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), methods for preparing them, pharmaceutical compositions containing them, and their use in treating disorders caused by IgE (e.g., allergic responses, non-allergic mast cell responses, or certain autoimmune responses), particularly disorders caused by the interaction between IgE and FcεRI receptors. [Background technology]

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

[0003] IgE is secreted by B cells and expressed on the surface of B cells. IgE synthesized by B cells is fixed 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 mammals are exposed to an allergen, B cells that synthesize IgE that binds to the allergen are clonally amplified. This IgE is then released into circulation by B cells, where it is bound by B cells (via FcεRII) and by mast cells and basophils via so-called high-affinity receptors (FcεRI) found on the surface of mast cells and basophils. Thus, such mast cells and basophils are sensitized to the allergen. Subsequent exposure to the allergen cross-links the FcεRI on these cells and thus activates the release of histamine and other factors that cause clinical hypersensitivity and anaphylaxis.

[0004] Currently, allergic diseases, urticaria, and asthma are typically treated with one or more of the following drugs: (1) antihistamines and anti-leukotrienes that antagonize inflammatory mediators histamine and leukotrienes; (2) topical or systemic (oral or injectable) corticosteroids or immunosuppressants that suppress broad-spectrum inflammatory mechanisms; (3) short- or long-acting bronchodilators that relax the smooth muscles of narrowed airways in asthma; or (4) mast cell stabilizers that inhibit mast cell degranulation, which is usually induced by IgE binding to FcεRI; or (5) biologics that prevent IgE binding to FcεRI. The use of peptides that modulate IgE binding to FcεRI has also been explored. As an example, International Publication No. 96 / 01643 describes a peptide consisting of 4 to 50 amino acids for treating immediate-type allergic responses.

[0005] However, there remains a need to identify compounds that have therapeutic utility in treating or preventing disorders caused by IgE, particularly those caused by the interaction between IgE and FcεRI receptors. [Overview of the project]

[0006] It has been found that compounds of formula (I) and pharmaceutically acceptable salts thereof can be used for this purpose. [Modes for carrying out the invention]

[0007] The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof: [ka] During the ceremony, R1 represents the following: 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 halogens, -OH, or C1~6-alkyl groups; -NH-C(O)-C1~6-alkanediyl-C(O)-aryl, optionally substituted with one or more hydroxyl;halogens;C1~6-alkyl groups; -NH-C(O)-C1~6-alkanediyl-NHC(O)-aryl, optionally substituted with one or more hydroxyl;halogens;C1~6-alkyl groups; -NH-C(O)-C1~6-alkanediyl-aryloxy, where one or more hydroxyl; halogen, C1~6-alkyl, optionally substituted; -NH-C(O)-NH-C(O)O-C1~6-alkyl; -NH-heteroaryl, but with one or more halogens; C1-6-alkyl; C1-6-alkoxy; cyano; heteroaryl, optionally substituted; -NH-C(S)-NH-Rc 1 ; -NH-aryl, but with one or more halogens; C1-6-alkyl; C1-6-alkoxy; cyano; heteroaryl, optionally substituted; -NH-C(O)O-Rd 1 -NH-C(N-CN)-NH-C1~6-alkyl; Heteroaryl, wherein one or more C1-6-alkyl; C1-6-alkylamino; heteroarylamino, optionally substituted; however, Ra 1 This represents the following: C1-6 alkyl, but optionally substituted with halogens; C1-6 alkoxys; or optionally substituted with aryl or heteroaryl groups optionally substituted with cyanos; Aryl, but with one or more halogens; C1-6-alkyl; C1-6-alkoxy; C1-6-alkylamino, optionally substituted; Heteroaryls, but with one or more halogens; C1-6-alkyl, C1-6-alkoxy; cyano; heterocycloalkyl, optionally substituted; -C2~6-Alkendiyl-aryl, optionally substituted with one or more C1~6-alkyl;halogens; -R1'C(O)OR1'' group, where R1'' is alkyl and R1' is alkanediyl; C3-8-cycloalkyl, but with one or more halogens; C1-6-alkyl; C1-6-alkoxy; cyano, optionally substituted. C3-8 heterocycloalkyl, provided one or more halogens are present; C1-6 alkyl; C1-6 alkoxy; cyano, optionally substituted; Rb 1 This represents the following: C1-6 alkyl, wherein one or more halogens, C1-6 alkoxys, and optionally substituted aryls; One or more halogens; C1-6 alkyls; C1-6 alkoxys, optionally substituted heteroaryls. And it is replaced as desired; One or more C1-6 alkyl, aryl, optionally substituted C3-12 cycloalkyl groups; An aryl, optionally substituted with one or more cyanoides; C2-6-alkenediylaryl, wherein one or more halogens; C1-6-alkyl;-OH; one or more halogens; C1-6-alkyl;-OH, optionally substituted with an aryl; Heteroaryls, but with one or more halogens; C1-6 alkyls; C1-6 alkoxys, optionally substituted; Heterocycloalkyl, but with one or more halogens; C1-C6 alkoxy; cyano, optionally substituted; amino; Rc 1 This represents the following: C1-6 alkyl; heteroaryl; Rd 1 is: represents C1-6 alkyl; R2 represents the following: hydroxy; -NH-C(O)O-C1-6 alkyl; -NH-C(S)-NH-Ra 2 ; -NH-C(O)-NH-Rb 2 ; -NH-aryl, provided that it is optionally substituted with one or more of C1-6 alkoxy; C1-6 alkylamino; heteroarylamino; -NH-C1-6 alkyl, provided that it is optionally substituted with one or more of C1-6 alkyl; C1-6 alkoxy; cyano; aryl; heteroaryl; C(O)O-C1-6 alkyl group; C1-6 alkylamino group, where the substituents are optionally substituted with one or more of hydroxy; halogen; oxo; heteroaryl, provided that it is optionally substituted with one or more of heteroaryl; hydroxy; oxo; C1-6 alkyl; C1-6 alkylamino or heteroarylamino; provided that the heteroaryl or heteroarylamino is optionally substituted with one or more groups selected from amino; C1-6 alkyl; C1-6 alkylamino; heteroarylamino; -NH-heteroaryl, provided that it is optionally substituted with one or more of 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, with one or more hydroxyl;C1~6-alkyl;halogens. Optionally substituted; -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; -NHSO2-C1~6-alkyl; -NHSO2-heteroaryl, provided one or more halogens; C1-6-alkyl; C1-6-alkoxy; optionally substituted with a C(O)OH group; -NH-C(S)-NH-C1~6-alkyl; -NHSO2-C1~6-alkoxy, optionally substituted with one or more halogen groups; -NH-C(N-CN)-NH-C1~6-alkyl; amino group; Ra 2 This represents the following: heteroaryl; C1-6 alkyl; Rb 2 This represents the following: C1-6 alkyl, provided that one or more aryl groups are present; alkoxy-aryl groups; heteroaryl groups optionally substituted with one or more C1-6 alkyl groups; Heteroaryl compounds, but with one or more halogens; C1-6 alkyl compounds; C1-6 alkoxy compounds; cyano compounds, optionally substituted; Cycloalkyl, but with one or more halogens; C1-6-alkyl, C1-6-alkoxy; cyano; aryl, optionally substituted; C1~6-Alkanediyl-C(O)O-C1~6-alkyl; Heterocycloalkyl; Aryl, but with one or more halogens; C1-6 alkyl; C1-6 alkoxy; cyano, optionally substituted; C1~6-alkyl-C(O)O-C1~6-alkyl; Rc 2 This represents the following: C1-6 alkyl; C3-8-cycloalkyl; C3-8-heterocycloalkyl; Aryl, but with one or more C1-6-alkyl; C1-6-alkylamino, optionally substituted; Heteroaryls, but with one or more halogens; C1-6-alkyls; C1-6-alkoxys; cyanos; heterocycloalkyls; aryls; aminos, optionally substituted; C2-6-Alkenediylaryl, wherein one or more halogens; C1-6-alkyl; -OH, optionally substituted; C2-6-alkanediyl heterocycloalkyl, optionally substituted with one or more C1-6-alkyl;-OH groups; A C2-6-alkanediyl-C1-6-alkoxy group, which may be optionally substituted with one oxo group; R3 represents the following: R3 a C1-6 alkyl groups optionally substituted with one or more groups selected from the following; One or more R3 a C1~3-alkanediyl-C3~6-cycloalkyl, which can be optionally substituted; One or more R3 a C1-3-alkanediyl-C3-6-heterocycloalkyl, which can be optionally substituted; One or more R3 a C3-6 heterocycloalkyl groups that are optionally substituted; One or more R3 a A group selected from C3-6 cycloalkyl groups that can be optionally substituted; R3a This represents a group selected from hydrogen, halogen, C1-2-alkyl, hydroxyl, and C1-2-alkoxy. R4 represents the following: One or more R4 a C3-6 cycloalkyl groups optionally substituted with a group; or one or more R4 groups. a C1-6-alkanediyl-C3-6-cycloalkyl groups optionally substituted with a group; or one or more R4 groups. a A group selected from among C1-6-alkanediyl-C3-6-heterocycloalkyl groups that can be optionally substituted with another group; R4 a The group represented is selected from hydroxyl, halogen, or C1-2-alkyl groups.

[0008] Compounds of formula (I) may contain one or more chiral carbon atoms. Therefore, they can exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof include racemic mixtures that form part of the present invention.

[0009] The compound of formula (I) may exist in the form of an addition salt with a base or acid. Such addition salts are part of the present invention. These salts are advantageously prepared using pharmaceutically acceptable acids. For example, salts of other acids useful for the purification or isolation of the compound of formula (I) are also part of the present invention.

[0010] The term "pharmaceutically acceptable salt" according to the present invention includes salts of the compound of formula (I) with a pharmaceutically acceptable acid or base, in particular acid addition salts. The acid addition salt form of the compound of formula (I) that arises in free form as a base can be obtained by treating the free base with an appropriate acid such as hydrohalic acid such as hydrochloric acid or hydrobromic acid, an inorganic acid such as sulfuric acid, nitric acid, or phosphoric acid; or an organic acid such as 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, or pamoic acid.

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

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

[0013] It should be understood that each atom present in formula (I) or the formulas shown herein may actually exist in any form of its naturally occurring isotope, and the most abundant isotope(s) is preferred. For example, each hydrogen atom present in formula (I) or the formulas shown herein may exist as a 1H, 2H (deuterium), or 3H (tritium) atom, preferably 1H. Similarly, for example, each carbon atom present in formula (I) or the formulas shown herein may exist as a 12C, 13C, or 14C atom, preferably 12C.

[0014] The present invention includes, within its scope, solvates of the compound of formula (I) described above. Such solvates can be formed using a common organic solvent or water.

[0015] The present invention also includes, within its scope, cocrystals of the compound of formula (I) above. The technical term "cocrystal" is used to describe a situation in which a neutral molecular component exists within a crystalline compound in a constant stoichiometric ratio. The preparation of pharmaceutical cocrystals allows for modification of the crystalline form of the pharmaceutical active ingredient, thereby altering its physicochemical properties without impairing its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0016] The compounds according to the present invention may exist in different polymorphs. 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) described above. The term "prodrug" means a compound that is metabolized in vivo to the compounds of the present invention or salts thereof. Prodrugs can be identified by administering the prodrug to mammals such as rats, mice, monkeys, or humans and identifying the compounds or salts 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 the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or cocrystal thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0019] In yet another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts, solvates, or cocrystals used as pharmaceuticals for methods of treating or preventing IgE-induced disorders, particularly allergies, type I hypersensitivity, familial sinusitis, urticaria, or related conditions, such as airway constriction in asthma, local inflammation in eczema, increased mucus secretion, increased vascular permeability in allergic rhinitis, eosinophilic granulomatosis with polyangiitis (also known as "Churg-Strauss syndrome"), aspirin-exacerbated respiratory disease, or cutaneous T-cell lymphoma.

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

[0021] Within the framework of this 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 groups are saturated, linear, or branched aliphatic groups. For example, C1-6 alkyl groups represent linear or branched carbon chains of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Alkyl groups have one or more hydrogen atoms that are deuterium atoms. 2 It includes deuterated groups replaced by H. -Alkanesyls are of general formula C such as -CH2-CH2-. n H 2n It is a divalent linear or branched saturated hydrocarbon group; -Alkendiyls are divalent straight-chain or branched-chain unsaturated hydrocarbon groups 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 alkylaminoones include methylamino, ethylamino, tertbutylamino, and dimethylamino; -Acyl, alkyl-C(O)- group; -Oxo, a=O group -Hydroxy is an -OH group; -Hydroxyalkyl is an alkyl group in which one or more hydrogen atoms are substituted with a hydroxyl group; -alkoxy, -O-alkyl groups; -alkylthio, -S-alkyl group; Halogen atoms, fluorine, chlorine, bromine, or iodine atoms; -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 cycloalkyls include cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; spiro-undecanyl; and spiro-[2,2]pentanyl. - Heterocycloalkyl groups refer to monocyclic or bicyclic saturated groups containing 3 to 14 atoms in the group, where one or more carbon atoms are replaced by atoms selected from nitrogen, oxygen, or sulfur. Examples of heterocycloalkyl groups include aziridinyl, pyrrolidinyl, piperidyl; oxetane; and oxa-spiro-undecanyl. -The aryl group refers to a monocyclic or bicyclic aromatic group containing 6 to 10 carbon atoms, where at least one ring is an aromatic group. Examples of aryl groups include the phenyl or naphthyl group. -A heteroaryl group refers to a monocyclic or bicyclic group containing 5 to 14 atoms, preferably 5 to 9 atoms, wherein at least one ring in the group 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 is 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 an -O-aryl group. Phenoxy is an example of an aryloxy.

[0022] In one embodiment, the compound of the present invention has formula R4, hydroxy; Chloro, fluoro, bromo The present invention is characterized by representing cyclopropyl or spiro[2.2]pentanyl, which is optionally substituted with one or more groups independently selected from methyl.

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

[0024] According to one embodiment, the compound of the present invention is of formula (wherein R1 and R2 are independently of each other, -NH-CO-Ra 1 Represents, Ra 1 This is characterized by a heteroaryl (C1-6-alkyl, C1-6-alkoxy, cyano, heterocycloalkyl, aryl, or -NH-heteroaryl (C1-6-alkyl, C1-6-alkoxy, cyano, heterocycloalkyl, aryl) optionally substituted with one or more halogens.

[0025] According to one aspect, the compound of the present invention has R1, Hydroxy;pyridine-carbonylamino;ethylcarbamoylamino;(methoxyphenyl)methylcarbamoylamino;[(bromophenyl)methyl]carbamoylamino;naphthalenylcarbamoylamino;(methyl-oxazolyl)methyl]carbamoylamino;ethoxycarbonyl-carbamoylamino;[(methoxyphenyl)ethyl]carbanylamino;(cyclopropylethyl)carbamoylamino;(methyl)cyclopropyl]carbamoylamino;(benzyl)carbamoylamino;(phenyl-cyclopropyl)carbamoylamino;(chromanil)carbamoylamino;(chlorophenyl)propenoyl]amino;(methoxypyridine-carbonyl)amino;[(methoxy-oxo-propanoyl)amino];(benzamidoacetyl)amino;(chloro-methoxy-thiophene-carbonyl) Characterized by representing: mino; (ethoxy-oxo-propanoyl)amino; methylbutanoylamino; [(chlorophenoxy)acetyl]amino; (methoxypyridinyl)amino; amino; benzimidazolyl-amino; ethylcarbamoylamino; (pyridinyl-thiazolyl)amino; [(ethyl-thiazolyl)amino; (ethylamino)-thiazolyl; ethylcarbamoylamino; (methyl-oxazolyl)anilino; tert-butoxycarbonylamino; [N'-cyano-N-ethyl-carbamimidoyl]amino; pyridine-3-yl-carbamoylamino; propan-2-yl-carbamoylamino; (5-methylpyridinyl-3-carbonyl)amino; (6-morpholine-4-ylpyridinyl-3-carbonyl)amino; benzamide; [(dimethylamino)benzoyl]amino; dimethylbutanoylamino.

[0026] According to one aspect, the compound of the present invention has R1, Hydroxy;pyridine-3-carbonylamino;ethylcarbamoylamino;(4-methoxyphenyl)methylcarbamoylamino;(3-cyanophenyl)carbamoylamino;[(4-bromophenyl)methyl]carbamoylamino;naphthalene-1-ylcarbamoylamino;[(5-methyl-1,2-oxazole-3-yl)methyl]carbamoylamino;ethoxycarbonylcarbamoylamino;[(1R)-1-(3-methoxyphenyl)ethyl]carbanylamino;(1 -Cyclopropylethylcarbamoylamino; 2-(methyl)cyclopropyl]carbamoylamino; (1-benzyl)carbamoylamino; (2-phenyl-cyclopropyl)carbamoylamino; (chroman-3-yl)carbamoylamino; (E)-3-(2-chlorophenyl)propo-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-methoxypyridine-3-yl)amino; amino; 1H-benzimidazole-2-ylamino; ethylcarbamoteoylamino; (4-pyridine-3-yl-1,2,4-thiazole-3-yl)amino; 3-(ethylamino)-1,2,4-thiazole-4-yl; 3-(5-methyl- It is characterized by representing 1,3,4-oxazole-2-yl)anilino; tert-butoxycarbonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; propane-2-ylcarbamoylamino; pyridine-3-ylcarbamoylamino; (5-methylpyridine-3-carbonyl)amino; 6-morpholine-4-ylpyridine-3-carbonyl)amino; benzamide; [4-(dimethylamino)benzoyl]amino; and 3,3-dimethylbutanoylamino.

[0027] According to one aspect, the compound of the present invention has R2, tert-butoxycarbonyl-amino;amino;pyridylcarbamoylamino;ethylcarbamoylamino;pyridinyl-amino;(pyridinyl-thiazolyl)amino;(pyridinyl-amino)-thiazolyl;(ethyl-thiazolyl)amino;benzylamino;propylamino;methylpropanoylamino;hydroxy;ethylcarbamoylamino;isoquinolinyl-amino;(methoxypyridinyl)amino;(pyridinyl)carbonylamino;benzimidazolylamino;[(phenyl)-oxazolyl]carbonylamino;quinoxaline- Carbonylamino; [(hydroxyphenyl)propenoyl]amino; pyridopyrazine-carbonylamino; benzoxazole-carbonylamino; [ethoxy-oxo-butenoyl]amino; (benzimidazolyl)propanoylamino; (oxopyrridinyl)propanoylamino; methoxy-benzofuran-carbonyl)amino; (oxopyrrolidinyl)propanoylamino; [(ethoxycarbonyl-pyridyl)amino]; (methoxyanilino); (cyanopyridyl)amino; [(methylpyridazinyl)amino]; quinolinyl-amino; (methyl-oxazolyl)methyl-carbamoyl-amino; (phenylcyclopropyl)carbamoylamino; [(tert-butoxymethyl-oxo-ethyl)carbamoylamino]; dihydro-2H-clomenylcarbamoylamino; [(methoxyphenyl)ethylcarbamoylamino]; oxanylcarbamoylamino; (chloromethylphenyl)carbamoylamino; methanesulfonamide; methylpropylsulfonylamino; pyridinylsulfonylamino; [(carboxypyridyl)amino]; pyridylcarbamoylamino; methoxy-py (Ridinyl)amino; Ethyl-carbamoyl-amino; (Pyridinyl-thiazolyl)amino; (Methoxy-pyridinyl)amino; [(Ethyl-thiazolyl)amino; (Ethylamino)-thiazolyl; (Methyl-oxazolyl)anilino; Trichloroethoxysulfonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; Pyridinylcarbamoylamino; Propanylcarbamoylamino; Pyridinylcarbamoylamino; Methylpyridinecarbonyl)amino; (Morpholinylpyridinecarbonyl)amino; Benzamide;[(dimethylamino)benzoyl]amino; characterized by representing dimethylbutanoylamino.

[0028] According to one aspect, the compound of the present invention has R2, tert-butoxycarbonyl-amino;amino;3-pyridylcarbamoylamino;ethylcarbamoylamino;pyridin-3-yl-amino;(4-pyridin-3-yl-1,2,4-thiazole-3-yl)amino;3-(pyridin-3-ylamino)-1,2,4-thiazole-4-yl;(4-ethyl-1,2,4-thiazole-3-yl)amino;benzylamino;propylamino;2-methylpropanoylamino;hydroxy;ethylcarbamoylamino;isoquinoline-4-ylamino;(5-methoxypyridine-3-yl) Mino; (pyridine-3-l)carbonylamino; 1H-benzimidazole-2-ylamino; [3-(phenyl)-1,2-oxazole-5-yl]carbonylamino; quinoxaline-6-carbonylamino; [3-(4-hydroxyphenyl)propo-2-enoyl]amino; pyrido2,3-b]pyrazine-7-carbonylamino; 1,3-benzoxazole-2-carbonylamino; [(E)-4-ethoxy-4-oxobuta-2-enoyl]amino; 3-(benzimidazole-1-yl)propanoylamino; 3-(2-oxopyridine (1-yl)propanoylamino; 4-methoxy-1-benzofuran-2-carbonyl)amino; 3-(2-oxopyrrolidine-1-yl)propanoylamino; [(5-ethoxycarbonyl-3-pyridyl)amino]; (2-methoxyanilino); (4-cyano-2-pyridyl)amino; [(6-methylpyridazine-3-yl)amino]; quinoline-4-ylamino; (5-methyl-1,2-oxazole-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; pyridine-3-ylsulfonylamino; [(5-carboxy-3-pyridyl)amino]; 3-pyridylcarbamoylamino; 5-methoxypyridine-3-yl)amino; ethylcarbamoylamino;Characterized by representing (4-pyridine-3-yl-1,2,4-thiazole-3-yl)amino; (5-methoxypyridine-3-yl)amino; [(4-ethyl-1,2,4-thiazole-3-yl)amino; 3-(ethylamino)-1,2,4-thiazole-4-yl; 3-(5-methyl-1,3,4-oxazole-2-yl)anilino; 2,2,2-trichloroethoxysulfonylamino; [(Z)-N'-cyano-N-ethyl-carbamimidoyl]amino; pyridine-3-ylcarbamoylamino; propane-2-ylcarbamoylamino; pyridine-3-ylcarbamoylamino; 5-methylpyridine-3-carbonyl)amino; (6-morpholine-4-ylpyridine-3-carbonyl)amino; benzamide; [4-(dimethylamino)benzoyl]amino; and 3,3-dimethylbutanoylamino.

[0029] According to one embodiment, the compound of the present invention is selected from the following: tert-butyl N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]carbamate; tert-butyl N-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]carbamate; N-trans-(7RS,9RS)-9-amino-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridine-3-ylcarbamoteoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-(ethylcarbamoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridine-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridine-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(4-pyridine-3-yl-1,2,4-thiazole-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(pyridine-3-ylamino)-1,2,4-thiazole-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-[(4-ethyl-1,2,4-thiazole-3-yl)amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-9-(benzylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(propylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-(2-methylpropanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]urea; 1-Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]urea 1-Ethyl-3-trans-(7RS,9RS)-3-cyclopropyl-7-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]urea; N-[cis-(7RS,9SR)-3-cyclopropyl-9-(isoquinoline-4-ylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; 1-[(4-methoxyphenyl)methyl]-3-trans-(7RS,9RS)-3-cyclopropyl-9-[(5-methoxypyridine-3-yl)amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]urea; N-trans-(7RS,9RS)-7-[(3-cyanophenyl)carbamoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-7-[(4-bromophenyl)methylcarbamoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(naphthalene-1-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]pyridine-3-carboxamide; 1-[(5-methyl-1,2-oxazole-3-yl)methyl]-3-trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]urea; Ethyl N-[trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]carbamoyl]carbamate; 1-Trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]-3-[rac-(1S)-1-(3-methoxyphenyl)ethyl]urea; 1-(1-cyclopropylethyl)-3-trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]urea; 1-(2-methylcyclopropyl)-3-trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]urea; 1-Benzyl-3-trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]urea; 1-(2-phenylcyclopropyl)-3-trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]urea; 1-(3,4-dihydro-2H-chromen-3-yl)-3-trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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]isoquinoline-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]isoquinoline-7-yl]pyridine-3-carboxamide; Methyl 3-oxo-3-[trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]amino]propanoate N-[2-oxo-2-[trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]amino]ethyl]benzamide; 5-Chloro-4-methoxy-N-trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]thiophene-3-carboxamide; Ethyl 3-oxo-3-[trans-(7RS,9RS)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]amino]propanoate; N-[cis-(7RS,9SR)-3-cyclopropyl-7-(2-methylbutanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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]isoquinoline-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]isoquinoline-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]isoquinoline-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]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]pyrido2,3-b]pyrazine-7-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]-1,3-benzoxazole-2-carboxamide; Ethylrac-(E)-4-oxo-4-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]amino]buta-2-enoate; N-trans-(7RS,9RS)-9-[3-(benzimidazole-1-yl)propanoylamino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(2-oxopyridine-1-yl)propanoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(2-oxopyrrolidine-1-yl)propanoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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]isoquinoline-9-yl]amino]pyridine-3-carboxylate; N-trans-(7RS,9RS)-3-cyclopropyl-9-(2-methoxyanilino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-9-[(4-cyanopyridine-2-yl)amino]-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(6-methylpyridazine-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(quinoline-4-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-[(5-methyl-1,2-oxazole-3-yl)methylcarbamoylamino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(2-phenylcyclopropyl)carbamoylamino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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]isoquinoline-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]isoquinoline-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]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(oxan-4-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-9-(methanesulfonamide)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(2-methylpropylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-(pyridine-3-ylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; 5-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]amino]pyridine-3-carboxylic acid; 1-Pyridine-3-yl-3-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]urea; cis-(7RS,9SR)-3-cyclopropyl-7,9-bis[(5-methoxypyridine-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; cis-(7RS,9SR)-7-amino-3-cyclopropyl-9-[(5-methoxypyridine-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; cis-(7RS,9SR)-7,9-bis(1H-benzimidazole-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; -Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-7-(ethylcarbamyoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]thiourea; cis-(7RS,9SR)-3-cyclopropyl-N-(2-methylpropyl)-7,9-bis[(4-pyridine-3-yl-1,2,4-thiazole-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[(5-methoxypyridine-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide; trans-(7RS,9RS)-7,9-bis(1H-benzimidazole-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-thiazole-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-thiazole-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]isoquinoline-9-yl]urea; trans-(7RS,9RS)-3-cyclopropyl-7,9-bis[3-(5-methyl-1,3,4-oxazol-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]isoquinoline-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]isoquinoline-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]isoquinoline-9-yl]urea; 1-Pyridine-3-yl-3-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]urea; 1-Propane-2-yl-3-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(propane-2-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]urea; 1-Pyridine-3-yl-3-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-ylcarbamoteoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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]isoquinoline-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]isoquinoline-7-yl]pyridine-3-carboxamide; N-trans-(7RS,9RS)-9-benzamide-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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]isoquinoline-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]isoquinoline-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]isoquinoline-9-yl]urea; N-[3-Cyclopropyl-5-[(2-Fluoro-2-methylpropyl)sulfamoyl]-9-(Pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide; N-[9-amino-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide.

[0030] The following examples illustrate how compounds encompassed by formula (I) may be synthesized. They are provided for illustrative purposes only and are not intended to limit the invention, nor should they be construed as limiting it. Those skilled in the art will understand that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.

[0031] Examples Abbreviation Acetic acid (ACOH) DCM Dichloromethane MTBE tert-butylmethyl ether Et2O Diethyl ether THF (Tetrahydrofuran) HCl ethyl acetate MeCN acetonitrile MeOH methanol h time rt room temperature M mass Saltwater, 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)]palladium(II) methanesulfonate TEA (Triethylamine) DMA N,N-dimethylacetamide TBME tert-butylmethyl ether (also abbreviated as MTBE) o / n overnight IPA Isopropyl Alcohol conc.concentration SCX Biotage® ISOLUTE® SCX-2 Propylsulfonic Acid Functionalized Silica

[0032] LCMS method Method 1: X-Bridge C18 Waters 2.1×20mm, 2.5μm column Column temperature: 40°C Mobile phase A: 10 mM ammonium formate + 0.1% formic acid in water 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 2.1×20mm, 2.5μM column Column temperature: 40°C Mobile phase A: 10 mM ammonium formate + 0.1% formic acid in water 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 (Registered Trademark) BEH (Trademark) C18, Part Number 186002352, 2.1 x 100 mm, 1.7 μm Column temperature: 40°C Mobile phase A: 2 mM ammonium bicarbonate buffered at pH 10 Mobile phase B: Acetonitrile Gradient program, flow rate 0.6 mL / 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 × 100 mm, 1.7 μm column Flow rate: 0.6mL / min Column temperature: 40℃ Injection volume: 1μL Gradient: Time (minutes): %A %B 0.00 95 5 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5 UV215 nM, PDA spectrum 200-400 nm, process: 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 (minutes): %A %B 0.00 95 5 5.50 0 100 5.90 0 100 5.92 95 5 UV215 nM, PDA spectrum 210-420 nm, process: 1 nm MSD Scan Positive 150-850

[0037] Method 6: A QDA Waters simple quadrupole mass spectrometer will be used for LCMS analysis. This spectrometer features the UPLC Acquity Classic, which has an ESI source and a diode array detector (210-400 nm). Data are acquired using basic elution with a full MS scan in positive mode from m / z 50 to 1000. For basic elution, reverse-phase separation was performed at 45°C using a Waters Acquity UPLC BEH C18 1.7 μm (2.1 × 50 mm) column. Gradient elution is Mobile phase A: H2O / acetonitrile / ammonium formate (95 / 5 / 63 mg / L) + 50 μL NH4OH Mobile phase B: Acetonitrile / H2O / Ammonium formate (95 / 5 / 63 mg / L) + 50 μL NH4OH 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 2.1×20mm, 2.5μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile phase B: Acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

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

[0040] Method 9: Stationary phase: X-Bridge C18 Waters 2.1×20mm, 2.5μM column Mobile phase A: 10 mM ammonium formate + 0.1% formic acid in water 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 2.1×20mm, 2.5μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile phase B: Acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0042] Method 11: Stationary phase: Waters Acquity UPLC BEH C18 2.1×50mm, 1.7μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile phase B: Acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1.5mL / min Gradient program: Time A% B% 0.00 95.00 5.00 0.10 95.00 5.00 3.50 5.00 95.00 4.00 5.00 95.00 4.05 95.00 5.00

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

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

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

[0046] Method 15: Stationary phase: X-Bridge C18 Waters 2.1×20mm, 2.5μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile phase B: Acetonitrile + 5% water + 0.1% ammonia solution Flow rate: Pump 1: 1 mL / min, Pump 2: 0.5 mL / min Gradient program: Pump 1: Pump 2: Time A% B% Time A% B% 0.00 95.10 4.90 0.10 5.00 95.00 4.00 5.00 95.00 1.00 5.00 95.00 5.00 5.00 95.00 1.10 95.00 5.00 5.10 95.10 4.90

[0047] Method 16: Stationary phase: Waters Acquity UPLC BEH C18 2.1×50mm, 1.7μm Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution 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 2.1×20mm, 2.5μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile phase B: Acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0049] Method 18: A SYNAPT G2-SI Waters Q-TOF mass spectrometer equipped with a Waters Acquity H-class UPLC featuring an ESI source and a diode array detector (210-400 nm). Data is acquired in positive mode with a full MS scan from m / z 50 to 1200. Reverse-phase separation was performed at 45°C using an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 × 50 mm). Gradient elution was performed using the following method. 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 (minutes) 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 related amine (1 equivalent) in DCM (unless otherwise specified), DIPEA (2-4 equivalents) and isocyanate / isothiocyanate (2-4 equivalents) were added. The reaction mixture was heated under reflux (unless otherwise specified). After completion, the reaction mixture was concentrated under vacuum and purified by column chromatography.

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

[0052] Intermediate 1 [ka] 3,6,7,8-Tetrahydro-2H-as-Indecane-1-one 3-Indan-5-ylpropanoic acid (100 g, 526 mol, commercially available from Angene, CAS number: 23291-98-7) in polyphosphate (320 mL) was heated to 140 °C for 6 minutes, then cooled to 10 °C and quenched by adding ice water (500 mL). The resulting mixture was extracted with DCM (25 L, followed by 15 L). The combined organic extract was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography with SiO₂, yielding the title compound as a brown solid (4.5 g, yield 5%). δ 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-indecane-1-one Intermediate 1 (85 g, 493 mmol) was treated with MTBE (1.27 L) solution, cooled to 0°C, and treated with isopentyl nitrite (100 mL, 740 mol) solution in ethanol (600 mL) [added dropwise over 5 minutes]. The resulting mixture was stirred at 0°C for 0.4 hours, and the solid was then collected by filtration, washed with MTBE, and dried to obtain the title compound as a brown solid (80 g, yield 81%). 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 A solution of intermediate 2 (83 g, 412.5 mol) in POCl3 (1.25 L) was cooled to 0°C and treated with PCl5 (94.5 g, 454 mol). The resulting mixture was treated with HCl (gas) until the reaction was saturated and stirred at 65°C for 1 hour. After this time, the mixture was further treated with PCl5 (34.4 g, 165 mmol) and stirred for a further 15 hours. The mixture was concentrated under vacuum, treated with water, and the resulting solid was recovered by filtration and dried to obtain the title compound (80 g, yield 81%). MS m / z = 238 [M + H] + .δ H( 400 MHz, CDCl3)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 siRNA (666 mL) was treated with phosphorus (27.4 g, 806.4 mmol) and HI (155 mL, 57% wt aqueous solution, 1.18 mol), and stirred at 120°C for 4 hours. The resulting mixture was filtered while still hot and concentrated under vacuum. The residue was dissolved in water, basicized by the addition of ammonia solution, and the resulting solid was recovered by filtration. The solid was dissolved in DCM, washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography with SiO2 to obtain the title compound as a white solid (38.5 g, yield 56%). MS m / z=204 [M+H] + .δ H( 400 MHz, CDCl3)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

Chem.

[0057] Intermediate 6

Chem.

[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 SiO2 (250 mL), 2,2'-azobis(2-methylpropionitrile) (240 mg, 1.4 mmol) and N-bromosuccinimide (3.3 g, 18 mmol) were added. The reaction mixture was stirred in the dark at 90°C for 2.5 hours. The reaction mixture was evaporated to obtain a crude 1:1 mixture of the title compound (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 (2.31 g, 6 mmol) of a crude 1:1 mixture of intermediates 7 and 8 were dissolved in 0.4 M ammonia (400 mL, 200 mmol) in THF in a round-bottom pressure flask. The reaction mixture was then heated at 70°C for 16 hours. The two reaction mixtures were cooled and evaporated. The resulting residue was returned to the above reaction conditions for 21 hours using THF containing half the amount of ammonia. The reaction mixtures were cooled, combined, and evaporated to obtain the title compound (4.7 g) in a ratio of approximately 1:1, which was used in the next step without further purification.

[0060] Intermediate 11 and 12 [ka] tert-butyl N-[3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]carbamate (11) tert-butyl N-[3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]carbamate (12) To a stirring mixture of intermediates 9 and 10 (2.88 g, 8.14 mmol) in dichloromethane (60 mL) in an approximately 1:1 ratio, di-tert-butyl dicarbonate (1.86 g, 8.52 mmol) was added, followed by triethylamine (2.26 mL, 16.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, and the crude product was purified by column chromatography (gradient of 0% to 100% ethyl acetate in isohexane) to obtain the title compound.

[0061] Intermediate 11 (877 mg, yield 39%) LCMS [M+H] + 454 / 456, RT 1.28 (Method 8). 1 1H 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 ¹H 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

change

[0064] Intermediate 14

Chemical Structure

[0065] Intermediate 15 [ka] tert-butyl N-[7-azido-3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]carbamate To a solution of intermediate 12 (2550 mg, 5.62 mmol) in siRNA (120 mL), 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) were added. The mixture was heated in the dark at 90°C for 30 minutes. The reaction product was cooled, and the solvent was removed to obtain 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 product was stirred for 10 minutes. siRNA (50 mL) was added to the reaction product, followed by the addition of water (30 mL). The organic layer was separated and further washed with water (2 × 20 mL) and brine (10 mL). The organic layer was dried (MgSO4), and the solvent was removed to obtain a brown solid. The solid was purified by flash column chromatography using a heptane gradient of 0–35% ethyl acetate, yielding the title compound as a brown solid (2.2 g, purity 53%, yield 42%). LCMS [M+H] + 495, RT 3.37 min (Method 1). Another 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]isoquinoline-9-yl]carbamate To a solution of intermediate 15 (19000 mg, 16.51 mmol, purity 43%) in ethyl acetate (100 mL), EtOH (50 mL) and 10% palladium carbon (3328 mg, 3.12 mmol) were added. The reaction mixture was evacuated and then placed under a hydrogen atmosphere and vigorously stirred for 2 hours. The palladium residue was filtered through a Celite plug to remove the solvent. The resulting residue was purified by flash column chromatography, eluting with 0-100% ethyl acetate in a heptane gradient, followed by 0-10% 7M NH3 in MeOH in ethyl acetate, to obtain the title compound as a brown solid (5.98 g, yield 77%); LCMS [M+H] +469, RT 2.49 min (Method 1), intermediate 12 (10 g, purity 60%) was recovered.

[0067] Intermediate 17 [ka] tert-butyl N-[7-(benzyloxycarbonylamino)-3-chloro-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]carbamate To a solution of intermediate 16 (5960 mg, 12.7 mmol) in DMF (40 mL), triethylamine (7.1 mL, 50.8 mmol) and benzyl carbonate (2,5-dioxopyrrolidine-1-yl) (4117 mg, 16.5 mmol) were added. The solution was stirred for 30 minutes. The reaction mixture was diluted with SiO2 (100 mL) and then washed with water (3 × 50 mL) and brine (30 mL). The organic layer was dried with (MgSO4), and the solvent was removed to obtain an oily substance. The oily substance was purified by flash column chromatography eluting with 0–40% ethyl acetate in a heptane gradient, yielding the title compound as a fluffy brown solid (7.7 g, yield 94%); LCMS [M+H] + 603, RT 3.39 and 3.47 mins [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]isoquinoline-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 mixture was heated at 105 °C for 4 hours. The reaction mixture was cooled, and the palladium residue was removed by filtration through a Celite plug. The Celite was washed with SiO2 (20 mL) and water (10 mL). The filtrate was diluted with SiO2 (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 (MgSO4), and the solvent was removed to obtain a brown oily substance. The oily substance was purified by flash column chromatography using elution with 0–40% ethyl acetate in a heptane gradient, yielding the title compound as a brown solid (8.35 g, yield 85%); LCMS [M+H] + 609, RT 3.46 and 3.54 mins [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]isoquinoline-7-yl]carbamate (19) Benzyl N-[cis-(7RS,9SR)-9-amino-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]carbamate (20) To a solution of intermediate 18 (850 mg, 1.40 mmol) in DCM (5 mL), trifluoroacetic acid (5 mL) was added. The solution was stirred at room temperature for 30 minutes. The solvent was removed, and the excess TFA was azeotropically mixed with 1:1 DCM / heptane to obtain a brown oily substance. The oily substance was purified by SCX cartridge elution with 0–100% 7M NH3 in a methanol gradient to obtain racemamine as an orange rubbery substance. The rubbery substance was further purified by flash column chromatography elution with 7M NH3 in MeOH in a 0–5% DCM gradient to obtain the title compound as a mixture of enantiomers:

[0070] Trans product (intermediate 19) as a white solid (250 mg, yield 35%); δ 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] The cis product (intermediate 20) as a white solid (305 mg, yield 42%); 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 [ka] Benzyl N-trans-(7SR,9SR)-9-[(2-aminophenyl)carbamateoylamino]-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]carbamate To a mixture of water (0.5 mL) and sodium bicarbonate (60 mg, 0.708 mmol) in DCM (1 mL), carbonothioyl dichloride (0.027 mL, 0.354 mmol) was added at 0°C. A solution of intermediate 19 (60 mg, 0.118 mmol) in DCM (1 mL) was then added. The mixture was vigorously stirred at 0°C for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried (MgSO4), and the solvent was removed to obtain the intermediate isothiocyanate as a solid. The solid was dissolved in THF, and benzene-1,2-diamine (22 mg, 0.200 mmol) was added. The solution was stirred for 18 hours. The solvent was removed to obtain a white solid. The solid was purified by flash column chromatography, eluting with a heptane gradient containing 0–100% ethyl acetate followed by an ¼ gradient containing 0–10% methanol, yielding the title compound as a mixture of trans-enantiomers (77 mg, 99% yield); LCMS [M+H] + 659, RT 2.03 minutes (Method 2).

[0073] Intermediate 22 [ka] Benzyl N-trans-(7SR,9SR)-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-5-(isobutylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]carbamate To a suspension of intermediate 21 (77 mg, 0.117 mmol) in MeOH (2 mL), 2-iodoacetic acid (26 mg, 0.140 mmol) was added. The reaction mixture was heated at 70°C for 90 minutes. Another portion of 2-iodoacetic acid (10 mg, 0.058 mmol) was added, and the reaction mixture was heated at 70°C for a further 30 minutes. The solution was cooled, and the solvent was removed to obtain the residue. The residue was partitioned into RINKAN (10 mL) and saturated NaHCO3 aqueous solution (5 mL). The organic layer was separated, and the aqueous layer was further extracted with RINKAN (2 × 10 mL). The combined organic layers were dried over (MgSO4), and the solvent was removed to obtain a solid. The solid was purified by flash column chromatography eluting with 7 M NH3 / methanol in a 0–5% DCM gradient, yielding the title compound as a mixture of trans-enantiomers (50 mg, yield 68%); LCMS [M+H] + 625, RT 1.77 min (method 2).

[0074] Intermediate 23 [ka] trans-(7SR,9SR)-7-amino-9-(1H-benzimidazole-2-ylamino)-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide To a partial solution of intermediate 22 (381 mg, 0.610 mmol) in acetic acid (3 mL), hydrogen bromide (45%, 3.5 mL, 27.4 mmol) in AcOH was added. The solid was slowly added to the solution over 30 minutes. The reaction mixture was stirred for 1 hour. Another portion of AcOH containing HBr (0.7 mL) was added, and the reaction mixture was stirred for a further 1 hour. The solvent was removed to obtain a brown residue. The residue was purified using an SCX cartridge eluted with 0-100% 7M NH3 in a methanol gradient to obtain 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]isoquinoline-7-yl]carbamate To a stirred solution of intermediate 20 (550 mg, 1.08 mmol) in THF (25 mL) at room temperature, N,N-diisopropylethylamine (419 mg, 3.24 mmol) and nicotinoyl chloride hydrochloride (211 mg, 1.19 mmol) were added. The reaction was monitored by LC-MS until completion, then diluted with RINKAN (30 mL) and washed with saturated aqueous NaHCO3 and brine. After removing volatiles under vacuum, the crude product was purified by column chromatography (elution with RINKAN in isohexane, followed by elution with MeOH in RINKAN) to obtain the title compound as a mixture of cis-enantiomers (550 mg, 81% yield). 1 1H 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]isoquinoline-9-yl]pyridine-3-carboxamide Intermediate 24 (550 mg, 0.8783 mmol) was dissolved in EtOH (2 mL), and palladium-carbon (0.087 mmol) was added. The solution was degassed and placed under a hydrogen atmosphere. Further palladium-carbon was added until the reaction was complete. The reaction mixture was then filtered through Celite and washed with siRNA. After removing the solvent, the crude product was purified by column chromatography with elution at a 20% gradient in DCM (3.5 N NH3MeOH in DCM) to obtain the title compound as a mixture of cis-enantiomers (175 mg, 41% yield). 1 1H 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]isoquinoline-9-yl]carbamate To a solution of intermediate 18 (300 mg, 0.493 mmol) in THF (3 mL), 10% palladium-carbon (600 mg, 0.564 mmol) was added. The mixture was evacuated and left under a hydrogen atmosphere for 4 hours. The palladium residue was removed by washing with excess siRNA (10 mL) and MeOH (10 mL) with Celite. The solvent was removed from the filtrate to obtain an oily substance. The oily substance was purified by flash column chromatography eluting with a 7 M NH3 / MeOH gradient in 0-10% DCM, yielding 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-diazide-3-chloro-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (27) trans-(7SR,9SR)-7,9-diazide-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), cooled in an ice bath, and then sodium azide (3.9 g, 60 mmol) was added in fractional amounts. The reaction mixture was stirred at this temperature for 1.5 hours. After cooling the reaction mixture in an ice bath, water (250 mL) and TBME (250 mL) were added. The resulting slurry was vigorously stirred and then partitioned, and the aqueous layer was extracted with TBME (2 × 250 mL). The combined organic extracts were dried and concentrated in vacuum. Purification by column chromatography (0–40% gradient of ethyl acetate in isohexane) yielded the title compound as a mixture of enantiomers:

[0079] Intermediate 27 (838 mg, yield 9%). 1 1H 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 ¹H 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

change

[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]isoquinoline-7-yl]carbamate To a stirred solution of intermediate 19 (490 mg, 0.96 mmol) in THF (25 mL) at room temperature, N,N-diisopropylethylamine (373 mg, 2.89 mmol) and nicotinoyl chloride hydrochloride (188 mg, 1.06 mmol) were added. The reaction was monitored by LC-MS until completion, then diluted with RINKAN (30 mL) and washed with saturated aqueous NaHCO3 and brine. After removing volatiles under vacuum, the crude product was purified by column chromatography (elution with RINKAN in isohexane, followed by elution with MeOH in RINKAN) to obtain the title compound as a mixture of enantiomers (500 mg, 83% yield). 1 1H 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]isoquinoline-9-yl]pyridine-3-carboxamide Intermediate 30 (500 mg, 0.81 mmol) was dissolved in EtOH (2 mL), and palladium-carbon (0.081 mmol) was added. The solution was degassed and placed under a hydrogen atmosphere. Further palladium-carbon was added until the reaction was complete. The reaction mixture was then filtered through Celite and washed with siRNA. After removing the solvent, the crude product was purified by column chromatography with elution at a 20% gradient in DCM (3.5 N NH3MeOH in DCM) to obtain the title compound as a mixture of enantiomers (157 mg, 40% yield). 1 1H 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]isoquinoline-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-methylpropane-2-oleate (227 mg, 2.36 mmol) were suspended in 1,4-dioxane (25 mL). The reaction mixture was placed under nitrogen, capped, and heated at 65°C for 2.5 hours. Most of the 1,4-dioxane was removed, and the residue was loaded onto an SCX column. Purification by SCX column chromatography eluting with 0-100% 7M NH3 in a methanol gradient yielded an oily substance. The oily substance still contained multiple components. Further purification by flash column chromatography eluting with a 7M NH3 / MeOH gradient in 0-5% DCM yielded 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), 10% Pd carbon (10%, 264 mg, 0.248 mmol) was added. The reaction mixture was left under hydrogen for 1 hour. The palladium residue was removed by Celite, and the solvent was removed to obtain a pale yellow solid. The solid was purified by flash column chromatography eluting with 7 M NH3 / MeOH in a 0-10% DCM gradient to obtain the title compound as a mixture of enantiomers (195 mg, yield 88%); LCMS [M+H] + 482, RT 1.85 minutes (Method 1).

[0088] Intermediate 34 [ka] N-trans-(7SR,9SR)-3-cyclopropyl-5-(isobutylsulfamoyl)-9-(3-pyridylcarbamoteoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide To a solution of Example 3 (50 mg, 0.104 mmol) in THF (1 mL), 3-isothiocyanatopyridine (0.013 mL, 0.115 mmol) was added. The solution was stirred for 10 minutes, by which time a white solid had precipitated from the solution. The solid was filtered, washed with DCM (1 mL), and dried under vacuum to obtain the title compound as a mixture of enantiomers (32 mg, yield 49%). After washing the filter paper, the harvested product of the title compound (16 mg, yield 25%) was obtained. 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]isoquinoline-7-yl]pyridine-3-carboxamide Trifluoroacetic acid (2.5 mL, 33.7 mmol) was added to a suspension of Example 2 (275 mg, 0.474 mmol) in DCM (2.5 mL). The resulting solution was stirred at room temperature for 45 minutes. The solvent was removed from the reaction product azeotropically with 1:1 DCM / heptane to remove excess TFA. The rubbery substance was purified by SCX column chromatography eluting with 0-10% 7M NH3 in a MeOH gradient to obtain 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]isoquinoline-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 hour. The reaction mixture was concentrated under vacuum to obtain a brown oily substance, which was dissolved in tetrahydrofuran (8 mL) and water (2 mL). Silver carbonate (425 mg, 1.53 mmol) was added at room temperature. The reaction was completed by LC-MS after 2.5 hours.

[0091] The reaction mixture was diluted with ethyl acetate, filtered, and the solvent was removed. The residue was then purified by column chromatography (elution under an isohexane gradient of ethyl acetate), yielding the title compound as a mixture of diastereoisomers (approximately 2:1) as a brown oily substance (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 The 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 minutes, the reaction mixture was quenched with saturated NaHCO3 solution (4 mL) and stirred for 1 hour. 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 under vacuum to obtain the title compound as a mixture of diastereoisomers (approximately 2:1) as a brown oily substance. LCMS [M+H] + 376 with retention times 0.904 min and 0.939 min(Method 8).

[0093] Intermediate 38

Chem.

[0094] Intermediate 39

Chem.

[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), 2,2'-azobis(2-methylpropionitrile) (445 mg, 2.65 mmol) and N-bromosuccinimide (11.8 g, 66.4 mmol) were added. The reaction mixture was sealed and heated at 90°C for 3 hours. The reaction mixture was washed with water (300 mL) and dried over Na2SO4. After removing the solvent under vacuum, the crude title compound was obtained 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-(Ethylcarbamyoylamino)-5-(Isobutylsulfamoyl)-8,9-Dihydro-7H-Cyclopenta[h]Isoquinoline-7-yl]pyridine-3-Carboxamide To a solution of Example 3 (50 mg, 0.104 mmol) in THF (1 mL), isothiocyanate (0.010 mL, 0.115 mmol) was added. The solution was stirred for 60 minutes. Another portion of isothiocyanate (0.010 mL, 0.115 mmol) was added, and the solution was stirred for 1 hour. The solvent was removed to obtain a white solid. Tritulation by DCM yielded 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-carbon (0.28 mmol) was added. The solution was degassed and placed under a hydrogen atmosphere. Further palladium-carbon was added until the reaction was complete. The reaction mixture was then filtered through Celite and washed with EtOH (15 mL). After removing the solvent, the crude product was purified by column chromatography eluting with a 0–100% gradient of MeOH in DCM to obtain the title compound as a mixture of enantiomers (851 mg, 52% yield). 1 1H NMR (300 MHz, Methanol-d4)δ H 9.68(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]isoquinoline-9-yl]carbamate To a stirred solution of intermediate 42 (3.7 g, 7.0 mmol) in 1,4-dioxane (80 mL), di-tert-butyl dicarbonate (3.8 g, 18 mmol), followed by triethylamine (3.9 mL, 28 mmol), was added. The reaction mixture was stirred overnight at ambient temperature. 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 under vacuum. The crude product was purified by flash column chromatography eluting with isohexane solutions of siRNA with a 0–40% gradient to obtain the title compound as a mixture of enantiomers (3.7 g, 7.0 mmol).1 H NMR (400 MHz, Chloroform-d) δ H 9.44 (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

Chemical Structure

[0100] Intermediate 45 [ka] cis-(7RS,9SR)-7,9-diamino-3-cyclopropyl-N-isobutyl-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamidedihydrochloride To a stirred suspension of intermediate 44 (1.25 g, 2.18 mmol) in methanol (20 mL) at ambient temperature, 4M hydrochloric acid (11 mL, 44 mmol) in dioxane was added. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum, and the resulting solid was trituated in diethyl ether (10 mL), filtered, and washed with additional diethyl ether (10 mL). The solid was dried to obtain the title compound as a mixture of the bisHCl salt and its enantiomer (1.02 g, quantitative). 1 1H 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-pyridylcarbamoteoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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, 3-isothiocyanatopyridine (74.5 μL, 0.66 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 minutes. The second portion of 3-isothiocyanatopyridine (16 μL) was added, and stirring was continued for 30 minutes. The reaction mixture was filtered and washed with diethyl ether (5 mL). The solid was tritulated and filtered first with DCM / MeOH (9:1) and then with MeOH to obtain the title compound as a mixture of enantiomers (117 mg, 67% yield). 1 1H 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]isoquinoline-9-yl]carbamate (47) tert-butyl N-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]carbamate (47a) A mixture of intermediates 29a and 29 in a ratio of approximately 5.5:1 (1135 mg, 2.40 mmol) 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 purged by vacuum / nitrogen (3 times). A solution of tricyclohexylphosphonium tetrafluoroborate (137 mg, 0.361 mmol) and tribasic potassium phosphate (1280 mg, 6.01 mmol) in water (1 mL) was added, the mixture was again degassed, and purged by vacuum / nitrogen (3 times). The reaction mixture was heated in a microwave at 120°C for 2 hours. After cooling, the mixture was diluted with RINKAN (100 mL), the solution was washed with water and then brine, passed through a phase separator cartridge, and evaporated. The crude product was purified by flash chromatography using a elution gradient of 10–60% phenylethylamine / hexane to obtain 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 Triphenylphosphine (4.95 g, 18.7 mmol) was added to a stirred solution of intermediate 28 (3.25 g, 7.72 mmol) in THF (80 mL) and H2O (10 mL). The reaction mixture was heated at 50°C for 30 minutes, after which H2O (20 mL) was added. After a further 23 hours, an additional triphenylphosphine (1.0 g, 3.8 mmol) was added, and heating was continued overnight at 50°C. The reaction mixture was then concentrated under vacuum and purified using an SCX cartridge eluted with 7N NH3 in MeOH to obtain 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]isoquinoline-9-yl]carbamate To a stirred solution of intermediate 48 (3.31 g, 7.17 mmol) in anhydrous 1,4-dioxane (80 mL), TEA (4 mL, 28.7 mmol) and di-tert-butyl dicarbonate (4.1 g, 18 mmol) were added at room temperature. After 1 hour and 15 minutes, the reaction mixture was concentrated to half its volume and diluted with a mixture of DCM (100 mL) and saturated NaHCO3 (100 mL) to separate the phases. The aqueous phase was extracted with DCM (3 × 30 mL), and the combined organic layers were dried (MgSO4) and concentrated under vacuum. Purification by column chromatography eluting with 0–30% SiO2 in isohexane yielded the title compound as a mixture of enantiomers (2.20 g, yield 54%). 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]isoquinoline-9-yl]carbamate To a stirred suspension of intermediate 49 (2.15 g, 3.78 mmol) in a mixture of toluene (20 mL), 1,4-dioxane (20 mL), and H2O (1 mL), cyclopropylboronic acid (1.36 g, 15 mmol), tribasic potassium phosphate (2.9 g, 13 mmol), tricyclohexylphosphonium tetrafluoroborate (360 mg, 0.95 mmol), and palladium(II) acetate (130 mg, 0.5675 mmol) were added. The mixture was placed under an N2 atmosphere and heated at 100°C in a sealed pressure round-bottom flask. After 4 hours and 25 minutes, the reaction mixture was diluted with a mixture of DCM (100 mL containing several mL of IPA) and H2O (200 mL), and the phases were separated. The aqueous layer was extracted with DCM (100 mL containing several mL of IPA) and DCM (4 × 30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. Purification by column chromatography eluting with 0–40% HCl in isohexane yielded 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-sulfonamidedihydrochloride To a stirred yellow semi-solution of intermediate 50 (1.8 g, 3.1 mmol) in MeOH (60 mL) in an ice bath, hydrochloric acid (4.0 mol / L) in dioxane (33 mL) was added. The reaction mixture was then raised to room temperature, stirred for 30 minutes (4 hours), and then concentrated under vacuum. The crude product was tritulated with Et2O (20 mL), filtered, and washed with Et2O (20 mL). The residue was dried under vacuum to obtain 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-(ethylcarbamyoylamino)-5-(isobutylsulfamoyl)-8,9-Dihydro-7H-Cyclopenta[h]Isoquinoline-9-yl]-3-Ethyl-thiourea Following general procedure 1, intermediate 51 (600 mg, 1.30 mmol) was used with a heating time of 10 hours. The reaction mixture was concentrated under vacuum, trituated with Et2O (80 mL), and filtered to obtain the title compound as a mixture of enantiomers (623 mg, yield 87%). 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), 2-fluoro-2-methyl-propane-1-amine hydrochloride (5.83 g, 45.7 mmol), followed by triethylamine (13.2 mL, 95.1 mmol), was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (200 mL). The organic layer was partitioned and further washed with water (200 mL). The organic layer was dried and concentrated under vacuum to obtain 11.8 g of green / black solid. This was triturated with hot IPA and filtered to obtain the title compound (10.4 g, yield 77%) as a gray powder. 1 1H 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 HCl (500 mL), 2,2'-azobis(2-methylpropionitrile) (506 mg, 3 mmol) and N-bromosuccinimide (6.24 g, 34.7 mmol) were added. The reaction mixture was stirred in the dark at 90°C for 1.5 hours. The reaction mixture was cooled and concentrated. The residual succinimide was filtered off, and the crude product was purified by column chromatography using a gradient of 0 to 25% HCl in isohexane to obtain the title compound (5.07 g, 44% yield). 1 1H 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 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 RINKAN (30 mL) were placed in a vial, sealed, and then heated at 90°C for 4 hours. The reaction mixture was concentrated. Purification by column chromatography under vacuum, eluting with 0-100% RINKAN in isohexane, yielded 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-diazide-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (56) cis-(7RS,9SR)-7,9-diazide-3-chloro-N-(2-fluoro-2-methyl-propyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide (57) Sodium azide (240 mg, 3.65 mmol) was added to a stirred solution of intermediate 55 (779 mg, 1.45 mmol) in anhydrous DMF (5 mL). The reaction mixture was stirred at room temperature for 1 hour and 35 minutes, then diluted with HCl (30 mL) and washed with brine (60 mL). The aqueous phase was extracted with HCl (2 × 20 mL), the combined organic layers were dried (phase separator), and concentrated under vacuum. Purification by column chromatography eluting with 0–30% HCl in isohexane yielded the title compound as a mixture of enantiomers:

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

[0115] Intermediate 57 (293 mg, yield 46%), LC-MS [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 (280 mg, 0.64 mmol) and equivalent stoichiometric reagents were used to synthesize the compound in the same manner as intermediate 48. Purification using an SCX cartridge eluting 7N NH3 in MeOH yielded the title compound as a mixture of enantiomers (255 mg, 83% yield). LC-MS [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-methylpropyl)sulfamoyl]-8,9-Dihydro-7H-cyclopenta[h]isoquinoline-9-yl]-3-ethyl-urea Purification by column chromatography using intermediate 58 (142 mg, 0.31 mmol) at room temperature, followed by elution with DCM containing 0-10% MeOH, yielded the title compound as a mixture of enantiomers (74 mg, 45% yield) via 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 Intermediate 48 (240 mg, 0.55 mmol) and equivalent stoichiometric reagents were used to synthesize the compound in the same manner as intermediate 57. Purification using an SCX cartridge eluting 7N NH3 in MeOH yielded the title compound as a mixture of enantiomers (209 mg, 79% yield). LC-MS [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-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]-3-ethyl-urea General procedure 1 was followed using intermediate 60 (100 mg, 0.22 mmol) at room temperature. Purification by column chromatography eluting with DCM containing 0-10% MeOH yielded 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-sulfonamidedihydrochloride Intermediate 47 (153 mg, 0.258 mmol) was dissolved in 4N HCl in dioxane (5 mL). The mixture was stirred at room temperature for 1 hour. After removing the solvent under vacuum, the title compound (120 mg, quantitative) was obtained and used without further purification. LC-MS [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]isoquinoline-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]isoquinoline-9-yl]carbamate (2) To a solution of intermediate 26 (1870 mg, 3.94 mmol) in THF (15 mL) at 0°C, DIPEA (2.4 mL, 13.8 mmol) and pyridine-3-carbonyl chloride hydrochloride (912 mg, 5.12 mmol) were added. The solution was stirred at room temperature for 10 minutes. The solvent was removed to obtain a brown solid. The solid was purified by flash column chromatography, eluting with a heptane gradient containing 0–100% ethyl acetate, followed by a gradient of DCM containing 0–5% 7M NH3 / MeOH, to obtain the title compound as a mixture of enantiomers: Example 1 (980 mg, 42% yield); LC-MS [M+H] + 580, RT 2.93 minutes (Method 1). Example 2 (1240 mg, yield 51%); LC-MS [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]isoquinoline-7-yl]pyridine-3-carboxamide To a suspension of Example 1 (200 mg, 0.345 mmol) in DCM (2.5 mL), trifluoroacetic acid (2.5 mL, 45.0 mmol) was added at 0°C. The resulting solution was stirred at room temperature for 30 minutes. The solvent was removed from the reaction product azeotropically with 1:1 DCM / heptane to remove excess TFA. The resulting rubbery substance was purified by SCX column chromatography eluting with 0-100% 7M NH3 in a methanol gradient to obtain the title compound as a mixture of enantiomers (165 mg, quantitative). δ 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-(pyridine-3-ylcarbamoteoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide To a solution of Example 3 (50 mg, 0.104 mmol) in THF (1 mL), 3-isothiocyanatopyridine (0.013 mL, 0.115 mmol) was added. The solution was stirred for 10 minutes. The solid from the reaction mixture was filtered, washed with DCM (1 mL), and dried under vacuum to obtain the title compound as a mixture of enantiomers (32 mg, 49% yield). A second product of the title compound was obtained from the filtrate (16 mg, 25% yield). 1 1H NMR (500 MHz, Methanol-d4)δ H9.51(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]isoquinoline-7-yl]pyridine-3-carboxamide To a solution of Example 3 (20 mg, 0.0417 mmol) in THF (1 mL), isocyanatoethane (0.004 mL, 0.046 mmol) was added. The solution was stirred for 18 hours. The solvent was removed to obtain a pale yellow residue. The residue was purified by reverse-phase HPLC (basic conditions) to obtain 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-(pyridine-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide In a pressure vial, tBuXPhosPdG3 (6.2 mg, 7.82 μmol), 3-bromopyridine (0.007 mL, 0.078 mmol), and sodium 2-methylpropane-2-oleate (12 mg, 0.12 mmol) were added to a solution of intermediate 35 (15 mg, 0.031 mmol) in 1,4-dioxane (1 mL). The solution was heated at 90°C for 150 minutes. The solvent was removed to obtain a pale yellow residue. The residue was purified by reverse-phase HPLC (basic conditions) to obtain the title compound as a mixture of enantiomers (8 mg, 46% yield). 1 1H 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-(pyridine-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide In a pressure vial, tBuXPhosPdG3 (2.9 mg, 3.65 μmol), 3-bromopyridine (0.003 mL, 0.036 mmol), and sodium 2-methylpropane-2-oleate (5.6 mg, 0.0584 mmol) were added to a solution of Example 3 (7.0 mg, 0.014 mmol) in 1,4-dioxane (1 mL). The solution was heated at 90°C for 90 minutes. The solvent was removed to obtain a pale yellow residue. The residue was purified by reverse-phase HPLC (basic conditions) to obtain 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-pyridine-3-yl-1,2,4-thiazole-3-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide (8) N-trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[3-(pyridine-3-ylamino)-1,2,4-thiazole-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide (9) To a solution of intermediate 34 (43 mg, 0.07 mmol) in DMF (2 mL), formic acid hydrazide (13 mg, 0.21 mmol) and mercury dichloride (57 mg, 0.21 mmol) were added. The mixture was stirred for 2 minutes, and then triethylamine (0.03 mL, 0.21 mmol) was added. The mixture was then heated at 90°C for 1 hour. Acetonitrile (10 mL) and Celite (3 g) were added to the mixture, and it was stirred for 5 minutes. The mixture was then filtered through Celite and washed with excess DCM and MeOH. The solvent was removed from the filtrate to obtain a brown oily substance. The oily substance was purified by reverse-phase HPLC (basic conditions) to obtain the title compound as a mixture of enantiomers:

[0128] Example 8 (17 mg, yield 39%); δ H(500 MHz, in 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, RT 3.34 minutes (Method 5).

[0129] Example 9 (8 mg, yield 18%); δ H( 500 MHz, in 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, 1.2 Hz, 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, RT 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]isoquinoline-7-yl]pyridine-3-carboxamide To the solution of Example 3 (15 mg, 0.031 mmol) in THF (1 mL) and DCM (1 mL), benzaldehyde (0.003 mL, 0.031 mmol) was added. The solution was stirred for 5 hours. Sodium triacetoxyborohydride (20 mg, 0.094 mmol) was added to the reaction product. The reaction product was stirred for a further 18 hours. The solvent was removed to obtain a pale yellow residue. The residue was purified by reverse-phase HPLC (basic conditions) to obtain the title compound as a mixture of enantiomers (11 mg, yield 62%). 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]isoquinoline-7-yl]pyridine-3-carboxamide To the solution of Example 3 (10 mg, 0.021 mmol) in THF (1 mL) and DCM (1 mL), propanal (0.002 mL, 0.031 mmol) was added. The solution was stirred for 5 hours. Sodium triacetoxyborohydride (13 mg, 0.062 mmol) was added to the reaction and stirred for 2 hours. The solvent was removed to obtain a pale yellow residue. The residue was purified by reverse-phase HPLC (basic conditions) to obtain 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]isoquinoline-7-yl]pyridine-3-carboxamide To a solution of Example 3 (20 mg, 0.042 mmol) in THF (1 mL), DIPEA (0.022 mL, 0.125 mmol) and 2-methylpropanoyl chloride (0.006 mL, 0.054 mmol) were added at 0°C. The solution was stirred at room temperature for 20 minutes. The solvent was removed to obtain a yellow rubbery substance. The rubbery substance was purified by reverse-phase HPLC (basic conditions) to obtain the title compound as a mixture of enantiomers (14 mg, yield 61%). 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]isoquinoline-7-yl]urea (14) 1-Ethyl-3-[cis-(7RS,9SR)-3-cyclopropyl-9-hydroxy-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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 overnight at room temperature. The reaction mixture was quenched with methanol and concentrated under vacuum to obtain a brown oily substance (28 mg) as a mixture of cis and trans diastereoisomers. The residue was purified by column chromatography to obtain 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 1H 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]isoquinoline-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 overnight at room temperature (a few drops of DMF were added to aid solubility). The reaction mixture was quenched with methanol and concentrated under vacuum to obtain a brown oily substance as a mixture of trans and cis isomers in approximately a 2:1 ratio. Separation of this mixture by column chromatography yielded the title compound (5 mg, 14%) as a mixture of enantiomers. 1 1H 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-(isoquinoline-4-ylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide 1,4-dioxane (0.20 mL) was added to a mixture of sodium tert-butoxide (20 mg, 0.2081 mmol), methanesulfonate (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). The reaction mixture was then heated at 90°C for 2 hours. Purification by column chromatography (basic conditions) yielded 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 prepared using the following stock solutions and following the procedure below: 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 isocyanates (1.3 equivalents, see table) were added to the relevant amine stock solution (500 μL - intermediates 23, 31, or 33 above), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by preparative LC-MS in basic mode (Examples 19 and 24 underwent additional preparative purification under acidic conditions and desalted by a third purification under basic conditions) to obtain the products shown in the table below as a mixture of enantiomers.

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

[0142] Examples 30-35 Examples 30-35 were prepared using the following stock solution and following the procedure below: 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 equivalent, see table*) was added to the relevant amine stock solution (500 μL - intermediate 23 or 31 above), and the reaction mixture was stirred overnight at room temperature. The solvent was removed, and the residue was purified by preparative LC-MS in basic mode (Example 34 underwent additional preparative purification under acidic conditions and desalted by a third purification under basic conditions) to obtain the products shown in the table below as a mixture of enantiomers. *In Example 31, acid (1.4 equivalents), followed by DIPEA (15 μL), TBTU (10 mg), and DMF (500 μL) were added to amine stock solution C (500 μL, intermediate 31).

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

[0145] Examples 36-37 Examples 36-37 were created following these steps: 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 hour and then purified by basic preparative LC-MS to obtain the products shown in the table below as a mixture of enantiomers.

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

[0147] Examples 38-47 Examples 38-47 were prepared using the following stock solution and following the procedure below: a) Example 3 in DMF (1800 μL) (9.6 mg, 0.020 mmol) 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 corresponding substrates (see table below). The reaction mixture was stirred overnight at room temperature and then purified by basic preparative LC-MS.

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

[0150] Examples 48-52 Examples 48-52 were created following these steps: A mixture of Example 3 (14 mg, 0.03 mmol), the related bromide (1.5 equivalents, see table below), methanesulfonate (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 hours or overnight. The reaction mixture was cooled to room temperature and purified by basic preparative LC-MS.

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

[0152] Examples 53-59 Examples 53-59 were created following these steps: Example 3 (8.4 mg, 0.018 mmol) was added to a solution of the related isocyanate (1.3 equivalents, see table below) in DCM (0.5 mL). Then, N,N-diisopropylethylamine (15 μL, 0.086 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was then removed, and the residue was purified by basic preparative LC-MS.

[0153] The LCMS data in the table were 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-(methanesulfonamide)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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), N,N-diisopropylethylamine (10 μL, 0.057 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and purified by reverse-phase column chromatography (basic conditions) to obtain 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]isoquinoline-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), N,N-diisopropylethylamine (15 μL, 0.086 mmol) was added. The reaction mixture was stirred overnight at room temperature. Then, the second and third portions of isobutanesulfonyl chloride (10 and 15 mg, respectively) were added, and the reaction mixture was stirred further at room temperature for 3 hours. The title compound (3.4 mg, 30% yield) was obtained by purification by reverse-phase column chromatography (basic conditions). 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-(pyridine-3-ylsulfonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-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), N,N-diisopropylethylamine (15 μL, 0.086 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed, and the residue was purified by reverse-phase column chromatography (basic conditions) to obtain 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]isoquinoline-9-yl]amino]pyridine-3-carboxylic acid By-products in the procedure used to prepare Example 48 above. The title compound was purified by preparative LC-MS (first under basic conditions, then under acidic conditions, and finally under basic conditions to obtain the free acid). LC-MS [M+H] + 601, retention time 1.74 minutes (method 6).

[0158] Example 64 [ka] 1-Pyridine-3-yl-3-[cis-(7RS,9SR)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7-(pyridine-3-ylcarbamoylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]urea To a stirred suspension of intermediate 45 (100 mg, 0.267 mmol) in DCM (3 mL) at room temperature, 3-isothiocyanatopyridine (90.9 mg, 0.75 mmol) was added. The reaction mixture was stirred at ambient temperature. DMF was added to aid in the solubilization of the isocyanate. A further 20 mg of 3-isothiocyanatopyridine was added, and stirring was continued for 90 minutes. Purification by HPLC (reverse-phase basic conditions) yielded the title compound (32 mg, yield 19%). 1 1H 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-methoxypyridine-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-methoxypyridine-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-methoxypyridine (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, after which 1,4-dioxane (4 mL) was added. The reaction mixture was sealed and stirred at ambient temperature for 2 hours and 45 minutes. The reaction product was filtered through Celite and washed with ethyl acetate. The solvent was removed under vacuum, and the resulting crude product was purified by HPLC (reverse-phase basic conditions) to obtain the title compound:

[0160] Example 65 (10.2 mg, yield 6.5%). 1 1H 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-(ethylcarbamyoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-9-yl]thiourea Intermediate 45 (200 mg) was dissolved in MeOH (5 mL) and absorbed into an SCX cartridge. The cartridge was washed with MeOH, and the free base was eluted with 4 M NH3 in MeOH. After removing the solvent, the obtained free base (150 mg, 0.40 mmol) was dissolved in DCM (9 mL), ethyl isothiocyanate (79.1 mg, 0.881 mmol) was added, and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum and purified by column chromatography (0-100% gradient of ethyl in isohexane) to obtain the title compound (7 mg, 3% yield). 1 1H 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-pyridine-3-yl-1,2,4-thiazole-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), formic acid hydrazide (42 mg, 0.701 mmol) and mercury chloride (143 mg, 0.52 mmol) were added. Then, triethylamine (0.097 mL, 0.701 mmol) was added, and the reaction suspension was heated at 80°C for 2 hours, and then left at room temperature overnight. The reaction mixture was filtered through a Celite plug and washed with SiO2 (10 mL). The solvent was removed under vacuum, and the crude residue containing several positional isomers was purified by HPLC to obtain the title compound (5 mg, 4% yield). 1 1H NMR (300 MHz, DMSO-d6)δ H 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-methoxypyridine-3-yl)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Intermediate 51 (50 mg, 0.11 mmol), 3-bromo-5-methoxypyridine (55 mg, 0.28 mmol), sodium tert-butoxide (42 mg, 0.44 mmol), methanesulfonate (2-di-tert-butylphosphin-2',4',6'-tri-isopopyr-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.03 mmol), and anhydrous dioxane (3 mL) were charged into a vial. The resulting mixture was subjected to vacuum, refilled with N2 (×2), purged with N2 for 5 minutes, and then heated to 80°C for 50 minutes. The reaction mixture was filtered through Celite (washed with siRNA using several mL of MeOH) and concentrated under vacuum. The title compound (31 mg, 49% yield) was obtained by purification using column chromatography eluting with 0-30% MeOH in DCM, followed by reversed-phase column chromatography eluting with 0-80% MeCN in H2O. 1 1H 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-benzimidazole-2-ylamino)-3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide 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) were placed in a microwave vial. The resulting mixture was heated at 175°C for 2 hours under microwave irradiation. The reaction mixture was concentrated in vacuum and purified by column chromatography eluting with DCM containing 0-30% MeOH, followed by a second column eluting with Â10% MeOH, to obtain the title compound (3 mg, 7% yield). 1 1H NMR (300 MHz, DMSO-d6)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-thiazole-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-thiazole-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), formate hydrazide (280 mg, 4.66 mmol) and mercury chloride (930 mg, 3.41 mmol) were added. Then, anhydrous TEA (650 μL, 4.66 mmol) was added, and the mixture was heated at 80°C for 16 hours. The reaction mixture was then filtered through Celite (MeCN washing) and concentrated under vacuum. The title compound was obtained by purification by column chromatography eluting with 0-50% MeOH in DCM, followed by basic reversed-phase column chromatography eluting with 0-80% MeCN in H2O:

[0168] Example 72 (135 mg, yield 21%). 1 1H 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, yield 1%) 1 1H 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]isoquinoline-9-yl]urea Intermediate 59 (74 mg, 0.14 mmol) and equivalent stoichiometric reagents heated at 120°C for 12 hours were used to synthesize the compound in the same manner as intermediate 50. The title compound (4 mg, 5% yield) was obtained by purification by reverse-phase column chromatography (basic conditions). 1 1H 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-oxazol-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 synthesized in the same manner as in Example 70 using reagents of equivalent stoichiometry. Purification by column chromatography eluting with DCM containing 0-30% MeOH, followed by reverse-phase HPLC (basic conditions), yielded the title compound (21 mg, 48% yield). 1 1H NMR (400 MHz, DMSO-d6)δ H 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]isoquinoline-7-yl]carbamate Magnesium oxide (160 mg, 3.97 mmol) and a 4 Å molecular sieve were placed in a vial and dried under vacuum. Then, 2,2,2-trichloroethyl sulfamate (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 under N2 conditions, followed by the addition of isopropyl acetate (7 mL) and intermediate 13 (450 mg, 0.98 mmol). After 5 minutes, iodobenzene diacetate (640 mg, 1.95 mmol) was added to the mixture and stirred at room temperature. After 2 hours and 40 minutes, the reaction mixture was quenched with saturated thiourea aqueous solution (2 mL), then diluted with DCM (40 mL) and H2O (40 mL), and the phases were separated. The aqueous layer was extracted with DCM (4 × 20 mL), dried (phase separator), and concentrated under vacuum. Purification by column chromatography eluting with 0-50% ethyl acetate in isohexane yielded a mixture of cis and trans isomers, which was further purified using reverse-phase HPLC (basic conditions) to obtain the title compound (6 mg, yield 1%). 1 1H NMR (300 MHz, DMSO-d6)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]isoquinoline-9-yl]guanidine 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) were placed in a vial, and the mixture was stirred at room temperature. After 3 hours, ethylamine (1 mL, 2 mmol) was added, and the mixture was heated at 70°C for 1 hour, and then concentrated under vacuum. The title compound (19 mg, 49% yield) was obtained by purification by reverse-phase HPLC (basic conditions). 1 1H 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]isoquinoline-9-yl]urea Intermediate 61 (60 mg, 0.11 mmol) and an equivalent stoichiometric reagent heated at 120°C for 2 hours were used to synthesize the compound in the same manner as intermediate 50. The title compound (10 mg, 16% yield) was obtained by purification by reverse-phase column chromatography (basic conditions). 1 1H NMR (400 MHz, DMSO-d6)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 of the information in the following table was provided using intermediate 51, following either general procedure 1 or general procedure 2 (depending on the substrate used).

[0176] The LCMS data in the table were 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]isoquinoline-7-yl]pyridine-3-carboxamide (88) N-[9-amino-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-yl]pyridine-3-carboxamide (89) Diisopropylethylamine (150 mg, 1.16 mmol) and nicotinoyl chloride hydrochloride (45.9 mg, 0.258 mmol) were added to a solution of intermediate 62 (120 mg, 0.258 mmol) in DCM (5 mL) at 0°C. The mixture was stirred for 48 hours (in the absence of a cooling bath). The reaction mixture was diluted with DCM, washed with water, then with brine, passed through a phase separator cartridge, and evaporated to leave a rubbery substance. The crude product was purified by flash chromatography with elution under a gradient of 1-50% MeOH in DCM to obtain the title compound, Example 88 (22 mg, 14%), as a grayish-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 yielded Example 89 with a purity of approximately 60%. Purification of this substance by preparative HPLC yielded Example 89 (3 mg, 2%) as a grayish-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 the preparation of IgE-Tb reagent 86 nmol of 172 μM IgE-Fc (N265Q, N371Q) (Young et al., 1995) in 100 mM NaHCO3, pH 9.5 was added to 1 mg of LanthaScreen™ amine-reactive Tb chelate (ThermoFisher catalog no. PV3583) and incubated at 20°C for 16 hours. The material was then buffer-changed with phosphate-buffered saline (i.e., 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 1.8 mM K2HPO4, pH 7.4), the material was quantified, and the degree of Tb conjugation was determined by measuring absorption at 280 nm and 343 nm.

[0180] The integrity of the composite material was determined by size exclusion chromatography using an S200 HR 10x300 column (GE Healthcare). The 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 the sFcεR1α-Y131A-AF488 reagent 400 nmol of 400 μM FcεR1α (Y131A mutant) (Cook et al., 1997) 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) at 22°C for 60 minutes. 40 μL of ethanediol was added, and the mixture was incubated at 22°C for 60 minutes to quench oxidation. The protein was then re-buffered in conjugation buffer (50 mM NaHCO3, 150 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 at 22°C for 16 hours. Sodium cyanoborohydride (100 mM in conjugation buffer) was added to a final concentration of 1 mM, and incubated on ice for 60 minutes. The protein was buffer-changed with phosphate-buffered saline (i.e., 137 mM NaCl, 2.7 mM KCl, 10 mM Na₂HPO₄, 1.8 mM K₂HPO₄, pH 7.4), the material was quantified, and the degree of Alexa Fluor® 488 conjugation was determined by measuring absorption at 280 nm and 495 nm.

[0183] The integrity of the composite material was determined by size exclusion chromatography using an S200 HR 10x300 column (GE Healthcare). A typical conjugation ratio was Alexa Fluor® 488:sFcεR1α at 2:1. Cook JPD., Henry AJ., McDonnell JM., Owens RJ., Sutton BJ., and Gould HJ (1997) Biochemistry 36:15579-15588

[0184] Preparation protocol for the sFcεR1α-AF488 reagent 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 while gently mixing to obtain a final concentration of 1 mM. The solution was incubated at 22°C for 60 minutes while gently mixing. A second aliquot of 50 mM sodium periodate (70 μL) was added, and the solution was incubated at 22°C for 60 minutes while gently mixing. Oxidation was stopped by slowly adding ethanediol (151.4 μL) while gently mixing to obtain a final concentration of 4% v / v. The solution was incubated at 22°C for 60 minutes while gently mixing. Using a PD10 column (GE Healthcare), the protein was buffer-exchanged with conjugation buffer (50 mM NaHCO3, 150 mM NaCl, pH 9.5) and concentrated to 1.13 mM using 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 at 22°C for 18 hours with gentle mixing. The mixture was cooled on ice, and ice-cold sodium borohydride (100 mM in conjugation buffer) was added to obtain a final concentration of 1 mM, and incubated on ice for 60 minutes. The protein was buffer-changed using a NAP-10 column (GE Healthcare) with phosphate-buffered saline (i.e., 137 mM NaCl, 2.7 mM KCl, 10 mM Na₂HPO₄, 1.8 mM K₂HPO₄, pH 7.4). The degree of Alexa Fluor® 488 conjugation was determined by quantifying the material and measuring absorption at 280 nm and 497 nm. A typical conjugation ratio was Alexa Fluor® 488:sFcεR1α at 2:1.

[0186] The objective was to measure the binding of IgE-Tb to the receptor and its inhibition by a compound 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 the 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, 0.002% Tween, and 1% DMSO.

[0188] Assay reaction For Examples 16 and 89, the assays were performed as follows: Each assay reaction was carried out in a 25 μl volume in a 384-well half-volume plate. Ten serial dilutions (3-fold) of the compound were prepared in DMSO at a concentration 50 times that of the final assay concentration (FAC). The compound solution was then prepared by diluting it 10-fold with IgE-Tb in assay buffer. For the assay, 5 μl of the diluted compound was added to 10 μl of IgE-Tb, followed by the addition of 10 μl of FcεRIα-Y131A-AF488. The FRET reagent FACs were 5 nM IgE-Tb and 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 a well containing the FRET reagent but without the compound.

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

[0190] FRET measurement FRET measurements for each well were performed using an Envision plate reader (Perkin Elmer) by excitation at 330 nm and emission measurement at 495 / 520 nm. The FRET ratio was calculated as follows: Radiation at 520 / Radiation at 495 × 1000.

[0191] The FRET ratio was used for data analysis.

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

[0193] The background signal (MIN) was subtracted from all wells. Using the background subtraction value, the percentage of inhibition by the compound in each test well was calculated as follows: 100 - Test well FRET ratio / MAX FRET ratio × 100.

[0194] The inhibition percentage was plotted against the compound concentration. The IC50 value for each compound was determined using a 4-parameter logistic fit model with the XLFIT5 software package.

[0195] For Examples 1-15, 36-47, 53-62, and 64-88, assays were performed as follows: Each assay reaction was carried out in a 25 μl volume in a 384-well half-volume plate. Ten serial dilutions (3-fold) of the compound were prepared in DMSO at a concentration 50-fold of the final assay concentration (FAC). Compound solutions were then prepared by diluting 10-fold with assay buffer. For the assay, 5 μl of the diluted compound was added to 10 μl of IgE-Tb, incubated for 30 minutes, and then 10 μl of sFcER1α-Y131A-AF488 was added. The FRET reagent FACs were 5 nM IgE-Tb and 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 a well containing the FRET reagent but without the compound.

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

[0197] FRET measurement FRET measurements for each well were performed using a PHERAstar FSX plate reader (BMG Labtech) by excitation at 337 nm and emission measurement at 490 / 520 nm. The FRET ratio was calculated as follows: Radiation at 520 / Radiation at 490 × 1000.

[0198] The FRET ratio was used for data analysis.

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

[0200] The background signal (MIN) was subtracted from all wells. Using the background subtraction value, the percentage of inhibition by the compound in each test well was calculated as follows: 100 - Test well FRET ratio / MAX FRET ratio × 100.

[0201] The inhibition percentage was plotted against the compound concentration. The IC50 value for each compound was determined using a 4-parameter logistic fit model with the XLFIT5 software package.

[0202] For Examples 17-35, 48-52, and 63, assays were performed as follows: Each assay reaction was carried out in a 25 μl volume in a 384-well half-volume plate. Ten serial dilutions (3-fold) of the compound were prepared in DMSO at a concentration 50-fold higher than the final assay concentration (FAC). Compound solutions were then prepared by 10-fold dilution with assay buffer. For the assay, 5 μl of the diluted compound was added to 10 μl of IgE-Tb, followed by 10 μl of sFcεR1α-AF488. The FRET reagent FACs were 0.75 nM for IgE-Tb and 0.9 nM for 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 at 1 μM (FAC = 200 nM) to the FRET reagent. The maximum FRET signal (MAX) was measured in a well containing the FRET reagent but not the compound.

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

[0204] FRET measurement FRET measurements for each well were performed using a PHERAstar FSX plate reader (BMG Labtech) by excitation at 337 nm and emission measurement at 490 / 520 nm. The FRET ratio was calculated as follows: Radiation at 520 / Radiation at 490 × 1000.

[0205] The FRET ratio was used for data analysis.

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

[0207] The background signal (MIN) was subtracted from all wells. Using the background subtraction value, the percentage of inhibition by the compound in each test well was calculated as follows: 100 - Test well FRET ratio / MAX FRET ratio × 100.

[0208] The inhibition percentage was plotted against the compound concentration. The IC50 value for each compound was determined using a 4-parameter logistic fit model with the XLFIT5 software package.

[0209] The 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 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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