.50 (m, 2H) LC-MS (ESI): m/z: [M+H]. ]+ = 523.2.

Example 37. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4-yl)[1(2,2,2 -trifluoroethyl)-1H-pyrazol-4-yl]sulfamoyl]urea

Step 1: 4-nitro-1-(2,2,2-trifluoroethyl)pyrazole. To a solution of 4-nitro-N-pyrazole (5.0 g, 44.2 mmol) in DMF (50 ml) was added 1,1,1-trifluoro-2-iodoethane (6.51 ml, 66.3 mmol) and Cs ₂ CO ₃ (17.29 g, 53.1 mmol). The RM was stirred at 60°C for 18 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3x30 ml). The combined organics were washed with brine (10 ml), dried over Na ₂ SO ₄ and filtered. The residue was purified with FCC (10-25% EtOAc in petroleum ether) to give the title compound as a light yellow solid (Y=30%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.30 (s, 1H), 8.16 (s, 1H), 4.81-4.73 (m, 2H).

Step 2: 1-(2,2,2-trifluoroethyl)pyrazol-4-amine. To a solution of 4-nitro-1-(2,2,2-trifluoroethyl)pyrazole (2.0 g, 10.25 mmol) in MeOH (30 mL) was added 10% Pd/C (200 mg) under N2. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ atmosphere at RT for 3 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound as a red-brown oil (Y=100%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.21 (s, 1H), 7.07 (s, 1H), 4.59-4.50 (m, 2H), 3.41 (s, 2H).

Step 3: 1-methyl-H-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]piperidin-4-amine trifluoroacetate. General Procedure A was followed and 1-(2,2,2-trifluoroethyl)pyrazol-4-amine and 1-methylpiperidin-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm 10 μm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-20%, 20 min) to obtain the title compound as white solid (Y=44%). ¹ H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.43 (s, 1H), 7.33 (s, 1H), 4.82-4.78 (m, 2H), 3.57 (d, J=13 Hz, 2H), 3.27-3 .21 (m, 1H), 3.08 (t, J=13 Hz, 2H), 2.87 (s, 3H), 2.26 (d, J=14 Hz, 2H), 1.71-1 .61 (m, 2H).

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Step 4: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4-yl)[1(2,2,2 -trifluoroethyl)-1H-pyrazol-4-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-H-[1-(2,2, 2trifluoroethyl)pyrazol-4-yl]piperidin-4-aminetrifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (0.05% ammonium hydroxide v/v) - ACN]; B: 2-38%, 20 min) and the title compound was obtained as a white solid (Y=6%). ¹ H NMR (400 MHz, methanolD ₄ ) δ ppm 7.86 (s, 1H), 7.56 (s, 1H), 6.94 (s, 1H), 5.00-4.90 (m, 2H), 4.27-4.24 (m, 1H), 3.18-3.13 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.70-2, 64 (m, 2H), 2.49 (s, 3H), 2.13-2.05 (m, 6H), 1.57-1.48 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 541.2.

Example 38. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-{[1-(2-methoxyethyl)-1Hpyrazol-4-yl] (1 -methylpiperidin-4-yl)sulfamoyl}urea

Step 1: N[1-(2-methoxyethyl)pyrazol-4-yl]-1-methylpiperidin-4-amine trifluoroacetate. General Procedure A was followed and 1-(2-methoxyethyl)pyrazol-4-amine (synthesis described in Example 29) and 1-methylpiperidin-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-10%, 20 min) to obtain the title compound as pale brown oil (Y=48%). ¹ H NMR (400 MHz, methanold4) δ ppm 7.84 (s, 1H), 7.57 (s, 1H), 4.32-4.24 (m, 2H), 3.75-3.69 (m, 2H), 3.65-3, 52 (m, 3H), 3.31 (s, 3H), 3.133.06 (m, 2H), 2.88 (s, 3H), 2.32-2.21 (d, 2H), 2.00 -1.89 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-{[1-(2-methoxyethyl)-1Hpyrazol-4-yl](1 -methylpiperidin-4-yl)sulfamoyl}urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonium chloride and A-|1-(2-methoxyethyl)pyrazole-4- yl]-1-methylpiperidin-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (0.05% ammonium hydroxide v/v) - ACN]; B: 5-35%, 20 min) and the title compound was obtained as a white solid (Y=3%). ¹ H NMR (400 MHz, methanolD ₄ ) δ ppm 7.72 (s, 1H), 7.46 (s, 1H), 6.95 (s, 1H), 4.27-4.23 (m, 3H), 3.71 (t, J=5 Hz , 2H), 3.30 (s, 3H), 3.18-3.10 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.81 (t, J=7 Hz , 4H), 2.67-2.60 (m, 2H), 2.47 (s, 3H), 2.10-2.03 (m, 6H), 1.59-1.50 (m, 2H ). LC-MS (ESI): m/z: [M+H]+ = 517.2.

Example 39. Sodium salt of 1-[(1-cyclopropyl-1H-pyrazol-4-yl)(1-methylpiperidin-4yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro^-indacene -4-yl)urea

Step 1: 1-cyclopropyl-4-nitropyrazole. To a solution of 4-nitro-1H-pyrazole (2.0 g, 17.7 mmol) in DCE (50 ml) was added cyclopropylboronic acid (3.04 g, 35.4 mmol), 4-tert-butyl-2-( 4-tert-butyl-2-pyridyl)pyridine (4.75 g, 17.7 mmol), Na ₂ CO ₃ (3.75 g, 35.4 mmol) and CuSO ₄ (2.71 ml, 17.7 mmol) . RM was heated at 70°C for 16 hours. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 ml) and H ₂ O (50 ml). The aqueous phase was extracted with EtOAc (3x50 ml) and the combined organics were washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified with FCC (5-33% EtOAc in petroleum ether) to give the title compound as a white solid (Y=41%). ^1H NMR (400 MHz, chloroformd) δ =8.20 (d, J=4 Hz, 1H), 8.04 (d, J=4 Hz, 1H), 3.71-3.66 (m, 1H ), 1.21-1.13 (m, 4H).

Step 2: 1-cyclopropylpyrazol-4-amine. To a solution of 1-cyclopropyl-4-nitropyrazole (700 mg, 4.57 mmol) in MeOH (20 ml) was added 10% Pd/C (100 mg) under nitrogen atmosphere. The suspension was degassed into

- 143 047011 vacuum and purged several times with H2. The mixture was then stirred at RT under ^H2 (15 psi) for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a purple oil (Y=99%). 1H NMR (400 MHz, chloroform-d) δ =7.13 (s, 1H), 7.07 (s, 1H), 3.51-3.45 (m, 1H), 2.86-2.75 (m, 2H), 1.08-1.04 (m, 2H), 0.97-0.92 (m, 2H).

Step 3: Na(1-cyclopropylpyrazol-4-yl)-1-methylpiperidin-4-amine trifluoroacetate. General Procedure A was followed and 1-cyclopropylpyrazol-4-amine and 1-methylpiperidin-4-one were used. The crude material was purified by preparative HPLC (column: Agela Innoval ods-2 250x80 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-9%, 20 min) to obtain the title compound as white solid (Y=46%). ¹ H NMR (400 MHz, methanolD ₄ ) δ ppm 7.80 (s, 1H), 7.48 (s, 1H), 3.67-3.52 (m, 3H), 3.50-3.45 (m, 1H), 3.14-3, 05 (m, 2H), 2.88 (s, 3H), 2.32-2.24 (m, 2H), 1.90-1.80 (m, 2H), 1.10-1.03 ( m, 4H).

Step 4: 1-[(1-cyclopropyl-1H-pyrazol-4-yl)(1-methylpiperidin-4yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro^-indacene) sodium salt -4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and N-(1cyclopropylpyrazol-4-yl)-1-methylpiperidin- 4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 5-35%, 20 min) and obtained the desired compound in the form of a white solid (Y=4%). 1H NMR (400 MHz, methanolD ₄ ) δ ppm 7.74 (s, 1H), 7.43 (s, 1H), 6.95 (s, 1H), 4.27-4.21 (m, 1H), 3.66-3.61 (m, 1H), 3.20-3.12 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.68-2, 60 (m, 2H), 2.50 (s, 3H), 2.11-2.02 (m, 6H), 1.57-1.48 (m, 2H), 1.07-1.02 ( m, 4H). LC-MS (ESI): m/z: [M+H]+ = 499.2.

Example 40. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4yl)(1H-pyrazol-4-yl)sulfamoyl ]urea

Step 1: 1-methyl-H-(1H-pyrazol-4-yl)piperidin-4-amine trifluoroacetate. General procedure A was followed and N-pyrazol-4-amine and 1-methylpiperidin-4-one were used. The crude product was purified by preparative HPLC (column: Acchrom C18ME 250x50 mm 7 µm; mobile phase: [water (0.1% TFA) - ACN]; 23 min) to obtain the title compound as a yellow solid (Y=34% ). ¹ H NMR (400 MHz, methanol-ph) δ ppm 7.82 (s, 2H), 3.51-3.45 (m, 1H), 3.18-3.01 (m, 2H), 2.88-2.75 (m, 5H), 2. 42-2.15 (m, 2H), 2.10-1.85 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4-yl)(1Hpyrazol-4-yl)sulfamoyl ]urea. General procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-(1H-pyrazol-4-yl)piperidine were used -4-amine trifluoroacetate. The crude product was purified using preparative HPLC (column: Nano-Micro UniSil 5-100 C18 Ultra 100x250 mm 5 µm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 5-35%, 20 min) and obtained the desired compound in the form of a white solid (Y=3%). 1H NMR (400 MHz, methanol^) δ ppm 7.82-7.45 (br.s, 2H), 6.95 (s, 1H), 4.38-4.22 (m, 1H), 3.21-3.12 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.72-2.61 (m, 2H), 2.50 (s, 3H), 2.15-2.01 (m, 6H), 1.63-1.48 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 459.2.

- 144 047011

Example 41. Sodium salt 3-(1,2,3,5,6,7-1'e1<ca1'idro^-indapen-4-yl)-1-[(oxan-4-yl)[1-( o1<setan-3yl)-1H-pyrazol-4-yl]sulfamoyl]urea

Step 1: 4-nitro-1-(oxetan-3-yl)pyrazole. To a solution of 4-nitro-III-pyrazole (5.0 g, 44.2 mmol) in DMF (50 ml) was added 3-iodoxetane (8.14 g, 44.2 mmol) and Cs ₂ CO ₃ (21.6 g, 66.3 mmol), then the mixture was stirred at 100°C for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3x50 ml). The combined organics were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting residue was purified with FCC (9-33% EtOAc in petroleum ether) to give the title compound as a yellow solid (Y=84%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.32 (s, 1H), 8.18 (s, 1H), 5.55-5.41 (m, 1H), 5.14-5.01 (m, 4H).

Step 2: 1-(oxetan-3-yl)pyrazol-4-amine. To a solution of 4-nitro-1-(oxetan-3-yl)pyrazole (1.2 g, 7.09 mmol) in MeOH (20 ml) was added 10% Pd/C (300 mg) under N2 atmosphere. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ (15 ^psi ) at RT for 3 hours. RM was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a purple solid (Y=99%). 'I NMR (400 MHz, methanolchd4) δ ppm 7.36 (s, 1H), 7.25 (s, 1H), 5.44-5.34 (m, 1H), 5.03-4.92 (m, 4H), 3.31 (s, 2H).

Step 3: 1-(oxetan-3-yl)-N-tetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1-(oxetan-3-yl)pyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a pale red oil (Y=76%). *H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.40 (s, 1H), 7.28 (s, 1H), 5.47-5.35 (m, 1H), 5.07-4.89 (m, 4H), 3.98-3, 94 (m, 2H), 3.49-3.42 (m, 2H), 3.15-3.04 (m, 1H), 1.98-1.90 (m, 2H), 1.50- 1.36 (m, 2H).

Step 4: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)[1-(oxetan-3-yl) 1H-pyrazol-4-yl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-(oxetan-3-yl)-N-tetrahydropyran-4ylpyrazol- 4-amine The crude product was purified using preparative HPLC (column: NanoMicro UniSil 5-100 C18 ULTRA 5 µm 100x250 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 5-35%, 20 min) to obtain the desired compound as a white solid (Y=7%). 'I NMR (400 MHz, methanol^) δ ppm 7.88 (s, 1H), 7.58 (s, 1H), 6.99 (s, 1H), 5.62-5.50 (m, 1H), 5.03 (d, J=7 Hz , 4H), 4.404.28 (m, 1H), 3.96-3.86 (m, 2H), 3.52-3.42 (m, 2H), 2.88 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.14-2.02 (m, 4H), 1.93-1.84 (m, 2H), 1.48-1.45 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 502.2.

Example 42. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4-yl)[1(oxetan-3-yl) )-1H-pyrazol-4-yl]sulfamoyl]urea

Step 1: 1-methyl-N-[1-(oxetan-3-yl)pyrazol-4-yl]piperidin-4-amine trifluoroacetate. General Procedure A was followed and 1-(oxetan-3-yl)pyrazol-4-amine (synthesis described in Example 41) and 1-methylpiperidin-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna 10 µm C18 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-10%, 20 min) to obtain the title compound as pale yellow solid (Y=52%). 'I NMR (400 MHz, methanol^ ₄ ) δ ppm 7.93 (s, 1H), 7.66 (s, 1H), 5.63-5.46 (m, 1H), 5.07-4.96 (m, 4H), 3.69-3, 52 (m, 3H), 3.17-3.03 (m, 2H), 2.88 (s, 3H), 2.36-2.24 (m, 2H), 1.99-1.80 ( m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-4-yl)[1(oxetan-3-yl) )-1H-pyrazol-4-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-[1-(oxetane-3

- 145 047011 yl)pyrazol-4-yl]piperidin-4-amine trifluoroacetate. The crude product was purified using preparative HPLC (column: Nano-Micro UniSil 5-100 C18 ULTRA 5 µm 100x250 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 3-32%, 20 min ) and obtained the desired compound in the form of a white solid (Y=3%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.86 (s, 1H), 7.57 (s, 1H), 6.95 (s, 1H), 5.59-5.47 (m, 1H), 5.07-4.95 (m, 4H), 4.34-4.19 (m, 1H), 3.20-3.12 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.80 (t, J =7 Hz, 4H), 2.73-2.55 (m, 2H), 2.50 (s, 3H), 2.14-2.01 (m, 6H), 1.65-1.45 ( m, 2H). LC-MS (ESI): m/z: [M+H]+ = 515.2.

Example 43. Sodium salt 1-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}(oxan-4yl)sulfamoyl)-3-(1,2,3,5,6,7 -hexahydro^-indacen-4-yl)urea

Step 1: X,X-dimethyl-2-(4-nitropyrazol-'1-yl)ethanamine. To a solution of 4-nitro-N-pyrazole (3.0 g, 26.53 mmol) in DMF (40 ml) was added 2-chloro-HX-dimethylethanamine hydrochloride (5.73 g, 39.80 mmol) and Cs ₂ CO ₃ (12.97 g, 39.80 mmol). The RM was stirred at 90°C for 3 hours, then the solvent was concentrated under reduced pressure. The residue was partitioned between EtOAc (50 ml) and H ₂ O (50 ml). The aqueous phase was further extracted with EtOAc (3x50 ml) and the combined organics were washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified with FCC (25-85% EtOAc in petroleum ether) to give the title compound as a white solid (Y=39%). 1H NMR (400 MHz, chloroform-d) δ ppm 8.29 (s, 1H), 8.06 (s, 1H), 4.23 (t, J=6 Hz, 2H), 2.75 (t, J=6 Hz, 2H), 2.28 ( s, 6H).

Step 2: 1-[2-(dimethylamino)ethyl]pyrazol-4-amine. To a solution of N,Ndimethyl-2-(4-nitropyrazol-1yl)ethanamine (1.2 g, 6.51 mmol) in MeOH (20 ml) was added 10% Pd/C (100 mg) under N2 atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times, then the mixture was stirred under H ₂ at RT for 3 hours. The reaction mixture was filtered and the solvent was removed under reduced pressure to obtain the title compound as a purple oil (Y=100%) . 1H NMR (400 MHz, methanolA) δ ppm 7.24 (s, 1H), 7.14 (s, 1H), 4.13 (t, J=7 Hz, 2H), 2.73 (t, J=7 Hz, 2H), 2.25 ( s, 6H).

Step 3: 1-[2-(dimethylamino)ethyl]-N-tetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1-[2-(dimethylamino)ethyl]pyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a colorless oil (Y=78%). 1H NMR (400 MHz, methanolA) δ ppm 7.35 (s, 1H), 7.26 (s, 1H), 4.43 (t, J=6 Hz, 2H), 3.99-3.92 (m, 2H), 3.57-3 .52 (m, 2H), 3.51-3.43 (m, 2H), 3.15-3.05 (m, 1H), 2.87 (s, 6H), 1.97-1.91 (m, 2H), 1.53-1.35 (m, 2H).

Step 4: sodium salt 1-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}(oxan-4-yl)sulfamoyl)3-(1,2,3,5,6, 7-hexahydro^-indacen-4-yl)urea. General Procedure B was used and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-[2-(dimethylamino)ethyl]-N-tetrahydropyran were used -4-ylpyrazol-4-amine. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) ACN]; B: 5-35%, 20 min) to obtain the title compound as a white solid ( Y=3%). 1H NMR (400 MHz, methanolA) δ ppm 7.80 (s, 1H), 7.48 (s, 1H), 6.97 (s, 1H), 4.40-4.25 (m, 3H), 3.92 (dd, J=4, 11 Hz, 2H), 3.48 (t, J=11 Hz, 2H), 3.03 (t, J=6 Hz, 2H), 2.88 (t, J=7 Hz, 4H), 2, 80 (t, J=7 Hz, 4H), 2.49 (s, 6H), 2.13-2.03 (m, 4H), 1.91-1.85 (m, 2H), 1.56 -1.41 (m, 2H). LC-MS (ESI): m/z: [M+H] ⁺ = 517.2.

Example 44. Sodium salt of A^-cyclobutyl-N-pyrazol^-ylHimethylpiperidin^yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)urea

Step 1: 1-cyclobutyl-4-nitropyrazole. To a solution of 4-nitro-1H-pyrazole (5 g, 44.22 mmol) in DMF (50 ml), cooled to 0°C, was added NaH (60% in mineral oil (3.54 g, 88.44 mmol) and then

- 146 047011 bromocyclobutane (4.17 ml, 44.22 mmol). RM was heated at 60°C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3x50 ml). The combined organics were washed with brine (20 ml), dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified with FCC (10-25% EtOAc in petroleum ether) to give the title compound as a colorless oil (Y=15%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.17 (s, 1H), 8.09 (s, 1H), 4.86-4.70 (m, 1H), 2.62-2.46 (m, 4H), 2.04-1, 84 (m, 2H).

Step 2: 1-cyclobutylpyrazole-4-amine. To a solution of 1-cyclobutyl-4-nitropyrazole (1.0 g, 5.98 mmol) in MeOH (20 ml) was added 10% Pd/C (100 mg) under N2. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ (15 ^psi ) at RT for 3 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil (Y=97%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.17 (s, 1H), 7.08 (s, 1H), 4.71-4.55 (m, 1H), 2.88 (br, 2H), 2.53-2.39 (m, 4H), 1.901.74 (m, 2H).

Step 3: N(1-cyclobutylpyrazol-4-yl)-1-methylpiperidin-4-amine trifluoroacetate. General Procedure A was followed and 1-cyclobutylpyrazol-4-amine and 1-methylpiperidin-4-one were used. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 250x50 mm; mobile phase: [water (0.1% TFA)-ACN]; B: 0-5%, 20 min) to obtain the title compound as white solid (Y=79%). ¹ H NMR (400 MHz, metyaol-f) δ ppm 7.75-7.57 (m, 1H), 7.50-7.38 (m, 1H), 4.79-4.73 (m, 1H), 3.64-3.56 (m, 2H ), 3.47-3.38 (m, 1H), 3.13-3.02 (m, 2H), 2.88 (s, 3H), 2.55-2.41 (m, 4H), 2.31-2.25 (m, 2H), 1.92-1.69 (m, 4H).

Step 4: sodium salt 1-[(1-cyclobutyl-1H-pyrazol-4-yl)(1-methylpiperidin-4-yl)sulfamoyl]3-(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and Na(1-cyclobutylpyrazol4-yl)-1-methylpiperidin-4 were used -amine trifluoroacetate. The crude product was purified using preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 3-35%, 20 min) and the title compound was obtained as a white solid (Y=5%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.78 (s, 1H), 7.48 (s, 1H), 6.95 (s, 1H), 4.84-4.73 (m, 1H), 4.31-4.18 (m, 1H), 3.19-3.11 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.63 (t, J=12 Hz, 2H), 2.552.41 (m, 7H), 2.13-2.02 (m, 6H), 1.93-1.83 (m, 2H), 1.61-1.50 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 513.2.

Example 45. Sodium salt of SCS^D-difluoroethyl^iperidin^-ylfCmethyl-III-pyrazol^yl)sulfamoyl}-3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)urea

Step 1: tert-butyl 4-[(1-methylpyrazol-4-yl)amino]piperidine-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl-4-oxopiperidine-1-carboxylate were used to obtain the title compound as a brown oil (Y=28%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.21 (s, 1H), 7.14 (s, 1H), 4.09-3.95 (m, 2H), 3.78 (s, 3H), 3.06-2.97 (m, 1H), 2.96-2.80 (m, 2H), 2.00-1.88 (m, 2H), 1.45 (s, 9H), 1.34-1.20 (m, 2H) .

Step 2: Na(1-methylpyrazol-4-yl)piperidin-4-amine hydrochloride. A mixture of tert-butyl 4-[(1methylpyrazol-4-yl)amino]piperidine-1-carboxylate (3.0 g, 10.70 mmol) and 4 M HCl in EtOAc (60 ml) was stirred at RT for 12 h The resulting solid was collected by filtration to give the title compound as a pale red solid (Y=99%). 1H NMR (400 MHz, methanol-3 ₄ ) δ ppm 8.07 (s, 1H), 7.73 (s, 1H), 3.95 (s, 3H), 3.84-3.74 (m, 1H), 3.60-3.52 (m, 2H), 3.17-3.06 (m, 2H), 2.35-2.25 (m, 2H), 2.05-1.97 (m, 2H).

Step 3: 1-(2,2-difluoroethyl)-N(1-methylpyrazol-4-yl)piperidin-4-amine trifluoroacetate. 1,1-Difluoro-2- iodoethane (440 μl, 4.99 mmol) and K ₂ CO ₃ (1.15 g, 8.32 mmol). The mixture was stirred at RT for 2 hours then concentrated under reduced pressure. The crude material was purified using preparative HPLC (column: Phenomenex Luna C18 10 µm, 250x50 mm;

- 147 047011 mobile phase: [water (0.1% TFA) - ACN]; B: 0-10%, 20 min) and the desired compound was obtained as a white solid (Y=35%). ¹ H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.75 (s, 1H), 7.43 (s, 1H), 6.39 (t, J=54 Hz, 1H), 3.82 (s, 3H), 3.51-3.18 (m , 5H), 2.98-2.62 (m, 2H), 2.12-1.92 (m, 2H), 1.65-1.55 (m, 2H).

Step 4: 1-{[1-(2,2-difluoroethyl)piperidin-4-yl](1-methyl-1H-pyrazol-4yl)sulfamoyl}-3-(1,2,3,5,6) sodium salt ,7-hexahydro^-indacen-4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-(2,2difluoroethyl)-H-(1-methylpyrazole) were used -4-yl)piperidin-4-amine trifluoroacetate. The crude product was purified using preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 3-33%, 20 min) and the title compound was obtained as a white solid (Y=8%). ¹ H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.71 (s, 1H), 7.42 (s, 1H), 6.98 (s, 1H), 6.03-5.73 (m, 1H), 4.19-4.01 (m, 1H), 3.89 (s, 3H), 3.00-2.92 (m, 2H), 2.88 (t, J=7 Hz, 4H), 2.79 (t, J=7 Hz, 4H), 2.72-2.62 (m, 2H), 2.32 (t, J=12 Hz, 2H), 2.13-2.02 (m, 4H), 1.95-1.85 (m, 2H), 1.56-1.40 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 523.2.

Example 46. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl) [2-(morpholin- 4 -yl)ethyl]sulfamoyl]urea

Step 1: 1-methyl-H-(2-morpholinoethyl)pyrazole-4-amine trifluoroacetate. To a solution of 1-methylpyrazol4-amine (400 mg, 4.12 mmol) in DMF (10 ml) was added 4-(2-chloroethyl)morpholine (616 mg, 4.12 mmol), Cs ₂ CO ₃ (2.01 g , 6.18 mmol) and KI (684 mg, 4.12 mmol). RM was stirred at 100°C for 12 h, then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-4%, 20 min) to obtain the title compound as a brown oils (Y=13%). ¹ H NMR (400 MHz, methanold ₄ ) δ ppm 7.30 (s, 1H), 7.21 (s, 1H), 3.95-3.90 (m, 4H), 3.80 (s, 3H), 3.40-3.33 (m, 8H).

Step 2: 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)[2( morpholin-4-yl)ethyl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-(2morpholinoethyl)pyrazole-4-aminetrifluoroacetate were used . The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 2-32%, 20 min) to obtain the title compound as a white solid (Y=7%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.74 (s, 1H), 7.55 (s, 1H), 6.95 (s, 1H), 3.99-3.92 (m, 2H), 3.92-3.83 (m, 7H), 3.27-3.20 (br. s, 4H), 3.12-3.06 (m, 2H), 2.88 (t, J=7 Hz, 4H), 2.82 (t , J=7 Hz, 4H), 2.14-2.02 (m, 4H). LC-MS (ESI): m/z: [M+H]+ = 489.2.

Example 47. Sodium salt of 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(1-methyl- 2-oxopiperidin-4-yl)sulfamoyl]urea

Step 1: 1-methyl-4-[(1-methylpyrazol-4-yl)amino]piperidin-2-one trifluoroacetate. General Procedure A was followed and 1-methylpyrazol-4-amine and 1-methylpiperidine-2,4-dione were used. The crude material was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-10%, 20 min) to obtain the title compound as pale yellow oil (Y=47%). ¹ H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.94 (s, 1H), 7.63 (s, 1H), 3.94 (s,

- 148 047011

3H), 3.91-3.81 (m, 1H), 3.51-3.38 (m, 2H), 2.94 (s, 3H), 2.82-2.73 (m, 1H) , 2.49-2.40 (m, 1H), 2.33-2.23 (m, 1H), 2.01-1.88 (m, 1H).

Step 2: sodium salt 3-(1.2.3.5.6.7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)(1methyl-2-oxopiperidin-4-yl) )sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl|amino;sul(|unyl chloride and 1-methyl-4-[(1methylpyrazol-4 -yl)amino]piperidin-2-one trifluoroacetate. The crude product was purified using preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN ]; B: 5-35%, 20 min) and obtained the desired compound as a white solid (Y=13%). 1H NMR (400 MHz, methanol^) δ ppm 7.77 (s, 1H) , 7.47 (s, 1H), 6.99 (s, 1H), 4.69-4.55 (m, 1H), 3.90 (s, 3H), 3.45-3.40 (m , 1H), 2.92-2.79 (m, 11H), 2.74-2.66 (m, 1H), 2.28-2.16 (m, 2H), 2.14-2.01 (m, 5H), 1.70-1.55 (m, 1H) LC-MS (ESI): m/z: [M+H]+ = 487.1.

Example 48. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)(1H-pyrazol-4yl)sulfamoyl]urea

Step 1: n-tetrahydropyran-4-yl-1H-pyrazol-4-amine trifluoroacetate. General procedure A was followed and N-pyrazol-4-amine and tetrahydropyran-4-one were used. The crude material was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-10%, 20 min) to obtain the title compound as white solid (Y=53%).

1H NMR (400 MHz, methanol^) δ ppm 7.89 (s, 2H), 4.03 (dd, J=4, 12 Hz, 2H), 3.68-3.58 (m, 1H), 3.463.38 (m, 2H), 2.00 -1.91 (m, 2H), 1.76-1.62 (m, 2H).

Step 2: 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(oxan-4-yl)(1H-pyrazol-4yl)sulfamoyl] sodium salt urea. General Procedure B was followed and {[(1.2.3.5.6.7-hexahydro^indacen-4-yl)carbamoyl]amino}sulfonyl chloride and n-tetrahydropyran-4-yl-1H-pyrazol-4-amine trifluoroacetate were used. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) -ACN]; B: 2-32%, 20 min) to obtain the title compound as white solid (Y=13%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.75 (s, 1H), 7.52 (s, 1H), 6.98 (s, 1H), 4.44-4.32 (m, 1H), 3.91 (dd, J=4, 12 Hz, 2H), 3.48 (t, J=11 Hz, 2H), 2.88 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2, 15-2.02 (m, 4H), 1.94-1.85 (m, 2H), 1.51-1.38 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 446.2.

Example 49. 3-[3,5-Bis-(propan-2-yl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(1methylpiperidin-4-yl)sulfamoyl]urea sodium salt

Step 1: 3,5-diisopropenylaniline. To a solution of 3,5-dibromoaniline (5.0 g, 19.9 mmol) in dioxane (50 ml) and H ₂ O (5 ml) was added 2-isopropynyl-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane (10.19 ml, 53.8 mmol) and Pd(dppf)Cl ₂ (729 mg, 1.00 mmol) and Cs ₂ CO ₃ (19.48 g, 59.8 mmol) at RT in atmosphere N2. The reaction mixture was stirred at 100°C for 12 hours under N2 atmosphere. The solution was concentrated in vacuo and the resulting residue was poured into water (50 ml) and stirred for 0.5 h. The aqueous phase was extracted with ethyl acetate (3x100 ml). The combined organic phase was concentrated in vacuo. The crude product was purified with FCC (17% EtOAc in petroleum ether) to give the title compound as a yellow oil (Y=78%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.76 (s, 1H), 6.64

- 149 047011 (s, 2H), 5.23 (s, 2H), 5.10 (s, 2H), 5.01 (s, 2H), 2.06 (s, 6H).

Step 2: 3,5-diisopropylaniline. To a solution of 3,5-diisopropenylaniline (1.0 g, 5.77 mmol) in MeOH (10 mL) was added 10% Pd/C (200 mg) at RT under N2. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was then stirred under H ₂ (15 ^psi ) at RT for 3 hours. RM was filtered and the solid was washed with MeOH (100 ml). The filtrate was concentrated in vacuo. The crude material was purified using FCC (17% EtOAc in petroleum ether) to obtain the title compound as an oil (Y=44%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.25 (s, 3H), 4.86 (s, 2H), 2.70-2.62 (m, 2H), 1.13 (d, J=7 Hz, 12H).

Step 3: N[(3,5-diisopropylphenyl)carbamoyl]sulfamoyl chloride. To a solution of N(oxomethylene)sulfamoyl chloride (50 μl, 0.58 mmol) in isopropyl ether (1 ml), cooled to -15°C, was added a solution of 3,5-diisopropylaniline (103 mg, 0.58 mmol) in isopropyl ether (1 ml). The mixture was stirred at -15°C for 0.5 h and the title compound was obtained as a solution in isopropyl ether (2 ml). The mixture was used in the next stage without treatment (Y=100%). LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 315.3.

Step 4: 3-[3,5-bis-(propan-2-yl)phenyl]-1-[(1-methyl-N-pyrazol-4-yl)(1methylpiperidin-4-yl)sulfamoyl]urea sodium salt . General procedure B was followed and N-[(3,5diisopropylphenyl)carbamoyl]sulfamoyl chloride and 1-methyl-N-(1-methylpyrazol-4-yl)piperidin-4-amine were used (synthesis described in Example 2). The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 2-32%, 20 min) to obtain the title compound as a white solid (Y=10%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.68 (s, 1H), 7.44 (s, 1H), 7.11 (s, 2H), 6.78 (s, 1H), 4.45-4.27 (m, 1H), 3 .82 (s, 3H), 3.30-3.26 (m, 2H), 2.95-2.76 (m, 4H), 2.63 (s, 3H), 2.20-2.12 (m, 2H), 1.66-1.51 (m, 2H), 1.23 (d, J=7 Hz, 12H). LC-MS (ESI): m/z: [M+H]+ = 477.3.

Example 50. Sodium salt of 1-[(1-ethylpyrrolidin-3-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea

Step 1: tert-butyl 3-[(1-methylpyrazol-4-yl)amino]pyrrolidine-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl N-oxopyrrolidine-1-carboxylate were used to obtain the title compound as a yellow oil (Y=73%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.70 (s, 1H), 7.42 (s, 1H), 5.29-5.21 (m, 1H), 3.88 (s, 3H), 3.80-3.69 (m, 1H), 3.48-3.40 (m, 1H), 3.35-3.22 (m, 2H), 3.07-3.01 (m, 1H), 1.81-1.75 ( m, 2H), 1.39 (s, 9H).

Step 2: 1-methyl-M-pyrrolidin-3-ylpyrazol-4-amine hydrochloride. To a solution of tert-butyl 3-[(1methylpyrazol-4-yl)amino]pyrrolidine-1-carboxylate (5.0 g, 18.77 mmol) was added 4 M HCl in EtOAc (51.6 mL). The RM was stirred at RT for 1 hour. The solution was filtered and the resulting solid was dried to obtain the title compound as a white solid (Y=100%). 1H NMR (400 MHz, methanol^) δ =8.05 (s, 1H), 7.82 (s, 1H), 4.05 (s, 3H), 3.69-3.67 (m, 1H) , 3.59-3.54 (m, 2H), 3.44-3.40 (m, 2H), 2.45-2.34 (m, 2H).

Step 3: Na(1-ethylpyrrolidin-3-yl)-1-methylpyrazol-4-amine trifluoroacetate. General Procedure A was followed and 1-methyl-M-pyrrolidin-3-ylpyrazol-4-amine hydrochloride and acetaldehyde were used. The crude material was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-25%, 20 min) to obtain the title compound as white solid (Y=24%). 1H NMR (400 MHz, DMSO-d ₆ ) δ =9.91 (s, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 3.88 (s, 3H), 3 .87-3.84 (m, 1H), 3.69-3.60 (m, 1H), 3.20-3.09 (m, 4H), 2.89-2.84 (m, 1H) , 2.43-2.40 (m, 1H), 2.22-2.10 (m, 1H), 1.83-1.80 (m, 1H), 1.20 (t, J=7 Hz , 3H).

Step 4: sodium salt 1-[(1-ethylpyrrolidin-3-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and Na(1-ethylpyrrolidin-3yl)-1-methylpyrazol-4 were used -amine trifluoroacetate. The crude product was purified using preparative

HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 3-33%, 20 min) and obtained the desired compound as white solid (Y=3%). 1H NMR (400 MHz, methanol^) δ ppm 7.73 (s, 1H), 7.50 (s, 1H), 6.94 (s, 1H), 5.02-4.97 (m, 1H), 3.87

- 150 047011 (s, 3H), 3.65-3.51 (m, 1H), 3.21-2.99 (m, 5H), 2.89-2.78 (m, 8H), 2, 40-2.25 (m, 1H), 2.10-1.94 (m, 5H), 1.24 (t, J=7 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 473.2.

Example 51. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[1-(propan- 2-yl)pyrrolidin-3-yl]sulfamoyl]urea

Step 1: N(1-isopropylpyrrolidin-3-yl)-1-methylpyrazol-4-amine trifluoroacetate. General procedure A was followed and 1-methyl-N-pyrrolidin-N-ylpyrazol-4-amine hydrochloride (synthesis described in Example 50) and acetone were used. The crude material was purified using preparative HPLC (column:

Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-25%, 20 min) and the title compound was obtained as a white solid (Y=52%). ^1H NMR (400 MHz, DMSO- _d6 ) δ = 10.05-9.96 (m, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 3.90 (s , 3H), 3.89-3.83 (m, 1H), 3.65-3.50 (m, 1H), 3.49-3.41 (m, 1H), 3.33-3.14 (m, 2H), 2.44-2.38 (m, 2H), 1.84-1.80 (m, 1H), 1.24 (d, J=3 Hz, 6H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)[1(propane -2-yl)pyrrolidin-3-yl]sulfamoyl]urea.

General procedure B was used and {[(1,2,3,5,6,7-hexahydro^-indacen-4yl)carbamoyl]amino}sulfonyl chloride and Na(1-isopropylpyrrolidin-3-yl)-1-methylpyrazol-4 -amine trifluoroacetate. The crude product was purified using preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 3-33%, 20 min) and the title compound was obtained as a white solid (Y=5%). 1H NMR (400 MHz, methanol^) δ ppm 7.72 (s, 1H), 7.50 (s, 1H), 6.92 (s, 1H), 4.97-4.92 (m, 1H), 3.87 (s, 3H), 3 .64-3.54 (m, 1H), 3.20-3.12 (m, 4H), 2.89-2.79 (m, 8H), 2.34-2.24 (m, 1H) , 2.11-2.07 (m, 4H), 1.99-1.88 (m, 1H), 1.32-1.23 (m, 6H). LC-MS (ESI): m/z: [M+H] ⁺ = 487.2.

Example 52. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[1-(propan- 2-yl)piperidin-3-yl]sulfamoyl]urea

Step 1: Na(1-methylpyrazol-4-yl)piperidin-3-amine hydrochloride. A solution of tert-butyl-3-[(1methylpyrazol-4-yl)amino]piperidine-1-carboxylate (2.0 g, 7.13 mmol) (synthesis described in Example 62) in 4 M HCl in EtOAc (21.4 ml) was stirred at RT for 1 hour. The solution was filtered to obtain the title compound as a yellow solid (Y=78%).

Step 2: 1-isopropyl-N-(1-methylpyrazol-4-yl)piperidin-3-amine trifluoroacetate. General Procedure A was followed and Na(1-methylpyrazol-4-yl)piperidin-3-amine hydrochloride and acetone were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna 10 µm C18 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-5%, 20 min) to obtain the title compound as yellow oil (Y=64%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 7.40 (s, 1H), 7.19 (s, 1H), 3.75 (s, 3H), 3.56-3.53 (m, 1H), 3 .44-3.33 (m, 3H), 2.89-2.79 (m, 1H), 2.70-2.63 (m, 1H), 2.03-1.92 (m, 2H) , 1.73-1.70 (m, 1H), 1.40-1.37 (m, 1H), 1.25-1.22 (m, 6H). One NH is not visible.

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl) [1(propane -2-yl)piperidin-3-yl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-isopropyl-N-(1-methylpyrazol-4-yl) were used )piperidine-3-amine trifluoroacetate. The crude product was purified using preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 3 -33%, 20 min) and the title compound was obtained as a white solid (Y=10%). 1H NMR (400 MHz, methanol^) δ ppm 7.66 (s, 1H), 7.44 (s, 1H), 6.92 (s, 1H), 4.45-4.35 (m,

- 151 047011

1H), 3.86 (s, 3H), 3.66-3.58 (m, 1H), 3.20-3.10 (m, 1H), 2.88-2.75 (m, 8H) , 2.65-2.50 (m, 2H), 2.10-1.92 (m, 6H), 1.85-1.70 (m, 1H), 1.32-1.20 (m, 8H). NH is not visible. LC-MS (ESI): m/z: [M+H]+ = 501.2.

Example 53 3-(3,5-diethylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(1-methylpiperidin4-yl)sulfamoyl]urea sodium salt

Step 1: 3,5-diethenylaniline. To a solution of 3,5-dibromoaniline (5.0 g, 19.9 mmol) in 1,4-dioxane (50 ml) and H ₂ O (5 ml) was added 4,4,5,5-tetramethyl-2-vinyl -1,3,2-dioxaborolane (9.13 ml, 53.8 mmol), Cs ₂ CO ₃ (19.5 g, 59.8 mmol) and Pd(dppf)Cl ₂ (729 mg, 1.0 mmol ). The mixture was stirred at 100°C under N2 for 5 hours. The solution was concentrated in vacuo and the residue was poured into water (60 ml) and the resulting mixture was stirred for 0.5 hours. The aqueous phase was extracted with ethyl acetate (3x100 ml). The combined organics were concentrated in vacuo. The crude material was purified using FCC (17% EtOAc in petroleum ether) to obtain the title compound as an oil (Y=17%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.71 (s, 1H), 6.60-6.52 (m, 4H), 5.70-5.64 (m, 2H), 5.17 (d, J=12 Hz, 2H), 5.105 .06 (m, 2H).

Step 2: 3,5-diethylaniline. To a solution of 3,5-diethenylaniline (600 mg, 4.13 mmol) in MeOH (8 ml) was added 10% Pd/C (200 mg) and the mixture was stirred under ^H ₂ (15 psi) for 2 hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was purified with FCC (25% EtOAc in petroleum ether) to give the title compound as a green oil (Y=18%). 1H NMR (400 MHz, DMSO-d ₆ ) δ =6.22-6.18 (m, 3H), 4.82 (s, 2H), 2.44-2.37 (m, 4H), 1, 14-1.09 (m, 6H).

Step 3: {[(3,5-diethylphenyl)carbamoyl]amino}sulfonyl chloride. General Procedure D was followed and 3,5-diethylaniline was used to obtain the title compound as a solution in isopropyl ether. LC-MS in MeOH (ESI): m/z: = 287.3.

Step 4: 3-(3,5-diethylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(1-methylpiperidin-4yl)sulfamoyl]urea sodium salt. General Procedure B was followed and {[(3,5-diethylphenyl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-(1-methylpyrazol-4-yl)piperidin-4-aminetrifluoroacetate were used (synthesis described in Example 2). The crude product was purified by preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH4HCO3)ACN]; B: 3 -33%, 20 min) to obtain the desired compound as a white solid (Y=7%). 1H NMR (400 MHz, methanol^) δ ppm 7.65 (s, 1H), 7.42 (s, 1H), 7.07 (s, 2H), 6.71 (s, 1H), 4.31-4.25 (m, 1H), 3 .81 (s, 3H), 3.23 (d, J=12 Hz, 2H), 2.76 (t, J=12 Hz, 2H), 2.63-2.53 (m, 7H), 2 .13 (d, J=13 Hz, 2H), 1.64-1.51 (m, 2H), 1.21 (t, J=8 Hz, 6H). LC-MS (ESI): m/z: [M+H]+ = 449.2.

Example 54. Sodium salt of 1-({1-azabicyclo[2.2.2]octan-3-yl}(1-methyl-1H-pyrazol-4yl)sulfamoyl)-3-(1,2,3,5,6, 7-hexahydro^-indacen-4-yl)urea

Step 1: tert-butyl-N-(1-methylpyrazol-4-yl)quinuclidine-3-amine trifluoroacetate. General procedure A was followed and 1-methylpyrazol-4-amine and quinuclidin-3-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-35%, 20 min) to obtain the title compound as yellow oil (Y=39%). 1H NMR (400 MHz, methanol^) δ ppm 7.24 (s, 1H), 7.17 (s, 1H), 3.80 (s, 3H), 3.68-3.62 (m, 2H), 3.36-3.27 (m, 4H), 3.02-3.00 (m, 1H), 2.29-2.16 (m, 2H), 2.12-2.06 (m, 1H), 2.02-1.91 ( m, 1H), 1.89-1.79 (m, 1H).

Step 2: 1-({1-azabicyclo[2.2.2]octan-3-yl}(1-methyl-1H-pyrazol-4yl)sulfamoyl)-3-(1,2,3,5,6, 7-hexahydro^-indacen-4-yl)urea. General procedure B was used and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and tert-butylN(1-methylpyrazol-4-yl)quinuclidine were used -3-amine trifluoroacetate. The crude product was purified using

- 152 047011 preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 3 -33%, 20 min) and obtained the desired compound in as a white solid (Y=30%). ¹ H NMR (400 MHz, methanol-^) δ ppm 7.69 (s, 1H), 7.50 (s, 1H), 6.91 (s, 1H), 4.54-4.52 (m,

1H), 3.86 (s, 3H), 3.68-3.60 (m, 1H), 3.52-3.44 (m, 1H), 3.42-3.34 (m, 1H) , 3.16-3.05 (m, 3H), 2.90-2.78 (m, 8H), 2.24 (s, 1H), 2.09-2.03 (m, 4H), 1 .99-1.89 (m, 3H), 1.56-1.53 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 485.3.

Example 55. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-3-yl)[1(propan-2-yl) )-III-pyrazol-4-yl]sulfamoyl]urea

Step 1: tert-butyl 3-[(1-isopropylpyrazol-4-yl)amino]piperidine-1-carboxylate. General procedure A was followed and 1-isopropylpyrazol-4-amine (synthesis described in Example 56) and t-butyl N-oxopiperidine-1-carboxylate were used. The crude product was purified using preparative

HPLC (column: Agela Innoval ods-2 250x80 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 20-60%, 20 min) and obtained the desired compound as a yellow liquid (Y=17 %). ¹ H NMR (400 MHz, methanold4) δ ppm 7.26 (s, 1H), 7.15 (s, 1H), 4.92-4.89 (m, 1H), 4.44-4.34 (m, 1H), 3.87-3, 67 (m, 1H), 3.15-2.90 (m, 3H), 2.07-2.01 (m, 1H), 1.76-1.73 (m, 1n), 1.52- 1.42 (m, 16H), 1.27-1.25 (m, 1H).

Step 2: Na(1-isopropylpyrazol-4-yl)-1-methylpiperidin-3-amine trifluoroacetate. Lithium aluminum hydride (677 mg, 17.8 mmol). The RM was stirred at 75°C for 2 hours. The RM was allowed to cool to rt and the reaction was quenched with H ₂ O (0.66 ml) and 10% sodium hydroxide solution (0.66 ml). The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-25%, 20 min) to obtain the title compound as yellow liquid (Y=32%). LC-MS (ESI): m/z: [M+H] ⁺ = 223.4.

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpiperidin-3-yl)[1(propan-2-yl) )-1H-pyrazol-4-yl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and Na(1-isopropylpyrazol4-yl)-1-methylpiperidin-3 were used -amine trifluoroacetate. The crude product was purified using preparative HPLC (column: YMC-Actus Triart C18 5 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 25-35%, 12 min) to obtain the desired compound as a white solid (Y=6%). ^1H NMR (400 MHz, methanolA) δ ppm 7.71 (s, 1H), 7.45 (s, 1H), 6.95 (s, 1H), 4.51-4.45 (m, 1H), 4.37-4.31 (m, 1H), 3.53-3.45 (m, 1H), 3.06-3.00 (m, 1H), 2.87 (t, J=7 Hz, 4H), 2.82 (t, J =7 Hz, 4H), 2.57 (s, 3H), 2.40-2.21 (m, 2H), 2.10-1.98 (m, 5n), 1.88-1.84 ( m, 1H), 1.79-1.69 (m, 1H), 1.48 (d, J=7 Hz, 6H), 1.22-1.12 (m, 1H). LC-MS (ESI): m/z: [M+H] ⁺ = 501.3.

Example 56. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpyrrolidin-3yl)[1 -(propan-2-yl) -1H-pyrazol-4-yl]sulfamoyl]urea

Step 1: 1-isopropyl-4-nitropyrazole. To a solution of 4-nitro-1H-pyrazole (10.0 g, 88.44 mmol) in THF (200 ml) was added propan-2-ol (8.12 ml, 106.1 mmol) and PPh ₃ (32.5 g, 123.8 mmol) at RT in an N2 atmosphere. RM cooled to 0°C was added, then DIAD (20.6 mL, 106.1 mmol). The RM was stirred at RT for 12 h, then the solvent was removed under reduced pressure. The residue was purified with FCC (9-20% EtOAc in petroleum ether) to give the title compound as a white solid (Y=58%).

Step 2: 1-isopropylpyrazol-4-amine. To a solution of 1-isopropyl-4-nitropyrazole (3.0 g, 19.34 mmol) in MeOH (40 ml) under nitrogen atmosphere was added 10% Pd/C (600 mg). The RM was purged then stirred under H ₂ at 15 ^psi for 2 hours. The mixture was evaporated under reduced pressure

- 153 047011 research and obtained the desired compound in the form of a brown liquid (Y=99%). ¹ H NMR (400 MHz, methanold4) δ ppm 7.23 (s, 1H), 7.13 (s, 1H), 4.40-4.33 (m, 1H), 1.42 (d, J=6 Hz, 6H).

Step 3: tert-butyl 3-[(1-isopropylpyrazol-4-yl)amino]pyrrolidine-1-carboxylate. General Procedure A was followed and 1-isopropylpyrazol-4-amine and tert-butyl N-oxopyrrolidine-1-carboxylate were used. The crude product was purified by preparative HPLC (column: Agela Innoval ods-2 250x80 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 27-57%, 20 min) to obtain the title compound as yellow liquid (Y=32%). ¹ H NMR (400 MHz, methanolD) δ ppm 7.68 (s, 1H), 7.37 (s, 1H), 5.12-5.02 (m, 1H), 3.85-3.77 (m, 1H), 3.61-3, 55 (m, 1H), 3.48-3.41 (m, 2H), 3.21 (dd, J=4, 11 Hz, 1H), 2.212.13 (m, 1H), 1.92-1 .78 (m, 1H), 1.50 (d, J=7 Hz, 6H), 1.46 (s, 9H).

Step 4: 1-isopropyl-N-(1-methylpyrrolidin-3-yl)pyrazol-4-amine. To a solution of tert-butyl-3-[(1isopropylpyrazol-4-yl)amino]pyrrolidine-1-carboxylate (600 mg, 0.204 mmol) in THF (10 ml), cooled to 0°C, was added portionwise lithium aluminum hydride (774 mg , 0.204 mmol). RM was heated at 80°C for 2 hours. The mixture was diluted with H ₂ O (1 ml and 10% aqueous NaOH (1 ml). The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was used in the next step without processing.

Step 5: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methylpyrrolidin-3-yl)[1(propan-2-yl) )-1H-pyrazol-4-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-isopropyl-N-(1methylpyrrolidin-3-yl)pyrazole were used -4-amine The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) -ACN]; B: 8-38%, 20 min) to obtain the title compound as white solid (Y=5%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.78 (s, 1H), 7.53 (s, 1H), 6.93 (s, 1H), 5.00-4.94 (m, 1H), 4.52-4.45 (m, 1H), 3.493.44 (m, 1H), 3.13-3.03 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.81 (t, J=7 Hz, 4H), 2.70 (s, 3H), 2.39-2.30 (m, 1H), 2.10-1.99 (m, 6H), 1.48 (d, J=7 Hz, 6H ). LC-MS (ESI): m/z: [M+H]+ = 487.2.

Example 57. Sodium salt of 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[(1-methylpyrrolidine -3 -yl)methyl]sulfamoyl]urea

Step 1: tert-butyl 2-[[(1-methylpyrazol-4-yl)amino]methyl]pyrrolidine-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl-N-formylpyrrolidine-1-carboxylate were used. The crude product was purified by preparative HPLC (column: Agela Innoval ods-2 250x80 mm; mobile phase: [water (0.1% TFA) - ACN]) to obtain the title compound as a red solid (Y=49%). 1H NMR (400 MHz, methanol-d^) δ ppm 7.94 (s, 1H), 7.65 (s, 1H), 3.92 (s, 3H), 3.64-3.57 (m, 1H), 3.54-3.47 (m, 1H), 3.41 (d, J=7 Hz, 2H), 3.36-3.33 (m, 1H), 3.13-3.01 (m, 1H), 2.622.49 (m, 1H ), 2.18-2.07 (m, 1H), 1.80-1.66 (m, 1H), 1.46 (s, 9H).

Step 2: 1-methyl-N-[(1-methylpyrrolidin-3-yl)methyl]pyrazol-4-amine trifluoroacetate. A mixture of tert-butyl-3-[[(1-methylpyrazol-4-yl)amino]methyl]pyrrolidine-1-carboxylate (1.0 g, 3.57 mmol) in THF (5 ml) was degassed and purged three times with N ₂ . The RM was cooled to 0°C and treated in portions with lithium aluminum hydride (134 mg, 3.57 mmol). The mixture was heated at 85°C for 5 hours under N ₂ atmosphere. The RM was allowed to cool to rt and treated with water (0.13 mL) and 10% NaOH aqueous solution (0.13 mL). The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: C18; mobile phase: [water (10 mM NH4HCO3) - ACN]) to obtain the title compound as a red oil (Y=54%). ^1H NMR (400 MHz, methanol-d^) δ =7.80 (s, 1H), 7.56 (s, 1H), 3.89 (s, 3H), 3.84-3.53 (m , 3H), 3.49-3.38 (m, 2H), 3.21-3.13 (m, 1H), 2.95 (s, 3H), 2.88-2.73 (m, 1H ), 2.42-2.27 (m, 1H), 2.04-1.90 (m, 1H).

Step 3: 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[(1-methylpyrrolidine) sodium salt -3-yl)methyl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-[(1methylpyrrolidin-3-yl) were used. methyl]pyrazole-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: C18; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]) to obtain the title compound as a white solid (Y=11%). ¹ H NMR (400 MHz, methanol-d^) δ ppm 7.68 (s, 1H), 7.51 (s, 1H), 6.91 (s, 1H), 3.92-3.75 (m, 4H), 3.68-3.42 (m, 3H), 3.27-3.16 (m, 1H), 3.15-3.06 (m, 1H), 2.90-2.73 (m, 11H), 2.69-2.55 ( m, 1H), 2.20-2.11 (m, 1H), 2.09 -1.95 (m, 4H), 1.91-1.83 (m, 1H). LC-MS (ESI): m/z: [M+H] ⁺ = 473.2.

- 154 047011

Example 58. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)({2-methyl- 2-azaspiro[3.3]heptan-6-yl})sulfamoyl]urea

Step 1: tert-butyl 6-[(1-methylpyrazol-4-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl-6-oxo-2azaspiro[3.3]heptane-2-carboxylate were used. The crude material was purified by preparative HPLC (column: C18; mobile phase: [water (0.1% TFA) - ACN]) to obtain the title compound as a red solid (Y=63%). ¹ H NMR (400 MHz, methanol-e ₄ ) δ ppm 7.90 (s, 1H), 7.59 (s, 1H), 3.99-3.87 (m, 8H), 2.65-2.56 (m, 2H), 2.44-2, 34 (m, 2H), 1.42 (s, 9H).

Step 2: 2-methyl^-(1-methylpyrazol-4-yl)-2-azaspiro[3.3]heptane-6-amine trifluoroacetate. To a solution of tert-butyl-6-[(1-methylpyrazol-4-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylate (945 mg, 3.23 mmol) in THF (10 ml), cooled to 0°C, lithium aluminum hydride (1.23 g, 32.3 mmol) was added in portions. RM was heated at 85°C for 12 h under N2 atmosphere. The reaction was stopped with water (1.3 ml) and 10% aqueous NaOH solution (1.3 ml). The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: C18; mobile phase: [water (0.1% TFA) - ACN]) to obtain the title compound as a red solid (Y=85%). ^1H NMR (400 MHz, methanol-ioD δ ppm 7.74 (s, 1H), 7.48 (s, 1H), 4.40-4.27 (m, 2H), 4.104.03 ( m, 2H), 3.94-3.90 (m, 1H), 3.88 (s, 3H), 2.88 (s, 3H), 2.78-2.65 (m, 2H), 2 .55-2.39 (m, 2H).

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)({2-methyl- 2-azaspiro[3.3]heptan-6-yl})sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 2-methyl-M-(1methylpyrazol-4-yl)- 2-azaspiro[3.3]heptane-6-aminetrifluoroacetate. The crude product was purified by preparative HPLC (column: C18; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]) to obtain the title compound as a white solid (Y=12%). ¹ H NMR (400 MHz, methanol-e ₄ ) δ ppm 7.63 (s, 1H), 7.43 (s, 1H), 6.92 (s, 1H), 4.58-4.46 (m, 1H), 4.02 (s, 2H), 3 .84 (s, 3H), 3.76 (s, 2H), 2.86 (t, J=7 Hz, 4H), 2.77 (t, J=7 Hz, 4H), 2.70 (s , 3H), 2.57-2.46 (m, 2H), 2.16-1.96 (m, 6H). LC-MS (ESI): m/z: [M+H]+ = 485.2.

Example 59. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(1-methylazetidin-3 -yl)sulfamoyl]urea

Step 1: tert-butyl 3-[(1-methylpyrazol-4-yl)amino]azetidine-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl-N-oxoazetidine-1-carboxylate were used. The crude product was purified by preparative HPLC (column: Agela Innoval ods-2 350x100 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 3-35%, 23 min) to obtain the title compound as red solid (Y=37%). ¹ H NMR (400 MHz, methanol-e ₄ ) δ ppm 7.12 (s, 1H), 7.08 (s, 1H), 4.50-4.47 (m, 1H), 4.19-4.09 (m, 4H), 3.77 (s, 3H), 1.44 (s, 9H).

Step 2: 1-methyl-N(1-methylazetidin-3-yl)pyrazol-4-amine trifluoroacetate. Lithium aluminum hydride was added to a solution of tert-butyl3-[(1-methylpyrazol-4-yl)amino]azetidine-1-carboxylate (1.0 g, 2.73 mmol) in THF (10 ml) cooled to 0°C (1.04 g, 27.3 mmol). The mixture was stirred at 0°C for 0.5 h, then the mixture was heated at 85°C for 2.5 h. RM was diluted with water (1 ml) and 8% NaOH solution

- 155 047011 (1 ml), then the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Xtimate C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO3) - ACN]; B: 0-8%, 20 min) to obtain the title compound as a red oil (Y=39%). ^1H NMR (400 MHz, methanol^) δ = 7.18 (s, 1H), 7.11 (s, 1H), 4.61-4.57 (m, 1H), 4.24-4.08 (m, 3H), 3.84-3.81 (m, 1H), 3.78 (s, 3H), 2.96 (s, 3H).

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)(1methylazetidin-3 -yl)sulfamoyl] urea. General Procedure B was used and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-\-(1methylazetidin-3-yl)pyrazole were used -4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: YMC-Triart prep C18-s 250x50 mm; mobile phase: [water (10 mM NH4HCO3) ACN]; B: 5-35%, 20 min) to obtain the title compound as white solid (Y=3%). 1H NMR (400 MHz, methanolIII ₄ ) δ ppm 7.68 (s, 1H), 7.51 (s, 1H), 6.91 (s, 1H), 5.00-4.96 (m, 1H), 4.02-3.96 (m, 2H), 3.88 (s, 3H), 3.64-3.58 (m, 2H), 2.88-2.84 (m, 4H), 2.82-2.78 (m, 4H) , 2.57 (s, 3H), 2.10-2.05 (m, 4H). LCMS (ESI): m/z: [M+H]+ = 445.1.

Example 60. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl) [ 1 -methyl-2 -(trifluoromethyl)piperidin-4-yl]sulfamoyl]urea

Step 1: tert-butyl 4-[(1-methylpyrazol-4-yl)amino]-2-(trifluoromethyl)piperidine-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl 4-oxo-2(trifluoromethyl)piperidine-1-carboxylate were used. The crude product was purified using preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 35-45%, 20 min) and the desired compound was obtained as a yellow oil (Y=23%). 1H NMR (400 MHz, DMSO- _d6 ) δ = 7.17 (s, 1H), 6.96 (s, 1H), 4.80-4.69 (m, 1H), 4.34-4, 26 (m, 1H), 3.87-3.80 (m, 1H), 3.68 (s, 3H), 3.10-3.03 (m, 1H), 2.19-2.13 ( m, 1H), 2.09-2.01 (m, 1H), 1.60-1.52 (m, 1H), 1.42 (s, 9H), 1.38-1.35 (m, 1H).

Step 2: 1-methyl-N-(1-methylpyrazol-4-yl)-2-(trifluoromethyl)piperidine-4-amine trifluoroacetate. To a solution of tert-butyl-4-[(1-methylpyrazol-4-yl)amino]-2-(trifluoromethyl)piperidine-1-carboxylate (250 mg, 0.72 mmol) in THF (3 ml), cooled to 0 °C, lithium aluminum hydride (272 mg, 7.2 mmol) was added. RM was heated at 90°C for 3.5 hours. RM was cooled to 0°C and H ₂ O (0.3 ml) was added to stop the reaction. The RM was then diluted with 10% NaOH aqueous solution and stirred for 10 min. The mixture was filtered and the solid was washed with 10:1 DCM/MeOH (20 ml) and filtered again. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-20%, 20 min) and the desired compound was obtained as a yellow oil (Y=37%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.84 (s, 1H), 7.49 (s, 1H), 3.83 (s, 3H), 3.45-3.25 (m, 3H), 3.09-3.01 (m, 1H), 2.41 (s, 3H), 2.14-2.03 (m, 1H), 1.94-1.84 (m, 1H), 1.64-1.48 (m, 2H) .

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)[1methyl-2 -(trifluoromethyl)piperidin-4-yl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-(1methylpyrazol-4-yl)- 2-(trifluoromethyl)piperidine-4-aminetrifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell C18 250x50 mm 10 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 10-40%, 20 min) to obtain the title compound in as a white solid (Y=8%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.85 (s, 1H), 7.80 (s, 1H), 7.31 (s, 1H), 6.96 (s, 1H), 4.17-4.11 (m, 1H), 3 .84 (s, 3H), 2.93-2.90 (m, 1H), 2.86-2.76 (m, 5H), 2.72-2.69 (m, 4H), 2.37 -2.34 (m, 1H), 2.20 (s, 3H), 2.03-1.95 (m, 5H), 1.76-1.70 (m, 1H), 1.34-1 .12 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 541.2.

- 156 047011

Example 61. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-III-pyrazol-4yl) [ 1 -(2, 2,2-trifluoroethyl)pyrrolidin-3-yl]sulfamoyl]urea

Step 1: tert-butyl 3-[(1-methylpyrazol-4-yl)amino]pyrrolidine-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl N-oxopyrrolidine-1-carboxylate were used to obtain the title compound as a yellow oil (Y=42%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ =7.08 (s, 1H), 6.93 (s, 1H), 4.56-4.50 (m, 1H), 3.68 (s , 3H), 3.63-3.53 (m, 1H), 3.45-3.38 (m, 1H), 3.28-3.23 (m, 1H), 3.083.03 (m, 1H ), 2.05-1.97 (m, 1H), 1.81-1.65 (m, 1H), 1.49-1.45 (m, 1H), 1.38 (s, 9H).

Step 2: 1-methyl-X-pyrrolidin-3-ylpyrazol-4-amine hydrochloride. A solution of tert-butyl 3-[(1methylpyrazol-4-yl)amino]pyrrolidine-1-carboxylate (3.0 g, 11.26 mmol) in 4 M HCl in EtOAc (2.82 mL, 11.26 mmol) stirred at RT for 12 hours. The solution was concentrated in vacuo to give the title compound as a yellow solid (Y=96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.61 (s, 1H), 9.50 (s, 1H), 7.87 (s, 1H), 7.57 (s, 1H), 3.90 (s, 3H), 3.54-3 .42 (m, 1H), 3.35-3.17 (m, 3H), 3.06-2.98 (m, 1H), 2.18-2.09 (m, 1H), 1.90 -1.81 (m, 1H).

Step 3: 2,2,2-trifluoro-1-[3-[(1-methylpyrazol-4-yl)amino]pyrrolidin-1-yl]ethanone. To a solution of 1methyl-N-pyrrolidin-3-ylpyrazol-4-amine hydrochloride (608 mg, 3.01 mmol) in MeOH (5 ml) was added ethyl 2,2,2-trifluoroacetate (5.00 ml, 36.3 mmol ). The RM was stirred at RT for 1 hour. DIPEA (2.10 mL, 12.0 mmol) was then added to the solution. The mixture was stirred at RT for another 10 hours. The RM was concentrated and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0- 22%, 20 min) and obtained the desired compound in the form of a yellow oil (Y=19%). LC-MS (ESI): m/z: [M+H]+ = 263.1.

Step 4: 1-methyl-N-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyrazol-4-amine trifluoroacetate. 2,2,2Trifluoro-1-[3-[(1-methylpyrazol-4-yl)amino]pyrrolidin-1-yl]ethanone trifluoroacetate (270 mg, 0.72 mmol) was added to 10 M BH ₃ -Me ₂ S (3 ml). The mixture was stirred at RT for 23 hours. The solution was cooled to 0°C and treated dropwise with MeOH (20 ml). The resulting solution was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-25%, 23 min) to obtain the title compound as yellow oil (Y=58%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.87 (s, 1H), 7.53 (s, 1H), 4.01-3.95 (m, 1H), 3.83 (s, 3H), 3.38 (kv, J=10 Hz , 2H), 3.00-2.86 (m, 3H), 2.72-2.66 (m, 1H), 2.19-2.11 (m, 1H), 1.85-1.76 (m, 1H). NH were not visible.

Step 5: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)[1(2 ,2,2-trifluoroethyl)pyrrolidin-3-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-[1-(2,2, 2trifluoroethyl)pyrrolidin-3-yl]pyrazol-4-aminetrifluoroacetate. The crude product was purified by preparative HPLC (column: Xtimate C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 1-35%, 30 min) to obtain the title compound as an off-white solid substances (Y=5%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.74 (s, 1H), 7.50 (s, 1H), 6.97 (s, 1H), 3.87 (s, 3H), 3.13-2.96 (m, 4H), 2 .88-2.77 (m, 8H), 2.71-2.67 (m, 1H), 2.65-2.53 (m, 2H), 2.22-2.12 (m, 1H) , 2.10-2.02 (m, 4H), 1.83-1.78 (m, 1H). LC-MS (ESI): m/z: [M+H] ⁺ = 527.2.

Example 62. Sodium salt of 1-[(1-ethylpiperidin-3-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea

Step 1: tert-butyl 3-[(1-methylpyrazol-4-yl)amino]piperidine-1-carboxylate. General procedure A was used and 1-methylpyrazol-4-amine and tert-butyl N-oxopiperidine-1-carboxylate were used and

- 157 047011 the desired compound was obtained in the form of a yellow oil (Y=55%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ =7.04 (s, 1H), 6.94 (s, 1H), 4.38-4.23 (m, 1H), 3.89-3 .79 (m, 1H), 3.68 (s, 3H), 2.92-2.61 (m, 2H), 1.96-1.84 (m, 1H), 1.66-1.63 (m, 1H), 1.37 (s, 9H), 1.34-1.27 (m, 2H).

Step 2: tert-butyl-3-[(1-methylpyrazol-4-yl)-(2,2,2-trifluoroacetyl)amino]piperidine-1 carboxylate. To a solution of tert-butyl-3-[(1-methylpyrazol-4-yl)amino]piperidine-1-carboxylate (3.0 g, 10.7 mmol) in DCM (20 ml), cooled to 0°C, was added triethylamine (2.23 ml, 16.1 mmol) and trifluoroacetic anhydride (1.49 ml, 10.7 mmol). The mixture was stirred at 0°C for 2 hours. The solution was concentrated in vacuo. The crude reaction product was purified using FCC (0-100% EtOAc in petroleum ether) to give the title compound as a yellow oil (Y=52%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.50 (s, 1H), 4.21-4.14 (m, 1H), 3.84 (s, 3H), 2.87-2.81 (m, 1H), 1.83-1.77 (m, 1H), 1.65-1.59 (m, 1H), 1.39 (s, 9H), 1.18-1.07 (m, 4H) .

Step 3: 2,2,2-trifluoro-H-(1-methylpyrazol-4-yl)-N-(3-piperidyl)acetamide hydrochloride. A solution of tert-butyl 3-[(1-methylpyrazol-4-yl)-(2,2,2-trifluoroacetyl)amino]piperidine-1-carboxylate (2.0 g, 5.31 mmol) and 4 M HCl in EtOAc (1.33 mL, 5.31 mmol) was stirred at RT for 3 hours. The solution was concentrated in vacuo to give the title compound as a yellow solid (Y=90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.99 (s, 1H), 7.92-7.62 (br.s, 2H), 7.52 (s, 1H), 4.73-4.66 (m, 1H), 3.85 ( s, 3H), 3.38-3.30 (m, 1H), 3.14-3.06 (m, 1H), 2.69-2.62 (m, 1H), 2.49-2. 43 (m, 1H), 1.87-1.75 (m, 3H), 1.36-1.26 (m, 1H).

Step 4: N-(1-ethyl-3-piperidyl)-2,2,2-trifluoro-N-(1-methylpyrazol-4-yl)acetamide trifluoroacetate. To a solution of 2,2,2-trifluoro-H-(1-methylpyrazol-4-yl)-N-(3-piperidyl)acetamide hydrochloride (1.13 g, 3.62 mmol) in DMF (10 ml) was added iodoethane 579 µl, 7.24 mmol) and K ₂ CO ₃ (1.00 g, 7.24 mmol). The mixture was stirred at RT for 3 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 250x50 mm; mobile phase: [water (0.1% TFA)-ACN]; B: 1-20%, 20 min) to obtain the title compound as yellow oils (Y=40%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 7.98 (s, 1H), 7.54 (s, 1H), 4.72-4.65 (m, 1H), 3.85 (s, 3H), 3 .61 (d, J=11 Hz, 1H), 3.37 (d, J=12 Hz, 1H), 3.16-3.08 (m, 2H), 2.74-2.59 (m, 2H), 1.93-1.84 (m, 2H), 1.78-1.68 (m, 1H), 1.27-1.20 (m, 4H).

Step 5: 1-ethyl-H-(1-methylpyrazol-4-yl)piperidin-3-amine trifluoroacetate. To a solution of H-(1-ethyl3-piperidyl)-2,2,2-trifluoro-H-(1-methylpyrazol-4-yl)acetamide trifluoroacetate (756 mg, 1.81 mmol) in MeOH (5 ml) and H ₂ O (5 ml) NaOH (145 mg, 3.61 mmol) was added. RM was stirred at RT for 5 hours. The solution was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-15%, 23 min) to obtain the title compound as yellow oil (Y=65%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.41 (s, 1H), 7.20 (s, 1H), 7.04 (s, 1H), 3.71 (s, 3H), 3.52-3.34 (m, 2H), 3 .24-3.00 (m, 4H), 2.81-2.69 (m, 1H), 2.02-1.89 (m, 2H), 1.77-1.65 (m, 2H) , 1.32-1.18 (m, 4H).

Step 6: sodium salt 1-[(1-ethylpiperidin-3-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro^- indacen-4-yl)urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-ethyl-N-(1-methylpyrazol-4-yl )piperidine-3-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Xtimate C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 133%, 25 min) to obtain the title compound as an off-white solid ( Y=10%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.67 (s, 1H), 7.44 (s, 1H), 6.94 (s, 1H), 4.41-4.33 (m, 1H), 3.87 (s, 3H), 3 .67-3.59 (m, 1H), 3.23-3.15 (m, 1H), 2.93-2.78 (m, 10H), 2.52-2.25 (m, 2H) , 2.12-1.98 (m, 5H), 1.94-1.85 (m, 1H), 1.831.69 (m, 1H), 1.31-1.18 (m, 4H). LC-MS (ESI): m/z: [M+H]+ = 487.2.

Example 63. Sodium salt 1-{[2-(azetidin-1-yl)ethyl](1-methyl-1H-pyrazol-4-yl)sulfamoyl}-3(1,2,3,5,6,7- hexahydro^-indacen-4-yl)urea

Step 1: N[2-(azetidin-1-yl)ethyl]-1-methylpyrazole-4-amine trifluoroacetate. To a solution of 1-methylpyrazol-4-amine (406 mg, 4.18 mmol) in DMF (2 ml) was added 1-(2-chloroethyl)azetidine (500 mg,

- 158 047011

4.18 mmol), Cs2CO3 (2.04 g, 6.27 mmol) and KI (763 mg, 4.60 mmol). The RM was stirred at 100°C for 12 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-5%, 20 min) to obtain the title compound as a colorless oils 1H NMR (400 MHz, methanol-d^δ ppm 7.20 (s, 1H), 7.13 (s, 1H), 4.29-4.02 (m, 4H), 3.78 ( s, 3H), 3.37-3.33 (m, 2H), 3.21-3.13 (m, 2H), 2.69-2.34 (m, 2H).

Step 2: sodium salt 1-{[2-(azetidin-1-yl)ethyl](1-methyl-1H-pyrazol-4-yl)sulfamoyl}-3(1,2,3,5,6,7- hexahydro^-indacen-4-yl)urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and Na[2-(azetidin-1yl)ethyl]-1- Methylpyrazole-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: YMC-Triart prep C18-s 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ ) ACN]; B: 1-31%, 20 min) to obtain the title compound as white solid (Y=5%). 1H NMR (400 MHz, methanol^) δ ppm 7.67 (s, 1H), 7.50 (s, 1H), 6.92 (s, 1H), 4.27-4.06 (m, 4H), 3.85 (s, 3H), 3 ,81-3.75 (m, 2H), 3.28-3.22 (m, 2H), 2.86 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.53-2.40 (m, 2H), 2.12-2.01 (m, 4H). LC-MS (ESI): m/z: [M+H]+ = 459.2.

Example 64. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-III-pyrazol-4yl) [ 1 -(propan- 2-yl)azetidin-3-yl]sulfamoyl]urea

Step 1: tert-butyl 3-[(1-methylpyrazol-4-yl)amino]azetidine-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl-N-oxoazetidine-1-carboxylate were used. The crude product was purified by preparative HPLC (column: Agela Innoval ods-2 350x100 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 3-35%, 23 min) to obtain the title compound as red solid (Y=58%). ^1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.24 (s, 1H), 7.16 (s, 1H), 4.22-4.14 (m, 2H), 4.03-3.99 (m, 1H), 3.80 (s, 3H), 3.76-3.70 (m, 2H), 1.44 (s, 9H).

Step 2: tert-butyl 3-[(1-methylpyrazol-4-yl)-(2,2,2-trifluoroacetyl)amino]azetidine-1-carboxylate. To a solution of tert-butyl-3-[(1-methylpyrazol-4-yl)amino]azetidine-1-carboxylate (1.5 g, 5.95 mmol) and triethylamine (1.65 ml, 11.9 mmol) in DCM (15 ml), cooled to 0°C, (2,2,2-trifluoroacetyl)2,2,2-trifluoroacetate (0.99 ml, 7.13 mmol) was added dropwise. The RM was stirred at 0°C for 2 hours. The solvent was removed under reduced pressure to leave a residue. The residue was purified with FCC (0-40% ethyl acetate in petroleum ether) to give the title compound as a yellow oil (Y=63%). 1H NMR (400 MHz, methanol-ph) δ = 7.94 (s, 1H), 7.62 (s, 1H), 5.23-5.16 (m, 1H), 4.17-4.11 (m, 2H), 3.95 (s, 3H), 3.83-3.77 (m, 2H), 1.38 (s, 9H).

Step 3: Na(azetidin-3-yl)-2,2,2-trifluoro-N-(1-methylpyrazol-4-yl)acetamide hydrochloride. A mixture of tert-butyl-3-[(1-methylpyrazol-4-yl)-(2,2,2-trifluoroacetyl)amino]azetidine-1-carboxylate (1.0 g, 2.16 mmol) and 4 M HCl in EtOAc (10 ml) was stirred at RT for 23 hours. The solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-20%, 20 min) to obtain the title compound as white solid (Y=49%). 1H NMR (400 MHz, methanol^ ₄ ) δ = 7.94 (s, 1H), 7.64 (s, 1H), 5.32 (sq, J=8 Hz, 1H), 4.28-4, 22 (m, 2H), 4.16-4.11 (m, 2H), 3.96 (s, 3H).

Step 4: 2,2,2-trifluoro-N-(1-isopropylazetidin-3-yl)-N-(1-methylpyrazol-4-yl)acetamide hydrochloride. General Procedure A was followed and Na(azetidin-3-yl)-2,2,2-trifluoro-N-(1methylpyrazol-4-yl)acetamide hydrochloride and acetone were used to obtain the title compound as a white solid (Y=89%) . 1H NMR (400 MHz, methanol^ ₄ ) δ =7.91 (s, 1H), 7.59 (s, 1H), 5.03-4.99 (m, 1H), 4.04-3.96 (m, 2H), 3.94 (s, 3H), 3.92-3.86 (m, 1H), 3.60-3.47 (m, 2H), 1.06 (d, J=6 Hz, 6H).

Step 5: N(1-isopropylazetidin-3-yl)-1-methylpyrazole-4-amine trifluoroacetate. To a solution of 2,2,2trifluoro-N-(1-isopropylazetidin-3-yl)-N-(1-methylpyrazol-4-yl)acetamide hydrochloride (254 mg, 0.78 mmol) in MeOH (1.5 ml) and H ₂ O (1.5 ml) was added NaOH (62 mg, 1.55 mmol). The mixture was stirred at RT for 2 hours. The solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-5%, 20 min) to obtain the title compound as a colorless

- 159 047011 liquid (Y=67%). 1H NMR (400 MHz, methanol-d^ δ = 7.22-7.14 (m, 1H), 7.12 (s, 1H), 4.50-4.42 (m, 1H), 4.34 -4.26 (m, 1H), 4.14-4.10 (m, 1H), 4.01-3.94 (m, 1H), 3.93-3.84 (m, 1H), 3 .78 (s, 3H), 3.45-3.38 (m, 1H), 1.25 (d, J=6 Hz, 6H).

Step 6: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)[1(propane -2-yl)azetidin-3-yl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and Na(1-isopropylazetidin3-yl)-1-methylpyrazol-4 were used -amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Xtimate C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 130%, 25 min) to obtain the title compound as a white solid (Y =11%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.70 (s, 1H), 7.52 (s, 1H), 6.92 (s, 1H), 5.09-5.05 (m, 1H), 4.21-4.11 (m, 2H), 3.883.82 (m, 5H), 3.16-3.08 (m, 1H), 2.86 (t, J=7 Hz, 4H), 2.79 (t, J=7 Hz, 4H), 2.11-2.01 (m, 4H), 1.11 (d, J=6 Hz, 6H). LC-MS (ESI): m/z: [M+H]+ = 473.2.

Example 65. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[1-(2, 2,2-trifluoroethyl)piperidin-4-yl]sulfamoyl]urea

F

Step 1: 2,2,2-trifluoro-1-[4-[(1-methylpyrazol-4-yl)amino]-1-piperidyl]ethanone. Ethyl 2,2,2-trifluoroacetate (6 .66 ml, 48.3 mmol) and DIPEA (1.29 ml, 7.38 mmol). RM was stirred at RT for 10 hours. The solution was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-30%, 20 min) to obtain the title compound as yellow oils (Y=85%). 1H NMR (400 MHz, DMSO-d6) δ =7.90 (s, 1H), 7.53 (s, 1H), 4.35-4.27 (m, 1H), 3.94-3.86 (m, 1H), 3.83 (s, 3H), 3.60-3.50 (m, 1H), 3.27 (t, J=12 Hz, 1H), 2.92 (t, J= 12 Hz, 1H), 2.08-1.98 (m, 2H), 1.53-1.37 (m, 2H). NH is not visible.

Step 2: N(1-methylpyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidine-4-amine trifluoroacetate. To a solution of 2,2,2-trifluoro-1-[4-[(1-methylpyrazol-4-yl)amino]-1-piperidyl]ethanone (870 mg, 3.15 mmol) was added 10 M BH ₃ -Me ₂ S (10 ml). The mixture was stirred at RT for 24 hours. The reaction was stopped by adding MeOH (10 ml) at 0°C, then concentrated in vacuo. The residue was purified using a preparative HPLC column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-25%, 20 min) and the desired compound was obtained (Y=10%). ^1H NMR (400 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.60 (s, 1H), 3.86 (s, 3H), 3.34-3.20 (m, 3H), 3.01-2.93 (m, 2H), 2.39 (t, J=12 Hz, 2H), 1.89-1.81 (m, 2H), 1.59-1.49 (m, 2H). NH were not visible.

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-III-pyrazol-4-yl)[1(2 ,2,2-trifluoroethyl)piperidin-4-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino} sulfonyl chloride and N-(1-methylpyrazol4-yl)-1-(2 ,2,2-trifluoroethyl) piperidine-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Xtimate C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 5-40%, 30 min) to obtain the title compound as yellow solid (Y=10%). 1H NMR (400 MHz, methanol^) δ ppm 7.71 (s, 1H), 7.43 (s, 1H), 6.99 (s, 1H), 4.17-4.02 (m, 1H), 3.90 (s, 3H), 3 .04-2.93 (m, 4H), 2.91-2.77 (m, 8H), 2.48 (t, J=12 Hz, 2H), 2.13-2.03 (m, 5H ), 1.94-1.84 (m, 2n), 1.54-1.41 (m, 2n). LC-MS (ESI): m/z: [M+H] ⁺ = 541.2.

- 160 047011

Example 66. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)({2-oxaspiro[ 3.3 ]heptan-6-yl})sulfamoyl]urea

ABOUT

Step 1: 1-methyl-X-(2-oxaspiro[3.3|heptan-6-yl)pyrazol-4-amine trifluoroacetate. General Procedure A was followed and 1-methylpyrazol-4-amine and 2-oxaspiro[3.3]heptan-6-one were used. The crude product was purified by preparative HPLC (column: C18; mobile phase: [water (0.1% TFA) ACN]) to obtain the title compound as a red oil (Y=36%). 1H NMR (400 MHz, methanol^) δ ppm 8.10 (s, 1H), 7.77 (s, 1H), 4.47 (s, 1H), 3.93 (s, 3H), 3.82 (s, 2H), 3.76 (s , 2H), 2.20 (d, J=6 Hz, 2H), 1.871.81 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)({2-oxaspiro[ 3.3]heptan-6-yl})sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-X-(2oxaspiro[3.3]heptane-6) were used -yl)pyrazol-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 5 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 1-35%, 20 min) to obtain the title compound as white solid (Y=1%). ¹ 11 NMR (400 MHz, methanol^) δ ppm 7.25 (s, 1H), 7.19 (s, 1H), 6.99 (s, 1H), 4.52 (s, 2H), 3.97 (s, 1H), 3.78 (s , 3H), 3.15 (s, 2H), 2.87 (t, J=7 Hz, 4H), 2.79 (t, J=7 Hz, 4H), 2.09-2.01 (m , 4H), 1.93-1.86 (m, 2H), 1.65-1.58 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 472.2.

Example 67. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(1-methylazepan-4 -yl)sulfamoyl]urea

Step 1: tert-butyl 4-[(1-methylpyrazol-4-yl)amino]azepane-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl 4-oxoazepane-1-carboxylate were used. The crude product was purified by preparative HPLC (column: Agela Innoval ods-2 250x80 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 5-38%, 20 min) to obtain the title compound as red solid (Y=33%). Jl NMR (400 MHz, methane. i-d4) δ ppm 7.16 (s, 1H), 7.11 (s, 1H), 3.78 (s, 3H), 3.52-3.45 (m, 1H), 3.43-3.40 (m, 1H), 3.39-3.36 (m, 1H), 3.27-3.25 (m, 1H), 3.01-2.96 (m, 1H), 2.06-1.96 ( m, 1H), 1.95-1.87 (m, 1H), 1.86-1.78 (m, 1H), 1.62-1.53 (m, 3H), 1.47 (s, 9H).

Step 2: 1-methyl-N(1-methylpyrazol-4-yl)azepan-4-amine trifluoroacetate. Aluminum hydride was added to a solution of tert-butyl-4[(1-methylpyrazol-4-yl)amino]azepan-1-carboxylate (1.0 g, 3.40 mmol) in THF (10 ml) cooled to 0°C lithium (0.93 g, 24.5 mmol). The RM was stirred at 0°C for 0.5 h, then heated at 85°C for 2.5 h. The reaction was stopped with water (1 ml) and 8% NaOH aqueous solution (1 ml). The mixture was filtered and the filtrate was evaporated under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-5%, 20 min) to obtain the title compound as yellow solid (Y=37%). 'I NMR (400 MHz, melanolE ₄ ) δ ppm 7.69 (s, 1H), 7.47 (s, 1H), 3.88 (s, 3H), 3.59-3.48 (m, 3H), 3.21-3.04 (m, 2H), 2.91 (s, 3H), 2.56-1.81 (m, 6H).

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)(1methylazepan-4 -yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-melyl-X-(1-melylpyrazol-4yl)azepan-4 were used -amine trifluoroacetate. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 5 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; V: 5

- 161 047011

35%, 20 min) and obtained the desired compound in the form of a white solid (Y=15%). 1H NMR (400

MHz, methanol^) δ ppm 7.69 (s, 1H), 7.45 (s, 1H), 6.94 (s, 1H), 4.43-4.38 (m, 1H), 3.86 (s, 3H), 3 .16-3.09 (m, 4H), 2.95-2.76 (m, 8H), 2.71 (s, 3H), 2.42-2.28 (m, 1H), 2.25 -2.12 (m, 1H), 2.05-1.95 (m, 4H), 1.86-1.78 (m, 3H), 1.62-1.58 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 487.2.

Example 68. Sodium salt 3-('1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-me'gyl-1H-pyrazol-4yl)[(1 -methylpyrrolidin-2-yl)methyl]sulfamoyl]urea

Step 1: tert-butyl 2-[[(1-methylpyrazol-4-yl)amino]methyl]pyrrolidine-1-carboxylate. General Procedure A was followed and 1-methylpyrazol-4-amine and tert-butyl 2-formylpyrrolidine-1-carboxylate were used. The crude product was purified using preparative HPLC (column: Phenomenex

Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 5-35%, 20 min) and the desired compound was obtained as a yellow oil (Y=28%). ^1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.20 (s, 1H), 7.11 (s, 1H), 4.01-3.91 (m, 1H), 3.76 (s, 3H), 3.38-3.30 (m, 2H), 3.18-3.10 (m, 1H), 2.90-2.85 (m, 1H), 1.95-1.75 (m, 4H), 1.47 (s, 9H) .

Step 2: 1-methyl-N[(1-methylpyrrolidin-2-yl)methyl]pyrazol-4-amine trifluoroacetate. Lithium aluminum hydride (68 mg, 1 .78 mmol). The RM was stirred at 80°C for 1 hour. The mixture was diluted with H ₂ O (0.8 ml) and then with 10% aqueous sodium hydroxide (0.8 ml). The RM was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (conditions; column: Phenomenex Luna C18 10 μm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-5%, 20 min) to obtain the title compound in in the form of a red liquid.

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[(1-methylpyrrolidin- 2-yl)methyl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-Y-[(1methylpyrrolidin-2-yl) were used. methyl]pyrazole-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 10 µm 150x40 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 15-35%, 11 min) to obtain the title compound as white solid (Y=3%). 1H NMR (400 MHz, methanol-^) δ ppm 7.70 (s, 1H), 7.55 (s, 1H), 6.92 (s, 1H), 4.214.13 (m, 1H), 3.86 (s, 3H), 3.82-3 .75 (m, 3H), 3.53-3.41 (m, 1H), 3.14-3.09 (m, 2H), 2.93 (s, 3H), 2.88-2.83 (m, 8H), 2.14-1.97 (m, 6H). LC-MS (ESI): m/z: [M+H]+ = 473.2.

Example 69. Sodium salt of 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[2-(2 ,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]sulfamoyl]urea

Step 1: Na(1-methylpyrazol-4-yl)-2-azaspiro[3.3]heptane-6-amine hydrochloride. Mixture of tert-butyl-6[(1-methylpyrazol-4-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 2.05 mmol) (synthesis described in example 58) with 4 M HCl in EtOAc (0.51 ml, 2.05 mmol) was stirred at RT for 16 hours. The solution was concentrated in vacuo to give the title compound as a yellow solid (Y=85%).

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1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.00-11.60 (br.s, 1H), 9.02 (s, 1H), 8.20 (s, 1H), 8.05-8.01 (m, 1H), 7.59 ( d, J=7 Hz, 1H), 4.09-3.90 (m, 5H), 3.85 (s, 3H), 3.11-3.04 (m, 1H), 2.56-2 .51 (m, 2H), 2.41-2.30 (m, 1H).

Step 2: 2,2,2-trifluoro-1-[6-[(1-methylpyrazol-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]ethanone. Ethyl 2,2,2-trifluoroacetate was added to a solution of H-(1-methylpyrazol-4-yl)-2-azaspiro[3.3]heptan-6-amine hydrochloride (400 mg, 1.75 mmol) in MeOH (1 ml). (3.36 ml, 24.4 mmol). The solution was stirred at RT for 1 hour. DIPEA (0.91 mL, 5.25 mmol) was added and RM was stirred at RT for 14 hours. The solution was concentrated in vacuo. The crude reaction product was purified by preparative TLC (10:1 ethyl acetate/methanol. Rf=0.56) to give the title compound as a yellow oil (Y=40%). LCMS (ESI): m/z: [M+H]+ = 289.2.

Step 3: H-(1-methylpyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptane-6-amine trifluoroacetate. A mixture of 2,2,2-trifluoro-1-[6-[(1-methylpyrazol-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]ethanone (200 mg, 0.69 mmol) in 10 M BH ₃ -Me ₂ S (3 ml) was stirred at RT for 7 hours. The solution was cooled to 0°C and MeOH (20 ml) was added dropwise. RM was concentrated in vacuo. The crude reaction product was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-20%, 20 min) to obtain the title compound in as a yellow oil (Y=22%). 1H NMR (400 MHz, DMSOY) δ ppm 8.35 (s, 1H), 7.69 (s, 1H), 4.31 (s, 1H), 3.80 (s, 3H), 3.69-3.58 (m, 6H), 3 .17-3.11 (m, 2H), 2.25-2.19 (m, 1H), 2.01 (s, 1H).

Step 4: sodium salt 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)[2( 2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and N-(1methylpyrazol-4-yl)-2-(2 ,2,2-trifluoroethyl)-2-azaspiro[3.3]heptane-6-aminetrifluoroacetate. The crude product was purified by preparative HPLC (column: Xtimate C18 5 µm 150x25 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 30-40%, 12 min) to obtain the title compound as almost white solid (Y=7%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.72 (s, 1H), 7.44 (s, 1H), 6.99 (s, 1H), 4.63-4.58 (m, 1H), 3.90 (s, 3H), 3 .44 (s, 2H), 3.19 (s, 2H), 3.08-3.00 (m, 2H), 2.90-2.76 (m, 8H), 2.46-2.41 (m, 2H), 2.12-2.00 (m, 6H). LC-MS (ESI): m/z: [M+H]+ = 553.2.

Example 70. Sodium salt of 3-(3,5-diethylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea

Step 1: N[(3,5-diethylphenyl)carbamoyl]sulfamoyl chloride. To a solution of Na(oxomethylene)sulfamoyl chloride (58 μl, 0.67 mmol) in isopropyl ether (1 ml), cooled to -30°C, was added a solution of 3,5-diethylaniline (156 μl, 0.67 mmol) in isopropyl ether (1 ml). RM was stirred at -30°C for 2 hours and the title compound was obtained as a solution in isopropyl ether (2 ml). It was used immediately.

Step 2: 3-(3,5-diethylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. General Procedure B was followed and N-[(3,5diethylphenyl)carbamoyl]sulfamoyl chloride and 1-methyl-Ntetrahydropyran-3-ylpyrazol-4-amine were used (synthesis described in Example 1). The crude product was purified using preparative HPLC (column: NanoMicro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 0-30%, 26 min) and obtained the desired compound in the form of a white solid (Y=2%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.68 (s, 1H), 7.42 (s, 1H), 7.07 (s, 2H), 6.70 (s, 1H), 4.38-4.19 (m, 1H), 3 ,96-3.88 (m, 2H), 3.83 (s, 3H), 3.52-3.44 (m, 2H), 2.58 (kV, J=7 Hz, 4H), 1, 94-1.86 (m, 2H), 1.51-1.38 (m, 2H), 1.21 (t, J=7 Hz, 6H). LC-MS (ESI): m/z: [M+H]+ = 436.2.

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Example 71. 1-[(1-Methyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3-[3-(propan-2yl)phenyl]urea sodium salt

Step 1: H-[(3-isopropylphenyl)carbamoyl]sulfamoyl chloride. To a solution of \-(oxomethylene)sulfamoyl chloride (96 μl, 1.11 mmol) in isopropyl ether (2 ml), cooled to -30°C, was added a solution of 3-isopropylaniline (156 μl, 1.11 mmol) in isopropyl ether ( 2 ml). The mixture was stirred at -30°C for 2 hours and the title compound was obtained as a solution in isopropyl ether (4 ml) (Y=98%). LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 273.1.

Step 2: 1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3-[3-(propan-2yl)phenyl]urea sodium salt. General procedure B was followed and H-[(3-isopropylphenyl)carbamoyl]sulfamoyl chloride and 1-methyl-N-tetrahydropyran-ylpyrazol-4-amine were used (synthesis described in Example 1). The crude product was purified using preparative HPLC (column: Nano-Micro

Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 0-30%, 25 min) and the title compound was obtained as a white solid (Y=24%). ¹ H NMR (400 MHz, methanold ₄ ) δ ppm 7.72 (s, 1H), 7.44 (s, 1H), 7.27-7.19 (m, 3H), 6.99 (d, J=6 Hz, 1H), 4.41-4 .31 (m, 1H), 3.99-3.88 (m, 2H), 3.86 (s, 3H), 3.54-3.44 (m, 2H), 2.99-2.82 (m, 1H), 1.92-1.84 (m, 2H), 1.52-1.42 (m, 2H), 1.24 (d, J=7 Hz, 6H). LC-MS (ESI): m/z: [M+H]+ = 422.1.

Example 72. Sodium salt of 3-(3,5-dichlorophenyl)-1-[(1-methyl-III-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea

Step 1: A[(3,5-dichlorophenyl)carbamoyl]sulfamoyl chloride. To a solution of N(oxomethylene)sulfamoyl chloride (169 µl 1.94 mmol) in isopropyl ether (3 ml), cooled to

-78°C. 3,5-dichloroaniline (196 µl, 1.85 mmol) in isopropyl ether (3 ml) was added. RM was stirred at -78°C for 2 hours and the title compound was obtained as a solution in isopropyl ether (6 ml). LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 299.0.

Step 2: 3-(3,5-dichlorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. General Procedure B was followed and N-[(3,5dichlorophenyl)carbamoyl]sulfamoyl chloride and 1-methyl-N-tetrahydropyran-3-ylpyrazol-4-amine were used (synthesis described in Example 1). The crude product was purified by preparative HPLC (column: NanoMicro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 0-30%, 25 min) to obtain the desired compound as a white solid (Y=17%). 1H NMR (400 MHz, methanolA) δ ppm 7.63 (s, 1H), 7.48 (d, J=2 Hz, 2H), 7.40 (s, 1H), 6.97-6.94 (d, J=2 Hz, 2H), 4.33-4.24 (m, 1H), 3.94-3.88 (m, 2H), 3.84 (s, 3H), 3.54-3.44 (m, 2H), 1. 91 (d, J=10 Hz, 2H), 1.45-1.39 (m, 2H). LC-MS (ESI): m/z: [M+H] ⁺ = 448.0.

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Example 73. Sodium salt of 3-[3,5-bis-(propan-2-yl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulf amoyl]urea

Step 1: ^[(3,5-diisopropylphenyl)carbamoyl]sulfamoyl chloride. To a solution of N(oxomethylene)sulfamoyl chloride (73 μl, 0.85 mmol) in diisopropyl ether (3 ml), cooled to -30°C, was added 3,5-diisopropylaniline (156 μl, 0.85 mmol) in diisopropyl ether ( 3 ml). RM was stirred at -30°C for 1 hour and the title compound was obtained as a solution in diisopropyl ether (6 ml). LC-MS in MeOH (ESI): m/z: = 315.3.

Step 2: 3-[3,5-bis-(propan-2-yl)phenyl]-1-[(1-methyl-III-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. General procedure B was followed and Na[(3,5-diisopropylphenyl)carbamoyl]sulfamoyl chloride and 1-methyl-N-tetrahydropyran-4-ylpyrazol-4-amine were used (synthesis described in Example 1). The crude product was purified by preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 5-35%, 28 min) and the title compound was obtained as a white solid (Y=10%). ¹ H NMR (400 MHz, methanol d4) δ ppm 7.70 (s, 1H), 7.42 (s, 1H), 7.10 (s, 2H), 6.84 (s, 1H), 4.43-4.33 (m, 1H), 3 .93 (dd, J=11, 4 Hz, 2H), 3.84 (s, 3H), 3.49 (t, J=12 Hz, 2H), 2.92-2.77 (m, 2H) , 1.89 (dd, J=12, 2 Hz, 2H), 1.50-1.36 (m, 2H), 1.24 (d, J=7 Hz, 12H). LC-MS (ESI): m/z: [M+H]+ = 464.2.

Example 74. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[2-(3 - methylazetidin-1-yl)ethyl]sulfamoyl]urea

Step 1: tert-butyl-N-(1-methylpyrazol-4-yl)carbamate. To a mixture of 1-methylpyrazol-4-amine (5.0 g, 51.5 mmol) with DCM (50 ml) was added triethylamine (14.33 ml, 103 mmol) and di-tert-butyl dicarbonate (14.2 ml, 61 .8 mmol). RM was stirred at RT for 3 hours. The solution was concentrated in vacuo. The crude product was purified with FCC (50% EtOAc in petroleum ether) to give the title compound as an oil (Y=98%). 1H NMR (400 MHz, DMSO-de) δ 9.09 (s, 1H), 7.60 (s, 1H), 7.24 (s, 1H), 3.72 (s, 3H), 1.41 (s, 9H).

Step 2: tert-butyl-N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-(1-methylpyrazol-4-yl)carbamate. To a solution of tert-butyl-N-(1-methylpyrazol-4-yl)carbamate (10 g, 50.7 mmol) in DMF (20 ml), cooled to 0°C, was added NaH (60% in mineral oil, 4 .06 g, 101 mmol). The RM was stirred at 0°C for 0.5 h. 2-bromoethoxy-tert-butyldimethylsilane (24.3 g, 101 mmol) was added while maintaining the reaction temperature at 0°C. The RM was allowed to warm to rt and stirred for 2 hours. H ₂ O (100 ml) was added and organics were extracted with EtOAc (3x100 ml). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified with FCC (9% EtOAc in petroleum ether) to give the title compound as a yellow oil (Y=51%). 1H NMR (400 MHz, DMSO- _d6 ) δ 7.80-7.50 (m, 1H), 7.45-7.25 (m, 1H), 3.75 (s, 3H), 3.69 -3.51 (m, 4H), 1.42 (s, 9H), 0.82 (s, 9H), -0.03 (s, 6H).

Step 3: tert-butyl-N-(2-hydroxyethyl)-N-(1-methylpyrazol-4-yl)carbamate. tert-Butyl-N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-(1-methylpyrazol-4-yl)carbamate (2.0 g, 5.63 mmol) was treated with 1 M TBAF in THF (8.44 ml) under N ₂ atmosphere. RM was stirred at RT for 2 hours. The solution was concentrated in vacuo. The crude product was purified with FCC (0-100% EtOAc in petroleum ether) to give the title compound as a yellow oil (Y=77%). 1H NMR (400 MHz, DMSO-de) δ 7.80-7.45 (m, 1H), 7.36 (s, 1H), 4.68 (s, 1H), 3.74 (s, 3H) , 3.52-3.47 (m, 4H), 1.40 (s, 9H).

Step 4: tert-butyl-N-(1-methylpyrazol-4-yl)-N-(2-oxoethyl)carbamate. Oxalyl chloride solution

- 165 047011 (330 µl, 3.77 mmol) in DCM (3 ml) was cooled to -78°C and treated with a solution of DMSO (567 µl, 7.25 mmol) in DCM (3 ml). The RM was stirred at -78°C for 10 min. The RM was treated dropwise with a solution of tert-butyl-Na-(2-hydroxyethyl)-Na(1-methylpyrazol-4-yl)carbamate (700 mg, 2.90 mmol) in DCM (3 ml). The RM was stirred at -78°C for 15 min, treated with triethylamine (2.10 ml, 15.1 mmol) and stirred for an additional 5 min. H ₂ O (10 ml) was added and the resulting mixture was extracted with DCM (10 ml). The organic phase was washed with NH ₄ Cl (3x10 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a yellow oil (Y=73%). ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.60-9.52 (m, 1H), 7.78-7.56 (m, 1H), 7.45-7.24 (m, 1H ), 4.41 (d, J=15 Hz, 2H), 3.76 (s, 3H), 1.41 (s, 9H).

Step 5: tert-butyl-N-[2-(3-methylazetidin-1-yl)ethyl]-N-(1-methylpyrazol-4-yl)carbamate trifluoroacetate. General Procedure A was followed and 3-methylazetidine and tert-butyl-N-(1methylpyrazol-4-yl)-N-(2-oxoethyl)carbamate were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-30%, 20 min) to obtain the title compound as white solid (Y=41%). 1H NMR (400 MHz, methanol^) δ ppm 10.08-9.96 (m, 1H), 7.74 (s, 1H), 7.45 (s, 1H), 4.12-4.04 (m, 2H), 3.79 (s, 3H), 3.733.68 (m, 4H), 3.32-3.26 (m, 2H), 2.86-2.82 (m, 1H), 1.44 (s, 9H), 1.18 -1.11 (m, 3H).

Step 6: 1-methyl-N-[2-(3-methylazetidin-1-yl)ethyl]pyrazol-4-amine. To a solution of tert-butyl-N-[2(3-methylazetidin-1-yl)ethyl]-N-(1-methylpyrazol-4-yl)carbamate trifluoroacetate (486 mg, 1.19 mmol) in DCM (5 ml) was added TFA (1 ml). RM was stirred at RT for 2 hours. The solution was concentrated in vacuo to give the title compound as a yellow oil (Y=100%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.29 (s, 1H), 7.11 (s, 1H), 6.24-5.50 (br. s, 2H), 4.11 (t , J=10 Hz, 2H), 3.73-3.67 (m, 5H), 3.32-3.24 (m, 2H), 3.11-3.03 (m, 2H), 3, 09-3.05 (m, 1H), 1.20-1.15 (m, 3H).

Step 7: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)[2(3 -methylazetidin-1-yl)ethyl]sulfamoyl]urea. General Procedure B was followed and N(1,2,3,5,6,7-hexahydro^-indacen-4-ylcarbamoyl)sulfamoyl chloride and 1-methyl-N-[2-(3-methylazetidin-1yl)ethyl] were used. pyrazole-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 5-40%, 28 min) and the title compound was obtained as a white solid (Y=4%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.67 (s, 1H), 7.50 (s, 1H), 6.92 (s, 1H), 4.28-4.16 (m, 2H), 3.85 (s, 3H), 3 .80-3.65 (m, 4H), 3.26-3.18 (m, 2H), 2.95-2.79 (m, 9H), 2.07-2.03 (m, 4H) , 1.26 (d, J=6 Hz, 3H). LCMS (ESI): m/z: [M+H]+ = 473.2.

Example 75. Sodium salt of 3-[3-ethyl-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(oxan4-yl) sul famoyl]m urea

Step 1: 3-ethyl-5-(trifluoromethyl)aniline. To a solution of 3-ethenyl-5-(trifluoromethyl)aniline (500 mg, 2.67 mmol) in MeOH (5 ml) under nitrogen atmosphere was added 10% Pd/C (100 mg). The suspension was degassed in vacuo and purged several times with H2. The mixture was stirred under H2 (15 psi) at ^RT for 12 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a green oil (Y=87%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.66 (s, 1H), 6.64 (s, 1H), 6.60 (s, 1H), 5.46 (s, 2H), 2.52-2.36 (m, 2H), 1 ,14 (t, J=7 Hz, 3H).

Step 2: ({[3-ethyl-5-(trifluoromethyl)phenyl]carbamoyl}amino)sulfonyl chloride. General Procedure D was followed and 3-ethyl-5-(trifluoromethyl)aniline was used to obtain the title compound as a solution in isopropyl ether. LC-MS in MeOH (ESI): m/z: = 327.2.

Step 3: 3-[3-ethyl-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. General Procedure B was followed and ({[3-ethyl-5(trifluoromethyl)phenyl]carbamoyl}amino)sulfonyl chloride and 1-methyl-N-tetrahydropyran-4-ylpyrazol-4amine were used (synthesis described in Example 1). The crude product was purified by preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH4HCO3)ACN]; B: 5 -35%, 25 min) to obtain the desired compound as a white solid (Y=14%). 1H NMR (400 MHz, methanol^) δ ppm 7.71 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.18 (s, 1H), 4.39-4 .30 (m, 1H), 3.95-3.90 (m, 2H), 3.85 (s, 3H), 3.53-3.46 (m, 2H), 2.70 (sq, J =8 Hz, 2H), 1.92-1.88 (m, 2H), 1.51-1.44 (m, 2H), 1.26 (t, J=8 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 476.1.

- 166 047011

Example 76. Sodium salt of 3-(3-ethyl-5-methylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea

Step 1: 3-ethenyl-5-methylaniline. To a solution of 3-bromo-5-methylaniline (2.0 g, 10.75 mmol) in dioxane (20 ml) and H2O (2 ml) was added 4,4,5,5-tetramethyl-2-vinyl-1,3 ,2-dioxaborolane (4.92 ml, 29.0 mmol), Pd(dppf)Cl ₂ (1.18 g, 1.61 mmol) and Cs ₂ CO ₃ (10.5 g, 32.3 mmol). The mixture was stirred at

100°C for 12 hours in N2 atmosphere. The solution was filtered and the filtrate was concentrated in vacuo. The residue was purified with FCC (25% EtOAc in petroleum ether) to give the title compound as a yellow oil. ¹ H NMR (400 MHz, DMSC-d6) δ ppm 6.57-6.49 (m, 1H), 6.45 (s, 1H), 6.43 (s, 1H), 6.32 (s, 1H), 5.62 (d, J=16 Hz , 1H), 5.12 (d, J=11 Hz, 1H), 4.97 (s, 2H), 2.15 (s, 3H).

Step 2: 3-ethyl-5-methylaniline. To a solution of 3-ethenyl-5-methylaniline (0.98 g, 7.36 mmol) in MeOH (10 ml) under nitrogen atmosphere was added 10% Pd/C (200 mg). The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ (15 psi) at ^RT for 12 hours. The solution was filtered and the filtrate was concentrated in vacuo to give the title compound as a black oil (Y=80%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.25-6.19 (m, 3H), 4.82 (s, 2H), 2.41 (kv, J=8 Hz, 2H), 2.11 (s, 3H), 1.11 (t , J=8 Hz, 3H).

Step 3: {[(3-ethyl-5-methylphenyl)carbamoyl]amino}sulfonyl chloride. General Procedure D was followed and 3-ethyl-5-methylaniline was used to obtain the title compound as a solution in isopropyl ether. LC-MS in MeOH (ESI): m/z: = 273.1

Step 4: 3-(3-ethyl-5-methylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. General Procedure B was followed and {[(3-ethyl-5methylphenyl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-tetrahydropyran-4-ylpyrazol-4-amine were used (synthesis described in Example 1). The crude product was purified using preparative HPLC (column: Nano-Micro Unisil 5-100 C18 Ultra 5 µm 250x100 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 5 -35%, 22 min ) and obtained the desired compound in the form of a white solid (Y=13%). 1H NMR (400 MHz, methanol^) δ ppm 7.70 (s, 1H), 7.41 (s, 1H), 7.04 (d, J=4 Hz, 2H), 6.77 (s, 1H), 4.40-4.35 (m , 1H), 3.943.87 (m, 2H), 3.85 (s, 3H), 3.49 (t, J=11 Hz, 2H), 2.58 (kv, J=8 Hz, 2H), 2.29 (s, 3H), 1.91-1.86 (m, 2H), 1.511.43 (m, 2H), 1.21 (t, J=8 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 422.1.

Example 77. Sodium salt of 3-(3-chloro-5-ethylphenyl)-1-[(1-methyl-III-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea

Step 1: 3-chloro-5-ethenylaniline. Mixture of 3-bromo-5-chloroaniline (5.0 g, 24.2 mmol), 4,4,5,5tetramethyl-2-vinyl-1,3,2-dioxaborolane (11.1 ml, 65.4 mmol) , Cs ₂ CO ₃ (7.89 g, 24.2 mmol) and Pd(dppf)Cl ₂ (2.66 g, 3.6 mmol) in dioxane (50 ml) and H ₂ O (5 ml) were heated at 100°C under N ₂ atmosphere for 22 hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was purified with FCC (0-100% EtOAc in petroleum ether) to give the title compound as a yellow oil (Y=24%). 1H NMR (400 MHz, DMSO-d ₆ ) δ =6.63 (s, 1H), 6.58-6.53 (m, 2H), 6.52-6.50 (m, 1H), 5, 71 (d, J=18 Hz, 1H), 5.41 (s, 2H), 5.22 (d, J=11 Hz, 1H).

Step 2: 3-chloro-5-ethylaniline. To a solution of 3-chloro-5-ethenylaniline (500 mg, 3.26 mmol) in MeOH (5 ml) was added 10% Pd/C (100 mg) under N ₂ atmosphere. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ² (30 psi) at RT for ¹² hours. RM was filtered and the filtrate was concentrated and diluted with water (20 ml). The aqueous phase was extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the title compound in

- 167 047011 in the form of oil. 1H NMR (400 MHz, DMSO-d6) δ =6.44 (t, J=2 Hz, 1H), 6.39 (s, 1H), 6.37 (s, 1H), 2.43 (sq, J=8 Hz, 2H), 1.11 (t, J=8 Hz, 3H). NH were not visible.

Step 3: {[(3-chloro-5-ethylphenyl)carbamoyl]amino}sulfonyl chloride. General Procedure D was followed and 3-chloro-5-ethylaniline was used to obtain the title compound as a solution in isopropyl ether. LC-MS in MeOH (ESI): m/z: = 293.2.

Step 4: 3-(3-chloro-5-ethylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. General Procedure B was followed and {[(3-chloro-5ethylphenyl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-tetrahydropyran-4-ylpyrazol-4-amine were used (synthesis described in Example 1). The crude product was purified by preparative HPLC (column: Xtimate C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ ) - ACN]; B: 2-30%, 27 min) to obtain the title compound as a yellow solid substances (Y=10%). 1H NMR (400 MHz, methanold4) δ ppm 7.60 (s, 1H), 7.48 (t, J=2 Hz, 1H), 7.40 (s, 1H), 7.05 (s, 1H), 6.75 (s, 1H), 4.28-4.20 (m, 1H), 3.90 (dd, J=4, 12 Hz, 2H), 3.83 (s, 3H), 3.53-3.46 (m, 2H) , 2.56 (kv, J=8 Hz, 2H), 1.95-1.89 (m, 2H), 1.47-1.36 (m, 2H), 1.20 (t, J=8 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 442.1.

Example 78. 1-[(3,3-Dimethyloxan-4-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro) sodium salt ^-indacen-4-yl)urea

Step 1: N(3,3-dimethyltetrahydropyran-4-yl)-1-methylpyrazole-4-amine trifluoroacetate. General Procedure A was followed and 1-methylpyrazol-4-amine and 3,3-dimethyltetrahydropyran-4-one were used. The crude material was purified by preparative HPLC (column: C18, mobile phase: [water (0.1% TFA) - ACN]) to obtain the title compound as a red solid (Y=43%). 1H NMR (400 MHz, methanol^) δ=7.98 (s, 1H), 7.68 (s, 1H), 4.01 (dd, J=5, 5 Hz, 1H), 3.94 (s , 3H), 3.51 (d, J=12 Hz, 1H), 3.39-3.31 (m, 2H), 3.18 (d, J=11 Hz, 1H), 1.87-1 .71 (m, 2H), 1.18 (s, 3H), 1.12 (s, 3H). LC-MS (ESI): m/z: [M+H] ⁺ = 210.3.

Step 2: 1-[(3,3-dimethyloxan-4-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro) sodium salt ^-indacen-4-yl)urea. General Procedure B was followed and N(1,2,3,5,6,7-hexahydro-N-indacen-4-ylcarbamoyl)sulfamoyl chloride and N(3,3-dimethyltetrahydropyran4-yl)-1-methylpyrazol-4-amine trifluoroacetate were used. The crude product was purified by preparative HPLC (column: C18; mobile phase: [water (10 mM NH4HCO3) - ACN]) to obtain the title compound as a pink solid (Y=2%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.73 (s, 1H), 7.43 (s, 1H), 6.98 (s, 1H), 4.27-4.20 (m, 1H), 4.02-3.92 (m, 1H), 3.89 (s, 3H), 3.51 (t, J=11 Hz, 1H), 3.40-3.35 (m, 1H), 3.22-3.14 (m, 1n ), 2.92-2.84 (m, 4H), 2.82-2.74 (m, 4H), 2.12-2.04 (m, 4H), 1.96-1.88 (m , 1H), 1.83-1.75 (m, 1H), 1.05 (s, 3H), 0.82 (s, 3H). LC-MS (ESI): m/z: [M+H] ⁺ = 488.2.

Example 79. 1-[(2,2-Dimethyloxan-4-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro) sodium salt ^-indacen-4-yl)urea

Step 1: N(2,2-dimethyltetrahydropyran-4-yl)-1-methylpyrazole-4-amine trifluoroacetate. General Procedure A was followed and 1-methylpyrazol-4-amine and 2,2-dimethyltetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: C18, mobile phase: [water (0.1% TFA) - ACN]) to obtain the title compound as a red solid (Y=25%). ^1H NMR (400 MHz, methanol^ ₄ ) δ = 7.97 (s, 1H), 7.66 (s, 1H), 3.95 (s, 3H), 3.86-3.67 (m, 3H), 1.97-1.93 (m, 2H), 1.60-1.41 (m, 2H), 1.27 (s, 3H), 1.23 (s, 3H). LC-MS (ESI): m/z: [M+H] ⁺ = 210.2.

Step 2: 1-[(2,2-dimethyloxan-4-yl)(1-methyl-1H-pyrazol-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro) sodium salt ^-indacen-4-yl)urea. General procedure B was followed and N(1,2,3,5,6,7-hexahydro-N-indacen-4-ylcarbamoyl)sulfamoyl chloride and N(2,2-dimethyltetrahydropyran) were used.

- 168 047011

4-yl)-1-methylpyrazole-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: C18; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]) to obtain the title compound as a solid (Y=12%). ^1H NMR (400 MHz, methanol-d^δ ppm 7.71 (s, 1H), 7.41 (s, 1H), 6.99 (s, 1H), 4.59-4.50 (m, 1H), 3.90 (s, 3H), 3.77-3.67 (m, 2H), 2.89 (t, J=8 Hz, 4H), 2.80 (t, J= 7 Hz, 4H), 2.12-2.05 (m, 4H), 1.86 (dd, J=4, 4 Hz, 2H), 1.35-1.24 (m, 5H), 1, 15 (s, 3H). LC-MS (ESI): m/z: [M+H]+ = 488.2.

Example 80: 3-(3,5-diethyl-4-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt

Step 1: 4-fluoro-3,5-ethenylaniline. To a solution of 3,5-dibromo-4-fluoroaniline (1.0 g, 3.72 mmol) in dioxane (10 ml) and H ₂ O (1 ml) was added 4,4,5,5-tetramethyl-2-vinyl -1,3,2-dioxaborolane (1.70 ml, 10.0 mmol), Pd(dppf)Cl ₂ (408 mg, 0.56 mmol) and Cs ₂ CO ₃ (3.63 g, 11.2 mmol ) at CT in an N2 atmosphere. The mixture was stirred at 100°C for 12 hours under N2 atmosphere. The solution was filtered and the filtrate was concentrated in vacuo. The residue was purified with FCC (25% ethyl acetate in petroleum ether) to give the title compound as a yellow solid (Y=25%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.806.68 (m, 4H), 5.72 (d, J=18 Hz, 2H), 5.34 (d, J=11 Hz, 2H), 4.96 (s, 2H).

Step 2: 3,5-diethyl-4-fluoroaniline. To a solution of 4-fluoro-3,5-ethenylaniline (150 mg, 0.92 mmol) in MeOH (3 ml) was added 10% Pd/C (50 mg) under N ₂ atmosphere. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ (15 psi) at ^RT for 12 hours. The solution was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (Y=98%). 1H NMR (400 MHz, methanol-d^δ ppm 6.34 (d, J=6 Hz, 2H), 2.49-2.41 (m, 4H), 1.12-1.05 ( m, 6H).

Step 3: {[(3,5-diethyl-4-fluorophenyl)carbamoyl]amino}sulfonyl chloride. General Procedure D was followed and 3,5-diethyl-4-fluoroaniline was used to obtain the title compound as a solution in isopropyl ether. LC-MS in MeOH (ESI): m/z: = 305.3.

Step 4: 3-(3,5-diethyl-4-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. General Procedure B was followed and {[(3,5-diethyl-4fluorophenyl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-tetrahydropyran-4-ylpyrazol-4-amine were used (synthesis described in Example 1). The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 5-30%, 20 min) to obtain the title compound as a white solid (Y=2%). 1H NMR (400 MHz, methanol-d^ δ ppm 7.61 (s, 1H), 7.41 (s, 1H), 7.10 (d, J=6 Hz, 2H), 4.26 -4.21 (m, 1H), 3.90 (dd, J=4, 12 Hz, 2H), 3.83 (s, 3H), 3.48 (t, J=11 Hz, 2H), 2 .59 (kv, J=8 Hz 4H), 1.95 -1.86 (m, 2H), 1.44 -1.38 (m, 2H), 1.20 (t, J=8 Hz, 6H LCMS (ESI): m/z: [M+H] ⁺ = 454.2.

Example 81. Sodium salt of 3-[3-ethyl-5-(propan-2-yl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea

Step 1: 3-ethenyl-5-(prop-1-en-2-yl)aniline. To a solution of 3-bromo-5-ethenylaniline (900 mg, 4.54 mmol) in dioxane (10 ml) and H ₂ O (1 ml) was added 2-isopropynyl-4,4,5,5-tetramethyl-1,3 ,2dioxaborolane (2.06 g, 12.3 mmol), Pd(dppf)Cl ₂ (0.50 g, 0.68 mmol) and Cs ₂ CO ₃ (4.44 g, 13.6 mmol). The RM was stirred at 100°C under N ₂ for 12 hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 5-35%, 20 min) to obtain the desired

- 169 047011 compound in the form of a white solid (Y=47%). LC-MS (ESI): m/z: [M+H]+ = 160.1.

Step 2: 3-ethyl-5-isopropylaniline. To a solution of 3-ethenyl-5-(prop-1-en-2-yl)aniline (400 mg, 2.51 mmol) in MeOH (5 ml) was added 10% Pd/C (100 mg) under H ₂ atmosphere. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred under H ₂ (15 psi) at RT for ² hours. The solution was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (Y=98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.95 (s, 1H), 6.86 (s, 1H), 6.83 (s, 1H), 4.00-3.28 (br. s, 2H), 2.87-2.80 ( m, 1H), 2.58 (kv, J=8 Hz, 2H), 1.19-1.15 (m, 9H).

Step 3: ({[3-ethyl-5-(propan-2-yl)phenyl]carbamoyl}amino)sulfonyl chloride. General Procedure D was followed and 3-ethyl-5-isopropylaniline was used to obtain the title compound as a solution in isopropyl ether. LC-MS in MeOH (ESI): m/z: = 301.1.

Step 4: 3-[3-ethyl-5-(propan-2-yl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. General procedure B was followed and ({[3-ethyl-5-(propan-2yl)phenyl]carbamoyl}amino)sulfonyl chloride and 1-methyl-N-tetrahydropyran-4-ylpyrazol-4-amine were used (synthesis described in Example 1) . The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ ) - ACN]; B: 5-35%, 20 min) to obtain the title compound as a white solid substances (Y=2%). 1H NMR (400 MHz, methanolIII ₄ ) δ ppm 7.71 (s, 1H), 7.42 (s, 1H), 7.08 (s, 2H), 6.83 (s, 1H), 4.42-4.32 (m, 1H), 3 .93 (dd, J=4, 12 Hz, 2H), 3.85 (s, 3H), 3.49 (t, J=10 Hz, 2H), 2.91-2.80 (m, 1H) , 2.61 (kv, J=8 Hz, 2H), 1.89 (dd, J=2, 12 Hz, 1H), 1.53-1.45 (m, 1H), 1.25-1, 20 (m, 9H). LC-MS (ESI): m/z: [M+H]+ = 450.2.

Example 82. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(1-methyl-6 -oxopiperidin-3-yl)sulfamoyl]urea

ABOUT

Step 1: 1-methyl-5-[(1-methylpyrazol-3-yl)amino]piperidin-2-one. Mixture of 5-amino-1methylpiperidin-2-one (100 mg, 0.78 mmol), 3-iodo-1-methylpyrazole (160 mg, 0.77 mmol), sodium tert-butoxide (142 mg, 1.48 mmol) and [2-(2-aminoethyl)phenyl]-chloro-palladium; Di-tert-butyl-[2-(2,4,6triisopropylphenyl)phenyl]phosphane (also known as tBuXPhos Pd G1) (51 mg, 74 µmol) in toluene (1 ml) was stirred at 110°C under N2 in for 1 hour. The solvent was removed under reduced pressure and the residue was purified using preparative HPLC (column: Nano-Micro Kromasil C18 5 μm 100x30 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-20 %, 10 min) and obtained the desired compound in the form of a colorless resinous substance (Y=26%). 1H NMR (400 MHz, methanolO) δ ppm 7.66 (s, 1H), 7.45 (s, 1H), 3.88 (s, 3H), 3.77-3.67 (m, 1H), 3.64-3.58 (m, 1H), 3.38-3.33 (m, 1H), 2.94 (s, 3H), 2.56-2.38 (m, 2H), 2.23-2.11 (m, 1H) , 1.98-1.85 (m, 1H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)(1methyl-6 -oxopiperidin-3-yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-5-[(1methylpyrazol-3-yl) were used. amino]piperidin-2-one. The crude product was purified by preparative HPLC (column: Luna C18 5 µm 100x30 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 20-37%, 10 min) to obtain the title compound as a white solid (Y=8%). 1H NMR (400 MHz, methanol^) δ ppm 7.76 (s, 1H), 7.47 (s, 1H), 7.00 (s, 1H), 4.69-4.60 (m, 1H), 3.89 (s, 3H), 3 .65-3.56 (m, 1H), 3.29-3.22 (m, 1H), 2.94-2.76 (m, 11H), 2.54-2.35 (m, 2H) , 2.14-2.04 (m, 5H), 1.68-1.54 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 487.2.

- 170 047011

Example 83. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)(1-methyl-5 -oxopyrrolidin-3-yl)sulfamoyl]urea

Step 1: 1-methyl-4-[(1-methylpyrazol-4-yl)amino]pyrrolidin-2-one trifluoroacetate. To a solution of 4amino-1-methylpyrrolidin-2-one (100 mg, 0.88 mmol) in toluene (2 ml) was added 4-iodo-1-methylpyrazole (200 mg, 0.96 mmol), sodium tert-butoxide (168 mg, 1.75 mmol) and [2-(2-aminoethyl)phenyl]-chloropalladium, di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (also known as tBuXPhos Pd G1 ) (60 mg, 88 µmol), then the mixture was stirred at 100°C for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 5 µm 150x30; mobile phase: [water (0.1% TFA) - ACN]; B: 1-30%, 10 min) to obtain the title compound as colorless resinous substance (Y=20%). ¹ H NMR (400 MHz, methanolI ₄ ) δ ppm 7.63 (s, 1H), 7.43 (s, 1H), 4.17-4.05 (m, 1H), 3.87 (s, 3H), 3.84-3.76 (m, 1H), 3.43 (dd, J=3, 11 Hz, 1H), 2.90-2.79 (m, 4H), 2.41 (dd, J=3, 18 Hz, 1H).

Step 2 sodium salt: 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4-yl)(1methyl-5 -oxopyrrolidin-3-yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-4-[(1-methylpyrazol-4- yl)amino]pyrrolidin-2-one trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 5-30%, 20 min) to obtain the title compound as a white solid substances (Y=6%). 1H NMR (400 MHz, methanolI ₄ ) δ ppm 7.73 (s, 1H), 7.49 (s, 1H), 6.94 (s, 1H), 5.10-4.96 (m, 1H), 3.85 (s, 3H), 3 .83-3.78 (m, 1H), 3.53-3.48 (m, 1H), 2.87 (t, J=7 Hz, 4H), 2.81 (t, J=7 Hz, 4H), 2.77-2.67 (m, 1H), 2.63 (s, 3H), 2.45-2.35 (m, 1H), 2.13-2.02 (m, 4H) . LC-MS (ESI): m/z: [M+H]+ = 473.2.

Example 84. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-III-pyrazol-4yl)[rac-trans-( 2-methyloxan-4-yl)]sulfamoyl]urea

Step 1: 1-methyl-N-(2-methyltetrahydropyran-4-yl)pyrazol-4-amine trifluoroacetate. General Procedure A was followed and 1-methylpyrazol-4-amine and 2-methyltetrahydropyran-4-one were used. The crude material was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-25%, 20 min) to obtain the title compound as solid (Y=38%). ¹ H NMR (400 MHz, methanolI ₄ ) δ = 7.96 (s, 1H), 7.66 (s, 1H), 4.06-3.99 (m, 1H), 3.95 (s, 3H ), 3.83-3.77 (m, 2H), 3.50-3.43 (m, 1H), 2.02-1.78 (m, 4H), 1.24-1.22 (m , 3H).

Step 2: tert-butyl (Imethyl-III-pyrazolI-ylC^ac-tran^A-methyltetrahydroAN-pyranNyl)carbamate and tert-butylC-methyl-III-pyrazolI-ylX^ac-ci^A-methyltetrahydroAN-pyranN-yl ^arbamat. To a solution of 1-methyl-N-(2-methyltetrahydropyran-4-yl)pyrazol-4-amine trifluoroacetate (400 mg, 2.05 mmol) in DCM (10 ml) was added di-tert-butyl dicarbonate (565 µl, 2.46 mmol) and Et ₃ N (0.57 ml, 4.10 mmol). The RM was stirred at RT for 12 hours. The solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 16-46%, 20 min) to obtain the desired compounds. tert-Butyl(1-methyl-1H-pyrazol-4-yl)((rac-cis)-2-methyltetrahydro-2H-pyran-4-yl)carbamate (350 mg) was obtained as a yellow oil. tert-Butyl(1-methyl-1H-pyrazol-4-yl)((rac-trans)-2methyltetrahydro-2H-pyran-4-yl)carbamate (320 mg) was obtained as a yellow oil.

tert-Butyl(1-methyl-1H-pyrazol-4-yl)((rac-cis)-2-methyltetrahydro-2H-pyran-4-yl)carbamate. 1H NMR (400 MHz, methanol^) δ =7.55 (s, 1H), 7.29 (s, 1H), 4.53-4.48 (m, 1H), 4.12-4.06 ( m, 1H), 3.88 (s, 3H), 3.82-3.78 (m, 1H), 3.63-3.60 (m, 1H), 1.70-1.63 (m, 3H), 1.47-1.42 (m, 1H), 1.40 (s, 9H), 1.30 (d, J=7 Hz, 3H).

- 171 047011 tert-Butyl(1-methyl-1H-pyrazol-4-yl)((rac-trans)-2-methyltetrahydro-2H-pyran-4-yl)carbamate. 1H NMR (400 MHz, methanol^) δ = 7.54 (s, 1H), 7.29 (s, 1H), 4.27-4.21 (m, 1H), 3.95-3.90 ( m, 1H), 3.88 (s, 3H), 3.53-3.47 (m, 2H), 1.77-1.66 (m, 3H), 1.48-1.37 (m, 10H), 1.13 (d, J=6 Hz, 3H).

Step 3: 1-methyl-N-((rac-trans)-2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine trifluoroacetate. To a solution of tert-butyl(1-methyl-1H-pyrazol-4-yl)((rac-trans)-2-methyltetrahydro-2H-pyran-4yl)carbamate (320 mg, 0.78 mmol) in DCM (2 ml) TFA (0.40 ml, 5.40 mmol) was added. The RM was stirred at RT for 3 hours. The solvent was removed under reduced pressure to give the title compound as a yellow oil (Y=42%). ^1H NMR (400 MHz, methanol^ ₄ ) δ = 7.98 (s, 1H), 7.66 (s, 1H), 4.04-4.00 (m, 1H), 3.94 (s, 3H), 3.84-3.78 (m, 3H), 2.10-1.99 (m, 1H), 1.98-1.86 (m, 1H), 1.81-1.74 ( m, 2H), 1.22 (d, J=6 Hz, 3H).

Step 4: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-III-pyrazol-4yl)[rac-trans-( 2-methyloxan-4-yl)]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-((ractrans)-2-methyltetrahydro -2H-pyran-4-yl)-1H-pyrazole-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 10-35%, 20 min) to obtain the title compound as a white solid substances (Y=2%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.72 (s, 1H), 7.42 (s, 1H), 6.99 (s, 1H), 4.63-4.57 (m, 1H), 4.12-3.97 (m, 1H), 3.90 (s, 3H), 3.86-3.74 (m, 1H), 3.65-3.54 (m, 1H), 2.88 (t, J=7 Hz, 4H ), 2.79 (t, J=7 Hz, 4H), 2.15-2.01 (m, 4H), 1.90-1.82 (m, 1H), 1.78-1.68 ( m, 1H), 1.67-1.62 (m, 1H), 1.56-1.42 (m, 1H), 1.27 (d, J=7 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 474.1.

Example 85. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[rac-cis-( 2-methyloxan-4-yl)]sulfamoyl]urea

Step 1: kmethyl-N-cras-cis^-methyltetrahydro^H-pyran^-ylyl-pyrazole^-amine trifluoroacetate. To a solution of tert-butylC-methyl-III-pyrazol^-ylX^ac-cis^-methyltetrahydro-3H-pyran^yl)carbamate (310 mg, 0.76 mmol) (synthesis described in example 84) in DCM (2 ml ) TFA (0.40 ml, 5.40 mmol) was added. The RM was stirred at RT for 3 hours. The solvent was removed under reduced pressure to give the title compound as a yellow oil (Y=43%). 1H NMR (400 MHz, methanol^ ₄ ) δ =7.97 (s, 1H), 7.65 (s, 1H), 4.04-4.02 (m, 1H), 3.94 (s, 3H ), 3.67-3.56 (m, 1H), 3.53-3.42 (m, 2H), 2.03-1.93 (m, 2H), 1.631.58 (m, 1H), 1.30-1.22 (m, 1H), 1.21 (d, J=6 Hz, 3H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[rac-cis-( 2-methyloxan-4-yl)]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-((rac-cis)-2methyltetrahydro -2H-pyran-4-yl)-1H-pyrazol-4-amine trifluoroacetate. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 10-35%, 20 min) to obtain the title compound in as a white solid (Y=4%). 1H NMR (400 MHz, methanol^) δ ppm 7.72 (s, 1H), 7.42 (s, 1H), 6.99 (s, 1H), 4.42-4.27 (m, 1H), 3.94-3.92 (m, 1H), 3.90 (s, 3H), 3.54-3.48 (m, 2H), 2.88 (t, J=7 Hz, 4H), 2.79 (t, J=7 Hz, 4H), 2.15-2.02 (m, 4H), 1.98-1.89 (m, 1H), 1.87-1.76 (m, 1H), 1.48-1.31 ( m, 1H), 1.11 (d, J=6 Hz, 3H), 1.09-1.01 (m, 1H). LCMS (ESI): m/z: [M+H] ⁺ = 474.1.

Example 86. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(2-methylpyrimidin-5yl)(oxan-4-yl)sulfamoyl]urea

Step 1: 2-methyl-N-tetrahydropyran-4-ylpyrimidin-5-amine. To a solution of 5-bromo-2-methylpyrimidine (700 mg, 4.05 mmol) and tetrahydropyran-4-amine (818 mg, 8.09 mmol) in toluene (12 ml) was added BINAP (504 mg, 0 .81 mmol), Pd(OAc)2 (91 mg, 0.40 mmol) and Cs2CO3 (2.64 g, 8.09 mmol). The mixture was stirred under N2 atmosphere at 100°C for 3 hours. The mixture was poured into ethyl acetate (100 ml) and washed with 10:1 N ₂ O/methanol (4x100 ml). The EtOAc-containing phase was concentrated in vacuo. The residue was purified with FCC (33-100% EtOAc in petroleum ether) to give the title compound as a white solid (Y=45%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.07 (s, 2H), 4.05-3.95 (m, 2H), 3.57-3.48 (m, 3H), 2.61 (s, 3H), 2.06-2, 00 (m, 2H), 1.55-1.44 (m, 2H).

Step 2: 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(2-methylpyrimidin-5yl)(oxan-4-yl)sulfamoyl]urea sodium salt . General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 2-methyl-H-tetrahydropyran-4ylpyrimidin-5-amine were used. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 5-30%, 20 min) to obtain the title compound in as a white solid (Y=7%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 8.63 (s, 2H), 7.00 (s, 1H), 5.17 (s, 1H), 4.54-4.40 (m, 1H), 3.93 (dd, J=4, 11 Hz, 2H), 3.53-3.43 (m, 2H), 2.89 (t, J=7 Hz, 4H), 2.81 (t, J=7 Hz, 4H), 2.75 (s, 3H), 2.13-2.03 (m, 4H), 2.01-1.94 (m, 2H), 1.47-1.30 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 472.1.

Example 87. Sodium salt of 1-[(3,4-dimethyl-1,2-oxazol-5-yl)(oxan-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro ^-indacen-4-yl)urea

Stage 1: tert-butyl-N-chlorosulfonylcarbamate. To a solution of N(oxomethylene)sulfamoyl chloride (491 μl, 5.65 mmol) in DCM (5 ml), cooled to 0°C in an atmosphere of N ₂ , was added a solution of tert-butanol (541 μl, 5.65 mmol) in DCM (5 ml) . RM was stirred at 0°C for 2 hours and a solution of the title compound in DCM (10 ml) was obtained. The mixture was used in the next step without treatment.

Step 2: 3,4-dimethyl-H-tetrahydropyran-4-ylisoxazole-5-amine trifluoroacetate. General Procedure A was followed and 3,4-dimethylisoxazol-5-amine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 5-35%, 20 min) to obtain the title compound as yellow oil (Y=58%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.75-8.25 (br. s, 1H), 4.06-4.01 (m, 2H), 3.753.65 (m, 1H), 3.55-3.49 (m, 2H), 2.18 (s, 3H), 2.05-1.99 (m, 2H), 1.77 (s, 3H), 1.61-1.52 (m, 2H).

Step 3: tert-butyl-H-[(3,4-dimethylisoxazol-5-yl)tetrahydropyran-4-ylsulfamoyl]carbamate. To a solution of 3,4-dimethyl-N-tetrahydropyran-4-ylisoxazol-5-amine trifluoroacetate (600 mg, 1.93 mmol) in DCM (6 ml) was added a solution of tert-butyl-N-chlorosulfonylcarbamate (417 mg, 1.93 mmol) in DCM (3.42 ml). DIPEA (1.01 mL, 5.80 mmol) was added and the RM was stirred at RT for 2 hours. The solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 20-50%, 20 min) to obtain the title compound as white solid (Y=16%). 1H NMR (400 MHz, methanol-ph) δ ppm 4.52-4.35 (m, 1H), 3.95 (dd, J=4, 11 Hz, 2H), 3.47 (t, J=11 Hz, 2H), 2.25 (s, 3H ), 2.021.98 (m, 2H), 1.95 (s, 3H), 1.51 (s, 9H), 1.49-1.42 (m, 2H).

Step 4: 3,4-dimethyl-5-[sulfamoyl(tetrahydropyran-4-yl)amino]isoxazole trifluoroacetate. To a solution of tert-butyl-H-[(3,4-dimethylisoxazol-5-yl)tetrahydropyran-4-ylsulfamoyl]carbamate (100 mg, 0.20 mmol) in DCM (2 ml) was added TFA (400 µl, 5 40 mmol), then RM was stirred at RT for 3 hours. The solvent was removed under reduced pressure to obtain the title compound as a white solid (Y=88%).

Step 5: sodium salt 1-[(3,4-dimethyl-1,2-oxazol-5-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydro^ -indacen-4-yl)urea. To a solution of 3,4-dimethyl-5-[sulfamoyl(tetrahydropyran-4yl)amino]isoxazole trifluoroacetate (100 mg, 0.26 mmol) in THF (2 ml), cooled to 0°C, was added NaH (60% in mineral oil , 41 mg, 1.03 mmol). The RM was stirred at 0°C for 0.5 h, then 4-isocyanato-1,2,3,5,6,7-hexahydro-indacene (51 mg, 0.26 mmol) was added. The RM was allowed to warm to rt and stirred for 1.5 hours. The solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 10-36%, 20 min) to obtain the title compound as a white solid ( Y=19%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 6.98 (s, 1H), 4.52-4.48 (m, 1H),

- 173 047011

3.96-3.88 (m, 2H), 3.46 (t, J=11 Hz, 2H), 2.93-2.78 (m, 8H), 2.24 (s, 3H), 2 .11-2.04 (m, 6H), 1.99 (s, 3H), 1.471.39 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 475.1.

Example 88. Sodium salt of 1-(2,6-dimethylcyclohexyl)-3-[(1-methyl-III-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea

Step 1: A-(2,6-dimethylcyclohexylidene)hydroxylamine. To a solution of 2,6-dimethylcyclohexanone (1.5 g, 11.9 mmol) in EtOH (15 ml) and H ₂ O (3 ml) was added hydroxylamine hydrochloride (1.24 g, 17.8 mmol) and sodium acetate (1 .56 g, 19.0 mmol). RM was heated at 80°C for 2 hours. RM was concentrated to remove EtOH, then diluted with water (10 ml). The aqueous phase was extracted with EtOAc (3x30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a yellow oil (Y=91%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.13 (s, 1H), 1.45-1.18 (m, 8H), 1.10-0.96 (m, 6H).

Step 2: 2,6-dimethylcyclohexanamine. Raney-Ni (400 mg) was added to a solution of Na(2,6-dimethylcyclohexylidene)hydroxylamine (1.52 g, 10.8 mmol) in MeOH (8 ml). The RM was stirred under H ₂ (50 psi) for ¹² hours. The RM was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (Y=64%). 1H NMR (400 MHz, DMSO-d ₆ ) δ = 2.50-2.44 (m, 1H), 2.06-2.02 (m, 2H), 1.74-1.71 (m, 2H ), 1.47 -1.35 (m, 6H), 0.89 (d, J=7 Hz, 6H).

Step 3: 2-isocyanato-1,3-dimethylcyclohexane. General Procedure C was followed and 2,6-dimethylcyclohexanamine was used to obtain the title compound as a yellow solid. LC-MS in benzylamine (ESI): m/z: = 261.2.

Step 4: tert-butyl-N-[(1-methylpyrazol-4-yl)tetrahydropyran-4-ylsulfamoyl]carbamate. To a solution of 1-methyl-N-tetrahydropyran-4-ylpyrazol-4-amine (1.26 g, 6.94 mmol) (synthesis described in Example 1) in DCM (20 ml) was added DIPEA (3.63 ml, 20 .8 mmol) and RM was stirred at RT for 0.5 h. RM was treated dropwise with a solution of tert-butyl-N-chlorosulfonylcarbamate (1.5 g, 6.96 mmol) (synthesis described in Example 87) in DCM (12 ml) and the mixture was stirred at RT for 4.5 hours. The solution was concentrated in vacuo. The crude product was purified with FCC (0-100% EtOAc in petroleum ether) to give the title compound as a pink solid (Y=76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (s, 1H), 7.73 (s, 1H), 7.25 (s, 1H), 4.21-4.13 (m, 1H), 3.84-3.81 (m, 5H), 3.37-3.34 (m, 2H), 1.72-1.69 (m, 2H), 1.45 (s, 9H), 1.35-1.24 (m, 2H) .

Step 5: 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole. A mixture of tert-butyl-N-[(1methylpyrazol-4-yl)tetrahydropyran-4-ylsulfamoyl]carbamate (1.0 g, 2.77 mmol)) with 4 M HCl in EtOAc (15 ml) was stirred at RT for 12 h. The solution was concentrated in vacuo to obtain the desired compound in the form of a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.72 (s, 1H), 7.35 (s, 1H), 5.50-4.98 (br. s, 2H), 4.05-3.95 (m, 1H), 3.85- 3.80 (m, 5H), 3.33 (t, J=12 Hz, 2H), 1.90-1.83 (m, 2H), 1.171.08 (m, 2H).

Step 6: 1-(2,6-dimethylcyclohexyl)-3-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. To a solution of 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole (147 mg, 0.49 mmol) in THF (1.5 ml) was added NaH (60% in mineral oil, 39 mg, 0 .98 mmol). 2-isocyanato-1,3-dimethylcyclohexane (60 mg, 0.39 mmol) was added to the RM and the RM was stirred for 2 hours. The solution was concentrated in vacuo. The residue was purified by preparative HPLC (column: Huapu C8 Extreme BDS 5 µm 15030 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 15-45%, 10 min) to obtain the title compound as a white solid substances (Y=7%). 1H NMR (400 MHz, methanolD ₄ ) δ ppm 7.64 (s, 1H), 7.37 (s, 1H), 4.29-4.25 (m, 1H), 3.93-3.87 (m, 4H), 3.50-3. 41 (m, 3H), 2.20-1.95 (m, 1H), 1.881.41 (m, 10H), 1.18-1.09 (m, 1H), 1.02-0.82 ( m, 7N). LC-MS (ESI): m/z: [M+H] ⁺ = 414.2.

- 174 047011

Example 89. Sodium salt of 1-[3-chloro-5-(propan-2-yl)phenyl]-3-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfame oil]urea

Step 1: 3-chloro-5-isopropenylaniline. To a solution of 3-bromo-5-chloroaniline (3.0 g, 14.5 mmol) in dioxane (30 ml) and H ₂ O (3 ml) was added 2-isopropynyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.93 g, 17.44 mmol), Pd(dppf)Cl ₂ (1.06 g, 1.45 mmol) and Cs ₂ CO ₃ (14.20 g, 43.6 mmol ). The mixture was stirred at 130°C for 3 hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was purified with FCC (25% ethyl acetate in petroleum ether) to give the title compound as a yellow oil (Y=82%). LC-MS (ESI): m/z: [M+H]+ = 168.3.

Step 2: 3-chloro-5-isopropylaniline. To a solution of 3-chloro-5-isopropenylaniline (2.0 g, 11.93 mmol) in MeOH (20 ml) was added 10% Pd/C (200 mg) under N2. The suspension was degassed in vacuo and purged several times with H2. The mixture was stirred under H2 (15 ^psi ) at RT for 2 hours. The solution was filtered and the filtrate was concentrated in vacuo to give the title compound as a green oil (Y=47%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.46-6.41 (m, 3H), 2.74-2.61 (m, 1H), 1.13 (d, J=7 Hz, 6H). NH2 is not visible.

Step 3: 1-chloro-3-isocyanato-5-(propan-2-yl)benzene. General Procedure C was followed and 3-chloro-5-isopropylaniline was used to obtain the title compound as a yellow solid.

Step 4: 1-[3-chloro-5-(propan-2-yl)phenyl]-3-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. To a solution of 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole (182 mg, 0.61 mmol) (synthesis described in example 88) in THF (2 ml), cooled to 0°C, in NaH (60% in mineral oil, 61 mg, 1.53 mmol) and then 1-chloro-3-isocyanato-5-(propan-2yl)benzene (120 mg, 0.61 mmol) were added under nitrogen atmosphere. RM was stirred at RT for 2 hours. The solution was concentrated in vacuo. The residue was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 8-38%, 20 min) to obtain the title compound as a white solid ( Y=47%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.70 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 4.43-4 .26 (m, 1H), 3.96-3.88 (m, 2H), 3.85 (s, 3H), 3.52-3.46 (m, 2H), 2.88-2.84 (m, 1H), 1.93-1.85 (m, 2H), 1.50-1.42 (m, 2H), 1.23 (d, J=7 Hz, 6H).

Example 90. Sodium salt of 3-(3,5-diethoxyphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfame oil]urea

Step 1: 1,3-diethoxy-5-isocyanatobenzene. General Procedure C was followed and 3,5diethoxyaniline was used to obtain the title compound as a yellow solid (Y=100%). LC-MS in MeOH (ESI): m/z: = 239.9.

Step 2: 3-(3,5-diethoxyphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. To a solution of 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole (150 mg, 0.40 mmol) (synthesis described in example 88) in THF (2 ml), cooled to 0°C, was added NaH (60% in mineral oil, 64 mg, 1.60 mmol). The RM was stirred at 0°C for 0.5 h, then 1,3-diethoxy-5-isocyanatobenzene (83 mg, 0.40 mmol) was added to the reaction mixture. The RM was stirred at 0°C for an additional 1.5 hours. The RM was diluted with MTBE (20 ml) and the solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 5-30%, 20 min) to obtain the title compound as a white solid ( Y=16%). 1H NMR (400 MHz, methanol^ ₄ ) δ

- 175 047011

m.d. 7.68 (s, 1H), 7.41 (s, 1H), 6.61 (s, 1H), 6.60 (s, 1H), 6.18 (s, 1H), 4.37-4 .30 (m, 1H), 3.99 (kv, J=7 Hz, 4H), 3.94-3.90 (m, 2H), 3.84 (s, 3H), 3.49 (t, J=11 Hz, 2H), 1.93-1.85 (m, 2H), 1.51-1.43 (m, 2H), 1.36 (t, J=7 Hz, 6H). LC-MS (ESI): m/z: [M+H]+ = 468.1.

Example 91 3-(3,5-dichlorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(1-methylpiperidin3-yl)sulfamoyl]urea sodium salt

Step 1: 1,3-dichloro-5-isocyanatobenzene. General Procedure C was followed and 3,5dichloroaniline was used to obtain the title compound as a brown liquid (Y=99%).

Step 2: tert-butyl-N-[(1-methyl-3-piperidyl)-(1-methylpyrazol-4-yl)sulfamoyl]carbamate trifluoroacetate. To a solution of 1-methyl-N-(1-methylpyrazol-4-yl)piperidin-3-amine (600 mg, 2.78 mmol) (synthesis described in Example 23) in DCM (10 ml) was added DIPEA (1.45 ml, 8.34 mmol) and the solution was stirred at RT for 0.5 h.

RM was treated dropwise with a solution of tert-butyl-N-chlorosulfonylcarbamate (599 mg, 2.78 mmol) (synthesis described in Example 87) in DCM (5 ml) and the mixture was stirred at RT for 0.5 h. The solution was concentrated in vacuo . The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 5-35%, 20 min) to obtain the title compound as yellow solid (Y=52%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.30 (s, 1H), 10.00 (s, 1H), 7.80 (s, 1H), 7.29 (s, 1H), 4.41-4.35 (m, 1H), 3 .85 (s, 3H), 3.48 (d, J=9 Hz, 1H), 3.28 (d, J=12 Hz, 1H), 2.78 (s, 3H), 2.77-2 .61 (m, 2H), 1.94-1.84 (m, 2H), 1.74-1.63 (m, 1H), 1.47 (s, 9H), 1.20-1.11 (m, 1H).

Step 3: 1-methyl-3-[(1-methylpyrazol-4-yl)-sulfamoylamino]piperidine trifluoroacetate. TFA (2 ml) and the reaction mixture was stirred at RT for 5 hours. The solution was concentrated in vacuo to give the title compound as a yellow oil (Y=96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 7.77 (s, 1H), 7.38 (s, 1H), 7.05 (s, 2H), 4.19-4.12 (m, 1H), 3 .82 (s, 3H), 3.54-3.50 (m, 1H), 3.29-3.25 (m, 1H), 2.76 (d, J=4 Hz, 3n), 2, 73-2.60 (m, 2H), 1.96-1.84 (m, 2H), 1.72-1.62 (m, 1H), 1.23-1.11 (m, 1H).

Step 4: 3-(3,5-dichlorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(1-methylpiperidin-3yl)sulfamoyl]urea sodium salt. NaH (60% in mineral oil, 41 mg, 1.0 mmol), then the mixture was stirred at 0°C for 0.5 h. To this mixture was added 1,3-dichloro-5-isocyanatobenzene (35 μl, 0.26 mmol) and The RM was stirred at 0°C for 1.5 hours. The mixture was diluted with MTBE (20 ml). The solvent was evaporated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Agela Durashell 10 µm

250x50 mm; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B: 8-35%, 20 min) and the title compound was obtained as a white solid (Y=19%). 1H NMR (400 MHz, methanolX) δ ppm 7.63 (s, 1H), 7.48 (s, 2H), 7.42 (s, 1H), 6.93 (t, J=2 Hz, 1H), 4.43-4.37 (m , 1H), 3.83 (s, 3H), 3.68-3.62 (m, 1H), 3.23-3.17 (m, 1H), 2.72 (s, 3H), 2. 56-2.49 (m, 2H), 2.11-2.05 (m, 1H), 1.96-1.92 (m, 1H), 1.87-1.77 (m, 1H), 1.30-1.20 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 461.0.

Example 92. Sodium salt of 1-[3-chloro-5-(trifluoromethoxy)phenyl]-3-[(1-methyl-N-pyrazol-4yl)(oxan-4-yl)sulfamoyl]urea

Step 1: 1-chloro-3-isocyanato-5-(trifluoromethoxy)benzene. General Procedure C was followed and 3-chloro-5-(trifluoromethoxy)aniline was used to obtain the title compound as a yellow solid (Y=100%). LC-MS in MeOH (ESI): m/z: = 270.2.

- 176 047011

Step 2: 1-[3-chloro-5-(trifluoromethoxy)phenyl]-3-[(1-methyl-1H-pyrazol-4-yl)(oxan4-yl)sulfamoyl]urea sodium salt. To a solution of 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole (150 mg, 0.51 mmol) (synthesis described in example 106) in THF (3 ml), cooled to 0°C, was added NaH (60% in mineral oil, 81 mg, 2.0 mmol). The RM was stirred at 0°C for 0.5 h then treated with 1-chloro-3-isocyanato-5-(trifluoromethoxy)benzene (120 mg, 0.50 mmol). RM was stirred at 0°C for 1.5 hours. RM was diluted with MTBE (20 ml) and the solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Xtimate C18 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 2-35%, 20 min) to obtain the title compound as white solid (Y=22%). ¹ H NMR (400 MHz, methanol-» δ ppm 7.67 (s, 1H), 7.52 (t, J=2 Hz, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 6.92 (s, 1H), 4.35-4.29 (m, 1H), 3.92 (dd, J=4, 12 Hz, 2H), 3.85 (s, 3H), 3.53-3.47 (m, 2H), 1.90 (dd, J=2, 12 Hz, 2H), 1.50-1.40 (m, 2H). ): m/z: [M+H]+ = 498.0.

Example 93. Sodium salt of 3-(3-chloro-5-methoxyphenyl)-1-[(1-methyl-III-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea

C.I.

Step 1: 3-chloro-5-methoxyaniline. To a solution of 1-chloro-3-methoxy-5-nitrobenzene (500 mg, 2.67 mmol) in MeOH (3 ml) was added NH ₄ Cl (1.28 g, 24.0 mmol), H ₂ O (1 ml ) and Fe (1.04 g, 18.7 mmol) in an N2 atmosphere. The mixture was stirred at 80°C for 1 hour. The reaction mixture was allowed to cool to rt, filtered and the filtrate was concentrated to give the title compound as a brown oil (Y=71%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.19 (t, J=4 Hz, 1H), 6.10 (t, J=4 Hz, 1H), 6.06 (t, J=4 Hz, 1H), 5.62-5.15 ( br. s, 2H), 3.65 (s, 3H).

Step 2: 1-chloro-3-isocyanato-5-methoxybenzene. General Procedure C was followed and 3chloro-5-methoxyaniline was used to obtain the title compound as a yellow solid (Y=86%). LCMS in MeOH (ESI): m/z: = 216.0.

Step 3: 3-(3-chloro-5-methoxyphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. To a solution of 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole (170 mg, 0.66 mmol) (synthesis described in Example 88) in THF (5 ml), cooled to 0°C, was added NaH (60% in mineral oil, 105 mg, 2.61 mmol). RM was stirred at 0°C for 0.5 h. RM was treated with 1-chloro-3-isocyanato-5-methoxybenzene (0.12 g, 0.66 mmol) and stirred at 0°C for an additional 0.5 h RM was diluted with MTBE (10 ml) and then concentrated. The resulting residue was purified by preparative HPLC (column: Agela Durashell 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 5-30%, 20 min) to obtain the title compound as white solid (Y=40%). 1H NMR (400 MHz, methanol-» δ ppm 7.69 (s, 1H), 7.41 (s, 1H), 7.10 (t, J=2 Hz, 1H), 6.96 ( t, J=2 Hz, 1H), 6.63 (t, J=2 Hz, 1H), 4.43-4.28 (m, 1H), 3.94-3.91 (m, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.523.46 (m, 2H), 1.90-1.87 (m, 2H), 1.50-1.40 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 444.1.

Example 94: 3-(3,5-Dichloro-2-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt

C.I.

Step 1: 1,5-dichloro-2-fluoro-3-isocyanatobenzene. General Procedure C was followed and 3,5-dichloro-2-fluoroaniline was used to obtain the title compound as a yellow solid (Y=87%). LC-MS in MeOH (ESI): m/z: = 238.0.

Step 2 sodium salt: 3-(3,5-dichloro-2-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea. To a solution of 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole

- 177 047011 (253 mg, 0.97 mmol) (synthesis described in example 88) NaH (60% in mineral oil, 155 mg, 3.88 mmol) was added to THF (3 ml), cooled to 0°C. RM was stirred at 0°C for 0.5 hours. RM was treated with 1,5-dichloro-2-fluoro-isocyanatobenzene (0.20 g, 0.97 mmol) and stirred at 0°C for another 0.5 parts RM was diluted with MTBE (10 ml) and then concentrated. The resulting residue was purified by preparative HPLC (column: Agela Durashell 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B: 10-35%, 20 min) to obtain the title compound as white solid (Y=10%). ^1H NMR (400 MHz, methanolA) δ ppm 8.21-8.18 (m, 1H), 7.71 (s, 1H), 7.41 (s, 1H), 7.20-7.18 (m, 1H), 4.37-4, 31 (m, 1H), 3.95-3.91 (m, 2H), 3.86 (s, 3H), 3.52-3.47 (m, 2H), 1.93-1.85 ( m, 2n), 1.51-1.42 (m, 2n). LC-MS (ESI): m/z: [M+H]+ = 466.0.

Example 95. Sodium salt of 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-[(1-methyl-1H-pyrrol-3yl)(oxan-4- yl)sulfamoyl]urea

Step 1: 1-methyl^-nitropyrrole. To a solution of 3-nitro-III-pyrrole (2.2 g, 19.63 mmol) in DMF (40 ml) was added K ₂ CO ₃ (5.43 g, 39.26 mmol) and MeI (2.44 ml, 39.26 mmol) and the mixture was stirred at RT for 12 hours. The solution was diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a yellow solid (Y=97%). 1H NMR (400 MHz, DMSO-d ₆ ) δ =7.91 (t, J=2 Hz, 1H), 6.87 (t, J=3 Hz, 1H), 6.73-6.59 (m , 1H), 3.70 (s, 3H).

Step 2: 1-methylpyrrol^-amine. To a solution of 1-methyl-3-nitropyrrole (0.5 g, 3.96 mmol) in MeOH (20 ml) was added 10% Pd/C (200 mg) under N2. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was stirred at RT under H ₂ (15 ^psi ) for 20 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a brown oil (Y=92%). 1H NMR (400 MHz, DMSO-d ₆ ) δ = 6.28 (t, J=2 Hz, 1H), 5.98 (t, J=2 Hz, 1H), 5.43 (t, J=2 Hz, 1H), 3.40 (s, 3H). NH ₂ is not visible.

Step 3: 1-methyl-Ntetrahydropyran-4-ylpyrrol-3-amine trifluoroacetate. General procedure A was followed and 1-methylpyrrol-N-amine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-20%, 20 min) to obtain the title compound as yellow oil (Y=33%). 1H NMR (400 MHz, methanol-d^ δ ppm 7.94 (s, 1H), 7.66 (s, 1H), 6.18 (t, J=55 Hz, 1H), 4.62 -4.58 (m, 2H), 3.65-3.57 (m, 3H), 3.15-3.05 (m, 2H), 2.88 (s, 3H), 2.36-2 .25 (m, 2H), 1.99-1.90 (m, 2H).

Step 4: tert-butyl-N[(1-methylpyrrol-3-yl)tetrahydropyran-4-ylsulfamoyl]carbamate. To a solution of 1-methyl-Ntetrahydropyran-4-ylpyrrol-3-amine trifluoroacetate (250 mg, 0.85 mmol) in DCM (2 mL) was added DIPEA (444 μL, 2.55 mmol) and the solution was stirred at RT for 0 .5 h. A solution of tert-butyl-Nchlorosulfonylcarbamate (183 mg, 0.85 mmol) in DCM (6 mL) was added to the solution and the RM was stirred at RT for 2 h. The solution was concentrated in vacuo. The crude product was purified with FCC (0-100% EtOAc in petroleum ether) to give the title compound as a yellow oil (Y=49%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 6.66-6.63 (m, 2H), 5.78 (t, J=2 Hz, 1H), 4.20-4.13 (m, 1H), 3 .85-3.73 (m, 2H), 3.60 (s, 3H), 3.36-3.31 (m, 1H), 3.15-3.09 (m, 1H), 1.70 -1.62 (m, 2H), 1.42 (s, 9H), 1.37-1.31 (m, 2H).

Step 5: 1-methyl-3-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrrole. A mixture of tert-butyl-N[(1methylpyrrol-3-yl)tetrahydropyran-4-ylsulfamoyl]carbamate (100 mg, 0.28 mmol) with TFA (0.4 ml) and DCM (2 ml) was stirred at RT for 7 min. The solution was concentrated in vacuo to give the title compound as a yellow oil (Y=96%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.67 (t, J=2 Hz, 1H), 6.61 (t, J=3 Hz, 1H), 5.92 (t, J=2 Hz, 1H), 3.97-3.87 ( m, 3H), 3.59 (s, 3H), 3.33 (t, J=11 Hz, 2H), 1.73-1.69 (m, 2H), 1.40-1.32 (m , 2H).

Step 6: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrrol-3yl)(oxan-4-yl) )sulfamoyl]urea. To a solution of 1-methyl^-[sulfamoyl(tetrahydropyran-4yl)amino]pyrrole (100 mg, 0.27 mmol) in THF (2 ml), cooled to 0°C, was added NaH (60% in mineral oil, 43 mg , 1.07 mmol). The RM was stirred at 0°C for 15 min. A solution of 4isocyanato-1,2,3,5,6,7-hexahydro-indacene (53 mg, 0.27 mmol) in THF (1 ml) was added and the RM was stirred at 0°C for 15 min. The solution was concentrated in vacuo. The crude product was purified using

- 178 047011 preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO3) - ACN]; B: 15-45%, 20 min) and obtained the title compound as a yellow solid (Y=23%). ¹ H NMR (400 MHz, methanol-0 ₄ ) δ ppm 6.98 (s, 1H), 6.71 (t, J=2 Hz, 1H), 6.64 (t, J=3 Hz, 1H), 6.02-6.00 (m, 1H), 4.38-4.28 (m, 1H), 3.92-3.87 (m, 2H), 3.66 (s, 3H), 3.49-3.42 (m, 2H), 2. 90-2.76 (m, 8H), 2.15-1.99 (m, 4H), 1.86-1.81 (m, 2H), 1.59-1.48 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 459.1.

Example 96. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(2-methyl-2H-1,2,3-triazol4-yl) (oxan-4-yl)sulfamoyl]urea

Step 1: 2-methyl-Ntetrahydropyran-4-yltriazol-4-amine trifluoroacetate. General Procedure A was followed and 2-methyltriazol-4-amine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-16%, 20 min) to obtain the title compound as white solid (Y=28%). ¹ H NMR (400 MHz, methanol^ ₄ ) δ ppm 6.92 (s, 1H), 4.85-4.58 (br.s, 2H), 3.88 (s, 3H), 3.86-3.80 (m, 2H), 3.39- 3.28 (m, 3H), 1.88-1.83 (m, 2H), 1.43-1.31 (m, 2H).

Step 2: tert-butyl-N-[(2-methyltriazol-4-yl)tetrahydropyran-4-ylsulfamoyl]carbamate. DIPEA (388 μL, 2.23 mmol) was added to a solution of 2-methyl-N-tetrahydropyran-4-yltriazol-4-amine trifluoroacetate (220 mg, 0.74 mmol) in DCM (5 mL). The solution was cooled to 0°C and treated dropwise with a solution of tert-butyl-N-chlorosulfonylcarbamate (160 mg, 0.74 mmol) (synthesis described in Example 87) in DCM (1 ml). The RM was stirred at RT for 1.5 h. The solution was concentrated in vacuo and the resulting residue was purified using preparative HPLC (column: Agela Durashell 10 μm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 1 -20%, 20 min) and obtained the desired compound in the form of a white solid (Y=71%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.45-1.19 (br.s, 1H), 7.64 (s, 1H), 4.25-4.16 (m, 1H), 4.13 (s, 3H), 3.87- 3.81 (m, 2H), 3.37-3.34 (m, 2H), 1.78-1.68 (m, 2H), 1.43 (s, 9H), 1.28-1, 20 (m, 2H).

Step 3: 2-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]triazole trifluoroacetate. A solution of tert-butyl-N-[(2-methyltriazol-4-yl)tetrahydropyran-4-ylsulfamoyl]carbamate (40 mg, 0.11 mmol) in 5:1 DCM/TFA (5 ml) was stirred at RT for 1 .5 hours. The solution was concentrated under reduced pressure to obtain the title compound as a yellow oil and used in the next step without further purification. LC-MS (ESI): m/z: [M+H]+ = 262.0.

Step 4: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(2-methyl-2H-1,2,3-triazol-4yl) (oxan-4-yl)sulfamoyl]urea. To a solution of 2-methyl-4-[sulfamoyl(tetrahydropyran-4yl)amino]triazole trifluoroacetate (30 mg, 0.10 mmol) in THF (0.5 ml), cooled to 0°C, was added NaH (60% in mineral oil , 12 mg, 0.30 mmol). The RM was treated dropwise with 4-isocyanato1,2,3,5,6,7-hexahydro^-indacene (22 mg, 0.11 mmol) and then stirred at RT for 1 h. The RM was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 10 μm 150x40 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 10-30%, 11 min) to obtain the title compound as white solid (Y=45%). ^1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.64 (s, 1H), 6.98 (s, 1H), 4.44-4.33 (m, 1H), 4.14 (s, 3H), 3.91 (dd, J=4, 12 Hz, 2H), 3.46 (t, J=12 Hz, 2H), 2.88 (t, J=7 Hz, 4H), 2.81 (t, J=7 Hz, 4H), 2, 11-2.03 (m, 4H), 1.96-1.88 (m, 2H), 1.61-1.47 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 461.2.

Example 97: 3-[3-Ethyl-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(1methylpiperidin-3-yl)sulfamoyl]urea sodium salt

Step 1: 1-ethyl-3-isocyanato-5-(trifluoromethyl)benzene. General Procedure C was followed and 3-ethyl-5-(trifluoromethyl)aniline was used (synthesis described in Example 75) to obtain the title compound as a yellow oil (Y=75%). LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 248.2.

- 179 047011

Step 2: 1-methyl-3-[(1-methylpyrazol-4-yl)-sulfamoylamino]piperidine trifluoroacetate. A solution of tert-butyl^-[(1-methyl-3-piperidyl)-(Gmethylpyrazol-4-yl)sulfamoyl]carbamate trifluoroacetate (200 mg, 0.41 mmol) (synthesis described in Example 91) in DCM (3 ml) and TFA (0.6 ml) was stirred at RT for 0.5 h. RM was concentrated in vacuo to give the title compound as a yellow oil. 1H NMR (400 MHz, DMSO- _d6 ) δ = 9.70 (s, 1H), 7.77 (s, 1H), 7.38 (s, 1H), 7.05 (s, 2H), 4 .20-4.13 (m, 1H), 3.82 (s, 3H), 3.56-3.48 (m, 1H), 3.31-3.23 (m, 1H), 2.77 (d, J=4 Hz, 3H), 2.71-2.59 (m, 2H), 1.99-1.83 (m, 2H), 1.72-1.62 (m, 1H), 1.26-1.08 (m, 1H).

Step 3: 3-[3-ethyl-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(1methylpiperidin-3-yl)sulfamoyl]urea sodium salt. To a solution of 1-methyl^-[(1-methylpyrazol-4-yl)-sulfamoylamino]piperidine trifluoroacetate (210 mg, 0.54 mmol) in THF (2 ml), cooled to 0°C, was added NaH (60% in mineral oil, 87 mg, 2.17 mmol) and the solution was stirred at 0°C for 15 minutes. 1-ethyls-isocyanamΌ-5-(mrifmΌrmethyl)benzene (117 mg, 0.54 mmol) was added and the mixture was stirred at 0°C for 1 hour. The solution was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 10-40%, 20 min) to obtain the title compound as a white solid (Y=18%). 'I NMR (400 MHz, methanold4) δ ppm 7.77 (s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.06 (s, 1H), 4.46-4 .37 (m, 1H), 3.82 (s, 3H), 3.71-3.63 (m, 1H), 3.26-3.22 (m, 2H), 2.76 (s, 3H ), 2.66 (kV, J=7 Hz, 3H), 2.12-2.04 (m, 1H), 2.00-1.91 (m, 1H), 1.87-1.71 ( m, 1H), 1.25 (t, J=7 Hz, 4H). LC-MS (ESI): m/z: [M+H]+ = 489.2.

Example 98. Sodium salt of 3-[3-chloro-5-(2-methylpropyl)phenyl]-1-[(1-methyl-1H-pyrazol-4yl)(oxan-4-yl)sulfamoyl]urea

Step 1: 3-chloro-5-(2-methylprop-1-enyl)aniline. _4,4,5,5 -tetramethyl-2-( 2-methylprop-1-enyl)-1,3,2dioxaborolane (529 mg, 2.90 mmol), Pd(dppf)Cl ₂ (177 mg, 0.24 mmol) and Cs ₂ cO ₃ (2.37 g, 7.26 mmol). RM was heated at 120°C for 12 h under N2 atmosphere. The solution was concentrated in vacuo. The residue was purified with FCC (25% EtOAc in petroleum ether) to give the title compound as a green oil (Y=41%). Ή NMR (400 MHz, DMSC-d ₆ ) δ ppm 6.42 (t, J=2 Hz, 1H), 6.37 (s, 1H), 6.34 (s, 1H), 6.08 (s, 1H), 5.35 (s, 2H), 1.83 (s, 3H), 1.80 (s, 3H).

Step 2: 3-chloro-5-isobutylaniline. To a solution of 3-chloro-5-(2-methylprop-1-enyl)aniline (75 mg, 0.41 mmol) in MeOH (5 ml) was added 10% Pd/C (50 mg) under N2 atmosphere. The suspension was degassed in vacuo and purged several times with H ₂ . The mixture was then stirred under H ₂ (15 ^psi ) at RT for 15 minutes. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a green oil. 'I NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.34 (t, J=8 Hz, 1H), 7.12-7.07 (m, 1H), 7.04 (s, 1H), 3.70-3.30 (br. s, 2H) , 2.47-2.42 (m, 2H), 1.83-1.77 (m, 1H), 0.86 (d, J=7 Hz, 6H).

Step 3: 1-chloro-3-isobutyl-5-isocyanatobenzene. General Procedure C was followed and 3chloro-5-isobutylaniline was used to obtain the title compound as a yellow oil. LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 242.1.

Step 4: 3-[3-chloro-5-(2-methylpropyl)phenyl]-1-[(1-methyl-N-pyrazol-4-yl)(oxan4-yl)sulfamoyl]urea sodium salt. To a solution of 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole (100 mg, 0.34 mmol) (synthesis described in example 88) in THF (2 ml), cooled to 0°C, was added NaH (60% in mineral oil, 27 mg, 0.67 mmol). 1-Chloro-3-isobutyl-5-isocyanatobenzene (71 mg, 0.34 mmol) was then added and the RM was stirred at RT for 2 hours. The residue was concentrated in vacuo and purified by preparative HPLC (column: HUAPU C8 Extreme BDS 5 µm 150x30 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 30-50%, 10 min) and the desired compound was obtained as a white solid (Y=16%). Il NMR (400 MHz, methanol^ ₄ ) δ ppm 7.71 (s, 1H), 7.46 (t, J=2 Hz, 1H), 7.41 (s, 1H), 7.03 (s, 1H), 6.87 (s, 1H), 4.43-4.26 (m, 1H), 3.92 (dd, J=5, 11 Hz, 2H), 3.85 (s, 3H), 3.49 (t, J=11 Hz, 2H ), 2.44 (d, J=7 Hz, 2H), 1.94-1.80 (m, 3H), 1.50-1.43 (m, 2H), 0.91 (d, J= 7 Hz, 6H). LC-MS (ESI): m/z: [M+H] ⁺ = 470.2.

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Example 99. Sodium salt of 1-[(1,3-dimethyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3(H,2,3,5,6,7-hexahydro^- indacen-4-yl)urea

Step 1: 1,3-dimethyl-N-tetrahydropyran-4-ylpyrazol-4-amine. General Procedure A was followed and 1,3-dimethylpyrazol-4-amine and tetrahydropyran-4-one were used to obtain the title compound as a white solid (Y=89%). ¹ H NMR (400 MHz, methanol-D) δ ppm 7.16 (s, 1H), 4.00-3.90 (m, 2H), 3.72 (s, 3H), 3.46-3.40 (m, 2H), 3.08-2, 92 (m, 1H), 2.13 (s, 3H), 1.97-1.86 (m, 2H), 1.53-1.38 (m, 2H).

Step 2: sodium salt 1-[(1,3-dimethyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydroA-indacene- 4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1,3-dimethyl-N-tetrahydropyran-4ylpyrazol-4-amine were used. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 10-35%, 20 min) to obtain the title compound in as a white solid (Y=10%). ¹ H NMR (400 MHz, methanol-D) δ ppm 7.58 (s, 1H), 6.98 (s, 1H), 4.42-4.28 (m, 1H), 3.93-3.89 (m, 2H), 3.82 (s, 3H), 3.53-3.42 (m, 2H), 2.88 (t, J=7 Hz, 4H), 2.77 (t, J=7 Hz, 4H), 2.19 (s, 3H), 2.14-2.01 (m, 4H), 1.96-1.82 (m, 2H), 1.50-1.38 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 474.2.

Example 100. Sodium salt of 1-[(2,4-dimethylpyrimidin-5-yl)(oxan-4-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro^-indacene-4- silt)urea

Step 1: 2,4-dimethyl-N-tetrahydropyran-4-ylpyrimidin-5-amine. To a solution of tetrahydropyran-4amine (1.35 g, 13.4 mmol) in toluene (5 ml) was added 5-bromo-2,4-dimethylpyrimidine (500 mg, 2.67 mmol), BINAP (333 mg, 0.53 mmol), Cs ₂ CO ₃ (1.74 g, 5.35 mmol) and Pd(OAc) ₂ (60 mg, 0.27 mmol) at RT in an N2 atmosphere. The mixture was heated at 120°C for 3 hours under N2 atmosphere. H ₂ O (10 ml) was added and the mixture was extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified with FCC (0-50% MeOH in EtOAc) to give the title compound as a brown solid (Y=90%). ¹ H NMR (400 MHz, methanolD) δ ppm 7.98 (s, 1H), 4.023.99 (m, 2H), 3.62-3.54 (m, 3H), 2.51 (s, 3H), 2.39 (s, 3H), 2 .05-1.92 (m, 2H), 1.66-1.56 (m, 2H).

Step 2: 1-[(2,4-dimethylpyrimidin-5-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydro^-indacen-4-yl) sodium salt )urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 2,4-dimethyl-N-tetrahydropyran-4ylpyrimidin-5-amine were used. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 10-35%, 20 min) to obtain the title compound as a white solid substances (Y=12%). ¹ H NMR (400 MHz, methanolD) δ ppm 8.58 (s, 1H), 6.92 (s, 1H), 4.46-4.39 (m, 1H), 3.97-3.87 (m, 2H), 3.50-3. 42 (m, 2H), 2.86 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.65 (s, 3H), 2.59 (s, 3H), 2.10-2.03 (m, 6H), 1.32-1.26 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 486.2.

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Example 101. Sodium salt of 3-[3-chloro-5-(propan-2-yl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(1methylpiperidin-3-yl)sulfamoyl]urea

Step 1: 1-chloro-3-isocyanato-5-isopropylbenzene. General Procedure C was followed and 3-chloro-5-isopropylaniline was used to obtain the title compound as a pale yellow gum. LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 228.2.

Step 2: 3-[3-chloro-5-(nropan-2-yl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(1methylpiperidin-3-yl)sulfamoyl]urea sodium salt . To a solution of 1-methyl-3-[(1-methylpyrazol-4-yl)sulfamoylamino]piperidine (104 mg, 0.27 mmol) (synthesis described in example 97) in THF (1 ml), cooled to 0°C, add NaH (60% in mineral oil, 43 mg, 1.07 mmol). The RM was stirred at 0°C for 15 min then treated with 1-chloro-isocyanato-5-isopropylbenzene (53 mg, 0.27 mmol). The RM was stirred at RT for an additional 2 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Xtimate C18 5 µm 150x25 mm; mobile phase: [water (10 mM NH4HCO ₃ ) - ACN]; B: 20-50%, 10 min) to obtain the title compound as a white solid (Y=8%). ¹ H NMR (400 MHz, methanol^) δ ppm 7.66 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 4.53-4 .36 (m, 1H), 3.84 (s, 3H), 3.73-3.63 (m, 1H), 3.27-3.23 (m, 1H), 2.88-2.80 (m, 1H), 2.79 (s, 3H), 2.72-2.46 (m, 2H), 2.17-2.03 (m, 1H), 2.01-1.91 (m , 1H), 1.89-1.76 (m, 1H), 1.36-1.25 (m, 1H), 1.23 (d, J=7 Hz, 6H). LC-MS (ESI): m/z: [M+H]+ = 469.2.

Example 102: 1-[3-Ethyl-5-(trifluoromethyl)phenyl]-3-[(1-methyl-1H-pyrazol-4yl)({[(2S)-1-methylpyrrolidin-2-yl]methyl) sodium salt })sulfamoyl]urea

Step 1: 1-ethyl-3-isocyanato-5-(trifluoromethyl)benzene. General Procedure C was followed and 3-ethyl-5-(trifluoromethyl)aniline was used to obtain the title compound as a yellow oil (Y=75%). LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 248.1.

Step 2: tert-butyl-N-[(1-methylpyrazol-4-yl)-[[(2S)-1-methyln-pyrrolidin-2-yl]methyl]sulfamoyl]carbamate trifluoroacetate. To a solution of 1-methyl-N[[^)-1-methylpyrrolidin-2-yl]methyl]pyrazol-4amine (1.32 g, 6.78 mmol) (synthesis described in Example 107) in DCM (10 ml) was added DIPEA (3.54 ml, 20.3 mmol). RM cooled to 0°C and treated with a solution of tert-butyl-Nchlorosulfonylcarbamate (1.9 g, 8.81 mmol) in THF (10 ml). RM was stirred at 0°C for 2 hours. The mixture was concentrated in vacuo. The residue was purified using preparative HPLC (column: Phenomenex Luna C18) to obtain the desired [M+H]+ = 374.1.

Stage 3:

µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 0-35%, 20 min) and the compound in the form of a white resinous substance (Y=60%). LC-MS (ESI): m/z:

-methyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methylsulfamoylamino]pyrazole trifluoroacetate. A solution of tert-butyl-N-[(1-methylpyrazol-4-yl)-[[(2S)-1-methylpyrrolidin-2-yl]methyl]sulfamoyl]carbamate trifluoroacetate (123 mg, 0.33 mmol) in DCM (3 ml) and TFA (0.6 ml) were stirred at RT for 1 hour. RM was concentrated in vacuo to give the title compound as a yellow oil (Y=100%). LC-MS (ESI): m/z: [M+H]+ = 274.1.

Step 4: 1-[3-ethyl-5-(trifluoromethyl)phenyl]-3-[(1-methyl-1H-pyrazol-4-yl)({[^)-1methylpyrrolidin-2-yl]methyl} sodium salt )sulfamoyl]urea. NaH (60% in mineral oil, 52 mg, 1.31 mmol) and the solution was stirred at 0°C for 15 minutes. RM was treated with 1-ethyl-isocyanato-5-(trifluoromethyl)benzene (71 mg, 0.33 mmol) and

- 182 047011

The RM was stirred at 0°C for 1 hour. The solution was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 10-40%, 20 min) to obtain the title compound as yellow solid (Y=31%). ^1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.85 (s, 1H), 7.66 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.06 (s, 1H), 4.23-4 .17 (m, 1H), 3.93-3.78 (m, 5H), 3.58-3.47 (m, 1H), 3.29-3.18 (m, 1H), 3.02 (s, 3H), 2.67 (kv, J=8 Hz, 2H), 2.18-2.07 (m, 3H), 2.05-1.94 (m, 1H), 1.25 ( t, J=8 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 489.2.

Example 103. Sodium salt of 1-[(1,3-dimethyl-1H-pyrazol-4-yl)(1-methylpiperidin-3yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro^ -indacen-4-yl)urea

Step 1: tert-butyl 3-[(1,3-dimethylpyrazol-4-yl)amino]piperidine-1-carboxylate. General Procedure A was followed and 1,3-dimethylpyrazol-4-amine and tert-butyl N-oxopiperidine-1-carboxylate were used to obtain the title compound as a yellow resinous substance (Y=68%). ^1H NMR (400 MHz, methanol-d^δ ppm 7.14 (s, 1H), 4.09-3.76 (m, 2H), 3.72 (s, 3H), 3.00 -2.81 (m, 2H), 2.12 (s, 3H), 2.08-2.00 (m, 1H), 1.84-1.66 (m, 1H), 1.52-1 .36 (m, 12N).

Step 2: Na(1,3-dimethylpyrazol-4-yl)-1-methylpiperidin-3-amine. To a solution of tert-butyl-3-[(1,3dimethylpyrazol-4-yl)amino]piperidine-1-carboxylate (1.0 g, 3.40 mmol) in THF (10 ml), cooled to 0°C, was added LiAlH ₄ (1.29 g, 34 mmol). RM was heated at 80°C for 5 hours. The reaction mixture was cooled to rt and the reaction was stopped with H ₂ O (1 ml) and 10% aqueous NaOH (1 ml). The RM was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a white solid (Y=64%). ^1H NMR (400 MHz, methanol^ ₄ ) δ ppm 7.12 (s, 1H), 3.72 (s, 3H), 3.00-2.89 (m, 2H), 2.79-2.70 (m, 1H), 2.27 (s, 3H), 2.12 (s, 3H), 1.97-1.86 (m, 2H), 1.78-1.72 (m, 1H), 1.66-1.53 (m, 1H) , 1.28-1.18 (m, 1H).

Step 3: 1-[(1,3-dimethyl-1H-pyrazol-4-yl)(1-methylpiperidin-3-yl)sulfamoyl]-3(1,2,3,5,6,7-hexahydro) sodium salt ^-indacen-4-yl)urea. General Procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and N-(1,3-dimethylpyrazol4-yl)-1- methylpiperidin-3-amine. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 1035%, 20 min) to obtain the title compound as a white solid ( Y=14%). 1H NMR (400

MHz, methanol-d^ δ ppm 7.54 (s, 1H), 6.94 (s, 1H), 4.45-4.32 (m, 1H), 3.79 (s, 3H), 3.53-3.44 (m, 1H), 3.3-2.97 (m, 1H), 2.87 (t, J=7 Hz, 4H), 2.79 (t, J=7 Hz, 4H), 2.54 (s, 3H), 2.34-2.17 (m, 5H), 2.13-1.98 (m, 5H), 1.89-1.68 (m, 2H), 1.25-1.06 ( m, 1H). LC-MS (ESI): m/z: [M+H] ⁺ = 487.3.

Example 104. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)[2-(propan-2yl)pyrimidin- 5-yl]sulfamoyl]urea

Step 1: 2-isopropyl->-tetrahydropyran-4-ylpyrimidin-5-amine. BINAP (310 mg, 0.50 mmol) was added to a solution of 5-bromo-2-isopropylpyrimidine (500 mg, 2.49 mmol) and tetrahydropyran-4-amine (1.26 g, 12.43 mmol) in toluene (8 ml). , Cs ₂ CO ₃ (1.62 g, 4.97 mmol) and Pd(OAc) ₂ (56 mg, 0.25 mmol).

RM was heated under nitrogen atmosphere at 120°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified with FCC (9-18% EtOAc in petroleum ether) to give the title compound as a dark brown solid (Y=55%). 1H NMR (400 MHz, methanol^ ₄ ) δ ppm 8.10 (s, 2H), 3.99-3.95 (m, 2H), 3.58-3.52 (m, 3H), 3.13-2.99 (m, 1H), 2. 01-1.95 (m, 2H), 1.55-1.44 (m, 2H), 1.26 (d, J=7 Hz, 6H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(oxan-4-yl)[2-(propan-2yl)pyrimidin- 5-yl]sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 2-isopropyl-Ntetrahydropyran-4 were used

- 183 047011 ilpyrimidin-5-amine. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 12-38%, 20 min) to obtain the title compound as a white solid substances (Y=17%). ¹ H NMR (400 MHz, chloroformd) δ ppm 8.61 (s, 2H), 7.04 (s, 1H), 4.52-4.40 (br. s, 1H), 4.00-3.90 (m, 2H), 3.49- 3.42 (m, 2H), 3.31-3.22 (m, 1H), 2.88 (t, J=7 Hz, 4H), 2.80-2.70 (m, 4H), 2 ,13-2.03 (m, 4H), 2.02-1.96 (m, 2H), 1.47-1.38 (m, 2H), 1.37 (d, J=7 Hz, 6H ). LC-MS (ESI): m/z: [M+H]+ = 500.2.

Example 105: 3-[3-(Butan-2-yl)-5-chlorophenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt

Step 1: 3-(but-2-en-2-yl)-5-chloroaniline. To a solution of 3-bromo-5-chloroaniline (280 mg, 1.36 mmol) in 1,4-dioxane (5 ml) and H ₂ O (0.5 ml) was added 4,4,5,5-tetramethyl-2 -[1-methylprop-1-enyl]-1,3,2dioxaborolane (296 mg, 1.63 mmol), Pd(dppf)Cl ₂ (99 mg, 0.14 mmol) and Cs ₂ CO ₃ (1.33 g, 4.07 mmol) in an N2 atmosphere. The mixture was heated at 130°C for 12 hours under N2 atmosphere. The solution was filtered and concentrated in vacuo. The residue was purified with FCC (25% EtOAc in petroleum ether) to give the compound as a green oil (Y=81%). LC-MS (ESI): m/z: [M+H]+ = 182.1.

Step 2: 3-Chloro-5-sec-butylaniline. To a solution of 3-(but-2-en-2-yl)-5-chloroaniline (160

0.88 mmol) in MeOH (5 ml) was added 10% Pd/C (20 mg) under N2 atmosphere. The suspension was degassed in ischem, vacuum and purged several times with H ₂ . The mixture was stirred at RT under H ₂ (15 ^psi ) for 10 minutes. The RM was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a green oil. LC-MS (ESI): m/z: [M+H]+ = 184.1.

Step 3: 1-Chloro-3-isocyanato-5-sec-butylbenzene. General Procedure C was followed and 3-chloro-5-sec-butylaniline was used to obtain the title compound as a yellow oil. LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 242.1.

Step 4: 3-[3-(Butan-2-yl)-5-chlorophenyl]-1-[(1-methyl-1H-pyrazol-4-yl)(oxan-4yl)sulfamoyl]urea sodium salt. To a solution of 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole (273 mg, 1.05 mmol) (synthesis described in Example 106) in THF (4 ml), cooled to 0°C, was added NaH (60% in mineral oil, 105 mg, 2.63 mmol). 1-Chloro-3-isocyanato-5-sec-butylbenzene (220 mg, crude, 1.05 mmol) was then added and the mixture was stirred at 0° C. for 2 hours. The residue was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 10 µm 150x40 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 15-35%, 11 min) to obtain the title compound as white solid (Y=14%). 1H NMR (400 MHz, methanol^) δ ppm 7.70 (s, 1H), 7.47 (t, J=2 Hz, 1H), 7.42 (s, 1H), 7.05 (s, 1H), 6.88 (s, 1H), 4.39-4.29 (m, 1H), 3.92 (dd, J=4, 11 Hz, 2H), 3.85 (s, 3H), 3.49 (t, J=11 Hz, 2H ), 2.59-2.53 (m, 1H), 1.93-1.86 (m, 2H), 1.65-1.54 (m, 2H), 1.51-1.40 (m , 2H), 1.22 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H). LC-MS (ESI): m/z: [M+H]+ = 470.2.

Example 106. 3-[3-Chloro-5-(2,2,2-trifluoroethoxy)phenyl]-1-[(1-methyl-1H-pyrazol-4yl)(oxan-4-yl)sulfamoyl]urea sodium salt

Step 1: 3-chloro-5-(2,2,2-trifluoroethoxy)aniline. To a solution of 3-amino-5-chlorophenol (350 mg, 2.44 mmol) and 1,1,1-trifluoro-2-iodoethane (263 µl, 2.68 mmol) in DMF (4 ml) was added K ₂ CO ₃ (505 mg, 3.66 mmol). RM was heated at 100°C for 8 hours. RM was diluted with H ₂ O (8 ml) and the mixture was extracted with EtOAc (3x12 ml). The combined organic phases were dried and concentrated under reduced pressure to give a residue. The residue was purified with FCC (0-100% EtOAc in pet.

- 184 047011 role ether) and obtained the desired compound in the form of a yellow oil (Y=27%). 1H NMR (400 MHz, chloroform-d) δ ppm 6.38 (t, J=2 Hz, 1H), 6.33 (t, J=2 Hz, 1H), 6.16 (t, J=2 Hz, 1H), 4.29 (kv, J= 8 Hz, 2H), 3.84-3.74 (br. s, 2H).

Step 2: 1-Chloro-3-isocyanato-5-(2,2,2-trifluoroethoxy)benzene. General Procedure C was followed and 3-chloro-5-(2,2,2-trifluoroethoxy)aniline was used to obtain the title compound as a yellow oil. LC-MS in MeOH (ESI): m/z: [M+MeOH+H]+ = 284.0.

Step 3: tert-butyl-N-[(1-methylpyrazol-4-yl)tetrahydropyran-4-ylsulfamoyl]carbamate. DIPEA was added to a solution of 1-methyl-N-tetrahydropyran-4-ylpyrazol-4-amine (7.0 g, 38.6 mmol) (synthesis described in Example 1) in DCM (70 ml) cooled to 0°C (20.2 ml, 116 mmol). To this solution was added tert-butyl-N-chlorosulfonylcarbamate (8.33 g, 38.6 mmol) in portions and the RM was stirred at 0° C. for 2 hours. The solution was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 250x100 mm; mobile phase: [water (0.1% TFA)-ACN]; B: 5-35%, 20 min) to obtain the title compound as yellow oils (Y=26%).

LC-MS (ESI): m/z: [M+H] ⁺ : 361.0.

Step 4: 1-methyl-4-[sulfamoyl(tetrahydropyran-4-yl)amino]pyrazole. A solution of tert-butyl-N-[(1methylpyrazol-4-yl)tetrahydropyran-4-ylsulfamoyl]carbamate (560 mg, 1.55 mmol) in 4 M HCl in EtOAc (10 ml) was stirred at RT for 12 h. The solution concentrated in vacuo to obtain the title compound as a white solid. LC-MS (ESI): m/z: [M+H] ⁺ : 261.0.

Step 5: 3-[3-chloro-5-(2,2,2-trifluoroethoxy)phenyl]-1-[(1-methyl-1H-pyrazol-4yl)(oxan-4-yl)sulfamoyl]urea sodium salt . NaH (60% in mineral oil, 40 mg, 1.0 mmol). The resulting mixture was treated dropwise with 1-chloro-3-isocyanato-5-(2,2,2trifluoroethoxy)benzene (112 mg, 0.44 mmol) and RM stirred at RT for 2 hours. The solution was concentrated in vacuo. The resulting residue was purified using preparative HPLC (column: Huapu C18 Extreme BDS 5 μm 150x30 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 20-40%, 10 min) and the desired compound was obtained as a white solid (Y=35%). ¹ H NMR (400 MHz, methanol-» δ ppm 7.67 (s, 1H), 7.41 (s, 1H), 7.19 (t, J=2 Hz, 1H), 7.10 (t, J=2 Hz, 1H), 6.70 (t, J=2 Hz, 1H), 4.53 (kv, J=8 Hz, 2H), 4.38-4.25 (m, 1H ), 3.95-3.90 (m, 2H), 3.84 (s, 3H), 3.49 (T, J=11 Hz, 2H), 1.93-1.86 (m, 2H) , 1.50-1.38 (m, 2H). LC-MS (ESI): m/z: [M+H] ⁺ : 512.1.

Example 107. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)({[(2S) -1-methylpyrrolidin-2-yl]methyl})sulfamoyl]urea

Step 1: tert-butyl (2S)-2-[(1-methylpyrazol-4-yl)carbamoyl]pyrrolidine-1-carboxylate. To a solution of (2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (5.0 g, 23.2 mmol) in DMF (60 ml), cooled to 0°C, was added HATU (13.25 g, 35 mmol and the mixture was stirred for 0.5 h. DIPEA (12.1 ml, 70 mmol) and 1-methylpyrazol-4-amine (2.48 g, 25.6 mmol) were added and RM was stirred at 0°C for 2 h. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EtOAc (3x10 ml), the combined organic layers were washed with H ₂ O (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. and the residue was purified with FCC (0-100% EtOAc in petroleum ether) to give the title compound as a yellow solid 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s. 1H), 7.84 (s, 1H), 7.40 (s, 1H), 4.11-4.06 (m, 1H), 3.77 (s, 3H), 3.67-3.56 (m, 1H), 3.16-3.11 (m, 1H), 2.21-2.07 (m, 1H), 1.91-1.72 (m, 3H), 1.26 (s , 9H).

Step 2: 1-methyl-N-[[(2S)-1-methylpyrrolidin-2-yl]methyl]pyrazol-4-amine. To a solution of tert-butyl(2S)-2-[(1-methylpyrazol-4-yl)carbamoyl]pyrrolidine-1-carboxylate (8.0 g, 27.2 mmol) in THF (100 ml), cooled to 0°C, lithium aluminum hydride (10.3 g, 272 mmol) was added. The RM was heated at 70°C for 12 hours. The RM was allowed to cool and poured into ice water (10 ml), then stirred for 20 minutes. The resulting mixture was poured into 1M NaOH (10 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (Y=78%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.02 (s, 1H), 6.93 (s, 1H), 4.05-4.01 (m, 1H), 3.67 (s, 3H), 3.40-3.36 (m, 1H), 2.97-2.88 (m, 2H), 2.74-2.67 (m, 1H), 2.25 (s, 3H), 1.89-1.81 (m, 1H) , 1.61-1.57 (m, 1H), 1.42-1.34 (m, 1H), 1.33-1.27 (m, 1H). NH is not visible.

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)({[(2S) -1-methylpyrrolidin-2-yl]methyl})sulfamoyl]urea. We used the general method B and

- 185 047011 used {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-K[[(2S)-1-methylpyrrolidin-2 -yl]methyl]pyrazol-4-amine. The crude product was purified by preparative HPLC (column: Huapu C8 Extreme BDS 5 µm 150x30 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 25-45%, 10 min) to obtain the title compound as a white solid (Y=9%). ¹ H NMR (400 MHz, methanol-SH) δ ppm 7.70 (s, 1H), 7.55 (s, 1H), 6.92 (s, 1H), 4.17 (dd, J=3, 16 Hz, 1H), 3.86 (s, 3H ), 3.84-3.72 (m, 2H), 3.52-3.44 (m, 1H), 3.14-3.07 (m, 1H), 2.93 (s, 3H), 2.89-2.78 (m, 8H), 2.112.00 (m, 7H), 1.99-1.90 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 473.2.

Example 108. Sodium salt of 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(4-methyl-1,3-thiazol-2yl)(oxan-4 -yl)sulfamoyl]urea

Step 1: 4-methyl-U-tetrahydropyran-4-ylthiazol-2-amine trifluoroacetate. General Procedure A was followed and 4-methylthiazol-2-amine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 1-20%, 22 min) to obtain the title compound as yellow solid (Y=10%). 1H NMR (400 MHz, DMSC-d ₆ ) δ ppm 9.43 (s, 1H), 6.47 (s, 1H), 5.82-5.66 (m, 1H), 3.893.85 (m, 3H), 3.41-3.35 (m, 2H), 2.17 (s, 3H), 1.94-1.88 (m, 2H), 1.55-1.38 (m, 2H).

Step 2: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(4-methyl-1,3-thiazol-2yl)(oxan-4 -yl)sulfamoyl]urea. General Procedure B was followed and {[(1,2,3,5,6,7hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 4-methyl-N-tetrahydropyran-4ylthiazol-2-amine trifluoroacetate were used. The crude product was purified by preparative HPLC (column: Huapu C8 Extreme BDS 5 µm 150x30 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 2040%, 10 min) to obtain the title compound as a white solid (Y=1%). 1H NMR (400 MHz, methanol^) δ ppm 7.16 (s, 1H), 6.99 (s, 1H), 4.52-4.40 (m, 1H), 3.94 (dd, J=5, 11 Hz, 2H), 3.47 (t, J=11 Hz, 2H), 2.92-2.78 (m, 8H), 2.38 (s, 3H), 2.09-2.01 (m, 4H), 2.00- 1.91 (m, 2H), 1.80-1.69 (m, 2H). LC-MS (ESI): m/z: [M+H]+ = 477.1.

Example 109. Sodium salt of 1-[(3-Ethyl-1,2-oxazol-5-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydro^-indacene -4-yl)urea

Step 1: 3-ethyl-N-tetrahydropyran-4-ylisoxazol-5-amine. General Procedure A was followed and 3-ethylisoxazol-5-amine and tetrahydropyran-4-one were used. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 5-40%, 23 min) to obtain the title compound as white solid (Y=38%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.87 (s, 1H), 4.43-4.35 (m, 1H), 4.04-3.98 (m, 2H), 3.523.45 (m, 3H), 2.55 (sq, J=8 Hz, 2H), 2.04-1.96 (m, 2H), 1.59-1.51 (m, 2H), 1.23 (t, J=8 Hz, 3H).

Step 2: tert-butyl-N-[(3-ethylisoxazol-5-yl)tetrahydropyran-4-ylsulfamoyl]carbamate. To a solution of 3-ethyl-N-tetrahydropyran-4-ylisoxazol-5-amine (200 mg, 1.02 mmol) in DCM (10 ml), cooled to 0°C, was added tert-butyl-N-chlorosulfonylcarbamate (220 mg , 1.02 mmol) and DIPEA (533 μl, 3.06 mmol). The RM was stirred at 0°C for 6 hours. The solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Welch Ultimate AQC18 5 µm 150x30 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 35-65%, 12 min) to obtain the title compound as white solid (Y=52%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.33 (s, 1H), 6.15 (s, 1H), 4.50-4.46 (m, 1H), 4.00 (dd, J=4, 11 Hz, 2H), 3.51 -3.46 (m, 2H), 2.71 (kv, J=8 Hz, 2H), 1.981.95 (m, 2H), 1.67-1.58 (m, 2H), 1.52 ( s, 9H), 1.30 (t, J=8 Hz, 3H).

Step 3: 4-Ethyl-5-[sulfamoyl(tetrahydropyran-4-yl)amino]isoxazole. To a solution of tert-butyl-N[(4-ethylisoxazol-5-yl)tetrahydropyran-4-ylsulfamoyl]carbamate (100 mg, 0.27 mmol) in DCM (1 ml)

- 186 047011 TFA (1.30 ml, 17.6 mmol) was added. The RM was stirred at RT for 4 hours. The solvent was removed under reduced pressure to give the title compound as a yellow oil.

Step 4: 1-[(3-ethyl-1,2-oxazol-5-yl)(oxan-4-yl)sulfamoyl]-3-(1,2,3,5,6,7hexahydro^-indacene) sodium salt -4-yl)urea. NaH (60% in mineral oil, 10 mg, 0.25 mmol). RM was stirred at 0°C for 0.5 h. RM was treated with 4-isocyanato-1,2,3,5,6,7-hexahydro-indacene (51 mg, 0.25 mmol) and stirred at RT for another 1 .5 hours. The solvent was removed under reduced pressure to leave a residue. The residue was purified by preparative HPLC (column: Agela Durashell 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 10-36%, 20 min) and the title compound was obtained as white solid (Y=20%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.04 (s, 1H), 6.16 (s, 1H), 4.34-4.27 (m, 1H), 3.98 (dd, J=4, 12 Hz, 2H), 3.43 (t, J=12 Hz, 2H), 2.89 (t, J=7 Hz, 4H), 2.80 (t, J=7 Hz, 4H), 2.67 (kv, J=8 Hz, 2H), 2.10-2.06 (m, 4H), 2.03-1.87 (m, 2H), 1.66-1.55 (m, 2H), 1.27 (t, J= 8 Hz, 3H). NH is not visible. LC-MS (ESI): m/z: [M+H]+ = 475.2.

Example 110. Sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)({ [(2K) -1-methylpyrrolidin-2-yl]methyl})sulfamoyl]urea

Step 1: tert-butyl (2K)-2-[(1-methylpyrazol-4-yl)carbamoyl]pyrrolidine-1-carboxylate. To a solution of 1-methylpyrazol-4-amine (2.48 g, 25.6 mmol) in DMF (60 ml) at 0°C was added HATU (13.25 g, 34.8 mmol) and the mixture was stirred for 0. 5 hours RM was treated with DIPEA (12.14 ml, 69.7 mmol) and (2K)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (5.00 g, 23.2 mmol) and stirred at 0° C for 2 hours. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EtOAc (3x10 ml). The combined organic layers were washed with H ₂ O (80 ml), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to leave a residue. The residue was purified with FCC (0-100% EtOAc in petroleum ether) to give the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.93 (s, 1H), 7.84 (s, 1H), 7.40 (s, 1H), 4.12-4.08 (m, 1H), 3.77 (s, 3H), 3 .45-3.37 (m, 2H), 2.25-2.08 (m, 2H), 1.84-1.78 (m, 2H), 1.40-1.25 (m, 9H) .

Step 2: 1-methyl-H-[[(2K.)-1-methylpyrrolidin-2-yl]methyl]pyrazol-4-amine. To a solution of tert-butyl(2K)-2-[(1-methylpyrazol-4-yl)carbamoyl]pyrrolidine-1-carboxylate (2.0 g, 6.79 mmol) in THF (20 ml), cooled to 0°C, lithium aluminum hydride (3.09 g, 81.5 mmol) was added. RM was heated at 70°C for 12 hours. The reaction mixture was cooled to rt, poured into ice water and stirred for 20 minutes. The resulting mixture was poured into 1 M NaOH (30 ml) and stirred. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (Y=61%). LC-MS (ESI): m/z: [M+H]+ = 195.2.

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)({[(2K) -1-methylpyrrolidin-2-yl]methyl})sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N[[(2K)-1-methylpyrrolidine were used -2-yl]methyl]pyrazol-4-amine. The crude product was purified by preparative HPLC (column: Huapu C8 Extreme BDS 5 µm 150x30 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B: 25-45%, 10 min) to obtain the title compound as white solid (Y=7%). ¹ H NMR (400 MHz, methanol-ph) δ ppm 7.70 (s, 1H), 7.55 (s, 1H), 6.92 (s, 1H), 4.16 (dd, J=3, 16 Hz, 1H), 3.86 (s, 3H ), 3.83-3.72 (m, 2H), 3.50-3.45 (m, 1H), 3.14-3.06 (m, 1H), 2.92 (s, 3H), 2.89-2.80 (m, 8H), 2.102.00 (m, 7H), 1.99-1.89 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 473.2.

- 187 047011

Example 111. Sodium salt of 3-(1.2.3.5.6.7-hexahydro^-indacen-4-yl)-1-|(1-methyl-1H-pyrazol-4yl) [(1-methylazetidin-2-yl)methyl] sulfamoyl]urea

Step 1: tert-butyl 2-[(1-methylpyrazol-4-yl)carbamoyl]azetidine-1-carboxylate. To a mixture of 1-tert-butoxycarbonyl azetidin-2-carboxylic acid (900 mg, 4.47 mmol) in DMF (9 ml), cooled to 0° C., HATU (2.04 g, 5.37 mmol) was added. The mixture was stirred at 0°C for 1 hour then treated with 1-methylpyrazol-4-amine (478 mg, 4.92 mmol) and DIPEA (1.56 ml, 8.95 mmol). The mixture was stirred at 0°C for 2 hours. H ₂ O (10 ml) was added and the RM was extracted with ethyl acetate (3x10 ml). The combined organic layers were washed with saturated brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified with FCC (20-100% EtOAc in petroleum ether) to give the title compound as a brown oil (Y=71%). ^! H NMR (400 MHz, methanol^) δ ppm 7.92 (s, 1H), 7.53 (s, 1H), 4.68-4.64 (m, 1H), 4.00-3.92 (m, 2H), 3.86 (s, 3H), 2.56-2.47 (m, 1H), 2.27-2.18 (m, 1H), 1.40-1.34 (m, 9H).

Step 2: 1-methylIII-[(1-methylazetidin-2-yl)methyl]pyrazol-4-amine. To a solution of tert-butyl 2-[(1methylpyrazol-4-yl)carbamoyl]azetidine-1-carboxylate (500 mg, 1.78 mmol) in THF (5 ml), cooled to 0°C under a nitrogen atmosphere, LiAlH was added portionwise ₄ (677 mg, 17.8 mmol). The mixture was stirred at 0°C for 20 minutes, then heated at 70°C for 1 hour. The reaction mixture was cooled to 0°C and the reaction was stopped by adding H ₂ O (0.6 ml) and 10% aqueous NaOH (0 .6 ml). The RM was filtered and concentrated under reduced pressure to give the title compound as a brown oil (Y=52%). ^! H NMR (400 MHz, methanol^) δ ppm 7.14 (s, 1H), 7.10 (s, 1H), 3.77 (s, 3H), 3.40-3.36 (m, 1H), 3.28-3.26 (m, 1H), 3.10-2.98 (m, 2H), 2.91-2.85 (m, 1H), 2.37 (s, 3H), 2.11-2.06 (m, 1H) , 1.98-1.89 (m, 1H).

Step 3: sodium salt 3-(1,2,3,5,6,7-hexahydro^-indacen-4-yl)-1-[(1-methyl-1H-pyrazol-4yl)[(1-methylazetidin- 2-yl)methyl]sulfamoyl]urea. General procedure B was followed and {[(1,2,3,5,6,7-hexahydro^-indacen-4-yl)carbamoyl]amino}sulfonyl chloride and 1-methyl-N-[(1-methylazetidin-2- yl)methyl]pyrazol-4-amine. The crude product was purified by preparative HPLC (column: Agela Durashell C18 10 µm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 15-40%, 20 min) to obtain the title compound in as a white solid (Y=18%). ¹ H NMR (400 MHz, meganol-f) δ ppm 7.73 (s, 1H), 7.57 (s, 1H), 6.94 (s, 1H), 4.44-4.39 (m, 2H), 4.02-3.92 (m, 1H), 3.87 (s, 3H), 3.78-3.71 (m, 1H), 3.50-3.44 (m, 1H), 2.91-2.83 (m, 11H) , 2.58-2.53 (m, 1H), 2.20-2.17 (m, 1H), 2.08-2.04 (m, 4H). LC-MS (ESI): m/z: [M+H]+ = 459.2.

Example 112. Sodium salt of 1-(3,5-dichlorophenyl)-3-[(1-methyl-1H-pyrazol-4-yl)({[(2R)-1methylpyrrolidin-2-yl]methyl})sulfamoyl]urea

C.I.

Step 1: 1,3-dichloro-5-isocyanatobenzene. General Procedure C was followed and 3,5dichloroaniline was used to obtain the title compound as a white solid (Y=100%). LC-MS in MeOH (ESI): m/z: = 220.0.

Stage 2: tert-butylIII-(chlorosulfonyl)carbamate. To a solution of Na(oxomethylene)sulfamoyl chloride (368 μl, 4.24 mmol) in THF (3 ml), cooled to 0° C., 2-methylpropan-2-ol (405 μl, 4.24 mmol) was added dropwise. RM was stirred at 0°C for 2 hours and the title compound was obtained as a solution in THF (3 ml).

Step 3: tert-butyl-N-[(1-methylpyrazol-4-yl)-[[(2R)-1-methylpyrrolidin-2-yl]methyl]sulfamoyl]carbamate trifluoroacetate. To a solution of 1-methyl-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]pyrazol-4

- 188 047011 amine (300 mg, 1.54 mmol) (synthesis described in example 110) in THF (4 ml), cooled to 0 ° C, added DIPEA (807 μl, 4.63 mmol) and tert-butyl-H -chlorosulfonylcarbamate (500 mg, 2.32 mmol). The RM was stirred at 0°C for 2 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Agela Durashell 10 µm 250x50 mm; mobile phase: [water (0.1% TFA) - ACN]; B: 2-30%, 20 min) to obtain the title compound as a white solid substances (Y=53%). 1H NMR (400 MHz, methanol-ph) δ =7.82 (s, 1H), 7.54 (s, 1H), 4.28-4.13 (m, 2H), 3.89 (s, 3H ), 3.813.71 (m, 1H), 3.61-3.52 (m, 1H), 3.25-3.18 (m, 1H), 3.04 (s, 3H), 2.36- 2.24 (m, 1H), 2.17-2.02 (m, 2H), 1.94-1.83 (m, 1H), 1.51 (s, 9H).

Step 4: 1-methyl-4-[[(2K)-1-methylpyrrolidin-2-yl]methylsulfamoylamino]pyrazole trifluoroacetate. To a solution of tert-butyl-N-[(1-methylpyrazol-4-yl)-[[(2K)-1-methylpyrrolidin-2yl]methyl]sulfamoyl]carbamate trifluoroacetate (100 mg, 0.21 mmol) in DCM (2 ml ) TFA (0.4 ml, 5.4 mmol) was added. The RM was stirred at RT for 1 hour. The solvent was removed under reduced pressure to obtain the title compound as a colorless resinous substance (Y=100%). LC-MS (ESI): m/z: [M+H]+ = 274.2.

Step 5: 1-(3,5-dichlorophenyl)-3-[(1-methyl-1H-pyrazol-4-yl)({[(2K)-1methylpyrrolidin-2-yl]methyl})sulfamoyl]urea sodium salt . NaH (60% in mineral oil, 33 mg, 0.82 mmol). The RM was stirred at 0°C for 15 min, then treated with 1,3-dichloro-5-isocyanatobenzene (39 mg, 0.21 mmol). The RM was stirred at RT for 1 hour. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Agela Durashell 10 μm 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B: 18-45%, 20 min) and the title compound was obtained as white solid (Y=45%). 1H NMR (400 MHz, meganol-f) δ ppm 7.67 (s, 1H), 7.52 (d, 2H), 7.49 (s, 1H), 6.97 (t, J=2 Hz, 1H), 4.18 (dd, J=3 , 16 Hz, 1H), 3.93-3.85 (m, 2H), 3.83 (s, 3H), 3.59-3.47 (m, 1H), 3.29-3.21 ( m, 1H), 3.03 (s, 3H), 2.19-2.08 (m, 3H), 2.01-1.92 (m, 1H). LC-MS (ESI): m/z: [M+H]+ = 461.1.

Example 113. Biological activity of the compounds proposed in the present invention.

The biological activity of the compounds of the present invention was examined using the assay described in the present invention.

Determination of PBMC IC ₅₀ .

The inhibitory activity of the compounds of the present invention on the release of IL-1e following activation of NLRP3 in peripheral blood mononuclear cells (PBMC) was studied.

Protocol A.

PBMCs were isolated from buffy coats by density gradient centrifugation using Histopaque-1077 (Sigma, cat no. 10771). The isolated cells were seeded into the wells of a 96-well plate and incubated for 3 hours with lipopolysaccharide (LPS). After replacing the medium, compounds of the present invention were added (one compound per well) and the cells were incubated for 30 minutes. Cells were then stimulated with ATP (5 mM) or nigericin (10 μM) for 1 h, and culture media from the wells were collected for analysis.

The release of IL1-e into the media was determined by quantitative detection of !P-1β in the media using the IL-1e enzyme-linked immunosorbent assay (ELISA) Ready-SET-Go!, eBioscience cat. No. 88-7261-88. Briefly, in the first step, high affinity binding plates (Corning, Costar 9018 or NUNC Maxisorp Cat No. 44-2404) were coated overnight at 4°C with the specific immobilized antibodies included in the kit (anti-human IL-1e ref. 14-7018- 68). The plates were then blocked with blocking buffer for 1 h at room temperature (rt) and, after washing with buffer (PBS with 0.05% Tween-20), incubated with standard protein and culture medium. After incubation for 2 h at RT, plates were washed and incubated with the biotinylated detection antibody included in the kit (IL-1e biotin anti-human ref. 33-7110-68) for 1 h at RT. The plates were washed and incubated with HRP-streptavidin for 30 min at RT and washed again. The signal developed after the addition of 3,3',5,5'-tetramethylbenzidine peroxidase (TMB) until color appeared and the reaction was stopped with 2 M H2SO4. To detect signals when

A microplate spectrophotometer (BioTek) was used at 450 nm. The detection range of the Ρ-1β ELISA was 2-150 ng/ml.

Protocol B.

PBMCs were isolated from buffy coats by density gradient centrifugation using Histopaque-1077 (Sigma, cat no. 10771). Isolated cells were seeded into wells (280,000 cells/well) of a 96-well plate and incubated for 3 h with lipopolysaccharide (LPS, 1 μg/ml diluted 1000x from a 1 mg/ml stock solution). Compounds of the present invention were added (one compound per well) and the cells were incubated for 30 minutes. Cells were then stimulated with ATP (5 mM final concentrations, diluted 20x from 100 mM original solution

- 189 047011 ra) for 1 hour and the culture media from the wells was collected for analysis.

Release of ΓΓ1-β into media was determined by quantitative detection of ΓΓ-1β in media using HTRF®, CisBio cat. No. 62HIL1BPEH. Briefly, cell culture supernatant was injected directly into an assay plate containing HTRF® donor and acceptor labeled antibodies. For signal detection at 655 nm, the detection range in IL-1e HTRF® was 39-6500 pg/ml.

Determination of IC ₅₀ values was determined using Graph Pad Prism software and the measured IC ₅₀ values for the compounds of the present invention are shown in Table 1 below. A (++++ means <1 µM; +++ means >1 and <3 µM; ++ means >3 and <10 µM; + means >10 and <50 µM). These results indicate that the compounds of the present invention can inhibit the release of ΓΓ-1β after activation of the inflammasome.

Table A

Connection No. Average value of PBMC 1C ₅₀ (µM) 1 ++++ 2 ++++

- 190 047011

3 +++ 4 ++++ 5 ++++ 6 ++++ 7 ++++ 8 ++++ 9 ++++ 10 ++++ AND ++++ 12 ++ 13 ++++ 14 ++++ 15 +++ 16 ++++ 17 ++++ 18 ++++ 19 ++ 20 ++++ 21 ++ 22 ++++ 23 ++++ 24 ++++ 25 ++++ 26 ++++ 27 ++++ 28 ++++ 29 ++++ thirty ++++ 31 ++++ 32 ++++ 33 +++ 34 ++++ 35 ++++ 36 ++++

- 191 047011

- 192 047011

- 193 047011

105 ++++ 106 ++++ 107 ++++ 108 ++++ 109 ++++ 110 ++++ 111 ++++ 112 ++++ FROM ++++ 114 ++++ 115 ++++ 116 ++++

Equivalents

A detailed description of one or more embodiments of the present invention is provided in the above description. Although any methods and materials similar or equivalent to those described in the present invention can be used in the practice or testing of the present invention, preferred methods and materials are described. Other features, objects and advantages of the present invention will be apparent from the description and claims. In the specification and claims, the singular forms also include the plural forms unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention relates. All patents and publications cited herein are incorporated herein by reference.

The foregoing description is presented for illustration only and is not intended to limit the present invention to the precise form disclosed, but is limited by the appended claims.

Claims (59)

1. Compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₁ is C3-C ₁₆ cycloalkyl or C ₆ -C ₁₀ aryl, wherein C3-C ₁₆ cycloalkyl or C ₆ -C ₁₀ aryl is optionally substituted with one or more R1S; where each R1S independently means C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or halogen; R2 is -(CX2X ₂ )nR _2S where n is 0, 1 or 2, and each X ₂ is independently H, C1-C6 alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, where C1-C6 alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally substituted by one or more of the following: halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group; R2S means 4-8 membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, - O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group; And R3 is a 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, optionally substituted by one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3- _C8 cycloalkyl, halogen or 3- 8-membered heterocycloalkyl, where C1-C6 alkyl, C1-C6 haloalkyl, C ₃ -C ₈ cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by the group -O(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , halogen or -CN; where heterocycloalkyl contains 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and heteroaryl contains 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. - 194 047011 2. A compound according to claim 1, where R ₁ means C ₉ -C ₁₀ bicyclic cycloalkyl. 3. A compound according to claim 1, where R1 is a C12-C16 tricyclic cycloalkyl. 4. The connection according to claim 1, where R1 means where n and n _a are all independently equal to 0, 1, 2 or 3. 5. The connection according to claim 1, where R1 means 6. A compound according to claim 1, wherein R1 is C ₆ -C ₁₀ aryl, optionally substituted with one or more R1S. 7. A compound according to claim 1, wherein R1 is phenyl, optionally substituted with one, two or three ^R 1S ^. 8. The connection according to claim 1, where R1 means 9. The connection according to claim 1, where R ₁ means - 195 047011 10. A compound according to claim 1, wherein R ₁ is cyclopentyl, cyclohexyl or cycloheptyl, wherein the cyclopentyl, cyclohexyl or cycloheptyl is optionally substituted with one or more R1S. 11. The connection according to claim 1, where R1 means 12. A compound according to any one of claims 1, 6, 7 or 10, where at least one R1S is methyl, ethyl, isopropyl, isobutyl, sec-butyl, methoxy, ethoxy, -CF3, -OCF3, -OCH ₂ CF3, F or Cl. 13. The connection according to any of the previous paragraphs, where R ₂ means -R2S. 14. The connection according to any one of claims 1 to 12, where R2 means -(CX ₂ X ₂ )-R _2S . 15. A compound according to any one of claims 1 to 12, where R2 means -(CX ₂ X ₂ ) ₂ -R _2S . 16. A compound according to any one of claims 1-12, 14 or 15, where each X ₂ means H. 17. A compound according to any one of claims 1-12, 14 or 15, where at least one X ₂ is C1-C6 alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, where C1-C6 alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally substituted by one or more of the following: halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl) , -N(C1-C ₆ alkyl) ₂ or oxo group. 18. A compound according to any of the preceding claims, wherein R2S is a 4-8 membered heterocycloalkyl, optionally substituted with one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl , halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH ₂ , -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group. 19. A compound according to any of the preceding claims, wherein _R2S is a 6-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH ₂ , -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl)2 or oxo group. 20. A compound according to any of the preceding claims, wherein R2S is tetrahydropyranyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl or oxo. 21. A compound according to any one of claims 1 to 19, wherein R _2S is piperidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl or oxo. 22. A compound according to any one of claims 1 to 18, where R _2S means a 5-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1- C6 haloalkyl, halogen, -CN, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group. 23. A compound according to any one of claims 1-18 or 22, wherein R _2S is tetrahydrofuranyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl or oxo. 24. A compound according to any one of claims 1-18 or 22, wherein R2S is pyrrolidinyl, optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl or oxo. 25. A compound according to any one of claims 1 to 18, wherein R2S is a 4-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group. 26. A compound according to any one of claims 1 to 18, wherein R2S is a 7-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group. 27. A compound according to any one of claims 1 to 18, wherein R2S is an 8-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1-C6 haloalkyl, halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group. - 196 047011 28. A compound according to any one of claims 1 to 18, wherein R _2S is a spiro-fused 7-membered heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl or oxo group. 29. A compound according to any one of claims 1 to 18, wherein R _2S is a bridged heterocycloalkyl, optionally substituted by one or more of the following: C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1-C6 haloalkyl , halogen, -CN, -OH, -O(C1-C ₆ alkyl), -NH2, -NH(C1-C ₆ alkyl), -N(C1-C ₆ alkyl) ₂ or oxo group. 30. The connection according to any one of claims 1 to 18, where R2S means 31. A compound according to any of the preceding claims, wherein R ₃ is a 7-12 membered heterocycloalkyl, optionally substituted with one or more R _3S . 32. A compound according to any one of claims 1 to 30, where R ₃ means 33. A compound according to any one of claims 1 to 30, wherein R ₃ is a 5- or 6-membered heteroaryl, optionally substituted with one or more R _3S , wherein each R _3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3 -C8 cycloalkyl, halogen or 3-8 membered heterocycloalkyl, wherein C1-C6 alkyl, C1C6 haloalkyl, _C3 - _C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by the group -O(C1- _C6 alkyl), -N (C1-C ₆ alkyl) ₂ , halogen or -CN. 34. A compound according to any one of claims 1 to 30, where R ₃ means pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, furanyl, oxazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl or 4,5,6,7- tetrahydrobenzo[c]isoxazole, wherein pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, furanyl, oxazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl or 4,5,6,7-tetrahydrobenzo[c]isoxazole is optionally substituted by one or more R3S ^. 35. A compound according to any one of claims 1 to 30, where R ₃ means - 197 047011 36. A compound according to any one of claims 1-31, 33 or 34, where at least one R _3S is C1-C6 alkyl, C1-C6 haloalkyl, C ₃ -C ₈ cycloalkyl, halogen or 3-8 membered heterocycloalkyl, wherein C1-C6 alkyl, C1-C6 haloalkyl, _C3 - _C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with -O(C1- _C6 alkyl), -N(C1- _C6 alkyl) ₂ , halogen or -CN. 37. The compound according to any one of claims 1 to 31, 33, 34 or 36, where at least one R _3S is methyl, ethyl, isopropyl, -CH2OCH3, -CH2CF3, -CH2CH2OCH3, -CH2CN, CH2CF2 or -CH ₂ CH ₂ N(CH3) ₂ . 38. A compound according to claim 1, where the compound is described by the formula (Ia-1) or (Ia-2) or a pharmaceutically acceptable salt. - 198 047011 39. A compound according to claim 1, where the compound is described by formulas (Ib-1), (Ib-2) or (Ib-3) or a pharmaceutically acceptable salt thereof. 40. A compound according to claim 1, where the compound is described by any of the formulas (Ib-1a), (Ib-1b) or (1b-1c) or a pharmaceutically acceptable salt thereof. 41. A compound according to claim 1, where the compound is described by the formulas (Ic-1), (Ic-2), (Ic-3) or (Ic-4) - 199 047011 or a pharmaceutically acceptable salt thereof. 42. A compound according to claim 1, where the compound is described by formulas (Ic-5), (Ic-6), (Ic-7) or (Ic-8) or a pharmaceutically acceptable salt thereof. 43. A compound according to claim 1, where the compound is described by formulas (Iab-1) or (Iab-2) - 200 047011 or a pharmaceutically acceptable salt thereof. 44. A compound according to claim 1, where the compound is described by the formulas (Iac-1), (Iac-2), (Iac-3) or (Iac-4) or a pharmaceutically acceptable salt thereof. 45. A compound according to claim 1, where the compound is described by the formula (Ibc-1) or (Ibc-2) Ooo G=A R _1s X 1st Μχ ^{Ν R} 3S th U AR ₃ s) ₀ - ₂ ^R 2S (Ibc R ^R 2S 1-3 (Ibc-2), - 201 047011 or a pharmaceutically acceptable salt thereof. 46. A compound according to claim 1, where the compound is described by the formulas (Iabc-1), (Iabc-1a) or (Iabc-1b) or a pharmaceutically acceptable salt thereof. 47. A compound according to any of the previous paragraphs, selected from the following compounds and their pharmaceutically acceptable salts: - 202 047011 - 203 047011 - 204 047011 - 205 047011 18 ΓΪί ° Ο Ο ON L II jj A'' k/-sn _:: /X x^A ^χΧ'^Ή. /<Х/ ·3 / Ν Ν Ν ^Ν · ό 0 19 Г\ сн ₃ ΓΗ й °',° Γ” ^Ν \ >ks .xk xk e>S^ .χ9ι 7 У Ν Ν Ν Ν ^Na ' ό 0 20 Κι Ο ο 0 к Д Д 'st Д z ^N ~CH ₃ / У^ Ν Ν Ν N ^r - ό N CH ₃ 21 ΓΐΤ ⁰ Ο 0 L 11 U 'V ^z ν, ^Ν “0Η ₃ / Ν Ν Ν ^Na ' ό 0 22 pil ⁰ Ο 0 G^CH k 1 DaХ D/ ^M ' ^CH z / y^ Ν Ν N ~ ό 23 9|f n ° ⁰ DD Dkk D>/' ^sn z γ J N | Na* \ ] to xA sn ₃ - 206 047011 24 Cll ίΐ °h/° A ⁴ AL AL Al-snz / NNN ό '—Ν ₄ ^H sn _e 25 (Αχρ o OO Г=Ч / L II 11 _c 's Lf~/ ΛΑνΑι'Ί'/\ Z 26 fY|Z ooo g=Ч 1 U with Ν—. 4 y NNN '' \ I ^N No.*D L 27 G Xt ooo g=H L 1| I - e to N—L Ν Ν 6— “ό 28 o o o g=Ч L Η π ₁₌ 7 L ν—χ ζγ^ Ν Ν Ν ₀ _ ό Ν 1 29 ρΛγ 0 OO Г=Ч 1 II j] * _s J. ν—, ΟΛ ..- _ό · 30 [AjA o o o g=h L II and k L ν—, Ζγ^ΝΝ ν ^ \, 74 ^Η _Νί 1 - 207 047011 31 Γ|[ ο ΟΟ f=4 YES A=s A/ ⁿ ~\ Ν Ν 'Ν k Ζ n _Νί ΐ ® 1 32 Γί| 0 Ο Ο f=4 1 II η _a ν— ΖΥ'ιΟν'' cr- γ Ν 33 Ζιί LLC Γ=4 1 II η _s L_ n— Ζγ ^χΧ4 'Ν'^>4'Ν'' ov YN 34 ZjZ o oo r=4 / L 1 U e LN—/ A>. AA e>,S. \ Z Ν NN ' _F “0 N 1 35 / \ F Du o oo Г^Ч )—FL II π „L. n—/ Zy ^X ^'N'^ ⁴ 'N ^> '0 36 / \ F YY 0 o 0 G=H )—F L JI u _e s jL·/ ¹ -'' /у ⁴ !/ ⁴ !?' Ar ^{H Ν} ό 1 37 ГД FF Z]Z 0 О О Г=Ч Λ-F L JI II „ kN—/ /y^N ⁷⁴ ^ ''ГТ'^ ^{7 H Ν} ”ό N 1 - 208 047011 - 209 047011 - 210 047011 - 211 047011 59 Χγ ο ο ο L II n γ L ν- A n _Na .d N 1 60 Χγ 9 ° ° f^' L II JI _e 's jL Ν— ^s, n' ^x ^ ^/ \ JH _f 1 '—' Na® k /k Z Ν V.' 1P 61 \n 9 ° ° 1 II H _Q ' ^% _s n— / A'T'G'M'· 'n''^ ⁷ VH _N ..^ N , ^F \__-4-f F 62 Γ|[ 9 ° ⁰ 1 II η _{e s} j/ n— Zy ^x4 N'^ ⁴ N'' \ JH ¢1 '—' Na® D-'M'xX' 63 in 9 ° ⁰ I II h % L n— Z Τ' Ν Ν N \ JH ® | '' Na® < *0* 64 _g Ш z® (-4 \ _A ωζ \ Z\ / ό )— z >—z z 1 65 Γϊί 9 о ⁰ r= ^N ' 1 II II _e 'y n— l\TNN ex'- Ν kz ^F Pf F - 212 047011 66 2 o o g=H 1 II ii ν L ν— Ζ γ Ν Ν N \ J N yes | ^- ⁷ Na* /k o ⁷ 67 Γϊί 2 o ° X 1 II JI, _{a s} to ^N - Ζγ ^χ ^'Ν'^ ⁴ 'Ν''<r. „ _ό \ 68 U|| ° 0 0 f=4 JL. doc. x-UX''· Z Ν Ν N \ JH yes | ^s ' Na* X. y-U 69 Zll ° o o X' ι ii u _{e s} jLy— Zy^'N^'N'' ^x N' ^X ^ ^/ \ JH yes I \ ^Z kz 1% F 70 Z|, O o o Г=Ч XJL. Αθχ X/~ Z^^NN N^ ‘Ό 71 УХ 2 ^{0 0} У ⁷ ι ii 0 „ _s Ху-- Χ''''^ζχ-'^rZ 'ι/ ' ⁷ У 72 Cl U|| O o o G=L L II and y _s L y— O - 213 047011 - 214 047011 - 215 047011 - 216 047011 - 217 047011 103 0 о 1 JI j] _А Ά L ν— ⁴ NV N·^ cl 104 J./ ^-N. 1. f Ύ ? °a if VAAA®^s^ A^n Z y ^- ^ NNN '0 105 L ⁰ o O A L JI A A A/ ^N ~~ cZ'Z/^ _N ^x _r y ⁴ 'N ^X ^ ^/ . ¢) 106 Cl Λ ? ° o F _x/ X XxJL A ©A. AA >K XT Ν Ν N A 107 ril? ⁰ o A' L JI D _e v Ln- At'An·'' ^, n ^x ^ ^/ \—J ^H l„ Na® TA NV 108 p ⁰ <3 0 S-^ yA AA a 's' Af a / Ν Ν' Ν N .y 109 o o o ii v LAA s A ' ^N /уАм' νΆ) ό 110 AY o 0 O A HA A « Ж >k/ ^N ~~ Z Г Ν Ν N \__/ n [ κι ® Na 1 ? nV - 218 047011 111 // ooo 1 II JI _{3 s} jL n— \___1 hi P / 112 Cl Г=А1 О о 0 A' 1 II Jl ,γ cd - α ^/ % ^/4 _Ν ^/4 Ν I 1 Na* lA n-У 117 rii π ° ° rV~ VJ ^H N# JL ⁴ cr 118 r^lf Ooo f= ^N ' kl Ah'S A/ ⁿ — V-1 ^H NP \— ^F _χ Ν—/ 119 AX ° o o g^h / IX Ao's А/Ч Ν NN \ I ^H N# A ⁴ cr 120 ΟΥ ooo /«=4 JLA AiX X// γ^ Ν NN V-/ ^H Na* l /X ° 121 Ooo r=4 kl Ao's A/ ^N — At NNN VJ ^H NcF l„ ___ \ \. ^,f /N-У 122 Γ= ^ίί:: ιΤ ⁰ 0 0 Г=Ч ΧΧν^^^ν^/Π Vj ^H n<F к____ Т[ \. ^,F /N-U - 219 047011 123 ί^ιί οοο r=4 zXJL. AaS -Ύ/ ^Ν V-/ ^Η NcP l„ zs \ F /N-У 124 LLC Γ=4 II C'z Ν___ kA zA.s,s^ χΆζ γΝΝ Ν 1 ^Η ν# 1 ⁴ ο^ 128 CI ^F LLC r=4 4 kl Ab's kA ZX z<^4 Zx. z^X “ζ>ν ₄ Z ⁴ ^/ ^F ^ X/ Ν N ^H A \r 129 А/о OO O-N_ . А^хк AAs zA/ ' Z^ZNNN D VJ h _NiF I \ ⁴ o^ 132 <Y 0 op O-N_/ zks Jk zA.©z's's zAtZ \ (jZ Ν Ν N D \ \—1 ^H NtF JL ' 136 ΓΥ о о of=4 kl Ah's zJAz ^N ~ ΖγΖ^ _N Z4 _N >x/ \—1 ^H NsP k/\xF 137 zY/zN. Xl·H ? °° il 3 zAxk zAk'sk zAzi-N Ζ^Γ Ν Ν N \—1 ^H N# A 141 Cl ^Ρ >Ύ|| LLC f=4 As A As's' Aa ^H Ni A. k^ ^N \ - 220 047011 142 SA LLC G=CH Ml LD AL ^N N# JL 143 ^Ρ γΑ ooo r=4 II \'ti 1 Μ____ \ /А XA»A /А/ NN Ν ^ ^{7 Η NjfS} /Н-J 144 Cl ^F yA o o o f=4 LI Jin's' AL~ ^H L--\ ^A-~J 145 о 0 0 N=N II C 'z 1 N___ yAJk Zsss/ NNN VJ ^H N(P JL XT 146 GT o O 0 N=N kl Ah's A z ⁿ — N^N VJ ^H N# A 155 Ml u °-° Mm NNN O VJ ^H Ni 1 ⁴ O^ 163 Mj/ 0 0 O N'N AA As s A z— /y ^z ^N' ^Z ^N'' ^S ^N^S Μ ^H N# A ⁴ O^ 48. The compound according to any of the previous paragraphs, selected from compounds Nos. 1A-166A and their pharmaceutically acceptable salts. Connection No. Structure 1A / N-N A\ /---\ a LL oU J'JI H \J - 221 047011 2A N-g/ Λ X /—\ ajTjl XU ο'Ή ΧΟ FOR Ν-Ν ^Ζ χΫ χ υόϋ ¹ / Υ Ν Ν' * \__/ Η Η ° 4A Ν-Ν^ V Α /L/ a ΛΑ □i /LA? 5A Ν-Ν^ V Λ /L/ a JUL Xj ό' 'Y YΑ> 6A Ν-Ν ^? V Λ /Л χ Υχ οχ /ΛΑ) 7A Ν-Ν^ V Λ αυ^/ a JUL °' ή « υ 8А Ν-Ν ^Ζ Λ X !---Α ^vX ^,p A JO °χ Τ /'Ν^Ν^νΥ \— ^J ° Η Η \__/ 9A b <χ XΥ) LU °'~th Η \J - 222 047011 10A °=( ο. A A '—ο IA \ Ν-Ν Αχ /—\ DZSr? Υη £j Αΐ\Γ Ο-Α ° Η Η \__/ 12A Π ο. /Αν? η Ύ] XX cH ^nAn τ> Ο^Α ° Η Η \__/ 13A Ο-Ν Ζ A !—ι ΥαΧ ^,? A JO 1 Τ η ^ζ Ν Ν^Αχ ο Η Η \__/ 14A \-Ν / Λ /—\ DGH/R ? YS IJ ΧΧνΑ) _γ ΝΑ ° Η Η \_/ 15A \-Ν Αχ /—\ Τ ο Ο ΓιΥ αΑ X Λ L 1 Τ X' ν^νΑΑ ° Η Η \__/ 16A Ν-Ν ^Ζ /—\ ο ο U Г~^р Il J 1 \__/ Η Η ° 17A ι\Αν L Η /—у α>Χ ^/? l JUL £ JX ^{/S N><N} 17 ° Η Η \__/ 18A B A ^A ⁿ 's X JL Λ 1 Τ Ι'ν^νΑΑ Ο^Α ° Η Η \_/ - 223 047011 19A Ο z—, ^N Y/ ^N / Λ A JO AZ °'~th hl) 20A b GA Ay § n AT ° Η Η V__/ 21A \ / ^N O Γ-у On < 1 ^O./P ? \ η SSr /OnO\ ° HH \__/ 22A NN ^Z AA /—\ Υί)° ? yS O η< Ss X z\A I '' NN AY ° HH \_/ 23A NN ^Z Λ λ /--\ n VS ϊθ /OnAD AY ° n n \_/ 24A 9 <Λ A L L ~~H 1 g? ° Η N \__/ 25A F Z~F NN V <х χχχΝ-/ I YES 1 1 /'Ν^Ν^ΥΥ O _{n n} \__/ 26A F /--(~F Ν-Ν g Υ <A D YES <and /LO) - 224 047011 27A A,. 28A m-|/~~ ⁰ V <x? Тд ,О°''й "and 29A 1 o ° \ L o. z ^ZT Α·<Χ ^ω ο f А _ζ ⁷ th 30A №—Ά Ν-Ν V <x A Tt oCT /LL) 31A Q a /^/Ν ζΡ ? ΤΙ /-Ν Τ /// ° Η Η V_y Ν 32A Q a l ΤΙ -Ν Τ 'Τν^ν^Οτ ° Η Η \__/ ZZA? % /^Χ° l XX -Ν / 'Τν^Ν^ΟΑ nA ⁰ Η Η \__/ - 225 047011 - 226 047011 41A 0--^ Ν-Ν V <Α /A/ s Υχ o ^r J Ly ^A yA> 42A °=< o. A /---K «K / \ / O - ^{Ζ Ζ} Η 7 43A \ Ν— Ν-Ν V <Λ /A/ Λ XX U °ΓΦ ^Α Ο 44A QA y\ ^{N //0} and III ^nX x? |Α ° η Η \__/ 45A Ν-Ν ^Ζ λ X !—ι f l χχ 1 Г Τ /'Ν ^Λ Ν ^Ζ γ\ _f A^n^A ο _{η η} \_] 46A Ν-Ν ^Ζ # X 1---\ Τ ο ο Γ Ν - S., Α χΑΑκ ¹ 1 A Ν Ν ⁰ Η Η \__/ 47A Ν-Ν ^Ζ λ X !--\ Τ o o tХц Ο<^\^Ν _χ /ζ Η S. Zs, 1 '' Ν Ν ° Η Η \___/ - 227 047011 - 228 047011 - 229 047011 - 230 047011 - 231 047011 - 232 047011 89A ZI O, z ^ZT ry _z ' ° V 90A C -i ΣΙ Μ o, ^ζτ f Ζ ^ζ ° V 91A / O O<- Hz ω,\ ΖΖ ° ΙΖ and O 92A and o and ΖΙ O=< o, ^ζτ f Vz '° k 93A ZI <4 O, z ^ZT ° Q 94A О о—(i fl \L ZI °4 O, z ^ZT f A _z ' Ό 0 95A b <x 's' 1 Λ J 1 T A' °HH\___/ 96A \-N T ο Ο Τι^Ι А Λ J 1 I '/ N Ν^γ\ 0^0 О _HH \ / 97A \ F Ν-Ν F, o _t D l XV I χ/ Ν Ι\Γ ΑΧ ° Η Η - 233 047011 98A o— ZI Ύ O. z ^ZX A 99A/NN X? a /—\ X/X /P π YS O |_| _H \___y 100 A N^N II JJ r~\ ALL Tl X T JO \ ? 101A \-N Pl Cl Υ-γΧ А ΧΛ I '' N NT CH ° η h | 102 A LL z=< ll '----( ZI ^o 4 Ox Z ^ZT iOz''° A ^Z ^ \ / Z~_ 103A Nr/ -Ab /—\ T ο Ο Γι^Λ γ /\ _ζ Νγ/ II Ν >< Sx X 1 ζ, Ν Ν ΧΧ ° Η Η \_/ 104 A Υ Λ Υγΐ/ Α XI ij χ HA) 105A \-Ν Γ 1 0! j? jTJl - 234 047011 106 A Nf/ Г 1 Cl A JUL /о F Г T /'n ^a n ^z V ^a _o ^/ \z о A ° η Η 1. F 107 A \N-N /—\ Λ Hd l vC-Q Z At NN'' \ \__1 and and ° 108A a1 ^s z Y A./ a JUL □A °' I and yj 109 A /=N / 'Γ' n S/° / 1 zJu/ a JUL Г ] /' _Ν ^Λ Ν I) 110A \-N 111 u °'tLO ΛΑ A n Z Ar Ν N % \ \__1 and and ° 111A \-N Ar o o i l ILL λ \__1 and and ° 112A\-N AV XX Xl a MA? SG Ν NA\HH ⁰ 113A 1 A /ο ^ν A 111 o _HH \__/ - 235 047011 114A \-N / Z A 1 Ο-X? I XXp /ANN ° Η Η 1. F 115A o^ ZT O. z ^{ZT ω} - XV z ° Q 116A N=\ ! \ Γ~ “i /YC /P π YY O DHM ° H H \__/ 117A '^N ^S XL to .ΥΥρ η ΥΥ XX /ιΧνΛΛ 118A ,_\-Ν ' όΥ /—\ Χ3·, ν./Р ft ιί^ι Ν '' S. X / '' 'ν^νΧλ °ΗΗ\__/ 119A Q , 1 ο Ο ΤΤι \ / ^ϊ ^Ζ ^Ν ''ς ^/ 11 1 J /4 / Χν^ή^Χ ⁷ ° Η Η 1 120 A \-Ν Π Vo O U A Λ1 ι o' th 121A ,_\-Ν h ν.. α VAX's? AXX/ANN °ΗΗ\__/ 122 A °c ο. f ΥΧζ ° ζ ^ζ Α \ 7 ζ^ L1X W - 236 047011 123A \ N-N f) L y /--V OA d jrS / '' N N °HH\__/ 124 A \-N z y X/tX ί T /'Ν ^Λ νΛ< oO ° η h | 125A \-N z ύ /—i aX° X xx / Ο-О ° Η Η 126 A \-N V o <yYaXjl _f £Jά'Ν 127 A \-N Z \\ !—\ x XX 1 TA ^z 'N ° η h 128A\-N X jo L ^f 129 A N=< / \ ---1 /A D Yj oCr //O 130A / N=< / \ ----i / o zp 9 jS £ T /'nOA) 0^/ ⁰ HH \__/ - 237 047011 131A °=κ ο _χ , ^ζζ u' 132A Ν=\ ο,Α / y '°a ¥X °ηΗ\__/ 133A Ν=\ /у Α XX Γ Τ ηθ'ΛθΔ ⁰ Η Η \__/ 134A Z-c/ Ν=< ouD / y ΖγΥ A XX 0 |_| |_| \____1 135A \-Ν V A A a yes _F4 £ _n °z Αό 136A F\-Ν l 1 ANN γ\ ¹ °HH\/ 137A ^s / A n-^yQ a XX 1 T ri''n^n^yA A _n 3 ⁰ Η H L7 138A \-N 'Ά l A ¹ ° HH \___/ - 238 047011 139A \ N-N 6 7 A /—i Oxi l dd / '' N N °HH\__/ 140 A X a XL· ϊ DD oD U И \J 141A \-N / \ Cl no ⁿ / a jCL· I AN N ΑΧ ° η h 142 A \-N Z 'f I -<Y ^N / A VC I AN N ΑΧ ° η h 143A \-N Z ъ I CX A° A JUX / ''n a^^— °HH 144 A ll \ O—<( fl ZT °=( O, 7 ^{ZT O} / Z~_ 145A \ NN U/ ^N / y oA'A ? DD AX oA O0 146 A \ N-N nXn хД./ x jA oU °'И ML·) 147 A Xf oO ^p A LA o ^r X oA th \J - 239 047011 148A ^Ο =Κ Ο„ ^ΖΙ od Гк ζ^ 1 149 A 0 <D zUL° Λ 1JL LDoD Η \J / 150A \ Ν-Ν Λ \\ /---Ί DBP Λ ΛΑ / '' Ν Ν Α \ °ΗΗ\__/ 151A \ Ν-Ν λ Λ /—ν Ε /—I \ JO AO ⁿ 's° l yes / '' Ν Ν V \ ° Η Η \__/ 152A 1 < ^N ^F /аХ° А Ды -Ν Τ Ν=^ ⁰ η Η \__/ 153A Α A / ^ζ \ 1 (Ζ)χ Ο \ ΙΖ ° >° 154A Α A ^/Ζ ~ΑJ ω _χ Ο τζ'Ό >° 155A α ^/Ν Ο/° / \ d JCI ΟχΑ ο _Η η \__/ - 240 047011 156A °K ck ___ _{_} ^<Z) _X ?Л>—z '° 157A '^=N °A/k ^Y/P ? jY YY °HH\__/ 158A νΛό / \ ^Y/P j jY YY /'νΛΑ) 159A hYb / \ /YCp h jY YY /'νΛΑα O^D ° H H \_/ 160 A ,°A „ Α,ν / A ^Ym u JI ij o ^sxn n Y^\ oA ° HH \_/ 161A Υλ z l T ο Ο ΤιΧ A Λ J oY°HH\_/ 162 A / ^S Y /-Л < к T ο Ο ΓιΧ OM's' A 1J 1 TA ^z N oO ° Η and V_y 163A N=^ nAs / \ T ο Ο ΤιΧ /y ^N h 'P ji II Ί oY ° HH \_/ 164 A Q <д n- ⁿ y ⁿ 's° a AD ||D °' y gO - 241 047011 49. A method for producing a compound of formula (I) according to claim 1, including carrying out steps (i)-(iii) described in scheme 1. Scheme 1 where R ₁ -R3 take the meaning specified in paragraph 1, and L ₁ means a suitable leaving group. 50. A method for obtaining a compound of formula (I) according to claim 1, including carrying out stages (i)-(vi) described in scheme 2. Scheme 2 θ O _b r RS Jk Ai R3 Ν Ν Ν ^{Η Η} R2 Formula I where R ₁ -R ₃ take the meaning specified in paragraph 1, and L ₁ means a suitable leaving group. 51. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. - 242 047011 52. The pharmaceutical composition according to claim 51, where the compound is selected from the following compounds: - 243 047011 - 244 047011 7 XSf o 0 0 g=A sn ₃ LI X/ / Ν Ν N -0 N CH ₃ 8 O o o g=H JL 1 AeX A/~ ^CH 3 C/ H _Na ^ o 9 U|G O OO GC k 1 U _p ς jL _z N-CH ₃ Ζη<Χ ι» Ο ν ο 10 τ. >=° ω -7 E-? Zw V .-O >—\ w C °νθ ^ζ/ '° Ο-“\ ο OJ And Ζ° V Ό / \ / ⁴ ο τ “° У~^ οΌ ;? τ “ ι ο τ 12 Γίτ 2 ο ο Τ°\ L II JJ „ ν JL A~ ^sn z Ζ*^ν /X XX ^ΰ / 7^ Ν Ν Ν ^Νί ό 0 - 245 047011 - 246 047011 - 247 047011 - 248 047011 32 ΥιΙ ° ° Ο Γ=4 1 II π θ ν— SG- ./ Ν 33 0 ο ο [=4 1 II π _ο ν— “ό Ν 34 GAG ° 0 0 f=4 F 1 U '/ I nA Ax AA o .S. \ Z γ^ Ν Ν N ' _F ” “ύ N 1 35 /\F // LLC f=4 F l· II II „ί. N—/ Zy'iYn'' 36 / \ F Αγ LLC Γ=4 )—F 1 II II „ Ln—/ ^{H Ν} ό N 1 37 /A FF o O O G=CH U-f 1 II Ji „n—/ Ζγ^ ^Χ Ν'^ ^ν Ν ^> Ά 0 N 1 38 ζγ o oo 1-==4 z~0 ^Z L 11 U c L n—/ 7 Ά ''Ν Ν N SG ./ N 1 - 249 047011 - 250 047011 - 251 047011 - 252 047011 - 253 047011 - 254 047011 - 255 047011 80 Vil Ooo [=4 L II ii A 81 ΓιΙ ? ⁰ ° 11 AA Ad Ν Ν NA 82 ΓιΓ ° о ° rA 1 II ji z _s L ^N — ZY'I'An'·''•n'^ A o 83 Yll ° 0 0 [==4 AAA ©A Ad Z Ν Ν N cr H _N , , 0 ^x 84 ° o o [=4 Lin zv 1, ^N - Zz ^x4 'N'^>k'N'' Y. 85 L/ o o o r=4 AL Ay's Ad Z Ν Ν N \ JH e, I '—' Na* A. O'' ⁴ ''* 86 AsZ Jk/ g Ύ ii ° ° i i As. A A yY A^n Ζγ·^ Ν N N ^' - 256 047011 - 257 047011 - 258 047011 103 γυ ο ο ο Ya k 1 I .=,''s' k. 104 g Ύ if °° if y А.А As,s ₄ As Z t Ν Ν N '0 105 L ⁰ 0 O r ^N ' L II A-.'s' k, ^N - CI' ^Z ^ ^XX 'N ^X ^'N ^> '0 106 Cl rYl 9 ° o fA F ζ-χ zYJL ζΑ-θζ'Α zY/ ^N ~~ >Z^o Ν Ν N 107 Πι? ⁰ o rA k 1 1 as zY/ ^N ~ kJ ⁿ i„ Na® ''kA NV 108 Γ|Α O (3 Q A- A A a 's' A / Ζτ^ Ν Ν' ν ν '0 109 θ 0 0 If VL II A s A ' ^N AA^n'^n'' n ^x ^o -., 7 110 ΓΥ О 0 О f=A AJk A«X xk/ ^N ~~ Z r Ν Ν N \___/ h [ KI ® X/X Na I ? - 259 047011 - 260 047011 - 261 047011 142 ^F >A LLC G=CH AA AD< Λ/ ^Ν ~- ^N N# JL L/Y 143 ^F 'Yi] ooo g=H κΧΙ Ab'S YES Ν NN ^H A /N-U 144 Cl ^Ρ γΛ ° ο ο rY Al JLa's AA ^H A-\ JA-~J 145 Ooo No. ^N ₄ II C 'z 1 M____ YES As^S^ A%/ Z^Y Ν Ν N VJ ^H N(P JL XT 146 (A/ OOO N=N kl Ah's D z ^N - VJ ^H Ni 1 ⁴ o^ 155 \ \ U °° ΓΛ—=N YES Ah.zS^ X z~=n Ν Ν Ν O vJ ^H Nf A ⁴ o^ 163 [AjZ Ooo N'N AsJA As^ Ay / Ν Ν N s \_J ^H N# A ⁴ o^ 53. Pharmaceutical composition according to claim 51, where the compound is selected from compounds Nos. 1A-166A. Connection No. Structure 1A / NN A \ /---\ xXQ A JO o ^r A ο'Ή SY) - 262 047011 2A NN ^Z Λ \ !----\ ααΧ' ^/Ο a DD KO ζη JSC FOR Ν-Ν ^Ζ l %Χο Ζ Ν Ν' * \__/ Η Η ° 4A Ο Ο. F AU ιζ ° 1 5A Ν-Ν^ V <Χ <γΝ./ § ΥΧ ^νΑ o''Y YL) 6A Ν-Ν ^Ζ V <λ <γΝ,/ J ΥΝ οΑ °' th Α) 7A , °=< D °Ά 9 8A Ν-Ν ^Ζ Λ X !---Λ l JA Ο AY 9A °=( Ο. ζ ^ΖΖ - 263 047011 10A °=( ο. ^ζζ Α '—ο IA \ Ν-Ν -Αχ /—\ ΧζΑ U Τ1 Ο η Η \__/ 12A b <χ /О? η Τι gTTG /'LYA Ο η Η \__/ 13A Ο-Ν Ζ \ !—ι a JO I Τ η' Ν Ν^Ά> ο Η Η \__/ 14A \-Ν ζ l /~~\ /OSr η Τι ⁰ Η Η \__/ 15A \-Ν eleven /-\ Τ ο Ο ΓιΑ Α X Λ L °ΗΗ\__/ 16A Ν-Ν ^Ζ /—\ PU ° Ο JJ Γ'? II J and vn^Lj \__/ n n ° 17A i\An Y A ϊ Xd U MA 18A k A Yxy ^N YX 11 1 G T ''NN^A> o n n \__/ - 264 047011 19A And G-y N^N / k d td <kJ im iAQ 20A b <χ Αχ n Ϊ1 YU ₀ θΑ AC\ X-^Χ ° Η Η V_/ 21A \ X Г-У Α,ν / А xUU η UU YU o ^,S ' ^N ^ ^N ^T? Ο Η Η \__/ 22A Ν-Ν ^Ζ // A /—\ Ok u J1 ο X AM I '' Ν Ν ΑΧ ° Η Η \_/ 23A Ν-Ν ^Ζ //λ /~~\ /^nSp π YS iUT UU ΑΑ ΑΧ ° η η \_/ 24A 9 <Λ ϊ 1 J -Ν Τ /Αν^Ν^Α °ηΗ\__/ 25A F Z~F Ν-Ν V Οχ οΛ/1XX 1 1 'Ρ'ιΆνΑμχ Ο _{Η Η} \__/ 26A F /~O~F Ν-Ν f V <0 ζον-/ 2 ΥΑ oCJ <00x5 - 265 047011 - 266 047011 - 267 047011 41A 0-NN AL u—ι AL A LA οχ ⁰ n n \_/ 42A Q a oO O A LA °\Z~~NJ ΛΛνΟα |\Х ⁰ Η Η \__/ 43A \ Ν— Ν-Ν Υ Λ /X/ A JUL <U χ ^Α Ο 44A Q „a ^//0 υ Υ1 \ζ~ ^ν 5Υ Αν'ή'χ? Α ⁰ η η \_/ 45A Nf/ λ X у—ι F ΛΑ Α LD 1 XT /'ν ^λ ν ^/ Υ) fA^NxX Ο η η \_у 46A Ν-Ν ^Ζ # χ у—\ Τ ο ο ιΧΑ ΖΚ^Ν ₄ // II ¹ 1 U Ν Ν οχ 0 Η η \ / 47A Ν-Ν ^Ζ l X У—\ Τ ο Ο Ο^ζΧχΝ ₄ / Η 1 ζζ ν Ν Α ° Η Η \__Χ - 268 047011 - 269 047011 - 270 047011 - 271 047011 72A о Т ZI °=( О. z ^ZT X-λ X f У ° A 73A \-N\/ AY 1 χ3ύ° j? XX AT x u^X 74A \ N-N A Y /—\ AY-? ? VS Γ~Ν S. X Aa\ Xj '' Ν Ν XA About |_| |_| \____/ 75A \F N-N F<,F A Y zW a A <U x th · 76A \-N AY 1 x3C° A XX 1 T A 'N N^^^^ 77A\-NAY ? XsX° A XX / Г ] /'ν ^λ νΑΑζ o n n 78A Ν-Ν ^Ζ λ \ !--\ xXf X LD 1 7 Ν Ν Ο Η Η \___/ 79A Ν-Ν ^Ζ \ /---\ 11/1 XT 1 Υ'ν^ν^υΥ ° Η Η \__/ 80A \-Ν / ΑΥ Γ ΑχΧΑ° A JXX ^F o ^r A °''v y ' - 272 047011 81A ζτ °=( Ο. ζ ^ΖΤ τ ° Q 82A Ν-ΐ/ V <Χ ' _Ν γ° a DD J D Ν Ν ο'-'' ⁰ Η Η YJ 83A Ν-Ν ^Ζ VU, /А Д A ΥΦ ~ ^N U ά 'И Μ A 0 84A / \ Η Η ο r^N ζϊ I /'θ ό.. 85A / \ Η Η ο Γ^Ν ΤΙ ϊ /уу 86A ι\Χν Υ αυ ⁷ / a LD ⁰ Η Η \__/ 87A >=Ν / ' !------1 / Λ υΥ'/ a JUL o ^g H <4 "and 88A \ Ν-Ν yOY s у l \ '' ν ν η< ° η h | - 273 047011 89A \-N Αγ a l xx / £ T /'Ν^Ν^ΥΑγ 90A X-N J V A /L/ j? jfl <U (Gy n °^' 91A o A ZI Os Z ^ZT fXaz ° b / 92A A o A ZI °b Os ^ZT f Xz ° b 93A A° ZI °b Os ^{ZT O} Q 94A О Ο—(ί γ U- ZI °=< Os ^ZT f A _Z ^z Ό b 95A 9 <x 1 Ο Ο γΛ ^O ^N 's A 1J oO ° HH \___/ 96A \-N n^y £~£ T ο Ο ΤιΥ X JI L 1 T zb oY O _H H \_/ 97A \F N-N Fs ^F ζγ yJJ a £o AY ° H H - 274 047011 98A ZI Οχ Z ^ZX f Days ° 99A / N-N A /—\ /OS? h YS j£Y DAM ° H H \__/ 100 A N^N |l Ϊ r~\ ΖυΥαΠ £ Τ l? 101A \-Ν /\Cl ΑΑ ° Η Η ι 102 A Α ΖΙ °=( Οχ 7 ^ΖΤ ^Days ° _Χ ^Ζ Α \ 103A ν-γ/ Α /—\ Τ ο ο τιΑ Ν >< Sx A False ι '' Ν Ν Ον ΑΑ ° Η Η \_/ 104 A Ν^ζΐ Υ 2 ΥΊ U°' yd> 105A \-Ν Γ 'J ci A JOI GD _d ZN Ν^ρ - 275 047011 106 A Nf/ V 9 ¹ A XjL F ° Η Η 1. F 107 A \N-N /-\ ABOUT YES 1 %X-Q Z Dg NN* \ \__1 and and ° 108A aZ)s / \ 8 jjl oU and up 109 A /=N / 'Γ'η S/° < 1 zJQ a XX zf T ° H H V__/ 110A \-N /—\ A Λ And n t 10o ZCC N N A \ \__1 and and ° 111A \-N /—\ \ „ ΊΓ n-~, A JL a Z£X^ N N ' A \__1 and and ° 112A\-N AW Xl a vOQ SG NNA\HH ⁰ 113A to A a L JL I I A 'n^n^W ° H H \__/ - 276 047011 114A \|-N / ZA 1 QX? IX _F / '' Ν NY _r ° Η Η 1. F 115A ^o— ZT °={ CA z ^{ZT ω} z' ° A 116A N=\ ! \G~ “i c^A < 1 '9 Η Ϊ] AO ° Η Η \_/ 117A 'Dm / \ ^ΧζΡ and Π DD cA ^AnA A 118A ,_ \-Ν ' /—\ ΖΖ·,, /Р 9 [ΐΖ ν ^Ζ// s _x A / '' Ν Ν ° Η Η \__/ 119A 0 4 Ji ο Ο \ 11 1 J /4 / a ^Ζ ° Η Η 1 120 A \-Ν π V _o o 9Ц BH/ ^y a. a YES ι o y d> 121A ,_ \-N h ν.. α \Α^ ^ν Α a DA / ''NN > ° Η Η \__/ 122 A \-Ν ν _ο ο α ^ν < a Λα 1 <3rd ν) - 277 047011 123A \-N ⁷ CX /—\ / '' Ν N ° HH \__/ 124 A \-N ZA Av ^N A° aCO ° η h | 125A \-N <0C° l Xjl / 0^0°HH 126 A \-N V A ZvMaXX f oA ο-ή gХ 127 A \-N zOC? X AJL 1 | Z 'Ν °HH 128A\-N Cl zOC ^? A Xjl a ^f 129 A N=< c\A^ / y tA/ s Ά. o ^r j °' and jA> 130A / N=< сОО A JCI 0^/ ⁰ Н Н \__/ - 278 047011 - 279 047011 139A X-N > l u /—\ UX? i ry / '' N N °HH\__/ 140 A A A 1J. <U Ai Y 141A XN f\Cl vW a JuO IA ^N N ° HH 142 A XN ZI a- _y a° to juC IA ^N N ° HH 143A X-N XXI oX's° a jux / '' N^N ^^^— °HH 144 A u_ \ O —J b ZI °=( Och Z ^ZT ° / Z~_ 145A \N-N A.N/y AJLJ. oU °''il «V) 146 A \ N-N nXn z~~x ohm/ Λ ΪΥ oU ° 'h h \J 147 A xXC° s VS o>J °'~th И \J - 280 047011 - 281 047011 156A ^: °K : ex P ^T ?Λ_ _Ζ ' ° X 157A X=n °Ά L to Up? jU YU /ΆνΑΑ 158A nCx / \ xUj /Р § uu YU cA ^AnA U> 159A hUo / \ xUCp u P YU A Υχ) 160 A Г-У χ,ν Z to xUYp u Ϊ1 lY _n ^{//S nn} 161A nCx / \ T ο Ο ΤιΧ ^^ ^Ν χΡ hi 1 Τ D'' ο^χ Ο _{Η Η} \_/ 162 A Г-У Α/ ^Ν / Д Τ ο Ο ΤιΑ ^^ ^Ν χΡ χ IJ 1 Τ Α ^ζ Ν Ν^Χ> ο Η Η ν__/ 163A N=J nAs / \ Τ o o tGA ^^ ^Ν χΡ χ χ J 1 Τ A νΑχχ ο.χ Ο _{Η Η} \_/ 164 A °Α Ο. ζ ^ΖΤ G '° - 282 047011 54. A method of inhibiting inflammasome activity, comprising contacting a cell with an effective amount of a compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof. 55. A method of treating or preventing a disease or disorder involving inflammasome activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof. 56. The method of claim 55, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer. 57. The method according to claim 55 or 56, where the disease or disorder is an inflammatory disorder, an autoinflammatory disorder or an autoimmune disorder; the disease or disorder is optionally selected from the group consisting of cryopyrin-associated autoinflammatory syndrome (CAPS), such as familial cold autoinflammatory syndrome (FCAS), McLawells syndrome (MWS), chronic infantile neurological cutaneous articular syndrome (CINCA), infantile multisystem inflammatory disease ( NOMID), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis , obesity, type 2 diabetes, multiple sclerosis, skin disease such as acne, and neuroinflammation occurring in protein misfolding diseases such as prion diseases. 58. The method of claim 55 or 56, wherein the disease or disorder is a neurodegenerative disease such as Parkinson's disease or Alzheimer's disease. 59. The method of claim 55 or 56, wherein the disease or disorder is cancer, such as metastatic cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung carcinoma, squamous cell carcinoma of the head and neck, or colorectal adenocarcinoma.