Dihydro-cyclopenta-isoquinoline derivatives

Abstract

The present invention relates to dihydro-cyclopenta-isoquinoline derivatives of formula (I), [Formula 1] JPEG2023508383000111.jpg4855 It relates to methods for their preparation, pharmaceutical compositions containing them, and their use in the treatment of disorders caused by IgE (such as allergic responses, non-allergic mast cell responses or certain autoimmune responses), particularly disorders caused by the interaction of IgE with the FcεRI receptor.

Description

[Technical field]

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

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

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

[0004] Currently, allergic diseases, urticaria and asthma are usually treated with one or more of the following drugs: (1) antihistamines and anti-leukotrienes that antagonize the inflammatory mediators histamine and leukotrienes, (2) 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 in asthma, or (4) mast cell stabilizers that inhibit the degranulation of mast cells that is normally triggered by IgE binding at FcεRI, (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-type 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, R1 represents: Hydroxy; amino; -NH-C(O)-Ra 1 ; -NH-C(O)-NH-Rb 1 ; -NH-C(O)-C1-6-alkanediyl-C(O)-C1-6-alkoxy, optionally substituted with one or more aryl substituted with one or more halogen, -OH, C1-6-alkyl; -NH-C(O)-C1-6-alkanediyl-C(O)-aryl, optionally substituted with one or more hydroxy; halogen; C1-6-alkyl; -NH-C(O)-C1-6-alkanediyl-NHC(O)-aryl, optionally substituted with one or more hydroxy; halogen; C1-6-alkyl; -NH-C(O)-C1-6-alkanediyl-aryloxy, optionally substituted with one or more hydroxy; halogen, C1-6-alkyl; -NH-C(O)-NH-C(O)O-C1~6-alkyl; -NH-heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; heteroaryl; -NH-C(S)-NH-Rc 1 ; -NH-aryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; heteroaryl; -NH-C(O)O-Rd 1 -NH-C(N-CN)-NH-C1-6-alkyl; Heteroaryl, provided that one or more of C1-6-alkyl is / are present; C1-6-alkylamino; heteroarylamino, optionally substituted; however, Ra 1 represents C1-6-alkyl, but with halogen; C1-6-alkoxy; aryl or heteroaryl, optionally substituted with cyano; Aryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; C1-6-alkylamino; Heteroaryl, optionally substituted with one or more halogens; C1-6-alkyl, C1-6-alkoxy; cyano; heterocycloalkyl; -C2-6-alkenediyl-aryl, provided that one or more of C1-6-alkyl are optionally substituted with halogen; -R1'C(O)OR1'' group, where R1'' is alkyl and R1' is alkanediyl; C3-8-cycloalkyl, optionally substituted with one or more halogens; C1-6-alkyl; C1-6-alkoxy; cyano C3-8-heterocycloalkyl optionally substituted with one or more halogens; C1-6-alkyl; C1-6-alkoxy; cyano; Rb 1 represents C1-6-alkyl, aryl optionally substituted with one or more halogen, C1-6-alkoxy; Heteroaryl optionally substituted with one or more halogens; C1-6-alkyl; C1-6-alkoxy. , optionally substituted; C3-12-cycloalkyl, optionally substituted with one or more C1-6-alkyl groups, aryl; aryl optionally substituted with one or more cyano; C2-6-alkenediyl-aryl, optionally substituted with one or more halogen; C1-6-alkyl; -OH; aryl substituted with one or more halogen; C1-6-alkyl; -OH; Heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; heterocycloalkyl, optionally substituted with one or more halogens; C1-C6-alkoxy; cyano; amino; Rc 1 represents C1-6-alkyl; Heteroaryl; Rd 1 teeth: Represents C1-6-alkyl; R2 represents: Hydroxy; -NH-C(O)O-C1~6-alkyl; -NH-C(S)-NH-Ra 2 ; -NH-C(O)-NH-Rb 2 ; -NH-aryl, optionally substituted with one or more of C1-6-alkoxy; C1-6-alkylamino; heteroarylamino; -NH-C1-6-alkyl, optionally substituted with one or more of C1-6-alkyl; C1-6-alkoxy; cyano; aryl; heteroaryl; C(O)O-C1-6-alkyl; C1-6-alkylamino, wherein the substituents are optionally substituted with one or more of hydroxy; halogen; oxo; Heteroaryl, optionally substituted with one or more of heteroaryl; hydroxy; oxo; C1-6-alkyl; C1-6-alkylamino or heteroarylamino; wherein said heteroaryl or heteroarylamino is optionally substituted with one or more of groups selected from amino; C1-6-alkyl; C1-6-alkylamino; heteroarylamino; -NH-heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; heteroaryl; C(O)OH; C(O)O-C1-6-alkyl; C1-6-alkylamino; Aryl-C1~6-alkylamino; -C1~6-alkylamino; -NH-C(O)-C1-6-alkyl; -NH-CO-Rc 2 ; -NH-C(O)-C2~6-alkenediyl-C(O)O-C1~6-alkyl; -NH-C(O)-C2-6-alkenediyl-aryl, optionally substituted with one or more hydroxy; C1-6-alkyl; halogen; -NH-C(O)-C1-6-alkanediyl-heteroaryl, optionally substituted with one or more oxo groups; -NH-C(O)-C1-6-alkanediyl-heterocycloalkyl, optionally substituted with one or more oxo groups; -NHSO 2 -C1~6-alkyl; -NHSO 2 -heteroaryl, optionally substituted with one or more halogens; C1-6-alkyl; C1-6-alkoxy; C(O)OH groups; -NH-C(S)-NH-C1~6-alkyl; -NHSO 2 -C1-6-alkoxy, optionally substituted with one or more halogen groups; -NH-C(N-CN)-NH-C1-6-alkyl; Amino group; Ra 2 represents Heteroaryl; C1-6-alkyl; Rb 2 represents C1-6-alkyl, provided that one or more aryls are present; alkoxy-aryl; heteroaryl, optionally substituted with one or more C1-6-alkyls; heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; Cycloalkyl, provided that one or more halogens are present; C1-6-alkyl, C1-6-alkoxy; cyano; aryl, optionally substituted; C1~6-alkanediyl-C(O)O-C1~6-alkyl; Heterocycloalkyl; aryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; C1~6-alkyl-C(O)O-C1~6-alkyl; Rc 2 represents C1-6-alkyl; C3-8-cycloalkyl; C3-8-heterocycloalkyl; aryl, optionally substituted with one or more C1-6-alkyl; C1-6-alkylamino; heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; heterocycloalkyl; aryl; amino; C2-6-alkenediyl-aryl, optionally substituted with one or more halogens; C1-6-alkyl; -OH; C2-6-alkanediyl-heterocycloalkyl, provided that one or more C1-6-alkyl are optionally substituted by -OH; C2-6-alkanediyl-C1-6-alkoxy group, optionally substituted with one oxo group; R3 represents: 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 aa group selected from C3-6-cycloalkyl optionally substituted with R3 a represents a group selected from hydrogen; halogen; C1-2-alkyl; hydroxy; and C1-2-alkoxy; R4 represents: 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 a group selected from 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] 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.

[0009] 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 pharmaceutically acceptable acids. 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.

[0010] The term "pharmaceutical acceptable salts" according to the present invention includes salts of compounds of formula (I) with pharmaceutical acceptable acids or bases, in particular acid addition salts. The acid addition salt forms of compounds of formula (I) occurring in free form as bases can be obtained by treating the free base with a suitable acid, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids, e.g., acetic acid, trifluoroacetic acid, oxalic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, or the like.

[0011] The present invention also relates to all stereoisomers, such as enantiomers and diastereoisomers, of the compounds of formula (I) or mixtures thereof (including all possible mixtures of stereoisomers, such as racemates). In the context of the present invention, reference to a compound(s) is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, unless a particular isomeric form is specifically mentioned.

[0012] Some of the compounds of formula (I) may exist in tautomeric forms. Such forms, although not explicitly shown in the above formula, are intended to be included within the scope of the present invention.

[0013] It should be understood that each atom present in formula (I) or any formula shown herein may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each hydrogen atom present in formula (I) or any formula shown herein may be present as 1H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, by way of example, each carbon atom present in formula (I) or any formula shown herein may be present as 12C, 13C or 14C atom, preferably 12C.

[0014] 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.

[0015] 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 compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0016] 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.

[0017] 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.

[0018] Another aspect 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.

[0019] In yet another aspect, the present invention relates to a compound of formula (I), a pharma- ceutically acceptable salt, solvate or co-crystal for use as a medicament, in particular in a method for treating or preventing disorders caused by IgE including allergy, type 1 hypersensitivity, familial sinusitis, urticaria or related conditions, e.g. airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, increased vascular permeability, eosinophilic granulomatosis with polyangiitis (also known as "Churg-Strauss syndrome"), aspirin-exacerbated respiratory disease or cutaneous T-cell lymphoma.

[0020] In a further aspect, the present invention relates to a method of treating or preventing allergy, type 1 hypersensitivity, familial sinusitis, urticaria or related conditions comprising the administration of a therapeutically effective amount of a compound of formula (I).

[0021] Within the framework of the present invention: Ct-z represents a carbon chain that may have t-z carbon atoms, for example a C1-7 carbon chain that may have 1-7 carbon atoms; Alkyl is a saturated, linear or branched aliphatic group, for example, a C1-6-alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, hexyl. Alkyl is a group in which one or more hydrogen atoms are replaced by a deuterium atom. 2 H-replaced deuterated groups are included. -Alkanediyl is -CH 2 -CH 2 General formula C n H 2n is a divalent linear or branched saturated hydrocarbon radical; -Alkenediyl is a divalent linear or branched unsaturated hydrocarbon radical exhibiting at least one double bond, such as -CH=CH-: -Alkylamino refers to one or more alkyl groups substituted on an amino radical. Examples of alkylamino groups include methylamino, ethylamino, tertbutylamino, dimethylamino; - acyl, alkyl-C(O)- groups; -oxo, a=O group -hydroxy is an -OH group; -hydroxyalkyl is an alkyl group having one or more hydrogen atoms replaced by a hydroxy group; -alkoxy, -O-alkyl groups; -Alkylthio, -S-alkyl group; a halogen atom, a fluorine, chlorine, bromine or iodine atom; -Cycloalkyl refers to a monocyclic or bicyclic saturated aliphatic group containing 3 to 14 atoms, preferably 3 to 9 atoms, in the group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro-undecanyl, and spiro-[2.2]pentanyl; -Heterocycloalkyl refers to a monocyclic or bicyclic saturated group containing 3 to 14 atoms in which one or more carbon atoms are replaced by an atom selected from the group consisting of 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 10 carbon atoms, in which at least one ring is an aromatic group. Examples of aryl groups include phenyl or naphthyl groups. -heteroaryl refers to a monocyclic or bicyclic group containing 5 to 14 atoms, preferably 5 to 9 atoms, in which at least one ring is aromatic and at least one atom in the group is selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include triazolyl, furanyl, pyrrolyl, chromanyl, and isoquinolinyl. -arylamino refers to an amino group -NH2 substituted with an aryl group. An example of an arylamino can be anilino; -Heteroarylamino refers to an amino group -NH2 substituted with a heteroaryl group. An example of a heteroaryl group can be pyridinylamino. -aryloxy refers to the group -O-aryl. An example of aryloxy is phenoxy.

[0022] According to one embodiment, the compounds of the invention have the formula R4: Hydroxy; Chloro, fluoro, bromo It is characterized in that it represents cyclopropyl or spiro[2.2]pentanyl, optionally substituted with one or more groups independently selected from methyl.

[0023] According to one aspect, the compounds of the invention are characterized by the formula in which R4 represents cyclopropyl.

[0024] According to one embodiment, the compound of the invention has the formula: 1 represents, Ra 1 represents heteroaryl optionally substituted with one or more halogens; C1-6-alkyl, C1-6-alkoxy; cyano; heterocycloalkyl; aryl; or -NH-heteroaryl optionally substituted with one or more halogens; C1-6-alkyl, C1-6-alkoxy; cyano; heterocycloalkyl; aryl).

[0025] According to one aspect, the compounds of the present invention are those in which R1 is Hydroxy;Pyridine-carbonylamino;Ethylcarbamoylamino;(Methoxyphenyl)methylcarbamoylamino;[(Bromophenyl)methyl]carbamoylamino;Naphthalenylcarbamoylamino;(Methyl-oxazolyl)methyl]carbamoylamino;Ethoxycarbonyl-carbamoylamino;[(Methoxyphenyl)ethyl]carbonylamino;(Cyclopropylethyl)carbamoylamino;(Methyl)cyclopropyl]carbamoylamino;(Benzyl)carbamoylamino;(Phenyl-cyclopropyl )carbamoylamino;(chromanyl)carbamoylamino;(chlorophenyl)propenoyl]amino;(methoxypyridine-carbonyl)amino;[(methoxy-oxo-propanoyl)amino];(benzamidoacetyl)amino;(chloro-methoxy-thiophene-carbonyl)amino;(ethoxy-oxo-propanoyl)amino;methylbutanoylamino;[(chlorophenoxy)acetyl]amino;(methoxypyridinyl)amino;amino;benzimidazolyl-amino;ethylcarbamothioylamino;(pyridinyl- Bird azolyl)amino;[(ethyl- Bird (Azolyl)amino;(Ethylamino)- Bird Azolyl;Ethylcarbamoylamino;(Methyl-oxa Zia (5-methylpyridine-3-carbonyl)amino; (6-morpholin-4-ylpyridine-3-carbonyl)amino; benzamido; [(dimethylamino)benzoyl]amino; dimethylbutanoylamino.

[0026] According to one aspect, the compounds of the present invention are those in which R1 is Hydroxy;Pyridine-3-carbonylamino;Ethylcarbamoylamino;(4-Methoxyphenyl)methylcarbamoylamino;(3-Cyanophenyl)carbamoylamino;[(4-Bromophenyl)methyl]carbamoylamino;Naphthalen-1-ylcarbamoylamino;[(5-Methyl-1,2-oxazol-3-yl)methyl]carbamoylamino;Ethoxycarbonyl-carbamoylamino;[(1R)-1-(3-Methoxyphenyl)ethyl]carbonylamino;(1-Cyclopropylethylcarbamoylamino);2-(Methyl)cyclopropyl]carbamoylamino;(1-Benzyl)carbamoylamino;(2-Phenyl-cyclopropyl)carba moylamino;(chroman-3-yl)carbamoylamino;(E)-3-(2-chlorophenyl)prop-2-enoyl]amino;(6-methoxypyridine-3-carbonyl)amino;[(3-methoxy-3-oxo-propanoyl)amino];(2-benzamidoacetyl)amino;(5-chloro-4-methoxy-thiophene-3-carbonyl)amino;(3-ethoxy-3-oxo-propanoyl)amino;2-methylbutanoylamino;[2-(4-chlorophenoxy)acetyl]amino;(5-methoxypyridin-3-yl)amino;Amino;1H-benzimidazol-2-ylamino;Ethylcarbamothioylamino;(4-pyridin-3-yl-1,2,4- Bird Azol-3-yl)amino; 3-(ethylamino)-1,2,4- Bird Azol-4-yl; 3-(5-methyl-1,3,4-oxa Zia (Z)-N'-N-(2-phenyl-2-yl)anilino; tert-butoxycarbonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; propan-2-ylcarbamoylamino; pyridin-3-ylcarbamothioylamino; (5-methylpyridine-3-carbonyl)amino; 6-morpholin-4-ylpyridine-3-carbonyl)amino; benzamide; [4-(dimethylamino)benzoyl]amino; 3,3-dimethylbutanoylamino.

[0027] According to one aspect, the compounds of the invention are those in which R2 is tert-Butoxycarbonyl-amino;Amino;Pyridylcarbamothioylamino;Ethylcarbamoylamino;Pyridinyl-amino;(Pyridinyl- Bird (Azolyl)amino;(Pyridinyl-amino)- Bird Azolyl; (Ethyl- Bird Azolyl)amino;Benzylamino;Propylamino;Methylpropanoylamino;Hydroxy;Ethylcarbamoylamino;Isoquinolinyl-amino;(Methoxypyridinyl)amino;(Pyridinyl)carbonylamino;Benzimidazolylamino;[(Phenyl)-oxazolyl]carbonylamino;Quinoxaline-carbonylamino;[(Hydroxyphenyl)propenoyl]amino;Pyrido-pyrazine-carbonylamino;Benzoxazole-carbonylamino;[Ethoxy-oxo-butenoyl]amino;(Benzimidazolyl)propanoylamino;(Oxopyridinyl)propanoylamino;Methoxy-benzofuran-carbonyl)amino;(Oxopyrrolidinyl)propanoylamino;[(Ethoxycarbonyl-pyridyl)amino no];(Methoxyanilino);(Cyano-pyridyl)amino;[(Methyl-pyridazinyl)amino];Quinolinyl-amino;(Methyl-oxazolyl)methyl-carbamoyl-amino;(Phenylcyclopropyl)carbamoylamino;[(tert-Butoxymethyl-oxo-ethyl)carbamoylamino];Dihydro-2H-chromenylcarbamoylamino;[(Methoxyphenyl)ethylcarbamoylamino];Oxanylcarbamoylamino;(Chloro-methylphenyl)carbamoylamino;Methanesulfonamido;Methylpropylsulfonylamino;Pyridinylsulfonylamino;[(Carboxypyridyl)amino];Pyridylcarbamoylamino;Methoxy-pyridinyl)amino;Ethyl-carbamothioyl-amino;(Pyridinyl- Bird (Azolyl)amino;(Methoxy-pyridinyl)amino;[(Ethyl- Bird (Azolyl)amino;(Ethylamino)- Bird Azolyl; (Methyl-Oxa Zia(Z)-N'-N-ethyl-carbamimidoyl]amino; (Z)-N'-zolyl)anilino; trichloroethoxysulfonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; pyridinylcarbamoylamino; propanylcarbamoylamino; pyridinylcarbamothioylamino; methylpyridinecarbonyl)amino; (morpholinylpyridinecarbonyl)amino; benzamido; [(dimethylamino)benzoyl]amino; dimethylbutanoylamino.

[0028] According to one aspect, the compounds of the invention are those in which R2 is tert-Butoxycarbonyl-amino;Amino;3-Pyridylcarbamothioylamino;Ethylcarbamoylamino;Pyridin-3-yl-amino;(4-Pyridin-3-yl-1,2,4- Bird 3-(Azol-3-yl)amino;3-(Pyridin-3-ylamino)-1,2,4- Bird Azol-4-yl; (4-ethyl-1,2,4- Birdazol-3-yl)amino;benzylamino;propylamino;2-methylpropanoylamino;hydroxy;ethylcarbamoylamino;isoquinolin-4-ylamino;(5-methoxypyridin-3-yl)amino;(pyridine-3-l)carbonylamino;1H-benzimidazol-2-ylamino;[3-(phenyl)-1,2-oxazol-5-yl]carbonylamino;quinoxaline-6-carbonylamino;[3-(4-hydroxyphenyl)prop-2 -enoyl]amino;pyrido 2,3-b]pyrazine-7-carbonylamino;1,3-benzoxazole-2-carbonylamino;[(E)-4-ethoxy-4-oxo-but-2-enoyl]amino;3-(benzimidazol-1-yl)propanoylamino;3-(2-oxopyrrolidin-1-yl)propanoylamino;4-methoxy-1-benzofuran-2-carbonyl)amino;3-(2-oxopyrrolidin-1-yl)propanoylamino;[(5-ethoxycarboxyl) (2-Methoxyanilino);(4-Cyano-2-pyridyl)amino;[(6-Methylpyridazin-3-yl)amino];Quinoline-4-ylamino;(5-Methyl-1,2-oxazol-3-yl)methylcarbamoylamino;(2-Phenylcyclopropyl)carbamoylamino;[(2-tert-Butoxy-1-methyl-2-oxo-ethyl)carbamoylamino];3,4-Dihydro-2H-chromen-3-ylcarbamoylamino ;[1-(3-Methoxyphenyl)ethylcarbamoylamino];Oxan-4-ylcarbamoylamino;(2-Chloro-6-methylphenyl)carbamoylamino;Methanesulfonamide;2-Methylpropylsulfonylamino;Pyridin-3-ylsulfonylamino;[(5-Carboxy-3-pyridyl)amino];3-Pyridylcarbamoylamino;5-Methoxypyridin-3-yl)amino;Ethylcarbamoylamino;(4-Pyridin-3-yl-1,2,4- Bird (5-Methoxypyridin-3-yl)amino;[(4-ethyl-1,2,4- Bird Azol-3-yl)amino; 3-(ethylamino)-1,2,4- BirdAzol-4-yl; 3-(5-methyl-1,3,4-oxa Zia (Z)-N'-(2-yl)anilino; 2,2,2-trichloroethoxysulfonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; pyridin-3-ylcarbamoylamino; propan-2-ylcarbamoylamino; pyridin-3-ylcarbamothioylamino; 5-methylpyridine-3-carbonyl)amino; (6-morpholin-4-ylpyridine-3-carbonyl)amino; benzamido; [4-(dimethylamino)benzoyl]amino; 3,3-dimethylbutanoylamino.

[0029] According to one embodiment, the compound of the invention is selected from among: tert-butyl N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate; tert-Butyl N-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate; N-trans-(7RS,9RS)-9-amino-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylcarbamothioylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-(ethylcarbamoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(4-pyridin-3-yl-1,2,4- Bird Azol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(pyridin-3-ylamino)-1,2,4- Bird Azol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-[(4-ethyl-1,2,4- Bird Azol-3-yl)amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-9-(benzylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(propylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-(2-methylpropanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-7-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; N-[cis-(7RS,9SR)-3-cyclopropyl-9-(isoquinolin-4-ylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 1-[(4-methoxyphenyl)methyl]-3-trans-(7RS,9RS)-3-cyclopropyl-9-[(5-methoxypyridin-3-yl)amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; N-trans-(7RS,9RS)-7-[(3-cyanophenyl)carbamoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-7-[(4-bromophenyl)methylcarbamoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(naphthalen-1-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; 1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; Ethyl N-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamoyl]carbamate; 1-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-[rac-(1S)-1-(3-methoxyphenyl)ethyl]urea; 1-(1-cyclopropylethyl)-3-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-(2-methylcyclopropyl)-3-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-Benzyl-3-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-(2-phenylcyclopropyl)-3-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-(3,4-dihydro-2H-chromen-3-yl)-3-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-[[rac-(E)-3-(2-chlorophenyl)prop-2-enoyl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; 6-Methoxy-N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; Methyl 3-oxo-3-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]amino]propanoate N-[2-oxo-2-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]amino]ethyl]benzamide; 5-Chloro-4-methoxy-N-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]thiophene-3-carboxamide; Ethyl 3-oxo-3-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]amino]propanoate; N-[cis-(7RS,9SR)-3-cyclopropyl-7-(2-methylbutanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; N-[cis-(7RS,9SR)-7-[[2-(4-chlorophenoxy)acetyl]amino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; 3-Phenyl-N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1,2-oxazole-5-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]quinoxaline-6-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[[rac-(E)-3-(4-hydroxyphenyl)prop-2-enoyl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyrido-2,3-b]pyrazine-7-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1,3-benzoxazole-2-carboxamide; Ethyl rac-(E)-4-oxo-4-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]but-2-enoate; N-trans-(7RS,9RS)-9-[3-(benzimidazol-1-yl)propanoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(2-oxopyridin-1-yl)propanoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-[(4-methoxy-1-benzofuran-2-carbonyl)amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; Ethyl 5-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-3-carboxylate; N-trans-(7RS,9RS)-3-cyclopropyl-9-(2-methoxyanilino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-9-[(4-cyanopyridin-2-yl)amino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(6-methylpyridazin-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(quinolin-4-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-[(5-methyl-1,2-oxazol-3-yl)methylcarbamoylamino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(2-phenylcyclopropyl)carbamoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; tert-Butyl 2-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamoylamino]propanoate; N-trans-(7RS,9RS)-3-cyclopropyl-9-(3,4-dihydro-2H-chromen-3-ylcarbamoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7SR,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[[rac-(1R)-1-(3-methoxyphenyl)ethyl]carbamoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(oxan-4-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-9-[(2-chloro-6-methylphenyl)carbamoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-(methanesulfonamido)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(2-methylpropylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 5-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-3-carboxylic acid; 1-Pyridin-3-yl-3-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridin-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; cis-(7RS,9SR)-3-cyclopropyl-7,9-bis[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; cis-(7RS,9SR)-7-amino-3-cyclopropyl-9-[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; cis-(7RS,9SR)-7,9-bis(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; -Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-7-(ethylcarbamothioylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]thiourea; Cis-(7RS,9SR)-3-cyclopropyl-N-(2-methylpropyl)-7,9-bis[(4-pyridin-3-yl-1,2,4- Bird Azol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-7,9-bis(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[(4-ethyl-1,2,4- Bird Azol-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[3-(ethylamino)-1,2,4- Bird Azol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[3-(5-methyl-1,3,4-oxa Zia [2-(2-phenyl-2-yl)anilino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; tert-Butyl N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(2,2,2-trichloroethoxysulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate; 2-Cyano-1-ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-[[rac-(E)-N'-cyano-N-ethylcarbamimidoyl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]guanidine; 1-Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; 1-Pyridin-3-yl-3-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridin-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; 1-propan-2-yl-3-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(propan-2-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; 1-Pyridin-3-yl-3-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridin-3-ylcarbamothioylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]thiourea; 5-Methyl-N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(5-methylpyridine-3-carbonyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 6-morpholin-4-yl-N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(6-morpholin-4-ylpyridine-3-carbonyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-9-benzamido-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]benzamide; 4-(Dimethylamino)-N-trans-(7RS,9RS)-3-cyclopropyl-9-[[4-(dimethylamino)benzoyl]amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]benzamide; 3,3-Dimethyl-N-trans-(7RS,9RS)-3-cyclopropyl-9-(3,3-dimethylbutanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]butanamide; 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-9-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[9-amino-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide.

[0030] The following Examples show how compounds encompassed by Formula (I) can be synthesized. They are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any way. Those skilled in the art will understand that routine variations and modifications of the following examples can be made without departing from the spirit or scope of the present invention.

[0031] Examples Abbreviation AcOH Acetic acid DCM Dichloromethane MTBE tert-butyl methyl ether Et2O Diethyl ether THF Tetrahydrofuran EtOAc Ethyl acetate MeCN Acetonitrile MeOH Methanol h time rt room temperature M Mass Salt water Saturated sodium chloride solution HPLC High Performance Liquid Chromatography LCMS Liquid Chromatography Mass Spectrometry MS mass spectrometry ES+ electrospray positive ionization DIPEA N,N-Diisopropylethylamine RT retention time DMF N,N'-Dimethylformamide TFA Trifluoroacetic acid DMSO Dimethyl sulfoxide TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate EtOH Ethanol sat. saturation aq. Water-based tBuXPhos Pd G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'biphenyl)]methanesulfonate palladium(II) TEA Triethylamine DMA N,N-Dimethylacetamide TBME tert-Butyl methyl ether (also abbreviated as MTBE) o / n overnight IPA Isopropyl Alcohol conc.concentration SCX Biotage® ISOLUTE® SCX-2 Propyl Sulfonic Acid Functionalized Silica

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

[0033] Method 2: 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

[0034] Method 3: Waters UPLC® BEH™ C18, part number 186002352, 2.1 x 100 mm, 1.7 μm Column temperature: 40℃ Mobile phase A: 2 mM ammonium bicarbonate buffered to pH 10 Mobile phase B: Acetonitrile Gradient program Flow rate 0.6mL / min Time A% B% 0.00 95.00 5.00 5.30 0 100 5.80 0 100 5.82 95.00 5.00 7.00 95.00 5.00

[0035] Method 4: Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Phenomenex, Kinetex-XB C18, 2.1 mm x 100 mm, 1.7 μm column Flow rate: 0.6mL / min Column temperature: 40℃ Injection volume: 1μL Gradient: Time (min): %A %B 0.00 95 5 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5 UV 215 nM, PDA spectrum 200-400 nm, step: 1 nm MSD Scan Positive 150-850

[0036] Method 5: Mobile phase A: 2 mM ammonium bicarbonate pH 10 Mobile phase B: Acetonitrile Phenomenex Gemini-NX C18 2.0mm x 50mm, 3μm column Flow rate: 0.6mL / min Column temperature: 40℃ Injection volume: 3μL Gradient: Time (min): %A %B 0.00 95 5 5.50 0 100 5.90 0 100 5.92 95 5 UV 215 nM, PDA spectrum 210-420 nm, step: 1 nm MSD Scan Positive 150-850

[0037] Method 6: A QDA Waters simple quadrupole mass spectrometer is used for LCMS analysis. The spectrometer is equipped with a UPLC Acquity Classic with an ESI source and a diode array detector (210-400 nm). Data is acquired as a full MS scan from m / z 50 to 1000 in positive mode using basic elution. Reverse phase separation is performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1×50 mm) column at 45° C. for basic elution. Gradient elution is Mobile phase A:H 2 O / acetonitrile / ammonium formate (95 / 5 / 63 mg / L) + 50 μL NH 4 OH Mobile phase B: Acetonitrile / H 2 O / Ammonium formate (95 / 5 / 63 mg / L) + 50 μL NH 4 OH Gradient Program: HPLC flow rate: 0.4mL / min~0.5mL / min Injection volume: 1μL Total flow rate in MS. Time (min) A (%) B (%) Flow rate (mL / min) 0 99 1 0.4 0.3 99 1 0.4 3.2 0 100 0.4 3.25 0 100 0.5 4 0 100 0.5 4.1 99 1 0.4 4.8 90 1 0.4

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

[0039] Method 8: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0040] Method 9: 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

[0041] Method 10: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0042] Method 11: Stationary phase: Waters Acquity UPLC BEH C18 2.1×50mm, 1.7μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 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

[0043] Method 12: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0044] Method 13: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0045] Method 14: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0046] Method 15: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 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

[0047] Method 16: Stationary phase: Waters Acquity UPLC BEH C18 2.1×50mm, 1.7μm Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 0.7mL / min 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

[0048] Method 17: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0049] Method 18: A SYNAPT G2-SI Waters Q-TOF mass spectrometer equipped with a Waters Acquity H-class UPLC with an ESI source and a diode array detector (210-400 nm). Data are acquired in a full MS scan from m / z 50 to 1200 in positive mode. Reversed phase separation is performed on an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 × 50 mm) at 45 °C. Gradient elution was performed using: Solvent C: Water / acetonitrile / formic acid (95 / 5 / 750 μl / L) Solvent D: Water / acetonitrile / formic acid (5 / 95 / 500 μl / L) pH approx. 3 Total flow rate in MS. Injection volume: 0.5~1μl Time (min) C (%) D (%) Flow 0 98 2 0.8 0.3 98 2 0.8 3 5 95 0.8 4 5 95 0.8 4.1 98 2 0.8 5.1 98 2 0.8

[0050] General Procedure General procedure 1: To a stirred solution of the relevant amine (1 eq.) in DCM (unless otherwise stated), DIPEA (2-4 eq.) and isocyanate / isothiocyanate (2-4 eq.) were added. The reaction was heated at reflux (unless otherwise stated). Upon completion, the reaction mixture was concentrated in vacuo and purified by column chromatography.

[0051] General procedure 2: To a stirred solution of the relevant amine (1 equiv.) in DCM (2 mL) at room temperature was added DIPEA (2-4 equiv.) and acid chloride (2-4 equiv.) After completion, the reaction mixture was concentrated in vacuo and purified by column chromatography.

[0052] Intermediate 1 [ka] 3,6,7,8-Tetrahydro-2H-as-indecan-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 diluted with Na 2 SO 4 The residue was dried over SiO 2 The product was purified by column chromatography at 67° C. to give the title compound as a brown solid (4.5 g, 5% yield). H( 400 MHz, CDCl3)7.42(m,1H),7.23(m,1H),3.21(m,2H),3.10(m,2H),2.94(m,2H),2.66(m,2H),2.14(m,2H).

[0053] Intermediate 2 [ka] (2E)-2-Hydroxyimino-3,6,7,8-tetrahydro-as-indecan-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). MS m / z=202 [M+H] + .δ H( 400 MHz,DMSO-d6)7.55(d,1H),7.34(d,1H),3.70(s,2H),3.12(t,2H),2.86(t,2H),2.04-2.11(m,2H).

[0054] Intermediate 3 [ka] 1,3-Dichloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline POCl 3 A solution of intermediate 2 (83 g, 412.5 mol) in (1.25 L) was cooled to 0° C. and added PCl 5 (94.5 g, 454 mol). The resulting mixture was treated with HCl (gas) until the reaction was saturated and stirred at 65° C. for 1 h. After this time, the mixture was treated with additional PCl 5 (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). MS m / z=238 [M+H] + .δ H( 400 MHz, CDCl 3 )7.64-7.56(m,3H),3.75(m,2H),3.09(m,2H),2.19-2.26(m,2H).

[0055] Intermediate 4 [ka] 3-Chloro-8,9-dihydro-7H-cyclopenta[h]isoquinoline A solution of intermediate 3 (80 g, 336 mol) in EtOAc (666 mL) was treated with 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 the addition of ammonia solution and the resulting solid was collected by filtration. The solid was dissolved in DCM, washed with brine and diluted with Na 2 SO 4 Dry and concentrate with SiO 2 Purification by column chromatography at rt afforded the title compound as a white solid (38.5 g, 56% yield). MS m / z=204 [M+H] + .δ H( 400 MHz, CDCl 3)9.04(s,1H),7.70(s,1H),7.56-7.63(m,2H),3.34(m,2H),3.11(m,2H),2.34-2.27(m,2H).

[0056] 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). 1 H NMR (300 MHz, Chloroform-d) δ H 9.20(d,J=0.9 Hz,1H),8.57(d,J=0.8 Hz,1H),8.46(s,1H),3.48(tt,J=8.0,1.2 Hz,2H),3.29-3.14(m,2H),2.50-2.32(m,2H).LCMS [M+H] + 302 / 304, RT 1.33 (Method 8)

[0057] 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). 1 H NMR (300 MHz, Chloroform-d) δ H 9.14(d,J=0.9 Hz,1H),8.48(d,J=0.9 Hz,1H),8.36(s,1H),4.67(t,J=6.4 Hz,1H),3.50-3.35(m,2H),3.18(t,J=7.4 Hz,2H),2.78-2.65(m,2H),2.45-2.28(m,2H),1.69(dq,J=13.4,6.7 Hz,1H),0.81(d,J=6.7 Hz,6H).LCMS [M+H] + 339 / 341, RT 1.26 (Method 8).

[0058] 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.

[0059] 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 the 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 reaction mixture was then heated at 70° C. for 16 h. The two reaction mixtures were cooled and evaporated. The resulting residue was resubmitted 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.

[0060] 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 0% to 100% ethyl acetate in isohexane) to give the title compound.

[0061] Intermediate 11 (877 mg, 39% yield) LCMS [M+H] + 454 / 456, RT 1.28 (Method 8). 1 H NMR (300 MHz, Chloroform-d) δ H9.15(d,J=0.8 Hz,1H),8.51(d,J=0.9 Hz,1H),8.42(s,1H),5.40(m,1H),4.88(m,1H),4.72(t,J=6.4 Hz,1H),3.54(ddd,J=17.1,9.1,3.3 Hz,1H),3.35-3.17(m,1H),2.95-2.63(m,3H),2.17-1.98(m,1H),1.77-1.66(m,1H),1.51(s,9H),0.83(dd,J=6.7,3.8 Hz,6H).

[0062] Intermediate 12 (1.00g, yield 46%) LCMS [M+H] + 454 / 456,RT 1.31(Method 8). 1 H NMR (300 MHz, Chloroform-d)δ H 9.40(d,J=0.8 Hz,1H),8.48(d,J=0.8 Hz,1H),8.33(s,1H),5.86(s,1H),4.94(m,J=9.5 Hz,1H),4.77(t,J=6.4 Hz,1H),3.27(dt,J=15.8,7.6 Hz,1H),3.07(ddd,J=16.8,9.0,4.6 Hz,1H),2.85-2.65(m,3H),2.20(m,1H),1.76-1.67(m,1H),1.46(s,9H),0.83(dd,J=6.7,1.8 Hz,6H).

[0063] Intermediate 13

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[0064] 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. Chloro(n2-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 (eluted with 20-70% EtOAc / Hexane) to give the title compound (332 mg, 66% yield). LCMS [M+H-tBu] + 404.0, RT 2.73 (Method 15).

[0065] Intermediate 15 [ka] tert-Butyl N-[7-azido-3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate To a solution of intermediate 12 (2550 mg, 5.62 mmol) in EtOAc (120 mL) was added 1-bromopyrrolidine-2,5-dione (1200 mg, 6.74 mmol) and 2-[({E})-(1-cyano-1-methyl-ethyl)azo]-2-methyl-propanenitrile (92 mg, 0.562 mmol). The mixture was heated in the dark at 90 °C for 30 min. The reaction was cooled and the solvent was removed to give a brown solid. The brown solid was dissolved in DMF (15 mL), cooled to 0 °C and sodium azide (657 mg, 10.1 mmol) was added. The reaction was stirred for 10 min. EtOAc (50 mL) was added to the reaction followed by water (30 mL). The organic layer was separated and further washed with water (2 x 20 mL) and brine (10 mL). The organic layer was dried (MgSO 4) and the solvent was removed to give a brown solid. The solid was purified by flash column chromatography eluting with a gradient of 0-35% ethyl acetate in heptane to give the title compound as a brown solid (2.2 g, 53% purity, 42% yield). LCMS [M+H] + 495, RT 3.37 min (Method 1). The other major peak in LCMS was unreacted intermediate 11.

[0066] Intermediate 16 [ka] tert-Butyl N-[7-amino-3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate To a solution of intermediate 15 (19000 mg, 16.51 mmol, 43% purity) in ethyl acetate (100 mL) was added EtOH (50 mL) and 10% palladium on carbon (3328 mg, 3.12 mmol). The reaction was evacuated and then placed under an atmosphere of hydrogen and stirred vigorously for 2 h. The palladium residues were filtered off through a plug of Celite and the solvent was removed. The resulting residue was purified by 0-100% ethyl acetate in heptane gradient followed by 0-10% 7M NH in MeOH in ethyl acetate. 3 Purification by flash column chromatography eluting with 50% hexane gave the title compound as a brown solid (5.98 g, 77% yield); LCMS [M+H] + 469, RT 2.49 min (Method 1), intermediate 12 (10 g, 60% purity) was recovered.

[0067] Intermediate 17 [ka] tert-Butyl N-[7-(benzyloxycarbonylamino)-3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate To a solution of intermediate 16 (5960 mg, 12.7 mmol) in DMF (40 mL) was added triethylamine (7.1 mL, 50.8 mmol) and benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (4117 mg, 16.5 mmol). The solution was stirred for 30 min. The reaction was diluted with EtOAc (100 mL) and then washed with water (3×50 mL) and brine (30 mL). The organic layer was dried (MgSO 4 ), and the solvent was removed to give an oil. The oil was purified by flash column chromatography eluting with 0-40% ethyl acetate in heptane gradient to give the title compound as a fluffy brown solid (7.7 g, 94% yield); LCMS [M+H] + 603, RT 3.39 and 3.47 min [cis and trans isomers] (Method 1).

[0068] Intermediate 18 [ka] tert-Butyl N-[7-(benzyloxycarbonylamino)-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate In a pressure tube, intermediate 17 (9.73 g, 16.1 mmol), tripotassium phosphate (12.2 g, 56.5 mmol), tricyclohexylphosphonium tetrafluoroborate (2.07 g, 5.65 mmol), diacetoxypalladium (1.10 g, 4.83 mmol) and cyclopropylboronic acid (6.24 g, 72.6 mmol) were suspended in a mixture of 1,4-dioxane (103 mL), toluene (51 mL) and water (8 mL). The system was evacuated three times, backfilled with nitrogen and capped. The reaction was heated at 105° C. for 4 h. The reaction was cooled and filtered through a Celite plug to remove palladium residues. The Celite was washed with EtOAc (20 mL) and water (10 mL). The filtrate was diluted with EtOAc (150 mL) and water (60 mL). The organic layer was separated and further washed with water (2×20 mL) and brine (20 mL). The organic layer was dried (MgSO 4), and the solvent was removed to give a brown oil. The oil was purified by flash column chromatography eluting with 0-40% ethyl acetate in heptane gradient to give the title compound as a brown solid (8.35 g, 85% yield); LCMS [M+H] + 609, RT 3.46 and 3.54 min [cis and trans isomers] (Method 1).

[0069] Intermediates 19 and 20 [ka] Benzyl N-trans-(7SR,9SR)-9-amino-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate (19) Benzyl N-[cis-(7RS,9SR)-9-amino-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate (20) To a solution of intermediate 18 (850 mg, 1.40 mmol) in DCM (5 mL) was added trifluoroacetic acid (5 ml). The solution was stirred at room temperature for 30 min. The solvent was removed and excess TFA was azeotroped with 1:1 DCM / heptane to give a brown oil. The oil was purified by azeotroping with 0-100% 7M NH 3 The racemic amine was purified by SCX cartridge eluting with 0-5% 7M NH in MeOH in a DCM gradient to give an orange gum. 3 Further purification by flash column chromatography eluting with 5% by volume afforded the title compound as a mixture of enantiomers:

[0070] The trans product (intermediate 19) as a white solid (250 mg, 35% yield); H(500 MHz,Chloroform-d)9.48(s,1H),8.32(s,1H),8.27(s,1H),7.46-7.30(m,5H),5.67(q,J=7.7 Hz,1H),5.22-5.08(m,3H),5.02(d,J=8.8 Hz,1H),4.69(t,J=6.3 Hz,1H),2.84-2.73(m,1H),2.73-2.54(m,2H),2.31(dt,J=13.6,7.4 Hz,1H),2.22(td,J=8.1,4.1 Hz,1H),1.70(dp,J=13.6,6.7 Hz,1H),1.16(tt,J=4.6,2.4 Hz,2H),1.12-1.03(m,2H),0.84(t,J=6.8 Hz,6H).LCMS [M+H] + 509, RT 2.55 minutes (Method 1).

[0071] White solid (305 mg, yield 42%) としてのシス product (intermediate 20); δ H( 500 MHz,Chloroform-d)9.71(s,1H),8.35(s,1H),8.28(s,1H),7.44-7.28(m,5H),5.52(d,J=8.4 Hz,1H),5.28-5.09(m,3H),5.01-4.87(m,1H),4.72(t,J=6.2 Hz,1H),3.08-2.93(m,1H),2.83-2.64(m,2H),2.22(ddd,J=13.0,8.2,4.8 Hz,1H),1.87(dt,J=13.6,4.3 Hz,1H),1.20-1.12(m,2H),1.12-1.02(m,2H),0.84(t,J=6.5 Hz,6H).LCMS [M+H] + 509, RT 2.55 minutes (Method 1).

[0072] Intermediate 21

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[0073] Intermediate 22 [ka] Benzyl N-trans-(7SR,9SR)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate To a suspension of intermediate 21 (77 mg, 0.117 mmol) in MeOH (2 mL) was added 2-iodoacetic acid (26 mg, 0.140 mmol). The reaction was heated at 70° C. for 90 min. Another portion of 2-iodoacetic acid (10 mg, 0.058 mmol) was added and the reaction was heated at 70° C. for an additional 30 min. The solution was cooled and the solvent was removed to give a residue. The residue was diluted with EtOAc (10 mL) and saturated NaHCO 3 The organic layer was separated and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic layers were dried (MgSO 4 ), and the solvent was removed to give a solid. The solid was dissolved in 7M NH 3Purification by flash column chromatography eluting with methanol gave the title compound as a mixture of trans enantiomers (50 mg, 68% yield); LCMS [M+H] + 625, RT 1.77 min (method 2).

[0074] Intermediate 23 [ka] trans-(7SR,9SR)-7-amino-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a portion of a solution of intermediate 22 (381 mg, 0.610 mmol) in acetic acid (3 mL) was added hydrogen bromide in AcOH (45%, 3.5 mL, 27.4 mmol). The solid was slowly spun into solution over 30 min. The reaction was stirred for 1 h. Another portion of HBr in AcOH (0.7 mL) was added and the reaction was stirred for an additional 1 h. The solvent was removed to give a brown residue. The residue was purified by 0-100% 7M NH 3 Purification on an SCX cartridge eluting with 5% ethyl acetate gave the title compound as a mixture of trans enantiomers (300 mg, 97% yield); LCMS [M+H] + 491, RT 1.48 min (method 2).

[0075] Intermediate 24 [ka] Benzyl N-[cis-(7RS,9SR)-3-cyclopropyl-5-(isobutylsulfamoyl)-9-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate To a stirred solution of intermediate 20 (550 mg, 1.08 mmol) in THF (25 mL) at room temperature was added N,N-diisopropylethylamine (419 mg, 3.24 mmol) and nicotinoyl chloride hydrochloride (211 mg, 1.19 mmol). The reaction was monitored by LCMS until completion, then diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3 and brine. The volatiles were removed in vacuo and the crude product was purified by column chromatography (eluting with EtOAc in isohexane followed by MeOH in EtOAc) to give the title compound as a mixture of cis enantiomers (550 mg, 81% yield). 1 H NMR (300 MHz, Methanol-d4) δ H 9.40-9.33(m,1H),9.00-8.92(m,1H),8.73-8.62(m,1H),8.43-8.38(m,1H),8.33(s,1H),8.27-8.19(m,1H),7.5 5-7.48(m,1H),7.42-7.26(m,5H),6.27-6.13(m,1H),5.31-5.07(m,3H),3.38-3.33(m,1H),2.65(dd,J=6.9,1.6 Hz,2H),2.27(p,J=6.6 Hz,1H),2.15(dt,J=14.3,5.0 Hz,1H),1.73-1.51(m,1H),1.10-1.04(m,4H),0.78(dd,J=6.7,2.8 Hz,6H).LCMS [M+H] + 614, RT 2.29 (Method 10).

[0076] Intermediate 25 [ka] N-[cis-(7RS,9SR)-7-amino-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide Intermediate 24 (550 mg, 0.8783 mmol) was dissolved in EtOH (2 mL) and palladium on carbon (0.087 mmol) was added. The solution was degassed and placed under a hydrogen atmosphere. Additional palladium on carbon was added until the reaction was complete. The reaction mixture was then filtered through Celite and washed with EtOAc. The solvent was removed and the crude product was purified by 20% in DCM (3.5N NH 3 MeOH) to afford the title compound as a mixture of cis enantiomers (175 mg, 41% yield). 1 H NMR (300 MHz, Methanol-d4) δ H 8.53(d,J=0.9 Hz,1H),8.18(dd,J=2.3,0.9 Hz,1H),7.87(dd,J=4.9,1.6 Hz,1H),7.71(s,1H),7.60(d,J=1.0 Hz,1H),7.45(ddd,J=8.0,2.3,1.6 Hz,1H),6.72(ddd,J=8.0,4.9,0.9 Hz,1H),5.37(dd,J=8.7,4.9 Hz,1H),3.73(dd,J=8.0,4.9 Hz,1H),2.49-2.39(m,2H),1.86(dd,J=6.9,0.9 Hz,2H),1.52-1.40(m,1H),0.89-0.76(m,1H),0.29-0.18(m,4H),-0.01(d,J=6.6 Hz,6H).LCMS [M+H] + 480, RT 1.02 (Method 10).

[0077] Intermediate 26 [ka] tert-Butyl N-[7-amino-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate To a solution of intermediate 18 (300 mg, 0.493 mmol) in THF (3 mL) was added 10% palladium on carbon (600 mg, 0.564 mmol). The mixture was evacuated and placed under an atmosphere of hydrogen for 4 h. Palladium residues were removed by washing the Celite with excess EtOAc (10 mL) and MeOH (10 mL). The filtrate was stripped of solvent to give an oil. The oil was purified by 0-10% 7M NH 3 Purification by flash column chromatography eluting with a 1:1 / MeOH gradient afforded the title compound as a brown solid (160 mg, 68% yield); LCMS [M+H] + 475, RT 1.75 min (method 2).

[0078] Intermediates 27 and 28 [ka] cis-(7RS,9SR)-7,9-diazido-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (27) trans-(7SR,9SR)-7,9-diazido-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (28) Intermediate 40 (12 g, 24.16 mmol) was dissolved in N,N-dimethylformamide (240 mL, 3.09 mol) and cooled in an ice bath before sodium azide (3.9 g, 60 mmol) was added in portions. The reaction mixture was stirred at this temperature for 1.5 h. The reaction was cooled in an ice bath before water (250 mL) and TBME (250 mL) were added. The resulting slurry was stirred vigorously then partitioned and the aqueous layer was extracted with TBME (2×250 mL). The combined organic extracts were dried and concentrated in vacuo. Purification by column chromatography (0-40% gradient of EtOAc in isohexane) afforded the title compound as a mixture of enantiomers:

[0079] Intermediate 27 (838 mg, 9% yield). 1 H NMR (400 MHz, Chloroform-d) δ H9.39(d,J=0.8 Hz,1H),8.52(d,J=0.8 Hz,1H),8.38(s,1H),5.42(dd,J=7.9,3.3 Hz,1H),4.88(t,J=6.3 Hz,1H),3.44-3.32(m,1H),3.15(ddd,J=16.9,8.9,3.9 Hz,1H),2.85-2.68(m,3H),2.55(ddt,J=14.3,8.5,3.7 Hz,1H),1.73-1.67(m,1H),0.82(dd,J=6.7,1.5 Hz,6H).LCMS [M+H] + 421,RT 2.81(Method 12).

[0080] Intermediate 28 (3.4g, yield 33%). 1 H NMR (400 MHz, Chloroform-d)δ H 9.49(d,J=0.8 Hz,1H),8.57(d,J=0.8 Hz,1H),8.46(s,1H),5.34(dd,J=7.8,4.0 Hz,1H),5.06(dd,J=7.7,3.9 Hz,1H),4.85(t,J=6.3 Hz,1H),3.25(dt,J=14.8,7.7 Hz,1H),2.80(dq,J=17.1,6.4 Hz,3H),2.51(dt,J=14.8,4.0 Hz,1H),1.79-1.64(m,1H),0.82(dd,J=6.7,3.4 Hz,6H).LCMS [M+H] + 421,RT 2.78(Method 12).

[0081] Intermediates 29 and 29a

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[0082] Intermediate 29 LCMS [M+H] + 587, RT 2.71 min (Method 13).

[0083] Intermediate 29a LCMS [M+H]+472, RT 2.55 min (Method 13).

[0084] Intermediate 30 [ka] Benzyl N-trans-(7RS,9RS)-3-cyclopropyl-5-(isobutylsulfamoyl)-9-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate To a stirred solution of intermediate 19 (490 mg, 0.96 mmol) in THF (25 mL) at room temperature was added N,N-diisopropylethylamine (373 mg, 2.89 mmol) and nicotinoyl chloride hydrochloride (188 mg, 1.06 mmol). The reaction was monitored by LCMS until complete, then diluted with EtOAc (30 mL) and washed with saturated NaHCO 3 It was washed with aqueous solution and brine. The volatiles were removed in vacuo and the crude product was purified by column chromatography (eluting with EtOAc in isohexane followed by MeOH in EtOAc) to give the title compound as a mixture of enantiomers (500 mg, 83% yield). 1 H NMR (300 MHz, Methanol-d4) δ H 9.34(s,1H),8.97-8.92(m,1H),8.65(dd,J=5.0,1.7 Hz,1H),8.46-8.39(m,1H),8.33(s,1H),8.27-8.20(m,1H),7.57-7.46(m,1H),7.46-7.24(m,5H),6.43-6.32(m,1H),5.70(t,J=7.6 Hz,1H),5.27-5.09(m,2H),2.74-2.46(m,3H),2.35-2.21(m,1H),1.72-1.57(m,1H),1.14-1.00(m,4H),0.83-0.68(m,6H).LCMS [M+H] + 614, RT 2.23 (Method 10).

[0085] Intermediate 31 [ka] N-trans-(7RS,9RS)-7-amino-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide Intermediate 30 (500 mg, 0.81 mmol) was dissolved in EtOH (2 mL) and palladium on carbon (0.081 mmol) was added. The solution was degassed and placed under a hydrogen atmosphere. Additional palladium on carbon was added until the reaction was complete. The reaction mixture was then filtered through Celite and washed with EtOAc. The solvent was removed and the crude product was purified by 20% in DCM (3.5N NH 3MeOH) to afford the title compound as a mixture of enantiomers (157 mg, 40% yield). 1 H NMR (300 MHz, Methanol-d4) δ H 9.34(d,J=0.9 Hz,1H),8.94(dd,J=2.3,0.9 Hz,1H),8.65(dd,J=5.0,1.7 Hz,1H),8.53(s,1H),8.42(d,J=1.0 Hz,1H),8.22(ddd,J=8.0,2.3,1.7 Hz,1H),7.50(ddd,J=8.0,4.9,0.9 Hz,1H),6.37(dd,J=8.4,2.5 Hz,1H),2.71-2.61(m,3H),2.54-2.40(m,1H),2.34-2.22(m,1H),1.66(dt,J=13.5,6.8 Hz,1H),1.12-1.04(m,4H),0.81(dd,J=6.7,1.1 Hz,6H).LCMS [M+H] + 480,RT 0.99 (Method 10).

[0086] Intermediate 32 [ka] Benzyl N-trans-(7SR,9SR)-3-cyclopropyl-5-(isobutylsulfamoyl)-9-[(5-methoxy-3-pyridyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate In a pressure vial, 3-bromo-5-methoxypyridine (277 mg, 1.47 mmol), tBuXPhos Pd G3 (117 mg, 0.147 mmol), Intermediate 19 (300 mg, 0.590 mmol) and sodium 2-methylpropan-2-olate (227 mg, 2.36 mmol) were suspended in 1,4-dioxane (25 mL). The reaction was placed under nitrogen, capped and the mixture was heated at 65 °C for 2.5 h. Most of the 1,4-dioxane was removed and the residue was loaded onto an SCX column. A gradient of 0-100% 7M NH in methanol was used. 3 Purification by SCX column chromatography eluting with 0-5% 7M NH in DCM gave an oil. The oil still contained several components. 3Further purification by flash column chromatography eluting with a / MeOH gradient afforded the title compound as a mixture of enantiomers (208 mg, 57% yield); LCMS [M+H] + 616, RT 3.31 minutes (Method 1).

[0087] Intermediate 33 [ka] trans-(7SR,9SR)-7-amino-3-cyclopropyl-N-isobutyl-9-[(5-methoxy-3-pyridyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 32 (283 mg, 0.460 mmol) in MeOH (5 mL) was added 10% Pd on carbon (10%, 264 mg, 0.248 mmol). The reaction was placed under hydrogen for 1 h. Palladium residues were removed through Celite and the solvent was removed to give a pale yellow solid. The solid was purified by elution with 7M NH in DCM gradient of 0-10%. 3 Purification by flash column chromatography eluting with 1,2-dichlorophenylmethylsulfonyl ether / MeOH afforded the title compounds as a mixture of enantiomers (195 mg, 88% yield); LCMS [M+H] + 482, RT 1.85 minutes (Method 1).

[0088] Intermediate 34 [ka] N-trans-(7SR,9SR)-3-cyclopropyl-5-(isobutylsulfamoyl)-9-(3-pyridylcarbamothioylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of Example 3 (50 mg, 0.104 mmol) in THF (1 mL) was added 3-isothiocyanatopyridine (0.013 mL, 0.115 mmol). The solution was stirred for 10 min, by which time a white solid had precipitated out of solution. The solid was filtered, washed with DCM (1 mL) and dried under vacuum to give the title compound as a mixture of enantiomers (32 mg, 49% yield). The filter was washed to give the title compound, title 2, crop (16 mg, 25% yield). LCMS [M+H] + 616,RT 2.90 minutes(Method 4).

[0089] Intermediate 35 [ka] N-[cis-(7RS,9SR)-9-amino-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a suspension of Example 2 (275 mg, 0.474 mmol) in DCM (2.5 mL) was added trifluoroacetic acid (2.5 mL, 33.7 mmol). The resulting solution was stirred at room temperature for 45 min. Solvent was removed from the reaction azeotropically with 1:1 DCM / heptane to remove excess TFA. The gum was purified by elution with 0-10% 7M NH in MeOH gradient. 3 Purification by SCX column chromatography eluting with 5% hexane gave the title compound as a mixture of enantiomers (226 mg, 97% yield); LCMS [M+H] + 480, RT 1.60 min (method 2).

[0090] Intermediate 36 [ka] tert-Butyl N-[3-cyclopropyl-7-hydroxy-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate A suspension of intermediate 14 (350 mg, 0.76 mmol), 2,2'-azobis(2-methylpropionitrile) (13 mg, 0.078 mmol) and N-bromosuccinimide (165 mg, 0.927 mmol) in ethyl acetate (10 mL) was stirred and heated in a microwave at 100 °C for 1 h. The reaction was concentrated in vacuo to give a brown oil which was dissolved in tetrahydrofuran (8 mL) and water (2 mL) to which silver carbonate (425 mg, 1.53 mmol) was added at room temperature. The reaction is complete by LCMS after 2.5 h.

[0091] The reaction was diluted with ethyl acetate, filtered, the solvent removed and the residue purified by column chromatography (eluting with a gradient of ethyl acetate in isohexane) to give the title compound as a mixture of diastereoisomers (approximately 2:1) as a brown oil (95 mg, 26%). LCMS [M+H] +476 with retention times 1.18 min and 1.21 min(Method 8).

[0092] Intermediate 37 [ka] 9-Amino-3-cyclopropyl-7-hydroxy-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A solution of Intermediate 36 (32 mg, 0.067 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (0.5 mL) was stirred at room temperature. After 30 min, the reaction was diluted with saturated NaHCO 3 The mixture was quenched with 30% isopropyl alcohol in chloroform (4 mL) and stirred for 1 h. The solution was diluted with 30% isopropyl alcohol in chloroform (10 mL) and the layers were separated. The aqueous layer was further extracted with 30% isopropyl alcohol in chloroform (3×5 mL) and the combined organic layers were washed with brine (5 mL), dried and concentrated in vacuo to give the title compound as a mixture of diastereoisomers (approximately 2:1) as a brown oil. LCMS [M+H] + 376 with retention times 0.904 min and 0.939 min(Method 8).

[0093] Intermediate 38 [ka] tert-Butyl N-[3-cyclopropyl-9-hydroxy-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate A suspension of Intermediate 13 (223 mg, 0.485 mmol), 2,2'-azobis(2-methylpropionitrile) (8 mg, 0.048 mmol) and N-bromosuccinimide (100 mg, 0.562 mmol) in ethyl acetate (5 mL) was heated in a microwave at 100°C for 1.5 h. The reaction was concentrated in vacuo to give a brown solid which was dissolved in tetrahydrofuran (8 mL) and water (2 mL) to which silver carbonate (425 mg, 1.53 mmol) was added. The reaction was stirred at room temperature overnight then diluted with ethyl acetate, filtered, washed with brine (20 mL), dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in isohexane to give the title compound as a mixture of diastereoisomers (approximately 1:1) as a brown oil (60 mg, 26%). LCMS [M+H] + 476 with retention times 1.235 min and 1.263 min(Method 8).

[0094] Intermediate 39 [ka] 7-Amino-3-cyclopropyl-9-hydroxy-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of Intermediate 38 (41 mg, 0.086 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) dropwise. After 30 min, the reaction was washed with saturated NaHCO 3 (3 mL) and stirred at room temperature for 1 h, the layers were separated and the aqueous phase was extracted with 30% isopropyl alcohol in chloroform (2 x 5 mL). The combined organic layers were dried and concentrated in vacuo to give the title compound as a mixture of diastereoisomers (23 mg, 72%) (ca. 1:1). LCMS [M+H] + 376 with retention times 0.955 min and 0.926 min(Method 8).

[0095] Intermediate 40 [ka] 7,9-Dibromo-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 6 (9 g, 26.5 mmol) in ethyl acetate (360 mL) was added 2,2'-azobis(2-methylpropionitrile) (445 mg, 2.65 mmol) and N-bromosuccinimide (11.8 g, 66.4 mmol). The reaction mixture was sealed and heated at 90° C. for 3 h. The reaction mixture was washed with water (300 mL) and diluted with Na 2 SO 4The solvent was removed in vacuo to give the crude title compound as a mixture of enantiomers (13.2 g, quantitative), which was used in the next step without further purification.

[0096] Intermediate 41 [ka] N-trans-(7SR,9SR)-3-cyclopropyl-9-(ethylcarbamothioylamino)-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of Example 3 (50 mg, 0.104 mmol) in THF (1 mL) was added isothiocyanatoethane (0.010 mL, 0.115 mmol). The solution was stirred for 60 min. Another portion of isothiocyanatoethane (0.010 mL, 0.115 mmol) was added and the solution was stirred for 1 h. The solvent was removed to give a white solid. Trituration with DCM afforded the title compound as a mixture of enantiomers (55 mg, 87% yield). LCMS [M+H] + 567,RT 3.03 minutes(Method 3).

[0097] Intermediate 42 [ka] cis-(7RS,9SR)-7,9-diamino-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 27 (1.2 g, 2.85 mmol) was dissolved in ethanol (12 mL) and palladium on carbon (0.28 mmol) was added. The solution was degassed and placed under a hydrogen atmosphere. More palladium on carbon was added until the reaction was complete. The reaction mixture was then filtered through Celite and washed with EtOH (15 mL). The solvent was removed and the crude product was purified by column chromatography eluting with a 0-100% gradient of MeOH in DCM to give the title compound as a mixture of enantiomers (851 mg, 52% yield). 1 H NMR (300 MHz, Methanol-d4) δ H9.68(d,J=0.8 Hz,1H),8.55(d,J=0.8 Hz,1H),8.46(s,1H),4.87(dd,J=7.8,5.3 Hz,1H),4.35(dd,J=8.0,5.5 Hz,1H),3.07(dt,J=13.7,7.9 Hz,1H),2.70-2.53(m,2H),1.75(dt,J=13.7,5.4 Hz,1H),1.65-1.50(m,1H),0.81-0.66(m,6H).LCMS(ES)m / z=369(M+H) + ,RT=1.76(Method 12)

[0098] Intermediate 43 [ka] tert-Butyl N-[cis-(7RS,9SR)-7-(tert-butoxycarbonylamino)-3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate To a stirred solution of intermediate 42 (3.7 g, 7.0 mmol) in 1,4-dioxane (80 mL) was added di-tert-butyl dicarbonate (3.8 g, 18 mmol) followed by triethylamine (3.9 mL, 28 mmol). The reaction was stirred at ambient temperature overnight. The reaction mixture was diluted with water (80 mL) and DCM (100 mL). The organic phase was partitioned and the aqueous layer was extracted with DCM (100 mL). The combined organic extracts were dried and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with a 0-40% gradient of EtOAc in isohexane to afford the title compound as a mixture of enantiomers (3.7 g, 7.0 mmol). 1 H NMR (400 MHz, Chloroform-d) δ H9.44(s,1H),8.48(d,J=0.9 Hz,1H),8.37(s,1H),5.79(s,1H),5.68(dt,J=13.4,6.5 Hz,1H),5.41(s,1H),5.05-4.91(m,1H),4.80-4.66(m,1H),3.26(dt,J=14.4,8.8 Hz,1H),2.83-2.63(m,2H),2.13-2.06(m,1H),1.69(dp,J=13.4,6.7 Hz,1H),1.46(s,9H),1.43(s,9H),0.82(dd,J=6.7,2.2 Hz,6H).LCMS [M+H] + 569, RT 1.67 (Method 7).

[0099] Intermediate 44 [ka] tert-Butyl N-[cis-(7RS,9SR)-7-(tert-butoxycarbonylamino)-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate To a stirred suspension of intermediate 43 (2 g, 3.51 mmol) in toluene (20 mL), 1,4-dioxane (20 mL) and water (1 mL) was added cyclopropylboronic acid (1.27 g, 14.1 mmol), tribasic potassium phosphate (2.66 g, 12.3 mmol), tricyclohexylphosphonium tetrafluoroborate (334 mg, 0.879 mmol) and palladium(II) acetate (121 mg, 0.527 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated at 100° C. overnight in a sealed pressure flask. The reaction was cooled and diluted with DCM (100 mL) and water (50 mL). The organic phase was partitioned and the aqueous layer was extracted with DCM (2×50 mL). The organic layer was dried and concentrated in vacuo. The crude product was purified by column chromatography eluting with a gradient of 0-45% EtOAc in isohexane to afford the title compound as a mixture of enantiomers (1.25 g, 59% yield). 1 H NMR (400 MHz, Chloroform-d) δ H9.48(s,1H),8.31(s,1H),8.24(s,1H),5.79-5.62(m,1H),5.62-5.49( m,1H),5.49-5.32(m,1H),5.17-4.95(m,1H),4.94-4.74(m,1H),3.29-3 .12(m,1H),2.84-2.57(m,2H),2.29-2.16(m,1H),2.06-1.97(m,1H),1 .75-1.63(m,1H),1.45(s,18H),1.18-1.01(m,4H),0.83(dd,J=6.7,3.3 Hz,6H).LCMS [M+H] + 575, RT 3.08 (Method 7).

[0100] Intermediate 45 [ka] cis-(7RS,9SR)-7,9-diamino-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide dihydrochloride To a stirred suspension of intermediate 44 (1.25 g, 2.18 mmol) in methanol (20 mL) at ambient temperature was added 4 M hydrochloric acid in dioxane (11 mL, 44 mmol). The reaction was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo and the resulting solid was triturated in diethyl ether (10 mL), filtered and washed with additional diethyl ether (10 mL). The solid was dried to give the title compound as a bis-HCl salt and a mixture of enantiomers (1.02 g, quantitative). 1 H NMR (400 MHz, Methanol-d4) δ H 9.80(d,J=0.9 Hz,1H),8.80(s,1H),8.66(d,J=0.9 Hz,1H),5.71(dd,J=8.9,2.8 Hz,1H),5.12(dd,J=9.3,3.1 Hz,1H),3.58-3.47(m,1H),2.72(d,J=7.0 Hz,2H),2.60-2.42(m,2H),1.64(hept,J=6.8 Hz,1H),1.38-1.23(m,4H),0.79(d,J=6.7 Hz,6H).LCMS [M+H] + 375, RT 1.54 (Method 15).

[0101] Intermediate 46 [ka] 1-[cis-(7RS,9SR)-3-cyclopropyl-5-(isobutylsulfamoyl)-7-(3-pyridylcarbamothioylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-(3-pyridyl)thiourea To a stirred suspension of intermediate 45 (100 mg, 0.26 mmol) in DCM (4 mL) at room temperature was added 3-isothiocyanatopyridine (74.5 μL, 0.66 mmol). The reaction was stirred at ambient temperature for 30 min. A second portion of 3-isothiocyanatopyridine (16 μL) was added and stirring was continued for 30 min. The reaction was filtered and washed with diethyl ether (5 mL). The solid was triturated and filtered first with DCM / MeOH (9:1) then MeOH to give the title compound as a mixture of enantiomers (117 mg, 67% yield). 1 H NMR (400 MHz, DMSO-d6) δ H 9.99-9.73(m,2H),9.43(s,1H),8.68-8.47(m,3H),8.46-8.26(m,4H),8.25-8.11(m,1H),7.96(dd,J=26.4,8.2 Hz,2H),7.51-7.29(m,2H),6.78-6.56(m,1H),6.23-5.90(m,1H),2.72-2.54(m,2H),2.38-2 .18(m,1H),2.15-1.93(m,1H),1.74-1.51(m,1H),1.17-0.99(m,4H),0.88-0.67(m,6H).LCMS [M+H] + 647,RT 2.19(Method 15).

[0102] Intermediates 47 and 47a [ka] tert-Butyl N-[7-(tert-butoxycarbonylamino)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate (47) tert-Butyl N-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate (47a) A mixture of intermediates 29a and 29 (1135 mg, 2.40 mmol) in a ratio of about 5.5:1, respectively, was dissolved in toluene (10 mL). Cyclopropylboronic acid (652 mg, 7.21 mmol) and palladium(II) acetate (27 mg, 0.120 mmol) were added, the mixture was degassed and vacuum / nitrogen purged (3 times). 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, the mixture was again degassed and vacuum / nitrogen purged (3 times). The reaction mixture was heated in a microwave at 120° C. for 2 h. After cooling, the mixture was diluted with EtOAc (100 mL) and the solution was washed with water, then with brine, passed through a phase separator cartridge and evaporated. The crude product was purified by flash chromatography eluting with a gradient of 10-60% EtOAc / hexanes to give the title compound:

[0103] Intermediate 47 (156 mg); LCMS [M+H]+593, RT 2.89 min (Method 17).

[0104] Intermediate 47a (938 mg); LCMS [M+H]+478, RT 2.70 min (Method 15).

[0105] Intermediate 48 [ka] trans-(7SR,9SR)-7,9-diamino-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide THF (80 mL) and H 2 To a stirred solution of intermediate 28 (3.25 g, 7.72 mmol) in HO (10 mL) was added triphenylphosphine (4.95 g, 18.7 mmol). The reaction mixture was heated at 50° C. for 30 min, then added with H 2 Further 20O (20 mL) was added. After another 23 h, additional triphenylphosphine (1.0 g, 3.8 mmol) was added and heating was continued at 50° C. overnight. The reaction mixture was then concentrated in vacuo and diluted with 7N NH 3Purification using an SCX cartridge eluting with 5% yield afforded the title compound as a mixture of enantiomers (3.31 g, 93% yield). LCMS [M+H] + 369,RT 1.16 minutes(Method 13).

[0106] Intermediate 49 [ka] tert-Butyl N-trans-(7RS,9RS)-7-(tert-butoxycarbonylamino)-3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate To a stirred solution of intermediate 48 (3.31 g, 7.17 mmol) in anhydrous 1,4-dioxane (80 mL) was added TEA (4 mL, 28.7 mmol) and di-tert-butyl dicarbonate (4.1 g, 18 mmol) at room temperature. After 1 h 15 min, the reaction mixture was concentrated to half the volume and washed with DCM (100 mL) and saturated NaHCO 3 (100 mL) of the mixture and the phases were separated. The aqueous phase was extracted with DCM (3 x 30 mL) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography eluting with 0-30% EtOAc in isohexane afforded the title compound as a mixture of enantiomers (2.20 g, 54% yield). LCMS [M+H] + 569,RT 2.46 minutes(Method 13).

[0107] Intermediate 50 [ka] tert-Butyl N-trans-(7RS,9RS)-7-(tert-butoxycarbonylamino)-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate Toluene (20 mL), 1,4-dioxane (20 mL) and H 2To a stirred suspension of intermediate 49 (2.15 g, 3.78 mmol) in a mixture of 2O (1 mL) was added cyclopropylboronic acid (1.36 g, 15 mmol), potassium phosphate tribasic (2.9 g, 13 mmol), tricyclohexylphosphonium tetrafluoroborate (360 mg, 0.95 mmol) and palladium(II) acetate (130 mg, 0.5675 mmol). The mixture was cooled to 5° C. for 2 h and cooled to 3° C. 2 The mixture was placed under atmosphere and heated in a sealed pressure round bottom flask at 100° C. After 4 h 25 min, the reaction mixture was diluted with DCM (100 mL with a few mL of IPA) and H 2 The mixture was diluted with 200 mL of HO (200 mL) and the phases were separated. The aqueous layer was extracted with DCM (100 mL with a few mL of IPA) and DCM (4 x 30 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography eluting with 0-40% EtOAc in isohexane afforded the title compound as a mixture of enantiomers (1.84 g, 80% yield). LCMS [M+H] + 575,RT 2.49 minutes(Method 13).

[0108] Intermediate 51 [ka] trans-(7RS,9RS)-7,9-diamino-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide dihydrochloride To a stirred yellow semi-solution of intermediate 50 (1.8 g, 3.1 mmol) in MeOH (60 mL) in an ice bath was added hydrochloric acid (4.0 mol / L) in dioxane (33 mL). The reaction mixture was then allowed to warm to room temperature and stirred for 30 min to 4 h, then concentrated in vacuo. The crude product was extracted with Et 2 Triturate with 20 mL of HO, filter, and 2 The residue was dried in vacuo to give the title compound as a mixture of enantiomers (1.51 g, quantitative). LCMS [M+H] + 375,RT 0.76 minutes(Method 8).

[0109] Intermediate 52 [ka] 1-trans-(7RS,9RS)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-ethyl-thiourea General procedure 1 was followed using intermediate 51 (600 mg, 1.30 mmol) with a heating time of 10 h. The reaction mixture was concentrated in vacuo and diluted with Et 2 Trituration with 2H2O (80 mL) and filtration afforded the title compound as a mixture of enantiomers (623 mg, 87% yield). LCMS [M+H] + 549,RT 1.04 minutes(Method 8).

[0110] Intermediate 53 [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. 1 H NMR (300 MHz, Chloroform-d) δ H 9.14(d,J=0.9 Hz,1H),8.46(d,J=0.8 Hz,1H),8.34(s,1H),4.98(t,J=6.5 Hz,1H),3.49-3.37(m,2H),3.17(t,J=7.5 Hz,2H),3.04(dd,J=19.8,6.5 Hz,2H),2.45-2.29(m,2H),1.31(d,J=21.4 Hz,6H).LCMS [M+H] + 357, RT 1.92 (Method 14).

[0111] Intermediate 54 [ka] 9-Bromo-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a stirred solution of intermediate 53 (10.47 g, 29.3 mmol) in EtOAc (500 mL) was added 2,2'-azobis(2-methylpropionitrile) (506 mg, 3 mmol) and N-bromosuccinimide (6.24 g, 34.7 mmol). The reaction mixture was stirred at 90° C. in the dark for 1.5 h. The reaction was cooled and concentrated. Residual succinimide was filtered off and the crude product was purified by column chromatography eluting with a gradient of 0-25% EtOAc in isohexane to give the title compound (5.07 g, 44% yield). 1 H NMR (300 MHz, Chloroform-d) δ H 9.34(d,J=0.8 Hz,1H),8.49(d,J=0.8 Hz,1H),8.36(s,1H),6.02(dd,J=4.6,2.6 Hz,1H),5.04(t,J=6.4 Hz,1H),3.47-3.32(m,1H),3.17-3.04(m,3H),2.85-2.75(m,2H),1.33(dd,J=21.4,4.7 Hz,6H).LCMS [M+H] + 434 / 436, RT 2.57 (Method 14).

[0112] Intermediate 55 [ka] 7,9-Dibromo-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A vial was charged with Intermediate 54 (750 mg, 1.72 mmol), N-bromosuccinimide (360 mg, 2.02 mmol), 2,2'-azobis(2-methylpropionitrile) (30 mg, 0.179 mmol) and EtOAc (30 mL), sealed and then heated at 90°C for 4 h. The reaction mixture was concentrated. Purification by column chromatography in vacuo eluting with 0-100% EtOAc in isohexane afforded the title compound (779 mg, 84% yield) as a mixture of cis and trans isomers. LCMS [M+H] + 515,RT 2.70 minutes(cis isomer)and RT 2.79 minutes(trans isomer)(Method 12).

[0113] Examples 56 and 57 [ka] trans-(7SR,9SR)-7,9-diazido-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (56) Cis-(7RS,9SR)-7,9-diazido-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (57) To a stirred solution of intermediate 55 (779 mg, 1.45 mmol) in anhydrous DMF (5 mL) was added sodium azide (240 mg, 3.65 mmol). The reaction mixture was stirred at room temperature for 1 h 35 min, then diluted with EtOAc (30 mL) and washed with brine (60 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organic layers were dried (phase separator) and concentrated in vacuo. Purification by column chromatography eluting with 0-30% EtOAc in isohexane afforded the title compound as a mixture of enantiomers:

[0114] Intermediate 56 (239 mg, 37% yield), LCMS [M+H] + 439, RT 1.54 min (method 7).

[0115] Intermediate 57 (293 mg, 46% yield), LCMS [M+H] + 439, RT 1.53 minutes (Method 7).

[0116] Intermediate 58 [ka] trans-(7RS,9RS)-7,9-diamino-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 56 was synthesized in the same manner as Intermediate 48 using (280 mg, 0.64 mmol) and equivalent stoichiometry of reagents. 7N NH 3 Purification using an SCX cartridge eluting with 5% yield afforded the title compound as a mixture of enantiomers (255 mg, 83% yield). LCMS [M+H] + 387,RT 1.01 minutes(Method 13).

[0117] Intermediate 59 [ka] 1-trans-(7RS,9RS)-3-chloro-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-ethyl-urea Purification by column chromatography following general procedure 1 using intermediate 58 (142 mg, 0.31 mmol) at room temperature eluting with DCM containing 0-10% MeOH afforded the title compound as a mixture of enantiomers (74 mg, 45% yield). LCMS [M+H] + 529,RT 1.32 minutes(Method 13).

[0118] Intermediate 60 [ka] Cis-(7RS,9SR)-7,9-diamino-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Synthesized in the same manner as Intermediate 57 using Intermediate 48 (240 mg, 0.55 mmol) and equivalent stoichiometry of reagents. 7N NH in MeOH 3 Purification using an SCX cartridge eluting with 5% yield afforded the title compound as a mixture of enantiomers (209 mg, 79% yield). LCMS [M+H] + 387,RT 1.09 minutes(Method 13).

[0119] Intermediate 61 [ka] 1-[cis-(7RS,9SR)-3-chloro-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-ethyl-urea General procedure 1 was followed with intermediate 60 (100 mg, 0.22 mmol) at room temperature. Purification by column chromatography eluting with 0-10% MeOH in DCM afforded the title compound as a mixture of enantiomers (68 mg, 59% yield). LCMS [M+H] + 529,RT 1.34 minutes(Method 13).

[0120] Intermediate 62 [ka] 7,9-Diamino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide dihydrochloride Intermediate 47 (153 mg, 0.258 mmol) was dissolved in 4N HCl in dioxane (5 mL). Stirred at room temperature for 1 h. The solvent was removed in vacuo to give the title compound (120 mg, quantitative), which was used without further purification. LCMS [M+H]+393,RT 0.83 minutes (Method 8).

[0121] Examples 1 and 2 [ka] tert-Butyl N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate (1) tert-Butyl N-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate (2) To a solution of intermediate 26 (1870 mg, 3.94 mmol) in THF (15 mL) at 0 °C was added DIPEA (2.4 mL, 13.8 mmol) and pyridine-3-carbonyl chloride hydrochloride (912 mg, 5.12 mmol). The solution was stirred at room temperature for 10 min. The solvent was removed to give a brown solid. The solid was purified by elution with a gradient of 0-100% ethyl acetate in heptane, followed by 0-5% 7M NH 3Purification by flash column chromatography eluting with a gradient of DCM containing / MeOH afforded the title compound as a mixture of enantiomers: Example 1 (980 mg, 42% yield); LCMS [M+H] + 580, RT 2.93 minutes (Method 1). Example 2 (1240 mg, 51% yield); LCMS [M+H] + 580, RT 2.98 minutes (Method 1).

[0122] Example 3 [ka] N-trans-(7RS,9RS)-9-amino-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a suspension of Example 1 (200 mg, 0.345 mmol) in DCM (2.5 mL) was added trifluoroacetic acid (2.5 mL, 45.0 mmol) at 0° C. The resulting solution was stirred at room temperature for 30 min. Solvent was removed from the reaction azeotropically with 1:1 DCM / heptane to remove excess TFA. The resulting gum was purified by elution with 0-100% 7M NH in methanol gradient. 3 The mixture was purified by SCX column chromatography eluting with 5% to give the title compound as a mixture of enantiomers (165 mg, quantitative). H( 500 MHz,Methanol-d4)9.50(s,1H),9.04(dd,J=2.2,0.8 Hz,1H),8.70(dd,J=4.9,1.6 Hz,1H),8.41(d,J=0.7 Hz,1H),8.35-8.25(m,2H),7.56(ddd,J=8.0,4.9,0.8 Hz,1H),6.13(t,J=7.7 Hz,1H),5.23(d,J=6.0 Hz,1H),3.38-3.31(m,1H),2.73-2.54(m,4H),2.31(ddd,J=13.5,8.1,5.0 Hz,1H),1.62(dp,J=13.5,6.7 Hz,1H),1.12(ddtd,J=15.9,8.0,5.3,1.8 Hz,4H),0.77(dd,J=9.7,6.7 Hz,6H).LCMS [M+H] +480,RT 1.55 minutes(Method 2).

[0123] Example 4 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylcarbamothioylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of Example 3 (50 mg, 0.104 mmol) in THF (1 mL) was added 3-isothiocyanatopyridine (0.013 mL, 0.115 mmol). The solution was stirred for 10 min. The solid from the reaction mixture was filtered, washed with DCM (1 mL) and dried under vacuum to give the title compound as a mixture of enantiomers (32 mg, 49% yield). The filtrate gave a second crop of the title compound (16 mg, 25% yield). 1 H NMR (500 MHz, Methanol-d4) δ H 9.51(s,1H),9.05(d,J=1.6 Hz,1H),8.71(dd,J=4.9,1.6 Hz,1H),8.58(d,J=2.4 Hz,1H),8.43(s,1H),8.37-8.24(m,3H),8.03(ddd,J=8.3,2.5,1.5 Hz,1H),7.61-7.49(m,1H),7.39(dd,J=8.2,4.9 Hz,1H),7.07-6.98(m,1H),6.08(t,J=7.3 Hz,1H),2.83-2.74(m,2H),2.66(qd,J=12.9,6.9 Hz,2H),2.31(ddd,J=13.4,7.9,5.1 Hz,1H),1.63(dp,J=13.5,6.8 Hz,1H),1.18-1.03(m,4H),0.77(t,J=6.7 Hz,6H).LCMS [M+H] + 616,RT 2.90 minutes(Method 3).

[0124] Example 5 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-9-(ethylcarbamoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of Example 3 (20 mg, 0.0417 mmol) in THF (1 mL) was added isocyanatoethane (0.004 mL, 0.046 mmol). The solution was stirred for 18 h. The solvent was removed to give a pale yellow residue. The residue was purified by reverse phase HPLC (basic conditions) to give the title compound as a mixture of enantiomers (18 mg, 76% yield). δ H( 500 MHz,Methanol-d4)9.40(d,J=0.7 Hz,1H),9.03(dd,J=2.3,0.8 Hz,1H),8.70(dd,J=4.9,1.6 Hz,1H),8.41(d,J=0.8 Hz,1H),8.33-8.26(m,2H),7.56(ddd,J=8.0,4.9,0.8 Hz,1H),6.14-5.97(m,2H),3.26-3.16(m,2H),2.72-2.58(m,4H),2.30(ddd,J=13.3,7.9,5.2 Hz,1H),1.61(dq,J=13.3,6.6 Hz,1H),1.16-1.07(m,7H),0.77(t,J=6.6 Hz,6H).LCMS [M+H] + 551,RT 2.69 minutes(Method 3).

[0125] Example 6 [ka] N-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of intermediate 35 (15 mg, 0.031 mmol) in 1,4-dioxane (1 mL) in a pressure vial was added tBuXPhosPdG3 (6.2 mg, 7.82 μmol), 3-bromopyridine (0.007 mL, 0.078 mmol) and sodium 2-methylpropan-2-olate (12 mg, 0.12 mmol). The solution was heated at 90° C. for 150 min. The solvent was removed to give a pale yellow residue. The residue was purified by reverse phase HPLC (basic conditions) to give the title compound as a mixture of enantiomers (8 mg, 46% yield). 1 H NMR (500 MHz, Methanol-d4) δ H9.57(s,1H),9.04(d,J=1.7 Hz,1H),8.72(dd,J=4.9,1.5 Hz,1H),8.44(d,J=0.7 Hz,1H),8.37(s,1H),8.31(dt,J=8.0,1.9 Hz,1H),8.12(s,1H),7.89(d,J=4.0 Hz,1H),7.58(ddd,J=8.0,4.9,0.7 Hz,1H),7.37-7.31(m,1H),7.27(dd,J=8.4,4.7 Hz,1H),5.80-5.69(m,2H),3.39(dt,J=13.5,8.0 Hz,1H),2.76-2.60(m,2H),2.37-2.25(m,1H),2.20(dt,J=13.4,6.1 Hz,1H),1.72-1.55(m,1H),1.15-1.04(m,4H),0.80(dd,J=9.5,6.7 Hz,6H).LCMS [M+H] + 557,RT 3.01 minutes(Method 3).

[0126] Example 7 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of Example 3 (7.0 mg, 0.014 mmol) in 1,4-dioxane (1 mL) in a pressure vial was added tBuXPhosPdG3 (2.9 mg, 3.65 μmol), 3-bromopyridine (0.003 mL, 0.036 mmol) and sodium 2-methylpropan-2-olate (5.6 mg, 0.0584 mmol). The solution was heated at 90° C. for 90 min. The solvent was removed to give a pale yellow residue. The residue was purified by reverse phase HPLC (basic conditions) to give the title compound as a mixture of enantiomers (5 mg, 60% yield). δ H(500 MHz,Methanol-d4)9.36-9.29(m,1H),9.04(d,J=1.6 Hz,1H),8.71(dd,J=4.9,1.6 Hz,1H),8.43(d,J=0.8 Hz,1H),8.35(s,1H),8.31(dt,J=8.0,1.9 Hz,1H),8.07(s,1H),7.88(t,J=2.9Hz,1H),7.57(ddd,J=8.0,4.9,0.8 Hz,1H),7.30-7.20(m,2H),6.03(t,J=7.4 Hz,1H),5.87(d,J=5.1 Hz,1H),2.81-2.60(m,4H),2.37-2.23(m,1H),1.69-1.56(m,1H),1.15-1.04(m,4H),0.79(t,J=6.7Hz,6H).LCMS [M+H] + 557,RT 2.92 minutes(Method 3).

[0127] Examples 8 and 9 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide (8) N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide (9) To a solution of intermediate 34 (43 mg, 0.07 mmol) in DMF (2 mL) was added formic hydrazide (13 mg, 0.21 mmol) and mercuric dichloride (57 mg, 0.21 mmol). The mixture was stirred for 2 min and then triethylamine (0.03 mL, 0.21 mmol) was added. The mixture was then heated at 90° C. for 1 h. Acetonitrile (10 mL) and Celite (3 g) were added to the mixture and stirred for 5 min and then filtered through Celite, washing with excess DCM and MeOH. The filtrate was stripped of solvent to give a brown oil. The oil was purified by reverse phase HPLC (basic conditions) to give the title compound as a mixture of enantiomers:

[0128] Example 8 (17 mg, 39% yield); H(500 MHz, in deuterated methanol (Methanol-d4): 9.46 - 9.39 (m, 1H), 9.04 (d, J = 1.7 Hz, 1H), 8.74 - 8.62 (m, 2H), 8.59 (dd, J = 4.9, 1.4 Hz, 1H), 8.41 (d, J = 0.8 Hz, 1H), 8.36 - 8.24 (m, 3H), 7.94 (ddd, J = 8.2, 2.5, 1.5 Hz, 1H), 7.62 - 7.50 (m, 2H), 6.11 (dd, J = 7.4, 2.9 Hz, 1H), 6.03 (t, J = 7.3 Hz, 1H), 2.87 - 2.71 (m, 2H), 2.70 - 2.55 (m, 2H), 2.35 - 2.25 (m, 1H), 1.69 - 1.56 (m, 1H), 1.18 - 1.05 (m, 4H), 0.83 - 0.70 (m, 6H). LCMS [M+H] + 624, retention time 3.34 minutes (Method 5).

[0129] Example 9 (8 mg, yield 18%); δ H( 500 MHz, in deuterated methanol (Methanol-d4) δ 9.03 (d, J = 1.6 Hz, 1H), 8.90 (s, 1H), 8.71 (dd, J = 4.9, 1.6 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.46 (d, J = 0.8 Hz, 1H), 8.39 (s, 1H), 8.31 - 8.25 (m, 1H), 8.16 (dd, J = 4.8, 1.2Hz, 1H), 7.97 - 7.87 (m, 2H), 7.57 (ddd, J = 8.0, 4.9, 0.8 Hz, 1H), 7.37 (dd, J = 8.4, 4.8 Hz, 1H), 6.70 (dd, J = 8.2, 2.5 Hz, 1H), 6.12 (t, J = 7.3 Hz, 1H), 3.08 - 2.92 (m, 2H), 2.78 - 2.62 (m, 2H), 2.33 - 2.23 (m, 1H), 1.71 - 1.55 (m, 1H), 1.16 - 1.03 (m, 4H), 0.84 - 0.71 (m, 6H). LCMS [M+H] + 624, retention time 3.34 minutes (Method 5).

[0130] Example 10

Chemical Structure

[0131] Example 11 [ka] N-trans-(7RS,9RS)-9-(benzylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of Example 3 (15 mg, 0.031 mmol) in THF (1 mL) and DCM (1 mL) was added benzaldehyde (0.003 mL, 0.031 mmol). The solution was stirred for 5 h. To the reaction was added sodium triacetoxyborohydride (20 mg, 0.094 mmol). The reaction was stirred for an additional 18 h. The solvent was removed to give a pale yellow residue. The residue was purified by reverse phase HPLC (basic conditions) to give the title compound as a mixture of enantiomers (11 mg, 62% yield). δ H( 500 MHz,Methanol-d4)9.46-9.40(m,1H),9.03(dd,J=2.2,0.7 Hz,1H),8.70(dd,J=4.9,1.6 Hz,1H),8.37(d,J=0.8 Hz,1H),8.33-8.25(m,2H),7.56(ddd,J=8.0,4.9,0.8 Hz,1H),7.44(d,J=7.1 Hz,2H),7.35(t,J=7.6 Hz,2H),7.26(t,J=7.3 Hz,1H),6.08(t,J=7.5 Hz,1H),5.02(d,J=6.0 Hz,1H),4.00-3.86(m,2H),2.95-2.88(m,1H),2.71-2.56(m,2H),2.42(dt,J=13.9,7.3 Hz,1H),2.35-2.27(m,1H),1.65-1.50(m,1H),1.16-1.04(m,4H),0.75(dd,J=9.5,6.7 Hz,6H).LCMS [M+H] + 570,RT 3.61 minutes(Method 3).

[0132] Example 12 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(propylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of Example 3 (10 mg, 0.021 mmol) in THF (1 mL) and DCM (1 mL) was added propanal (0.002 mL, 0.031 mmol). The solution was stirred for 5 h. Sodium triacetoxyborohydride (13 mg, 0.062 mmol) was added to the reaction, which was stirred for 2 h. The solvent was removed to give a pale yellow residue. The residue was purified by reverse phase HPLC (basic conditions) to give the title compound as a mixture of enantiomers (11 mg, 95% yield). δ H( 500 MHz,Methanol-d4)9.56(s,1H),9.03(dd,J=2.2,0.7 Hz,1H),8.70(dd,J=4.9,1.6 Hz,1H),8.40(d,J=0.7 Hz,1H),8.36-8.23(m,2H),7.56(ddd,J=8.0,4.9,0.8 Hz,1H),6.07(t,J=7.6 Hz,1H),5.09(d,J=6.3 Hz,1H),2.81(ddd,J=13.6,7.7,1.9 Hz,1H),2.77-2.56(m,4H),2.45(dt,J=13.7,7.4 Hz,1H),2.31(ddd,J=13.2,8.1,5.1 Hz,1H),1.65-1.50(m,3H),1.17-1.06(m,4H),0.96(t,J=7.4 Hz,3H),0.75(dd,J=10.4,6.7 Hz,6H).LCMS [M+H] + 522,RT 3.30 minutes(Method 4).

[0133] Example 13 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-9-(2-methylpropanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a solution of Example 3 (20 mg, 0.042 mmol) in THF (1 mL) at 0° C. was added DIPEA (0.022 mL, 0.125 mmol) and 2-methylpropanoyl chloride (0.006 mL, 0.054 mmol). The solution was stirred at room temperature for 20 min. The solvent was removed to give a yellow gum. The gum was purified by reverse phase HPLC (basic conditions) to give the title compound as a mixture of enantiomers (14 mg, 61% yield). δH( 500 MHz,Methanol-d4)9.27(s,1H),9.04(d,J=1.6 Hz,1H),8.75-8.67(m,1H),8.41(d,J=0.7 Hz,1H),8.35-8.27(m,2H),7.57(dd,J=7.7,5.2 Hz,1H),6.21(dd,J=8.0,2.5 Hz,1H),6.10(t,J=7.5 Hz,1H),2.74-2.57(m,4H),2.42(p,J=6.9 Hz,1H),2.30(tt,J=7.8,5.4 Hz,1H),1.62(dp,J=13.5,6.8 Hz,1H),1.20-1.05(m,10H),0.77(t,J=6.8 Hz,6H).LCMS [M+H] + 550,RT 2.95 minutes(Method 3).

[0134] Examples 14 and 15 [ka] 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea (14) 1-Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea (15) A solution of intermediate 39 (23 mg, 0.061 mmol) and ethyl isocyanate (30 μL, 0.38 mmol) in dichloromethane (1 mL) was stirred at room temperature overnight. The reaction was quenched with methanol and concentrated in vacuo to give a brown oil (28 mg) as a mixture of cis and trans diastereoisomers. The residue was purified by column chromatography to give the title compound as a mixture of enantiomers:

[0135] Example 14, trans (1.9 mg, 7%): LCMS [M+H] + 447, RT 1.68 min (Method 9).

[0136] Example 15, cis, (2.2 mg, 8%): LCMS [M+H] + 447, RT 1.71 min (Method 9). 1 H NMR (300 MHz, DMSO-d6) δ H9.68(s,1H),8.36(s,1H),8.09(s,1H),6.41(d,J=8.5 Hz,1H),5.95(d,J=5.5 Hz,1H),5.54(s,1H),5.09(d,J=8.1 Hz,1H),3.17-3.01(m,2H),2.91(m,1H),2.53(m,2H),2.32(m,1H),1.76(m,1H),1.55(m,1H),1.03(t,J=7.2 Hz,7H),0.76(d,J=3.5 Hz,3H),0.74(d,J=3.6 Hz,3H).

[0137] Example 16 [ka] 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-7-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea A solution of intermediate 37 (30 mg, 0.08 mmol) and ethyl isocyanate (19 μL, 0.24 mmol) in dichloromethane (1 mL) was stirred at room temperature overnight (a few drops of DMF were added to aid solubility). The reaction was quenched with methanol and concentrated in vacuo to give a brown oil as a ca. 2:1 mixture of trans and cis isomers, which was separated by column chromatography to give the title compound (5 mg, 14%) as a mixture of enantiomers. 1 H NMR (300 MHz, DMSO-d6) δ H 9.34(s,1H),8.40(s,1H),8.23(s,1H),8.10(br,1H),6.49(d,J=8.9 Hz,1H),5.89-5.75(m,1H),5.69(t,J=5.6 Hz,1H),5.60(br,1H),5.39(t,J=6.2 Hz,1H),3.12-2.92(m,2H),2.54(d,J=7.0 Hz,2H),2.28(ddd,J=12.6,6.8,3.7 Hz,3H),1.59(dt,J=13.2,6.6 Hz,1H),1.10-0.88(m,7H),0.76(dd,J=6.6,1.0 Hz,6H).LCMS [M+H] + 447.4 with retention time 1.95 min(Method 16).

[0138] Example 17 [ka] N-[cis-(7RS,9SR)-3-cyclopropyl-9-(isoquinolin-4-ylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a mixture of sodium tert-butoxide (20 mg, 0.2081 mmol), methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (3.3 mg, 0.004 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.8 mg, 0.004 mmol), 4-bromoisoquinoline (12.5 mg, 0.06 mmol) and intermediate 35 (18 mg, 0.03753 mmol) was added 1,4-dioxane (0.20 mL). The reaction mixture was then heated at 90° C. for 2 h. Purification by column chromatography (basic conditions) afforded the title compound as a mixture of enantiomers (9.8 mg). LCMS (ES+) m / z=607 (M+H). + RT=2.55(Method 6).

[0139] Examples 18-29 Examples 18-29 were made according to the following procedures using the following stock solutions: Intermediate 23 (130 mg) dissolved in a mixture of DCM (6 mL) and DMA (500 μL) Intermediate 33 (130 mg) dissolved in DCM (6.5 mL) Intermediate 31 (91 mg) dissolved in DCM (6.5 mL)

[0140] The relevant isocyanate (1.3 equivalents, see table) was added to the relevant amine stock solution (500 μL-intermediate 23, 31 or 33 above) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by preparative LCMS in basic mode (examples 19 and 24 underwent an additional preparative purification under acidic conditions and desalted by a third purification under basic conditions) to give the products in the table below as mixtures of enantiomers.

[0141] The LCMS data in the table was obtained using LCMS method 18. [Table 1-1] [Table 1-2] [Table 1-3]

[0142] Examples 30-35 Examples 30-35 were made according to the following procedures using the following stock solutions: Intermediate 23 (100 mg) dissolved in a mixture of DCM (4.5 mL) and DMF (500 μL) Intermediate 31 (70 mg) dissolved in DCM (5 mL)

[0143] The relevant acyl chloride (1.4 equivalents, see table*) was added to the relevant amine stock solution (500 μL—intermediate 23 or 31 above) and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by preparative LCMS in basic mode (example 34 underwent an additional preparative purification under acidic conditions and was desalted by a third purification under basic conditions) to give the products in the table below as a mixture of enantiomers. *For Example 31, acid (1.4 eq.) was added to amine stock solution C (500 μL, Intermediate 31) followed by DIPEA (15 μL), TBTU (10 mg) and DMF (500 μL).

[0144] The LCMS data in the table was obtained using LCMS method 18. [Table 2-1] [Table 2-2]

[0145] Examples 36-37 Examples 36-37 were made according to the following procedure: The relevant acyl chloride (1.1 equivalents, see table below) was added to intermediate 25 (7 mg, 0.014 mmol) in a mixture of DCM (500 μL) and N,N-diisopropylethylamine (5 μL, 0.029 mmol). The reaction mixture was stirred at room temperature for 1 h and then purified by basic preparative LCMS to give the products in the table below as a mixture of enantiomers.

[0146] The LCMS data in the table was obtained using LCMS method 18. [Table 3]

[0147] Examples 38-47 Examples 38-47 were made according to the following procedures using the following stock solutions: a) Example 3 (9.6 mg, 0.020 mmol) in DMF (1800 μL) b) TBTU (7.5 mg, 0.023 mmol) in DMF (1800 μL) c) N,N-Diisopropylethylamine (20 μL, 0.115 mmol) in DMF (1800 μL)

[0148] 200 μL of each stock solution (a, b and c) were combined and added to the relevant substrate (see table below). The reaction mixture was stirred at room temperature overnight and then purified by basic preparative LCMS.

[0149] The LCMS data in the table was obtained using LCMS method 18. [Table 4-1] [Table 4-2] [Table 4-3]

[0150] Examples 48-52 Examples 48-52 were made according to the following procedure: A mixture of Example 3 (14 mg, 0.03 mmol), the relevant bromide (1.5 equiv., see table below), methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (2.4 mg, 0.003 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.3 mg, 0.003 mmol) and sodium tert-butoxide (15 mg, 0.15 mmol) was suspended in 1,4-dioxane (0.15 mL) and heated at 90° C. for 2 h or overnight. The reaction mixture was cooled to room temperature and purified by basic preparative LCMS.

[0151] The LCMS data in the table was obtained using LCMS method 18. [Table 5]

[0152] Examples 53-59 Examples 53-59 were made according to the following procedure: Example 3 (8.4 mg, 0.018 mmol) was added to a solution of the relevant isocyanate (1.3 eq., see table below) in DCM (0.5 mL). N,N-diisopropylethylamine (15 μL, 0.086 mmol) was then added and the reaction mixture was stirred at room temperature for 2 h. The solvent was then removed and the residue was purified by basic preparative LCMS.

[0153] The LCMS data in the table was obtained using LCMS method 18. [Table 6-1] [Table 6-2] [Table 6-3]

[0154] Example 60 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-9-(methanesulfonamido)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a mixture of Example 3 (10 mg, 0.02 mmol) and methanesulfonyl chloride (5 mg, 0.043 mmol) in DCM (0.6 mL, 9 mmol) was added N,N-diisopropylethylamine (10 μL, 0.057 mmol). The reaction mixture was stirred at room temperature for 1 h and purified by reverse phase column chromatography (basic condition) to give the title compound (7.1 mg, 60% yield). LCMS(ES+)m / z=558(M+H) + RT=3.78(Method 6).

[0155] Example 61 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(2-methylpropylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a mixture of Example 3 (9.6 mg, 0.02 mmol) and isobutanesulfonyl chloride (5 mg, 0.031 mmol) in DCM (500 μL) was added N,N-diisopropylethylamine (15 μL, 0.086 mmol). The reaction mixture was stirred at room temperature overnight. A second and third portion of isobutanesulfonyl chloride (10 and 15 mg, respectively) was then added and the reaction was stirred at room temperature for an additional 3 h. Purification by reverse phase column chromatography (basic conditions) afforded the title compound (3.4 mg, 30% yield). LCMS (ES+) m / z=600 (M+H). + RT=4.11(Method 6).

[0156] Example 62 [ka] N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide To a mixture of Example 3 (10 mg, 0.02 mmol) and pyridine-3-sulfonyl chloride (6 mg, 0.03 mmol) in DCM (500 μL) was added N,N-diisopropylethylamine (15 μL, 0.086 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed and the residue was purified by reverse phase column chromatography (basic condition) to give the title compound (7 mg, 60% yield). LCMS (ES+) m / z=621 (M+H). + RT=2.25(Method 6).

[0157] Example 63 [ka] 5-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-3-carboxylic acid A by-product in the procedure used to make Example 48 above. The title compound was purified by preparative LCMS (first under basic conditions, then under acidic conditions, and finally under basic conditions to give the free acid). LCMS [M+H] + 601, retention time 1.74 minutes (method 6).

[0158] Example 64 [ka] 1-Pyridin-3-yl-3-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridin-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea To a stirred suspension of intermediate 45 (100 mg, 0.267 mmol) in DCM (3 mL) at room temperature was added 3-isothiocyanatopyridine (90.9 mg, 0.75 mmol). The reaction was stirred at ambient temperature. DMF was added to aid in solubilization of the isocyanate. Additional 3-isothiocyanatopyridine (20 mg) was added and stirring was continued for 90 min. Purification by HPLC (reverse phase basic conditions) afforded the title compound (32 mg, 19% yield). 1 H NMR (400 MHz, DMSO-d6) δ H9.49-9.40(m,1H),8.90(d,J=12.9 Hz,2H),8.58(t,J=2.5 Hz,2H),8.37(d,J=0.9 Hz,1H),8.20(s,1H),8.18-8.08(m,3H),7.99-7.89(m,2H),7.33-7.24(m,2H),7.16(d,J=8.4 Hz,1H),7.00(d,J=8.0 Hz,1H),5.86-5.74(m,1H),5.30-5.20(m,1H),3.22-3.10(m,1H),2.61-2.52(m,2H),2.31-2.22(m,1H),1.99(dt,J=13.4,5.9 Hz,1H),1.59(hept,J=6.7 Hz,1H),1.12-0.92(m,4H),0.72(dd,J=8.4,6.7 Hz,6H).LCMS(ES+)m / z=615(M+H) + ,RT=1.80(Method 15).

[0159] Examples 65 and 66 [ka] cis-(7RS,9SR)-3-Cyclopropyl-7,9-bis[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (65) cis-(7RS,9SR)-7-amino-3-cyclopropyl-9-[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (66) A mixture of intermediate 45 (100 mg, 0.27 mmol), 3-bromo-5-methoxy-pyridine (125 mg, 0.66 mmol), sodium tert-butoxide (103 mg, 1.07 mmol) and tBuXPhos PD G3 (54.67 mg, 0.067 mmol) was placed under a nitrogen atmosphere and then 1,4-dioxane (4 mL) was added. The reaction mixture was sealed and stirred at ambient temperature for 2 h 45 min. The reaction was filtered through Celite and washed with EtOAc. The solvent was removed in vacuo and the resulting crude product was purified by HPLC (reverse phase basic conditions) to give the title compound:

[0160] Example 65 (10.2 mg, 6.5% yield). 1 H NMR (300 MHz, DMSO-d6) δ H9.45 (d, J = 0.9 Hz, 1H), 8.39 (d, J = 0.9 Hz, 1H), 8.21 (s, 1H), 8.15 (t, J = 6.0 Hz, 1H), 7.75 (t, J = 2.5 Hz, 2H), 7.59 (t, J = 2.1 Hz, 2H), 6.77 (dt, J = 8.9, 2.4 Hz, 2H), 6.61 (d, J = 9.4 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 5.76 - 5.59 (m, 1H), 5.25 - 5.09 (m, 1H), 3.82 - 3.69 (m, 6H), 3.25 - 3.12 (m, 1H), 2.61 - 2.52 (m, 2H), 2.34 - 2.25 (m, 1H), 1.92 - 1.74 (m, 1H), 1.70 - 1.49 (m, 1H), 1.16 - 0.91 (m, 4H), 0.76 (dd, J = 6.7, 5.0 Hz, 6H). LCMS(ES+) m / z = 589 (M + H) + , RT = 2.23 (Method 15).

[0161] Example 66 (4.7 mg, yield 3.7%). 1 1H NMR (300 MHz, DMSO-d6) δ H 9.81 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 8.12 (t, J = 5.7 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 6.73 (t, J = 2.4 Hz, 1H), 6.38 (d, J = 9.1 Hz, 1H), 5.22 - 4.98 (m, 2H), 3.78 (s, 3H), 3.12 - 2.99 (m, 1H), 2.60 - 2.52 (m, 2H), 2.36 - 2.19 (m, 1H), 1.94 - 1.77 (m, 1H), 1.70 - 1.46 (m, 1H), 1.20 - 0.91 (m, 4H), 0.76 (dd, J = 6.7, 4.8 Hz, 6H). LCMS(ES+) m / z = 482 (M + H) + , RT = 1.94 (Method 15).

[0162] Example 67

Chemical Structure

[0163] Example 68 [ka] 1-Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-7-(ethylcarbamothioylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]thiourea Intermediate 45 (200 mg) was dissolved in MeOH (5 mL) and absorbed onto an SCX cartridge. The cartridge was washed with MeOH and the free base was extracted with 4M NH 3The solvent was removed and the resulting free base (150 mg, 0.40 mmol) was dissolved in DCM (9 mL) and ethyl isothiocyanate (79.1 mg, 0.881 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was concentrated in vacuo and purified by column chromatography (0-100% gradient of EtOAc in isohexane) to give the title compound (7 mg, 3% yield). 1 H NMR (300 MHz, DMSO-d6) δ H 9.35(s,1H),8.36(d,J=1.0 Hz,1H),8.22(s,1H),8.13(t,J=5.9 Hz,1H),8.07-7.89(m,1H),7.87-7.50(m,3H),6.71-6.42(m,1H),6.02-5.74(m,1H),3.80-3.35(m,4H),3.14(dt,J=13.2,8.2 Hz,1H),2.63-2.53(m,2H),2.34-2.21(m,1H),1.92-1.74(m,1H),1.62(hept,J=6.7 Hz,1H),1.19-0.96(m,10H),0.77(dd,J=6.7,4.9 Hz,6H).LCMS(ES+)m / z=549(M+H) + ,RT=2.22(Method 15)

[0164] Example 69 [ka] Cis-(7RS,9SR)-3-Cyclopropyl-N-(2-methylpropyl)-7,9-bis[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a solution of intermediate 46 (113 mg, 0.1747 mmol) in N,N-dimethylformamide (6 mL) was added formic hydrazide (42 mg, 0.701 mmol) and mercuric chloride (143 mg, 0.52 mmol). Triethylamine (0.097 mL, 0.701 mmol) was then added and the reaction suspension was heated to 80° C. for 2 h and then left at room temperature overnight. The reaction mixture was filtered through a plug of Celite and washed with EtOAc (10 mL). The solvent was removed in vacuo and the resulting crude residue containing several regioisomers was purified by HPLC to give the title compound (5 mg, 4% yield). 1H NMR(300MHz,DMSO-d6)δH 9.62(s,1H),8.76-8.64(m,3H),8.49-8.38(m,1H),8.33(s,1H),8.29-8.20(m,1H),8.12-8.01(m ,2H),8.01-7.91(m,1H),7.88-7.79(m,1H),7.67-7.56(m,1H),7.41-7.19(m,2H),6.00(t,J=8.1 Hz,1H),5.91-5.76(m,1H),3.50-3.37(m,1H),2.45-2.19(m,4H),1.55-1.3 6(m,1H),1.24(s,1H),1.09-1.00(m,4H),0.89-0.80(m,1H),0.66(dd,J=6.4 Hz,6H).LCMS(ES+)m / z=663(M+H)+,RT=1.53(Method 15).

[0165] Example 70 [ka] trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A vial was charged with Intermediate 51 (50 mg, 0.11 mmol), 3-bromo-5-methoxypyridine (55 mg, 0.28 mmol), sodium tert-butoxide (42 mg, 0.44 mmol), methanesulfonato(2-di-tert-butylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.03 mmol) and anhydrous dioxane (3 mL) and the resulting mixture was subjected to vacuum and cooled with N 2 (x2) Refill with N for 5 min. 2 The mixture was purged with 0.5 mL of MeOH and then heated to 80° C. for 50 min. The reaction mixture was filtered through Celite (EtOAc wash with a few mL of MeOH) and concentrated in vacuo. Column chromatography eluting with 0-30% MeOH in DCM followed by H 2 Purification by reverse-phase column chromatography eluting with 0-80% MeCN in O afforded the title compound (31 mg, 49% yield). 1 H NMR (400 MHz, DMSO-d6) δ H 9.28(d,J=0.9 Hz,1H),8.39(d,J=0.9 Hz,1H),8.16(d,J=5.2 Hz,2H),7.71(dd,J=3.8,2.3 Hz,2H),7.58(dd,J=8.8,2.4 Hz,2H),6.72(t,J=2.4 Hz,1H),6.65(t,J=2.4 Hz,1H),6.48(d,J=8.8 Hz,1H),6.42(d,J=8.6 Hz,1H),5.82(t,J=7.7 Hz,1H),5.50-5.38(m,1H),3.78(s,3H),3.75(s,3H),2.59-2.51(m,3H),2.38(dt,J=13.5,7.0 Hz,1H),2.28(q,J=6.4 Hz,1H),1.59(dt,J=13.4,6.7 Hz,1H),1.08-0.98(m,4H),0.75(d,J=6.7 Hz,6H).LCMS [M+H] + 589,RT 2.12 minutes(Method 10).

[0166] Example 71 [ka] trans-(7RS,9RS)-7,9-bis(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide A microwave vial was charged with intermediate 51 (30 mg, 0.07 mmol), 1-butanol (2 mL), DIPEA (25 μL, 0.14 mmol) and 2-chlorobenzimidazole (25 mg, 0.1638 mmol). The resulting mixture was heated under microwave irradiation at 175° C. for 2 h. The reaction mixture was concentrated in vacuo and purified by column chromatography eluting with 0-30% MeOH in DCM followed by a second column eluting with 10% MeOH in EtOAc to give the title compound (3 mg, 7% yield). 1 H NMR (300 MHz, DMSO-d 6 )δ H 10.89(s,1H),10.75(s,1H),9.43(s,1H),8.36(d,J=0.9 Hz,1H),8.29(s,1H),8.10(t,J=5.9 Hz,1H),7.42(d,J=9.0 Hz,1H),7.29-7.11(m,5H),7.00-6.83(m,4H),6.27(t,J=7.7 Hz,1H),5.95(q,J=7.7 Hz,1H),2.72-2.51(m,4H),2.26(s,1H),1.56(p,J=6.8 Hz,1H),1.08-0.93(m,4H),0.71(d,J=6.7 Hz,6H).LCMS [M+H] + 607,RT 2.14 minutes(Method 10).

[0167] Examples 72 and 73 [ka] trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[(4-ethyl-1,2,4-triazol-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (72) trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[3-(ethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (73) To a solution of intermediate 52 (623 mg, 1.14 mmol) in anhydrous DMF (30 mL) was added formic hydrazide (280 mg, 4.66 mmol) and mercuric chloride (930 mg, 3.41 mmol). Anhydrous TEA (650 μL, 4.66 mmol) was then added and the mixture was heated to 80° C. for 16 h. The reaction mixture was then filtered through Celite (MeCN wash) and concentrated in vacuo. Column chromatography eluting with 0-50% MeOH in DCM followed by H 2 Purification by basic reverse-phase column chromatography eluting with 0-80% MeCN in O afforded the title compound:

[0168] Example 72 (135 mg, 21% yield). 1 H NMR (400 MHz, Methanol-d4) δ H 9.32(d,J=0.9 Hz,1H),8.43(d,J=0.9 Hz,1H),8.38(s,1H),8.12(d,J=3.0 Hz,2H),6.01(dd,J=7.5,2.3 Hz,1H),5.70(t,J=7.3 Hz,1H),3.91(q,J=7.2 Hz,2H),3.82(q,J=7.2 Hz,2H),2.84(ddd,J=14.0,7.6,2.4 Hz,1H),2.72-2.55(m,3H),2.34-2.26(m,1H),1.65(dt,J=13.5,6.7 Hz,1H),1.39(t,J=7.3 Hz,3H),1.31-1.26(m,3H),1.13-1.07(m,4H),0.81(dd,J=6.7,3.9 Hz,6H).LCMS [M+H] + 565,RT 1.60 minutes(Method 10).

[0169] Example 73 (4 mg, 1% yield). 1 H NMR (400 MHz, Methanol-d4) δ H8.90(d,J=0.9 Hz,1H),8.51(d,J=0.9 Hz,1H),8.18(s,1H),7.81(s,1H),7.50(s,1H),6.50(dd,J=7.3,3.9 Hz,1H),6.19(t,J=6.9 Hz,1H),3.53-3.39(m,4H),3.04-2.95(m,2H),2.69(dd,J=6.9,3.9 Hz,2H),2.37-2.27(m,1H),1.62(dt,J=13.4,6.7 Hz,1H),1.35(dt,J=20.5,7.2 Hz,6H),1.14-1.08(m,4H),0.79(dd,J=6.7,4.1 Hz,6H).LCMS [M+H] + 565,RT 1.52 minutes(Method 10).

[0170] Example 74 [ka] 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea Synthesized in the same manner as Intermediate 50 using Intermediate 59 (74 mg, 0.14 mmol) and equivalent stoichiometry of reagents heated at 120° C. for 12 h. Purification by reverse phase column chromatography (basic conditions) afforded the title compound (4 mg, 5% yield). 1 H NMR (400 MHz, DMSO-d6) δ H 9.37(s,1H),8.40(s,2H),8.11(s,1H),6.62(d,J=8.8 Hz,1H),6.38(d,J=8.6 Hz,1H),5.95-5.82(m,2H),5.62(t,J=5.6 Hz,1H),5.54(d,J=8.0 Hz,1H),3.16-2.98(m,5H),2.91(d,J=19.5 Hz,2H),2.24(ddd,J=21.3,12.7,7.5 Hz,2H),1.23(dd,J=21.4,6.0 Hz,6H),1.03(dd,J=8.3,6.2 Hz,6H),0.98(t,J=7.2 Hz,4H).LCMS [M+H] + 535,RT 1.61 minutes(Method 10).

[0171] Example 75 [ka] trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[3-(5-methyl-1,3,4-oxadiazol-2-yl)anilino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 51 (30 mg, 0.07 mmol) and 2-(3-bromophenyl)-5-methyl-1,3,4-oxadiazole were used with equivalent stoichiometry of reagents in the same manner as in Example 70. Purification by column chromatography eluting with 0-30% MeOH in DCM followed by reverse phase HPLC (basic conditions) afforded the title compound (21 mg, 48% yield). 1H NMR(400 MHz,DMSO-d6)δH 9.29(s,1H),8.39(s,1H),8.19(s,1H),8.14(t,J=6.0 Hz,1H),7.39-7.28(m,4H),7.20(ddt,J=10.3,7.8,1.1 Hz,2H),7.03-6.92(m,2H),6.63(dd,J=19.5,8.6 Hz,2H),5.88(t,J=7.7 Hz,1H),5.51(q,J=7.4 Hz,1H),2.66-2.58(m,1H),2.57-2.52(m,8H),2.45-2.37(m,1H),2.31-2.24(m,1H),1.58(hept,J=6.7 Hz,1H),1.11-0.97(m,4H),0.73(dd,J=6.7,2.5 Hz,6H).LCMS [M+H]+691,RT 2.46 minutes(Method 10).

[0172] Example 76 [ka] tert-Butyl N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(2,2,2-trichloroethoxysulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate A vial was charged with magnesium oxide (160 mg, 3.97 mmol) and 4 Å molecular sieves and dried under vacuum, then 2,2,2-trichloroethylsulfamate (300 mg, 1.27 mmol), 2-methyl-2-phenylpropionic acid (80 mg, 0.48 mmol) and bis[rhodium(alpha,alpha,alpha',alpha'-tetramethyl-1,3-benzenedipropionic acid)] (40 mg, 0.05 mmol) were added to the vial vial. 2 The mixture was added under reduced pressure, followed by isopropyl acetate (7 mL) and intermediate 13 (450 mg, 0.98 mmol). After 5 min, iodobenzene diacetate (640 mg, 1.95 mmol) was added to the mixture, which was stirred at room temperature. After 2 h 40 min, the reaction mixture was quenched with saturated aqueous thiourea (2 mL), followed by DCM (40 mL) and H 2 The mixture was diluted with 0H2O (40 mL) and the phases were separated. The aqueous layer was extracted with DCM (4 x 20 mL), dried (phase separator) and concentrated in vacuo. Purification by column chromatography eluting with 0-50% EtOAc in isohexane afforded a mixture of cis and trans isomers which was further purified using reverse phase HPLC (basic conditions) to afford the title compound (6 mg, 1% yield). 1 H NMR (300 MHz, DMSO-d 6 )δ H 9.56(s,1H),8.33(s,1H),8.09(s,2H),7.41(s,1H),5.51(s,1H),5.37( s,1H),4.72(s,2H),2.60-2.53(m,3H),2.33-2.24(m,2H),1.61(q,J=6.6 Hz,1H),1.44(s,9H),1.12-0.97(m,4H),0.77(d,J=6.6 Hz,6H)[Note:1H is missing due to a weak NMR].LCMS [M+H] + 687,RT 2.31 minutes(Method 11).

[0173] Example 77 [ka] 2-Cyano-1-ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-[[rac-(E)-N'-cyano-N-ethylcarbamimidoyl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]guanidine A vial was charged with intermediate 51 (30 mg, 0.07 mmol), DCM (2 mL), DIPEA (100 μL, 0.57 mmol) and diphenyl N-cyanocarbonimidate (35 mg, 0.14 mmol) and the mixture was stirred at room temperature. After 3 h, ethylamine (1 mL, 2 mmol) was added and the mixture was heated at 70° C. for 1 h and then concentrated in vacuo. Purification by reverse phase HPLC (basic conditions) afforded the title compound (19 mg, 49% yield). 1 H NMR (400 MHz, DMSO-d6) δ H 9.24(d,J=0.9 Hz,1H),8.38(d,J=1.0 Hz,1H),8.20(s,1H),8.11(s,1H),7.50(d,J=8.8 Hz,1H),7.34(d,J=8.5 Hz,1H),7.28-7.17(m,2H),6.11(s,1H),5.83(q,J=7.7 Hz,1H),3.22-3.05(m,4H),2.64-2.52(m,3H),2.42(ddd,J=13.7,8.1,3.0 Hz,1H),2.32-2.25(m,1H),1.64(hept,J=6.7 Hz,1H),1.09-1.03(m,7H),0.98(t,J=7.1 Hz,3H),0.79(dd,J=6.6,1.5 Hz,6H).LCMS [M+H] + 565,RT 1.82 minutes(Method 10).

[0174] Example 78 [ka] 1-Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea Synthesized in the same manner as Intermediate 50 using Intermediate 61 (60 mg, 0.11 mmol) and equivalent stoichiometry of reagents heated at 120° C. for 2 h. Purification by reverse phase column chromatography (basic conditions) afforded the title compound (10 mg, 16% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ H9.39(s,1H),8.41(s,2H),8.09(s,1H),6.62(d,J=8.9 Hz,1H),6.43(d,J=8.5 Hz,1H),6.02(t,J=5.6 Hz,1H),5.97(d,J=6.0 Hz,1H),5.64(q,J=7.9 Hz,1H),5.09(q,J=7.9 Hz,1H),3.12-3.03(m,4H),3.02-2.94(m,1H),2.90(d,J=21.6 Hz,2H),2.27(s,1H),1.79-1.66(m,1H),1.21(dd,J=21.4,9.3 Hz,6H),1.09-0.96(m,10H).LCMS [M+H] + 535,RT 1.62 minutes(Method 10).

[0175] Examples 79-87 All entries in the following table were carried out using intermediate 51 following either general procedure 1 or general procedure 2 (depending on the substrate used).

[0176] The LCMS data in the table was obtained using LCMS method 10. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0177] Examples 88 and 89 [ka] N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-9-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide (88) N-[9-amino-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide (89) To a solution of intermediate 62 (120 mg, 0.258 mmol) in DCM (5 mL) at 0° C. was added diisopropylethylamine (150 mg, 1.16 mmol) and nicotinoyl chloride hydrochloride (45.9 mg, 0.258 mmol). The mixture was stirred (in the absence of a cooling bath) for 48 h. The reaction mixture was diluted with DCM, washed with water, then brine, passed through a phase separator cartridge and evaporated to leave a gum. The crude product was purified by flash chromatography eluting with a gradient of 1-50% MeOH in DCM to give the title compound, Example 88 (22 mg, 14%) as an off-white solid. δ H( 300 MHz,MeOD-d4)9.40-9.31(m,2H),9.20(d,J=8.4 Hz,1H),9.09(dd,J=2.3,0.9 Hz,1H),9.03(dd,J=2.4,0.9 Hz,1H),8.77-8.67(m,2H),8.54-8.46(m,1H),8.43(d,J=0.9 Hz,1H),8.31-8.19(m,2H),8.17(s,1H),7.59-7.47(m,2H),6.44-6.34(m,1H),6.25-6.15(m,1H),3 .03-2.86(m,2H),2.76-2.60(m,2H),2.35-2.23(m,1H),1.30-1.14(m,6H),1.09-0.97(m,4H).LCMS [M+H] + 603,RT 1.38 minutes(Method 11)

[0178] Subsequent fractionation from the column afforded Example 89 in approximately 60% purity. This material was purified by preparative HPLC to afford Example 89 (3 mg, 2%) as an off-white solid. δ H(300 MHz,MeOD-d4)9.51(d,J=1.0 Hz,1H),9.05(dd,J=2.3,1.0 Hz,1H),8.72(dd,J=4.9,1.6 Hz,1H),8.44(d,J=1.0 Hz,1H),8.36-8.27(m,2H),7.58(ddd,J=8.0,5.0,1.0 Hz,1H),6.14(t,J=7.6 Hz,1H),5.21(d,J=6.9 Hz,1H),3.13-2.91(m,2H),2.73-2.51(m,2H),2.39-2.28(m,1H),1.32-1.20(m,6H),0.90(d,J=7.6 Hz,4H)[4 NH protons not seen].LCMS [M+H] + 498,RT 1.50 minutes(Method 15).

[0179] In vitro biochemical assays: Protocol for preparation of IgE-Tb reagent 100 mM NaHCO 3 86 nmol of IgE-Fc (N265Q, N371Q) (Young et al., 1995) at 172 μM in pH 9.5 was added to 1 mg of LanthaScreen™ amine-reactive Tb chelate (ThermoFisher catalog no. PV3583) and incubated for 16 hours at 20° C. The material was then diluted with phosphate buffered saline (i.e., 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 1.8 mM K 2 HPO 4 The material was quantified and the extent of Tb conjugation was determined by measuring absorbance at 280 nm and 343 nm.

[0180] The integrity of the conjugate was determined by analytical size exclusion chromatography on a S200 HR 10x300 column (GE Healthcare).Typical conjugation ratio was 4:1 Tb:IgE-Fc. Young RJ., Owens, RJ., MacKay GA., Chan CMW., Shi J., Hide M., Francis DM., Henry AJ., Sutton BJ., and Gould HJ (1995) Protein Engineering 8:193-199

[0181] 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 then resuspended in conjugation buffer (50 mM NaHCO 3 The solution was buffer exchanged into 100 mM NaCl, pH 9.5) and concentrated to 750 μM.

[0182] 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. Protein was resuspended in phosphate buffered saline (i.e., 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 1.8 mM K 2 HPO 4 The solution was buffer exchanged into 100% ethanol (pH 7.4), the material was quantified, and the extent of Alexa Fluor™ 488 conjugation was determined by measuring absorbance at 280 nm and 495 nm.

[0183] The integrity of the conjugate was determined by analytical size-exclusion chromatography on a S200 HR 10x300 column (GE Healthcare).Typical conjugation ratio was 2:1 Alexa Fluor™ 488:sFcεR1α. Cook JPD., Henry AJ., McDonnell JM., Owens RJ., Sutton BJ., and Gould HJ (1997) Biochemistry 36:15579-15588

[0184] sFcεR1α-AF488 Reagent Preparation Protocol To a solution of 1.32 μmol of WT FcεR1α (377 μM) in 100 mM NaOAc (pH 5.5), 50 mM sodium periodate (70 μL) in 100 mM NaOAc (pH 5.5) was slowly added with gentle mixing to give a final concentration of 1 mM. The solution was incubated for 60 min at 22°C with gentle mixing. A second aliquot of 50 mM sodium periodate (70 μL) was added and the solution was incubated for 60 min at 22°C with gentle mixing. Oxidation was stopped by the slow addition of ethanediol (151.4 μL) with gentle mixing to give a final concentration of 4% v / v. The solution was incubated for 60 min at 22°C with gentle mixing. The protein was conjugated using a PD10 column (GE Healthcare) with conjugation buffer (50 mM NaHCO 3 , 150 mM NaCl, pH 9.5) and concentrated to 1.13 mM using an Amicon Ultra 15 (10 kDa cutoff, Merck).

[0185] 175 nmol of protein was added to 1 mg of Alexa Fluor™ 488 hydrazide (Invitrogen) and incubated for 18 hours with gentle mixing at 22° C. The mixture was cooled on ice and ice-cold sodium cyanoborohydride (100 mM in conjugation buffer) was added to give a final concentration of 1 mM and incubated on ice for 60 minutes. The protein was conjugated using a NAP-10 column (GE Healthcare) in phosphate buffered saline (i.e., 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 1.8 mM K 2 HPO 4The material was quantified and the extent of Alexa Fluor™ 488 conjugation was determined by measuring absorbance at 280 nm and 497 nm. Typical conjugation ratio was 2:1 Alexa Fluor™ 488:sFcεR1α.

[0186] The aim was to measure the binding of IgE-Tb to the receptor and its inhibition by compounds using an in vitro fluorescence resonance energy transfer (FRET) assay.

[0187] reagent The FRET reagents used were terbium-labeled IgE (FRET donor), Alexa Fluor™ 488-labeled soluble IgE receptor FcεRIα (FRET acceptor) and Alexa Fluor™ 488-labeled soluble IgE receptor FcεRIα with a Y131A mutation (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.

[0188] Assay reaction For examples 16 and 89, the assay was performed as follows: each assay reaction was performed in a volume of 25 μl in a 384-well half-volume plate. A 10-point compound serial dilution (3-fold) was generated in DMSO at a concentration 50-fold higher than the final assay concentration (FAC). Compound solutions were then prepared by diluting 10-fold in assay buffer with IgE-Tb. For the assay, 5 μl of diluted compound was added to 10 μl of IgE-Tb, followed by 10 μl of FcεRIα-Y131A-AF488. The FRET reagent FAC was 5 nM IgE-Tb, 25 nM FcεRIα-Y131A-AF488. Typically, the top FAC of the compound in the assay was 10 μM. The final DMSO concentration was 2%. The minimum signal (MIN) was measured by adding 5 μl of 1 μM unlabeled FcεRIα (FAC=200 nM) to the FRET reagent. The maximum FRET signal (MAX) was measured in wells containing the FRET reagent but no compound.

[0189] The assay was incubated for 2 hours at room temperature, protected from light and evaporation and gently agitated.

[0190] FRET measurements FRET measurements for each well were performed using an Envision plate reader (Perkin Elmer) by exciting at 330 nm and measuring emission at 495 / 520 nm. The FRET ratio was calculated as follows: Radiation at 520 / radiation at 495x1000.

[0191] FRET ratio was used for data analysis.

[0192] 4. Data Analysis Z' was calculated as follows (σ=standard deviation, μ=mean): 1-((3xσ MAX )+(3xσ MIN )) / (μ MAX -μ MIN ) A Z' above 0.5 was considered a good assay.

[0193] Background signal (MIN) was subtracted from all wells. The background subtracted values ​​were used to calculate the percent inhibition by compound in each test well as follows: 100-Test well FRET ratio / MAX FRET ratio x 100.

[0194] Percent inhibition was plotted versus compound concentration. IC50 values ​​for each compound were determined using a four-parameter logistic fit model using the XLFIT5 software package.

[0195] For examples 1-15, 36-47, 53-62 and 64-88, the assays were performed as follows: each assay reaction was performed in a volume of 25 μl in a 384-well half-volume plate. A 10-point compound serial dilution (3-fold) was generated in DMSO at a concentration 50-fold higher than the final assay concentration (FAC). Compound solutions were then prepared by diluting 10-fold with assay buffer. For the assay, 5 μl of diluted compound was added to 10 μl of IgE-Tb and incubated for 30 minutes before adding 10 μl of sFcER1α-Y131A-AF488. The FRET reagent FAC was 5 nM IgE-Tb, 25 nM sFcER1α-Y131A-AF488. Typically, the top FAC of the compound in the assay was 10 μM. The final DMSO concentration was 2%. The minimum signal (MIN) was measured by adding 5 μl of 1 μM unlabeled sFcER1a (FAC=200 nM) to the FRET reagent. The maximum FRET signal (MAX) was measured in wells containing the FRET reagent but no compound.

[0196] The assay was incubated for 18 hours at room temperature, protected from light and evaporation and gently agitated.

[0197] FRET measurements FRET measurements for each well were performed using a PHERAstar FSX plate reader (BMG Labtech) by exciting at 337 nm and measuring emission at 490 / 520 nm. The FRET ratio was calculated as follows: Radiation at 520 / radiation at 490x1000.

[0198] FRET ratio was used for data analysis.

[0199] 4. Data Analysis Z' was calculated as follows (σ=standard deviation, μ=mean): 1-((3xσ MAX )+(3xσ MIN )) / (μ MAX -μ MIN ) A Z' above 0.5 was considered a good assay.

[0200] Background signal (MIN) was subtracted from all wells. The background subtracted values ​​were used to calculate the percent inhibition by compound in each test well as follows: 100-Test well FRET ratio / MAX FRET ratio x 100.

[0201] Percent inhibition was plotted versus compound concentration. IC50 values ​​for each compound were determined using a four-parameter logistic fit model using the XLFIT5 software package.

[0202] For examples 17-35, 48-52 and 63, the assays were performed as follows: each assay reaction was performed in a volume of 25 μl in a 384-well half-volume plate. A 10-point compound serial dilution (3-fold) was generated in DMSO at a concentration 50-fold higher than the final assay concentration (FAC). Compound solutions were then prepared by diluting 10-fold with assay buffer. For the assay, 5 μl of diluted compound was added to 10 μl of IgE-Tb, followed by 10 μl of sFcεR1α-AF488. The FRET reagent FAC was 0.75 nM IgE-Tb, 0.9 nM sFcεR1α-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 unlabeled sFcεR1α to the FRET reagent at 1 μM (FAC=200 nM). The maximum FRET signal (MAX) was measured in wells containing the FRET reagent but no compound.

[0203] The assay was incubated for 18 hours at room temperature, protected from light and evaporation and gently agitated.

[0204] FRET measurements FRET measurements for each well were performed using a PHERAstar FSX plate reader (BMG Labtech) by exciting at 337 nm and measuring emission at 490 / 520 nm. The FRET ratio was calculated as follows: Radiation at 520 / radiation at 490x1000.

[0205] FRET ratio was used for data analysis.

[0206] 4. Data Analysis Z' was calculated as follows (σ=standard deviation, μ=mean): 1-((3xσ MAX )+(3xσ MIN )) / (μ MAX -μ MIN ) A Z' above 0.5 was considered a good assay.

[0207] Background signal (MIN) was subtracted from all wells. The background subtracted values ​​were used to calculate the percent inhibition by compound in each test well as follows: 100-Test well FRET ratio / MAX FRET ratio x 100.

[0208] Percent inhibition was plotted versus compound concentration. IC50 values ​​for each compound were determined using a four-parameter logistic fit model using the XLFIT5 software package.

[0209] Compounds tested in the above assay exhibit IC50 values ​​in the range of 4 nM to 1975 nM.

[0210] The table below shows the range of IC50 values ​​for each example: [Table 8]

Claims

1. A compound of general formula (I) or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, R1 represents: Hydroxy; amino; -NH-C(O)-Ra １ ; -NH-C(O)-NH-Rb １ ; -NH-C(O)-C1-6-alkanediyl-C(O)-C1-6-alkoxy, optionally substituted by one or more aryl substituted by one or more halogen, -OH, C1-6-alkyl; -NH-C(O)-C1-6-alkanediylC(O)-aryl, optionally substituted with one or more hydroxy; halogen; C1-6-alkyl; -NH-C(O)-C1-6-alkanediyl-NHC(O)-aryl, optionally substituted with one or more hydroxy; halogen; C1-6-alkyl; -NH-C(O)-C1-6-alkanediyl-aryloxy, optionally substituted with one or more hydroxy; halogen, C1-6-alkyl; —NH—C(O)—NH—C(O)O—C1-6-alkyl; -NH-heteroaryl, provided that one or more halogens are present; C1-6-alkyl; C1-6-alkoxy; cyano; heteroaryl, optionally substituted; -NH-C(S)-NH-Rc １ ; -NH-aryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; heteroaryl; -NH-C(O)O-Rd １ -NH-C(N-CN)-NH-C1-6-alkyl; Heteroaryl, provided that one or more of C1-6-alkyl is / are present; C1-6-alkylamino; heteroarylamino, optionally substituted; however, Ra １ represents C1-6-alkyl, provided that it is halogen; C1-6-alkoxy; aryl or heteroaryl, optionally substituted with cyano; aryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; C1-6-alkylamino; Heteroaryl, provided that one or more halogens are substituted; C1-6-alkyl, C1-6-alkoxy; cyano; heterocycloalkyl, optionally substituted; -C2-6-alkenediyl-aryl, provided that one or more C1-6-alkyl groups are optionally substituted with halogen; -R1'C(O)OR1'' group, where R1'' is alkyl and R1' is alkanediyl; C3-8-cycloalkyl, optionally substituted with one or more halogens; C1-6-alkyl; C1-6-alkoxy; cyano; C3-8-heterocycloalkyl optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; Rb １ represents C1-6-alkyl, aryl optionally substituted with one or more halogen, C1-6-alkoxy; Heteroaryl optionally substituted with one or more halogens; C1-6-alkyl; C1-6-alkoxy. , optionally substituted; C3-12-cycloalkyl optionally substituted with one or more C1-6-alkyl groups, aryl; aryl optionally substituted with one or more cyano; C2-6-alkenediyl-aryl, optionally substituted with one or more halogen; C1-6-alkyl; -OH; aryl substituted with one or more halogen; C1-6-alkyl; -OH; heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; heterocycloalkyl, optionally substituted with one or more halogen; C1-C6-alkoxy; cyano; amino; Rc １ represents C1-6-alkyl; Heteroaryl; Rd １ teeth: represents C1-6-alkyl; R2 represents: Hydroxy; -NH-C(O)O-C1-6-alkyl; -NH-C(S)-NH-Ra ２ ; -NH-C(O)-NH-Rb ２ ; -NH-aryl, optionally substituted with one or more of C1-6-alkoxy; C1-6-alkylamino; heteroarylamino; -NH-C1-6-alkyl, optionally substituted with one or more C1-6-alkyl; C1-6-alkoxy; cyano; aryl; heteroaryl; C(O)O-C1-6-alkyl; C1-6-alkylamino groups, wherein the substituents are optionally substituted with one or more hydroxy; halogen; oxo; heteroaryl, optionally substituted with one or more heteroaryls; C1-6-alkylamino or heteroarylamino, wherein said heteroaryl or heteroarylamino is optionally substituted with one or more groups selected from amino; C1-6-alkyl; C1-6-alkylamino; heteroarylamino; -NH-heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; heteroaryl; C(O)OH; C(O)O-C1-6-alkyl group; C1-6-alkylamino group; aryl-C1-6-alkylamino; -C1-6-alkylamino; -NH-C(O)-C1-6-alkyl; -NH-CO-Rc ２ ; —NH—C(O)—C2-6-alkenediyl-C(O)O—C1-6-alkyl; -NH-C(O)-C2-6-alkenediyl-aryl, optionally substituted with one or more hydroxy; C1-6-alkyl; halogen; -NH-C(O)-C1-6-alkanediyl-heteroaryl optionally substituted with one or more oxo groups; -NH-C(O)-C1-6-alkanediyl-heterocycloalkyl optionally substituted by one or more oxo groups; -NHSO ２ -C1-6-alkyl; -NHSO ２ -heteroaryl, optionally substituted with one or more halogens; C1-6-alkyl; C1-6-alkoxy; C(O)OH groups; —NH—C(S)—NH-C1-6-alkyl; -NHSO ２ -C1-6-alkoxy, optionally substituted with one or more halogen groups; -NH-C(N-CN)-NH-C1-6-alkyl; represents an amino group; Ra ２ represents Heteroaryl; C1-6-alkyl; Rb ２ represents C1-6-alkyl, provided that one or more aryls are present; alkoxy-aryl; heteroaryl, optionally substituted with one or more C1-6-alkyls; heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; Cycloalkyl, provided that one or more halogens are present; C1-6-alkyl, C1-6-alkoxy; cyano; aryl, optionally substituted; C1-6-alkanediyl-C(O)O-C1-6-alkyl; Heterocycloalkyl; aryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; C1-6-alkyl-C(O)O-C1-6-alkyl; Rc ２ represents C1-6-alkyl; C3-8-cycloalkyl; C3-8-heterocycloalkyl; aryl, optionally substituted with one or more C1-6-alkyl; C1-6-alkylamino; heteroaryl, optionally substituted with one or more halogen; C1-6-alkyl; C1-6-alkoxy; cyano; heterocycloalkyl; aryl; amino; C2-6-alkenediyl-aryl, optionally substituted with one or more halogen; C1-6-alkyl; -OH; C2-6-alkanediyl-heterocycloalkyl, provided that one or more C1-6-alkyl groups are optionally substituted by -OH; C2-6-alkanediyl-C1-6-alkoxy group, optionally substituted by one oxo group; R3 represents 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 A group selected from C3-6-cycloalkyl optionally substituted with R3 ａ represents a group selected from hydrogen; halogen; C1-2-alkyl; hydroxy; and C1-2-alkoxy; R4 represents the following: One or more R4 ａ or one or more R4 ａ C1-6-alkanediyl-C3-6-cycloalkyl optionally substituted with a group; or one or more R4 ａ a group selected from C1-6-alkanediyl-C3-6-heterocycloalkyl optionally substituted by a group; R4 ａ represents a group selected from hydroxy; halogen; and C1-2-alkyl.

2. R3 represents C3-6-cycloalkyl optionally substituted with one or more R3 a ; 2. A compound according to claim 1, wherein R3 a represents a group selected from among hydrogen; halogen; C1-2-alkyl; hydroxy; C1-2-alkoxy.

3. R4 represents a C3-6-cycloalkyl optionally substituted with one or more R4 a groups; 2. The compound of claim 1, wherein R4 a represents a group selected from the group consisting of hydroxy; halogen; and C1-2-alkyl.

4. 2. The compound of claim 1, wherein R4 represents cyclopropyl optionally substituted with one or more groups independently selected from hydroxy, chloro, fluoro, bromo, methyl.

5. A compound according to any one of claims 1 to 4, wherein R4 represents cyclopropyl.

6. The compound according to any one of claims 1 to 5, wherein R1 represents: Hydroxy; Pyridine-carbonylamino; Ethylcarbamoylamino; (Methoxyphenyl)methylcarbamoylamino; [(Bromophenyl)methyl]carbamoylamino; Naphthalenylcarbamoylamino; [(Methyl-oxazolyl)methyl]carbamoylamino; Ethoxycarbonyl-carbamoylamino; [(Methoxyphenyl)ethyl]carbonylamino; (Cyclopropylethyl)carbamoylamino; [(Methyl)cyclopropyl]carbamoylamino; (Benzyl)carbamoylamino; (Phenyl-cyclopropyl)carbamoylamino; (Chromanyl)carbamoylamino; [(Chlorophenyl)propenoyl]amino; (Methoxypyridine-carbonyl)amino; [(Methoxy-oxo-propanoyl)amino]; (Benzamidoacetyl)amino; (Chloro-methoxy-thiophene-carbamoylamino) N'-N-(2-methyl-1,2-phenyl)phenyl)phenylamino; (N'-methyl-1,2- ...

7. The compound according to any one of claims 1 to 5, wherein R1 represents: Hydroxy; Pyridine-3-carbonylamino; Ethylcarbamoylamino; (4-Methoxyphenyl)methylcarbamoylamino; (3-Cyanophenyl)carbamoylamino; [(4-Bromophenyl)methyl]carbamoylamino; Naphthalen-1-ylcarbamoylamino; [(5-Methyl-1,2-oxazol-3-yl)methyl]carbamoylamino; Ethoxycarbonyl-carbamoylamino; [(1R)-1-(3-Methoxyphenyl)ethyl]carbonylamino; (1-Cyclopropylethylcarbamoylamino); [2-( (methyl)cyclopropyl]carbamoylamino; (1-benzyl)carbamoylamino; (2-phenyl-cyclopropyl)carbamoylamino; (chroman-3-yl)carbamoylamino; [(E)-3-(2-chlorophenyl)prop-2-enoyl]amino; (6-methoxypyridine-3-carbonyl)amino; [(3-methoxy-3-oxo-propanoyl)amino]; (2-benzamidoacetyl)amino; (5-chloro-4-methoxy-thiophene-3-carbonyl)amino; (3-ethoxy-3-oxo-propanoyl)amino; 2-Methylbutanoylamino; [2-(4-chlorophenoxy)acetyl]amino; (5-methoxypyridin-3-yl)amino; Amino; 1H-benzimidazol-2-ylamino; Ethylcarbamothioylamino; (4-pyridin-3-yl-1,2,4-triazol-3-yl)amino; 3-(ethylamino)-1,2,4-triazol-4-yl; 3-(5-methyl-1,3,4-oxadiazol-2-yl)anilino; tert-butoxycarbonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; propan-2-ylcarbamoylamino; pyridin-3-ylcarbamothioylamino; (5-methylpyridine-3-carbonyl)amino; (6-morpholin-4-ylpyridine-3-carbonyl)amino; benzamido; [4-(dimethylamino)benzoyl]amino; 3,3-dimethylbutanoylamino.

8. The compound according to any one of claims 1 to 5, wherein R2 represents: tert-Butoxycarbonyl-amino; Amino; Pyridylcarbamothioylamino; Ethylcarbamoylamino; Pyridinyl-amino; (Pyridinyl-triazolyl)amino; (Pyridinyl-amino)-triazolyl; (Ethyl-triazolyl)amino; Benzylamino; Propylamino; Methylpropanoylamino; Hydroxy; Ethylcarbamoylamino; Isoquinolinyl-amino; (Methoxypyridinyl)amino; (Pyridinyl)carbonylamino; Benzimidazolylamino; [(Phenyl)-oxazolyl]carbonylamino; Quinoxaline- Carbonylamino; [(hydroxyphenyl)propenoyl]amino; pyrido-pyrazine-carbonylamino; benzoxazole-carbonylamino; [ethoxy-oxo-butenoyl]amino; (benzimidazolyl)propanoylamino; (oxopyridinyl)propanoylamino; (methoxy-benzofuran-carbonyl)amino; (oxopyrrolidinyl)propanoylamino; [(ethoxycarbonyl-pyridyl)amino]; (methoxyanilino); (cyano-pyridyl)amino; [(methyl-pyridazinyl)amino]; quinolinyl-amino; ( Methyl-oxazolyl)methyl-carbamoyl-amino; (phenylcyclopropyl)carbamoylamino; [(tert-butoxymethyl-oxo-ethyl)carbamoylamino]; dihydro-2H-chromenylcarbamoylamino; [(methoxyphenyl)ethylcarbamoylamino]; oxanylcarbamoylamino; (chloro-methylphenyl)carbamoylamino; methanesulfonamide; methylpropylsulfonylamino; pyridinylsulfonylamino; [(carboxypyridyl)amino]; pyridylcarbamoylamino; (methoxy-pyridyl N'-N-ethyl-carbamimidoyl)amino; (methylpyridinecarbon ...triazolyl)amino; (ethylamino)triazolyl; (methyloxadiazolyl)anilino; trichloroethoxysulfonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; pyridinylcarbamoylamino; propanylcarbamoylamino; pyridinylcarbamoylamino; (methylpyridinecarbonyl)amino; (morpholinylpyridinecarbonyl)amino; benzamide;[(Dimethylamino)benzoyl]amino; dimethylbutanoylamino;

9. The compound according to any one of claims 1 to 5, wherein R2 represents: tert-Butoxycarbonyl-amino; Amino; 3-Pyridylcarbamothioylamino; Ethylcarbamoylamino; Pyridin-3-yl-amino; (4-Pyridin-3-yl-1,2,4-triazol-3-yl)amino; 3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl; (4-ethyl-1,2,4-triazol-3-yl)amino; benzylamino; propylamino; 2-methylpropanoylamino; hydroxy; ethylcarbamoylamino; isoquinolin-4-ylamino; (5-methoxypyridin-3-yl)amino; (pyridin-3-yl)carbonylamino; 1H-benzimidazol-2-ylamino; [3-(phenyl)-1,2-oxazol-5-yl]carbonylamino; quinoxaline-6-carbonylamino; [3-(4-hydroxyphenyl)propo- 2-enoyl]amino; pyrido[2,3-b]pyrazine-7-carbonylamino; 1,3-benzoxazole-2-carbonylamino; [(E)-4-ethoxy-4-oxo-but-2-enoyl]amino; 3-(benzimidazol-1-yl)propanoylamino; 3-(2-oxopyridin-1-yl)propanoylamino; (4-methoxy-1-benzofuran-2-carbonyl)amino; 3-(2-oxopyrrolidin-1-yl)propanoylamino; [(5-ethoxycarbonyl-3-pyridyl)amino]; (2-methoxyanilino); (4-cyano-2-pyridyl)amino; [(6-methylpyridazin-3-yl)amino]; quinolin-4-ylamino; (5-methyl-1,2-oxazol-3-yl)methylcarbamoylamino; (2-phenylcyclopropyl)carbamoylamino; [(2-tert-butoxy-1-methyl-2-oxo-ethyl)carbamoylamino]; 3,4-dihydro-2H-chromen-3-ylcarbamoylamino; [1-(3-methoxyphenyl)ethylcarbamoylamino]; oxan-4-ylcarbamoylamino; (2-chloro-6 -methylphenyl)carbamoylamino; methanesulfonamide; 2-methylpropylsulfonylamino; pyridin-3-ylsulfonylamino; [(5-carboxy-3-pyridyl)amino]; 3-pyridylcarbamoylamino; (5-methoxypyridin-3-yl)amino; ethylcarbamothioylamino; (4-pyridin-3-yl-1,2,4-triazol-3-yl)amino; (5-methoxypyridin-3-yl)amino; (4-ethyl-1,2,4-triazol-3-yl)amino; 3-(ethylamino)-1,2,4-triazol-4-yl; 3-(5-methyl-1,3,4-oxadiazol-2-yl)anilino; 2,2,2-Trichloroethoxysulfonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; pyridin-3-ylcarbamoylamino; propan-2-ylcarbamoylamino; pyridin-3-ylcarbamothioylamino; (5-methylpyridine-3-carbonyl)amino; (6-morpholin-4-ylpyridine-3-carbonyl)amino; benzamido; [4-(dimethylamino)benzoyl]amino; 3,3-dimethylbutanoylamino.

10. A compound according to any one of claims 1 to 9, selected from the following list: tert-Butyl N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate; tert-Butyl N-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamate; N-[trans-(7RS,9RS)-9-amino-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylcarbamothioylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-9-(ethylcarbamoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(pyridin-3-ylamino)-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-9-[(4-ethyl-1,2,4-triazol-3-yl)amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-9-(benzylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(propylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-9-(2-methylpropanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 1-ethyl-3-[trans-(7RS,9RS)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-ethyl-3-[trans-(7RS,9RS)-3-cyclopropyl-7-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; N-[cis-(7RS,9SR)-3-cyclopropyl-9-(isoquinolin-4-ylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 1-[(4-methoxyphenyl)methyl]-3-[trans-(7RS,9RS)-3-cyclopropyl-9-[(5-methoxypyridin-3-yl)amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; N-[trans-(7RS,9RS)-7-[(3-cyanophenyl)carbamoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-7-[(4-bromophenyl)methylcarbamoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(naphthalen-1-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; 1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; Ethyl N-[[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamoyl]carbamate; 1-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-[rac-(1S)-1-(3-methoxyphenyl)ethyl]urea; 1-(1-cyclopropylethyl)-3-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-(2-methylcyclopropyl)-3-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-benzyl-3-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-(2-phenylcyclopropyl)-3-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; 1-(3,4-dihydro-2H-chromen-3-yl)-3-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]urea; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-[[rac-(E)-3-(2-chlorophenyl)prop-2-enoyl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; 6-Methoxy-N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; methyl 3-oxo-3-[[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]amino]propanoate; N-[2-oxo-2-[[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]amino]ethyl]benzamide; 5-chloro-4-methoxy-N-[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]thiophene-3-carboxamide; Ethyl 3-oxo-3-[[trans-(7RS,9RS)-9-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]amino]propanoate; N-[cis-(7RS,9SR)-3-cyclopropyl-7-(2-methylbutanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; N-[cis-(7RS,9SR)-7-[[2-(4-chlorophenoxy)acetyl]amino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyridine-3-carboxamide; 3-phenyl-N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1,2-oxazole-5-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]quinoxaline-6-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[[rac-(E)-3-(4-hydroxyphenyl)prop-2-enoyl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]pyrido[2,3-b]pyrazine-7-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-1,3-benzoxazole-2-carboxamide; Ethyl rac-(E)-4-oxo-4-[[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]but-2-enoate; N-[trans-(7RS,9RS)-9-[3-(benzimidazol-1-yl)propanoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(2-oxopyridin-1-yl)propanoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-9-[(4-methoxy-1-benzofuran-2-carbonyl)amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; Ethyl 5-[[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-3-carboxylate; N-[trans-(7RS,9RS)-3-cyclopropyl-9-(2-methoxyanilino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-9-[(4-cyanopyridin-2-yl)amino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(6-methylpyridazin-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(quinolin-4-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-9-[(5-methyl-1,2-oxazol-3-yl)methylcarbamoylamino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(2-phenylcyclopropyl)carbamoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; tert-butyl 2-[[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]carbamoylamino]propanoate; N-[trans-(7RS,9RS)-3-cyclopropyl-9-(3,4-dihydro-2H-chromen-3-ylcarbamoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7SR,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[[rac-(1R)-1-(3-methoxyphenyl)ethyl]carbamoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(oxan-4-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-9-[(2-chloro-6-methylphenyl)carbamoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-9-(methanesulfonamido)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(2-methylpropylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridin-3-ylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 5-[[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]amino]pyridine-3-carboxylic acid; 1-pyridin-3-yl-3-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridin-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; cis-(7RS,9SR)-3-cyclopropyl-7,9-bis[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; cis-(7RS,9SR)-7-amino-3-cyclopropyl-9-[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; cis-(7RS,9SR)-7,9-bis(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; 1-Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-7-(ethylcarbamothioylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]thiourea; cis-(7RS,9SR)-3-cyclopropyl-N-(2-methylpropyl)-7,9-bis[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[(5-methoxypyridin-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-7,9-bis(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[(4-ethyl-1,2,4-triazol-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[3-(ethylamino)-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; 1-ethyl-3-[trans-(7RS,9RS)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[3-(5-methyl-1,3,4-oxadiazol-2-yl)anilino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; tert-Butyl N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(2,2,2-trichloroethoxysulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]carbamate; 2-cyano-1-ethyl-3-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-[[rac-(E)-N'-cyano-N-ethylcarbamimidoyl]amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]guanidine; 1-ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; 1-pyridin-3-yl-3-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridin-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; 1-propan-2-yl-3-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(propan-2-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; 1-pyridin-3-yl-3-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridin-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]thiourea; 5-methyl-N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(5-methylpyridine-3-carbonyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 6-morpholin-4-yl-N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(6-morpholin-4-ylpyridine-3-carbonyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-9-benzamido-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]benzamide; 4-(dimethylamino)-N-[trans-(7RS,9RS)-3-cyclopropyl-9-[[4-(dimethylamino)benzoyl]amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]benzamide; 3,3-dimethyl-N-[trans-(7RS,9RS)-3-cyclopropyl-9-(3,3-dimethylbutanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]butanamide; N,N'-[trans-(7RS,9RS)-3-cyclopropyl-5-(N-isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7,9-diyl]diacetamide; N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-9-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[9-amino-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide.

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

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, for use in a method for treating or preventing a disorder caused by IgE.

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

14. 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharma- ceutical acceptable salt thereof for use in a method for the treatment or prevention of airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, urticaria, or increased vascular permeability.

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

16. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, in association with a pharma- ceutically acceptable carrier.

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 treating and / or preventing 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 treating and / or preventing allergy, non-allergic mast cell response, type 1 hypersensitivity, urticaria, or familial sinusitis.

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