Dihydro-cyclopenta-isoquinoline sulfonamide derivatives

Abstract

The present invention relates to dihydro-cyclopenta-isoquinoline derivatives of formula (I), [Formula 1] JPEG2023508384000413.jpg4847 It relates to 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.

Description

[Technical field]

[0001] The present invention relates to dihydro-cyclopenta-isoquinoline 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 the well-known 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) local 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 of asthma, or (4) mast cell stabilizers that inhibit the degranulation of mast cells that is normally caused by IgE binding at FcεRI, and (5) biologics that prevent IgE binding at FcεRI. The use of peptides that modulate IgE binding to FcεRI has also been attempted. As an example, WO 96 / 01643 describes peptides consisting of 4-50 amino acids for treating immediate allergic responses.

[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 or O; When Y is O, R1 is hydrogen or hydroxy, R1' is hydrogen, and R2, R2' are absent; R1 is, hydrogen, Hydroxy, oxo group, amino, C1-6-alkyl, C1-6-alkylamino, C(O)OH, C(O)NH-heteroaryl, -NH-C1-6-alkyl-C3-6-cycloalkyl, -NH-C1-6-alkyl-C(O)OH optionally substituted with an amino group; -NH-cycloalkyl optionally substituted by one or more groups selected from among halogen, oxo, C1-6-alkyl, C1-6-alkylamino, C1-6-alkyl-C1-4-alkylamino, C3-8-cycloalkyl-C1-6-alkylamino, heteroaryl, heteroarylamino optionally substituted by one or more C1-6-alkyl, heteroaryl optionally substituted by one or more groups selected from among halogen, hydroxy, oxo, amino, cyano, -C(O)-C1-6-alkyl, C1-6-alkyl, C1-6-alkylamino, C1-6-alkoxy, -NH-(C1-6-alkyl)-heterocycloalkyl, -NH-(C1-6-alkyl)-heteroaryl optionally substituted by one or more C1-6-alkyl, -NH-C1-6-alkyl-cycloalkyl, -NH-C(O)-cycloalkyl, -NH-heteroaryl substituted by one or more C1-6-alkyl, -NH-C1-6-alkyl-C(O)OH; heteroaryl substituted by heteroarylamino optionally substituted by C1-6-alkyl, C1-6-alkoxy, C3-6-cycloalkyl, C1-6-haloalkoxy, C1-6-haloalkyl, CN, halogen, C(O)OH, -C(O)O-C1-6-alkyl; -NH-C(S)-NH-Ra 1 , -NH-SO2-Rb 1 , -NH-heteroaryl optionally substituted by one or more groups selected from among oxo, C1-6-alkyl, C1-6-alkylamino, heteroaryl optionally substituted by one or more oxo, C1-6-alkyl, -C(O)-NHNH-C(O)CH3, aryl, heteroarylamino, C1-6-alkoxy, C3-6-cycloalkyl, C1-6-haloalkoxy, C1-6-haloalkyl, CN, halogen, C(O)OH, -C(O)O-C1-6-alkyl; Halogen, C1-6-alkyl, oxo, heteroaryl, C(O)ORb 1 , C1-6-Alkyl-NRb 1 Rb 1 -NH-heterocycloalkyl optionally substituted with one or more groups selected from among NHC(O)-aryl, NHC(O)-heteroaryl; -NH-C1-6-alkyl substituted by one heteroaryl group optionally substituted by one or more groups selected from among C1-6-alkyl, amino; -NH-C(O)O-Rb 1 , -NH-C(NCN)-NH-Ra 1 , -NH-C(NCN)-NH-heteroaryl, -NH-C(O)-C3-8-heterocycloalkyl-C(O)O-Rb 1 , -C(O)NH-C1-6-alkyl, -NH-C(O)NH-C1-6-alkyl optionally substituted by one or more C3-8-heterocycloalkyl; -NH-C(O)NH-heterocycloalkyl-C1-6-alkyl, -NH-C1-6-alkyl-C(O)-C1-6-alkylamino, Heteroaryloxy, -NH-C(O)-aryl, -NH-C(O)-heteroaryl, -NH-C(O)-heterocycloalkyl, -NH-C(O)-C1-6-alkyl optionally substituted by one or more amino groups; Amino, -NH-C(O)ORb 1 -NH-C(O)-C1-6-alkyl-C(O)ORb 1 , Amino, -C(O)NH-Rb 1 , -C(O)ORb 1 , -NHC(O)-heteroaryl optionally substituted with one or more C1-6-alkyl, -NHC(O)-C1-6-alkyl optionally substituted with an amino group, -NHC(O)O-C1-6-alkyl, -NH-C(O)Rb 1 Heterocycloalkyl optionally substituted with one or more groups selected from represents a -C2-6-alkene group which may be substituted by one or more groups selected from the group consisting of halogen and =NH; Ra 1 teeth, C1-6-alkyl, or Aryl optionally substituted with one or more C1-6-alkyl; or represents heteroaryl optionally substituted with one or more C1-6-alkyl; Rb 1 teeth, Hydrogen, or C1-6-alkyl, or aryl optionally substituted with one or more halogen, C1-6-alkyl, hydroxy; R1' is hydrogen, represents hydroxy, R2 is hydrogen, halogen, Hydroxy groups, oxo group, C1-6-alkyl, C3-8-heterocycloalkyl optionally substituted with one or more hydroxy, halogen, amino, amino-C-1-6-alkyl, C1-6-alkyl, C(O)O-C1-6-alkyl, C(O)NH2; C1-6-alkylamino, heteroaryl optionally substituted with one or more groups selected from C1-6-alkyl, and halogen; heteroaryl optionally substituted by one or more -NH-heteroaryl optionally substituted by C1-6-alkyl, halogen, cyano, -C(O)OH, -C(O)O-C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C3-6-cycloalkyl; -NH-cycloalkyl optionally substituted by one or more groups selected from among halogen, oxo, C1-6-alkyl, C1-6-alkylamino, C1-6-alkyl-C1-4-alkylamino, C3-8-cycloalkyl-C1-6-alkylamino, aryl, heteroaryl, heteroarylamino optionally substituted by one or more C1-6-alkyl, -NH-heteroaryl optionally substituted with one or more groups selected from among hydroxy, halogen, oxo, C1-6-alkyl, C1-6-alkoxy, heteroaryl optionally substituted with one or more hydroxy, halogen, oxo, C1-6-alkyl, C(O)O-C1-6-alkyl, C(O)OH, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C3-6-cycloalkyl, C1-6-alkylamino, cyano, heterocycloalkyl substituted with one or more hydroxyhalogens, and oxo groups; -NH-C1-6-alkyl substituted by one heteroaryl group, which may be substituted by one or more groups selected from among C1-6-alkyl; -NH-SO2-heteroaryl, optionally substituted with one or more groups selected from among halogen; -NHC(O)-Ci-6-alkyl optionally substituted with one or more halogen, C1-6-alkoxy, amino, C3-8-cycloalkyl, C3-8-heterocycloalkyl, heteroaryl; -NHC(O)-heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, oxo, C1-6-alkyl, heteroaryl, C1-6-alkylamino, S(O)2-C1-3-alkyl, -NHC(O)-C1-6-alkyl, -NHC(O)-C3-8-heterocycloalkyl optionally substituted with one or more oxo, C1-6-alkyl; -NHC(O)O-C1-6-alkyl, -NHC(O)O-C1-6-alkyl-Ra 2 , -NHC(O)O-aryl, -NHC(O)NH-Ra 2 -NHC(O)NH-C1-6-alkyl-Ra 2 -NH-C(NCN)-NH-Ra 1 , -NHC(O)-C3-8-cycloalkyl, -NH-SO2-Rb 2 , -NH-C(S)-NH-Rb 2 , -NH-C3-8-heterocycloalkyl optionally substituted with one or more groups selected from oxo, C1-6-alkyl; Aryloxy groups, represents a heteroaryloxy group, Ra 2 teeth, hydrogen, aryl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, C1-6-alkyl; represents heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, C1-6-alkyl, Rb 2 teeth, C1-6-alkyl, represents heteroaryl, R2' is hydrogen, represents hydroxy, 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 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 C1-6-alkanediyl-C3-6-heterocycloalkyl optionally substituted by a group; R4 a represents a group selected from hydroxy, halogen and C1-2-alkyl.

[0008] R5 is, represents hydrogen, methyl or halogen; however, - when R1' is hydroxy, R1 is selected from among pyridyl, C1-6-alkyl; - when R2' is hydroxy, R2 is selected from among pyridyl, C1-6-alkyl; - if R1 is different from hydrogen, R2 and R2' are hydrogen; - when R2 is different from hydrogen, R1 and R1' are hydrogen; When R1 is oxo, R1' is absent; When R2 is oxo, then R2' is absent.

[0009] The compounds of formula (I) may contain one or more asymmetric carbon atoms. They may therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, form part of the present invention.

[0010] The compounds of formula (I) can exist in the form of bases or addition salts with acids. Such addition salts are part of the present invention. These salts are advantageously prepared with pharma-ceutically acceptable acids. The salts of other acids, useful for example for the purification or isolation of the compounds of formula (I), are also part of the present invention.

[0011] Within the framework of the present invention -Ct-z represents a carbon chain that may have t to z carbon atoms, for example a C1-7 carbon chain that may have 1 to 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, for example, 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. -Alkylamino refers to one or more alkyl groups substituted on an amino radical. Examples of alkylamino include methylamino, ethylamino, tertbutylamino, and dimethylamino; -acyl is an alkyl-C(O)- group, -hydroxy is an -OH group; -alkoxy is an -O-alkyl group; halogen atom is a fluorine, chlorine, bromine or iodine atom, -haloalkyl is an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms; -haloalkoxy is an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms; -oxo is an oxygen that represents a double bond such as =O; -Cycloalkyl refers to a monocyclic or bicyclic aliphatic group that is not aromatic and may contain double bonds and that contains 3 to 14 atoms, preferably 3 to 9 atoms, in the group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, spiro[2.2]pentanyl, spiro-undecanyl; -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 among nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl include aziridinyl, pyrrolidinyl, piperidyl, oxetane, and oxa-spiro-undecanyl. -aryl refers to a monocyclic or bicyclic aromatic group containing 6 to 14 carbon atoms, in which at least one ring is aromatic. Examples of aryl groups include phenyl or naphthyl groups; Heteroaryl refers to a monocyclic or bicyclic group containing 5 to 14 atoms, preferably 3 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. -heteroarylamino refers to an amino group -NH2 substituted with a heteroaryl group. An example of a heteroaryl group can be pyridinylamino; -Aryloxy refers to an aryl substituted with an oxygen radical. An example of an aryloxy is phenoxy. -Heteroaryloxy is a heteroaryl group substituted with an oxygen radical. An example of heteroaryloxy is pyridyloxy.

[0012] 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 such as inorganic acids, for example hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or with a suitable acid such as organic acids, for example 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, and the like.

[0013] The present invention also relates to all stereoisomers, such as the 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 one or more compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, unless a particular isomeric form is specifically mentioned.

[0014] Some of the compounds of formula (I) may exist in tautomeric forms. Although not explicitly shown in the above formula, such forms are intended to be included within the scope of the present invention.

[0015] It should be understood that each of the individual atoms 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 of the individual hydrogen atoms present in formula (I) or any formula shown herein can be present as 1H, 2H (deuterium) or 3H (tritium) atoms, preferably 1H. Similarly, by way of example, each of the individual carbon atoms present in formula (I) or any formula shown herein can be present as 12C, 13C or 14C atoms, preferably 12C.

[0016] 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.

[0017] 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 the intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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 for use in a method for the treatment or prevention of disorders caused by IgE, including allergies, type 1 hypersensitivity, well-known sinusitis, urticaria or related conditions, e.g. airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, increased vascular permeability, eosinophilic granulomatosis with polyangiitis (also known as "Churg-Strauss syndrome"), aspirin-exacerbated respiratory disease or cutaneous T-cell lymphoma.

[0022] In a further embodiment, the present invention relates to a method for treating or preventing allergies, type 1 hypersensitivity, common sinusitis, urticaria or related conditions comprising the administration of a therapeutically effective amount of a compound of formula (I).

[0023] According to one embodiment, the compounds of the invention are characterized by formula (I), in which R4 represents cyclopropyl or spiro[2.2]pentanyl, hydroxy, Chloro, fluoro, bromo, and optionally substituted with one or more groups independently selected from methyl.

[0024] According to one embodiment, the compounds of the invention are characterized by formula (I) in which R4 represents cyclopropyl.

[0025] According to one embodiment, the compounds of the invention are characterized by formula (I), wherein R1 is -heteroaryl-NH-Ra 1 R2 represents NH-heteroaryl, optionally substituted with one or more groups selected from heteroaryl, C1-6-alkyl, -C(O)OH, in which Ra 1 is C1-6-alkyl or heteroaryl optionally substituted with one or more C1-6-alkyl.

[0026] According to one embodiment, the compounds of the invention are characterized by formula (I): R1 represents the following: Hydrogen, methoxyimidazopyridinyl, carboxy group, cyclopropyl-methyl-carbamoyl-amino, pyridine-carbonylamino, hydroxy(pyridyl), [(fluorocarbonimidoyl)propenyl], [(cyclopropylmethylamino)imidazolyl], [[(cyclopropylmethyl)imidazolyl]amino], [(dimethylpyrazolyl)carbamoylamino], [[(dimethylpyrazolyl)-triazolyl]amino], (pyridylamino), (tert-butoxycarbonylamino), amino, [(cyclopropylmethylamino)-triazolyl], pyridylcarbamoyl, [(cyclopropanecarbonylamino)pyrazolyl], (aminotetrazolyl), [[(methyltetrazolyl)pyridyl]amino], [(methylpyrazolopyridinyl)amino], [[(methyl-oxadiazolyl)-pyridyl]amino], oxo, hydroxy(methyl), ethylcarbamoylamino), [(ethylamino)- triazolyl], [[(ethylamino)-dioxo-cyclobutenyl]amino], [(ethylamino)-dioxo-thiadiazolyl]amino], [[N'-cyano-N-(p-tolyl)carbamimidoyl]amino], [(tert-butoxycarbonylazetidine-carbonyl)amino], [aminopiperidyl], [(methylcarbamoyl)pyrrolidinyl], [[(dimethylpyrazole-carbonyl)amino]azetidinyl], [(dimethyl-oxo-cyclo butenyl)amino], (indolylmethylamino), methanesulfonamide, [[dioxo(pyridylamino)cyclobutenyl]amino], ethylcarbamoylamino, [[(dimethylpyrazolyl)amino]-triazolyl], [[(methyl-pyridyl)amino]-triazolyl], [[(pyridyl)-triazolyl]amino], [(pyridylamino)-triazolyl], (benzimidazolylamino), pyridyloxy, (pyridylcarbamothioylamino).

[0027] According to one embodiment, the compounds of the invention are characterized by formula (I): R2 represents the following: Hydrogen, [(methylbenzotriazolyl)-triazolyl]methyl, [[(methylpyrazolyl)-triazolyl]amino], [[(methylpyrazolyl)amino]-triazolyl], [[(fluoro-pyridyl)-triazolyl]amino], [[(fluoro-pyridyl)amino]-triazolyl], (pyridylmethylamino), (pyridylsulfonylamino), [(fluoro-indolecarbonyl)amino], [(methylbenzimidazolyl)amino], [(methoxycarbonyl-pyridyl)amino], [(carboxypyridyl)amino], [(methyl-pyrazole-carbonyl)amino], (pyridine-carbonylamino), [(methylcyclopropanecarbonyl)amino], (pyrimidinylamino), [(oxoindolinyl)amino], [(methoxypyridyl)amino], (pyridylamino), [(methylpyrazolopyridinyl)amino], benzylamino, benzyloxycarbonylamino, [(bromophenyl)carbamoylamino], [(dimethylpyrazolyl)methylcarbamoylamino], hydroxy, oxo, methyl, fluorine, [[(ethylamino)-dioxo-thiadiazolyl]amino], [(cyanomethyl-pyrazolyl)amino], (isoquinolylamino), [[N'-cyano-N-(p-tolyl)carbamimidoyl]amino], methanesulfonamido, ethylcarbamothioylamino, [(ethylamino)-triazolyl], [(ethyl-triazolyl)amino], (pyridylcarbamothioylamino), [[(pyridyl)-triazolyl]amino], [[(methyltetrazolyl)-pyridyl]amino], [[dioxo-(pyridylamino)cyclobutenyl]amino], [[(ethylamino)-dioxo-cyclobutenyl]amino], (benzimidazolylamino), pyridyloxy.

[0028] According to one embodiment, the compounds of the invention are characterized by formula (I): R1 represents the following: Hydrogen, (7-methoxyimidazo[4,5-b]pyridin-3-yl), carboxy group, cyclopropyl-methyl-carbamoyl-amino, pyridine-3-carbonylamino, hydroxy(3-pyridyl), [1-(fluorocarbonimidoyl)prop-1-enyl], [2-(cyclopropylmethylamino)imidazol-1-yl], [[1-(cyclopropylmethyl)imidazol-2-yl]amino], [(2,5-dimethylpyrazol-3-yl)carbamoylamino], [[4-(2,5-dimethylpyrazol-3-yl)-1 ,2,4-triazol-3-yl]amino], (3-pyridylamino), (tert-butoxycarbonylamino), amino, [3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl], 3-pyridylcarbamoyl, [5-(cyclopropanecarbonylamino)pyrazol-1-yl], (5-aminotetrazol-1-yl), [[6-(2-methyltetrazol-5-yl)-3-pyridyl]amino], [(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino], [[6-(5-methyl-1,3,4- oxadiazol-2-yl)-3-pyridyl]amino], oxo, hydroxy(methyl), (ethylcarbamothioylamino), [3-(ethylamino)-1,2,4-triazol-4-yl], [[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino], [[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino], [[N'-cyano-N-(p-tolyl)carbamimidoyl]amino], [(1-tert-butoxycarbonylazetidine-3-carbonyl)amino] , [3-amino-1-piperidyl], [(2R)-2-(methylcarbamoyl)pyrrolidin-1-yl], [3-[(2,5-dimethylpyrazole-3-carbonyl)amino]azetidin-1-yl], [(4,4-dimethyl-3-oxo-cyclobuten-1-yl)amino], (1H-indol-2-ylmethylamino), methanesulfonamide, [[3,4-dioxo-2-(3-pyridylamino)cyclobuten-1-yl]amino], ethylcarbamoylamino, [3-[(2,5-dimethylpyrazole-3-yl)amino]-1,2,4-triazol-4-yl], [3-[(5-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl], [[4-(3-pyridyl)-1,2,4-triazol-3-yl]amino], [3-(3-pyridylamino)-1,2,4-triazol-4-yl], (1H-benzimidazol-2-ylamino), 3-pyridyloxy, (3-pyridylcarbamothioylamino).,

[0029] According to one embodiment, the compounds of the invention are characterized by formula (I): R2 represents the following: Hydrogen, [4-(1-methylbenzotriazol-4-yl)-1,2,4-triazol-3-yl]methyl, [[4-(2-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino], [3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl], [[4-(5-fluoro-3-pyridyl)-1,2,4-triazol-3-yl]amino], [3-[(5-fluoro-3-pyridyl)amino]-1,2,4-triazol-4-yl], (3-pyridylmethylamino), (3-pyridyl sulfonylamino), [(6-fluoro-1H-indole-3-carbonyl)amino], [(1-methylbenzimidazol-2-yl)amino], [(6-methoxycarbonyl-3-pyridyl)amino], [(6-carboxy-3-pyridyl)amino], [(5-methyl-1H-pyrazole-3-carbonyl)amino], (pyridine-3-carbonylamino), [(2-methylcyclopropanecarbonyl)amino], (pyrimidin-5-ylamino), (2-oxoindolin-5-yl)amino], [(5-methoxy-3-pyridyl)amino] , (3-pyridylamino), [(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino], benzyloxycarbonylamino, [(4-bromophenyl)carbamoylamino], [(2,5-dimethylpyrazol-3-yl)methylcarbamoylamino], hydroxyoxo, methyl, fluorine, [[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino], [(4-cyano-1-methyl-pyrazol-3-yl)amino], (4-isoquinolylamino), [[N'-cyano-N-(p-tolyl)carbamoylamino] bamimidoyl]amino], methanesulfonamide, ethylcarbamothioylamino, [3-(ethylamino)-1,2,4-triazol-4-yl], [(4-ethyl-1,2,4-triazol-3-yl)amino], (3-pyridylcarbamothioylamino), [[4-(3-pyridyl)-1,2,4-triazol-3-yl]amino], [[6-(2-methyltetrazol-5-yl)-3-pyridyl]amino], [[3,4-dioxo-2-(3-pyridylamino)cyclobuten-1-yl]amino], [[2-(ethylamino)-3,4-Dioxo-cyclobuten-1-yl]amino], (1H-benzimidazol-2-ylamino), 3-pyridyloxy.,

[0030] According to one embodiment, the compound of the invention is selected from: 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(7-methoxyimidazo[4,5-b]pyridin-3-yl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-isobutyl-9-[[4-(1-methylbenzotriazol-4-yl)-1,2,4-triazol-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-isobutyl-9-[[4-(2-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-isobutyl-9-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-[[4-(5-fluoro-3-pyridyl)-1,2,4-triazol-3-yl]amino]-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-[3-[(5-fluoro-3-pyridyl)amino]-1,2,4-triazol-4-yl]-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylic acid, 1-(cyclopropylmethyl)-3-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea[* or S], N-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide [* or S], 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-hydroxy-7-pyridin-3-yl-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(2-fluoropyridin-3-yl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (7R*)-3-cyclopropyl-7-[2-(cyclopropylmethylamino)imidazol-1-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], (7R*)-3-cyclopropyl-7-[[1-(cyclopropylmethyl)imidazol-2-yl]amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 3-cyclopropyl-N-(2-methylpropyl)-9-(pyridin-3-ylmethylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-methylpropyl)-9-(pyridin-3-ylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 6-Fluoro-N-[(9R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1H-indole-3-carboxamide[* or S], 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(1-methylbenzimidazol-2-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, Methyl 5-[[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-2-carboxylate, 5-[[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-2-carboxylic acid, 5-Methyl-N-[(9R*)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1H-pyrazole-3-carboxamide[* or S], N-[(9R*)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide [* or S], 3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide, 1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]cinnolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea, 3-cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide, (7R*)-3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide[* or S], N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-2-methylcyclopropane-1-carboxamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-(pyrimidin-5-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(2-oxo-1,3-dihydroindol-5-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(5-methoxypyridin-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, tert-butyl N-[3-cyclopropyl-5-[(1,1-dideuterio-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate, 7-amino-3-cyclopropyl-N-(1,1-dideuterio-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(1,1-dideuterio-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 7-cyclopropyl-N-(2-fluoro-2-methylpropyl)-3-hydroxy-2,3-dihydrofuro[3,2-h]isoquinoline-5-sulfonamide, (7R*)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-N-pyridin-3-yl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxamide[* or S], N-[2-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyrazol-3-yl]cyclopropanecarboxamide, 7-(5-aminotetrazol-1-yl)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, benzyl N-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate, 1-(4-bromophenyl)-3-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea, 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]urea, 3-cyclopropyl-7-hydroxy-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-methylpropyl)-7-oxo-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-hydroxy-7-methyl-N-(2-methylpropyl)-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 7-amino-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-ethylthiourea, (7R*)-3-cyclopropyl-7-[3-(ethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (* or S), (7R*)-3-Cyclopropyl-7-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (* or S), 3-cyclopropyl-7-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 2-cyano-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(4-methylphenyl)guanidine, tert-Butyl 3-[[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamoyl]azetidine-1-carboxylate[*orS], 7-[(3R)-3-aminopiperidin-1-yl]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (2R)-1-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-N-methylpyrrolidine-2-carboxamide[* or S], N-[1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]azetidin-3-yl]-2,5-dimethylpyrazole-3-carboxamide, 3-cyclopropyl-7-[(4,4-dimethyl-3-oxocyclobuten-1-yl)amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(1H-indol-2-ylmethylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-hydroxy-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-methylpropyl)-9-oxo-7,8-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-hydroxy-9-methyl-N-(2-methylpropyl)-7,8-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-fluoro-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 9-[(4-cyano-1-methylpyrazol-3-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-(isoquinolin-4-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 2-cyano-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-(4-methylphenyl)guanidine, 3-cyclopropyl-9-(methanesulfonamido)-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-ethylthiourea, 3-cyclopropyl-9-[3-(ethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (9R*)-3-Cyclopropyl-9-[(4-ethyl-1,2,4-triazol-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-pyridin-3-yl thiourea, 3-cyclopropyl-N-(2-methylpropyl)-9-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-[[3,4-dioxo-2-(pyridin-3-ylamino)cyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (9R*)-3-Cyclopropyl-9-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], (9R*)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 3-cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(3,3-difluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(3-fluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-(methanesulfonamido)-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-[[3,4-dioxo-2-(pyridin-3-ylamino)cyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 1-Ethyl-3-[(7R*)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea[* or S], (7R*)-3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], (7R*)-3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 3-cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (7R*)-3-cyclopropyl-N-(2-methylpropyl)-7-[3-[(5-methylpyridin-3-yl)amino]-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 3-cyclopropyl-N-(2-methylpropyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-methylpropyl)-7-[3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 7-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-pyridin-3-yloxy-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-pyridin-3-yloxy-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 1-[3-Cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(3-pyridyl)thiourea.

[0031] The following examples show how compounds covered 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 of the following examples can be made without departing from the spirit or scope of the present invention.

[0032] example Abbreviation DCM Dichloromethane MTBE tert-butyl methyl ether Et2O Diethyl ether THF Tetrahydrofuran EtOAc Ethyl acetate MeCN Acetonitrile MeOH Methanol Broad s Broad singlet M mass or mole Brine 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 DMAP 4-Dimethylaminopyridine TFA Trifluoroacetic acid DMSO Dimethyl sulfoxide TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate EtOH Ethanol sat. saturation aq. aqueous solution BOC tert-butoxycarbonyl 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 hrs time IPA Isopropyl Alcohol conc. concentration TBDMSCl tert-Butyldimethylsilyl chloride equiv. equivalent amount TBAB Tetra-n-butylammonium bromide NBS N-Bromosuccinimide NIS N-iodosuccinimide SCX Biotage® ISOLUTE® SCX-2 Propyl Sulfonic Acid Functionalized Silica SFC Supercritical Fluid Chromatography

[0033] LCMS method Method 1: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution 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 Method 2: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution 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 Method 3: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: Pump 1: 1 mL / min, Pump 2: 0.5 mL / min Gradient Program: Pump 1: Pump 2: Time A% B% Time A% B% 0.00 95.10 4.90 0.10 5.00 95.00 4.00 5.00 95.00 1.00 5.00 95.00 5.00 5.00 95.00 1.10 95.00 5.00 5.10 95.10 4.90 Method 4: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution 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 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00 Method 5: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution 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 Method 6: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution 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 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00 Method 7: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution 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 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00 Method 8: 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 Method 9: 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 Method 10: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: Pump 1: 1 mL / min, Pump 2: 0.5 mL / min Gradient Program: Pump 1: Pump 2: Time A% B% Time A% B% 0.00 95.10 4.90 0.10 5.00 95.00 4.00 5.00 95.00 1.00 5.00 95.00 5.00 5.00 95.00 1.10 95.00 5.00 5.10 95.10 4.90 Method 11: Fixed layer: Waters Acquity UPLC BEH C18 2.1×50mm, 1.7μM column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1.5mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 0.10 95.00 5.00 3.50 5.00 95.00 4.00 5.00 95.00 4.05 95.00 5.00 Method 12: 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: 1 μL 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 215nM, PDA spectrum 200~400nm, step: 1nm MSD scan positive 150-850 Method 13: Column: Waters UPLC X Bridge BEH (C18, 2.1 x 50 mm, 2.5 μm) Temperature: 45℃ Injection volume: 1.0 μL Flow rate: 1.00mL / min Detection: Mass spectrometry - + / - detection in the same run PDA: 210~400nm Solvent A: 10 mM ammonium formate aqueous solution + 0.1% ammonia Solvent B: 95% acetonitrile + 5% H2O + 0.1% ammonia 10 [Table 1] Method 14: Column: Waters UPLC X Bridge BEH (C18, 2.1 x 50 mm, 2.5 μm) 20 Temperature: 45℃ Injection volume: 1.0 μL Flow rate: 1.00mL / min Detection: Mass spectrometry - + / - detection in the same run PDA: 210~400nm 25 Solvent A: 10 mM ammonium formate + 0.1% formic acid in water Solvent B: 95% acetonitrile + 5% H2O + 0.1% formic acid [Table 2] Method 15: Column: Waters XBridge MS C18 column (3.5 μm, 100 × 4.6 mm) Temperature: 45℃ Injection volume: 5.0 μL Flow rate: 1.9~2.4mL / min Detection: Mass Spectrometry - Positive Detection PDA: 210~400nm Solvent A: Water Solvent B: Acetonitrile Solvent D: 630 mg / L ammonium formate aqueous solution + 500 μL / L NH4OH 30% (pH about 8.5) [Table 3] Method 16: Fixed layer: Waters Acquity UPLC BEH, C18, 2.1×50mm, 1.7μm Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 0.7mL / min Temperature: 40℃ Gradient Program: Time A% B% 0.00 98.00 2.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 98.00 2.00 Method 17: Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Kinetex Core-Shell C18 50 × 2.1 mm, 5 μm column, protected by a Phenomenex “Security Guard” column. Flow rate: 1.2mL / min Column temperature: 40℃ Injection volume: 3 μL Gradient: Time (min): %A %B 0.00 95 5 1.20 0 100 1.30 0 100 1.31 95 5 UV 215nM, PDA spectrum 210~420nm, step: 1nm MSD Scan Positive 100-1000

[0034] General Procedure General Step 1: A solution of mercuric chloride (2 equiv.) and formic hydrazide (3 equiv.) in anhydrous N,N-dimethylformamide (1 mL) was added to the thiourea intermediate. Triethylamine (3 equiv.) was added and the reaction was heated to 80° C. with stirring for 8 h. The reaction was filtered through Celite and washed with MeCN (2-3 mL). The solvent was removed in vacuo and the product was purified by column chromatography.

[0035] General procedure 2: To a solution of aryl chloride (1 equiv.) in 1,4-dioxane (20 mL / g) was added cyclopropaneboronic acid (3 equiv.), tricyclohexylphosphonium tetrafluoroborate (2 equiv.) and Pd(OAc)2 (0.1 equiv.). The mixture was degassed with a stream of N2 gas for 5 min, then K3PO4 (1 equiv.) was added. The mixture was degassed with a stream of N2 gas for an additional 5 min, sealed and heated to 110 °C until the reaction was deemed complete by LCMS. The reaction was cooled, diluted with EtOAc (20 mL / g) and washed with saturated aqueous NaHCO3 (20 mL / g). The organic extract was dried over Na2SO4 and concentrated in vacuo.

[0036] General procedure 3: To a solution of the amine (1 eq.), sodium tert-butoxide (3 eq.), aryl halide (2.5 eq.) and tBuXPhos Pd G3 (0.15 eq.) was added anhydrous 1,4-dioxane (20 mL / g). The mixture was degassed with three cycles of vacuum / N2, then sealed and heated to 100° C. with stirring until the reaction was deemed complete by LCMS. The reaction was diluted with EtOAc (20 mL / g) and washed with water (10 mL / g). The aqueous layer was re-extracted with EtOAc (20 mL / g) and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo.

[0037] General procedure 4: To a stirred suspension of the relevant intermediate (1 equiv.) in dichloromethane (40 mL) was added N,N-diisopropylethylamine (1.5 equiv.) and the relevant isothiocyanate (1.5 equiv.), unless otherwise stated. The mixture was stirred at room temperature for 1-3 days. The reaction mixture was evaporated in vacuo and the residue was dry loaded onto silica and purified by column chromatography.

[0038] General procedure 5: To a stirred solution of the relevant thiourea in N,N-dimethylformamide (15 mL) was added formic hydrazide (about 3 equiv.) followed by mercuric chloride (about 2 equiv.). The mixture was stirred at room temperature for 5 min, after which triethylamine (about 3 equiv.) was added. The resulting reaction mixture was stirred at 80° C. for 16 h. The cooled reaction mixture was diluted with acetonitrile and filtered through a celite pad, which was then washed with acetonitrile (30 mL×3). The filtrate was evaporated and the residue was purified by column chromatography to give the desired product.

[0039] Intermediates Intermediate 1 [ka] 3,6,7,8-Tetrahydro-2H-as-indacen-1-one 3-Indan-5-ylpropanoic acid (100 g, 526 mol, commercially available from Angene, CAS number: 23291-98-7) in polyphosphoric acid (320 mL) was heated to 140° C. for 6 min, then cooled to 10° C. and quenched by the addition of ice water (500 mL). The resulting mixture was extracted with DCM (25 L, followed by 15 L). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 to give the title compound as a brown solid (4.5 g, 5% yield).

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[0040] Intermediate 2 [ka] 2-Hydroxyimino-3,6,7,8-tetrahydro-as-indacen-1-one A solution of intermediate 1 (85 g, 493 mmol) in MTBE (1.27 L) was treated with HCl (12 M in EtOH, 20.6 mL), cooled to 0° C., and treated with a solution of isopentyl nitrite (100 mL, 740 mol) in ethanol (600 mL) [added dropwise over 5 min]. The resulting mixture was stirred at 0° C. for 0.4 h, then the solid was collected by filtration, washed with MTBE, and dried to give the title compound as a brown solid (80 g, 81% yield).

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[0041] Intermediate 3 [ka] 1,3-Dichloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline A solution of intermediate 2 (83 g, 412.5 mol) in POCl3 (1.25 L) was cooled to 0° C. and treated with PCl5 (94.5 g, 454 mol). The resulting mixture was treated with HCl (g) until the reaction was saturated and stirred at 65° C. for 1 h. After this time, the mixture was treated with additional PCl5 (34.4 g, 165 mmol) and stirred for an additional 15 h. The mixture was concentrated in vacuo, treated with water and the resulting solid was collected by filtration and dried to give the title compound (80 g, 81% yield).

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[0042] Intermediate 4 [ka] 3-Chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline A solution of intermediate 3 (80 g, 6 mol) in EtOAc (666 mL) was treated with red phosphorus (27.4 g, 806.4 mmol) and HI (155 mL, 57% wt in water, 1.18 mol) and stirred at 120° C. for 4 h. The resulting mixture was filtered while hot and concentrated in vacuo. The residue was dissolved in water and basified by addition of ammonia solution and the resulting solid was collected by filtration. The solid was dissolved in DCM, washed with brine, dried over Na2SO4, concentrated and purified by column chromatography on SiO2 to give the title compound as a white solid (38.5 g, 56% yield).

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[0043] Intermediate 5 [ka] 3-Chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonyl chloride Intermediate 4 (10 g, 49 mmol) was charged to a sealed 250 mL round bottom pressure flask and chlorosulfonic acid (35 mL, 520 mmol) was added (evolution of hydrogen chloride gas was observed upon addition). The resulting dark red / brown solution was purged under a stream of nitrogen for 5 min. The flask was sealed and heated at 80° C. for 3 h. The reaction mixture was diluted with dichloromethane (100 mL) and then carefully added to stirred ice water (500 mL) over 45 min. The two phases were separated and the aqueous layer was further extracted into dichloromethane (200 mL×2) and the combined organic extracts were washed with brine (200 mL), dried over sodium sulfate and evaporated to give the title compound (14.6 g, 98% yield).

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[0044] Intermediate 6 [ka] 3-Chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a stirred solution of intermediate 5 (14.6 g, 48 mmol) in anhydrous DCM (125 mL) under nitrogen was added isobutylamine (12 mL, 120 mmol) dropwise (gas evolution was observed). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was washed with water (125 mL). The aqueous layer was separated and further extracted into dichloromethane (125 mL x 2) and the combined organic extracts were washed with brine (150 mL), dried over sodium sulfate and evaporated to dryness. The crude product was purified by chromatography (gradient 0% to 100% ethyl acetate in isohexane) to give the title compound (10.7 g, 65% yield).

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[0045] Intermediates 7 and 8 [ka] 7-Bromo-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (7) 9-Bromo-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (8) To a stirred solution of intermediate 6 (4.77 g, 14.1 mmol) in EtOAc (250 mL) was added 2,2'-azobis(2-methylpropionitrile) (240 mg, 1.4 mmol) and N-bromosuccinimide (3.3 g, 18 mmol). The reaction mixture was stirred in the dark at 90° C. for 2.5 h. The reaction mixture was evaporated to give a crude 1:1 mixture of the title compounds (9.24 g), which was used in the next step without further purification.

[0046] Intermediates 9 and 10 [ka] 7-Amino-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (9) 9-Amino-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (10) Two batches of a crude 1:1 mixture of intermediates 7 and 8 (2.31 g, 6 mmol) were dissolved in 0.4 M ammonia in THF (400 mL, 200 mmol) in a round bottom pressure flask. The sealed reaction mixture was heated at 70° C. for 16 h. The two reaction mixtures were cooled and evaporated. The resulting residue was recharged to the above reaction conditions with half the amount of ammonia in THF for 21 h. The reaction mixtures were cooled, combined and evaporated to give the title compounds (4.7 g) in approximately 1:1 ratio, which were used in the next step without further purification.

[0047] Intermediates 11 and 12 [ka] tert-Butyl N-[3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate (11) tert-Butyl N-[3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate (12) To a stirred approximately 1:1 mixture of intermediates 9 and 10 (2.88 g, 8.14 mmol) in dichloromethane (60 mL) was added di-tert-butyl dicarbonate (1.86 g, 8.52 mmol) followed by triethylamine (2.26 mL, 16.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the crude product was purified by column chromatography (gradient of 0% to 100% ethyl acetate in isohexane) to give the title compound. Intermediate 11 (877 mg, 39% yield).

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[0048] Intermediate 13 [ka] tert-Butyl N-[3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate A mixture of intermediate 11 (910 mg, 2.0 mmol), cyclopropylboronic acid (540 mg, 6.0 mmol) and cesium carbonate (1.6 g, 4.9 mmol) in 1,4-dioxane (20 mL) was placed in a round-bottom pressure flask under a nitrogen atmosphere. 2-P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (210 mg, 0.20 mmol) was added and the sealed reaction mixture was heated at 100° C. for 17 h. The cooled reaction mixture was evaporated. The resulting residue was partitioned between dichloromethane (50 mL) and water (25 mL). The aqueous layer was separated and further extracted into dichloromethane (50 mL×2) and the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and evaporated to dryness. The crude product was purified by chromatography (gradient 0% to 100% ethyl acetate in isohexane) to give the title compound (694 mg, 75% yield).

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[0049] Intermediate 14 [ka] tert-Butyl N-[7-cyclopropyl-5-(isobutylsulfamoyl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-yl]carbamate A mixture of intermediate 12 (500 mg, 1.10 mmol), cyclopropylboronic acid (299 mg, 3.304 mmol) and cesium carbonate (906 mg, 2.753 mmol) in anhydrous 1,4-dioxane (5 mL) was degassed and backfilled with nitrogen. 2 -P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (117.6 mg, 0.11 mmol) was added and the reaction mixture was heated in a microwave at 120 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure and then partitioned between DCM and water. The organic phase was washed with brine, passed through a phase separator cartridge and evaporated. The crude product was purified by column chromatography (eluting with 20-70% EtOAc in isohexane) to give the title compound (332 mg, 66% yield).

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[0050] Intermediate 15 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a stirred solution of intermediate 5 (11.5 g, 38.1 mmol) in DCM (200 mL) was added 2-fluoro-2-methyl-propan-1-amine hydrochloride (5.83 g, 45.7 mmol) followed by triethylamine (13.2 mL, 95.1 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction was washed with water (200 mL). The organic layer was partitioned and washed with more water (200 mL). The organic layer was dried and concentrated in vacuo to give 11.8 g of a green / black solid. This was triturated with hot IPA and filtered to give the title compound (10.4 g, 77% yield) as a grey powder.

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[0051] Intermediates 16 and 17 [ka] 9-Bromo-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (16) 7-Bromo-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (17) To a stirred solution of intermediate 15 (3.0 g, 8.4 mmol) in ethyl acetate (180 mL) under nitrogen was added 2,2'-azobis(2-methylpropionitrile) (140 mg, 0.84 mmol) and N-bromosuccinimide (2.0 g, 11 mmol). The mixture was stirred in the dark at 90° C. for 1.5 h. The reaction mixture was evaporated in vacuum to give the crude product as a 1:1 mixture of title compound 16 (1.65 g, 44% yield) and title compound 17 (1.65 g, 44% yield).

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[0052] Intermediate 18 [ka] tert-Butyl N-[(3R)-1-[3-chloro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-piperidyl]carbamate To a solution of intermediate 17 (200 mg, 0.46 mmol) in DMF (2 mL) was added potassium carbonate (128 mg, 0.92 mmol) followed by (R)-3-boc-aminopiperidine (190 mg, 0.95 mmol). The mixture was stirred for 18 h. Water (10 mL) and EtOAc (20 mL) were added to the mixture. The organic layer was separated and further washed with water (2×5 mL). The organic layer was passed through a phase separator and the solvent removed to give a brown oil. The oil was purified by flash column chromatography eluting with a gradient of 0-100% EtOAc in heptane to give the title compound as a brown gum (240 mg, 94% yield).

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[0053] Intermediate 19 [ka] tert-Butyl N-[(3R)-1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-piperidyl]carbamate To a solution of intermediate 18 (240 mg, 0.43 mmol) in a mixture of toluene (2 mL) and 1,4-dioxane (3 mL) was added cyclopropylboronic acid (117 mg, 1.30 mmol) followed by palladium(II) acetate (4.8 mg, 0.022 mmol). Nitrogen gas was bubbled through the mixture for 2 minutes, then tricyclohexylphosphonium tetrafluoroborate (25 mg, 0.065 mmol) and potassium phosphate tribasic (230 mg, 1.08 mmol) were added. Nitrogen was bubbled through for 5 minutes, then the microwave vial was capped and heated in a microwave at 130° C. for 18 hours. Saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL) were added to the mixture. The organic layer was separated, passed through a phase separator and the solvent was removed to give a green oil. The oil was purified by flash column chromatography eluting with a gradient of 0-100% EtOAc in heptane followed by a gradient of 0-10% MeOH in EtOAc to afford the title compound as a brown gum (231 mg, 95% yield).

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[0054] Intermediate 20 [ka] To a solution of intermediate 17 (100 mg, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (96.1 mg, 0.69 mmol) followed by (2R)-N-methylpyrrolidine-2-carboxamide (59 mg, 0.46 mmol). The mixture was allowed to stand for 18 h. Water (10 mL) and EtOAc (20 mL) were added to the mixture. The organic layer was separated and further washed with water (2×10 mL). The organic layer was passed through a phase separator and the solvent removed to give a brown oil. The oil was purified by flash column chromatography eluting with a gradient of 0-100% EtOAc in heptane followed by a gradient of 0-10% MeOH in EtOAc to give the title compound as a mixture of two diastereoisomers (96 mg, 87% yield).

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[0055] Intermediate 21 [ka] tert-Butyl N-[1-[3-chloro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]azetidin-3-yl]carbamate To a solution of intermediate 17 (160 mg, 0.37 mmol) in DMF (2 mL) was added 3-N-Boc-aminoazetidine (130 mg, 0.73 mmol) followed by potassium carbonate (154 mg, 1.10 mmol). The mixture was stirred for 18 h. Ethyl acetate (15 mL) was added to the mixture. The suspension was washed with water (2×15 mL) and brine (15 mL). The combined organic layers were then passed through a phase separator and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient of 0-100% EtOAc in heptane followed by a gradient of 0-20% MeOH in EtOAc to afford the title compound as a light brown glass (119 mg, 61% yield).

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[0056] Intermediate 22 [ka] tert-Butyl N-[1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]azetidin-3-yl]carbamate A mixture of intermediate 21 (119 mg, 0.23 mmol), cyclopropylboronic acid (61 mg, 0.67 mmol), palladium(II) acetate (2.5 mg, 0.011 mmol), tricyclohexylphosphonium tetrafluoroborate (13 mg, 0.034 mmol), potassium phosphate tribasic (120 mg, 0.57 mmol) and water (20 μL) was suspended in toluene (2 mL). The mixture was purged with nitrogen and then heated to 120° C. for 14 h. The reaction mixture was diluted with water (5 mL) and DCM (10 mL). The biphasic layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were passed through a phase separator and concentrated under reduced pressure to give an oil. The oil was purified by flash column chromatography eluting with a gradient of 0-100% EtOAc in isohexane followed by a gradient of 0-20% MeOH in EtOAc to afford the title compound as a light brown glass (55 mg, 46% yield).

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[0057] Intermediate 23 [ka] 7-(3-aminoazetidin-1-yl)-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 22 (47 mg, 0.088 mmol) in DCM (2 mL) was added TFA (2 mL). The solution was stirred for 1 h. The solvent was removed and excess TFA was azeotroped using a 1:1 mixture of DCM and isohexane. The resulting brown gum was purified by SCX column chromatography eluting with a gradient of 0-100% 7M ammonia in MeOH to afford the title compound as a light brown solid (36 mg, 94% yield).

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[0058] Intermediate 24 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-7-(1H-indol-2-ylmethylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 17 (100 mg, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (64 mg, 0.46 mmol) followed by (1H-indol-2-ylmethyl)amine (69 mg, 0.46 mmol). The mixture was left stirring for 18 h. Water (5 mL) and EtOAc (10 mL) were added to the mixture. The organic layer was separated and further washed with water (2×5 mL). The organic layer was passed through a phase separator and the solvent removed to give a green oil. The oil was purified by flash column chromatography eluting with a gradient of 0-100% EtOAc in isohexane to give the title compound as a brown foam (95 mg, 82% yield).

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[0059] Intermediates 25 and 26 [ka] 3-Chloro-7-hydroxy-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (25) 3-Chloro-9-hydroxy-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (26) To a mixture of intermediates 7 and 8 (1480 mg, 3.54 mmol) in THF (6 mL) / water (3 mL) was added silver carbonate (1973 mg, 7.09 mmol). The reaction was stirred vigorously for 18 h. The mixture was filtered through Celite to remove silver salts and washed with EtOAc (20 mL) and water (5 mL). The organic layer was separated and passed through a phase separator. The solvent was removed to give a brown gum. The gum was purified by flash column chromatography eluting with a gradient of 0-50% EtOAc in isohexane to give intermediate 26 (280 mg, 22% yield), intermediate 25 (200 mg, 16% yield) and a 1:1 mixture of intermediates 25 and 26 (113 mg, 9% yield). Intermediate 25.

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[0060] Intermediate 27 [ka] 3-Chloro-9-fluoro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 26 (48 mg, 0.14 mmol) in DCM (2 mL) at 0° C. was added DAST (44 mg, 0.27 mmol). The mixture was stirred at 0° C. for 10 min and then at room temperature for 1 h. Saturated aqueous NaHCO3 (5 mL) was added and the organic layer was separated and passed through a phase separator. The solvent was removed to give a gum. The gum was purified by flash column chromatography eluting with a gradient of 0-50% EtOAc in isohexane to give the title compound as a white solid (43 mg, 89% yield).

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[0061] Intermediate 28 [ka] 7-[tert-Butyl(dimethyl)silyl]oxy-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 25 (200 mg, 0.56 mmol) in DMF (3 mL) was added imidazole (78 mg, 1.13 mmol), 4-dimethylaminopyridine (3.4 mg, 0.028 mmol) and TBDMSCl (127 mg, 0.85 mmol). The mixture was stirred for 6 h, 4-dimethylaminopyridine (0.1 eq) was added and the reaction was heated at 40° C. for 18 h. Another portion of TBDMSCl (127 mg, 0.85 mmol) and imidazole (3.4 mg, 0.028 mmol) was added and the mixture was heated for 5 h. Water (10 mL) and EtOAc (20 mL) were added to the mixture. The organic layer was separated, washed with water (10 mL) and passed through a phase separator. The solvent was removed to give a brown gum. The gum was purified by flash column chromatography eluting with a gradient of 0 to 20% EtOAc in isohexane to give the title product as a white solid (190 mg, 72% yield).

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[0062] Intermediate 29 [ka] 7-[tert-Butyl(dimethyl)silyl]oxy-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 28 (135 mg, 0.29 mmol) was suspended in 1,4-dioxane (3 mL) in a microwave vial and cesium carbonate (237 mg, 0.72 mmol) was added followed by cyclopropylboronic acid (78 mg, 0.86 mmol). The flask was evacuated and placed under a nitrogen atmosphere for 5 min. Chloro(η 2 -P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (31 mg, 0.029 mmol) was added and the flask was again evacuated and placed under a nitrogen atmosphere. The reaction was then heated at 120° C. for 2.5 h. The solvent was removed and the residue partitioned between water (10 mL) and EtOAc (15 mL). The organic layer was separated and passed through a phase separator. The solvent was removed to give a brown oil. The oil was purified by flash column chromatography eluting with a gradient of 0-20% EtOAc in isohexane to give the title product as an off-white solid (74 mg, 54% yield).

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[0063] Intermediate 30 [ka] 3-Cyano-2-phenyl-1-(p-tolyl)isourea Diphenyl N-cyanocarbonimidate (500 mg, 2.10 mmol) and p-toluidine (240 mg, 2.24 mmol) were dissolved in dichloromethane (70 mL). N,N-diisopropylethylamine (397 mg, 3.15 mmol) and 2-propanol (2 mL) were added. The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was triturated with EtOAc, filtered, and washed three times with EtOAc to give the title compound as a white solid (210 mg, 40% yield).

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[0064] Intermediates 31 and 32 [ka] 9-Amino-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (31) 7-Amino-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (32) A crude mixture containing intermediate 16 (1.65 g, 3.79 mmol) and intermediate 17 (1.65 g, 3.79 mmol) was dissolved in tetrahydrofuran (200 mL) and the mixture was charged to a sealed 500 mL round-bottom pressure flask. Ammonia gas was bubbled through the reaction mixture for 5 minutes. The sealed mixture was heated at 70° C. for 2 days. The cooled reaction mixture was evaporated in vacuo to give a crude product containing a 1:1 mixture of title compound 31 (1.71 g / quantitative yield, 3.79 mmol) and title compound 32 (1.71 g / quantitative yield, 3.79 mmol).

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[0065] Intermediates 33 and 34 [ka] tert-Butyl N-[3-chloro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate (33) tert-Butyl N-[3-chloro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate (34) To a stirred crude mixture of intermediate 31 (3.79 mmol) and intermediate 32 (3.79 mmol) in dichloromethane (100 mL) was added di-tert-butyl dicarbonate (2.1 g, 9.5 mmol) followed by triethylamine (2.5 mL, 18 mmol). The mixture was stirred under nitrogen at room temperature for 3 h. The reaction mixture was evaporated under vacuum and purified via column chromatography using a gradient of 0-40% ethyl acetate in isohexane. Intermediate 33 was isolated as a yellow foam (1.2 g, 85% purity, 2.16 mmol, 57% yield).

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[0066] Intermediate 35 [ka] tert-Butyl N-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate A mixture of intermediate 34 (870 mg, 1.8 mmol), cyclopropylboronic acid (500 mg, 5.5 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in anhydrous 1,4-dioxane (20 mL) was placed in a 50 mL pressure flask and purged under a stream of nitrogen for 5 minutes. 2 -P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (200 mg, 0.19 mmol) was added and the sealed mixture was heated at 100 °C for 16 h. The cooled reaction mixture was evaporated under vacuum and the resulting residue was partitioned between dichloromethane (100 mL) and water (50 mL). The aqueous layer was separated and further extracted into dichloromethane (2 x 100 mL) and the combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and evaporated under vacuum. The residue was purified via column chromatography using a gradient of 0-80% ethyl acetate in isohexane to give the title compound (571 mg, 65% yield).

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[0067] Intermediate 36 [ka] 7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A solution of intermediate 35 (570 mg, 1.2 mmol) in 4 M hydrochloric acid in dioxane (15 mL) was stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo and the residue was purified via SCX column eluted with 100% methanol followed by 7N ammonia solution in methanol to give the title compound (438 mg, 97% yield).

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[0068] Intermediates 37 and 38 [ka] (7R)-7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (7S)-7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 36 was separated by chiral HPLC to give the title compound using the following conditions: LUX Cellulose-4, 250×21.2 mm, 5 μM column, flow rate 10 mL / min. Column temperature: 40° C., mobile phase: MeOH+0.1% NH4OH. Run time: 20 min. Note: In intermediates 37 and 38, one is the R-enantiomer and the other is the S-enantiomer, and we have not assigned which enantiomer is which intermediate. Intermediate 37: Chiral RT**=2.50 min.

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[0069] Intermediate 39 [ka] 9-Amino-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide hydrochloride 9-Amino-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 14 (1.81 g, 3.47 mmol) was dissolved in 4 M hydrochloric acid in dioxane (20 mL) and stirred at ambient temperature for 30 min. The reaction was concentrated in vacuo to give the title compound as the hydrochloride salt. This was then dissolved in MeOH (10 mL) and absorbed onto an SCX cartridge, first washed with MeOH (50 mL) and then eluted with 7N NH3 in MeOH (75 mL). The methanolic ammonia was removed in vacuo to give the title compound as the free base (1.18 g, 95% yield).

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[0070] Intermediate 40~42 Intermediates 40-42 were synthesized according to the following procedure. To a solution of intermediate 39 (50 mg, 0.14 mmol) in DCM (1 mL) and THF (1 mL) was added isothiocyanate (1.2 eq.). The reaction was stirred overnight at ambient temperature, concentrated in vacuo, and then purified using column chromatography to give the title compounds. Method 5 was used to obtain the LCMS data shown in the table below. [Table 4]

[0071] Intermediate 43 [ka] 3-(6-iodoindan-5-yl)propanoic acid To a mixture of 3-indan-5-ylpropanoic acid (5.14 kg, 27 mol) and TFA (6.9 L) in DCM (26 L) at 0-10° C. was added N-iodosuccinimide (1.0 equiv.). The solution was stirred at 10-15° C. for 20 h and then poured onto ice. The aqueous mixture was extracted with DCM and washed with a 10% aqueous solution of Na2S2O3. The dichloromethane solution was applied directly to the next step. Assuming quantitative yield (8.5 kg, mw=315.1).

[0072] Intermediate 44 [ka] 4-Iodo-3,6,7,8-tetrahydro-2H-as-indacen-1-one A solution of intermediate 43 (8.5 kg, 27 mol) in DCM (127 L) at 0° C. was treated with DMF followed by oxalyl chloride (6.8 kg, 54 mol) and the reaction mixture was stirred at 10-15° C. for 3 h. The mixture was concentrated in vacuo, dissolved in DCM (127 L), cooled to 0° C. and treated with AlCl3 (10.8 kg, 81 mol). The mixture was stirred at 0° C. for 2 h, then quenched by the addition of ice water (85 L) and extracted with DCM (85 L). The organic extract was concentrated in vacuo and purified by column chromatography to give the title compound (approximately 750 g, approximately 12% yield).

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[0073] Intermediate 45 [ka] 2-Hydroxyimino-4-iodo-3,6,7,8-tetrahydro-as-indacen-1-one Intermediate 44 (100 g, 335 mmol) was suspended in a mixture of Et2O (800 mL) and EtOH (100 mL). HCl (4 mol / L) in 1,4-dioxane (16 mL) was added at room temperature followed by butyl nitrite (58 mL, 471 mmol) at 0 °C. The ice bath was removed and the reaction mixture was allowed to warm with stirring overnight. The white solid precipitate was collected by filtration, rinsed with MeOH and EtOAc, and dried under vacuum to give the title compound (109 g, 99% yield).

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[0074] Intermediate 46 [ka] 3-Chloro-5-iodo-8,9-dihydro-7H-cyclopenta[h]isoquinoline The title compound was obtained using the following two steps. Step 1: To a suspension of intermediate 45 (50 g, 152 mmol) in phosphoryl chloride (280 mL, 3010 mmol) at room temperature, phosphorus pentachloride (36 g, 172 mmol) was added. After a few minutes, most of the precipitate in the reaction mixture dissolved, giving a dark orange suspension (a small amount of gas evolution was observed). While the reaction mixture was maintained at room temperature, HCl (generated in situ by stepwise addition of sulfuric acid to NaCl) was bubbled through the reaction mixture for 30 minutes. The mixture was then heated to 80°C. A slow but steady evolution of gas was observed. After 15 minutes, gas evolution ceased. Note: After the first hour of heating, additional phosphorus pentachloride (6 g, 28.8 mmol) was added. After a total of about 4 hours of heating, the mixture was concentrated under reduced pressure. The residue (green solid) was cooled in an ice / water bath and treated with water (about 80 mL). The grey precipitate was collected by filtration. Step 2: To a solution of the grey precipitate from step 1 above (50 g, 137 mmol) in AcOH was added HCl (70 mL, 514 mmol, 57% by weight) followed by red phosphorus (9.5 g, 310 mmol). The mixture was heated to 110° C. for approximately 15 h. The volatiles were evaporated and the crude product was suspended in water. Concentrated ammonium hydroxide solution was added to adjust the pH to 8-9. DCM and water were added to the slurry and the layers were separated. The organics were dried over sodium sulfate and evaporated to give the title compound (33 g, 62% yield).

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[0075] Intermediates 47 and 48 [ka] 3-Chloro-5-iodo-7,8-dihydrocyclopenta[h]isoquinolin-9-one (47) 3-Chloro-5-iodo-8,9-dihydrocyclopenta[h]isoquinolin-7-one (48) Intermediate 46 (47 mmol, 15.5 g) was suspended in DCM (500 mL). Chromium(VI) oxide (5 mmol, 500 mg) and 70% aqueous t-butyl hydroperoxide (930 mmol, 120 mL) were added at room temperature and the reaction was stirred vigorously overnight. The reaction mixture was then quenched with a saturated aqueous solution of Na2S2O5 at 0 °C. The two layers were then separated and the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The resulting residue was dry loaded onto silica and purified by column chromatography eluting with a gradient of 0-20% EtOAc in toluene to give the title compound. Intermediate 47 (5.9 g, 37% yield).

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[0076] Intermediate 49 [ka] 3-Chloro-5-iodo-7-(3-pyridyl)-8,9-dihydrocyclopenta[h]isoquinolin-7-ol To a stirred solution of 3-bromopyridine (0.1 g, 0.63 mmol) in anhydrous THF (2 mL) at −78° C. under a N2 atmosphere was added 2.5 M n-butyllithium in hexanes (0.30 mL, 0.75 mmol). The reaction mixture was stirred at −78° C. for 20 min, then a solution of intermediate 48 (217 mg, 0.63 mmol) in anhydrous THF (3 mL) was added dropwise over 10 min. Once the addition was complete, the cooling bath was removed and the reaction was allowed to warm to ambient temperature overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl (3 mL) and diluted with a mixture of water (5 mL) and EtOAc (5 mL). The organic layer was partitioned, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound (53 mg, 20% yield).

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[0077] Intermediate 50 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-7-hydroxy-7-(3-pyridyl)-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide Intermediate 49 (53 mg, 0.12 mmol), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (19 mg, 0.08 mmol), palladium(II) acetate (1.5 mg, 0.006 mmol) and butyldi-1-adamantylphosphine (3.4 mg, 0.009 mmol) were charged to a sealed tube. Triethylamine (52 μL, 0.38 mmol) and anhydrous IPA (2 mL) were added and the reaction was sealed and heated to 75° C. overnight. The reaction was treated with 2-fluoro-2-methylpropan-1-amine HCl (51 mg, 0.38 mmol) and aqueous sodium hypochlorite (0.16 mL, 0.25 mmol) and stirred at ambient temperature for 3 h. The reaction was diluted with EtOAc (5 mL) and washed with water (5 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound (11 mg, 10% yield).

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[0078] Intermediate 51 [ka] 3-Chloro-5-iodo-7-trimethylsilyloxy-8,9-dihydrocyclopenta[h]isoquinoline-7-carbonitrile To a solution of intermediate 48 (1.2 g, 3.5 mmol) in toluene (20 mL) and acetonitrile (10 mL) was added zinc iodide (110 mg, 0.35 mmol) and trimethylsilyl cyanide (1.3 mL, 10 mmol). The reaction was heated to 75° C. overnight with stirring, then treated with trimethylsilyl cyanide (2.0 mL) and heated at 75° C. for 4.5 h. The reaction was cooled, quenched with saturated aqueous NaHCO3 (25 mL) and extracted with EtOAc (100 mL). The organic phase was partitioned, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography afforded the title compound (694 mg, 45% yield).

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[0079] Intermediate 52 [ka] 3-Chloro-5-iodo-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylic acid Stannous chloride (1.69 g, 8.70 mmol) was added to intermediate 51 (967 mg, 2.18 mmol) followed by glacial acetic acid (4.0 mL) and then concentrated hydrochloric acid (4.0 mL). The reaction vessel was sealed and placed in a preheated block (140 °C) with vigorous stirring for 2.5 h. The reaction was cooled, diluted with water (10 mL) and extracted with 10% MeOH in DCM (3 x 20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound (0.58 g, 50% yield).

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[0080] Intermediate 53 [ka] Methyl 3-chloro-5-iodo-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylate To an ice-cold suspension of Intermediate 52 (0.58 g, 0.93 mmol) in methanol (10 mL) was added thionyl chloride (0.14 mL, 1.9 mmol) dropwise. Once the addition was complete, the ice bath was removed and the reaction was allowed to warm to ambient temperature for 2 h. The reaction was concentrated in vacuo and the crude product was purified by column chromatography to give the title compound (125 mg, 35% yield).

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[0081] Intermediate 54 [ka] Methyl 5-benzylsulfanyl-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylate A mixture of intermediate 53 (125 mg, 0.32 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.039 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.019 mmol) and N,N-diisopropylethylamine (135 μL, 0.77 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen for 5 min before adding benzyl mercaptan (61 mg, 0.48 mmol). The mixture was heated to 85 °C with stirring for 1.5 h. The mixture was cooled, diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 (5 mL). The organic layer was passed through a phase separator and the volatiles were removed in vacuo. The crude product was purified by column chromatography to give the title compound (102 mg, 76% yield).

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[0082] Intermediate 55 [ka] Methyl 3-chloro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylate To an ice-cold solution of intermediate 54 (350 mg, 0.87 mmol) in a mixture of acetonitrile (6 mL), water (0.100 mL) and acetic acid (0.06 mL), 1,3-dichloro-5,5-dimethylhydantoin (380 mg, 1.93 mmol) was added and the reaction was stirred for 10 minutes. 2-Fluoro-2-methyl-propan-1-amine hydrochloride (232 mg, 1.82 mmol) was added, followed by N,N-diisopropylethylamine (0.60 mL, 3.5 mmol). The mixture was stirred at ambient temperature for 15 minutes and then concentrated in vacuo. The crude residue was purified by column chromatography to give the title compound (160 mg, 42% yield).

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[0083] Intermediate 56 [ka] Methyl 3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylate To a solution of intermediate 55 (65 mg, 0.16 mmol) in 1,4-dioxane (1 mL) was added cyclopropylboronic acid (42 mg, 0.47 mmol), chloro(η 2 -P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (17 mg, 0.016 mmol) and cesium carbonate (128 mg, 0.39 mmol) were added. The mixture was degassed under a stream of N2 for 5 min, sealed and heated to 120 °C for 2 h. The reaction was diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 (2.5 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography to give the title compound (3 mg, 4.5% yield).

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[0084] Intermediate 57 [ka] 1-(Cyclopropylmethyl)-1-[(2,4-dimethoxyphenyl)methyl]-3-[(7S*)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]thiourea[*orR] To a stirred solution of intermediate 38 (75 mg, 0.20 mmol) in dichloromethane (1 mL) was added 1,1'-thiocarbonyldiimidazole (43 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1.5 h. N-(cyclopropylmethyl)-1-(2,4-dimethoxyphenyl)methanamine (66 mg, 0.30 mmol) was then added and the reaction was stirred for an additional 1 h. The reaction mixture was diluted with DCM (1 mL) and saturated aqueous NH4Cl (1 mL) and 0.5 M aqueous HCl (1 mL) were added to give the title compound (168 mg, 60% pure, 79%).

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[0085] Intermediate 58 [ka] 3-Chloro-N-isobutyl-7-(methanesulfonamido)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a stirred solution of intermediate 9 (330 mg, 0.61 mmol, 65%) in anhydrous DCM (10 mL) was added DIPEA (0.32 mL, 1.87 mmol) and methanesulfonyl chloride (87.2 μl, 1.12 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was then washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography using a gradient of 2-20% MeOH in DCM to afford the title compound (0.26 g, 62% yield) as a beige foam.

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[0086] Intermediates 59 and 60 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-7-oxo-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide (59) 3-Chloro-N-(2-fluoro-2-methyl-propyl)-9-oxo-7,8-dihydrocyclopenta[h]isoquinoline-5-sulfonamide (60) To a solution of potassium tetrachloroaurate(III) (2.6 mg, 7.0 μmol) in pyridine (0.2 mL, 2 mmol) was added Intermediate 15 (50 mg, 0.14 mmol) followed by tert-butyl hydroperoxide (0.05 mL, 0.28 mmol). The reaction was sealed and heated to 90° C. with stirring for 1 h. The reaction was cooled and purified by column chromatography to give the title compound. Intermediate 59 (15 mg, 29% yield):

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[0087] Intermediate 61 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-7-(2-fluoro-3-pyridyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 59 (270 mg, 0.73 mmol) and 4-methylbenzenesulfonhydrazide (140 mg, 0.73 mmol) were suspended in anhydrous 1,4-dioxane (7.0 mL) and the mixture was heated to 80° C. for 45 min. Potassium carbonate (251 mg, 1.82 mmol) and 2-fluoropyridine-3-boronic acid hydrate (177 mg, 1.09 mmol) were added and heating was continued at 110° C. for 4 h. The reaction was cooled, diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (25 mL). The aqueous phase was extracted with EtOAc (25 mL) and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography afforded the title compound (122 mg, 32% yield).

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[0088] Intermediate 62 [ka] tert-Butyl N-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate A mixture of intermediate 33 (1140 mg, 2.41 mmol), cyclopropylboronic acid (652 mg, 7.214 mmol) and palladium(II) acetate (27 mg, 0.120 mmol) in toluene (10 mL) was degassed and placed under nitrogen. A solution of tricyclohexylphosphonium tetrafluoroborate (137 mg, 0.361 mmol) and potassium phosphate tribasic (1280 mg, 6.01 mmol) in water (1 mL) was added and the mixture was degassed and placed under nitrogen. The reaction mixture was heated in a microwave at 120° C. for 2 h. The reaction mixture was cooled, then diluted with EtOAc, washed with water, then brine, passed through a phase separator and evaporated. The crude material was purified by flash chromatography eluting with a gradient of 10-60% EtOAc in hexane to give the title compound as an off-white solid (938 mg, 82% yield).

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[0089] Intermediates 63 and 64 [ka] tert-Butyl N-[(9R)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate tert-Butyl N-[(9S)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate The title compound was obtained by separation of intermediate 62 using chiral SFC under the following conditions: Column-Chir AS 265×50 mm, 5 μM. Flow rate-360 mL / min. Column temperature-30° C. Mobile phase 10% EtOH in CO2. Run time-10 min. Note: In intermediates 63 and 64, one is the R-enantiomer and the other is the S-enantiomer, and we have not assigned which enantiomer is which intermediate. Intermediate 63: Chiral RT**=2.55 min.

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[0090] Intermediate 65 [ka] (9R*)-9-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] Intermediate 63 (200 mg, 0.42 mmol) was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (1.0 mL) was added. The reaction was stirred at ambient temperature overnight, concentrated in vacuo, then dissolved in MeOH (1.5 mL) and absorbed onto an SCX cartridge. The cartridge was washed with MeOH (10 mL) and the product was eluted with 7N MeOH in ammonia (10 mL). The methanolic ammonia was removed in vacuo to give the title compound (155 mg, 93% yield).

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[0091] Intermediate 66 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-9-[(1-methylbenzimidazol-2-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 16 (50 mg, 0.12 mmol) and 2-amino-1-methylbenzimidazole (36 mg, 0.24 mmol) were suspended in anhydrous toluene (1 mL) and the mixture was heated to 70° C. overnight. The reaction was cooled, diluted with EtOAc (2 mL) and washed with saturated aqueous NaHCO3 (1 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound (13 mg, 23% yield).

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[0092] Intermediates 67 and 68 [ka] (9S)-9-Amino-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (9R)-9-Amino-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide The title compound was obtained by separation of intermediate 39 using chiral SFC under the following conditions: Column-Chiralcel OJ-H 250×20 mm, 5 μM. Flow rate-100 mL / min. Column temperature-40° C. Mobile phase-Gradient of 10-25% MeOH+0.1% NH4OH in CO2. Run time-6 min. Note: In intermediates 67 and 68, one is the R-enantiomer and the other is the S-enantiomer, and we have not assigned which enantiomer is which intermediate. Intermediate 67: Chiral SFC RT**=2.28 min Intermediate 68: Chiral SFC RT**=3.23 min **Chiral analysis performed using Waters UPC 2 -Performed by SFC using a Chiralcel OJ-3 4.6 x 150 mm, 3 μm column, eluting with 10-25% methanol (0.1% ammonium hydroxide), flow rate 3.5 mL / min, using a 6 min run time on the SQD system.

[0093] Intermediate 69 [ka] 1-(4-aminoindan-5-yl)-2-chloro-ethanone To an ice-cold solution of boron trichloride-methylsulfide complex (25.4 g, 140 mmol) in 1,2-dichloroethane (400 mL) was added indan-4-amine (17 g, 128 mmol) dropwise over 5 min. The solution was stirred at 0° C. for 10 min. Chloroacetonitrile (10 mL, 160 mmol) and aluminum chloride (18.7 g, 140 mmol) were added and the reaction was warmed to ambient temperature over 10 min and then refluxed for 2 h. The reaction was cooled to ambient temperature and 2 M HCl (300 mL) was added in portions. The quench was heated to 80° C. for 20 min, cooled and diluted with DCM (250 mL). The organic phase was partitioned and the aqueous phase was extracted with DCM (2×250 mL). The combined organic extracts were dried over Na2SO4 and the solvent removed in vacuo. The solid was triturated with EtOAc and dried to give the title compound (7.13 g, 27% yield).

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[0094] Intermediate 70 [ka] 4-Chloro-8,9-dihydro-7H-cyclopenta[h]cinnolin-3-ol Intermediate 69 (7100 mg, 34 mmol) was dissolved in acetic acid (35 mL) and aqueous hydrochloric acid (1.2 M, 35 mL) and cooled in an ice bath before sodium nitrite (12 g, 170 mmol) was added portionwise. Once the addition was complete, the reaction was stirred at 0° C. for 5 min and then at ambient temperature for 2 h. Sodium nitrite (5.4 g, 78.4 mmol) was added at ambient temperature and stirring was continued for 30 min. The reaction was diluted with water (50 mL) and extracted with 1:1 CHCl3:IPA (3×100 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography followed by trituration with EtOAc to give the title compound (0.96 g, 13% yield).

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[0095] Intermediate 71 [ka] 3,4-Dichloro-8,9-dihydro-7H-cyclopenta[h]cinnoline A slurry of intermediate 70 (3.6 g, 16.3 mmol) in phosphorus oxychloride (127 mmol, 12.0 mL) was stirred at 75° C. for 45 min. The reaction mixture was then cooled, concentrated in vacuo, and the residue was dissolved in DCM (100 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was partitioned and the aqueous layer was extracted with DCM (50 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo to give the title compound (3.29 g, 80% yield).

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[0096] Intermediate 72 [ka] 3-Chloro-8,9-dihydro-7H-cyclopenta[h]cinnoline Intermediate 71 (3.29 g, 13.8 mmol) was dissolved in chloroform (50 mL) and 4-methylbenzenesulfonhydrazide (5280 mg, 27.5 mmol) was added. The reaction was heated at 60° C. overnight, then cooled and concentrated in vacuo. The residue was dissolved in a mixture of water (150 mL) and 1,4-dioxane (15 mL). Sodium carbonate (13.1 g, 124 mmol) was added and the reaction was heated to 95° C. with vigorous stirring for 3 h. The reaction was cooled and extracted with DCM (4×150 mL). The combined organic extracts were dried over Na2SO4 and the solvent removed in vacuo to give a brown solid which was triturated with Et2O (20 mL), filtered and dried to give the title compound (1.63 g, 49% yield).

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[0097] Intermediate 73 [ka] 3-Chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide Intermediate 72 (225 mg, 1.1 mmol) was added to a sealed tube before the addition of chlorosulfonic acid (1.94 g, 16.5 mmol). The reaction was sealed and heated to 120° C. with stirring for 6 min. The reaction was slowly poured into a mixture of ice and DCM (100 mL) and diluted with a mixture of DCM and brine (100 mL). The organic phase was dried over Na2SO4, treated with 2-methylpropan-1-amine (1608 mg, 21.99 mmol) and stirred at room temperature for 15 min. The reaction was concentrated in vacuo and the crude product was purified by column chromatography to give the title compound (77 mg, 21% yield).

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[0098] Intermediate 74 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide To a sealed pressure tube was added intermediate 72 (1.63 g, 7.96 mmol) followed by chlorosulfonic acid (8.03 mL, 119 mmol). The flask was sealed and heated at 120° C. overnight. The reaction mixture was diluted with dichloromethane (200 mL) and then added to stirred ice water (200 mL) over 25 min. The organic layer was dried over Na2SO4, concentrated in vacuo, and then dissolved in DCM (100 mL). 2-Fluoro-2-methylpropan-1-amine HCl (1.28 g, 9.56 mmol) was added followed by triethylamine (2.01 g, 19.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h, washed with water (100 mL), and the organic layer was partitioned. The aqueous phase was extracted with DCM (50 mL) and the combined organic extracts were dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified by column chromatography to give the title compound (480 mg, 17% yield).

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[0099] Intermediates 75 and 76 [ka] 7-Bromo-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide (75) 9-Bromo-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide (76) To a stirred solution of intermediate 74 (455 mg, 1.27 mmol) in EtOAc (10 mL) at ambient temperature was added N-bromosuccinimide (294 mg, 1.65 mmol) followed by 2,2'-azobis(2-methylpropionitrile) (21 mg, 0.13 mmol). The reaction was sealed and heated to 70°C for 1 h, then cooled and concentrated in vacuo to give a mixture of the title compounds intermediates 75 and 76, which were used in the next step without further purification.

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[0100] Intermediates 77 and 78 [ka] 7-Amino-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide (77) 9-Amino-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide (78) The crude mixture of intermediates 75 and 76 (460 mg, 0.53 mmol) was dissolved in ammonia (100 mL, saturated sol in THF). The reaction mixture was sealed and heated at 70° C. The reaction was cooled and concentrated in vacuo to give the title compound, a mixture of intermediates 77 and 78 (390 mg), which was used in the next step.

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[0101] Intermediates 79 and 80 [ka] tert-Butyl N-[3-chloro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]cinnolin-7-yl]carbamate (79) tert-Butyl N-[3-chloro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]cinnolin-9-yl]carbamate (80) To a stirred mixture of intermediates 77 and 78 (390 mg, 0.52 mmol) in DCM (25 mL) was added di-tert-butyl dicarbonate (240 mg, 1.1 mmol) followed by triethylamine (0.29 mL, 2.1 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with DCM (50 mL) and water (50 mL). The aqueous phase was partitioned and extracted with DCM (50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography to give the title compound. Intermediate 79 (58 mg, 23% yield).

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[0102] Intermediate 81 [ka] tert-Butyl N-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]cinnolin-7-yl]carbamate A slurry of intermediate 79 (58 mg, 0.13 mmol), cyclopropylboronic acid (33 mg, 0.37 mmol) and palladium(II) acetate (1.4 mg, 6.1 μmol) in toluene (1 mL) was degassed under a stream of nitrogen for 5 min. Tricyclohexylphosphonium tetrafluoroborate (7 mg, 0.018 mmol) and potassium phosphate tribasic (65 mg, 0.31 mmol) were added and degassing was continued for 5 min. The reaction was sealed and heated at 115° C. under microwave irradiation for 1 h. The reaction was diluted with water (2 mL) and EtOAc (2 mL). The organic phase was partitioned and the aqueous phase was extracted with EtOAc (2 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound (51 mg, 87% yield).

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[0103] Intermediate 82 [ka] 7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide hydrochloride To a stirred solution of intermediate 81 (51 mg, 0.11 mmol) in DCM (0.5 mL) was added hydrochloric acid (4 mol / L) in 1,4-dioxane (0.11 mL) and the reaction was stirred at ambient temperature for 2.5 h. The reaction was concentrated in vacuo to give the title compound as the HCl salt (44 mg, quantitative).

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[0104] Intermediate 83 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[(4-methoxy-3-nitro-2-pyridyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 36 (0.42 mmol) was suspended in CH3CN (4 mL) and treated with DIPEA (0.183 mL, 1.05 mmol) and stirred at room temperature. The mixture was then treated with 2-chloro-4-methoxy-3-nitropyridine (80 mg, 0.42 mmol) and the reaction was stirred at room temperature overnight. The reaction was then treated with DIPEA (0.18 mL, 1.05 mmol) and 2-chloro-4-methoxy-3-nitropyridine (80 mg, 0.42 mmol) and heated to 100°C for 24 hours. The reaction mixture was cooled to room temperature, dry loaded onto silica and purified by column chromatography using a gradient of ethyl acetate in isohexane to give the title compound (34 mg (81% pure by LCMS), 0.052 mmol, 12%).

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[0105] Intermediate 84 [ka] 9-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide 1,4-Dioxane-infused HCl (4 mol / L, 24 mL, 96 mmol) was added to intermediate 62 (2 g, 4.18 mmol). MeOH (8 mL, 198 mmol) was then added and the resulting solution was stirred at ambient temperature. After 1 h, the mixture was concentrated under reduced pressure to give a yellow solid, which was then dissolved in MeOH (20 mL) and passed through an SCX column eluting first with methanol and then with 7N NH3 in methanol. The methanolic ammonia solution was concentrated under reduced pressure and the resulting solid was triturated with diethyl ether to give the title compound as a white solid (1.3 g, 82% yield).

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[0106] Intermediate 85 [ka] 3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylic acid Intermediate 56 (145 mg, 0.33 mmol) was dissolved in THF (3 mL) and water (2 mL) and lithium hydroxide monohydrate (27 mg, 0.64 mmol) was added. The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure and the resulting residue was diluted with water and diethyl ether. The aqueous layer was partitioned, acidified to pH 1 and extracted with EtOAc. The organic layer was dried and evaporated to give the title compound as a white solid (139 mg, quantitative).

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[0107] Intermediate 86 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-7-hydrazino-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 17 (320 mg, 0.73 mmol) and hydrazine (1 mol / L, 15 mL, 15 mmol) in THF were heated with stirring for 20 min at 70° C. The solvent was removed in vacuo and the residue was loaded onto an SCX cartridge eluted with MeOH followed by 4N ammonia in MeOH to give the title compound (298 mg, quantitative).

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[0108] Intermediate 87 [ka] 7-(5-aminopyrazol-1-yl)-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A mixture of intermediate 86 (190 mg, 0.49 mmol) and 3,3-dimethoxypropanenitrile (0.06 mL, 0.5 mmol) was dissolved in EtOH (6 mL) and HCl (0.2 mL, 2 mmol, 37% by weight) was added. The reaction mixture was heated at 80° C. overnight in a sealed tube. The volatiles were evaporated and the resulting residue was diluted with DCM and washed with water. The organics were dried and evaporated to give a solid which was triturated with hexane and purified by reverse phase column chromatography (basic conditions) to give the title compound (134 mg, 62% yield) as a white solid.

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[0109] Intermediate 88 [ka] N-[2-[3-chloro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyrazol-3-yl]cyclopropanecarboxamide Intermediate 87 (135 mg, 0.30 mmol) was dissolved in pyridine (5 mL) and cyclopropanecarbonyl chloride (0.030 mL, 0.32 mmol) was added followed by DMAP (5 mg, 0.040 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with a mixture of DCM and saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of 0-50% EtOAc in hexanes followed by 0-2% MeOH in DCM to give the title compound (105 mg, 67% yield).

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[0110] Intermediate 89 [ka] 7-(Cyanoamino)-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 36 (140 mg, 0.37 mmol) was dissolved in THF (10 mL) and N,N-diisopropylethylamine (0.130 mL, 0.74 mmol) was added followed by cyanogen bromide (51 mg, 0.48 mmol). After stirring at room temperature for 30 min, the reaction mixture was washed with saturated aqueous NaHCO3 [Note: partial decomposition was observed by LCMS]. Due to suspected instability, the reaction mixture was used in the next step without further purification.

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[0111] Intermediate 90 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-7-(3-pyridyloxy)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 17 (95 mg, 0.22 mmol) in anhydrous DMF (5 mL) was added 3-hydroxypyridine (25 mg, 0.26 mmol) and sodium carbonate (28 mg, 0.26 mmol) and the resulting solution was stirred at room temperature. After 2 h, 3-hydroxypyridine (25 mg, 0.26 mmol) was added followed by sodium carbonate (28 mg, 0.26 mmol). After a further 1 h, the reaction mixture was concentrated in vacuo and purified by column chromatography eluting with a gradient of 0-100% EtOAc in isohexane to give the title compound (25 mg, 26% yield).

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[0112] Intermediate 91 [ka] 3-Chloro-N-(2-fluoro-2-methyl-propyl)-9-(3-pyridyloxy)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Synthesized in the same manner as Intermediate 90 using Intermediate 16 (95 mg, 0.22 mmol) and equivalent stoichiometry of reagents. Purification by column chromatography eluting with a gradient of 0-100% EtOAc in isohexane afforded the title compound (37 mg, 38% yield).

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[0113] Intermediate 92 [ka] 3-Chloro-N-(1,1-dideuterio-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 5 (3.45 g, 11.4 mmol) in dichloromethane (25 mL) was added 1,1-dideuterio-2-methyl-propan-1-amine hydrochloride (1.34 g, 12.0 mmol) followed by triethylamine (6.4 mL, 46 mmol). After 30 min the suspension was diluted with water (50 mL) and dichloromethane (20 mL). The aqueous layer was extracted with dichloromethane (2×40 mL). The combined organics were washed with brine (50 mL), passed through a hydrophobic frit and concentrated under reduced pressure. Purification by flash chromatography afforded the title compound as a cream solid (3.15 g, 81% yield).

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[0114] Intermediates 93 and 94 [ka] 7-Bromo-3-chloro-N-(1,1-dideuterio-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (93) 9-Bromo-3-chloro-N-(1,1-dideuterio-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (94) To a solution of intermediate 92 (3.15 g, 9.24 mmol) in ethyl acetate (200 mL) was added 2,2'-azobis(2-methylpropionitrile) (152 mg, 0.92 mmol) and N-bromosuccinimide (recrystallized from water and dried) (1.9 g, 11 mmol). The mixture was heated to 90° C. under the exclusion of light. After 1.5 h, the mixture was concentrated under reduced pressure to give the title compound as a brown solid, which was used crude in the next step.

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[0115] Intermediates 95 and 96 [ka] 7-Amino-3-chloro-N-(1,1-dideuterio-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (95) 9-Amino-3-chloro-N-(1,1-dideuterio-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (96) To the crude mixture of intermediates 93 and 94 was added tetrahydrofuran (200 mL). Gaseous ammonia was passed through the solution for 20 min, after which the mixture was heated to 70° C. in a sealed vessel for 16 h. The mixture was concentrated under reduced pressure to give the mixture of the title compounds as a green / brown solid, which was used crude in the next step.

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[0116] Intermediates 97 and 98 [ka] tert-Butyl N-[3-chloro-5-[(1,1-dideuterio-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate (97) tert-Butyl N-[3-chloro-5-[(1,1-dideuterio-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate (98) To the crude mixture of intermediates 95 and 96 was added dichloromethane (150 mL), triethylamine (3.2 mL, 23 mmol) and di-tert-butyl dicarbonate (3.0 g, 14 mmol). After 72 h the mixture was washed with saturated ammonium chloride solution (80 mL), passed through a hydrophobic frit and purified by flash chromatography to give the title compound as a cream solid. Intermediate 97 (1.24 g, 29% yield).

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[0117] Intermediate 99 [ka] 3-Methoxy-4-(3-pyridylamino)cyclobut-3-ene-1,2-dione To a solution of 3-aminopyridine (500 mg, 5.26 mmol) in DCM (20 mL) was added 3,4-dimethoxy-3-cyclobutene-1,2-dione (822 mg, 5.79 mmol) and N,N-diisopropylethylamine (1020 mg, 7.89 mmol). The mixture was stirred at room temperature overnight. The resulting precipitate was filtered off and the filtrate was evaporated. The residue was triturated with 5% MeOH in DCM and the precipitate was filtered off and washed with DCM to give the title compound as a yellow solid (382 mg, 36% yield).

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[0118] Intermediate 100 [ka] 4-(5-Bromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl)-N-(cyclopropylmethyl)-N-[(2,4-dimethoxyphenyl)methyl]-1,2,4 triazol-3-amine Intermediate 137 (480 mg, 0.83 mmol) was dissolved in dry DMF (8 mL). Formic acid hydrazide (149.5 mg, 2.49 mmol) and mercuric chloride (II) (676 mg, 2.49 mmol) were added and the reaction was stirred for 5 minutes. Triethylamine (0.34 mL, 2.49 mmol) was added and the reaction was heated to 90° C. with stirring for 2 hours, resulting in a black suspension. Once at room temperature, the reaction was diluted with DCM (20 mL), diatomaceous earth was added and the mixture was stirred for 5 minutes, then filtered through a plug of diatomaceous earth and washed with DCM. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with saturated NH4Cl (30 mL), water (30 mL), brine (30 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography using a gradient of 0-10% MeOH in DCM afforded the title compound (295 mg, 57% yield) as a black solid.

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[0119] Intermediate 101 [ka] 3-Cyclopropyl-7-[3-[cyclopropylmethyl-[(2,4-dimethoxyphenyl)methyl]amino]-1,2,4-triazol-4-yl]-N-(1,1-dideuterio-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a suspension of Example 34 (420 mg, 1.16 mmol) in dichloromethane (20 mL) was added 1,1'-thiocarbonyldiimidazole (230 mg, 1.16 mmol). After 3 h, N-(cyclopropylmethyl)-1-(2,4-dimethoxyphenyl)methanamine (280 mg, 1.26 mmol) was added as a solution in dichloromethane (5 mL). After 90 min, the mixture was diluted with dichloromethane (20 mL) and washed successively with water (20 mL), 10% ammonium chloride solution (40 mL), water (40 mL) and brine (40 mL). After concentration under reduced pressure, the residue was dissolved in N,N-dimethylformamide (15 mL). Formic hydrazide (210 mg, 3.50 mmol) and mercuric chloride (630 mg, 2.32 mmol) were added. After 5 min, triethylamine (0.5 ml, 4 mmol) was added and the mixture was heated to 80° C. After 2 h 20 min, the mixture was cooled, filtered through diatomaceous earth and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (80 mL), washed with 10% ammonium chloride solution (2×40 mL), brine (50 mL), passed through a hydrophobic frit and concentrated under reduced pressure. Purification by flash chromatography afforded the title compound as a yellow glass (407 mg, 55% yield).

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[0120] Intermediate 102 [ka] 2-Hydroxyimino-7-methoxy-indan-1-one To a suspension of 7-methoxy-1-indanone (4.5 g, 28 mmol) in diethyl ether (80 mL) at 0°C was added hydrochloric acid (4 mol / L) in 1,4-dioxane (1.7 mL), followed by dropwise addition of 10-20% ethyl nitrite in ethanol (25 mL, 39.6 mmol). After 5 min, the mixture was allowed to warm to ambient temperature. After 2 h, 10-20% ethyl nitrite in ethanol (5 mL, 7.9 mmol) was added. After 30 min, diethyl ether (50 mL) was added and the off-white precipitate was collected on a sinter. The title compound was obtained as an off-white solid (3.90 g, 72% yield).

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[0121] Intermediate 103 [ka] 3-Chloro-8-methoxy-isoquinoline To a suspension of intermediate 102 (5.2 g, 27 mmol) in phosphoryl chloride (63 mL, 680 mmol) at 0 °C was added phosphorus pentachloride (6.5 g, 31 mmol). After 5 min, hydrogen chloride was bubbled through the mixture for 20 min. After 3 h, the mixture was cooled to ambient temperature, treated with phosphorus pentachloride (2.2 g, 11 mmol) and heated to 80 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was suspended in water (60 mL) and ammonium hydroxide was added to adjust the pH to 8-9. Dichloromethane (150 mL) was added and the suspension was filtered through diatomaceous earth. The filtrate was separated using a hydrophobic frit and the organics were concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound as a cream solid (3.0 g, 58% yield).

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[0122] Intermediate 104 [ka] 5-Bromo-3-chloro-8-methoxy-isoquinoline Intermediate 103 (1 g, 5.16 mmol) was added portionwise to sulfuric acid (15 mL) at 0° C. The mixture was then further cooled to −20° C. before being treated portionwise with N-bromosuccinimide (920 mg, 5.17) over 5 min. After 30 min, ice (30 g) and dichloromethane (50 mL) were added. The pH was adjusted to 7-8 with ammonium hydroxide solution. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organics were passed through a hydrophobic frit, concentrated and the residue was purified by flash chromatography to give the title compound as a pale pink solid (1.02 g, 70% yield).

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[0123] Intermediate 105 [ka] 3-Chloro-7-[3-[cyclopropylmethyl-[(2,4-dimethoxyphenyl)methyl]amino]-1,2,4-triazol-4-yl]-N-(3-fluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A sealable tube was charged with Intermediate 100 (75 mg, 0.013 mmol), potassium metabisulfite (58 mg, 0.26 mmol), TBAB (46.7 mg, 0.14 mmol), sodium formate (19.7 mg, 0.29 mmol), Pd(OAc)2 (1.48 mg, 0.007 mmol), triphenylphosphine (5.18 mg, 0.02 mmol) and 1,10-phenanthroline (3.56 mg, 0.02 mmol). DMSO (1.0 mL) was added and the suspension was degassed and placed under a nitrogen atmosphere. The tube was sealed and heated to 70 °C for 3 h. Once at room temperature, a mixture of 3-fluorocyclobutan-1-amine hydrochloride (33.1 mg, 0.26 mmol) and triethylamine (36.6 μL, 0.26 mmol) in THF (1.5 mL) was added and the reaction was cooled to 0° C. Then a solution of NBS (46.9 mg, 0.26 mmol) in THF (2 mL) was added dropwise. The reaction was then stirred for 1 hour while the reaction was allowed to warm to room temperature. The mixture was diluted with ethyl acetate (20 mL) and water (15 mL). The organic layer was washed with water (15 mL), brine (10 mL), dried (magnesium sulfate) and concentrated under reduced pressure. Purification by column chromatography afforded the title compound (65 mg, 38% yield) as a pale yellow gum.

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[0124] Intermediate 106 [ka] Methyl 2-[(5-bromo-3-chloro-8-isoquinolyl)oxy]acetate To a solution of intermediate 104 (200 mg, 0.55 mmol) in dichloromethane (5 mL) at -40°C was added boron tribromide in dichloromethane (1 mol / L, 2.2 mL, 2.2 mmol) dropwise. The mixture was allowed to warm to ambient temperature. After 18 h, boron tribromide in dichloromethane (1 mol / L, 0.5 mL, 0.5 mmol) was added. After a further 24 h, methanol (3 mL) was added to the solution at 0°C. The mixture was concentrated under reduced pressure to give a yellow solid which was dissolved in N,N-dimethylformamide (4 mL). Potassium carbonate (230 mg, 1.74 mmol) was added followed by methyl bromoacetate (75 μL, 0.77 mmol). After 20 h, the mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The organics were washed with brine, passed through a hydrophobic frit and concentrated under reduced pressure. The residue was purified by flash chromatography to give a white solid (220 mg, quantitative).

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[0125] Intermediate 107 [ka] 2-[(5-bromo-3-chloro-8-isoquinolyl)oxy]acetic acid To a suspension of intermediate 106 (580 mg, 1.54 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (120 mg, 5.010 mmol) followed by water (1 mL). After 4 h, the mixture was acidified to pH 2-3 using 2 M HCl. The mixture was extracted with ethyl acetate. The organics were concentrated under reduced pressure to give the crude title compound as a white solid (600 mg, quantitative yield).

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[0126] Intermediates 108 and 109 [ka] (7R*)-3-Cyclopropyl-7-[3-[cyclopropylmethyl-[(2,4-dimethoxyphenyl)methyl]amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] (108) N-(cyclopropylmethyl)-N-[(2,4-dimethoxyphenyl)methyl]-N'-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]imidazole-1-carboxamidine[* or S] (109) The title compound was prepared following general procedure 1 using intermediate 57 (60 mg (50% purity), 0.047 mmol). The product was purified using basic reverse phase column chromatography to give: Intermediate 108 (7 mg, 23% yield).

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[0127] Intermediate 110 [ka] 5-Bromo-7-chloro-2,3-dihydrofuro[3,2-h]isoquinolin-3-ol To a suspension of intermediate 107 (450 mg, 1.35 mmol) in 1,2-dichloroethane (4 mL) was added thionyl chloride (8 mL). The mixture was heated to 60° C. for 3 h and then concentrated under reduced pressure. 1,2-dichloroethane (9 mL) was added to the residue and cooled to 0° C. The suspension was treated with aluminum chloride (660 mg, 4.95 mmol). After 1.5 h aluminum chloride (50 mg, 0.37 mmol) was added and the mixture was heated to 45° C. After 15 min the mixture was cooled in an ice / water bath, diluted with dichloromethane (50 mL) and quenched with ice (10 g). Saturated Rochelle's salt solution (20 mL) and water (20 mL) were added. Separation using a hydrophobic frit and concentration of the organics under reduced pressure gave a beige solid (406 mg). Methanol (8 mL) and dichloromethane (8 mL) were added and the suspension was cooled to -20°C. Sodium borohydride (50 mg, 1.59 mmol) was added. After 30 min, the mixture was warmed to ambient temperature and the reaction was quenched with water (10 mL). The mixture was diluted with dichloromethane (20 mL) and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography to give the title compound as an off-white solid (189 mg, 44% yield).

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[0128] Intermediate 111 [ka] (5-bromo-7-chloro-2,3-dihydrofuro[3,2-h]isoquinolin-3-yl)oxy-tert-butyl-dimethyl-silane To a solution of intermediate 110 (189 mg, 0.6 mmol) in N,N-dimethylformamide (4 mL) was added imidazole (82 mg, 1.2 mmol) and tert-butyldimethylchlorosilane (126 mg, 0.84) and the mixture was stirred at ambient temperature for 18 h. Imidazole (50 mg, 0.74 mmol) and tert-butyldimethylchlorosilane (50 mg, 0.33) were added. After a further hour the mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The organics were washed with brine before being passed through a hydrophobic frit and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound as a white solid (250 mg, 97% yield).

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[0129] Intermediate 112 [ka] (5-benzylsulfanyl-7-chloro-2,3-dihydrofuro[3,2-h]isoquinolin-3-yl)oxy-tert-butyl-dimethyl-silane To a nitrogen purged solution of intermediate 111 (250 mg, 0.58 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (42 mg, 0.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol) and N,N-diisopropylethylamine (0.24 ml, 1.4 mmol) in 1,4-dioxane (3 mL) was added benzyl mercaptan (103 μL, 0.87 mmol). The mixture was heated to 85° C. for 3.5 h, cooled, filtered through diatomaceous earth washing with ethyl acetate, then concentrated under reduced pressure. Purification by flash chromatography afforded the desired compound as an orange oil (305 mg, 79% yield).

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[0130] Intermediate 113 [ka] 3-Cyclopropyl-7-[3-[cyclopropylmethyl-[(2,4-dimethoxyphenyl)methyl]amino]-1,2,4-triazol-4-yl]-N-(3-fluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Toluene (5 mL) and water (0.075 mL) were added to a mixture of intermediate 105 (65 mg, 0.101 mmol), cyclopropylboronic acid (21.7 mg, 0.25 mmol), Pd(OAc)2 (1.1 mg, 5.0 μmol), P(Cy)3.HBF4 (5.6 mg, 15.2 μmol) and K3PO4 (53.8 mg, 0.25 mmol). The biphasic solution was heated at 120 °C for 5 h. The reaction mixture was then diluted with DCM (20 mL), dried (MgSO4) and filtered through celite (washed with DCM). The filtrate was concentrated under reduced pressure and purified by column chromatography eluting with a gradient of 0% to 10% MeOH in DCM to give the title compound (46 mg, 33% yield) as a pale yellow gum.

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[0131] Intermediate 114 [ka] 3-[tert-Butyl(dimethyl)silyl]oxy-7-chloro-N-(2-fluoro-2-methyl-propyl)-2,3-dihydrofuro[3,2-h]isoquinoline-5-sulfonamide To a solution of intermediate 112 (305 mg, 0.46 mmol) in a mixture of acetonitrile (5 mL), acetic acid (30 μL, 0.52 mmol), water (60 μL, 3.3 mmol) and dichloromethane (2 mL) at −20° C. was added 1,3-dichloro-5,5-dimethylhydantoin (181 mg, 0.92 mmol) in portions. After 35 min, 1,3-dichloro-5,5-dimethylhydantoin (25 mg, 0.13 mmol) was added. After a further 15 min, a solution of fluoroisobutylamine hydrochloride (120 mg, 0.94) in a mixture of N,N-diisopropylethylamine (0.4 mL, 2 mmol), acetonitrile (1 mL) and dichloromethane (0.2 mL) was added. After 20 min, the mixture was diluted with water (10 mL) and dichloromethane (20 mL). The organics were separated using a hydrophobic frit and concentrated under reduced pressure to give an oil. To the residue was added N,N-dimethylformamide (3 mL), imidazole (63 mg, 0.91 mmol) and tert-butyldimethylchlorosilane (97 mg, 0.64). After 2 h the mixture was diluted with ethyl acetate (20 mL) and water (10 mL). The organics were washed with brine, passed through a hydrophobic frit and concentrated under reduced pressure. Purification by flash chromatography gave the title compound as a white gum (134 mg, 57% yield).

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[0132] Intermediate 115 [ka] 5-Bromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline Intermediate 4 (1.0 g, 0.98 mmol) was added batchwise to a mixture of sulfuric acid (4.09 mL) and DCM (50 mL) at 0 °C. The reaction mixture was cooled at -10 °C and NBS (961 mg, 5.4 mmol) was added portionwise. The reaction mixture was stirred at -10 °C for 2 h. NBS (0.2 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ice water (50 mL) and the pH was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with DCM (2 x 50 mL) and the combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0% to 20% EtOAc in heptane to afford the title compound (1.26 g, 75% yield) as an off-white solid.

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[0133] Intermediate 116 [ka] 1-[3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea The title compound was prepared following general procedure 4 using intermediate 36 (378 mg, 1.00 mmol), 5-isothiocyanato-1,3-dimethyl-1H-pyrazole (250 mg, 1.6 mmol), N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) and dichloromethane (40 mL). Purification by column chromatography using a gradient of 0-100% ethyl acetate in isohexane followed by 1-30% methanol in ethyl acetate afforded the title compound (416 mg, 78% yield).

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[0134] Intermediate 117 [ka] 1-[3-Cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea The title compound was prepared following general procedure 4 using Example 50 (100 mg, 0.28 mmol), 5-isothiocyanato-1,3-dimethyl-1H-pyrazole (0.05 mL, 0.4 mmol), N,N-diisopropylethylamine (0.07 mL, 0.4 mmol) and dichloromethane (10 mL). Purification by column chromatography using a gradient of 0-100% ethyl acetate in isohexane followed by 1-30% methanol in ethyl acetate afforded the title compound (147 mg, 100% yield).

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[0135] Intermediate 118 [ka] 1-[3-Cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(5-methyl-3-pyridyl)thiourea The title compound was prepared following general procedure 4 using Example 50 (100 mg, 0.28 mmol), 3-isothiocyanato-5-methyl-pyridine (63 mg, 0.42 mmol), N,N-diisopropylethylamine (0.07 mL, 0.4 mmol) and dichloromethane (10 mL). Purification by column chromatography using a gradient of 0-100% ethyl acetate in isohexane followed by 1-20% methanol in ethyl acetate afforded the title compound (140 mg, 99% yield).

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[0136] Intermediate 119 [ka] 3-Cyclopropyl-7-[3-[cyclopropylmethyl-[(2,4-dimethoxyphenyl)methyl]amino]-1,2,4-triazol-4-yl]-N-(3,3-difluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A mixture of intermediate 131 (51 mg, 0.077 mmol), cyclopropylboronic acid (16.6 mg, 0.19 mmol), Pd(OAc)2 (0.87 mg, 3.8 μmol), P(Cy)3.HBF4 (4.27 mg, 11.6 μmol) and K3PO4 (41.0 mg, 0.19 mmol) in a biphasic solution of toluene (5 mL) and water (0.075 mL) was heated at 120 °C for 5 h. The reaction mixture was diluted with DCM (20 mL), dried (MgSO4) and filtered through celite (washed with DCM). The filtrate was concentrated under reduced pressure and purified by column chromatography eluting with a gradient of 0% to 10% MeOH in DCM to give the title compound (35 mg, 55% yield) as a pale yellow gum.

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[0137] Intermediate 120 [ka] 3-Cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A mixture of intermediate 6 (300 mg, 0.886 mmol), cyclopropylboronic acid (240 mg, 2.66 mmol) and cesium carbonate (729 mg, 2.21 mmol) in 1,4-dioxane (5 mL) was degassed and placed under a N2 atmosphere. 2-P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (95 mg, 0.0886 mmol) was added and the reaction mixture was heated in a microwave at 120 °C for 90 min. The solvent was evaporated and the residue was partitioned between DCM and water. The organic phase was washed with brine, passed through a phase separator and evaporated. The crude material was purified by flash chromatography eluting with a gradient of 20-70% EtOAc in hexanes to give the title product as an off-white solid (214 mg, 70% yield).

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[0138] Intermediates 121 and 122 [ka] 9-Bromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline (121) 7-Bromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline (122) Intermediate 4 (2.5 g, 12.2 mmol) was dissolved in EtOAc (150 mL) and NBS (2.4 g, 13.5 mmol) was added. The reaction mixture was irradiated with light for 1 h. The solvent was removed and the crude title compound mixture (4.9 g) was used in the next step without further purification.

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[0139] Intermediates 123 and 124 [ka] 3-Chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-amine (123) 3-Chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-amine (124) In a pressure flask, a mixture of intermediates 121 and 122 (3.46 g, 12.25 mmol) was dissolved in THF (160 mL). Ammonia gas was bubbled in for 5 min and then the reaction mixture was stirred at 60° C. for 3 h and then at room temperature for 16 h. Ammonia gas was bubbled in for approximately 5 min and the reaction mixture was heated at 60° C. for 5 h and then at room temperature for 16 h. The solvent was removed in vacuo to give the title compound mixture (3.4 g) as a black gum. The material was used in the next step without further purification.

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[0140] Intermediates 125 and 126 [ka] tert-Butyl N-(3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl)carbamate (125) tert-Butyl N-(3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl)carbamate (126) To a stirred mixture of intermediates 123 and 124 (2.6 g, 11.8 mmol) in DCM (100 mL) was added di-tert-butyl dicarbonate (2.8 g, 13.0 mmol) followed by triethylamine (3.31 mL, 23.7 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (100 mL) and washed with water (100 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. Purification by column chromatography using 0-50% ethyl acetate in heptane gave the title compound. Intermediate 125 (940 mg, 24% yield).

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[0141] Intermediate 127 [ka] 3-Chloro-5-iodo-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-amine Intermediate 126 (1.0 g, 3.13 mmol) was added batchwise to a solution of sulfuric acid (2.6 mL) in DCM (50 mL) at 0° C. The reaction mixture was cooled at −10° C. and NIS (847 mg, 3.76 mmol) was added portionwise. The reaction mixture was stirred at −10° C. for 2 h and then at room temperature for 16 h. Then, over a period of 32 h, two portions of NIS (2 equiv. each) were added. The reaction mixture was diluted with ice water (750 mL) and the pH was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with DCM (2×70 mL) and the combined organic layers were washed with sodium thiosulfate, dried (sodium sulfate) and concentrated under reduced pressure. The crude title compound (650 mg) was used in the next step without further purification.

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[0142] Intermediate 128 [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 then cooled to room temperature and sodium borohydride (0.50 g, 13.24 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NH4Cl, water and brine (30 mL each). The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography eluting with a gradient of 0% to 20% MeOH in DCM afforded the title compound (2.1 g, 72% yield) as a colorless oil.

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[0143] Intermediate 129 [ka] 3-(3-chloro-5-iodo-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl)-1-(cyclopropylmethyl)-1-[(2,4-dimethoxyphenyl)methyl]thiourea A mixture of intermediate 127 (650 mg, 1.64 mmol, 87% purity) and triethylamine (0.68 mL, 4.9 mmol) in DCM (15 mL) was added dropwise to a stirred solution of phenylchloromethanethioate (0.25 mL, 1.8 mmol) in DCM (15 mL) at 0 °C. The reaction was stirred at 0 °C for 30 min. Then, a solution of intermediate 128 (626 mg, 2.83 mmol) in DCM (15 mL) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The reaction was diluted with DCM (30 mL) and washed with water (30 mL) followed by saturated aqueous NaHCO3 (30 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. Purification by column chromatography using a gradient of 0-50% ethyl acetate in heptane afforded the title compound (305 mg, 29% yield) as a light brown solid.

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[0144] Intermediate 130 [ka] 4-(3-chloro-5-iodo-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl)-N-(cyclopropylmethyl)-N-[(2,4-dimethoxyphenyl)methyl]-1,2,4 triazol-3-amine Intermediate 129 (305 mg, 0.48 mmol) was dissolved in dry DMF (7 mL). Formic hydrazide (87.6 mg, 1.46 mmol) and mercuric chloride (396.3 mg, 1.46 mmol) were added and the reaction was stirred for 5 minutes. Triethylamine (0.20 mL, 1.46 mmol) was added and the reaction was heated to 90° C. with stirring for 4 hours, resulting in a black suspension. Once at room temperature, the reaction was diluted with DCM (20 mL), diatomaceous earth was added and the mixture was stirred for 5 minutes, then filtered through a plug of diatomaceous earth, washing with DCM. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with saturated NH4Cl (30 mL), water (30 mL) and brine (30 mL), then dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography using a gradient of 0-10% MeOH in DCM afforded the title compound (175 mg, 54% yield) as a grey solid.

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[0145] Intermediate 131 [ka] 3-Chloro-7-[3-[cyclopropylmethyl-[(2,4-dimethoxyphenyl)methyl]amino]-1,2,4-triazol-4-yl]-N-(3,3-difluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A sealable tube was charged with Intermediate 130 (90 mg, 0.14 mmol), potassium metabisulfite (64.9 mg, 0.29 mmol), TBAB (51.8 mg, 0.16 mmol), sodium formate (21.8 mg, 0.32 mmol), Pd(OAc)2 (1.6 mg, 0.007 mmol), triphenylphosphine (5.7 mg, 0.022 mmol) and 1,10-phenanthroline (3.9 mg, 0.022 mmol). The mixture was suspended in DMSO (1.0 mL), degassed and placed under a nitrogen atmosphere. The tube was sealed and heated to 70 °C for 2 h. Once at room temperature, a solution of 3,3-difluorocyclobutan-1-amine hydrochloride (41.9 mg, 0.29 mmol) and triethylamine (40.5 mL, 0.29 mmol) in THF (1.5 mL) was added and the reaction was cooled to 0° C. A solution of NBS (52.0 mg, 0.29 mmol) in THF (2 mL) was added dropwise and the reaction was allowed to warm to room temperature. After 1 h, the mixture was diluted with ethyl acetate (20 mL) and water (15 mL). The organic layer was washed with water (15 mL) and brine (10 mL), dried (magnesium sulfate) and concentrated under reduced pressure. Purification by flash column chromatography afforded the title compound (51 mg, 50%) as a film.

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[0146] Intermediates 132 and 133 [ka] 5,9-Dibromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline (132) 5,7-Dibromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline (133) Intermediate 115 (200 mg, 0.70 mmol) was dissolved in EtOAc (13 mL) and NBS (132.2 mg, 0.74 mmol) was added followed by azobisisobutyronitrile (11.6 mg, 0.07 mmol). The reaction mixture was exposed to light for 1 h. Due to suspected instability of the product, the solvent was removed and the crude title compound (310 mg) was used in the next step without further purification.

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[0147] Intermediates 134 and 135 [ka] 5-Bromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-amine (134) 5-Bromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-amine (135) A mixture of intermediates 132 and 133 (1.61 g, 4.4 mmol) was dissolved in THF (95 mL) in a sealed tube. Ammonia gas was bubbled through for 5 min and the reaction mixture was stirred at 60° C. for 16 h. The solvent was removed and the crude title compound (1.6 g) was used in the next step without further purification.

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[0148] Intermediates 136 and 137 [ka] 3-(5-Bromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl)-1-(cyclopropylmethyl)-1-[(2,4-dimethoxyphenyl)methyl]thiourea (136) 3-(5-Bromo-3-chloro-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl)-1-(cyclopropylmethyl)-1-[(2,4-dimethoxyphenyl)methyl]thiourea (137) A mixture of intermediates 134 and 135 (788 mg, 2.64 mmol) and triethylamine (1.10 mL, 7.94 mmol) in DCM (20 mL) was added dropwise to a stirred solution of phenylchloromethanethioate (0.404 mL, 2.91 mmol) in DCM (20 mL) at 0 °C. The reaction was stirred at 0 °C for 30 min. Then a solution of intermediate 128 (879 mg, 3.92 mmol) in DCM (20 mL) was added and the reaction mixture was allowed to warm to room temperature. After 20 h, the reaction was diluted with DCM (30 mL), washed with water (30 mL), saturated aqueous NaHCO3 (30 mL), dried over sodium sulfate and concentrated under vacuum. Purification by column chromatography using a gradient of 0-50% ethyl acetate in heptane gave the title compound. Intermediate 136 (770 mg, 52% yield).

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[0149] example Example 1 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(7-methoxyimidazo[4,5-b]pyridin-3-yl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 83 (34 mg 0.052 mmol) was dissolved in acetic acid (0.5 mL) and treated with iron powder (25 mg, 0.44 mmol). The resulting mixture was stirred at room temperature for 1 h. Then, acetic acid (0.5 mL), MeOH (1 mL) and a second portion of iron powder (25 mg, 0.44 mmol) were added and the mixture was heated at 80° C. for 8 h. A third portion of iron powder (35 mg, 0.63 mmol) was added and the reaction was heated at 80° C. for 3 h. The reaction was diluted with water (20 mL) and EtOAc (30 mL), the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography using a gradient of ethyl acetate in isohexane gave the title compound (4 mg).

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[0150] Example 2 [ka] 3-Cyclopropyl-N-isobutyl-9-[[4-(1-methylbenzotriazol-4-yl)-1,2,4-triazol-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide General procedure 1 using intermediate 40 (71 mg) afforded the title compound (13 mg, 19% yield).

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[0151] Examples 3 and 4 [ka] 3-Cyclopropyl-N-isobutyl-9-[[4-(2-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (3) 3-Cyclopropyl-N-isobutyl-9-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (4) General procedure 1 using intermediate 41 (30 mg) gave the title compound. Example 3 (5 mg, 16% yield).

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[0152] Examples 5 and 6 [ka] 3-Cyclopropyl-9-[[4-(5-fluoro-3-pyridyl)-1,2,4-triazol-3-yl]amino]-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (5) 3-Cyclopropyl-9-[3-[(5-fluoro-3-pyridyl)amino]-1,2,4-triazol-4-yl]-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (6) General procedure 1 using intermediate 42 (15 mg) gave the title compound. Example 5 (5 mg, 33% yield).

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[0153] Example 7 [ka] 3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylic acid Intermediate 56 (3 mg, 7.1 μmol) was dissolved in a mixture of tetrahydrofuran (1.0 mL) and water (0.5 mL). Lithium hydroxide (5 mg, 21.4 μmol) was added and the reaction was stirred at ambient temperature for 1 h. The reaction was concentrated to remove the organic solvent and diluted with Et2O (2 mL). The ether layer was partitioned and discarded, and the pH of the aqueous layer was adjusted to 1 using aqueous HCl (0.5 M). The acidic aqueous layer was extracted with EtOAc (2 mL). The organic solvent was removed in vacuo to give the title compound (0.8 mg, 30% yield).

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[0154] Example 8 [ka] 1-(Cyclopropylmethyl)-3-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea[* or S] Intermediate 109 (12 mg, 0.018 mmol) was dissolved in dichloromethane (0.225 mL), trifluoroacetic acid (0.025 mL, 0.32 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was concentrated in vacuo and the crude product was purified using a reverse phase column (acidic conditions) to give the title compound (1.4 mg, 17% yield).

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[0155] Example 9 [ka] N-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide [* or S], To a stirred solution of intermediate 38 (50 mg, 0.13 mmol), nicotinic acid (20 mg, 0.16 mmol) and N,N-diisopropylethylamine (69 μl, 0.40 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added HATU (78 mg, 0.199 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography to give the title compound (35 mg, 55%).

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[0156] Example 10 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-hydroxy-7-pyridin-3-yl-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide General procedure 2 using intermediate 50 (10 mg, 0.011 mmol) and reverse phase HPLC (basic conditions) for product purification afforded the title compound (0.3 mg, 6% yield).

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[0157] Example 11 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(2-fluoropyridin-3-yl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide General procedure 2 using intermediate 61 (110 mg, 0.24 mmol) and reverse phase HPLC (basic conditions) for product purification afforded the title compound (40 mg, 36% yield).

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[0158] Examples 12 and 13 [ka] (7R*)-3-Cyclopropyl-7-[2-(cyclopropylmethylamino)imidazol-1-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] (12) (7R*)-3-Cyclopropyl-7-[[1-(cyclopropylmethyl)imidazol-2-yl]amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] (13) To a stirred solution of intermediate 57 (134 mg, 0.21 mmol) in DMF (1.0 mL) was added aminoacetaldehyde diethyl acetal (84 mg, 0.63 mmol) followed by mercuric chloride (113.5 mg, 0.42 mmol). The mixture was stirred at room temperature for 5 min, after which triethylamine (63 mg, 0.63 mmol) was added. The resulting reaction mixture was stirred at 80° C. for 1 h. The reaction was diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 (3 mL). The aqueous phase was re-extracted with EtOAc (3 mL) and the combined organic extracts were filtered through a pad of celite and Na2SO4. The solvent was removed in vacuo to give the crude material which was subjected to reverse phase HPLC (basic conditions) purification to give the title compound. Example 12 (5 mg, 5% yield).

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[0159] Example 14 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-9-(pyridin-3-ylmethylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide The hydrochloride salt form of intermediate 39 (50 mg, 0.13 mmol) was suspended in 1,2-dichloroethane (1 mL) followed by the addition of N,N-diisopropylethylamine (44 μL, 0.25 mmol), 3-pyridinecarboxaldehyde (14 mg, 0.13 mmol) and acetic acid (1 drop). The reaction was stirred at ambient temperature for 1 h. Sodium borohydride (48 mg, 1.26 mmol) was added along with a few drops of MeOH and the reaction was stirred at ambient temperature overnight. The reaction was diluted with MeOH (1 mL) and saturated aqueous NaHCO3 (2 mL) was added. The organic layer was separated and the aqueous layer was extracted with DCM (2 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The product was purified using reverse phase HPLC (basic conditions) to give the title compound (8 mg, 14% yield).

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[0160] Example 15 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-9-(pyridin-3-ylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 39 (50 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL) and N,N-diisopropylethylamine (45 mg, 0.3477 mmol). Pyridine-3-sulfonyl chloride (34 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction was diluted with DCM (2 mL) and MeOH (1 mL) and washed with water (2 mL). The solvent was removed in vacuo and the product was purified by reverse phase HPLC (basic conditions) to give the title compound (21 mg, 30% yield).

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[0161] Example 16 [ka] 6-Fluoro-N-[(9R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1H-indole-3-carboxamide[* or S] 6-Fluoro-1H-indole-3-carboxylic acid (12 mg, 0.064 mmol) was dissolved in a solution of N,N-diisopropylethylamine (0.13 mmol, 0.023 mL) and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (31 mg, 0.079 mmol) in DMF (0.25 mL). The reaction was stirred for 10 min before a solution of intermediate 65 (20 mg, 0.053 mmol) in DMF (0.25 mL) was added. The reaction was stirred overnight at ambient temperature, diluted with water (2 mL) and extracted with EtOAc (2 x 2 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The product was purified by reverse phase HPLC (basic conditions) to give the title compound (4 mg, 14% yield).

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[0162] Example 17 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(1-methylbenzimidazol-2-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide General procedure 2 using intermediate 66 (13 mg, 0.026 mmol) and reverse phase column chromatography (basic conditions) afforded the title compound (0.5 mg, 4% yield).

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[0163] Example 18 [ka] Methyl 5-[[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-2-carboxylate General procedure 3 using intermediate 39 (50 mg, 0.14 mmol), methyl 5-bromopyridine-2-carboxylate (77 mg, 0.35 mmol) and column chromatography for purification afforded the title compound (28 mg, 39% yield).

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[0164] Example 19 [ka] 5-[[3-Cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-2-carboxylic acid Example 18 (26 mg, 0.053 mmol) was dissolved in a mixture of tetrahydrofuran (0.75 mL) and water (0.5 mL). Lithium hydroxide monohydrate (8.5 mg, 0.20 mmol) was added and the reaction was heated with stirring at 50° C. for 1 h. The reaction was cooled, concentrated in vacuo and the crude residue was purified by basic reverse phase column chromatography to give the title compound (11 mg, 45% yield).

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[0165] Example 20 [ka] 5-Methyl-N-[(9R*)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1H-pyrazole-3-carboxamide[* or S] HATU (82 mg, 0.21 mmol) was added to a stirred solution of the hydrochloride salt form of intermediate 39 (50 mg, 0.14 mmol), 5-methyl-1h-pyrazole-3-carboxylic acid (21 mg, 0.167 mmol) and N,N-diisopropylethylamine (54 mg, 0.42 mmol) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was then purified using reverse phase column chromatography (acidic conditions) followed by reverse phase HPLC (basic conditions) to give the title compound (39 mg, 60% yield) as a mixture of enantiomers. The mixture was separated using chiral SFC to give the title compound as a single isomer (2 mg). Chiral SFC RT**=2.31 min.

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[0166] Example 21 [ka] N-[(9R*)-3-Cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide[* or S] HATU (16 mg, 0.042 mmol) was added to a stirred solution of intermediate 67 (10 mg, 0.028 mmol), nicotinic acid (4 mg, 0.033 mmol) and N,N-diisopropylethylamine (15 μL, 0.084 mmol) in anhydrous N,N-dimethylformamide (0.2 mL, 3 mmol). The reaction mixture was stirred at room temperature for 1 h. It was then purified by basic reverse phase column chromatography to give the title compound (8 mg, 60% yield).

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[0167] Example 22 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide A mixture of intermediate 73 (77 mg, 0.23 mmol), cyclopropylboronic acid (61 mg, 0.68 mmol) and cesium carbonate (186 mg, 0.57 mmol) in anhydrous 1,4-dioxane (1.5 mL) was sparged with nitrogen for 5 min. 2-P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (24 mg, 0.023 mmol) was added and the reaction mixture was heated in a microwave at 120° C. for 1 h. The reaction was diluted with DCM (3 mL) and washed with water (1 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was purified by column chromatography to give the title compound (21 mg, 27% yield).

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[0168] Example 23 [ka] 1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]cinnolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea To a stirred suspension of intermediate 82 (42 mg, 0.10 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (26 mg, 0.20 mmol) and 5-isothiocyanato-1,3-dimethyl-1h-pyrazole (24 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with MeOH and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound (41 mg, 76% yield).

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[0169] Examples 24 and 25 [ka] 3-Cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide (24) (7R*)-3-Cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide[* or S] (25) General procedure 1 using Example 23 (50 mg, 0.094 mmol) and column chromatography for purification gave a racemic mixture of Example 24 (21 mg, 41% yield) and Example 25 (14 mg, 28% yield). The racemic mixture of Example 25 was purified by chiral HPLC (column: LUX Cullulose-2 250×21.2 mm, 5 uM, flow rate 10 mL / min, column temperature 40° C. Mobile phase: MeOH+0.1% NH4OH. Run time: 20 min) to give Example 25 as the first eluting peak. Example 24

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[0170] Example 26 [ka] N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-2-methylcyclopropane-1-carboxamide 2-Methylcyclopropanecarboxylic acid (5.2 mg, 0.05 mmol) was treated with a solution of intermediate 84 (19 mg, 0.05 mmol) in DMF (0.4 mL). A solution of TBTU (19 mg, 0.05 mmol) in DMF (416 μL) was then added, followed by a solution of DIPEA (9 μL, 0.05 mmol) in DMF (50 μL). The resulting mixture was stirred at ambient temperature for 18 h and then purified by preparative HPLC to provide the title compound (12.4 mg, 53% yield).

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[0171] Example 27 [ka] 3-Cyclopropyl-4-fluoro-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A suspension of intermediate 120 (22 mg, 0.064 mmol), N-fluorobenzenesulfonamide (63 mg, 0.2 mmol) and lithium carbonate (6 mg, 0.08 mmol) in MeCN (0.3 mL) was heated to 75 °C under an argon atmosphere for 3 days, after which the mixture was filtered and the filtrate was purified by preparative HPLC to give the title compound (1.2 mg, 5% yield).

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[0172] Examples 28, 29, and 30 procedure A solution of intermediate 84 (18.9 mg, 0.05 mmol) and tBuXPhos Pd G3 (6.2 mg, 0.0075 mmol) in dioxane (0.5 mL) was treated with sodium tert-butoxide (14.4 mg, 0.15 mmol) and the appropriate aryl bromide (0.072 mmol, see table below), and the resulting mixture was heated to 100° C. under argon for 18 h. Products were isolated by preparative HPLC and analyzed by LCMS method 13 (**) or 14 (***). [Table 5]

[0173] Example 31 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 36 (36.0 mg, 0.0954 mmol), 3-bromopyridine (20 μL, 0.21 mmol), sodium tert-butoxide (18.0 mg, 0.187 mmol), (+ / -)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (18.0 mg, 0.0280 mmol) and palladium(II) acetate (2.8 mg, 0.012 mmol) were placed in a flask and suspended in toluene (1.5 mL). The flask was sealed, degassed and placed under a nitrogen atmosphere. The sealed reaction was stirred at 80 °C for 18 h. The reaction was cooled to room temperature and then diluted with 5% MeOH in DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with 5% MeOH in DCM (2 x 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude product which was purified by basic preparative HPLC to give the title compound (1 mg, 2% yield).

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[0174] Example 32 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 84 (50.0 mg, 0.132 mmol), 3-bromopyridine (0.020 ml, 0.21 mmol), sodium tert-butoxide (27.5 mg, 0.286 mmol), (+ / -)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (17.0 mg, 0.0265 mmol) and palladium(II) acetate (3.5 mg, 0.016 mmol) were placed in a flask and suspended in toluene (1.7 mL). The flask was sealed, degassed and placed under a nitrogen atmosphere. The sealed reaction was stirred at 70 °C for 18 h. The reaction was cooled to room temperature and then diluted with 5% MeOH in DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with 5% MeOH in DCM (2 x 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude product, which was purified by flash column chromatography on silica (gradient elution from 0% to 100% EtOAc in isohexane) and then basic preparative HPLC to give the title compound (7 mg, 12% yield).

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[0175] Example 33 [ka] tert-Butyl N-[3-cyclopropyl-5-[(1,1-dideuterio-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate To a suspension of intermediate 97 (1.2 g, 2.6 mmol) in toluene (15 mL) was added cyclopropylboronic acid (710 mg, 7.9 mmol), potassium phosphate tribasic (1400 mg, 6.6 mmol), tricyclohexylphosphonium tetrafluoroborate (150 mg, 0.39 mmol), palladium(II) acetate (30 mg, 0.13 mmol) and water (0.15 mL). The mixture was purged with nitrogen and then heated to 115° C. in a microwave for 2 h. The mixture was diluted with dichloromethane (20 mL) and washed with water (30 mL). The aqueous layer was extracted with dichloromethane (2×10 mL). The combined organics were passed through a hydrophobic frit and purified by flash chromatography to give the title compound as a cream solid (1.05 g, 2.27 mmol, 86%).

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[0176] Example 34 [ka] 7-Amino-3-cyclopropyl-N-(1,1-dideuterio-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To Example 33 (15 mg, 0.032 mmol) was added hydrochloric acid (4 mol / L) in 1,4-dioxane (0.2 ml, 0.8 mmol). After 30 min, hydrochloric acid (4 mol / L) in 1,4-dioxane (0.2 ml, 0.8 mmol) and methanol (50 μL) were added. After 20 min, the mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography to give the title compound as a white solid (8 mg, 68%).

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[0177] Example 35 [ka] 3-Cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(1,1-dideuterio-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 101 (407 mg, 0.611 mmol) in dichloromethane (50 mL, 780 mmol) cooled in an ice / water bath was added trifluoroacetic acid (5 mL). After 20 min, saturated sodium bicarbonate solution (20 mL) and water (10 mL) were added to the mixture. The aqueous layer was extracted with dichloromethane (4×20 mL) and dichloromethane:methanol 5:1 (3×10 mL). The combined extracts were passed through a hydrophobic frit, concentrated and the residue purified by reverse phase flash chromatography to give the title compound as a white solid (173 mg, 0.36 mmol, 58%).

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[0178] Example 36 [ka] 7-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-3-hydroxy-2,3-dihydrofuro[3,2h]isoquinoline-5-sulfonamide Toluene (0.2 mL) was added to intermediate 114 (9 mg, 0.016 mmol), followed by palladium(II) acetate (0.4 mg, 0.002 mmol), tricyclohexylphosphonium tetrafluoroborate (1.8 mg, 0.005 mmol) and potassium phosphate tribasic (17 mg, 0.08 mmol), cyclopropylboronic acid (9 mg, 0.1 mmol) and water (2 μL). The mixture was heated to 115° C. in a microwave. After cooling, filtering through diatomaceous earth and concentrating under reduced pressure, tetrahydrofuran (1 mL) and a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (24 μL, 0.024 mmol, 1 mol / L) were added. After 2.5 h, the mixture was concentrated, diluted with ethyl acetate (10 mL) and washed with 10% ammonium chloride solution (2×5 mL) and water (5 mL). After concentration under reduced pressure, purification by flash chromatography afforded the title compound as a white solid (6.5 mg, 43%).

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[0179] Example 37 [ka] (7R*)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-N-pyridin-3-yl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxamide[* or S] Intermediate 85 (70 mg, 0.17 mmol) was dissolved in DCM (3 mL) and HATU (81 mg, 0.20 mmol) was added followed by triethylamine (0.1 mL, 0.7 mmol). The reaction mixture was stirred at room temperature for 5 min and then 3-aminopyridine (33 mg, 0.34 mmol) was added. After about 1 h, the crude product was diluted with EtOAc and the organic layer was washed with water and brine. Purification by column chromatography using a gradient of 0-100% EtOAc in hexanes followed by a gradient of 0-10% MeOH in DCM afforded the title compound as a mixture of enantiomers (34 mg, 41% yield). The racemate was separated using chiral HPLC (Waters UV prep system using 2996 PDA). Lux Cellulose-1 21.2×250 mm 5 μm column, flow rate 10 mL / min) afforded the title compound (7 mg). Chiral RT**=2.39 min.

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[0180] Example 38 [ka] N-[2-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyrazol-3-yl]cyclopropanecarboxamide A mixture of intermediate 88 (105 mg, 0.20 mmol), cyclopropaneboronic acid (56 mg, 0.61 mmol) and palladium(II) acetate (2.3 mg, 0.010 mmol) in 1,4-dioxane (3 mL) was sparged with nitrogen for 5 min. Tricyclohexylphosphonium tetrafluoroborate (12 mg, 0.031 mmol) and potassium phosphate tribasic (110 mg, 0.51 mmol) were added and the reaction mixture was sparged with nitrogen for 5 min. The reaction was then heated at 120° C. for 2 h. It was then filtered through celite and the solvent was concentrated under reduced pressure. Purification by column chromatography afforded the title compound (38 mg, 36% yield).

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[0181] Example 39 [ka] 7-(5-aminotetrazol-1-yl)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 89 (160 mg, 0.31 mmol) was dissolved in DMF (5 mL). Ammonium chloride (42 mg, 0.78 mmol) was added followed by sodium azide (52 mg, 0.80 mmol) and the resulting mixture was heated at 80° C. overnight. Volatiles were evaporated followed by DCM / water extraction. Organics were dried over sodium sulfate and evaporated. The crude residue was purified by reverse phase column chromatography using basic conditions to give the title compound (45 mg, 32% yield).

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[0182] Example 40 [ka] 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, Intermediate 36 (35 mg, 0.09272 mmol) and 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)-pyridine (45 mg, 0.1875 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL) under nitrogen. Sodium tert-butoxide (27 mg, 0.28 mmol) and tert-BuXphos-Pd-G3 (6 mg, 0.007 mmol) were then added and the reaction vessel was stirred at room temperature overnight. Sodium tert-butoxide (27 mg, 0.28 mmol) and tert-BuXphos-Pd-G3 (6 mg, 0.007 mmol) were then added to the reaction mixture and the reaction mixture was heated to 80° C. for 4 hours. The reaction was cooled to room temperature and then concentrated in vacuo and purified by column chromatography to give the title compound (21 mg).

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[0183] Example 41 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide The title compound (13 mg, 0.026 mmol) was obtained by the method described for Example 40 using Intermediate 36 (0.093 mmol) and 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (41 mg, 0.1854 mmol).

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[0184] Example 42 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide The title compound (13 mg, 0.024 mmol) was obtained by the method described for Example 40 using Intermediate 36 (0.093 mmol) and 2-(5-bromo-2-pyridyl)-5-methyl-1,3,4-oxadiazole (46 mg, 0.19 mmol).

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[0185] Example 43 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide The title compound (18 mg, 0.032 mmol) was obtained by the method described for Example 40 using Intermediate 84 (0.093 mmol) and 4-bromo-1-methyl-1H-pyrazolo[3,4-C]pyridine (41 mg, 0.185 mmol).

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[0186] Example 44 [ka] Benzyl N-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate Intermediate 39 (25 mg, 0.07 mmol) was dissolved in DCM (1 mL) and treated with DIPEA (25 μL, 0.143 mmol) at room temperature, then benzyl chloroformate (12 μL, 0.082 mmol) was added dropwise. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with MeOH (0.5 mL) and NaOH (4N in water, 0.5 mL) and stirred vigorously at room temperature for 72 h. The mixture was then warmed to 48° C. for 5 h. The reaction mixture was diluted with water (5 mL) and DCM (5 mL), stirred vigorously, and the layers were separated through a phase separator. The aqueous layer was extracted with DCM (2×) and the combined organic layers were dried and concentrated in vacuo. Purification by column chromatography with a gradient of methanol in DCM gave the title compound (31 mg, 0.026 mmol).

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[0187] Example 45 [ka] 1-(4-Bromophenyl)-3-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea Intermediate 39 (25 mg, 0.07 mmol) was dissolved in DCM (1 mL) at room temperature and treated with DIPEA (25 μL, 0.143 mmol) and 4-bromophenyl-isocyanate (16 mg, 0.081 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the crude residue was purified by column chromatography with a gradient of methanol in DCM to give the title compound (32 mg, 0.05 mmol).

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[0188] Example 46 [ka] 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]urea To a solution of (1,3-dimethyl-1H-pyrazol-5-yl)methylamine (10 mg, 0.08 mmol) in acetonitrile (1 mL, 19.1 mmol) under nitrogen, triethylamine (22 μL, 0.16 mmol) was added, followed by 1,1′-carbonyl-diimidazole (12 mg, 0.074 mmol). The mixture was stirred at room temperature for 1 h, and then intermediate 39 (25 mg, 0.07 mmol) was added. The resulting mixture was stirred at room temperature for 36 h. The reaction mixture was concentrated and purified by column chromatography with a gradient of methanol in ethyl acetate to give the title compound (20 mg, 0.28 mmol).

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[0189] Example 47 [ka] 3-Cyclopropyl-7-hydroxy-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 29 (73 mg, 0.15 mmol) in THF (3 mL) at 0° C. was added 1 M tetrabutylammonium chloride in THF (0.22 mL, 0.22 mmol). The solution was stirred at 0° C. for 5 min and then at room temperature for 90 min. The reaction was diluted with water (10 mL) and EtOAc (15 mL). The organic layer was separated, washed with brine and passed through a phase separator frit. The solvent was removed to give a brown oil which was purified by flash column chromatography (eluting with a gradient of 0-70% EtOAc in isohexane) to give the title product as a white solid (53 mg, 96% yield).

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[0190] Example 48 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-7-oxo-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide To a solution of Example 47 (60 mg, 0.17 mmol) in DCM (4 mL) at 0° C. was added Dess-Martin periodinane (109 mg, 0.25 mmol). The mixture was stirred for 2.5 h. A 1:1 mixture of saturated aqueous sodium thiosulfate and saturated NaHCO3 solutions (10 mL) was added and the mixture was stirred vigorously for 15 min. The organic layer was separated and further washed with saturated aqueous NaHCO3 (10 mL) then passed through a phase separator frit. The solvent was removed to give a solid which was purified by flash column chromatography (eluting with a gradient of 0-70% EtOAc in isohexane) to give the title product as a white solid (56 mg, 94% yield).

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[0191] Example 49 [ka] 3-Cyclopropyl-7-hydroxy-7-methyl-N-(2-methylpropyl)-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide To a solution of Example 48 (10.5 mg, 0.12 mmol) in THF (1 mL) was added 1M methyllithium in THF (0.349 ml, 0.35 mmol) at 0° C. The mixture was stirred at 0° C. for 10 min and then at room temperature for 1 h. The THF was removed and the residue was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was passed through a phase separator and the solvent removed to give a gum which was purified by flash column chromatography (eluting with a gradient of 0-70% EtOAc in isohexane) to give the title product as a white solid (10 mg, 90% yield).

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[0192] Example 50 [ka] 7-Amino-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 13 (308 mg, 0.78 mmol) was suspended in 4 M HCl in dioxane (5 mL, 0.02 mmol) and the mixture was stirred for 2 h. The solvent was removed to give a solid. Purification by SCX column chromatography eluting with a gradient of 0-100% NH3 in methanol afforded the title product as a brown solid (279 mg, quantitative).

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[0193] Example 51 [ka] 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-ethylthiourea Example 50 (120 mg, 0.33 mmol) was suspended in a mixture of DCM (5 mL) and THF (5 mL). To this suspension was added DIPEA (0.089 mL, 0.50 mmol) and ethyl isothiocyanate (0.044 mL, 0.50 mmol). The reaction was stirred for 18 h. The solvent was removed to give the title product as a white solid (130 mg, 87% yield).

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[0194] Example 52 [ka] (7R*)-3-Cyclopropyl-7-[3-(ethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (* or S) To a solution of Example 51 (118 mg, 0.26 mmol) in DMF (5 mL) was added formic hydrazide (40 mg, 0.67 mmol) followed by mercuric chloride (181 mg, 0.67 mmol). The mixture was stirred for 2 min, then triethylamine (0.093 mL, 0.67 mmol) was added and the mixture was heated at 80° C. for 18 h. The reaction was cooled and CH3CN (10 mL) was added to the mixture which was then filtered through Celite and washed with excess CH3CN (25 mL). The solvent was removed to give a brown oil. Purification by flash column chromatography followed by reverse phase chromatography gave the racemic product as a white solid (9 mg, 6% yield). The racemate was purified by chiral SFC to give the title compound as a white solid (2 mg, 1.6% yield). Chiral SFC RT** 6.34 min

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[0195] Example 53 [ka] (7R*)-3-Cyclopropyl-7-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (* or S) To a suspension of Example 50 (45 mg, 0.13 mmol) in DCM (5 mL) was added DIPEA (0.033 mL, 0.19 mmol) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (27 mg, 0.19 mmol). The mixture was stirred for 18 h. The residue was dissolved in DCM (5 mL) and 2M ethylamine in THF (3 mL) was added. The mixture was stirred for 1 h. The solvent was removed and the solid was triturated with DCM (3 mL) and filtered to give the racemic product as a white solid (50 mg, 83% yield). The racemate was separated by chiral SFC to give the title product as a white solid (10 mg, 21% yield).

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[0196] Example 54 [ka] 3-Cyclopropyl-7-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of Example 50 (31 mg, 0.086 mmol) in DCM (10 mL) was added DIPEA (0.023 mL, 0.13 mmol) and 3,4-diethoxy-1,2,5-thiadiazole-1,1-dioxide (0.027 mL, 0.13 mmol). The solution was stirred for 3 h. 2M ethylamine in THF (0.085 mL, 0.17 mmol) was added to the solution which was stirred for 18 h. The solvent was removed and the resulting residue was purified by flash column chromatography (eluting with a gradient of 0-100% EtOAc in isohexane, then 0-10% methanol in ethyl acetate) to give the title product as a white solid (35 mg, 80% yield).

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[0197] Example 55 [ka] 2-Cyano-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(4-methylphenyl)guanidine To a suspension of Example 50 (45 mg, 0.13 mmol) in a mixture of DCM (10 mL) and THF (5 mL) was added DIPEA (0.058 mL, 0.19 mmol) and Intermediate 30 (47 mg, 0.19 mmol). The mixture was stirred for 18 h. The solvent was removed to give a residue which was purified by flash column chromatography (eluting with a gradient of 0-90% EtOAc in isohexane) to give the title product as a colorless gum (28 mg, 43% yield).

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[0198] Example 56 [ka] tert-Butyl 3-[[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamoyl]azetidine-1-carboxylate[*orS] To a solution of intermediate 38 (33 mg, 0.087 mmol) in DMF (2 mL) was added DIPEA (0.046 mL, 0.26 mmol), followed by 1-Boc-azetidine-3-carboxylic acid (21.7 mg, 0.105 mmol) and HATU (41 mg, 0.10 mmol). The mixture was stirred for 18 h. Then water (10 mL) and EtOAc (15 mL) were added. The organic layer was separated and washed with water (2×10 mL) and brine (10 mL), then passed through a phase separator and the solvent removed to give a brown oil. Purification by flash column chromatography eluting with a gradient of 0-100% EtOAc in isohexane followed by 0-10% methanol in DCM afforded the title product as a white solid (49 mg, 100% yield).

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[0199] Example 57 [ka] 7-[(3R)-3-aminopiperidin-1-yl]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 19 (216 mg, 0.39 mmol) in DCM (2 mL) was added TFA (2 mL). The solution was stirred for 1 h. The solvent was removed and excess TFA was azeotroped with 1:1 DCM / iso-hexane (2×10 mL). The resulting brown gum was purified by SCX column chromatography eluting with a gradient of 0-100% ammonia in methanol to give a brown gum. Further purification by reverse phase column chromatography afforded the title product as a white solid (17 mg, 10% yield).

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[0200] Example 58 [ka] (2R)-1-[(7R*)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-N-methylpyrrolidine-2-carboxamide[* or S] To a solution of intermediate 20 (96 mg, 0.20 mmol) in a mixture of 1,4-dioxane (3 mL) and toluene (2 mL) was added cyclopropylboronic acid (54 mg, 0.60 mmol) followed by palladium(II) acetate (2.2 mg, 0.010 mmol). Nitrogen gas was bubbled through the mixture for 2 min, then tricyclohexylphosphonium tetrafluoroborate (11 mg, 0.030 mmol) and potassium phosphate tribasic (106 mg, 0.50 mmol) were added. Nitrogen was bubbled through for 5 min, then the microwave vial was capped and heated at 130° C. for 18 h. Saturated aqueous Na2CO3 (10 mL) and EtOAc (10 mL) were added to the mixture. The mixture was filtered through Celite to remove Pd residues. The organic layer was separated and further washed with saturated aqueous Na2CO3 (15 mL) and brine (10 mL) then the solution was passed through a phase separator. The solvent was removed to give a brown oil. Purification by flash column chromatography eluting with a gradient of 0-100% EtOAc in isohexane followed by a gradient of 0-10% methanol in DCM afforded the product as a mixture of diastereoisomers (42 mg, 43% yield). The mixture was separated by SFC to give the title compound as a single diastereoisomer (4 mg, 13% yield).

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[0201] Example 59 [ka] N-[1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]azetidin-3-yl]-2,5-dimethylpyrazole-3-carboxamide To a solution of intermediate 23 (15 mg, 0.035 mmol) in DMF (1 mL) was added DIPEA (0.018 mL, 0.10 mmol) followed by 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (5.5 mg, 0.042 mmol) and HATU (16.31 mg, 0.042 mmol). The reaction mixture was stirred for 2 h. Water (10 mL) and EtOAc (15 mL) were added to the mixture. The organic layer was separated and further washed with water (2×10 mL), brine (10 mL) and then passed through a phase separator. The solvent was removed to give a brown oil. Purification by flash column chromatography eluting with a gradient of 0-10% methanol (containing 7M NH3) in ethyl acetate afforded the title product as a white solid (7.7 mg, 40% yield).

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[0202] Example 60 [ka] 3-Cyclopropyl-7-[(4,4-dimethyl-3-oxocyclobuten-1-yl)amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 36 (90 mg, 0.24 mmol) in THF (3 mL) was added DIPEA (0.062 mL, 0.36 mmol) followed by 2,2-dimethylcyclobutane-1,3-dione (40 mg, 0.36 mmol). The mixture was stirred at 70° C. for 18 h. The solvent was removed to give a brown gum. Purification by flash column chromatography eluting with a gradient of 0-100% EtOAc in isohexane followed by a gradient of 0-10% methanol in DCM afforded the title product as a light brown solid (68 mg, 60% yield).

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[0203] Example 61 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(1H-indol-2-ylmethylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 24 (95 mg, 0.19 mmol) in a mixture of 1,4-dioxane (3 mL) and toluene (2 mL) was added cyclopropylboronic acid (51 mg, 0.57 mmol) followed by palladium(II) acetate (2.1 mg, 0.0095 mmol). Nitrogen gas was bubbled through the mixture for 2 minutes, then tricyclohexylphosphonium tetrafluoroborate (11 mg, 0.028 mmol) and potassium phosphate tribasic (101 mg, 0.47 mmol) were added. Nitrogen was bubbled through for 5 minutes, then the microwave vial was capped and heated in a microwave at 130° C. for 18 hours. Saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL) were added to the mixture. The organic layer was separated, passed through a phase separator and the solvent was removed to give a green oil. Purification by flash column chromatography eluting with a gradient of 0 to 100% EtOAc in isohexane afforded the title product as a brown gum (45 mg, 47% yield).

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[0204] Example 62 [ka] 3-Cyclopropyl-9-hydroxy-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide In a microwave vial, intermediate 26 (53 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2.5 mL) and cesium carbonate (123 mg, 0.37 mmol) and cyclopropylboronic acid (41 mg, 0.45 mmol) were added. The flask was evacuated and placed under a nitrogen atmosphere for 5 min. Then, chloro(η 2 -P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (16 mg, 0.015 mmol) was added and the flask was again evacuated and placed under a nitrogen atmosphere. The reaction was then heated in a microwave at 120 °C for 3 h. The mixture was diluted with EtOAc (10 mL) and filtered through Celite. Purification by flash column chromatography eluting with a gradient of 0-50% EtOAc in isohexane afforded the title product as a white solid (5 mg, 9% yield).

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[0205] Example 63 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-9-oxo-7,8-dihydrocyclopenta[h]isoquinoline-5-sulfonamide To a suspension of Example 62 (44 mg, 0.12 mmol) in DCM (4 mL) at 0° C. was added Dess-Martin periodinane (160 mg, 0.37 mmol). The mixture was stirred for 18 h. A 1:1 mixture of saturated aqueous sodium thiosulfate and saturated NaHCO3 solutions (10 mL) was added and the mixture was stirred vigorously for 15 min. The organic layer was separated and further washed with saturated aqueous NaHCO3 (10 mL) then passed through a phase separator frit. The solvent was removed to give a solid. Purification by flash column chromatography eluting with a gradient of 0-50% EtOAc in isohexane gave the title product as a yellow solid (28 mg, 64% yield).

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[0206] Example 64 [ka] 3-Cyclopropyl-9-hydroxy-9-methyl-N-(2-methylpropyl)-7,8-dihydrocyclopenta[h]isoquinoline-5-sulfonamide To a solution of Example 63 (18 mg, 0.050 mmol) in THF (1 mL) at 0° C. was added 1M methyllithium in THF (0.151 mL, 0.15 mmol). The mixture was stirred for 2 h. The solvent was removed and the residue partitioned between HO (3 mL) and EtOAc (10 mL). The product went into the organic layer which was then passed through a phase separator frit. The solvent was removed to give a yellow gum. Purification by flash column chromatography eluting with a gradient of 0-50% EtOAc in isohexane gave the title product as a white solid (4 mg, 21% yield).

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[0207] Example 65 [ka] 3-Cyclopropyl-9-fluoro-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 27 (43 mg, 0.12 mmol) was suspended in toluene (3 mL) in a microwave vial and cyclopropylboronic acid (33 mg, 0.36 mmol) and potassium phosphate tribasic (64 mg, 0.30 mmol) were added. The flask was evacuated and placed under a nitrogen atmosphere for 5 minutes. Tricyclohexylphosphonium tetrafluoroborate (6.8 mg, 0.018 mmol) and palladium(II) acetate (1.35 mg, 0.006 mmol) were then added and the flask was again evacuated and placed under a nitrogen atmosphere. The reaction was then heated in a microwave at 110° C. for 1 hour and 15 minutes. The mixture was re-treated with cyclopropylboronic acid (33 mg, 0.36 mmol) and potassium phosphate tribasic (64 mg, 0.30 mmol), tricyclohexylphosphonium tetrafluoroborate (6.8 mg, 0.018 mmol) and palladium(II) acetate (1.35 mg, 0.006 mmol). The mixture was sparged with nitrogen and heated at 110° C. for 2 h. The solvent was removed to give a residue. Purification by flash column chromatography eluting with a gradient of 0-20% EtOAc in isohexane afforded the title product as an off-white solid (13 mg, 30% yield).

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[0208] Example 66 [ka] 3-Cyclopropyl-9-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 39 (55 mg, 0.139 mmol) was dissolved in a mixture of dichloromethane (5 mL) and N,N-diisopropylethylamine (54 mg, 0.417 mmol). 3,4-diethoxy-1,2,5-thiadiazole-1,1-dioxide (45 mg, 0.208 mmol) was added and the mixture was stirred at room temperature for 2 h. Further (14 mg, 0.070 mmol) 3,4-diethoxy-1,2,5-thiadiazole-1,1-dioxide and N,N-diisopropylethylamine (18 mg, 0.139 mmol) were added. The mixture was stirred at room temperature for another 1 h. Ethylamine solution (2M in THF) (2.8 mL, 5.56 mmol) was added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the crude material was purified by flash chromatography (eluting with 75-100% EtOAc in hexanes followed by 0-15% MeOH in EtOAc) to give the title compound (63 mg, 87% yield).

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[0209] Example 67 [ka] 9-[(4-cyano-1-methylpyrazol-3-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A mixture of intermediate 84 (50 mg, 0.132 mmol), 3-bromo-1-methyl-1H-pyrazole-4-carbonitrile (37 mg, 0.198 mmol) and sodium tert-butoxide (40 mg, 0.413 mmol) in anhydrous 1,4-dioxane (2 mL) was degassed and vacuum / nitrogen purged (3 times). tBuXPhos Pd G3 (17 mg, 0.021 mmol) was added and the mixture was again degassed and vacuum / nitrogen purged (3 times). The reaction mixture was heated at 70° C. for 16 h, then cooled to room temperature and filtered through celite, washing with dioxane. The solvent was evaporated and the crude material was purified by column chromatography to give the title compound (23 mg, 36% yield).

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[0210] Example 68 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-(isoquinolin-4-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A mixture of intermediate 84 (50 mg, 0.132 mmol), 4-bromoisoquinoline (41 mg, 0.198 mmol) and sodium tert-butoxide (40 mg, 0.413 mmol) in anhydrous 1,4-dioxane (2 mL) was degassed and vacuum / nitrogen purged (3 times). tBuXPhos Pd G3 (17 mg, 0.021 mmol) was added and the mixture was again degassed and vacuum / nitrogen purged (3 times). The reaction mixture was heated at 70° C. for 16 h, then cooled to room temperature and filtered through celite, washing with dioxane. The solvent was evaporated and the crude material was purified by flash column chromatography to give the title compound (25 mg, 37% yield).

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[0211] Example 69 [ka] 2-Cyano-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-(4-methylphenyl)guanidine Intermediate 39 (43 mg, 0.109 mmol) was dissolved in a mixture of dichloromethane (10 mL) and N,N-diisopropylethylamine (42 mg, 0.326 mmol). Intermediate 30 (41 mg, 0.163 mmol) was then added and the mixture was stirred in a microwave at 120° C. for 4 h. The solvent was evaporated and the crude material was purified by flash column chromatography to give the title compound (28 mg, 50% yield).

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[0212] Example 70 [ka] 3-Cyclopropyl-9-(methanesulfonamido)-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 39 (16 mg, 0.040 mmol) was dissolved in dichloromethane (2 mL) and N,N-diisopropylethylamine (68 mg, 0.527 mmol). Methanesulfonyl chloride (31 mg, 0.274 mmol) was added. The mixture was stirred at room temperature for 1 h. The crude material was purified by flash chromatography (eluted with 30-100% EtOAc in hexanes) to give the title compound (8.5 mg, 48% yield).

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[0213] Example 71 [ka] 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-ethylthiourea Intermediate 39 (129 mg, 0.326 mmol) was dissolved in a mixture of dichloromethane (5 mL) and N,N-diisopropylethylamine (63 mg, 0.489 mmol). Ethyl isothiocyanate (86 mg, 0.978 mmol) was added and the mixture was stirred at room temperature for 20 h and then at 45° C. for 2 h. The crude material was purified by flash chromatography (eluted with 30-100% EtOAc in hexanes, then 0-10% MeOH in EtOAc) to give the title compound (93 mg, 64% yield).

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[0214] Examples 72 and 73 [ka] 3-Cyclopropyl-9-[3-(ethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (72) (9R*)-3-Cyclopropyl-9-[(4-ethyl-1,2,4-triazol-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] (73) Example 71 (105 mg, 0.235 mmol) was dissolved in N,N-dimethylformamide (5 mL). Formic hydrazide (47 mg, 0.705 mmol) and mercuric chloride (128 mg, 0.470 mmol) were added. The mixture was stirred at room temperature for 5 min. Triethylamine (72 mg, 0.705 mmol) was added and the mixture was stirred at 90° C. for 3 h. The reaction mixture was diluted with MeCN (10 mL), filtered through a celite pad and washed with MeCN (3×10 mL). The filtrate was evaporated and the crude material was purified by flash column chromatography followed by SFC to give a racemic mixture of Example 72 and Example 73. Example 72 (11 mg, 10% yield).

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[0215] Example 74 [ka] 1-[3-Cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-pyridin-3-ylthiourea Intermediate 39 (100 mg, 0.278 mmol) was dissolved in a mixture of dichloromethane (5 mL) and N,N-diisopropylethylamine (54 mg, 0.417 mmol). 3-Pyridyl isothiocyanate (60 mg, 0.417 mmol) was added and the mixture was stirred at room temperature overnight. The crude material was purified by flash chromatography eluting with 60-100% EtOAc in hexanes, then 0-20% MeOH in EtOAc to give the title compound (104 mg, 75% yield).

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[0216] Example 75 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-9-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Example 74 (102 mg, 0.206 mmol) was dissolved in N,N-dimethylformamide (5 mL). Formic acid hydrazide (41 mg, 0.618 mmol) and mercuric chloride (112 mg, 0.412 mmol) were added. The mixture was stirred at room temperature for 5 min. Triethylamine (63 mg, 0.618 mmol) was added. The mixture was stirred at 90° C. for 5 h and then cooled to room temperature. The reaction mixture was then diluted with MeCN (10 mL), filtered through a celite pad and washed with MeCN (3×10 mL). The filtrate was evaporated. The crude material was purified by reverse phase flash column chromatography to give the title compound (9 mg, 9% yield).

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[0217] Example 76 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A mixture of intermediate 84 (52 mg, 0.138 mmol), 2-(5-bromo-2-pyridyl)-5-methyl-1,3,4-oxadiazole (50 mg, 0.207 mmol) and sodium tert-butoxide (40 mg, 0.413 mmol) in anhydrous 1,4-dioxane (2 mL) was degassed and vacuum / nitrogen purged (3 times). tBuXPhos Pd G3 (17 mg, 0.021 mmol) was added and the mixture was degassed again and vacuum / nitrogen purged (3 times). The reaction mixture was heated at 70° C. for 16 h. It was cooled to room temperature and filtered through Celite, washing with dioxane. The solvent was evaporated and the crude material was purified by flash column chromatography to give the title compound (11 mg, 15% yield).

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[0218] Example 77 [ka] 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, A mixture of intermediate 84 (52 mg, 0.138 mmol), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)-pyridine (50 mg, 0.207 mmol) and sodium tert-butoxide (40 mg, 0.413 mmol) in anhydrous 1,4-dioxane (2 mL) was degassed and vacuum / nitrogen purged (3 times). tBuXPhos Pd G3 (17 mg, 0.021 mmol) was added and the mixture was degassed again and vacuum / nitrogen purged (3 times). The reaction mixture was heated at 70° C. for 16 h, then cooled to room temperature and filtered through celite, washing with dioxane. The solvent was evaporated and the crude material was purified by flash column chromatography to give the title compound (16 mg, 22% yield).

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[0219] Example 78 [ka] 3-Cyclopropyl-9-[[3,4-dioxo-2-(pyridin-3-ylamino)cyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide 3-Methoxy-4-(3-pyridylamino)cyclobut-3-ene-1,2-dione (43 mg, 0.209 mmol) was suspended in dichloromethane (3 mL). N,N-diisopropylethylamine (27 mg, 0.209 mmol) and methanol (2 mL) were added. Intermediate 39 (50 mg, 0.139 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The formed precipitate was filtered off and washed with DCM to give the title compound (5.7 mg, 8% yield).

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[0220] Example 79 [ka] (9R*)-3-Cyclopropyl-9-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] Intermediate 39 (43 mg, 0.109 mmol) was dissolved in a mixture of dichloromethane (10 mL) and N,N-diisopropylethylamine (21 mg, 0.163 mmol). 3,4-Dimethoxy-3-cyclobutene-1,2-dione (23 mg, 0.163 mmol) was added and the mixture was stirred at room temperature for 16 h. Ethylamine solution (2M in THF, 2.17 mL, 4.34 mmol) was added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the crude material was purified by flash column chromatography to give the title compound as a racemic mixture (26.5 mg, 51% yield). The racemate was separated using chiral HPLC in polar organic mode to give the title compound as a single isomer (6.2 mg, 23% yield).

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[0221] Example 80 [ka] (9R*)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] Intermediate 39 (50 mg, 0.139 mmol), 2-chlorobenzimidazole (32 mg, 0.209 mmol) and 1-butanol (3 mL) were charged to a microwave tube. 4M Hydrochloric acid in dioxane (0.03 mL, 0.14 mmol) was added. The sealed reaction mixture was heated in a microwave at 160° C. for 4.5 h and cooled to room temperature. The solvent was evaporated and the residue was partitioned between DCM and saturated aqueous NaHCO3. The organic phase was washed with brine, passed through a phase separator cartridge and evaporated. The crude material was purified by flash chromatography to give the title compound as a racemic mixture (26 mg, 39% yield). The racemate (20 mg) was then separated by chiral SFC to give the title compound as a single isomer (4 mg, 20% yield from chiral separation, peak 1). Chiral SFC RT**=6.36 min.

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[0222] Example 81 [ka] 3-Cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(3,3-difluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 119 (35 mg, 0.026 mmol, 50% purity) was stirred in DCM (3 mL) and TFA (30.2 μl, 0.39 mmol) was added. The reaction was stirred at room temperature for 30 min. The orange suspension was quenched with saturated aqueous NaHCO3 (10 mL), the organic layer was separated and the aqueous layer was extracted with additional DCM (3×20 mL). The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The orange residue was purified by acidic preparative HPLC to give the title compound (1 mg, 7% yield) as a white solid.

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[0223] Example 82 [ka] 3-Cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(3-fluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 113 (46 mg, 0.034 mmol) was stirred in DCM (4 mL) and TFA (39 μl, 0.51 mmol) was added. The reaction was stirred at room temperature for 30 min. The orange suspension was quenched with saturated aqueous NaHCO3 (15 mL), the organic layer was separated and the aqueous layer was extracted with additional DCM (3×20 mL). The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The orange residue was purified by HPLC (basic conditions) to give the title compound (4.1 mg, 24% yield) as a approx. 7:3 mixture of diastereoisomers (as observed by NMR).

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[0224] Example 83 [ka] 3-Cyclopropyl-7-(methanesulfonamido)-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A mixture of intermediate 58 (255 mg, 0.59 mmol), cyclopropylboronic acid (152 mg, 1.77 mmol) and cesium carbonate (385 mg, 1.18 mmol) in anhydrous 1,4-dioxane (1.5 mL) was degassed by sonication for 5 min under a stream of nitrogen. Bedford catalyst: (2-{[bis(2,4-di-tert-butylphenoxy)phosphanyl]oxy}-3,5-di-tert-butylphenyl)(chloro)palladium-tricyclohexylphosphane (1:1) (63.06 mg, 0.06 mmol) was then added, the tube was sealed and the mixture was heated to 120° C. for 2 h with stirring in a microwave reactor. Further Bedford catalyst (63.06 mg, 0.06 mmol) and cyclopropylboronic acid (152 mg, 1.77 mmol) were then added and the mixture was sealed and heated to 120° C. with stirring in a microwave reactor for an additional hour. The mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (5 mL) and washed with water (5 mL). An emulsion formed and the mixture was passed through a plug of diatomaceous earth. The removed solid was washed with EtOAc (5 mL). The two phases present in the filtrate were separated and the aqueous phase was extracted with EtOAc (5 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC under basic conditions to give the title compound (28 mg, 16.3% yield) as a white solid.

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[0225] Example 84 [ka] 3-Cyclopropyl-7-[[3,4-dioxo-2-(pyridin-3-ylamino)cyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a stirred suspension of intermediate 99 (45 mg, 0.22 mmol) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.2 mmol) followed by methanol (2 mL) to solubilize the mixture. Example 50 (50 mg, 0.14 mmol) was added and the resulting mixture was stirred at room temperature for 17 h. The reaction mixture was evaporated under vacuum and the residue was purified via column chromatography using a gradient of 0-100% ethyl acetate in isohexane followed by 1-20% methanol in ethyl acetate to give the title compound (62 mg, 84% yield).

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[0226] Example 85 [ka] 1-Ethyl-3-[(7R*)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea[* or S] A mixture of Example 50 (60 mg, 0.15 mmol) and ethyl isocyanate (33 μL, 0.41 mmol) in dichloromethane (3 mL) was stirred at room temperature for 3 h. The reaction mixture was quenched by addition of methanol (1.5 mL) and evaporated under vacuum. The residue was purified by column chromatography using a gradient of 0-100% ethyl acetate in isohexane to give the product (51 mg) as a mixture of enantiomers. Purification by chiral chromatography afforded the title compound (14 mg, 29% yield). Chiral SFC*RT=4.01 min.

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[0227] Example 86 [ka] (7R*)-3-Cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] The title compound was prepared following general procedure 2 using intermediate 116 (410 mg, 0.77 mmol), formic hydrazide (150 mg, 2.2 mmol), mercuric chloride (420 mg, 1.5 mmol), N,N-dimethylformamide (15 mL) and triethylamine (0.32 mL, 2.3 mmol). Purification using chromatography using a gradient of 0-15% methanol in dichloromethane followed by reverse phase column chromatography using a gradient of 0-100% acetonitrile in water (+0.1% ammonia) afforded the title compound (229 mg) as a mixture of enantiomers. The sample was purified by chiral SFC to afford the title compound as a single isomer (8 mg). Chiral SFC RT**=6.62 min.

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[0228] Examples 87 and 88 [ka] (7R*)-3-Cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] (87) 3-Cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (88) The title compound was prepared following general procedure 5 using intermediate 117 (145 mg, 0.28 mmol), formic hydrazide (60 mg, 0.90 mmol), mercuric chloride (155 mg, 0.57 mmol), N,N-dimethylformamide (5 mL) and triethylamine (0.12 mL, 0.86 mmol). Purification by reverse phase column chromatography using a gradient of 0-100% acetonitrile in water (+0.1% formic acid), followed by column chromatography using a gradient of 0-100% ethyl acetate in isohexane, and then 1-50% methanol in ethyl acetate gave the title compound. Example 87 (23 mg) was obtained as a mixture of enantiomers which was separated by chiral chromatography to give the title compound (6 mg) as a single isomer. Chiral HPLC RT**=2.60 min.

number

number

[0229] Example 89 [ka] (7R*)-3-Cyclopropyl-N-(2-methylpropyl)-7-[3-[(5-methylpyridin-3-yl)amino]-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S] The title compound was prepared following general procedure 5 using intermediate 118 (135 mg, 0.26 mmol), formic acid hydrazide (55 mg, 0.82 mmol), mercuric chloride (145 mg, 0.53 mmol), N,N-dimethylformamide (5 mL) and triethylamine (0.11 mL, 0.79 mmol). Purification by reverse phase column chromatography using a gradient of 0-100% acetonitrile in water (+0.1% formic acid) afforded the title compound (61 mg) as a mixture of enantiomers. Purification by chiral chromatography afforded the title compound as a single isomer (17 mg). Chiral HPLC RT**=2.13 min.

number

[0230] Examples 90 and 91 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (90) 3-Cyclopropyl-N-(2-methylpropyl)-7-[3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (91) The title compound was prepared following general procedure 5 using Example 95 (105 mg, 0.21 mmol), formic hydrazide (42 mg, 0.63 mmol), mercuric chloride (115 mg, 0.42 mmol), N,N-dimethylformamide (5 mL) and triethylamine (0.09 mL, 0.60 mmol). Purification by reverse phase column chromatography using a gradient of 0-100% acetonitrile in water (+0.1% ammonia) gave the product (115 mg) as a mixture. The sample was purified by SFC to give the title compound. Example 90 (4 mg).

number

number

[0231] Example 92 [ka] 7-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Example 50 (50 mg, 0.14 mmol), 2-chlorobenzimidazole (32 mg, 0.21 mmol) and 1-butanol (3 mL) were charged to a microwave tube. A 4M solution of hydrochloric acid in dioxane (0.03 mL, 0.1 mmol) was added and the sealed mixture was heated in a microwave at 160° C. for 2 h. Further 2-chlorobenzimidazole (10 mg, 0.07 mmol) and a 4M solution of hydrochloric acid in dioxane (2 drops) were added and the mixture was heated in a microwave at 160° C. for 1 h. The cooled reaction mixture was quenched with 25% aqueous ammonia solution (2 mL) and partitioned between dichloromethane (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous layer was separated and further extracted into dichloromethane (10 mL) and the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate and evaporated under vacuum. The residue was purified using column chromatography using a gradient of 0-100% ethyl acetate in isohexane followed by 1-30% methanol in ethyl acetate then reverse phase column chromatography using a gradient of 0-100% acetonitrile in water (+0.1% ammonia) to give the title compound (12 mg, 18% yield).

number

[0232] Example 93 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-pyridin-3-yloxy-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Synthesized in the same manner as in Example 94 using intermediate 91 (36 mg, 0.08 mmol) and equivalent stoichiometric reagents. Purification by reverse phase HPLC (basic conditions) afforded the title compound (0.4 mg, 1% yield).

number

[0233] Example 94 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-pyridin-3-yloxy-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 90 (25 mg, 0.056 mmol) in 1,4-dioxane (2 mL) was added cyclopropylboronic acid (22 mg, 0.2433 mmol) and cesium carbonate (66 mg, 0.20 mmol). The mixture was degassed and chloro(η 2 -P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (9 mg, 0.01 mmol) was added and then purged with N2 for 5 min. The resulting mixture was heated at 100° C. for 10 h. The reaction mixture was then filtered through celite (30 mL DCM wash). The solution was diluted with H2O (50 mL) and the phases were separated. The aqueous layer was extracted with DCM (2×30 mL) and the combined organics were dried (phase separator) and concentrated in vacuo. Purification by reverse phase HPLC (basic conditions) afforded the title compound (0.6 mg, 2% yield).

number

[0234] Example 95 [ka] 1-[3-Cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(3-pyridyl)thiourea The title compound was prepared following general procedure 4 using Example 50 (100 mg, 0.28 mmol), 3-pyridyl isothiocyanate (0.05 mL, 0.42 mmol), N,N-diisopropylethylamine (0.07 mL, 0.4 mmol) and dichloromethane (10 mL). Purification by column chromatography using a gradient of 0-100% ethyl acetate in isohexane followed by 1-20% methanol in ethyl acetate afforded the title compound (120 mg, 87% yield).

number

[0235] 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 (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.

[0236] The integrity of the conjugated material was determined by analytical size exclusion chromatography on a S200 HR 10x300 column (GE Healthcare).Typical conjugation ratio was 4:1 = Tb:IgE-Fc.

[0237] See 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.

[0238] 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.

[0239] 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 (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 absorbance at 280 nm and 495 nm.

[0240] The integrity of the conjugated material 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.

[0241] See Cook JPD., Henry AJ., McDonnell JM., Owens RJ., Sutton BJ., and Gould HJ (1997) Biochemistry 36:15579-15588.

[0242] The aim was to measure IgE-Tb binding to the receptor and its inhibition by compounds using an in vitro Fluorescence Resonance Energy Transfer (FRET) assay.

[0243] 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.

[0244] Assay reaction 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 of ×50 of 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, 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.

[0245] The assay was incubated for 2 hours at room temperature, protected from light and evaporation and gently agitated.

[0246] 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: Illumination at 520 / Illumination at 495x1000

[0247] FRET ratios were used for data analysis.

[0248] Data analysis Z' was calculated as follows (σ=standard deviation and μ=mean): 1-((3×σ MAX )+(3×σ MIN )) / (μ MAX -μ MIN )

[0249] A Z' above 0.5 was considered a good assay.

[0250] Background signal (MIN) was subtracted from all wells. The background subtracted values ​​were used to calculate the percentage inhibition by compound in each test well as follows: 100-Test well FRET ratio / MAX FRET ratio x 100

[0251] Percentage of inhibition was plotted versus compound concentration. IC50 values ​​for each compound were determined using a four-parameter logistic fit model with the XLFIT5 software package.

[0252] The compounds exhibit IC50 values ​​ranging from 4 nM to 3602 nM.

[0253] The table below shows the range of IC50 values ​​for each example. [Table 6]

Claims

1. A compound of general formula (I) or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, X is CH or N; Y is C or O; When Y is O, R1 is hydrogen or hydroxy, R1' is hydrogen, and R2, R2' are absent; R1 is hydrogen, Hydroxy, oxo group, amino, C1-6-alkyl, C1-6-alkylamino, C(O)OH, C(O)NH-heteroaryl, —NH-C1-6-alkyl-C3-6-cycloalkyl, -NH-C1-6-alkyl-C(O)OH optionally substituted with an amino group; -NH-cycloalkyl optionally substituted by one or more groups selected from among halogen, oxo, C1-6-alkyl, C1-6-alkylamino, C1-6-alkyl-C1-4-alkylamino, C3-8-cycloalkyl-C1-6-alkylamino, heteroaryl, heteroarylamino optionally substituted by one or more C1-6-alkyl, heteroaryl optionally substituted by one or more groups selected from among halogen, hydroxy, oxo, amino, cyano, -C(O)-C1-6-alkyl, C1-6-alkyl, C1-6-alkylamino, C1-6-alkoxy, -NH-(C1-6-alkyl)-heterocycloalkyl, -NH-(C1-6-alkyl)-heteroaryl optionally substituted by one or more C1-6-alkyl, -NH-C1-6-alkyl-cycloalkyl, -NH-C(O)-cycloalkyl, -NH-heteroaryl substituted by one or more C1-6-alkyl, -NH-C1-6-alkyl-C(O)OH; heteroaryl substituted by heteroarylamino optionally substituted by C1-6-alkyl, C1-6-alkoxy, C3-6-cycloalkyl, C1-6-haloalkoxy, C1-6-haloalkyl, CN, halogen, C(O)OH, -C(O)O-C1-6-alkyl; -NH-C(S)-NH-Ra １ 、 -NH-SO ２ -Rb １ 、 -NH-heteroaryl optionally substituted with one or more groups selected from among oxo, C1-6-alkyl, C1-6-alkylamino, heteroaryl optionally substituted with one or more oxo, C1-6-alkyl, -C(O)-NHNH-C(O)CH3, aryl, heteroarylamino, C1-6-alkoxy, C3-6-cycloalkyl, C1-6-haloalkoxy, C1-6-haloalkyl, CN, halogen, C(O)OH, -C(O)O-C1-6-alkyl; Halogen, C1-6-alkyl, oxo, heteroaryl, C(O)ORb １ , C1-6-alkyl-NRb １ Rb １ , -NH-heterocycloalkyl optionally substituted with one or more groups selected from NHC(O)-aryl, NHC(O)-heteroaryl; -NH-C1-6-alkyl substituted by one heteroaryl group optionally substituted by one or more groups selected from among C1-6-alkyl, amino; -NH-C(O)O-Rb １ 、 -NH-C(NCN)-NH-Ra １ 、 —NH—C(NCN)—NH-heteroaryl, -NH-C(O)-C3-8-heterocycloalkyl-C(O)O-Rb １ , —C(O)NH—C1-6-alkyl, -NH-C(O)NH-C1-6-alkyl optionally substituted by one or more C3-8-heterocycloalkyl; —NH—C(O)NH-heterocycloalkyl-C1-6-alkyl, —NH—C1-6-alkyl-C(O)—C1-6-alkylamino, Heteroaryloxy, —NH—C(O)-aryl, —NH—C(O)-heteroaryl, —NH—C(O)-heterocycloalkyl, -NH-C(O)-C1-6-alkyl optionally substituted by one or more amino groups; Amino, -NH-C(O)ORb １ -NH-C(O)-C1-6-alkyl-C(O)ORb, optionally substituted with a group selected from １ , Amino, -C(O)NH-Rb １ , -C(O)ORb １ , —NHC(O)-heteroaryl optionally substituted with one or more C1-6-alkyls, —NHC(O)-C1-6-alkyl optionally substituted with an amino group, —NHC(O)O-C1-6-alkyl, —NH—C(O)Rb １ Heterocycloalkyl optionally substituted with one or more groups selected from among represents a -C2-6-alkene group which may be substituted by one or more groups selected from halogen, ═NH group; Ra １ teeth, C1-6-alkyl, or aryl optionally substituted with one or more C1-6-alkyl; or represents heteroaryl optionally substituted with one or more C1-6-alkyl; Rb １ teeth, Hydrogen, or C1-6-alkyl, or aryl optionally substituted with one or more halogen, C1-6-alkyl, hydroxy; R1′ is hydrogen, represents hydroxy, R2 is, hydrogen, halogen, Hydroxy groups, oxo group, C1-6-alkyl, C3-8-heterocycloalkyl optionally substituted with one or more hydroxy, halogen, amino, amino-C-1-6-alkyl, C1-6-alkyl, C(O)O-C1-6-alkyl, C(O)NH2; C1-6-alkylamino, heteroaryl optionally substituted with one or more groups selected from C1-6-alkyl, and halogen; heteroaryl optionally substituted by one or more -NH-heteroaryl optionally substituted by C1-6-alkyl, halogen, cyano, -C(O)OH, -C(O)O-C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C3-6-cycloalkyl; -NH-cycloalkyl optionally substituted by one or more groups selected from among halogen, oxo, C1-6-alkyl, C1-6-alkylamino, C1-6-alkyl-C1-4-alkylamino, C3-8-cycloalkyl-C1-6-alkylamino, aryl, heteroaryl, heteroarylamino optionally substituted by one or more C1-6-alkyl, -NH-heteroaryl optionally substituted with one or more groups selected from among hydroxy, halogen, oxo, C1-6-alkyl, C1-6-alkoxy, heteroaryl optionally substituted with one or more hydroxy, halogen, oxo, C1-6-alkyl, C(O)O-C1-6-alkyl, C(O)OH, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C3-6-cycloalkyl, C1-6-alkylamino, cyano, heterocycloalkyl substituted with one or more hydroxyhalogens, and oxo groups; -NH-C1-6-alkyl substituted by one heteroaryl group optionally substituted by one or more groups selected from among C1-6-alkyl; -NH-SO2-heteroaryl, optionally substituted with one or more groups selected from halogen; -NHC(O)-C1-6-alkyl optionally substituted with one or more halogen, C1-6-alkoxy, amino, C3-8-cycloalkyl, C3-8-heterocycloalkyl, heteroaryl; Halogen, hydroxy, oxo, C1-6-alkyl, heteroaryl, C1-6-alkylamino, S(O) ２ -NHC(O)-heteroaryl optionally substituted by one or more groups selected from among -C1-3-alkyl, -NHC(O)-C1-6-alkyl, -NHC(O)-C3-8-heterocycloalkyl optionally substituted with one or more oxo, C1-6-alkyl; —NHC(O)O—C1-6-alkyl, -NHC(O)O-C1-6-alkyl-Ra ２ , -NHC(O)O-aryl, -NHC(O)NH-Ra ２ -NHC(O)NH-C1-6-alkyl-Ra ２ -NH-C(NCN)-NH-Ra １ 、 —NHC(O)—C3-8-cycloalkyl, -NH-SO ２ -Rb ２ 、 -NH-C(S)-NH-Rb ２ 、 -NH-C3-8-heterocycloalkyl optionally substituted with one or more groups selected from oxo, C1-6-alkyl Aryloxy groups, represents a heteroaryloxy group, Ra ２ teeth, hydrogen, aryl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, C1-6-alkyl; represents heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, C1-6-alkyl, Rb ２ teeth, C1-6-alkyl, represents heteroaryl, R2′ is hydrogen, represents hydroxy, R3 is, R3 ａ C1-6-alkyl optionally substituted with one or more groups selected from One or more R ａ C1-3-alkanediyl-C3-6-cycloalkyl optionally substituted with One or more R ａ C1-3-alkanediyl-C3-6-heterocycloalkyl optionally substituted with One or more R ａ C3-6-heterocycloalkyl optionally substituted with One or more R ａ represents a group selected from among C3-6-cycloalkyl optionally substituted by R3 ａ represents a group selected from among hydrogen, halogen, C1-2-alkyl, hydroxy and 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 C1-6-alkanediyl-C3-6-heterocycloalkyl optionally substituted by a group; R4 ａ represents a group selected from hydroxy, halogen, C1-2-alkyl, R5 is, represents hydrogen, methyl or halogen; however, When R1' is hydroxy, R1 is selected from among pyridyl, C1-6-alkyl; When R2' is hydroxy, R2 is selected from among pyridyl, C1-6-alkyl; When R1 is different from hydrogen, R2 and R2' are hydrogen; When R2 is different from hydrogen, R1 and R1' are hydrogen; When R1 is oxo, R1′ is absent; When R2 is oxo, R2' is absent; A compound of formula (I) or a pharma- ceutically acceptable salt thereof:

2. R3 is C1-6-alkyl optionally substituted with one or more groups selected from R3 a ; C1-3-alkanediyl-C3-6-cycloalkyl optionally substituted by one or more R3 a , or represents a group selected from C3-6-cycloalkyl optionally substituted by one or more R3 a ; R3 a represents a group selected from among hydrogen, halogen, C1-2-alkyl, hydroxy and C1-2-alkoxy; A compound of general formula (I) according to claim 1.

3. R4 is C3-6-cycloalkyl optionally substituted with one or more R4 a groups; or represents a group selected from among C1-6-alkanediyl-C3-6-cycloalkyl, optionally substituted by one or more R4 a groups; R4 a represents a group selected from among hydroxy, halogen and C1-2-alkyl; A compound of general formula (I) according to claim 1.

4. R4 represents cyclopropyl or spiro[2.2]pentanyl, optionally substituted with one or more groups independently selected from hydroxy, chloro, fluoro, bromo, and methyl; A compound of general formula (I) according to claim 1.

5. A compound of general formula (I) according to any one of claims 1 to 4, wherein R4 represents cyclopropyl.

6. R1 is, Hydrogen, methoxyimidazopyridinyl, carboxy group, cyclopropyl-methyl-carbamoyl-amino, pyridine-carbonylamino, hydroxy(pyridyl), [(fluorocarbonimidoyl)propenyl], [(cyclopropylmethylamino)imidazolyl], [[(cyclopropylmethyl)imidazolyl]amino], [(dimethylpyrazolyl)carbamoylamino], [[(dimethylpyrazolyl)-triazolyl]amino], (pyridylamino), (tert-butoxycarbonylamino), amino, [(cyclopropylmethylamino)-triazolyl], pyridylcarbamoyl, [(cyclopropanecarbonylamino)pyrazolyl], (aminotetrazolyl), [[(methyltetrazolyl)pyridyl]amino], [(methylpyrazolopyridinyl)amino], [[(methyl-oxadiazolyl)-pyridyl]amino], oxo, hydroxy(methyl), ethylcarbamoylamino), [(ethylamino)- triazolyl], [[(ethylamino)-dioxo-cyclobutenyl]amino], [(ethylamino)-dioxo-thiadiazolyl]amino], [[N'-cyano-N-(p-tolyl)carbamimidoyl]amino], [(tert-butoxycarbonylazetidine-carbonyl)amino], [aminopiperidyl], [(methylcarbamoyl)pyrrolidinyl], [[(dimethylpyrazole-carbonyl)amino]azetidinyl], [(dimethyl-oxo-cyclo butenyl)amino], (indolylmethylamino), methanesulfonamide, [[dioxo(pyridylamino)cyclobutenyl]amino], ethylcarbamoylamino, [[(dimethylpyrazolyl)amino]-triazolyl], [[(methyl-pyridyl)amino]-triazolyl], [[(pyridyl)-triazolyl]amino], [(pyridylamino)-triazolyl], (benzimidazolylamino), pyridyloxy, (pyridylcarbamothioylamino) A compound of general formula (I) according to any one of claims 1 to 5, which represents

7. R2 is, hydrogen, [(methylbenzotriazolyl)-triazolyl]methyl, [[(methylpyrazolyl)-triazolyl]amino], [[(methylpyrazolyl)amino]-triazolyl], [[(fluoro-pyridyl)-triazolyl]amino], [[(fluoro-pyridyl)amino]-triazolyl], (pyridylmethylamino), (pyridylsulfonylamino), [(fluoro-indolecarbonyl)amino], [(methylbenzimidazolyl)amino], [(methoxycarbonyl-pyridyl)amino], [(carboxypyridyl)amino], [(methyl-pyrazole-carbonyl)amino], (pyridine-carbonylamino), [(methylcyclopropanecarbonyl)amino], (pyrimidinylamino), [(oxoindolinyl)amino], [(methoxypyridyl)amino], (pyridylamino), [(methylpyrazolopyridinyl)amino], benzyloxycarbonylamino, [(bromophenyl)carbamoylamino], [(dimethylpyrazolyl)methylcarbamoylamino], hydroxy, oxo, methyl, fluorine, [[(ethylamino)-dioxo-thiadiazolyl]amino], [(cyanomethyl-pyrazolyl)amino], (isoquinolylamino), [[N'-cyano-N-(p-tolyl)carbamimidoyl]amino], methanesulfonamido, ethylcarbamothioylamino, [(ethylamino)-triazolyl], [(ethyl-triazolyl)amino], (pyridylcarbamothioylamino), [[(pyridyl)-triazolyl]amino], [[(methyltetrazolyl)-pyridyl]amino], [[dioxo-(pyridylamino)cyclobutenyl]amino], [[(ethylamino)-dioxo-cyclobutenyl]amino], (benzimidazolylamino), pyridyloxy A compound of general formula (I) according to any one of claims 1 to 6, which represents

8. R1 is, Hydrogen, (7-methoxyimidazo[4,5-b]pyridin-3-yl), carboxy group, cyclopropyl-methyl-carbamoyl-amino, pyridine-3-carbonylamino, hydroxy(3-pyridyl), [1-(fluorocarbonimidoyl)prop-1-enyl], [2-(cyclopropylmethylamino)imidazol-1-yl], [[1-(cyclopropylmethyl)imidazol-2-yl]amino], [(2,5-dimethylpyrazol-3-yl)carbamoylamino], [[4-(2,5-dimethylpyrazol-3-yl)-1 ,2,4-triazol-3-yl]amino], (3-pyridylamino), (tert-butoxycarbonylamino), amino, [3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl], 3-pyridylcarbamoyl, [5-(cyclopropanecarbonylamino)pyrazol-1-yl], (5-aminotetrazol-1-yl), [[6-(2-methyltetrazol-5-yl)-3-pyridyl]amino], [(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino], [[6-(5-methyl-1,3,4- oxadiazol-2-yl)-3-pyridyl]amino], oxo, hydroxy(methyl), (ethylcarbamothioylamino), [3-(ethylamino)-1,2,4-triazol-4-yl], [[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino], [[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino], [[N'-cyano-N-(p-tolyl)carbamimidoyl]amino], [(1-tert-butoxycarbonylazetidine-3-carbonyl)amino] , [3-amino-1-piperidyl], [(2R)-2-(methylcarbamoyl)pyrrolidin-1-yl], [3-[(2,5-dimethylpyrazole-3-carbonyl)amino]azetidin-1-yl], [(4,4-dimethyl-3-oxo-cyclobuten-1-yl)amino], (1H-indol-2-ylmethylamino), methanesulfonamide, [[3,4-dioxo-2-(3-pyridylamino)cyclobuten-1-yl]amino], ethylcarbamoylamino, [3-[(2,5-dimethylpyrazole-3-yl)amino]-1,2,4-triazol-4-yl], [3-[(5-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl], [[4-(3-pyridyl)-1,2,4-triazol-3-yl]amino], [3-(3-pyridylamino)-1,2,4-triazol-4-yl], (1H-benzimidazol-2-ylamino), 3-pyridyloxy, (3-pyridylcarbamothioylamino), A compound of general formula (I) according to any one of claims 1 to 7, which represents

9. R2 is, Hydrogen, [4-(1-methylbenzotriazol-4-yl)-1,2,4-triazol-3-yl]methyl, [[4-(2-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino], [3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl], [[4-(5-fluoro-3-pyridyl)-1,2,4-triazol-3-yl]amino], [3-[(5-fluoro-3-pyridyl)amino]-1,2,4-triazol-4-yl], (3-pyridylmethylamino), (3-pyridyl sulfonylamino), [(6-fluoro-1H-indole-3-carbonyl)amino], [(1-methylbenzimidazol-2-yl)amino], [(6-methoxycarbonyl-3-pyridyl)amino], [(6-carboxy-3-pyridyl)amino], [(5-methyl-1H-pyrazole-3-carbonyl)amino], (pyridine-3-carbonylamino), [(2-methylcyclopropanecarbonyl)amino], (pyrimidin-5-ylamino), (2-oxoindolin-5-yl)amino], [(5-methoxy-3-pyridyl)amino] , (3-pyridylamino), [(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino], benzyloxycarbonylamino, [(4-bromophenyl)carbamoylamino], [(2,5-dimethylpyrazol-3-yl)methylcarbamoylamino], hydroxyoxo, methyl, fluorine, [[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino], [(4-cyano-1-methyl-pyrazol-3-yl)amino], (4-isoquinolylamino), [[N'-cyano-N-(p-tolyl)carbamoylamino] bamimidoyl]amino], methanesulfonamide, ethylcarbamothioylamino, [3-(ethylamino)-1,2,4-triazol-4-yl], [(4-ethyl-1,2,4-triazol-3-yl)amino], (3-pyridylcarbamothioylamino), [[4-(3-pyridyl)-1,2,4-triazol-3-yl]amino], [[6-(2-methyltetrazol-5-yl)-3-pyridyl]amino], [[3,4-dioxo-2-(3-pyridylamino)cyclobuten-1-yl]amino], [[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino], (1H-benzimidazol-2-ylamino), 3-pyridyloxy, A compound of general formula (I) according to any one of claims 1 to 8, which represents

10. 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(7-methoxyimidazo[4,5-b]pyridin-3-yl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-isobutyl-9-[[4-(1-methylbenzotriazol-4-yl)-1,2,4-triazol-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-isobutyl-9-[[4-(2-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-isobutyl-9-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-[[4-(5-fluoro-3-pyridyl)-1,2,4-triazol-3-yl]amino]-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-[3-[(5-fluoro-3-pyridyl)amino]-1,2,4-triazol-4-yl]-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylic acid, 1-(cyclopropylmethyl)-3-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea[* or S], N-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide[* or S], 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-hydroxy-7-pyridin-3-yl-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(2-fluoropyridin-3-yl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (7R*)-3-cyclopropyl-7-[2-(cyclopropylmethylamino)imidazol-1-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], (7R*)-3-cyclopropyl-7-[[1-(cyclopropylmethyl)imidazol-2-yl]amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 3-cyclopropyl-N-(2-methylpropyl)-9-(pyridin-3-ylmethylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-methylpropyl)-9-(pyridin-3-ylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 6-fluoro-N-[(9R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1H-indole-3-carboxamide[* or S], 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(1-methylbenzimidazol-2-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, methyl 5-[[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-2-carboxylate, 5-[[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-2-carboxylic acid, 5-methyl-N-[(9R*)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1H-pyrazole-3-carboxamide[* or S], N-[(9R*)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide[* or S], 3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide, 1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]cinnolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea, 3-cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide, (7R*)-3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide[* or S], N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-2-methylcyclopropane-1-carboxamide, 3-cyclopropyl-4-fluoro-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-(pyrimidin-5-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(2-oxo-1,3-dihydroindol-5-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(5-methoxypyridin-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, tert-butyl N-[3-cyclopropyl-5-[(1,1-dideuterio-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate, 7-amino-3-cyclopropyl-N-(1,1-dideuterio-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(1,1-dideuterio-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 7-cyclopropyl-N-(2-fluoro-2-methylpropyl)-3-hydroxy-2,3-dihydrofuro[3,2-h]isoquinoline-5-sulfonamide, (7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-N-pyridin-3-yl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxamide[* or S], N-[2-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyrazol-3-yl]cyclopropanecarboxamide, 7-(5-aminotetrazol-1-yl)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, benzyl N-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate, 1-(4-bromophenyl)-3-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea, 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]urea, 3-cyclopropyl-7-hydroxy-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-methylpropyl)-7-oxo-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-hydroxy-7-methyl-N-(2-methylpropyl)-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 7-amino-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-ethylthiourea, (7R*)-3-cyclopropyl-7-[3-(ethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (* or S), (7R*)-3-cyclopropyl-7-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (* or S), 3-cyclopropyl-7-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 2-cyano-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(4-methylphenyl)guanidine, tert-butyl 3-[[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamoyl]azetidine-1-carboxylate[*or S], 7-[(3R)-3-aminopiperidin-1-yl]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (2R)-1-[(7R*)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-N-methylpyrrolidine-2-carboxamide[* or S], N-[1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]azetidin-3-yl]-2,5-dimethylpyrazole-3-carboxamide, 3-cyclopropyl-7-[(4,4-dimethyl-3-oxocyclobuten-1-yl)amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(1H-indol-2-ylmethylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-hydroxy-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-methylpropyl)-9-oxo-7,8-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-hydroxy-9-methyl-N-(2-methylpropyl)-7,8-dihydrocyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-fluoro-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 9-[(4-cyano-1-methylpyrazol-3-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-(isoquinolin-4-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 2-cyano-1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-(4-methylphenyl)guanidine, 3-cyclopropyl-9-(methanesulfonamido)-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-ethylthiourea, 3-cyclopropyl-9-[3-(ethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (9R*)-3-cyclopropyl-9-[(4-ethyl-1,2,4-triazol-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-pyridin-3-yl thiourea, 3-cyclopropyl-N-(2-methylpropyl)-9-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-9-[[3,4-dioxo-2-(pyridin-3-ylamino)cyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (9R*)-3-cyclopropyl-9-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], (9R*)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 3-cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(3,3-difluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-N-(3-fluorocyclobutyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-(methanesulfonamido)-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-7-[[3,4-dioxo-2-(pyridin-3-ylamino)cyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 1-ethyl-3-[(7R*)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea[* or S], (7R*)-3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], (7R*)-3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 3-cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, (7R*)-3-cyclopropyl-N-(2-methylpropyl)-7-[3-[(5-methylpyridin-3-yl)amino]-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide[* or S], 3-cyclopropyl-N-(2-methylpropyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-methylpropyl)-7-[3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 7-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-pyridin-3-yloxy-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-pyridin-3-yloxy-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide, and 1-[3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(3-pyridyl)thiourea 2. The compound of general formula (I) according to claim 1, selected from:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 11, further comprising a pharma- ceutically acceptable carrier.

13. 13. A pharmaceutical composition according to claim 11 or 12 for treating or preventing a disorder caused by IgE.

14. 13. A pharmaceutical composition according to claim 11 or 12 for treating or preventing allergies, non-allergic mast cell responses, type 1 hypersensitivity, urticaria or the well-known sinusitis.

15. 13. The pharmaceutical composition according to claim 11 or 12 for treating or preventing airway narrowing in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, urticaria, or increased vascular permeability.

16. 13. The pharmaceutical composition of claim 11 or 12 for treating or preventing eosinophilic granulomatosis with polyangiitis (also known as "Churg-Strauss syndrome"), aspirin-exacerbated respiratory disease, or cutaneous T-cell lymphoma.

17. Use of a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament.

18. Use of a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of disorders caused by IgE.

19. Use of a compound according to any one of claims 1 to 10 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 well-known sinusitis.

20. Use of a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof for the manufacture of a pharmaceutical for treating or preventing airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, urticaria, or increased vascular permeability.

21. Use of a compound according to any one of claims 1 to 10 or a pharma- ceutical agent thereof for the manufacture of a medicament for the treatment or prevention of eosinophilic granulomatosis with polyangiitis (also known as Churg-Strauss syndrome), aspirin-exacerbated respiratory disease or cutaneous T-cell lymphoma.

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