Tetrahydrobenzo-quinoline sulfonamide derivative compounds

Abstract

The present invention relates to tetrahydrobenzo-isoquinoline sulfonamide derivatives of formula (I), [Case 1] JPEG2023508159000062.jpg4985 It relates to methods for their preparation, pharmaceutical compositions containing them, and their use in the treatment of disorders caused by IgE (such as allergic responses, non-allergic mast cell responses or certain autoimmune responses), particularly disorders caused by the interaction of IgE with the FcεRI receptor.

Description

[Technical field]

[0001] The present invention relates to tetrahydrobenzo-isoquinoline sulfonamide derivatives of formula (I), processes for their preparation, pharmaceutical compositions containing them, and their use in the treatment of disorders caused by IgE (such as allergic responses, non-allergic mast cell responses or certain autoimmune responses), in particular disorders caused by the interaction of IgE with the FcεRI receptor. [Background technology]

[0002] IgE (immunoglobulin E) is a member of the immunoglobulin family that mediates allergic reactions such as asthma, food allergies, type 1 hypersensitivity, and familial sinusitis.

[0003] IgE is secreted by B cells and expressed on their surface. IgE synthesized by B cells is anchored to the B cell membrane by a transmembrane domain linked to the mature IgE sequence by a short membrane-binding region. IgE also binds to B cells (and monocytes, eosinophils and platelets) via its Fc region to the low affinity IgE receptor (FcεRII). When a mammal is exposed to an allergen, B cells that synthesize IgE that binds to the allergen are clonally expanded. This IgE is then released by B cells into the circulation, where it is bound by B cells (via FcεRII) and by mast cells and basophils via the so-called high affinity receptor (FcεRI) found on the surface of mast cells and basophils. Such mast cells and basophils are thereby sensitized to the allergen. Subsequent exposure to the allergen crosslinks the FcεRI on these cells, thus activating the release of histamine and other factors that are responsible for clinical hypersensitivity and anaphylaxis.

[0004] Currently, allergic diseases, urticaria and asthma are usually treated with one or more of the following drugs: (1) antihistamines and anti-leukotrienes that antagonize the inflammatory mediators histamine and leukotrienes, (2) topical or systemic (oral or injectable) corticosteroids or immunosuppressants that suppress a wide range of inflammatory mechanisms, (3) short- or long-acting bronchodilators that relax the smooth muscle of the narrowed airways in asthma, or (4) mast cell stabilizers that inhibit the degranulation of mast cells that is normally triggered by IgE binding at FcεRI, and (5) biologics that prevent IgE binding at FcεRI. For example, U.S. Patent No. 4,857,301 describes isoquinoline sulfonamide compounds that are useful for treating allergies. As another example, U.S. Patent No. 5,340,811 describes quinolines and isoquinolines that affect mammalian bronchial smooth muscle.

[0005] However, there remains a need to identify compounds that have therapeutic utility in the treatment or prevention of disorders caused by IgE, particularly disorders caused by the interaction of IgE with the FcεRI receptor. Summary of the Invention

[0006] It has been found that compounds of formula (I) and their pharma- ceutically acceptable salts may be used for this purpose. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] The present invention provides compounds of formula (I) and pharma- ceutically acceptable salts thereof: [ka] During the ceremony, X is C or N; Y is -(C=N)- or -(N=N)- or O or -(O-NH)-; R1 is, Hydrogen; or Amino; C(O)O-C1-6-alkyl; C(O)NH-C1-6-alkyl; NH-C1-6-alkyl; NH-C1-6-alkanediyl-C3-6-cycloalkyl; heteroaryl; NH-heteroaryl optionally substituted with one or more groups selected from Ra; or NHC(NCN)NH-aryl optionally substituted with one or more Ra; or NH-heteroaryl optionally substituted with one or more groups selected from C1-6-alkyl; heteroaryl optionally substituted with one or more Ra; or C(O)NH-C1-6-alkyl; or C(O)NH-C1-6-alkanediyl-aryl optionally substituted with one or more Ra; or C(O)NH-C1-6-alkanediyl-heteroaryl optionally substituted with one or more Ra; or NHC(O)heteroaryl optionally substituted with one or more Ra; or NH-C3-8-cycloalkyl substituted with one or more of C1-6-alkylamino; oxo; Ra represents a group selected from R2 is hydrogen; or C(O)NH-C1-6-alkyl optionally substituted with aryl optionally substituted with one or more Ra; or heteroaryl optionally substituted with one or more groups selected from: heteroaryl optionally substituted with one or more R; heteroarylamino optionally substituted with one or more R; or NH-heteroaryl substituted with heteroaryl optionally substituted with one or more Ra or R3 is R3 a C1-6-alkyl optionally substituted with one or more groups selected from: One or more R3 aC1-3-alkanediyl-C3-6-cycloalkyl optionally substituted with; One or more R3 a C1-3-alkanediyl-C3-6-heterocycloalkyl optionally substituted with One or more R3 a C3-6-heterocycloalkyl optionally substituted with; One or more R3 a C3-6-cycloalkyl optionally substituted with represents a group selected from R3 a represents a group selected from hydrogen; halogen; C1-2-alkyl; hydroxy; C1-2-alkoxy; R4 is, One or more R4 a C3-6-cycloalkyl optionally substituted with a group; or one or more R4 a C1-6-alkanediyl-C3-6-cycloalkyl optionally substituted with a group; or one or more R4 a represents a group selected from C1-6-alkanediyl-C3-6-heterocycloalkyl optionally substituted by a group; R4 a represents a group selected from the group consisting of hydroxy; halogen; and C1-2-alkyl; Ra represents a group selected from halogen; nitrile; C1-6-alkyl; C1-6-haloalkyl; C1-6-alkoxy; C1-6-haloalkoxy; C(O)O-C1-6-alkyl; and C(O)OH.

[0008] According to one embodiment, the compounds of the invention are selected from compounds of formula (I) in which X is C and Y is -(C=N)-.

[0009] According to one embodiment, the compounds of the invention are selected from compounds of formula (I) in which X is N and Y is O.

[0010] According to one embodiment, the compounds of the invention are selected from compounds of formula (I) in which X is N and Y is -(O=N)-.

[0011] According to one embodiment, the compounds of the invention are selected from compounds of formula (I) in which R3 represents C1-6-alkyl optionally substituted with a fluorine atom, the other substituents being as defined herein above and below.

[0012] According to one embodiment, the compounds of the invention are selected from compounds of formula (I) in which R4 represents cyclopropyl, the other substituents being as defined hereinbefore and hereinafter.

[0013] According to one embodiment, the compound of the invention is selected from compounds of formula (I) in which When R1 is different from hydrogen, R2 is hydrogen; When R2 is different from hydrogen, R1 is hydrogen; The other substituents are defined as herein above and below.

[0014] The term "pharmaceutical acceptable salts" according to the present invention includes salts of compounds of formula (I) with pharmaceutical acceptable acids or bases, in particular acid addition salts. The acid addition salt forms of compounds of formula (I) occurring in free form as bases can be obtained by treating the free base with a suitable acid, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids, e.g., acetic acid, trifluoroacetic acid, oxalic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, or the like.

[0015] The present invention also relates to all stereoisomers, such as enantiomers and diastereoisomers, of the compounds of formula (I) or mixtures thereof (including all possible mixtures of stereoisomers, such as racemates). In the context of the present invention, reference to a compound(s) is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, unless a particular isomeric form is specifically mentioned.

[0016] Some of the compounds of formula (I) may exist in tautomeric forms. Such forms, although not explicitly shown in the above formula, are intended to be included within the scope of the present invention.

[0017] It should be understood that each atom present in formula (I) or any formula shown herein may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each hydrogen atom present in formula (I) or any formula shown herein may be present as 1H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, by way of example, each carbon atom present in formula (I) or any formula shown herein may be present as 12C, 13C or 14C atom, preferably 12C.

[0018] The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed using common organic solvents or water.

[0019] The present invention also includes within its scope co-crystals of compounds of formula (I) above. The technical term "co-crystal" is used to describe a situation in which neutral molecular components are present in a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals allows modifications to be made to the crystalline form of a pharma- ceutical active ingredient, thereby altering its physicochemical properties without impairing its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0020] Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly shown in the above formula, such forms are intended to be included within the scope of the present invention.

[0021] The present invention also includes within its scope prodrugs of the compounds of formula (I) above. The term "prodrug" refers to a compound that is metabolized in vivo to a compound of the present invention or a salt thereof. A prodrug can be identified by administering the prodrug to a mammal, such as a rat, mouse, monkey or human, and identifying the compound or a salt thereof, for example, in the blood or urine.

[0022] Within the framework of the present invention: Ct-z represents a carbon chain which may have t-z carbon atoms, for example a C1-7 carbon chain which may have 1-7 carbon atoms. Alkyl is a saturated, linear or branched aliphatic group, for example, a C1-6-alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, hexyl. Alkyl is a group in which one or more hydrogen atoms are replaced by a deuterium atom. 2 H-replaced deuterated groups are included.

[0023] Alkanediyl is a group of the general formula C, such as -CH-CH-. n H 2n is a divalent linear or branched saturated hydrocarbon group of Alkylamino refers to one or more alkyl groups substituted on an amino radical. Examples of alkylamino include methylamino, ethylamino, tertbutylamino, dimethylamino. Hydroxy is an -OH group; Hydroxyalkyl is an alkyl group in which one or more hydrogen atoms are replaced by hydroxy groups; Haloalkyl is an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom, an alkoxy, an -O-alkyl group; Haloalkoxy is an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms; the halogen atoms are fluorine, chlorine, bromine or iodine atoms; Cycloalkyl refers to a monocyclic or bicyclic aliphatic group that is not aromatic and may contain double bonds and contains 3 to 14 atoms, preferably 3 to 9 atoms in the group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, spiro-undecanyl, and spiro-[2.2]pentanyl. Heterocycloalkyl refers to a monocyclic or bicyclic saturated group containing 3 to 14 atoms, preferably 3 to 9 atoms, in a group that is not aromatic and may contain a double bond, in which one or more carbon atoms are replaced by an atom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl include aziridinyl, pyrrolidinyl, piperidyl, oxetane, oxa-spiro-undecanyl; Hydroxyheterocycloalkyl is a heterocycloalkyl group in which one or more hydrogen atoms are replaced by a hydroxy group. Heteroaryl refers to a monocyclic or bicyclic group containing 5 to 14 atoms, preferably 5 to 9 atoms, in which at least one ring is aromatic and at least one atom in the group is selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include triazolyl, furanyl, pyrrolyl, chromanyl, and isoquinolinyl.

[0024] Heteroarylamino refers to an amino group -NH2 substituted with a heteroaryl group. An example of a heteroaryl group can be pyridinylamino.

[0025] Another embodiment of the present invention relates to a pharmaceutical composition comprising a detectable amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or co-crystal thereof in combination with a pharma- ceutically acceptable diluent or carrier.

[0026] In yet another embodiment, the present invention relates to a compound of formula (I), a pharma- ceutically acceptable salt, solvate or co-crystal thereof, for use as a medicament, in particular in a method for treating or preventing disorders caused by IgE, including allergies, type 1 hypersensitivity, familial sinusitis, urticaria or related conditions, e.g. airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, or increased vascular permeability.

[0027] In a further embodiment, the present invention relates to a method for treating or preventing allergy, type 1 hypersensitivity, familial sinusitis, urticaria or related conditions comprising the administration of a therapeutically effective amount of a compound of formula (I).

[0028] According to one embodiment, the compound of the invention is selected from: Ethyl 5-amino-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]imidazole-4-carboxylate; 3-Cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 2-cyano-1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-3-(p-tolyl)guanidine; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2,2-dimethylpropyl)-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxamide; 3-Cyclopropyl-N-(2,2-dimethylpropyl)-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxamide; N-Benzyl-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxamide; N-Benzyl-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxamide; 2-Cyclopropyl-6-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzoxazole-4-sulfonamide; 3-Cyclopropyl-N-isobutyl-6,7,8,9-tetrahydro-4H-benzo[g][1,2,4]benzoxadiazine-5-sulfonamide; N-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-6-methyl-1H-indole-3-carboxamide; 3-Cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-methylpropyl)-7-[3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-methylpropyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; (7S)-3-Cyclopropyl-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-7-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-7-[[1-(2,5-dimethylpyrazol-3-yl)imidazol-2-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-methylpropyl)-7-(5-pyridin-3-yl-1H-imidazol-2-yl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-methylpropyl)-8-(5-pyridin-3-yl-1H-imidazol-2-yl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-8-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-8-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-fluoro-2-methyl-propyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide formic acid.

[0029] The following examples show how compounds encompassed by Formula (I) can be synthesized. They are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any way. Those skilled in the art will recognize that routine variations and modifications can be made to the following examples without departing from the spirit or scope of the invention.

[0030] example The following examples show how compounds encompassed by formula I can be synthesized. They are provided for illustrative purposes only and are not intended or should be construed as limiting the present invention in any way. Those skilled in the art will understand that routine variations and modifications can be made to the following examples without departing from the spirit or scope of the present invention.

[0031] Abbreviation DCM Dichloromethane THF Tetrahydrofuran EtOAc Ethyl acetate MeCN Acetonitrile MeOH Methanol br s wide singlet hept Heptane M mass or mole Salt water Saturated sodium chloride solution HPLC High Performance Liquid Chromatography LCMS Liquid Chromatography Mass Spectrometry DIPEA N,N-Diisopropylethylamine RT retention time DMF N,N'-Dimethylformamide NaOH Sodium hydroxide LiOH Lithium hydroxide TFA Trifluoroacetic acid DMSO Dimethyl sulfoxide EtOH Ethanol sat. saturation aq. Water-based tBuXPhos Pd G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'biphenyl)]methanesulfonate palladium(II) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate min IPA Isopropyl Alcohol SFC Supercritical Fluid Chromatography TEA Triethylamine Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene TBME tert-Butyl methyl ether KP-NH Biotage® SNAP KP-NH, Flash Chromatography Cartridges

[0032] Method 1: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: flow rate 1 mL / min Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0033] Method 2: Column: Kinetex Core-Shell C18 Part No. 00B-4601-AN 2.1 x 50 mm, 5 μm Column temperature: 40℃ Mobile phase A: Water + 0.1% formic acid Mobile phase B: Acetonitrile + 0.1% formic acid Flow rate 1.2ml / min Injection volume 3μl Detection signal UV215 PDA spectrum range: 210~420nm step: 1nm Gradient Time (min) % Organic 0.00 5 1.20 100 1.30 100 1.31 5

[0034] Method 3: Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Phenomenex, Kinetex-XB C18, 2.1 mm x 100 mm, 1.7 μm column Flow rate: 0.6mL / min Column temperature: 40℃ Injection volume: 1μL Gradient: Time (min): %A %B 0.00 95 5 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5 UV 215 nM, PDA spectrum 200-400 nm, step: 1 nm MSD Scan Positive 150-850

[0035] Method 4: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Column temperature: 40℃ Mobile phase A: 10 nM ammonium formate in water + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: flow rate 1 mL / min Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0036] Method 5: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: flow rate 1 mL / min Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0037] Method 6: Waters UPLC® BEH™ C18, part number 186002352, 2.1 x 100 mm, 1.7 μm Column temperature: 40℃ Mobile phase A: 2 mM ammonium bicarbonate buffered to pH 10 Mobile phase B: Acetonitrile Gradient program Flow rate 0.6mL / min Time A% B% 0.00 95.00 5.00 5.30 0 100 5.80 0 100 5.82 95.00 5.00 7.00 95.00 5.00

[0038] Method 7: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0039] Intermediates Intermediate 1 [ka] 2-Chloro-5-(methoxymethoxy)pyridine A solution of 6-chloropyridin-3-ol (34 g, 262 mmol) and chloromethyl methyl ether (42.3 g, 525 mmol) in DCM (300 mL) was stirred in an ice bath and N,N-diisopropylethylamine (50 mL, 289 mmol) in DCM (50 mL) was added dropwise and stirred for 15 min. The reaction mixture was treated with water and stirred for 10 min, then NaHCO3 (sat. aq.) was added and the mixture was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with NaHCO3 (sat. aq.) and dried (MgSO4). The crude material was purified by column chromatography eluting with a gradient of EtOAc in hexane to give the title compound (40.5 g, 89% yield) as an oil. 1H NMR(400 MHz,Chloroform-d)δ 8.19(dd,J=3.1,0.6 Hz,1H),7.37(dd,J=8.7,3.1 Hz,1H),7.31-7.20(m,1H),5.19(s,2H),3.50(s,3H).

[0040] Intermediate 2 [ka] [2-Chloro-5-(methoxymethoxy)-4-pyridyl]-triethylsilane A solution of intermediate 1 (17.2 g, 96.1 mmol) in THF (300 mL) was cooled to -40°C and treated with a solution of n-butyllithium in hexanes (2.5 M, 60 mL, added over 30 min). After stirring for an additional 5 min, triethylchlorosilane (25 mL, 149 mmol) was added and the reaction mixture was allowed to warm to room temperature. The mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give 40 g of the desired product as an impure oil (containing excess silane material). 1 H NMR(400 MHz,Chloroform-d)δ 8.15(s,1H),7.21(d,J=0.5 Hz,1H),5.19(s,2H),3.47(s,3H),0.97-0.91(m,9H),0.87-0.79(m,6H).

[0041] Intermediate 3 [ka] 6-Chloro-4-triethylsilyl-pyridin-3-ol To a solution of intermediate 2 (31 g, 97 mmol) in dioxane (100 mL) was added HCl (4 M in dioxane, 100 mL). The resulting mixture was stirred at room temperature for 16 h. After this time, a white solid precipitated. The mixture was diluted with diethyl ether (100 mL) and the resulting solid was removed by filtration (washed with ether) and dried in vacuo to give the title compound as a white solid (13.6 g, 50% yield), which was used in the next step without characterization.

[0042] Intermediate 4 [ka] (6-Chloro-4-triethylsilyl-3-pyridyl)trifluoromethanesulfonate A solution of intermediate 3 (13.6 g, 48.5 mmol) and DIPEA (21 mL, 120.5 mmol) in DCM (250 mL) was cooled to -78 °C and treated with trifluoromethanesulfonic anhydride (1 M in DCM, 100 mL, 100 mmol, dropwise). After the addition was complete, the mixture was allowed to warm to room temperature and quenched with NaHCO3 (sat. aq. 100 mL). The layers were separated and the aqueous phase was extracted with DCM (100 mL). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure and purified by column chromatography eluting with a gradient of EtOAc in hexanes to give the title compound (17.7 g, 97% yield) as a liquid. 1 H NMR(250 MHz,Chloroform-d)δ 8.37(s,1H),7.39(s,1H),1.03-0.86(m,15H).

[0043] Intermediate 5 [ka] (6-Cyclopropyl-4-triethylsilyl-3-pyridyl)trifluoromethanesulfonate A mixture of intermediate 4 (28.4 g, 75.6 mmol), cyclopropylboronic acid (16 g, 187 mmol), Pd(OAc)2 (850 mg, 3.8 mmol), P(tBu)3.HBF4 (3.3 g, 11.4 mmol) and K3PO4 (40 g, 188.44 mmol) in a biphasic solution of toluene (300 mL) and water (30 mL) was stirred and heated to reflux for 30 min. The mixture was cooled to room temperature, the layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over MgSO4, filtered through Celite (washed with EtOAc) and concentrated under reduced pressure. Purification by column chromatography eluting with a gradient of EtOAc in hexanes afforded the title compound (26.9 g, 93% yield) as an oil. 1 H NMR(500 MHz,Chloroform-d)δ 8.39(s,1H),7.23(s,1H),2.04(tt,J=7.8,5.1 Hz,1H),1.06-1.01(m,4H),1.00-0.88(m,15H).LCMS [M+H] + 383, RT 2.43 min (Method 1).

[0044] Intermediates 6 and 7 [ka] Methyl 3-cyclopropyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxylate (6) Methyl 3-cyclopropyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxylate (7) Cesium fluoride (14.0 g, 94.4 mmol), Ni(cod)2 (0.81 g, 2.94 mmol) and PPh3 (3.14 g, 12.0 mmol) were added to a N2 flushed round bottom flask equipped with a dropping funnel and acetonitrile (100 mL) was added. The mixture was stirred at room temperature for 5 min, changing from a yellow solution to a dark orange mixture. A solution of intermediate 5 (12.0 g, 31.5 mmol) and methyl 2-prop-2-ynylhex-5-ynoate (7.75 g, 47.2 mmol) in acetonitrile (100 mL) was added (first 10 mL immediately, then the rest dropwise over 10 min). After complete substrate addition, the mixture was stirred at room temperature for 3.5 h. The reaction mixture was filtered through Celite and washed with ethyl acetate. Concentration under reduced pressure and purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (2.53 g, 29% yield) as a 1:1 mixture of regioisomers. LCMS [M+H] + 282.2, RT 1.61 min (Method 1).

[0045] Intermediates 8 and 9 [ka] Methyl 3-cyclopropyl-5-iodo-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxylate (8) Methyl 3-cyclopropyl-5-iodo-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxylate (9) A mixture of intermediates 6 and 7 (1:1, 2.53 g, 8.99 mmol) was suspended in acetonitrile (100 mL) and cooled to 0° C. with stirring before adding trifluoromethanesulfonic acid (2.26 mL, 25.6 mmol). After warming the solution to room temperature, N-iodosuccinimide (3.03 g, 13.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then quenched with sodium carbonate (2.86 g, 27.0 mmol). The mixture was then filtered through Celite, washed with acetonitrile, and concentrated under reduced pressure. Dichloromethane (100 mL) was added and the solution was washed with 10% aqueous sodium thiosulfate solution (2×50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (1.98 g, 45% yield) as a 1:1 mixture of regioisomers. LCMS [M+H] + 408.0,RT 2.08&2.12 mins(Method 1).

[0046] Intermediates 10 and 11 [ka] 5-Benzylsulfanyl-3-cyclopropyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxylate hydrochloride (10) 5-Benzylsulfanyl-3-cyclopropyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxylate hydrochloride (11) Benzyl mercaptan (0.71 mL, 6.05 mmol) was added to a mixture of intermediates 8 and 9 (1:1, 83% purity, 1.98 g, 4.04 mmol), DIPEA (2.1 mL, 12.1 mmol), Pd2(dba)3 (111 mg, 0.12 mmol) and Xantphos (140 mg, 0.24 mmol) in dioxane (20 mL). The reaction was then stirred at 100 °C for 2 h and once at room temperature the mixture was diluted with dichloromethane (20 mL), filtered through celite (washed with dichloromethane) and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane gave a 1:1 mixture of methyl 5-benzylsulfanyl-3-cyclopropyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxylate and methyl 5-benzylsulfanyl-3-cyclopropyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxylate.

[0047] The mixture (2.1 g, 4.53 mmol, 87% purity) was then dissolved in THF (25 mL), 2M aqueous LiOH (7.0 mL) was added and the solution was stirred at room temperature for 16 h. The mixture was diluted with water (25 mL) and the THF was removed under reduced pressure. The remaining solution was acidified with 3M aqueous HCl to give a precipitate which was collected by vacuum filtration and washed with 1M aqueous HCl. The solid was dissolved in acetonitrile and concentrated under reduced pressure (×2) to give the title compound (1.94 g, quantitative) as a 1:1 mixture of HCl salt regioisomers. LCMS [M+H] + 390.2, RT 1.86&1.91 mins(Method 1).

[0048] Intermediates 12 and 13 [ka] 5-Chlorosulfonyl-3-cyclopropyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxylate hydrochloride (12) 5-Chlorosulfonyl-3-cyclopropyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxylate hydrochloride (13) A mixture of intermediates 10 and 11 (1:1, 1.94 g, 4.98 mmol) was suspended in acetonitrile (25 mL) and stirred with cooling in an ice-water bath. Acetic acid (1.63 mL, 28.5 mmol), water (513 μL, 28.5 mmol) and then 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.96 g, 9.96 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. The precipitate was collected by vacuum filtration and washed with acetonitrile to give the title compound (1.43 g, 79% yield) as a 1:1 mixture of HCl salt regioisomers. LCMS [M+H] + 366 / 368, RT 1.90&1.93 mins(Method 1).

[0049] Intermediates 14 and 15 [ka] 3-Cyclopropyl-5-(isobutylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxylate hydrochloride (14) 3-Cyclopropyl-5-(isobutylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxylate hydrochloride (15) 2-Methylpropan-1-amine (3.19 mL, 32.1 mmol) was dissolved in dichloromethane (50 mL) and cooled in an ice-water bath with stirring, followed by the addition of a mixture of intermediates 12 and 13 (1:1, 2.35 g, 6.42 mmol). The mixture was allowed to warm to room temperature and stirred for 10 min. The solution was concentrated under reduced pressure and saturated aqueous ammonium chloride (20 mL) was added. The pH was adjusted to pH 4 using 1 M aqueous HCl to give a cloudy mixture and the product was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.65 g, 92% yield, 90% purity) as a 1:1 mixture of HCl salt regioisomers. LCMS [M+H] + 403.0, RT 1.05 min (Method 2).

[0050] Intermediates 16 and 17 [ka] 7-Amino-3-cyclopropyl-N-isobutyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (16) 8-Amino-3-cyclopropyl-N-isobutyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (17) A mixture of intermediates 14 and 15 (1:1, 1.5 g, 3.73 mmol) was dissolved in dry THF (20 mL) followed by the addition of DIPEA (1.95 mL, 11.18 mmol) and diphenylphosphoryl azide (0.88 mL, 4.1 mmol). The reaction mixture was heated to reflux with stirring for 3 h. Once at room temperature, the reaction mixture was added to cold 2 M aqueous NaOH (20 mL) and stirred at room temperature for 10 min. The pH was adjusted to pH 9-10 and the product was extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography using a gradient of methanol in dichloromethane gave the title compound: Intermediate 16 (465 mg, 32% yield): δ H( 500 MHz, d6-DMSO) 9.12(s,1H), 8.52(s,1H), 8.05(s,1H), 3.99(dd,J=17.6,4.6 Hz,1H), 3.40-3.33(m,1H), 3.21-3.10(m,2H), 3.08-2.99(m,1H), 2.59(d,J=6.6 Hz,2H), 2.29-2.22(m,1H), 2.14-2.07(m,1H), 1.76-1.66(m,1H), 1.62-1.53(m,1H), 1.03-0.98(m,4H), 0.74-0.71(m,6H). 3× No exchangeable protons observed. LCMS [M+H] + 374.2, RT 1.68 min (Method 3). Intermediate 17 (505 mg, 35% yield): δ H(500 MHz, d6-DMSO) 9.08(s,1H), 8.57(s,1H), 7.98(s,1H), 3.60(dt,J=18.1,5.5 Hz,1H), 3.30-3.22(m,1H), 3.17-3.08(m,2H), 2.73-2.65(m,1H), 2.62-2.54(m,2H), 2.26-2.18(m,1H), 2.00-1.91(m,1H), 1.61-1.50(m,1H), 1.50-1.41(m,1H), 1.02-0.96(m,4H), 0.70(d,J=6.7 Hz,6H). 3 × No exchangeable protons observed. LCMS [M+H] + 374.2, RT 1.64 min (Method 3).

[0051] Intermediates 18 and 19 [ka] 3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxylic acid (18) 3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxylic acid (19) 2-Fluoro-2-methylpropan-1-amine hydrochloride (0.49 g, 3.85 mmol) was suspended in dichloromethane (40 mL) and DIPEA (1.83 mL, 10.5 mmol) was added. The solution was stirred at room temperature until a clear solution was obtained. A mixture of intermediates 12 and 13 (1:1, 1.28 g, 3.5 mmol) was added in portions over 5 minutes and the resulting reaction mixture was stirred at room temperature for 15 minutes. The mixture was then concentrated under reduced pressure and 1M aqueous NaOH (40 mL) was added. The resulting precipitate was removed by vacuum filtration. The filtrate was washed with ethyl acetate (2×50 mL) and then acidified with 3M aqueous HCl. The solution was extracted with ethyl acetate (3×50 mL) followed by a 1:1 mixture of IPA / chloroform (2×50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography using a gradient of methanol in dichloromethane afforded the title compound (520 mg, 35% yield) as a 1:1 mixture of regioisomers. LCMS [M+H] +421.2, RT 1.73&1.75 mins(Method 1).

[0052] Intermediates 20 and 21 [ka] 7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (20) 8-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (twenty one) A mixture of intermediates 18 and 19 (1:1, 98%, 330 mg, 0.77 mmol) was dissolved in dry THF (15 mL) followed by the addition of DIPEA (402 μL, 2.31 mmol) and diphenylphosphoryl azide (182 μL, 0.85 mmol). The reaction mixture was heated to reflux with stirring for 3 h and then cooled to room temperature. The reaction mixture was added to cold 2 M aqueous NaOH (20 mL) and stirred at room temperature for 10 min. The pH was adjusted to pH 9-10 and the product was extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography using a gradient of methanol in dichloromethane gave the title compound: Intermediate 20 (110 mg, 31% yield, 85% purity); 1 H NMR (500 MHz, d6-DMSO) δ H 9.11(s,1H), 8.53(s,1H), 8.04(s,1H), 3.93(dd,J=17.6,4.7 Hz,1H), 3.19-3.09(m,3H), 3.06-2.96(m,3H), 2.28(p,J=6.2 Hz,1H), 2.07(s,1H), 1.71-1.61(m,1H), 1.16(d,J=21.4 Hz,6H), 1.03-0.97(m,4H). 3× No exchangeable protons observed. LCMS [M+H] + 392.2,RT 2.45 min (Method 4). Intermediate 21 (99 mg, 25% yield, 76% purity); 1 H NMR (500 MHz, d6-DMSO) δ H9.08(s,1H), 8.58(s,1H), 7.97(s,1H), 3.61(dt,J=18.1,5.4 Hz,1H), 3.28-3.22(m,1H), 3.16-3.05(m,2H), 3.01-2.94(m,2H), 2.71-2.65(m,1H), 2.28-2.20(m,1H), 1.99-1.91(m,1H), 1.50-1.41(m,1H), 1.15(d,J=21.4 Hz,6H), 1.02-0.97(m,4H). 3× No exchangeable protons observed. LCMS [M+H] + 392.2,RT 2.39 min (Method 4).

[0053] Intermediate 22 [ka] N'-Acetyl-5-bromo-pyridine-2-carbohydrazide Acetohydrazide (0.37 g, 4.99 mmol) was stirred in DCM (10 mL) and DIPEA (0.87 mL, 4.99 mmol). 5-Bromopyridine-2-carbonyl chloride (1 g, 4.54 mmol) was added in small portions and the reaction was stirred for 15 min. The reaction was concentrated under vacuum and then water (10 mL) and DCM (30 mL) were added, which gave an emulsion and further water and DCM were added to form a brown precipitate which was collected by vacuum filtration. The filtrate was separated and the DCM layer was concentrated under vacuum to give a brown residue. The aqueous layer was added to the residue, sonicated and the resulting brown solid was collected by vacuum filtration and combined with the original brown solid to give the title compound (683 mg, 55% yield). δ H( 250 MHz,d6-DMSO)10.44(s,1H),9.98(s,1H),8.80(d,J=1.8 Hz,1H),8.28(dd,J=8.4,2.3 Hz,1H),7.95(dd,J=8.4,0.5 Hz,1H),1.91(s,3H).LCMS [M-acetyl+H] + 216.0 / 218.0, RT 0.67 min(Method 1)

[0054] Intermediate 23 [ka] 2-(5-Bromo-2-pyridyl)-5-methyl-1,3,4 oxadiazole Intermediate 22 (90%, 856 mg, 2.99 mmol) was stirred in DCM (15 mL) and NEt3 (2.8 mL, 20 mmol) was added followed by 4-methylbenzenesulfonyl chloride (700 mg, 3.67 mmol). The reaction was stirred for 3 h and then quenched with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (2 x 20 mL). The organics were dried over sodium sulfate and concentrated under vacuum. Purification by column chromatography using ethyl acetate in heptane afforded the title compound (572 mg, 80% yield). δ H( 250 MHz,d6-DMSO)8.91(dd,J=2.3,0.7 Hz,1H),8.31(dd,J=8.5,2.3 Hz,1H),8.09(dd,J=8.5,0.7 Hz,1H),2.61(s,3H).LCMS [M+H] + 240.0 / 242.0,RT 1.42 min(Method 1)

[0055] Intermediate 24 [ka] 3-Cyano-2-phenyl-1-(p-tolyl)isourea 4-Methylaniline (100 mg, 0.93 mmol) was dissolved in dichloromethane (5 mL) and diphenylcyanocarbonimidate (200 mg, 0.84 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure to give the title compound (300 mg, quantitative, 78% purity). LCMS [M+H] + 252.0,RT 1.16 min (Method 2).

[0056] Intermediate 25 [ka] N-(cyclopropylmethyl)-1-(2,4-dimethoxyphenyl)methanamine 2,4-Dimethoxybenzaldehyde (2.0 g, 12.04 mmol) and MgSO4 (400 mg) were added to 1-cyclopropylmethanamine (0.85 g, 12.04 mmol) in ethanol (10 mL). The reaction mixture was stirred at 78 °C for 4 h. The reaction mixture was cooled to room temperature, and then sodium borohydride (0.50 g, 13.24 mmol) was carefully added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NH4Cl, water and brine (30 mL each), then dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography eluting with 0%-20% MeOH in DCM afforded the title compound (2.1 g, 72% yield) as a colorless oil. LCMS [M+H] + 222,RT 0.83 min (Method 2).

[0057] Intermediate 26 [ka] N-[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]imidazole-1-carbothioamide A suspension of thiocarbonyldiimidazole (107.3 g, 572 mmol) in DCM (275 mL) was cooled to -10°C and treated with a solution of 5-(difluoromethyl)-2-methyl-pyrazol-3-amine (42.0 g, 285 mmol) in DCM (210 mL) over 40 min, maintaining the internal temperature at -9°C to -10°C. The resulting mixture was stirred at -10°C for 18 h, then filtered and the solid washed with DCM (300 mL) to give the title compound as a pale solid (71.4 g, 49% yield). The observed LCMS ion was C7H9F2N3OS [M+H] as a result of solvolysis with MeOH. + 222, RT 0.34 min (Method 7).

[0058] Intermediate 27 [ka] 1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea To a suspension of intermediate 20 (49 mg, 0.125 mmol) in anhydrous dichloromethane (3 mL) at room temperature, dry tetrahydrofuran was introduced until a homogeneous solution was obtained. Then, diisopropylethylamine (17 mg, 0.125 mmol in 0.5 mL of dry dichloromethane) and 5-isothiocyanato-1,3-dimethyl-pyrazole (21 mg, 0.138 mmol in 0.5 mL of dry dichloromethane) were introduced. After 2.5 h, the reaction mixture was treated with a second portion of isothiocyanato-1,3-dimethyl-pyrazole (7 mg, 0.046 mmol in 0.5 mL of dry dichloromethane) and the reaction was continued for 1.5 h. The reaction mixture was adsorbed onto silica in vacuo and the dry loaded material was purified by flash column chromatography using a 50-100% gradient of ethyl acetate in heptane to afford the title compound (42 mg, 0.068 mmol, 55% yield) as an oil. 1 H NMR(500 MHz,d-chloroform)δ H 9.07(s,1H),8.66(s,1H),7.89(s,1H),7.87(br.s,1H),6.60(s,1H),5.94(s,1H),5.78(s,1H),4.68-4.61(m,1H),4.03(dd,J=17.0,4.4 Hz,1H),3.70(s,3H),3.28(dd,J=17.0,9.4 Hz,1H),3.16-3.11(m,2H),3.07(dd,J=19.2,6.7 Hz,2H),2.38-2.31(m,1H),2.30-2.23(m,1H),2.18(s,3H),1.79-1.71(m,1H),1.318(d,J=21.4 Hz,3H),1.312(d,J=21.4 Hz,3H),1.18-1.13(m,2H),1.13-1.09(m,2H);LCMS [M+H] + 545, RT 2.77 min (Method 5).

[0059] Intermediate 28 [ka] 1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-6,7,8,9-tetrahydrobenzo[g]isoquinolin-8-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea To a stirred solution of intermediate 21 (99 mg, 0.19 mmol, 80% purity) in DCM (4.5 mL) was added DIPEA (33.5 μL, 0.19 mmol) followed by 5-isothiocyanato-1,3-dimethyl-pyrazole (35.3 mg, 0.23 mmol) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by column chromatography using a gradient of methanol in TBME to give the title compound (105 mg, 95% yield) as an off-white powder. 1 H NMR (500 MHz, CDCl3) δ H 9.06-9.01(m,1H),8.50(s,1H),7.82(s,1H),7.38(s,1H),6.19-6.01(m,1H),5.84(s,1 H),5.21-5.14(m,1H),4.84-4.74(m,1H),3.87-3.79(m,1H),3.66(s,3H),3.53-3.46(m, 1H),3.40-3.31(m,1H),3.14-2.90(m,3H),2.39-2.32(m,1H),2.26-2.20(m,1H),2.15( s,3H),1.77-1.68(m,1H),1.36-1.25(m,6H),1.17-1.12(m,2H),1.09-1.06(m,2H).LCMS [M+H] + 545.1, RT 1.06 min (Method 2).

[0060] Intermediate 29 [ka] 3-[3-cyclopropyl-5-(isobutylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-1-(cyclopropylmethyl)-1-[(2,4-dimethoxyphenyl)methyl]thiourea To a stirred solution of phenyl chloromethanethioate (0.04 mL, 0.29 mmol) in DCM (5 mL) at 0° C. was added intermediate 16 (100 mg, 0.26 mmol) and triethylamine (0.11 mL, 0.78 mmol) as a solution in DCM (5 mL). The reaction was stirred at 0° C. for 30 min, then intermediate 25 (95 mg, 0.24 mmol, 56% purity) was added. The mixture was stirred at 0° C. for 2 h, then warmed to room temperature. A second amount of intermediate 25 (95 mg, 0.24 mmol, 56% purity) was added and the mixture was stirred overnight. The solution was then stirred at 40° C. for 36 h before a third portion of intermediate 25 (103 mg, 0.26 mmol, 56% purity) was added. The mixture was stirred at 40° C. for a further 2 h. The mixture was then diluted with water (5 mL) and the aqueous layer was extracted with DCM (2×5 mL). The organic fractions were combined, dried over sodium sulfate, and purified by column chromatography using a gradient of TBME in heptane to give the title compound (70 mg, 37% yield, 87% purity) as a white powder. 1 H NMR (500 MHz, d6-DMSO) δ H 9.10(s,1H),8.51(s,1H),8.01(s,1H),7.96-7.90(m,1H),7.22(d,J=7.6 Hz,1H),6.94(d,J=8.4 Hz,1H),6.52(d,J=2.4 Hz,1H),6.45(dd,J=8.4,2.4 Hz,1H),4.85(s,2H),4.74-4.62(m,1H),3.96(dd,J=17.6,4.8 Hz,1H),3.77(s,3H),3.72(s,3H),3.19(dd,J=17.5,10.1 Hz,1H),3.08-3.02(m,2H),2.61(s,2H),2.29-2.20(m,1H),2.07-1.97( m,1H),1.85-1.75(m,1H),1.61-1.53(m,1H),1.07(s,1H),1.01(d,J=5.3 Hz,5H),0.72(t,J=6.3 Hz,7H),0.44-0.38(m,2H),0.25-0.20(m,2H).LCMS [M+H] + 637.3 RT 1.43 min (Method 2).

[0061] Intermediate 30 [ka] 3-Cyclopropyl-7-[3-[cyclopropylmethyl-[(2,4-dimethoxyphenyl)methyl]amino]-1,2,4-triazol-4-yl]-N-isobutyl-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide To a stirred solution of intermediate 29 (70 mg, 0.1 mmol, 87% purity) in DMF (2 mL) was added formic hydrazide (17.3 mg, 0.29 mmol) followed by mercuric dichloride (77.9 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 5 min and then TEA (0.04 mL, 0.29 mmol) was added. The reaction mixture was then stirred at 90° C. for 1 h, diluted with DCM and diatomaceous earth was added. The suspension was stirred for 1 min and then filtered. The filtrate was then purified by KP-NH column using a gradient of methanol in DCM to give the title compound (60 mg, 63% yield, 65% purity) as a white powder. LCMS [M+H] + 645.4, RT 1.23 min (Method 2).

[0062] Intermediate 31 [ka] 1-[3-Cyclopropyl-5-(isobutylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-3-(3-pyridyl)thiourea To a solution of intermediate 16 (50 mg, 0.13 mmol) in DCM (3 mL) was added DIPEA (22.6 μL, 0.13 mmol) followed by 3-isothiocyanatopyridine (17.4 μL, 0.16 mmol). The reaction mixture was stirred at room temperature for 1 h and then purified by column chromatography using a gradient of methanol in TBME to give the title compound (37 mg, 55% yield) as a white powder. δ H(500 MHz,d6-DMSO)9.54(s,1H),9.12(s,1H),8.57(d,J=2.5 Hz,1H),8.52(s,1H),8.30-8.26(m,1H),8.15-8.08(m,1H),8.07(s,1H),8.02-7.96(m,2H),7.34(dd,J=8.2,4.7 Hz,1H),4.58(s,1H),3.95(dd,J=17.6,4.6 Hz,1H),3.31-3.27(m,1H),3.20-3.06(m,2H),2.65-2.59(m,2H),2.28-2.22(m,1H),2. 20-2.13(m,1H),1.87-1.78(m,1H),1.61-1.52(m,1H),1.03-0.99(m,4H),0.71(d,J=3.2 Hz,3H),0.70(d,J=3.2 Hz,3H).LCMS [M+H] + 510.1 RT 1.09 min (Method 2).

[0063] Intermediate 32 [ka] 1-[3-Cyclopropyl-5-(isobutylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea To a solution of intermediate 16 (100 mg, 0.26 mmol) in DCM (4.5 mL) was added DIPEA (45.2 μL, 0.26 mmol) followed by 5-isothiocyanato-1,3-dimethyl-pyrazole (47.7 mg, 0.31 mmol) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 30 min and then purified by column chromatography using a gradient of methanol in TBME to give the title compound (120 mg, 75% yield) as a yellow powder. δ H(500 MHz,d6-DMSO)9.16(s,1H),9.11(s,1H),8.52(s,1H),8.05(s,1H),8.03-7.92(m,2H), 5.91(s,1H),4.54(s,1H),3.97-3.86(m,1H),3.57-3.51(m,3H),3.26(dd,J=17.7,9.6 Hz,1H),3.17-3.02(m,2H),2.65-2.57(m,2H),2.28-2.21(m,1H),2.14-2.09(m,4H),2.08(s,3H),1.86-1.76(m,1H),1.57(hept,J=6.7 Hz,1H),1.03-0.98(m,4H),0.74-0.70(m,6H).LCMS [M+H] + 527.1 RT 1.11 min (Method 2).

[0064] Intermediate 33 [ka] 6-Nitrotetralin-5-amine Acetic anhydride (45 mL) was added to a 250 mL three-necked round bottom flask equipped with a thermometer and a dropping funnel, and 5,6,7,8-tetrahydronaphthalen-1-amine (6.94 g, 47 mmol) was added dropwise. An orange precipitate immediately crashed and more acetic anhydride (15 mL) was added to aid stirring. The reaction mixture was stirred for 30 min. The mixture was then cooled in an ice bath (internal temperature 5° C.) and 90% nitric acid (4.4 mL, 94 mmol) was added dropwise (15 min) at such a rate as to maintain the internal temperature below 10-12° C. The reaction mixture was stirred for 15 min, then poured onto ice and allowed to warm to room temperature. The precipitate was suction filtered and washed with water to give an orange solid. This was treated with concentrated aqueous HCl (100 mL) and refluxed overnight. The mixture was poured into ice-cold water, neutralized with 4 M NaOH and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water (100 mL), brine (80 mL), dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (4.87 g, 54% yield). δ H(250 MHz,Chloroform-d)δ 7.93(d,J=8.9 Hz,1H),6.46(d,J=8.9 Hz,1H),6.27(bs,2H),2.74(t,J=6.1 Hz,2H),2.45(t,J=6.3 Hz,2H),1.97-1.84(m,2H),1.83-1.69(m,2H).LCMS [M+H] + 193, RT 1.18 min (Method 2).

[0065] Intermediate 34 [ka] N-isobutyl-6-nitro-tetralin-5-sulfonamide To a stirred solution of intermediate 33 (1.50 g, 7.80 mmol) in concentrated aqueous HCl (20 mL) at −5° C., a solution of sodium nitrite (590 mg, 8.60 mmol) in water (10 mL) was added, the resulting mixture was stirred at this temperature for 1 h, and then it was added dropwise to a solution of copper(II) chloride dihydrate (400 mg, 2.34 mmol) and sodium hydrogen sulfite (3.30 g, 31.3 mmol) in concentrated aqueous HCl (20 mL) at −5° C. The resulting suspension was allowed to slowly reach room temperature and stirred for 16 h. The mixture was poured into ice water and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and cooled to 0° C. before the addition of 2-methylpropan-1-amine (2.00 mL, 20.1 mmol). The solution was warmed to room temperature, washed with 1M aqueous HCl (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (1.79 g, 73% yield). LCMS [M+H] + 313.2, RT 1.95 min (Method 1).

[0066] Intermediate 35 [ka] 6-Amino-N-isobutyl-tetralin-5-sulfonamide To a solution of intermediate 34 (1.79 g, 5.73 mmol) in ethyl acetate (50 mL) was added 10% Pd on charcoal (2 g, 50% wet) and the mixture was stirred under 1 atm of H2 at room temperature for 4 h. The reaction was flushed with N2, filtered through a pad of Celite, washed with ethyl acetate and concentrated under reduced pressure to give the title compound (1.7 g, quantitative). LCMS [M+H] + 283.2, RT 1.93 min (Method 1).

[0067] Intermediate 36 [ka] 6-Amino-7-bromo-N-isobutyl-tetralin-5-sulfonamide Intermediate 35 (1.53 g, 5.42 mmol) was dissolved in DMF (50 mL) and cooled to 0° C. before adding N-bromosuccinimide (1.06 g, 5.96 mmol) in portions. The solution was warmed to room temperature and stirred for 30 min before diluting with ethyl acetate (50 mL) and washing with water (50 mL). The aqueous layer was extracted with ethyl acetate (25 mL) and the combined organic extracts were washed with water (50 mL). Dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (1.40 g, 72% yield). LCMS [M+H] + 361 / 363, RT 2.12 min(Method 1).

[0068] Intermediate 37 [ka] 6-Amino-N-isobutyl-7-methoxy-tetralin-5-sulfonamide A mixture of intermediate 36 (970 mg, 2.68 mmol), copper iodide (51 mg, 0.268 mmol), 1,10-phenanthroline (97 mg, 0.537 mmol) and caesium carbonate (1.75 g, 5.37 mmol) in methanol (5 mL) was heated to 120° C. in a microwave for 8 h. The reaction was filtered through celite, washed with methanol and concentrated under reduced pressure before being dissolved in dichloromethane (20 mL) and washed with water (20 mL). The solution was passed through a hydrophobic frit and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane gave the title compound (300 mg, 31% yield). LCMS [M+H] + 313.0,RT 1.98 min (Method 1).

[0069] Intermediate 38 [ka] N-[5-[allyl(isobutyl)sulfamoyl]-7-methoxy-tetralin-6-yl]cyclopropanecarboxamide Intermediate 37 (330 mg, 0.951 mmol) was dissolved in DMF (5 mL) and cesium carbonate (186 mg, 0.570 mmol) was added followed by 3-bromoprop-1-ene (90 μL, 1.05 mmol). The mixture was stirred at room temperature for 5 h. Further cesium carbonate (186 mg, 0.570 mmol) was added and stirring was continued at room temperature for 2.5 days. The mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) followed by brine (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the intermediate arylsulfonamide. This was dissolved in dichloromethane (5 mL) and N-ethyl-N-isopropyl-propan-2-amine (0.25 mL, 1.43 mmol) was added followed by cyclopropanecarbonyl chloride (104 μL, 1.14 mmol). The solution was stirred at room temperature for 3 h. Additional N-ethyl-N-isopropyl-propan-2-amine (50 μL) and cyclopropanecarbonyl chloride (20 μL) were added and the solution was stirred at room temperature for 1 h. The solution was purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (312 mg, 70% yield).H( 500 MHz,d-chloroform)8.35(s,1H),6.86(s,1H),5.68(ddt,J=16.8,10.1,6.6 Hz,1H),5.19-5.12(m,2H),3.81(s,3H),3.77(d,J=6.6 Hz,2H),3.07-3.02(m,2H),3.00(d,J=7.5 Hz,2H),2.85-2.78(m,2H),1.87-1.77(m,1H),1.76-1.71(m,4H),1.66-1.56(m,1H),1.04-1.00(m,2H),0.85-0.78(m,8H).LCMS [MH] - 419.0,RT 2.03 min (Method 1).

[0070] Intermediate 39 [ka] N-[5-[allyl(isobutyl)sulfamoyl]-7-hydroxy-tetralin-6-yl]cyclopropanecarboxamide Intermediate 38 (312 mg, 0.668 mmol) was dissolved in dichloromethane (15 mL) and a solution of BBr3 in dichloromethane (1 M, 2.0 mL, 2.00 mmol) was added. The reaction mixture was stirred for 0.5 h and then quenched by the addition of water. Dichloromethane (5 mL) was added and the solution was passed through a hydrophobic frit. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (253 mg, 93% yield). δ H( 500 MHz,d-chloroform)10.45(s,1H),8.64(s,1H),7.02(s,1H),5.67-5.53(m,1H),5.20-5.14(m,2H),3.80(d,J=6.6 Hz,2H),3.04(t,J=5.9 Hz,2H),2.97(d,J=7.5 Hz,2H),2.77(t,J=6.0 Hz,2H),1.85-1.69(m,6H),1.16-1.12(m,2H),0.98-0.94(m,2H),0.78(d,J=6.6 Hz,6H).LCMS [MH] - 405.0, RT 2.01 (Method 1).

[0071] Intermediate 40 [ka] N-Allyl-3-cyclopropyl-N-isobutyl-6,7,8,9-tetrahydro-4H-benzo[g][1,2,4]benzoxadiazine-5-sulfonamide Intermediate 39 (233 mg, 0.573 mmol) was dissolved in methanol (3 mL) and potassium tert-butoxide (64 mg, 0.573 mmol) was added. The mixture was stirred at room temperature for 10 min, and then methanol was removed under reduced pressure. The residue was suspended in 1,4-dioxane (2 mL) and a solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (222 mg, 1.03 mmol) in 1,4-dioxane (2 mL) was added under ice cooling. The ice bath was removed and the solution was stirred for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography using a gradient of dichloromethane in heptane followed by acidic reverse phase column chromatography to give the title compound (50 mg, 22% yield). δ H( 500 MHz,d-chloroform)8.87(s,1H),6.62(s,1H),5.65(ddt,J=17.0,10.4,6.7 Hz,1H),5.24-5.16(m,2H),3.80(d,J=6.7 Hz,2H),2.98(d,J=7.5 Hz,2H),2.82(t,J=5.9 Hz,2H),2.64(t,J=6.0 Hz,2H),1.90-1.79(m,1H),1.75-1.65(m,4H),1.54-1.51(m,1H),0.97-0.92(m,2H),0.92-0.86(m,2H),0.83(d,J=6.7 Hz,6H).LCMS [M+H] + 404.0,RT 2.22 min (Method 1).

[0072] Intermediate 41 [ka] 2,2,2-Trifluoro-N-[3-[(2,2,2-trifluoroacetyl)amino]tetralin-6-yl]acetamide To a suspension of 1,2,3,4-tetrahydronaphthalene-2,7-diamine dihydrochloride (CAS861352-50-3, 15 g, 63.8 mmol) in DCM (150 mL) at 0° C. was added DIPEA (67 mL, 382 mmol). The reaction was stirred for 10 min and then trifluoroacetic anhydride (19 mL, 134 mmol) was added over 5 min. The reaction was stirred at 0° C. for 10 min and then at room temperature for 2 h. The reaction was diluted with DCM (150 mL) and washed with 1N HCl (2×90 mL). At this point a black precipitate crashed out (this was not the desired product). The organic layer was then washed with saturated aqueous NaHCO3 (60 mL) and brine (60 mL). The organic layer was dried (MgSO4) and the solvent removed to give a brown gum. Purification by flash column chromatography eluting with 0 to 20% EtOAc in heptane gradient afforded the title compound as a brown solid (10.5 g, 46% yield). H( 250 MHz,DMSO-d6)11.15(s,1H),9.50(d,J=7.9 Hz,1H),7.40(d,J=9.2 Hz,2H),7.14(d,J=8.1 Hz,1H),4.17-3.95(m,1H),3.05-2.71(m,4H),1.97(d,J=11.1 Hz,2H),1.82-1.66(m,1H).LCMS [MH] - 353,RT 1.79 minutes(Method 1).

[0073] Intermediate 42 [ka] 2,2,2-Trifluoro-N-[5-iodo-3-[(2,2,2-trifluoroacetyl)amino]tetralin-6-yl]acetamide Intermediate 41 (9.50 g, 26.8 mmol) was dissolved in acetonitrile (200 mL) and N-iodosuccinimide (13.3 g, 59.0 mmol) was added followed by 4-methylbenzenesulfonic acid monohydrate (5.10 g, 26.8 mmol). The solution was stirred at room temperature for 2.5 days. The solution was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate (250 mL). The solution was washed successively with saturated aqueous sodium thiosulfate (2×100 mL) and saturated aqueous sodium bicarbonate (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (1.70 g, 13% yield). δ H( 500 MHz,d6-DMSO)11.21(s,1H),9.59(d,J=7.4 Hz,1H),7.21(d,J=8.1 Hz,1H),7.14(d,J=8.0 Hz,1H),4.15-4.06(m,1H),3.02(dd,J=17.0,5.8 Hz,1H),2.95-2.83(m,2H),2.65(dd,J=17.0,9.6 Hz,1H),1.96-1.89(m,1H),1.78-1.67(m,1H).LCMS [MH] - 478.8,RT 2.99 min (Method 1).

[0074] Intermediate 43 [ka] N-(7-amino-8-iodo-tetralin-2-yl)-2,2,2-trifluoroacetamide Intermediate 42 (1.00 g, 2.08 mmol) was dissolved in methanol (10 mL) and 7M ammonia in methanol (0.89 mL, 6.25 mmol) was added. The solution was heated in a sealed vial at 45° C. for 16 h and then at 55° C. for 2 h, after which the solvent was removed under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (960 mg, 79% yield). LCMS [M+H] + 385.0,RT 1.84 min (Method 1).

[0075] Intermediate 44 [ka] N-[5-iodo-3-[(2,2,2-trifluoroacetyl)amino]tetralin-6-yl]cyclopropanecarboxamide Intermediate 43 (980 mg, 1.68 mmol) was dissolved in dichloromethane (20 mL) and N-ethyl-N-isopropyl-propan-2-amine (382 μL, 2.19 mmol) was added followed by cyclopropanecarbonyl chloride (168 μL, 1.85 mmol). The solution was stirred at room temperature for 15 min before being diluted with dichloromethane (10 mL). Saturated aqueous NaHCO3 (10 mL) was added and the mixture was passed through a hydrophobic frit and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane gave the title compound (620 mg, 81% yield). LCMS [M+H] + 453.0,RT 1.84 min (Method 1).

[0076] Intermediate 45 [ka] N-(2-cyclopropyl-4-iodo-5,6,7,8-tetrahydrobenzo[f][1,3]benzoxazol-6-yl)-2,2,2-trifluoroacetamide Intermediate 44 (530 mg, 1.17 mmol) and diacetoxypalladium (27 mg, 0.117 mmol) were added to a solution of dipotassium sulfonate sulfate (475 mg, 1.76 mmol) in a mixture of acetic acid (5.5 mL) and DMF (0.7 mL). The reaction mixture was then treated with trifluoromethanesulfonic acid (104 μL, 1.17 mmol) and heated to 100° C. in a sealed tube under air for 24 hours. Once at room temperature, the mixture was filtered through Celite and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (120 mg, 19% yield). δ H(400 MHz,d6-DMSO)9.56(d,J=7.5 Hz,1H),7.38(s,1H),4.18-4.04(m,1H),3.07(dd,J=16.5,5.9 Hz,1H),3.01-2.91(m,2H),2.74-2.64(m,1H),2.31-2.22(m,1H),1.99-1.91(m,1H),1.79-1.65(m,1H),1.21-1.04(m,4H).LCMS [M+H] + 451.0, RT 2.00 min (Method 1).

[0077] Intermediate 46 [ka] N-(4-benzylsulfanyl-2-cyclopropyl-5,6,7,8-tetrahydrobenzo[f][1,3]benzoxazol-6-yl)-2,2,2-trifluoroacetamide Benzyl mercaptan (47 μL, 0.400 mmol) and DIPEA (140 μL, 0.800 mmol) were added to a mixture of intermediate 45 (120 mg, 0.267 mmol), Pd2(dba)3 (15 mg, 16.0 μmol) and Xantphos (19 mg, 32.0 μmol) in 1,4-dioxane (3 mL). The reaction mixture was then heated at 90° C. for 2 h in a sealed tube with stirring. The mixture was cooled to room temperature and diluted with dichloromethane (10 mL). The solution was filtered through Celite and then concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane gave the title compound (110 mg, 92% yield). δ H( 500 MHz,d6-DMSO)9.46(d,J=7.4 Hz,1H),7.29(s,1H),7.25-7.13(m,5H),4.47(s,2H),3.98-3.88(m,1H),3.15(dd,J=16.7,5.1 Hz,1H),2.94-2.89(m,2H),2.57(dd,J=16.5,10.3 Hz,1H),2.34-2.26(m,1H),1.97-1.88(m,1H),1.72-1.59(m,1H),1.25-1.13(m,4H).LCMS [M+H] + 447.0,RT 2.17 min (Method 1).

[0078] Intermediate 47 [ka] N-[2-cyclopropyl-4-(isobutylsulfamoyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzoxazol-6-yl]-2,2,2-trifluoroacetamide Intermediate 46 (100 mg, 0.224 mmol) was dissolved in a mixture of acetonitrile (3 mL) and water (20 μL, 1.12 mmol). Acetic acid (64 μL, 1.12 mmol) was added followed by 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (88 mg, 0.448 mmol). The reaction mixture was stirred at room temperature for 15 min. 2-Methylpropan-1-amine (223 μL, 2.24 mmol) was then added and the mixture was stirred at room temperature for 15 min. The solution was then concentrated under reduced pressure and purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (60 mg, 58% yield). LCMS [M+H] + 460.0,RT 2.09 min (Method 1).

[0079] Intermediate 48 [ka] 1-[2-Cyclopropyl-4-(isobutylsulfamoyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzoxazol-6-yl]-3-[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]thiourea Intermediate 47 (55 mg, 0.120 mmol) was dissolved in a mixture of methanol (5 mL) and water (0.5 mL). K2CO3 (83 mg, 0.599 mmol) was added and the mixture was stirred at 60 °C in a sealed vial for 3 h. The solvent was removed under reduced pressure and dichloromethane (10 mL) was added. The solution was passed through a hydrophobic frit and the filtrate was treated with Intermediate 26 (31 mg, 0.120 mmol) with stirring at room temperature for 5 min. The solution was then directly purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (45 mg, 65% yield). LCMS [M+H] + 553.0,RT 2.08 min (Method 1).

[0080] example Example 1 [ka] Ethyl 5-amino-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]imidazole-4-carboxylate A stock solution of ethyl 2-cyano-2-(dimethoxymethylamino)acetate was prepared: a mixture of ethyl 2-amino-2-cyano-acetate* (70%, 16.3 mg, 0.09 mmol) and triethyl orthoformate (0.01 mL, 0.09 mmol) in CH3CN (1 mL) was heated at 90° C. for 1 h. The solution was cooled and kept in the refrigerator (4° C.) as a stock solution.

[0081] Intermediate 16 (20 mg) was partially dissolved in EtOH (2 mL) and a freshly prepared stock solution of ethyl 2-cyano-2-(dimethoxymethylamino)acetate (750 μL) was added. The reaction was stirred for 18 h. Another portion of the stock solution (250 μL) was added and the reaction was heated at 50° C. for 2 h. The solvent was removed in vacuo and the residue was purified by column chromatography (eluting with 0-100% EtOAc in isohexane, then 0-10% EtOH in EtOAc) to give the title compound as a white solid (3.3 mg, 10% yield). δ H( 250 MHz,MeOD-d6)9.07(s,1H),8.64(s,1H),8.08(s,1H),7.21(s,1H),4.62-4.46(m,2H),4.29(q,J=7.1 Hz,2H),4.13(dd,J=17.9,5.1 Hz,1H),3.70(dd,J=17.5,9.4 Hz,1H),3.26(d,J=6.9 Hz,1H),2.72-2.55(m,2H),2.47-2.19(m,3H),1.60(dt,J=13.4,6.7 Hz,1H),1.34(t,J=7.1 Hz,4H),1.07(d,J=6.6 Hz,4H),0.76(dd,J=6.7,1.5 Hz,6H).LCMS [M+H] + 512,RT 3.10 minutes(Method 6). *Prepared according to the procedures of the following patent: WO 2008 / 59368, 2008, A2.

[0082] Example 2 [ka] 3-Cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide To a solution of intermediate 27 (42 mg, 0.068 mmol) in N,N-dimethylformamide (1.5 mL) was introduced a solution of formic hydrazide (14 mg, 0.229 mmol) in N,N-dimethylformamide (0.3 mL) followed by mercury(II) chloride (62 mg, 0.229 mmol). After stirring for 5 min at room temperature under nitrogen atmosphere, a solution of triethylamine (23 mg, 0.229 mmol) in N,N-dimethylformamide (0.2 mL) was introduced and the reaction was warmed to 80° C. for 1.7 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (10 mL), diatomaceous earth (1.0 g) was introduced and the suspension was stirred for 10 min. The suspension was then filtered and the filter cake was washed with dichloromethane (10 mL). The combined filtrates were evaporated in vacuo to give a residue which was purified by low pH preparative liquid chromatography to give the title compound (88% pure LCMS-UV 215 2.3 mg, 5% yield, was obtained as a colorless solid. LCMS [M+H] + 553, RT 2.07 min (Method 3). [Note that the title compound was found to be thermally unstable].

[0083] Example 3 [ka] 2-Cyano-1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-3-(p-tolyl)guanidine Intermediate 20 was dissolved in IPA (1 mL) in a sealable tube and intermediate 24 (19.3 mg, 0.08 mmol) was added. The tube was sealed and heated to 100° C. for 2 h, then cooled to room temperature. The mixture was concentrated under reduced pressure and purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (10 mg, 23%). δ H(500 MHz,d6-DMSO)9.10(s,1H),8.98(s,1H),8.56(s,1H),8.35(s,1H),8.03(s,1 H),7.22-7.15(m,1H),7.12(s,4H),4.14-4.03(m,1H),3.92(dd,J=17.6,4.7 Hz,1H),3.27-3.19(m,1H),3.15-3.02(m,2H),2.99(d,J=19.8 Hz,2H),2.31-2.23(m,4H),2.09-2.01(m,1H),1.86-1.74(m,1H),1.18(d,J=21.4 Hz,3H),1.15(d,J=21.4 Hz,3H),1.05-0.97(m,4H).LCMS [M+H] + 549.3, RT 3.27 min (Method 3).

[0084] Example 4 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide Intermediate 20 (50 mg, 0.13 mmol), intermediate 23 (43 mg, 0.18 mmol), tBuONa (37 mg, 0.38 mmol) and tBuXPhosPdG3 (15 mg, 0.02 mmol) were dissolved in a mixture of dioxane (3 mL) and tBuOH (1.5 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with ethyl acetate, filtered through Celite and washed with ethyl acetate. The solution was concentrated under reduced pressure and the residue was purified by column chromatography (eluted with a gradient of ethyl acetate in heptane) followed by reverse phase HPLC (acidic conditions) to give the title compound (5.5 mg, 8% yield). δ H(500 MHz,d6-DMSO)9.13(s,1H),8.54(s,1H),8.32(s,1H),8.15(d,J=2.7 Hz,1H),8.08(s,1H),7.84(d,J=8.7 Hz,1H),7.14(dd,J=8.8,2.8 Hz,1H),6.79(d,J=7.7 Hz,1H),3.96(dd,J=17.3,4.6 Hz,1H),3.91-3.82(m,1H),3.29-3.24(m,1H),3.20-3.09(m,2H),3.00-2.90(m,2H), 2.54(s,3H),2.31-2.23(m,1H),2.22-2.14(m,1H),1.77-1.66(m,1H),1.14(d,J=21.4 Hz,3H),1.11(d,J=21.4 Hz,3H),1.04-0.96(m,4H).LCMS [M+H] + 551.4, RT 2.87 min (Method 3).

[0085] Examples 5 and 6 [ka] 3-Cyclopropyl-N-(2,2-dimethylpropyl)-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxamide (5) 3-Cyclopropyl-N-(2,2-dimethylpropyl)-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxamide (6) A solution of intermediates 14 and 15 (100 mg, 0.25 mmol) and DIPEA (87 μL, 0.5 mmol) in dichloromethane (2 mL) was treated with HATU (104 mg, 0.27 mmol) and stirred at room temperature for 10 min. 2,2-Dimethylpropan-1-amine (32 μL, 0.27 mmol) was then added and the solution was stirred at room temperature for 1 h. The solution was washed with saturated aqueous NH4Cl (2 mL), filtered through a hydrophobic frit and purified by column chromatography (eluting with a gradient of ethyl acetate in heptane) followed by preparative HPLC (acidic conditions) to give the title compound: Example 5 (16.7 mg, 14% yield): δ H(500 MHz, d6-DMSO) 9.10 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.98 (t, J = 5.5 Hz, 1H), 7.85 (t, J = 6.2 Hz, 1H), 3.74 (dd, J = 17.7, 5.0 Hz, 1H), 3.32 - 3.26 (m, 1H), 3.09 - 2.94 (m, 3H), 2.88 (dd, J = 13.0, 6.0 Hz, 1H), 2.70 - 2.54 (m, 3H), 2.29 - 2.20 (m, 1H), 1.99 - 1.89 (m, 1H), 1.84 - 1.74 (m, 1H), 1.63 - 1.51 (m, 1H), 1.06 - 0.96 (m, 4H), 0.86 (s, 9H), 0.73 (d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.4 Hz, 3H). LCMS [M + H] + 472.4, RT 3.58 min (Method 3). Example 6 (23.6 mg, yield 20%): δ H( 500 MHz, d6-DMSO) 9.09 (s, 1H), 8.57 (s, 1H), 8.04 (s, 1H), 7.96 (t, J = 5.8 Hz, 1H), 7.84 (t, J = 6.2 Hz, 1H), 3.51 (dt, J = 17.7, 5.5 Hz, 1H), 3.41 - 3.37 (m, 1H), 3.07 (d, J = 7.8 Hz, 2H), 2.97 - 2.87 (m, 2H), 2.74 - 2.65 (m, 1H), 2.61 - 2.55 (m, 2H), 2.27 - 2.19 (m, 1H), 2.01 - 1.92 (m, 1H), 1.84 - 1.74 (m, 1H), 1.61 - 1.50 (m, 1H), 1.03 - 0.97 (m, 4H), 0.85 (s, 9H), 0.70 (d, J = 6.7 Hz, 6H). LCMS [M + H] + 472.4, RT 3.42 min (Method 3).

[0086] Examples 7 and 8

Chemical Structure

[0087] Example 9 [Chemical formula] 2-Cyclopropyl-6-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzoxazole-4-sulfonamide Intermediate 48 (45 mg, 81.4 μmol) was dissolved in dichloromethane (1 mL) and triethylamine (34.0 μL, 0.244 mmol) was added followed by methanesulfonyl chloride (6.9 μL, 89.6 μmol). The reaction mixture was stirred at room temperature for 45 min. Further methanesulfonyl chloride (3.2 μL, 40.7 μmol) was added and the solution was stirred for 15 min and then diluted with dichloromethane (10 mL). Saturated aqueous NH4Cl (10 mL) was added and the biphasic solution was passed through a hydrophobic frit and concentrated under reduced pressure. The residue was treated with a solution of formic acid hydrazide (20 mg, 0.326 mmol) in methanol (1 mL) and stirred at room temperature for 30 min. Sodium carbonate (35 mg, 0.326 mmol) was added and the mixture was heated to 40° C. with stirring for 16 h. The mixture was concentrated under reduced pressure, dissolved in a 9:1 mixture of dichloromethane and methanol (10 mL) and washed with water (10 mL). The aqueous layer was extracted with a 9:1 mixture of dichloromethane and methanol (5 mL) and the combined organic extracts were passed through a hydrophobic frit. The solution was concentrated under reduced pressure and the residue was purified by column chromatography with a gradient of methanol in dichloromethane to give the title compound (26 mg, 57% yield). δ H( 500 MHz,d6-DMSO)12.03(s,1H,Rotamer 1),8.83(s,1H,Rotamer 2),8.43-8.14(m,1H),7.72(s,1H),7.45(t,J=6.0 Hz,1H),6.76(t,J=55.1 Hz,1H),6.23(s,1H),4.50(s,1H),3.91(dd,J=17.0,3.6 Hz,1H),3.66-3.55(m,3H),3.24(dd,J=16.8,10.7 Hz,1H),3.18-3.12(m,2H),2.76-2.65(m,2H),2.33-2.13(m,3H),1.78-1.67(m,1H),1.29-1.20(m,4H),0.85(d,J=6.7 Hz,3H),0.84(d,J=6.7 Hz,3H).LCMS [M+H] + 561.1, RT 3.21 min (Method 1).

[0088] Example 10 [ka] 3-Cyclopropyl-N-isobutyl-6,7,8,9-tetrahydro-4H-benzo[g][1,2,4]benzoxadiazine-5-sulfonamide Intermediate 40 (15 mg, 37.2 μmol) was dissolved in THF (1.0 mL) and Pd(PPh3)4 (4.3 mg, 3.72 μmol) was added. The pale yellow solution was cooled in an ice-water bath and a solution of lithium borohydride in THF (0.04 M, 310 μL, 12.4 μmol) was added dropwise over 5 min. After stirring the reaction mixture in the ice bath for 1 h, the reaction mixture was quenched with water (5 mL) and diluted with dichloromethane (5 mL). The solution was passed through a hydrophobic frit and concentrated under reduced pressure. Purification by column chromatography eluting with a gradient of ethyl acetate in heptane gave the title compound (2.2 mg, 16% yield). δ H( 500 MHz,d-chloroform)8.75(s,1H),6.63(s,1H),4.56(t,J=6.4 Hz,1H),2.90(t,J=6.1 Hz,2H),2.73(t,J=6.6 Hz,2H),2.66(t,J=6.2 Hz,2H),1.80-1.68(m,5H),1.54-1.51(m,1H),0.97-0.87(m,10H).LCMS [M+H] + 364.3, RT 3.92 min (Method 1).

[0089] Example 11 [ka] N-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-6-methyl-1H-indole-3-carboxamide A solution of 6-methyl-1H-indole-3-carboxylic acid (20 mg, 0.11 mmol) and DIPEA (36.2 μL, 0.21 mmol) in DCM (1 mL) was treated with HATU (104 mg, 0.27 mmol) and stirred at room temperature for 5 min. Intermediate 16 (40 mg, 0.1 mmol) was then added and the solution was stirred at room temperature for 2 h. The solution was diluted with water (3 mL) and the organic layer was collected. The aqueous layer was extracted with DCM (2×5 mL). The organic fractions were combined, filtered through a phase separator and the solvent was removed under reduced pressure to give a yellow powder. The powder was suspended in a 1:1 mixture of DMSO and MeOH (2 mL), filtered and the filtrate was purified by column chromatography to give the title compound as a pale yellow gum (11 mg, 20% yield). δ H( 500 MHz,d4-Methanol)11.01(s,1H),9.20(s,1H),8.84(s,1H),8.15(s,1H),7.91(d,J=8.2 Hz,1H),7.86-7.82(m,1H),7.21(s,1H),6.97(d,J=8.3 Hz,1H),4.43-4.34(m,1H),4.02(dd,J=17.6,4.7 Hz,1H),3.49(dd,J=17.6,9.6 Hz,1H),3.29-3.16(m,2H),2.74-2.65(m,2H),2.43(s,3H),2.36-2.27(m,2H),1.98- 1.89(m,1H),1.66-1.56(m,1H),1.19-1.14(m,2H),1.11-1.07(m,2H),0.75(d,J=1.5 Hz,3H),0.74(d,J=1.5 Hz,3H).LCMS [M+H] + 531.3 RT 3.51 min (Method 3).

[0090] Examples 12 and 13 [ka] 3-Cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (12) 3-Cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (13) To a stirred solution of intermediate 32 (60 mg, 0.097 mmol, 85% purity) in DMF (1 mL) was added formic hydrazide (17.4 mg, 0.29 mmol) followed by mercuric dichloride (78.9 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 5 min, then TEA (40.5 μL, 0.29 mmol) was added and the resulting suspension was heated to 70° C. for 5 h. The suspension was cooled to room temperature, diluted with DCM and diatomaceous earth was added. The mixture was stirred for 1 min and then filtered. The solvent was removed under reduced pressure to give a pale yellow gum which was purified by reverse phase HPLC (acidic conditions) to give two sets of fractions, each of which was neutralized with aqueous ammonia and the aqueous layer was extracted with DCM (3×40 mL). For each set, the organic fractions were combined, dried over sodium sulfate and the solvent was removed under reduced pressure. The two resulting residues were each dissolved in a 1:1 mixture of MeCN and water and lyophilized to give the title compounds: Example 12 (4.2mg):δ H( 500 MHz,d6-DMSO)9.11(s,1H),8.58(s,1H),8.20(s,1H),8.13(t,J=5.9 Hz,1H),8.04(s,1H),6.35(d,J=7.5 Hz,1H),6.29(s,1H),4.02(dd,J=17.1,4.4 Hz,1H),3.88-3.78(m,1H),3.51(s,3H),3.19-3.12(m,1H),3.12-2.99(m,2H),2.60-2.53(m,2H),2.27-2.21( m,1H),2.18(s,3H),2.15-2.08(m,1H),1.85-1.76(m,1H),1.65-1.54(m,1H),1.03-0.95(m,4H),0.73(d,J=6.7 Hz,3H),0.71(d,J=6.7 Hz,3H).LCMS [M+H] + 535.3 RT 2.60 min (Method 3). Example 13 (5.5mg):δ H(500 MHz,d6-DMSO)9.15(s,1H),8.58-8.53(m,1H),8.44-8.35(m,1H),8.16-7. 98(m,3H),5.93-5.69(m,1H),4.56-4.46(m,1H),4.17-4.07(m,1H),3.57-3 .44(m,5H),3.28-3.14(m,2H),2.60-2.54(m,2H),2.32-2.19(m,3H),2.10- 2.03(m,3H),1.59-1.49(m,1H),1.05-0.98(m,4H),0.72-0.64(m,6H).LCMS [M+H] + 535.3 RT 2.31 min (Method 3).

[0091] Examples 14 and 15 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-7-[3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (14) 3-Cyclopropyl-N-(2-methylpropyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (15) To a stirred solution of intermediate 31 (35 mg, 0.069 mmol) in DMF (1 mL) was added formic hydrazide (12.4 mg, 0.21 mmol), followed by mercuric dichloride (55.9 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 5 min, then TEA (28.7 μL, 0.21 mmol) was added and the resulting suspension was heated to 70° C. for 1 h. The suspension was cooled to room temperature, diluted with DCM and diatomaceous earth was added. The mixture was stirred for 1 min and then filtered. The solvent was removed under reduced pressure to give a pale yellow gum. The gum was purified by reverse phase HPLC (acidic conditions). The resulting aqueous fraction was neutralized with aqueous ammonia (to approximately pH 8) and then extracted with DCM (3×15 mL). The organic fractions were combined, dried over sodium sulfate and the solvent was removed under reduced pressure to give the title compound: Example 14 (2.7mg):δ H(500 MHz, d6-DMSO) 9.06 (s, 1H), 8.72 - 8.68 (m, 1H), 8.54 (s, 1H), 8.02 - 7.97 (m, 4H), 7.87 - 7.81 (m, 1H), 7.26 - 7.21 (m, 1H), 6.60 - 6.55 (m, 1H), 2.94 (t, J = 7.6 Hz, 2H), 2.57 (d, J = 6.8 Hz, 3H), 2.34 - 2.29 (m, 3H), 2.25 - 2.20 (m, 1H), 1.59 - 1.49 (m, 1H), 1.02 - 0.98 (m, 4H), 0.70 (d, J = 6.7 Hz, 6H). LCMS [M + H] + 518.5 RT 2.83 min (Method 6). Example 15 (3 mg): δ H( 500 MHz, d6-DMSO) 9.12 (s, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.67 (dd, J = 4.8, 1.3 Hz, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 8.27 - 8.21 (m, 1H), 8.05 (s, 1H), 7.98 - 7.93 (m, 1H), 7.61 (dd, J = 8.2, 4.8 Hz, 1H), 6.33 (d, J = 7.0 Hz, 1H), 4.12 (dd, J = 16.9, 4.4 Hz, 1H), 3.85 - 3.74 (m, 1H), 3.16 - 3.00 (m, 3H), 2.61 - 2.54 (m, 2H), 2.27 - 2.20 (m, 1H), 2.19 - 2.10 (m, 1H), 1.89 - 1.79 (m, 1H), 1.66 - 1.57 (m, 1H), 1.03 - 0.98 (m, 4H), 0.75 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H). LCMS [M + H] + 518.3 RT 2.38 min (Method 3).

[0092] Example 16

Chem.

[0093] Examples 17 and 18 [ka] (7R)-3-Cyclopropyl-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (7S)-3-Cyclopropyl-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide Intermediate 16 (138 mg, 0.24 mmol, 65% pure), Intermediate 23 (80.7 mg, 0.34 mmol), tBuONa (80.8 mg, 0.84 mmol) and tBuXPhosPdG3 (28.6 mg, 0.04 mmol) were dissolved in dioxane (6 mL) and tBuOH (3 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with water (5 mL) and EtOAc (10 mL) and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (3×10 mL). The organic fractions were combined, dried over sodium sulfate and the solvent was removed under reduced pressure to give an orange gum. The resulting brown gum was purified by column chromatography using a gradient of methanol in TBME to give a pale yellow solid. The solid was then separated by chiral chromatography to give the title compounds: Example 17 (24 mg): Chiral RT** = 14.8 min δ H( 500 MHz,d6-DMSO)9.13(s,1H),8.53(s,1H),8.15(d,J=2.7 Hz,1H),8.08(s,1H),7.97(t,J=5.9 Hz,1H),7.84(d,J=8.7 Hz,1H),7.14(dd,J=8.8,2.8 Hz,1H),6.78(d,J=7.5 Hz,1H),3.96-3.85(m,2H),3.30-3.27(m,1H),3.20-3.08(m,2H),2.60-2.53(m,5H),2.29-2.22(m,1H) ),2.22-2.15(m,1H),1.77-1.66(m,1H),1.61-1.48(m,1H),1.04-0.97(m,4H),0.73-0.64(m,6H).LCMS [M+H] + 533.3 RT 2.98 min (Method 3). Example 18 (25.5 mg): Chiral RT** = 24.9 min δ H(500 MHz,d6-DMSO)9.13(s,1H),8.53(s,1H),8.15(d,J=2.7 Hz,1H),8.08(s,1H),7.97(s,1H),7.84(d,J=8.7 Hz,1H),7.14(dd,J=8.8,2.7 Hz,1H),6.78(d,J=7.5 Hz,1H),3.96-3.86(m,2H),3.30-3.27(m,1H),3.21-3.08(m,2H),2.61-2.52(m,5H),2.28-2.22(m,1H) ),2.22-2.14(m,1H),1.76-1.66(m,1H),1.58-1.49(m,1H),1.04-0.97(m,4H),0.72-0.64(m,6H).LCMS [M+H] + 533.3 RT 2.97 min (Method 3). **Chiral analysis was performed using: SFC CHIRALPAK AD (250mm x 4.6) 5μm 60 / 40%CO2 / (MeOH + 0.5% iso-propylamine) 2.4mL / min 100 Bar 40℃ 5μL of 1mg / mL MeOH run for 35min.

[0094] Example 19 [ka] 3-Cyclopropyl-7-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide Intermediate 16 (30 mg, 0.08 mmol) was dissolved in ethanol (1 mL) and DIPEA (21.2 μL, 0.12 mmol) was added followed by 3,4-diethoxycyclobut-3-ene-1,2-dione (17.8 μL, 0.12 mmol). The solution was stirred at room temperature for 30 min. 2M ethanamine in THF (64.3 μL) was added and the solution was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure and dissolved in a mixture of 1:1 DMSO and MeOH (1 mL) and the solution was purified by reverse phase HPLC (acidic conditions) to give the title compound (15.7 mg, 39% yield) as a white powder. δ H(500 MHz, d6-DMSO) 9.13 (s, 1H), 8.54 (s, 1H), 8.08 (s, 1H), 8.01 (br s, 1H), 7.58 (br s, 1H), 7.37 (br s, 1H), 4.38 - 4.24 (m, 1H), 3.88 - 3.79 (m, 1H), 3.57 - 3.48 (m, 2H), 3.19 - 3.04 (m, 2H), 2.62 - 2.54 (m, 2H), 2.28 - 2.22 (m, 1H), 2.21 - 2.12 (m, 1H), 1.86 - 1.76 (m, 1H), 1.61 - 1.51 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H), 1.03 - 0.98 (m, 4H), 0.72 (d, J = 2.2 Hz, 3H), 0.70 (d, J = 2.2 Hz, 3H). LCMS [M+H] + 497.3 RT 3.03 min (Method 6).

[0095] Example 20 [Chemical Structure] 3-Cyclopropyl-7-[[1-(2,5-dimethylpyrazol-3-yl)imidazol-2-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide To a stirred solution of intermediate 32 (60 mg, 0.097 mmol, 85% purity) in DMF (1 mL) was added 2,2-diethoxyethanamine (0.04 mL, 0.29 mmol) followed by mercuric dichloride (78.9 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 5 min, then TEA (40.5 μL, 0.29 mmol) was added and the resulting suspension was heated to 70° C. for 5 h. Paratoluenesulfonic acid hydrate (110.5 mg, 0.581 mmol) was added and the mixture was stirred at 70° C. for 1 h. The suspension was cooled to room temperature, diluted with DCM and diatomaceous earth was added. The mixture was stirred for 1 min and then filtered. The solvent was removed under reduced pressure to give a pale yellow gum. The gum was dissolved in DMF (1.5 mL) and stirred at 90° C. for 2 h and then at 110° C. for 4 h. The reaction mixture was concentrated under reduced pressure and then dissolved in methanol (1 mL). The resulting solution was purified by reverse phase HPLC (acidic conditions) to give a brown gum. The gum was dissolved in a 1:1 mixture of MeCN and water and lyophilized to give a brown powder. The solid was dissolved in DCM, washed with saturated sodium bicarbonate (2 mL) and dried over sodium sulfate. The sample was concentrated under nitrogen to give the title compound (6.3 mg, 12% yield) as a brown gum. δ H( 500 MHz, CDCl3)9.02(s,1H),8.97(s,1H),8.10-8.02(m,1H),7.81(s,1H),6.78(d,J=1.3 Hz,1H),6.60(d,J=1.5 Hz,1H),6.10(s,1H),4.59-4.51(m,1H),3.88(d,J=6.0 Hz,1H),3.66-3.58(m,4H),3.15-2.99(m,2H),2.75-2.62(m,2H),2.50-2.43(m,1H),2.34-2.21( m,5H),1.91-1.81(m,1H),1.72-1.65(m,1H),1.16-1.08(m,2H),1.07-1.00(m,2H),0.94(d,J=6.7 Hz,3H),0.87(d,J=6.7 Hz,3H).LCMS [M+H] + 534.3 RT 2.24 min (Method 3).

[0096] Examples 21 and 22 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-7-(5-pyridin-3-yl-1H-imidazol-2-yl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (twenty one) 3-Cyclopropyl-N-(2-methylpropyl)-8-(5-pyridin-3-yl-1H-imidazol-2-yl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide (twenty two) DIPEA (245 μL, 1.41 mmol) was added to a stirred solution of 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (1:1) (189 mg, 0.67 mmol) and intermediates 14 and 15 (1:1 mixture of isomers, 300 mg, 0.34 mmol, 90% purity) in MeCN (3 mL) at room temperature. The mixture was stirred at room temperature for 1.5 h. Additional DIPEA (58.4 μL, 0.34 mmol) was added and the reaction was stirred at room temperature for 1 h. 2-Bromo-1-(pyridin-3-yl)ethanone hydrobromide (1:1) (47.1 mg, 0.17 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (20 mL) and then washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), the organic fractions were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in dry toluene (4.5 mL) and treated with ammonium acetate (255 mg, 3.35 mmol). The suspension was stirred at 110° C. for 1 h, then diluted with toluene (2 mL), treated with ammonium acetate (128 mg, 1.68 mmol), and stirred at 110° C. for 16 h. The solution was then cooled to room temperature and diluted with EtOAc (20 mL). The mixture was washed with saturated aqueous NaHCO3 (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting brown gum was purified by column chromatography using a gradient of methanol in TBME to give a yellow solid (180 mg). The solid was purified by reverse phase HPLC (basic conditions) to give the title compound. Example 21 (10 mg) δ HH (500 MHz, d6-DMSO) 9.12 (s, 1H), 8.95 (d, J = 1.7 Hz, 1H), 8.60 (s, 1H), 8.35 (dd, J = 4.7, 1.6 Hz, 1H), 8.08 (s, 1H), 8.05 (dt, J = 7.9, 1.9 Hz, 1H), 7.66 (s, 1H), 7.34 (dd, J = 7.8, 4.8 Hz, 1H), 4.09 (s, 1H), 3.66 (dt, J = 18.0, 5.3 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.27 - 3.20 (m, 1H), 2.62 - 2.53 (m, 2H), 2.30 - 2.20 (m, 2H), 2.08 - 1.97 (m, 1H), 1.60 - 1.50 (m, 1H), 1.02 - 0.98 (m, 4H), 0.71 - 0.67 (m, 6H). LCMS [M+H] + 502.4, RT 3.11 min (Method 6). Example 22 (30 mg) δ H H (500 MHz, d6-DMSO) 9.10 (s, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.61 (s, 1H), 8.35 (dd, J = 4.7, 1.6 Hz, 1H), 8.07 - 8.02 (m, 2H), 7.66 (s, 1H), 7.34 (dd, J = 7.9, 4.8 Hz, 1H), 3.96 (dd, J = 17.7, 4.7 Hz, 1H), 3.61 - 3.53 (m, 1H), 3.23 - 3.19 (m, 1H), 3.15 - 3.09 (m, 2H), 2.62 - 2.53 (m, 2H), 2.26 - 2.14 (m, 2H), 2.09 - 2.00 (m, 1H), 1.61 - 1.51 (m, 1H), 1.03 - 0.96 (m, 4H), 0.72 - 0.67 (m, 6H). LCMS [M+H] + 502.4, RT 3.24 min (Method 6).

[0097] Examples 23 and 24

Chemical Structure

[0098] In vitro biochemical assays: Protocol for preparation of IgE-Tb reagent 86 nmol of IgE-Fc (N265Q, N371Q) (Young et al., 1995) at 172 μM in 100 mM NaHCO3, pH 9.5 was added to 1 mg of LanthaScreen™ amine-reactive Tb chelate (ThermoFisher catalogue no. PV3583) and incubated for 16 hours at 20° C. The material was then buffer exchanged into phosphate buffered saline (i.e., 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 1.8 mM K2HPO4, pH 7.4) and the material was quantified and the extent of Tb conjugation determined by measuring absorbance at 280 nm and 343 nm.

[0099] The integrity of the conjugate was determined by analytical size exclusion chromatography on a S200 HR 10x300 column (GE Healthcare).Typical conjugation ratio was 4:1 Tb:IgE-Fc. Young RJ., Owens, RJ., MacKay GA., Chan CMW., Shi J., Hide M., Francis DM., Henry AJ., Sutton BJ., and Gould HJ (1995) Protein Engineering 8:193-199

[0100] Preparation protocol for sFcεR1α-Y131A-AF488 reagent 400 nmol of FcεR1α (Y131A mutant) (Cook et al., 1997) at 400 μM in 100 mM NaOAc, pH 5.5 was reacted with a final concentration of 1 mM sodium periodate (in 100 mM NaOAc, pH 5.5) for 60 min at 22 °C. Oxidation was quenched by adding 40 μL of ethanediol and incubating for 60 min at 22 °C. The protein was buffer exchanged into conjugation buffer (50 mM NaHCO3, 150 mM NaCl, pH 9.5) and concentrated to 750 μM.

[0101] 175 nmol of protein was added to 1 mg of Alexa Fluor™ 488 hydrazide (Invitrogen) and incubated for 16 hours at 22° C. Sodium cyanoborohydride (100 mM in conjugation buffer) was added to a final concentration of 1 mM and incubated on ice for 60 minutes. The protein was buffer exchanged into phosphate buffered saline (i.e., 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 1.8 mM K2HPO4, pH 7.4) and the material was quantified and the extent of Alexa Fluor™ 488 conjugation was determined by measuring the absorbance at 280 nm and 495 nm.

[0102] The integrity of the conjugate was determined by analytical size-exclusion chromatography on a S200 HR 10x300 column (GE Healthcare).Typical conjugation ratio was 2:1 Alexa Fluor™ 488:sFcεR1α. Cook JPD., Henry AJ., McDonnell JM., Owens RJ., Sutton BJ., and Gould HJ (1997) Biochemistry 36:15579-15588

[0103] The aim was to measure the binding of IgE-Tb to the receptor and its inhibition by compounds using an in vitro fluorescence resonance energy transfer (FRET) assay.

[0104] reagent The FRET reagents used were IgE labeled with terbium (FRET donor) and soluble IgE receptor FcεRIα with the Y131A mutation labeled with Alexa Fluor™ 488 (FRET acceptor). Unlabeled FcεRIα was also used to generate a background control. The assay buffer consisted of 20 mM Tris pH 7.2, 150 mM NaCl and 0.002% Tween, 1% DMSO.

[0105] Assay reaction For most examples, the assay was performed as follows: each assay reaction was performed in a volume of 25 μl in a 384-well half-volume plate. A 10-point compound serial dilution (3-fold) was generated in DMSO at a concentration 50-fold higher than the final assay concentration (FAC). Compound solutions were then prepared by diluting IgE-Tb 10-fold in assay buffer. For the assay, 5 μl of diluted compound was added to 10 μl of IgE-Tb, followed by 10 μl of FcεRIα-Y131A-AF488. The FRET reagent FAC was 5 nM IgE-Tb, 25 nM FcεRIα-Y131A-AF488. Typically, the top FAC of the compound in the assay was 10 μM. The final DMSO concentration was 2%. The minimum signal (MIN) was measured by adding 5 μl of 1 μM unlabeled FcεRIα (FAC=200 nM) to the FRET reagent. The maximum FRET signal (MAX) was measured in wells containing the FRET reagent but no compound.

[0106] The assay was incubated for 2 hours at room temperature, protected from light and evaporation and gently agitated.

[0107] FRET measurements FRET measurements for each well were performed using an Envision plate reader (Perkin Elmer) by exciting at 330 nm and measuring emission at 495 / 520 nm. The FRET ratio was calculated as follows: Radiation at 520 / radiation at 495x1000.

[0108] FRET ratio was used for data analysis.

[0109] 4. Data Analysis Z' was calculated as follows (σ=standard deviation, μ=mean): 1-((3xσ MAX )+(3xσ MIN )) / (μ MAX -μ MIN )

[0110] A Z' above 0.5 was considered a good assay.

[0111] Background signal (MIN) was subtracted from all wells. The background subtracted values ​​were used to calculate the percent inhibition by compound in each test well as follows: 100-Test well FRET ratio / MAX FRET ratio x 100.

[0112] Percent inhibition was plotted versus compound concentration. IC50 values ​​for each compound were determined using a four-parameter logistic fit model using the XLFIT5 software package.

[0113] For examples 9 and 10, the assay was performed as follows: each assay reaction was performed in a volume of 25 μl in a 384-well half-volume plate. A 10-point compound serial dilution (3-fold) was generated in DMSO at a concentration 50-fold higher than the final assay concentration (FAC). Compound solutions were then prepared by diluting 10-fold with assay buffer. For the assay, 5 μl of diluted compound was added to 10 μl of IgE-Tb and incubated for 30 minutes before adding 10 μl of sFcER1α-Y131A-AF488. The FRET reagent FAC was 5 nM IgE-Tb, 25 nM sFcER1α-Y131A-AF488. Typically, the top FAC of the compound in the assay was 10 μM. The final DMSO concentration was 2%. The minimum signal (MIN) was measured by adding 5 μl of 1 μM unlabeled sFcER1a (FAC=200 nM) to the FRET reagent. The maximum FRET signal (MAX) was measured in wells containing the FRET reagent but no compound.

[0114] The assay was incubated for 18 hours at room temperature, protected from light and evaporation and gently agitated.

[0115] FRET measurements FRET measurements for each well were performed using a PHERAstar FSX plate reader (BMG Labtech) by exciting at 337 nm and measuring emission at 490 / 520 nm. The FRET ratio was calculated as follows: Radiation at 520 / radiation at 490x1000.

[0116] FRET ratio was used for data analysis.

[0117] 4. Data Analysis Z' was calculated as follows (σ=standard deviation, μ=mean): 1-((3xσ MAX )+(3xσ MIN )) / (μ MAX -μ MIN )

[0118] A Z' above 0.5 was considered a good assay.

[0119] Background signal (MIN) was subtracted from all wells. The background subtracted values ​​were used to calculate the percent inhibition by compound in each test well as follows: 100-Test well FRET ratio / MAX FRET ratio x 100.

[0120] Percent inhibition was plotted versus compound concentration. IC50 values ​​for each compound were determined using a four-parameter logistic fit model using the XLFIT5 software package.

[0121] The compounds of the present invention exhibit IC50 values ​​in the range of 10 nM to 3131 nM.

[0122] The table below shows the range of IC50 values ​​for each example: [Table 1]

Claims

1. Compounds of formula (I) and pharma- ceutically acceptable salts thereof: 【Chemistry 1】 During the ceremony, X is C or N; Y is -(C=N)- or -(N=N)- or O or -(O-NH)-; R1 represents a group selected from the following: Hydrogen; or heteroaryl, optionally substituted by one or more groups selected from amino; C(O)O-C1-6-alkyl; C(O)NH-C1-6-alkyl; NH-C1-6-alkyl; NH-C1-6-alkanediyl-C3-6-cycloalkyl; heteroaryl; NH-heteroaryl optionally substituted by one or more R; or NHC(NCN)NH-aryl optionally substituted with one or more Ra; or NH-heteroaryl, where C1-6-alkyl; heteroaryl optionally substituted with one or more groups selected from R; or C(O)NH-C1-6-alkyl; or C(O)NH-C1-6-alkanediyl-aryl optionally substituted with one or more Ra; or C(O)NH-C1-6-alkanediyl-heteroaryl optionally substituted with one or more Ra; or NHC(O)heteroaryl optionally substituted with one or more Ra; or NH-C3-8-cycloalkyl, substituted by one or more of C1-6-alkylamino; oxo; Ra; R2 represents a group selected from the following: Hydrogen; or C(O)NH-C1-6-alkyl, optionally substituted with aryl, which is optionally substituted with one or more Ra; or heteroaryl, provided that the heteroaryl is optionally substituted with one or more R; heteroarylamino, optionally substituted with one or more R; or NH-heteroaryl substituted with heteroaryl optionally substituted with one or more Ra; R3 represents a group selected from the following: R3 ａ C1-6-alkyl optionally substituted with one or more groups selected from One or more R3 ａ C1-3-alkanediyl-C3-6-cycloalkyl optionally substituted with One or more R3 ａ C1-3-alkanediyl-C3-6-heterocycloalkyl optionally substituted with One or more R3 ａ C3-6-heterocycloalkyl optionally substituted with One or more R3 ａ C3-6-cycloalkyl optionally substituted with R3 ａ represents a group selected from hydrogen; halogen; C1-2-alkyl; hydroxy; C1-2-alkoxy; R4 represents a group selected from the following: One or more R4 ａ C3-6-cycloalkyl optionally substituted with a group; or one or more R4 ａ C1-6-alkanediyl-C3-6-cycloalkyl optionally substituted with a group; or one or more R4 ａ C1-6-alkanediyl-C3-6-heterocycloalkyl optionally substituted by a group; R4 ａ represents a group selected from hydroxy; halogen; C1-2-alkyl; Ra is selected from halogen; nitrile; C1-6-alkyl; C1-6-haloalkyl; C1-6-alkoxy; C1-6-haloalkoxy; C(O)O-C1-6-alkyl; C(O)OH.

2. 2. The compound of claim 1, wherein X is C and Y is -(C=N)-.

3. 2. The compound of claim 1, wherein X is N and Y is O.

4. The compound of claim 1, wherein X is N and Y is -(O=N)-.

5. R3 represents C1-6-alkyl optionally substituted with a fluorine atom; The compound according to any one of claims 1 to 4.

6. R4 represents cyclopropyl; The compound according to any one of claims 1 to 5.

7. R1 is not hydrogen and R2 is hydrogen, or R2 is not hydrogen and R1 is hydrogen; The compound according to any one of claims 1 to 6.

8. The compound of claim 1 selected from the following: Ethyl 5-amino-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]imidazole-4-carboxylate; 3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 2-cyano-1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-3-(p-tolyl)guanidine; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2,2-dimethylpropyl)-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxamide; 3-cyclopropyl-N-(2,2-dimethylpropyl)-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxamide; N-benzyl-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-8-carboxamide; N-benzyl-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-7-carboxamide; 2-cyclopropyl-6-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzoxazole-4-sulfonamide; 3-Cyclopropyl-N-isobutyl-6,7,8,9-tetrahydro-4H-benzo[g][1,2,4]benzoxadiazine-5-sulfonamide; N-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-6,7,8,9-tetrahydrobenzo[g]isoquinolin-7-yl]-6-methyl-1H-indole-3-carboxamide; 3-cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-methylpropyl)-7-[3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-methylpropyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; (7S)-3-cyclopropyl-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[[1-(2,5-dimethylpyrazol-3-yl)imidazol-2-yl]amino]-N-(2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-methylpropyl)-7-(5-pyridin-3-yl-1H-imidazol-2-yl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-methylpropyl)-8-(5-pyridin-3-yl-1H-imidazol-2-yl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-8-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-8-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-fluoro-2-methyl-propyl)-6,7,8,9-tetrahydrobenzo[g]isoquinoline-5-sulfonamide formic acid.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, for use in treatment.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, for use in a method for treating or preventing a disorder caused by IgE.

12. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, for use in a method for treating or preventing allergy, non-allergic mast cell response, type 1 hypersensitivity, urticaria, or familial sinusitis.

13. Use of a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament.

14. Use of a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for treating and / or preventing disorders caused by IgE.

15. Use of a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of allergy, non-allergic mast cell response, type 1 hypersensitivity, urticaria or familial sinusitis.

16. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharma- ceutical acceptable salt thereof for use in a method for the treatment or prevention of airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, urticaria, or increased vascular permeability.

17. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharma- ceutical acceptable salt thereof, for use in a method for treating or preventing eosinophilic granulomatosis with polyangiitis (also known as Churg-Strauss syndrome), aspirin-exacerbated respiratory disease, or cutaneous T-cell lymphoma.

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