Dihydrocyclopenta-isoquinoline-sulfonamide derivative compounds

Abstract

The present invention relates to a compound of formula (I) [Formula 1] JPEG2023508943000540.jpg5376 The present invention relates to dihydrocyclopenta-isoquinoline-sulfonamide derivatives of the formula (I), methods for preparing the derivatives, pharmaceutical compositions containing the derivatives, and uses of the derivatives in treating 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 dihydrocyclopenta-isoquinoline-sulfonamide derivatives of formula (I), processes for preparing the derivatives, pharmaceutical compositions containing the derivatives, and their use in treating disorders caused by IgE (such as allergic responses, non-allergic mast cell responses, or certain autoimmune responses), in particular disorders caused by the interaction of IgE with the FcεRI receptor. [Background technology]

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

[0003] IgE is secreted by B cells and expressed on their surface. IgE synthesized by B cells is anchored to the B cell membrane by a transmembrane domain linked to the mature IgE sequence by a short membrane-binding region. IgE also binds to B cells (as well as monocytes, eosinophils, and platelets) via the Fc region of IgE to the low-affinity IgE receptor (FcεRII). When a mammal is exposed to an allergen, B cells that synthesize IgE that binds the allergen are clonally expanded. This IgE is then released into the circulation by B cells, where it is bound by B cells (via FcεRII) and by mast cells and basophils via the so-called high-affinity receptor (FcεRI) found on the surface of mast cells and basophils. These mast cells and basophils are thereby sensitized to the allergen. Subsequent exposure to allergen crosslinks the FcεRI on these cells, thus activating them to release histamine and other factors responsible for 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, which antagonize the inflammatory mediators histamine and leukotrienes; (2) topical or systemic (oral or injectable) corticosteroids or immunosuppressants, which suppress a wide range of inflammatory mechanisms; (3) short- or long-acting bronchodilators, which relax the smooth muscle of the narrowed airways in asthma; (4) mast cell stabilizers, which inhibit mast cell degranulation, normally triggered by IgE binding at the FcεRI; and (5) biologics, which prevent IgE binding at the FcεRI. Attempts have also been made to use peptides that modulate IgE binding to the FcεRI. For example, International Publication No. WO 96 / 01643 describes peptides 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 the treatment or prevention of disorders caused by IgE, particularly disorders caused by the interaction of IgE with the FcεRI receptor. Summary of the Invention

[0006] It has been discovered that compounds of formula (I) and their pharmaceutically acceptable salts can be used for this purpose. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof: [ka] During the ceremony, X and Y independently represent C or N; V and W independently represent C or O; when either V or W represents O, Y represents C; When Y represents N, R1' is absent; When V represents O, R2 is absent; When W represents O, R7 is absent; R1 is Hydrogen; or C(O)NH-C1-6-alkyl; or C(O)NH-heteroaryl; or optionally one or more of oxo; hydroxy; amino; C(O)NH2; C(O)O-C1-6-alkyl; heteroaryl; NH-C1-6-alkyl; NH-C1-6-alkyl-C 3 6-cycloalkyl; optionally one or more R a heteroaryl substituted with NH-heteroaryl substituted with; or C1-6-alkyl-C(O)-C1-6-alkylamino; or C1-6-alkyl-heteroaryl; or C(O)-C1-6-alkyl-heteroaryl; or optionally one or more R1 a NHC(O)-heteroaryl substituted with; or optionally one or more R a NH—C3-8-cycloalkyl substituted with; or optionally one or more R1 a NH-C3-8-heterocycloalkyl optionally substituted with one or more aryl; NHC(O)-C1-6-alkyl substituted with heteroaryl; or NHC(O)-NH-C1-6-alkyl; or NHC(O)O-C1-6-alkyl; or optionally one or more C1-6-alkyl; C(O)-C1-6-alkyl; NH-aryl optionally substituted with heteroaryl substituted with one or more C1-6-alkyl; or SO2-C1-6-alkyl; or SO2-NH-C1-6-alkyl; or NH-SO2-C1-6-alkyl; or NHC(O)-C(O)-heteroaryl optionally substituted with one or more halogen; C1-6-alkyl. represents a group selected from R1 a represents a group selected from the following: hydrogen; halogen; hydroxy; oxo; amino; C1-6-alkyl; C1-6-alkoxy; C(O)O-C1-6-alkyl; C1-6-alkylamino; cyano; C1-6-haloalkyl; C1-6-haloalkoxy; C(O)OH; C3-8-cycloalkyl; Alternatively, R1 is -NH-heteroaryl substituted with one or more groups selected from the following: Hydrogen; R1 b ;Hydroxy;Halogen;Oxo;C1~6-Alkyl;C1~6-Alkoxy;C1~6-Hydroxyalkyl;C1~6-Haloalkyl;C1~6-Alkyl-C(O)OH;C(O)NH2;SO2NH2;S(O)-C1~6-Alkyl;SO2-C1~6-Alkyl;SO2NHC(O)-C1~6-Alkyl;SO2-C1~6-Alkylamino;S(O)(NH)-C1~6-Alkyl;C1~6-Alkyl-C3~ 8-Cycloalkyl;C3~8-Cycloalkyl-C1~6-alkyl;C1~6-alkoxy-C3~8-cycloalkyl;C3~8-Cycloalkyl-C1~6-alkoxy;C1~6-Alkylamino-C3~8-cycloalkyl;C3~8-Cycloalkyl-C1~6-alkylamino;C(O)OH;C(O)O-C1~6-alkyl;C(O)NH-C1~6-alkyl;NHC(O)-C1~6-alkyl;Cyano; or C3-8-heterocycloalkyl optionally substituted with one or more hydroxy; oxo; C1-6-alkyl; or cyano; or heterocycloalkyloxy optionally substituted with one or more of hydroxy; oxo; C1-6-alkyl; C1-6-alkoxy; C3-8-cycloalkyl-C1-6-alkoxy; C(O)NH—C1-6-alkyl; NHSO2—C1-6-alkyl; or heteroaryloxy optionally substituted with one or more of hydroxy; oxo; C1-6-alkyl; C1-6-alkoxy; or heteroarylamino optionally substituted with one or more of hydroxy; oxo; C1-6-alkyl; or C1-6-alkoxy; or SO2-heteroaryl optionally substituted with one or more C1-3-alkyl; oxo; R1 b represents a group selected from the following: heteroaryl optionally substituted with one or more halogen; hydroxy; oxo; C1-6-alkyl; C1-6-alkanediyl-C(O)OH; C(O)NH2; carbamoyl; C(O)O-C1-6-alkyl; S(O)NH-C1-6-alkyl; C3-8-cycloalkyl; heteroarylamino; C1-6-alkoxy; cyano; C1-6-haloalkyl; C1-6-haloalkoxy; C(O)OH; R1' represents hydrogen; C1-3-alkyl; C1-3-hydroxyalkyl; R2 represents a group selected from the following: hydrogen; NHC(O)NH—C1-6-alkyl; hydroxy; R1' and R2 can together form a cyclopropyl ring incorporating V and Y. R1 and R1' can together form a heterocycloalkyl ring optionally substituted with one or more oxo; halogen; C1-6-alkyl; R3 represents a group selected from the following: Possibly R3 a C1-6-alkyl substituted with one or more groups selected from: Possibly one or more R3 a C1-3-alkanediyl-C3-6-cycloalkyl substituted with; Possibly one or more R3 a C1-3-alkanediyl-C3-6-heterocycloalkyl substituted with; Possibly one or more R3 a C3-6-heterocycloalkyl substituted with; Possibly one or more R3 a is a C3-6-cycloalkyl substituted with R3 a represents a group selected from hydrogen, halogen, C1-2-alkyl, hydroxy, and C1-2-alkoxy; R4 represents a group selected from the following: Possibly one or more R4 aC3-6-cycloalkyl substituted with a group; or optionally one or more R4 a C1-6-alkanediyl-C3-6-cycloalkyl substituted with a group; or optionally one or more R4 a C1-6-alkanediyl-C3-6-heterocycloalkyl substituted with a group; R4 a represents a group selected from hydroxy; halogen; and C1-2-alkyl. R5 represents a group selected from the following: hydrogen; hydroxy; halogen; C1-3-alkyl optionally substituted with one or more halogens; C1-3-alkoxy; R6 represents a group selected from the following: hydrogen; halogen; amino; NHC(O)C1-6-alkyl; C1-3-alkyl optionally substituted with one or more halogens; C1-3-alkoxy; R7 represents a group selected from the following: hydrogen; NHC(O)NH—C1-6-alkyl; halogen; hydroxy; R1' and R7 can together form a cyclopropyl ring incorporating W and Y; R8 represents hydrogen, halogen, hydroxy, C1-3 alkyl, or cyclopropyl.

[0008] According to one embodiment, the compounds of the invention are characterized by the formula (wherein R4 represents cyclopropyl or spiro[2.2]pentanyl) substituted with one or more groups, said one or more groups being hydroxy; Chloro, fluoro, bromo; methyl.

[0009] According to one embodiment, the compounds of the invention are characterized by the formula wherein R1', R2, R7 are hydrogen, and the other substituents are defined hereinbefore and hereinafter.

[0010] According to one embodiment, the compounds of the invention are characterized by the formula wherein R4 represents cyclopropyl.

[0011] According to one embodiment, the compounds of the invention are characterized by formula (I), in which R1 represents a group chosen from among: Hydrogen; or C(O)NH-C1-6-alkyl; or C(O)NH-heteroaryl; or optionally one or more of oxo; hydroxy; amino; C(O)NH2; C(O)O-C1-6-alkyl; heteroaryl; NH-C1-6-alkyl; NH-C1-6-alkyl-C 3 6-cycloalkyl; optionally one or more R a heteroaryl substituted with NH-heteroaryl substituted with; or C1-6-alkyl-C(O)-C1-6-alkylamino; or C1-6-alkyl-heteroaryl; or C(O)-C1-6-alkyl-heteroaryl; or optionally one or more R1 a NHC(O)-heteroaryl substituted with; or optionally one or more R a NH—C3-8-cycloalkyl substituted with; or optionally one or more R1 a NH-C3-8-heterocycloalkyl optionally substituted with one or more aryl; NHC(O)-C1-6-alkyl substituted with heteroaryl; or NHC(O)-NH-C1-6-alkyl; or NHC(O)O-C1-6-alkyl; or optionally one or more C1-6-alkyl; C(O)-C1-6-alkyl; NH-aryl optionally substituted with heteroaryl substituted with one or more C1-6-alkyl; or SO2-C1-6-alkyl; or SO2-NH-C1-6-alkyl; or NH-SO2-C1-6-alkyl; or NHC(O)-C(O)-heteroaryl optionally substituted with one or more halogen; C1-6-alkyl; R1 a represents a group selected from the following: It represents hydrogen, halogen, hydroxy, oxo, amino, C1-6-alkyl, C1-6-alkoxy, C(O)O-C1-6-alkyl, C1-6-alkylamino, cyano, C1-6-haloalkyl, C1-6-haloalkoxy, C(O)OH, or C3-8-cycloalkyl.

[0012] According to another embodiment, the compounds of the invention are characterized by formula (I), in which R1 represents -NH-heteroaryl substituted with one or more groups chosen from the following: Hydrogen; R1 b ;Hydroxy;Halogen;Oxo;C1~6-Alkyl;C1~6-Alkoxy;C1~6-Hydroxyalkyl;C1~6-Haloalkyl;C1~6-Alkyl-C(O)OH;C(O)NH2;SO2NH2;S(O)-C1~6-Alkyl;SO2-C1~6-Alkyl;SO2NHC(O)-C1~6-Alkyl;SO2-C1~6-Alkylamino;S(O)(NH)-C1~6-Alkyl;C1~6-Alkyl-C3~ 8-Cycloalkyl;C3~8-Cycloalkyl-C1~6-alkyl;C1~6-alkoxy-C3~8-cycloalkyl;C3~8-Cycloalkyl-C1~6-alkoxy;C1~6-Alkylamino-C3~8-cycloalkyl;C3~8-Cycloalkyl-C1~6-alkylamino;C(O)OH;C(O)O-C1~6-alkyl;C(O)NH-C1~6-alkyl;NHC(O)-C1~6-alkyl;Cyano; or C3-8-heterocycloalkyl optionally substituted with one or more hydroxy; oxo; C1-6-alkyl; or cyano; or heterocycloalkyloxy optionally substituted with one or more of hydroxy; oxo; C1-6-alkyl; C1-6-alkoxy; C3-8-cycloalkyl-C1-6-alkoxy; C(O)NH—C1-6-alkyl; NHSO2—C1-6-alkyl; or heteroaryloxy optionally substituted with one or more of hydroxy; oxo; C1-6-alkyl; C1-6-alkoxy; or heteroarylamino optionally substituted with one or more of hydroxy; oxo; C1-6-alkyl; or C1-6-alkoxy; or optionally one or more C1-3-alkyl; SO2-heteroaryl substituted with oxo; and R1 b is as follows: Heteroaryl optionally substituted with one or more halogen; hydroxy; oxo; C1-6-alkyl; C1-6-alkanediyl-C(O)OH; C(O)NH2; carbamoyl; C(O)O-C1-6-alkyl; S(O)NH-C1-6-alkyl; C3-8-cycloalkyl; heteroarylamino; C1-6-alkoxy; cyano; C1-6-haloalkyl; C1-6-haloalkoxy; or C(O)OH.

[0013] The term "pharmaceutically acceptable salts" according to the present invention encompasses salts, particularly acid addition salts, of compounds of formula (I) with pharmaceutically acceptable acids or bases. Acid addition salt forms of compounds of formula (I) that occur in free form as bases can be obtained by treating the free base with a suitable acid, such as an inorganic acid, e.g., a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or an organic acid, e.g., acetic acid, trifluoroacetic acid, oxalic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.

[0014] The present invention also relates to all stereoisomeric forms, such as enantiomeric and diastereomeric forms, of the compounds of formula (I), or mixtures thereof (including all possible mixtures of stereoisomers, such as racemates). In the context of the present invention, reference to one or more compounds is intended to encompass that compound in each of its possible isomeric forms, and mixtures thereof, unless a particular isomeric form is specifically mentioned.

[0015] Some of the compounds of formula (I) may also exist in tautomeric forms. Such forms, although not explicitly shown in the above formula, are intended to be included within the scope of the present invention.

[0016] It is understood that each individual atom present in formula (I) or in any formula shown herein may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope being preferred.Thus, by way of example, each individual hydrogen atom present in formula (I) or in any formula shown herein may be present as a 1H atom, a 2H (deuterium) atom or a 3H (tritium) atom, preferably as a 1H atom.Similarly, by way of example, each individual carbon atom present in formula (I) or in any formula shown herein may be present as a 12C atom, a 13C atom or a 14C atom, preferably as a 12C atom.

[0017] The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed using common organic solvents or water.

[0018] The present invention also includes within its scope co-crystals of compounds of formula (I) above. The term "co-crystal" is used to describe a situation in which neutral molecular components exist in a crystalline compound in a definite stoichiometric ratio. In the preparation of pharmaceutical co-crystals, the crystalline form of an active pharmaceutical ingredient can be modified, thereby altering the physicochemical properties of the active pharmaceutical ingredient without impairing its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0019] Compounds according to the present invention may exist in different polymorphic forms, and although not explicitly shown in the above formula, such forms are intended to be included within the scope of the present invention.

[0020] The present invention also includes within its scope prodrugs of the compounds of formula (I) above. The term "prodrug" means a compound that is metabolized in vivo to a compound of the present invention or a salt thereof. A prodrug may be identified by administering the prodrug to a mammal, such as a rat, mouse, monkey, or human, and identifying the compound or a salt thereof, for example, in the blood or urine.

[0021] Within the scope of the present invention, Ct-z represents a carbon chain which may have t-z carbon atoms, for example, a C1-7 carbon chain which may have 1-7 carbon atoms. Alkyl is a saturated, linear or branched aliphatic group, for example, a C1-6-alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, hexyl. Alkyl is a group in which one or more hydrogen atoms are replaced by a deuterium atom. 2 Includes deuterated groups replaced with H.

[0022] Alkanediyl is a group of the general formula C, such as -CH-CH- n H 2n is a divalent linear or branched saturated hydrocarbon group of the formula: Alkylamino refers to one or more alkyl groups substituted on an amino radical. Examples of alkylamino include methylamino, ethylamino, tertbutylamino, and dimethylamino. Hydroxy is an -OH group; Hydroxyalkyl is an alkyl group in which one or more hydrogen atoms have been replaced by a hydroxy group; Alkoxy, -O-alkyl groups; Haloalkoxy, -O-haloalkyl groups; halogens, i.e., fluorine, chlorine, bromine or iodine atoms; Haloalkyl refers to an alkyl group substituted with one or more halogen atoms. Examples of haloalkyl include difluoromethyl, fluoroisopropyl, and chloro-tert-butyl. Cycloalkyl refers to a monocyclic or bicyclic aliphatic group containing 3 to 14 atoms, preferably 3 to 10 atoms, in the group, which may contain a non-aromatic double bond. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, spiro-undecanyl, and spiro-[2.2]pentanyl. Heterocycloalkyl refers to a monocyclic or bicyclic saturated group containing 3 to 14 atoms, preferably 3 to 10 atoms, and preferably 3 to 9 atoms, optionally containing a non-aromatic double bond, in which one or more carbon atoms are replaced by an atom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl include aziridinyl, pyrrolidinyl, piperidyl, oxetane, and oxa-spiro-undecanyl. Heterocycloalkyloxy refers to a heterocycloalkyl substituted with an oxygen radical. An example of heterocycloalkyloxy is tetrahydropyranyloxy.

[0023] Aryl refers to a monocyclic or bicyclic aromatic group containing 6 to 14 carbon atoms, in which at least one ring in the group is aromatic. Examples of aryl groups include phenyl and naphthyl groups. Heteroaryl refers to a monocyclic or bicyclic group containing 5 to 14 atoms, in which 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. Heteroarylamino refers to an amino group -NH2 substituted with a heteroaryl group. An example of a heteroaryl group can be pyridinylamino. Heteroaryloxy refers to a heteroaryl group substituted with an oxygen radical. An example of heteroaryloxy is pyridyloxy.

[0024] Another embodiment of the present invention relates to a pharmaceutical composition comprising a detectable amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0025] In yet another embodiment, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt, solvate, or co-crystal thereof, for use as a pharmaceutical, in particular in a method for the treatment or prevention of disorders caused by IgE, including allergies, type 1 hypersensitivity, the well-known sinusitis, urticaria or related conditions, e.g., airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, or increased vascular permeability.

[0026] In a further embodiment, the present invention relates to a method for the treatment or prevention of allergies, type 1 hypersensitivity, common sinusitis, urticaria or related conditions comprising the administration of a therapeutically effective amount of a compound of formula (I).

[0027] In one embodiment, the compound of the 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]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-ylcarbamothioylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]thiourea; 5-methyl-N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(5-methylpyridine-3-carbonyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 6-morpholin-4-yl-N-[trans-(7RS,9RS)-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-9-[(6-morpholin-4-ylpyridine-3-carbonyl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[trans-(7RS,9RS)-9-benzamido-3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]benzamide; 4-(Dimethylamino)-N-[trans-(7RS,9RS)-3-cyclopropyl-9-[[4-(dimethylamino)benzoyl]amino]-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]benzamide; 3,3-Dimethyl-N-[trans-(7RS,9RS)-3-cyclopropyl-9-(3,3-dimethylbutanoylamino)-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]butanamide; 1-Ethyl-3-[trans-(7RS,9RS)-3-cyclopropyl-7-(ethylcarbamoylamino)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]urea; N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-9-(pyridine-3-carbonylamino)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; N-[9-amino-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]pyridine-3-carboxamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(4-oxo-1,5-dihydroimidazo[4,5-c]pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 7-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-2-(2-pyridin-3-ylacetyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-fluoropyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(3,3-difluorocyclobutyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-[(2-oxo-1H-pyridin-4-yl)oxy]pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-[(3-hydroxyoxetan-3-yl)methyl]-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]-N-propan-2-ylpyridine-2-carboxamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(2-methylpyridin-3-yl)-1,2,4-triazol-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(1,2-oxazol-5-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-hydroxy-2-methylpropyl)-7-[(6-methylpyridazin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-5-[(2,2-dimethylcyclopropyl)sulfamoyl]-N-pyridin-3-yl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide; 6-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxamide; 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-(1H-pyrazolo[3,4-c]pyridin-4-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide, formate; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; tert-Butyl 5-[[(7R)-3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylate; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(pyridin-3-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-2-phenylacetamide; 5-[[3-Cyclopropyl-5-(isobutylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid; hydrochloride; 5-[[3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid; 5-Amino-1-[(7S)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]imidazole-4-carboxamide; 7-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-2-(3-pyridylmethyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide; Formic acid; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxopyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(methylsulfamoyl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 6-[[(7R)-3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxamide; N-[5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridin-2-yl]sulfonylacetamide; 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[(1-methyl-2-oxo-4-pyridyl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; formate salt; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-7-[(4,4-dimethyl-3-oxocyclobuten-1-yl)amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 7-Cyclopropyl-9-N-(2-fluoro-2-methylpropyl)-2-N-(2-methylpropyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-2,9-disulfonamide; 7-Cyclopropyl-N-ethyl-9-(2-methylpropylsulfamoyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-carboxamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 7-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-2-(1H-pyrazol-5-ylmethyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide; 3-Cyclopropyl-N-isobutyl-7-(pyridazin-4-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; Formic acid; N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-2-methylpyrazole-3-carboxamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[1-(2-hydroxyethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(2-hydroxyethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 13-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-12-azatetracyclo[8.4.0.03,8.04,6]tetradeca-1(10),2,8,11,13-pentaene-2-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(1-methylpyrazol-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(imidazo[1,2-a]pyrazin-5-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-pyridin-3-yl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(3,3-difluorocyclobutyl)-7-(3-oxo-2-pyridin-3-yl-1H-pyrazol-5-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-hydroxy-2-methylpyrazol-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2,2-dimethylpropyl)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxamide; (7R)-7-(4-acetylanilino)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(4-methyltriazol-1-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(4-methyltriazol-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(1,2,4-triazol-1-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-7-[[6-(difluoromethyl)pyridin-3-yl]amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-7-[[6-chloro-4-(cyclopropylmethoxy)pyridin-3-yl]amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(oxan-4-yloxy)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[5-[[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridin-3-yl]acetamide; 7-[(5-cyanopyridin-3-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-methylsulfonylpyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(1H-tetrazol-5-yl)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[4-(2-methyltetrazol-5-yl)anilino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-7-[[6-chloro-4-(1H-tetrazol-5-yl)pyridin-3-yl]amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-oxo-2H-pyran-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(1-methylpyrazol-3-yl)oxypyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1H-indole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-5-fluoro-1H-indole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1-methylindole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-6-methoxy-1H-indole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-4-methyl-1,3-thiazole-5-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]isoquinoline-1-carboxamide; tert-Butyl 5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamoyl]-1,3-dihydroisoindole-2-carboxylate; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-2-(1-methylpyrazol-4-yl)-2-oxoacetamide; Lithium;4-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]isoquinoline-1-carboxylate; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-(methylsulfinylpyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methyl-6-oxopyridazin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 6-Bromo-N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1H-indazole-3-carboxamide; 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-oxo-2H-furan-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide.

[0028] The following examples demonstrate how compounds encompassed by formula (I) can be synthesized. The examples are provided for illustrative purposes only and are not intended or should not be construed as limiting the invention in any manner. Those skilled in the art will understand that routine variations and modifications of the following examples can be made without departing from the spirit or scope of the invention.

[0029] example The following examples demonstrate how compounds encompassed by Formula I can be synthesized. The examples are provided for illustrative purposes only and are not intended or should not be construed as limiting the invention in any manner. Those skilled in the art will understand that routine variations and modifications of the following examples can be made without departing from the spirit or scope of the present invention.

[0030] Abbreviation DCM dichloromethane THF tetrahydrofuran EtOA ethyl acetate MeCN acetonitrile MeOH Methanol br s wide single line obs observed values hept M mass or molar concentration Brine saturated sodium chloride solution HPLC High Performance Liquid Chromatography LCM Liquid chromatography-mass spectrometry DIPE N,N-Di-iso-propylethylamine RT retention time DMF N,N'-dimethylformamide NaOH Sodium hydroxide TFA trifluoroacetic acid DMSO dimethyl sulfoxide EtOH ethanol sat. saturation aq.water-based tBuXPhos Pd G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'biphenyl)]palladium(II) methanesulfonate Xantphos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate h or hrs hours min IPA Isopropyl Alcohol conc. concentration equiv. equivalent amount SCX Biotage® ISOLUTE® SCX-2 Propyl Sulfonic Acid Functionalized Silica SFC Supercritical Fluid Chromatography DPPA Diphenyl azidophosphate TEA Triethylamine Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Xantphos 4,5-bis((diphenylphosphino)-9,9-dimethylxanthene) AcOH acetic acid AIBN 2,2'-azobis(2-methylpropionitrile) TBME tert-butyl methyl ether LiHMDS Lithium bis(trimethylsilyl)amide SEMCl 2-(chloromethoxy)ethyl-trimethyl-silane Bedford Catalyst Chloro(η 2 -P,C-Tris(2,4-di-tertbutylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) NBS N-Bromosuccinimide BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine TBAB Tetrabutylammonium bromide TBAF Tetrabutylammonium fluoride DIPEA N,N-Diisopropylethylamine tBuOH tert-butanol T3P Propylphosphonic Anhydride Xantphos 4,5-bis((diphenylphosphino)-9,9-dimethylxanthene) DBU 1,8-diazabicyclo[5.4.0]undec-7-ene tBuXPhos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl Pd(OAc)2 Palladium(II) diacetate TMSCl Chlorotrimethylsilane 2-Me-THF 2-methyltetrahydrofuran DMF-DMA N,N-dimethylformamide dimethyl acetal DIBAL-H Diisobutylaluminum hydride EDC-HCl N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0031] LCMS method Method 1: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Column temperature: 40°C Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: flow rate 1 mL / min Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0032] Method 2: Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Phenomenex, Kinetex-XB C18, 2.1 mm x 100 mm, 1.7 μm column Flow rate: 0.6mL / min Column temperature: 40℃ Injection volume: 1μL Gradient: Time (min): %A %B 0.00 95 5 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5 UV 215nM, PDA spectrum 200~400nm, step: 1nm MSD scan positive 150-850

[0033] Method 3: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Column temperature: 40°C Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: flow rate 1 mL / min Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0034] Method 4: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column [From 2019 - Phenomenex Gemini NX-C18 2×20mm, 3μM] 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

[0035] Method 5: Column: Kinetex Core-Shell C18, Part Number 00B-4601-AN, 2.1 x 50 mm, 5 μm Column temperature: 40°C Mobile phase A: Water + 0.1% formic acid Mobile phase B: acetonitrile + 0.1% formic acid Flow rate 1.2ml / min Injection volume 3μl Detection signal UV 215 PDA spectrum range: 210~420nm step: 1nm Gradient Time (min) % Organics 0.00 5 1.20 100 1.30 100 1.31 5

[0036] Method 6: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% 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

[0037] Method 7: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% 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

[0038] Method 8: Column: Kinetex Core-Shell C8, Part Number 00B-4608-AN, 2.1 x 50 mm, 5 μm Column temperature: 40°C Mobile phase A: Water + 0.1% formic acid Mobile phase B: acetonitrile + 0.1% formic acid Flow rate 1.2ml / min Injection volume 3μl Detection signal UV 215 PDA spectrum range: 210~420nm step: 1nm Gradient Time (min) % Organics 0.00 5 1.83 100 2.25 100 2.26 5

[0039] Method 9: Waters UPLC® BEH™ C18, part number 186002352, 2.1 x 100 mm, 1.7 μm Column temperature: 40°C Mobile phase A: 2 mM ammonium bicarbonate, buffered to 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

[0040] Method 10: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% 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

[0041] Method 11: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 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 12: Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% 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

[0043] Method 13: Column: Waters XBridge MS C18 column (3.5 μm, 100 × 4.6 mm) Temperature: 45℃ Injection volume: 5.0μL Flow rate: 1.9→2.4mL / min Detection: Mass spectrometry - positive detection PDA: 210-400nm Solvent A: Water Solvent B: Acetonitrile Solvent D: 630 mg / L ammonium formate in water + 500 μL / L NH4OH 30% (pH approximately 8.5) [Table 1]

[0044] HPLC method HPLC Method 1: Column: XBridge™ Preparative C18 10 um OBD™, 30 x 100 mm, Mobile Phase: 5 to 95% acetonitrile (0.2% ammonium hydroxide) in water (0.2% ammonium hydroxide) over 14 min, Flow Rate: 40 mL / min, UV: 215 and 254 nm

[0045] HPLC Method 2: Column: Sunfire™ Preparative C18 10 um OBD™, 30 x 100 mm; Mobile Phase: 5 to 95% acetonitrile (0.1% formic acid) in water (0.1% formic acid) over 14 min, Flow Rate: 40 mL / min, UV: 215 and 254 nm

[0046] HPLC Method 3: Column: XBridge™ Preparative C18 10 um OBD™, 30 x 100 mm, Mobile Phase: 30 to 95% acetonitrile (0.2% ammonium hydroxide) in water (0.2% ammonium hydroxide) for 10 min, Flow Rate: 40 mL / min, UV: 215 and 254 nm

[0047] General Procedure General Procedure 1 To a solution of amine (1 equiv.), sodium tert-butoxide (3 equiv.), aryl halide (2.5 equiv.), and tBuXPhos Pd G3 (0.15 equiv.) was added anhydrous 1,4-dioxane (20 mL / g). The mixture was degassed with three vacuum / N2 cycles, then sealed and heated to 100 °C with stirring until the reaction was deemed complete by LCMS. The reaction was diluted with EtOAc (20 mL / g) and washed with water (10 mL / g). The aqueous layer was extracted with EtOAc (20 mL / g), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo.

[0048] General Procedure 2 A mixture of amine (1 equiv.), aryl halide (1.5 equiv.), tBuXPhos Pd G3 (0.1 equiv.), and sodium tert-butoxide (3 equiv.) in anhydrous dioxane / tert-butanol (2:1, 30–50 vol.) was sonicated under a stream of nitrogen for 5 min and then stirred at the indicated temperature until the reaction was deemed complete by LCMS. The reaction mixture was diluted with ethyl acetate or DCM (20 mL) and washed with water (10 mL) / saturated aqueous NH4Cl (10 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate or DCM (20 mL). The combined organic layers were washed with saturated aqueous NH4Cl (10 mL), brine (10 mL), and then dried over either magnesium sulfate or sodium sulfate, filtered, and concentrated in vacuo.

[0049] General Procedure 3 Thiourea (1 equiv.) was dissolved in anhydrous DMF (10-20 volumes). Formic hydrazide (3 equiv.) was added, followed by mercuric dichloride (3 equiv.). The reaction was stirred for 5 minutes, after which triethylamine (3 equiv.) was added. The reaction was heated to 90°C with stirring for 1-4 hours. The reaction was allowed to cool, diluted with ethyl acetate (50 mL), and diatomaceous earth was added. The mixture was stirred for 5 minutes, then filtered through diatomaceous earth, washing with ethyl acetate (50 mL). The filtrate was washed with saturated aqueous NH4Cl and brine, then dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography.

[0050] General Procedure 4 The relevant carboxylic acid (1.2 equiv.) was dispensed into a vial containing a solution of DIPEA (2.5 equiv.) and HBTU (1.5 equiv.) in DMF (0.5 mL). The reaction was stirred for 10 minutes, after which a solution of Intermediate 15 (20 mg, 0.053 mmol) in DMF (0.5 mL) was added. The reaction was stirred overnight at ambient temperature, diluted with DCM (2 mL), and washed with water (1 mL). The organic phase was separated and purified using column chromatography.

[0051] Intermediates Intermediate 1 [ka] 2-Chloro-5-(methoxymethoxy)pyridine A solution of 6-chloropyridin-3-ol (34 g, 262 mmol) and chloromethyl methyl ether (42.3 g, 525 mmol) in DCM (300 mL) was stirred in an ice bath, and N,N-diisopropylethylamine (50 mL, 289 mmol) in DCM (50 mL) was added dropwise and stirred for 15 minutes. The reaction mixture was treated with water and stirred for 10 minutes. NaHCO3 (saturated aqueous solution) was then added, and the mixture was stirred for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with NaHCO3 (saturated aqueous solution) and dried (MgSO4). The crude material was purified by column chromatography eluting with a gradient of EtOAc in hexane to give the title compound (40.5 g, 89% yield) as an oil.

number

[0052] Intermediate 2 [ka] [2-chloro-5-(methoxymethoxy)-4-pyridyl]triethyl-silane A solution of Intermediate 1 (17.2 g, 96.1 mmol) in THF (300 mL) was cooled to −40° C. and treated with a solution of n-butyllithium in hexanes (2.5 M, 60 mL, added over 30 min). After stirring for an additional 5 min, triethylchlorosilane (25 mL, 149 mmol) was added and the reaction mixture was allowed to warm to room temperature. The mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (2×200 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give 40 g of the desired product as an impure oil (containing excess silane material).

number

[0053] Intermediate 3 [ka] 6-chloro-4-triethylsilyl-pyridin-3-ol To a solution of intermediate 2 (31 g, 97 mmol) in dioxane (100 mL) was added HCl (4 M in dioxane, 100 mL). The resulting mixture was stirred at room temperature for 16 hours. After this time, a white solid precipitated. The mixture was diluted with diethyl ether (100 mL), and the resulting solid was removed by filtration (washed with ether) and dried under vacuum to give the title compound as a white solid (13.6 g, 50% yield), which was used in the next step without characterization.

[0054] Intermediate 4 [ka] (6-chloro-4-triethylsilyl-3-pyridyl)trifluoromethanesulfonate A solution of intermediate 3 (13.6 g, 48.5 mmol) and DIPEA (21 mL, 120.5 mmol) in DCM (250 mL) was cooled to −78° C. and treated with trifluoromethanesulfonic anhydride (1 M in DCM, 100 mL, 100 mmol, added dropwise). After the addition was complete, the mixture was allowed to warm to room temperature and quenched with NaHCO (saturated aqueous solution, 100 mL). The layers were separated and the aqueous phase was extracted with DCM (100 mL). The combined organic extracts were dried over MgSO, concentrated under reduced pressure, and purified by column chromatography eluting with a gradient of EtOAc in hexanes to give the title compound (17.7 g, 97% yield) as a liquid.

number

[0055] Intermediate 5 [ka] (6-Cyclopropyl-4-triethylsilyl-3-pyridyl)trifluoromethanesulfonate A mixture of Intermediate 4 (28.4 g, 75.6 mmol), cyclopropylboronic acid (16 g, 187 mmol), Pd(OAc) (850 mg, 3.8 mmol), P(tBu) HBF (3.3 g, 11.4 mmol), and KPO (40 g, 188.44 mmol) in a biphasic solution of toluene (300 mL) and water (30 mL) was stirred and heated to reflux for 30 min. The mixture was cooled to room temperature, the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over MgSO, filtered through Celite (rinsing with EtOAc), and concentrated under reduced pressure. Purification by column chromatography eluting with a gradient of EtOAc in hexanes afforded the title compound (26.9 g, 93% yield) as an oil.

number

[0056] Intermediate 6 [ka] Methyl 3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylate A suspension of CsF (35 g, 230.41 mmol), Ni(cod) (2 g, 7.27 mmol), and PPh (8 g, 30.5 mmol) in MeCN (250 mL) was stirred at room temperature under N for 5 min until the yellow solution turned to a dark orange mixture. This mixture was treated with a solution of intermediate 5 (30 g, 78.6 mmol) and methyl 2-(prop-2-yn-1-yl)pent-4-ynoate (17.7 g, 117.8 mmol) in MeCN (250 mL). (The first 25 mL was added immediately, followed by the remaining solution slowly over 10 min.) The resulting mixture was stirred at room temperature under N for 3 h and then passed through a silica gel plug eluting with EtOAc. The solvent was removed under reduced pressure, and the residue was purified by column chromatography eluting with a gradient of EtOAc in hexane to give the title compound (11 g, 51% yield) as a solid.

number

[0057] Intermediate 7 [ka] Methyl 3-cyclopropyl-5-iodo-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylate Intermediate 6 (30 g, 112 mmol) was suspended in anhydrous MeCN (1.2 L) and cooled to 4 °C in an ice bath before adding CFSOH (29 mL, 333 mmol) via a glass addition funnel. The temperature reached 8 °C during the addition. The solution was allowed to warm to 9 °C, and N-iodosuccinimide (37.9 g, 168 mmol) was added in one portion. The dark brown mixture was stirred at room temperature for 20 h. Solid NaCO (35.7 g, 337 mmol) was added and stirred for 30 min. The reaction was repeated with an additional 30 g of starting material. Both batches were filtered through diatomaceous earth and washed with MeCN. The filtrate was concentrated in vacuo to give a brown, sticky solid. 10% aqueous sodium thiosulfate solution (1 L) was added to the solid and stirred for 5 min. DCM (1 L) was added, and the mixture was separated. The aqueous layer was extracted with DCM (2 x 500 mL), and the organics were combined, dried over magnesium sulfate, and concentrated in vacuo. This material was purified by dry flash column chromatography eluting with ethyl acetate in DCM to afford the title compound (69 g, 74% yield).

number

[0058] Intermediate 8 [ka] Methyl 5-benzylsulfanyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylate Intermediate 7 (69 g, 168 mmol, 95% purity) was stirred in anhydrous dioxane (500 mL). DIPEA (87 mL, 500 mmol), Xantphos (5.8 g, 10 mmol), Pd(dba) (4.6 g, 5 mmol), and benzyl mercaptan (25 mL, 217 mmol) were added. The reaction was heated to 100 °C with stirring for 1 hour 45 minutes. The reaction was cooled to room temperature, filtered through diatomaceous earth, and washed with DCM. The filtrate was concentrated in vacuo and purified by dry flash using ethyl acetate in heptane to give the title compound (75.3 g, estimated quantitative, 86% purity).

number

[0059] Intermediate 9 [ka] 5-Benzylsulfanyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid hydrochloride Intermediate 8 (75.3 g, 166 mmol, 86% purity), THF (700 mL), and 2M aqueous LiOH (250 mL) were mixed at 50° C. for 1 hour. Water (500 mL) was added, and the THF was removed under vacuum. The resulting aqueous solution was acidified with 3M aqueous HCl (350 mL), then cooled in an ice bath, and the solid was collected by vacuum filtration. The solid was washed with 1M aqueous HCl, then with ether (4×500 mL), transferred to a flask using MeCN, and concentrated under vacuum to give the title compound (140 g, estimated quantitative, 45% purity, wet with MeCN and water) as the HCl salt. LCMS [M+H] + 376.2, retention time 1.80 minutes (method 1).

[0060] Intermediate 10 [ka] 5-Chlorosulfonyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid hydrochloride Intermediate 9 (62.4 g, 166 mmol) was stirred in MeCN (700 mL), acetic acid (50 mL, 873 mmol), and water (15 mL, 833 mmol) until a suspension was obtained. The mixture was cooled in an ice bath, and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (65.5 g, 332 mmol) was added in one portion. The suspension was stirred for 1 hour while warming to room temperature. The solid was collected by vacuum filtration, washed with MeCN, followed by ether (2×250 mL), and dried in a vacuum oven at 50° C. to give the title compound (64 g, 100% at 91% purity) as the HCl salt. LCMS was quenched with isobutylamine to give [M+H]. + 389.2, retention time 1.73 min was obtained (Method 1).

[0061] Intermediate 11 [ka] 3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid hydrochloride 2-Fluoro-2-methylpropan-1-amine hydrochloride (25.5 g, 200 mmol) was stirred in DCM (700 mL) and DIPEA (116 mL, 666 mmol) was added. Intermediate 10 (64 g, 166 mmol, 91% purity) was added slowly in small portions over 1 hour. The reaction was stirred for 30 minutes and concentrated under vacuum. 1 M aqueous HCl (1 L) was added and the mixture was stirred for 30 minutes, resulting in a brown suspension. The solid was collected by vacuum filtration and washed with 1 M aqueous HCl to give a brown solid. 1 M aqueous NaOH (600 mL) and 4 M aqueous NaOH (200 mL) were added and washed with ethyl acetate (2 × 250 mL). The organic layers were combined and extracted with 2 M aqueous NaOH (2 × 200 mL). The insoluble solid was removed by filtration. The combined aqueous layers were acidified with 6 M aqueous HCl to give a thick white suspension, which was collected by vacuum filtration. The solid was transferred to a flask with water, and further 3 M aqueous HCl was added to break up the clumps. The solid was collected by filtration and washed with a small amount of water, followed by diethyl ether (2 x 250 mL). The solid was dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (55.5 g, 82%).

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[0062] Intermediate 12 [ka] 7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 11 (45.5 g, 112 mmol) was stirred in anhydrous THF (500 mL). Triethylamine (39 mL, 280 mmol) and DPPA (29.4 mL, 137 mmol) were added. The reaction was heated to 75° C. with stirring for 1 hour 45 minutes. The reaction was cooled in an ice bath and added to 3 M aqueous HCl (550 mL) at 0° C. The brown solution was stirred at room temperature for 1 hour 15 minutes. The aqueous solution was washed with ethyl acetate (450 mL, then 4×200 mL) to remove diphenyl phosphate, and then 4 M aqueous NaOH (400 mL) followed by 1 M aqueous NaOH (200 mL) was added. The product was extracted with ethyl acetate (3×300 mL), dried over sodium sulfate, and concentrated in vacuo. This material was combined with a previous 10 g batch and purified by dry flash chromatography and column chromatography using MeOH in DCM to give the title compound (36 g, 66% yield at 95% purity).

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[0063] Intermediate 13 and Intermediate 14 [ka] tert-Butyl N-[(7S)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate (13) tert-Butyl N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate (14) Intermediate 12 (29.5 g, 74.2 mmol, 95% purity), di-tert-butyl dicarbonate (17.8 g, 81.7 mmol), and triethylamine (10.4 mL, 74.2 mmol) were stirred in DCM (500 mL) at room temperature for 2.5 h, and then additional di-tert-butyl dicarbonate (250 mg) was added and stirred for 30 min. The reaction was washed with water (2 × 200 mL) and brine (50 mL), then dried over sodium sulfate and concentrated in vacuo to give a brown foam. Diethyl ether was added, and upon standing, a white precipitate formed which was collected by filtration and washed with ether. The filtrate was concentrated in vacuo and triturated twice with diethyl ether. The combined solids were dried in a vacuum oven to give the title compound as a racemic mixture (34.9 g, 98%).

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[0064] The mixture of enantiomers (34.9 g) was purified by supercritical fluid LC using a CHIRALPAK IA column (50 x 266 mm) at 30 °C and eluted with 20% IPA in CO2 to give the title compound.

[0065] Intermediate 13 (16.0 g); Chiral retention time** 1.92 min (see methods below).

[0066] Intermediate 14 (15.8 g); Chiral retention time** 1.73 min (see methods below). **Analytical chiral HPLC was performed using a CHIRALPAK IB column (4.6 x 150 mm) eluted with 50% IPA, 50% n-heptane, 0.1% DEA at 30°C at a rate of 1.5 mL / min.

[0067] Intermediate 15 [ka] (7R)-7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a stirred solution of Intermediate 14 (15.6 g, 32.7 mmol) in DCM (160 mL) cooled in an ice bath was added trifluoroacetic acid (25.2 mL, 327 mmol). The reaction was stirred at room temperature for 22 h. The mixture was cooled in an ice bath and then basified to pH 12 with 4 M aqueous NaOH (80 mL) followed by 1 M aqueous NaOH (approximately 120 mL). The layers were separated, and the aqueous phase was extracted with a mixture of CHCl3:IPA (3:1, 2 × 150 mL). The layers were separated, and the aqueous layer was adjusted to pH 10 with 1 M aqueous HCl and then extracted with CHCl3:IPA (3:1, 2 × 100 mL). The layers were separated, and the aqueous layer was adjusted to pH 8-9 with 1 M aqueous HCl and then extracted again with CHCl3 / IPA (3:1, 2 × 100 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (11.7 g, 95%).

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[0068] Intermediate 16 [ka] 2-Hydroxyimino-5,6-dimethyl-indan-1-one To a solution of 5,6-dimethyl-2,3-dihydro-1H-inden-1-one (5.0 g, 31.21 mmol) in ether (82 mL) was added dropwise first saturated HCl in ethanol (1.30 mL), then 15% ethanolic solution of ethyl nitrite (28.0 mL, 44.32 mmol) at 0° C. After 30 min at 0° C., the precipitated product was collected by filtration, washed with ether, and dried. The crude title compound (5.2 g, 83%) was used in the next step without further purification. LCMS [M+H] + 190, retention time 1.70 minutes (method 1).

[0069] Intermediate 17 [ka] 1,3-Dichloro-6,7-dimethyl-isoquinoline To a suspension of intermediate 16 (5.2 g, 26.1 mmol) in POCl3 (157.7 mL) was added PCl5 (5.98 g, 28.72 mmol) at 0 °C. Gaseous HCl was then introduced until the solution was saturated, and the reaction was stirred at 60 °C for 4 h. A second portion of PCl5 (1.9 g) was added, and stirring was continued at 80 °C for 2 h. After evaporation of the solvent, water was added, and the precipitate was collected by filtration, washed with water, and dried to give the title compound (5.9 g, 99%), which was used in the next step without further purification. LCMS [M+H] + 226, retention time 3.22 minutes (method 3).

[0070] Intermediate 18 [ka] 3-chloro-6,7-dimethyl-isoquinoline A mixture of intermediate 17 (5.9 g, 26.0 mmol), red phosphorus (1.94 g, 62.63 mmol) and HI (57%) (11.7 mL, 88.7 mmol) in AcOH (32 mL) was heated at 110° C. for 6 h. The hot reaction mixture was filtered and evaporated under pressure. The residue was dissolved in water and basified by the addition of concentrated aqueous NHOH. The precipitate was collected by filtration, then dissolved in DCM, washed with brine, dried over MgSO, and evaporated under pressure. Purification by column chromatography eluting with 8% to 50% EtOAc in heptane gave the title compound (3.8 g, 76%). LCMS [M+H] + 192, retention time 1.86 minutes (method 1).

[0071] Intermediate 19 [ka] 5-Bromo-3-chloro-6,7-dimethyl-isoquinoline Intermediate 18 (1.0 g, 5.22 mmol) was added batchwise to sulfuric acid (5.79 mL) in DCM (50 mL) at 0 °C. The reaction mixture was cooled to -10 °C, and N-bromosuccinamide (1.02 g, 5.7 mmol) was added portionwise. The reaction mixture was maintained at -10 °C for 1 h and then stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (100 mL), and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with DCM (2 × 50 mL), and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by column chromatography eluting with 5% → 30% EtOAc in heptane to give the title compound (1.08 g, 76%). LCMS [M+H] + 270 / 272, retention time 3.12 minutes (method 3).

[0072] Intermediate 20 [ka] 5-Bromo-6,7-bis(bromomethyl)-3-chloro-isoquinoline Intermediate 19 (1.1 g, 4.06 mmol) was dissolved in EtOAc (25 mL). N-Bromosuccinimide (1.6 g, 0.77 mmol) was then added, followed by AIBN (66.76 mg, 0.40 mmol). The reaction mixture was refluxed at 90° C. for 5 h. Additional N-Bromosuccinimide (1.5 equiv.) and a catalytic amount of AIBN were added, and the reaction mixture was heated at reflux for an additional 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with aqueous NaSO, water, and brine. The solution was dried over MgSO and concentrated under reduced pressure to give the crude product, which was purified by column chromatography eluting with 0% to 20% EtOAc in heptane to give the title compound (647 mg, 37%). LCMS [M+H] + 428 / 430, retention time 3.17 minutes (method 3).

[0073] Intermediate 21 [ka] 9-Bromo-7-chloro-2-trityl-1,3-dihydropyrrolo[3,4-g]isoquinoline Intermediate 20 (565 mg, 1.31 mmol), tritylamine (410 mg, 1.58 mmol), and N,N-diisopropylethylamine (574 mL, 3.29 mmol) in anhydrous DMF (14 mL) were stirred at 70° C. for 5 hours. After removing the solvent in vacuo, the residue was diluted to 15 mL with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous MgSO and filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography eluting with hexane / EtOAc (9:1) to give the title compound (693 mg, 71%). LCMS [M+H] + 525 / 527, retention time 2.61 minutes (method 1).

[0074] Intermediate 22 [ka] 9-Bromo-7-chloro-2,3-dihydro-1H-pyrrolo[3,4-g]isoquinoline Intermediate 21 (504 mg, 0.93 mmol) was dissolved in 5% CF3CO2H in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 30 min, then diluted to 10 mL with EtOH and stirred for an additional 15 min. It was evaporated to dryness under reduced pressure to give the crude product, which was diluted with DCM (50 mL) and washed with saturated NaHCO3. The aqueous layer was extracted with a 1:1 mixture of IPA and CHCl3 (3 x 30 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the crude title compound (305 mg, 97%, 85% pure), which was used in the next step without further purification. LCMS [M+H] + 283 / 285, retention time 1.30 minutes (method 1).

[0075] Intermediate 23 [ka] 1-(9-Bromo-7-chloro-1,3-dihydropyrrolo[3,4-g]isoquinolin-2-yl)-2,2,2-trifluoroethanone Intermediate 22 (220 mg, 0.77 mmol) was dissolved in THF (15 mL), and then NaHCO (97.7 mg, 1.16 mmol) was added, followed by trifluoroacetic anhydride (130.3 μL, 0.93 mmol). The solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (50 mL), washed with water (2×40 mL), dried over MgSO, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 5%→50% EtOAc in heptane to give the title compound (140 mg, 48%). LCMS [M+H] + 379 / 381, retention time 1.97 minutes (method 1).

[0076] Intermediate 24 [ka] 1-(9-benzylsulfanyl-7-chloro-1,3-dihydropyrrolo[3,4-g]isoquinolin-2-yl)-2,2,2-trifluoroethanone A flask was charged with Intermediate 23 (4.32 g, 11.38 mmol), phenylmethanethiol (1.33 mL, 11.4 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (395.1 mg, 0.68 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) (313 mg, 0.34 mmol), and DIPEA (4 mL, 22.7 mmol) in dioxane (200 mL). The mixture was flushed with nitrogen for 10 minutes and heated at 85° C. for 16 hours. After cooling to room temperature, the solvent was removed and DCM followed by water was added. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a yellow solid which was purified by column chromatography eluting with 10% to 50% EtOAc to give the title compound (4.48 g, 84%). LCMS [M+H] + 423, retention time 2.08 minutes (method 1).

[0077] Intermediate 25 [ka] 7-chloro-2-(2,2,2-trifluoroacetyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonyl chloride Intermediate 24 (5.1 g, 12.06 mmol) was dissolved in MeCN (120 mL) and cooled to 0 °C. Water (3 mL) and AcOH (4.5 mL) were added, followed by 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (4.75 g, 24.12 mmol, portionwise), and stirring was continued at 0 °C for 1 h. The reaction mixture was concentrated to near dryness under vacuum (bath temperature ca. 20 °C). The crude product was diluted with CHCl (150 mL), and the solution was cooled to ca. 0 °C. 5% aqueous NaHCO (166 mL) was added slowly at <10 °C. The mixture was stirred at 0–5 °C for 15 min, and the lower organics were washed once more with water at <10 °C. The lower organics were dried over MgSO4, filtered and concentrated to dryness (bath temperature ca. 20°C) to give the crude title compound (5.23g, 73%, 67% purity) which was used in the next step without further purification. LCMS [M+H] + 399, retention time 1.95 minutes (method 1).

[0078] Intermediate 26 [ka] 7-chloro-N-(2-fluoro-2-methyl-propyl)-2-(2,2,2-trifluoroacetyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide A premixed solution of 2-fluoro-2-methylpropan-1-amine hydrochloride (2.3 g, 18.09 mmol) and DIPEA (6.3 mL, 36.18 mmol) in DCM (75 mL) was added dropwise to the crude reaction mixture of Intermediate 25 (4.8 g, 12.06 mmol) in DCM (75 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes and then diluted with DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (50 mL x 2), and the combined organics were washed with water, dried (NaSO), filtered, and concentrated under reduced pressure. Purification by column chromatography eluting with 30% → 80% EtOAc in heptane gave the title compound (3.15 g, 56%). LCMS [M+H] +454, retention time 1.84 minutes (method 1).

[0079] Intermediate 27 [ka] 7-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-2,3-dihydro-1H-pyrrolo[3,4-g]isoquinoline-9-sulfonamide To a mixture of Intermediate 26 (1.2 g, 1.58 mmol, 60% pure), cyclopropylboronic acid (0.409 g, 4.75 mmol), and CsCO (1.5 g, 4.75 mmol) in nitrogen-flushed dioxane (20 mL) was added Bedford Catalyst (169.4 mg, 0.159 mmol). The reaction mixture was heated to 110 °C for 16 h and then diluted with DCM (150 mL). The solution was dried over MgSO, filtered through Celite, and washed with DCM and a 1:1 mixture of DCM and MeOH. The solution was concentrated under reduced pressure and purified by column chromatography eluting with 0 to 30% MeOH in DCM to give the title compound (285 mg, 46%). LCMS [M+H] + 364, retention time 1.46 minutes (method 1).

[0080] Intermediate 28 [ka] 7-chloro-N-isobutyl-2-(2,2,2-trifluoroacetyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide Intermediate 24 (50 mg, 0.11 mmol) was dissolved in DCM (4 mL) and cooled to 0 °C. Water (12.7 μL), AcOH (33.8 μL), and SO2Cl2 (47.7 μL, 0.59 mmol) were added, and stirring was continued at 0 °C for 5 min and at room temperature for 1 h. The reaction mixture was cooled to 0 °C, and excess isobutylamine (94 μL, 0.94 mmol) was added and stirred at room temperature for 1 h. The reaction was diluted with water (10 mL). The aqueous phase was extracted with DCM (10 mL × 2), and the combined organics were washed with water, dried (Na2SO4), filtered, and concentrated to give the crude product. The crude was purified by column chromatography eluting with 50% → 100% EtOAc to give the title compound (18 mg, 35%). LCMS [M+H] + 436, retention time 1.91 minutes (method 1).

[0081] Intermediate 29 [ka] 7-Cyclopropyl-N-isobutyl-2-(2,2,2-trifluoroacetyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide A mixture of intermediate 28 (18 mg, 0.041 mmol), cyclopropylboronic acid (8.8 mg, 0.10 mmol), Pd(OAc) (0.46 mg, 2.0 μmol), P(Cy) HBF (2.2 mg, 6.19 μmol), and KPO (21.9 mg, 0.10 mmol) in a mixture of toluene (1 mL) and water (0.05 mL) was heated at 120 °C for 2 h. The mixture was then diluted with DCM (5 mL), dried over MgSO, filtered through Celite, and washed with DCM. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography eluting with 12→50% EtOAc / heptane to give the title compound (13 mg, 71%). LCMS [M+H] + 442, retention time 1.94 minutes (method 1).

[0082] Intermediate 30 [ka] 1,3-Benzodioxole-5-carbaldehyde To a solution of 3,4-dihydroxybenzaldehyde (2 g, 14.48 mmol) in DMF (30 mL) was added cesium carbonate (7.08 g, 20.17 mmol) and dibromomethane (3.78 g, 20.17 mmol). The mixture was heated at 110° C. for 2 h. Water (70 mL) was then added, followed by EtOAc (40 mL). The organic layer was separated, washed with water (2×20 mL), followed by brine (10 mL), and passed through a phase separator frit. The solvent of the filtrate was removed, and the resulting oil was purified by flash column chromatography eluting with a gradient of 0 to 40% EtOAc in heptane to give the title compound as a white solid (2.17 g, 100% yield). LCMS [2M-H] - 299, retention time 1.13 minutes (method 4).

[0083] Intermediate 31 [ka] 6-Bromo-1,3-benzodioxole-5-carbaldehyde To a solution of intermediate 30 (2170 mg, 14.5 mmol) in acetic acid (10 mL) was added bromine (2.4 g, 15.0 mmol). The solution was stirred for 5 hours, after which bromine (2.4 g) was added. The solution was stirred for an additional 18 hours. The solvent was removed and the oil was preabsorbed onto silica. Purification by flash column chromatography eluting with a gradient of 0 to 20% EtOAc in heptane gave the title compound (1.1 g, 33% yield) as a pale yellow solid and a 2:1 mixture of intermediate 31 and intermediate 30 (2.67 g). LCMS [M+H] + 228 / 230, retention time 1.81 minutes (method 4).

[0084] Intermediate 32 [ka] 6-(2-cyclopropylethynyl)-1,3-benzodioxole-5-carbaldehyde To a solution of intermediate 31 (200 mg, 0.87 mmol) in THF (2.5 mL) was added cyclopropylacetylene (71.4 mg, 1.05 mmol), triethylamine (177 mg, 1.75 mmol), cuprous iodide (8.35 mg, 0.044 mmol), and bis(triphenylphosphine)palladium(II) dichloride (18.4 mg, 0.026 mmol). The mixture was placed under a nitrogen atmosphere and heated at 50° C. for 18 hours. The reaction was cooled and the solvent removed to give a brown oil. The oil was purified by flash column chromatography eluting with a gradient of 0 to 20% EtOAc in heptane to give the title compound as an off-white solid (90 mg, 48% yield). LCMS [M+H] + 215, retention time 2.26 minutes (method 4).

[0085] Intermediate 33 [ka] 7-Cyclopropyl-[1,3]dioxolo[4,5-g]isoquinoline To a suspension of Intermediate 32 (90 mg, 0.42 mmol) in tert-butanol (4 mL) was added ammonium acetate (81 mg, 1.05 mmol) and silver nitrate (7.14 mg, 0.042 mmol). The mixture was placed under a nitrogen atmosphere and heated at 35° C. for 1.5 h. The solvent was removed and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO (10 mL). The organic layer was separated, washed with brine (10 mL), dried (MgSO), and the solvent removed to give an oil. The oil was purified by flash column chromatography eluting with a gradient of 0 to 25% EtOAc in heptane to give the title compound as a light brown solid (70 mg, 78% yield). LCMS [M+H] + 214, retention time 1.97 minutes (method 4).

[0086] Intermediate 34 [ka] 5-Bromo-2-methylsulfinyl-pyridine Sodium periodate (4.2 g, 20 mmol) was added as a slurry in water (4 mL) to a stirred solution of 5-bromo-2-methylthiopyridine (1 g, 4.8 mmol) in glacial AcOH (25 mL, 436 mmol) at 0 °C. Upon completion of the addition, the ice bath was removed, and the mixture was stirred at room temperature for 3.5 h. The mixture was treated with water (50 mL) and basified by the addition of solid potassium carbonate powder. The reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were then washed with 10% aqueous sodium thiosulfate solution (50 mL), dried over NaSO, and concentrated in vacuo. The resulting crude oil was purified by column chromatography to afford the title compound (838 mg, 80% yield).

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[0087] Intermediate 35 [ka] Methyl 3-cyclopropyl-7-(hydroxymethyl)-5-iodo-6,8-dihydrocyclopenta[g]isoquinoline-7-carboxylate hydrochloride Intermediate 82 (72%, 9 g, 12.5 mmol) was stirred in MeOH (200 mL) and 12 M aqueous HCl (27 mL) was added. The reaction was heated to 75° C. with stirring for 18 h, then 12 M aqueous HCl (10 mL) was added and the reaction was stirred at 75° C. for a further 24 h. The suspension was concentrated to 25% volume and the solid was collected by vacuum filtration and washed with a small amount of methanol followed by TBME to give the title compound (7.28 g, 62% over two steps). LCMS [M+H] +424.0, retention time 1.82 minutes (method 1).

[0088] Intermediate 36 [ka] Methyl 3-cyclopropyl-5-iodo-7-(p-tolylsulfonyloxymethyl)-6,8-dihydrocyclopenta[g]isoquinoline-7-carboxylate To a solution of Intermediate 35 (7.28 g, 17.2 mmol) in pyridine (50 mL) was added 4-methylbenzenesulfonyl chloride (6.56 g, 34.4 mmol) in portions, and the reaction was heated to 80 °C for 2.5 h. The reaction was allowed to cool to room temperature, quenched with saturated aqueous NH4Cl (100 mL), and then extracted with ethyl acetate (200 mL, then 100 mL). The combined organics were washed with saturated aqueous NH4Cl (100 mL), water (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (30 mL). The organics were then dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography using ethyl acetate in heptane afforded the title compound (7.94 g, 76% at 95% purity).

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[0089] Intermediate 37 [ka] Methyl 13-cyclopropyl-2-iodo-12-azatetracyclo[8.4.0.0^{3.8}.0^{4,6}]tetradeca-1(10),2,8,11,13-pentaene-6-carboxylate Intermediate 36 (7.94 g, 13.8 mmol) was dissolved in anhydrous THF (100 mL) and cooled to −78° C. 1 M LiHMDS in THF (27.5 mL) was added dropwise, and the reaction was stirred at −78° C. for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and water (50 mL). The reaction was extracted with ethyl acetate (200 mL, then 100 mL), and the organics were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography using ethyl acetate in heptane afforded the title compound (5.04 g, 86% at 95% purity).

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[0090] Intermediate 38 [ka] Methyl 2-benzylsulfanyl-13-cyclopropyl-12-azatetracyclo[8.4.0.0^{3.8}.0^{4,6}]tetradeca-1(10),2,8,11,13-pentaene-6-carboxylate Intermediate 37 (95%, 5.04 g, 11.8 mmol) was stirred in anhydrous dioxane (70 mL). Xantphos (410 mg, 0.71 mmol), Pd2(dba)3 (324 mg, 0.354 mmol), and DIPEA (6.17 mL, 35.5 mmol) were added, followed by benzyl mercaptan (1.8 mL, 15.4 mmol). The reaction was heated to 100 °C with stirring for 1 hour and 15 minutes. The reaction was cooled to room temperature, filtered through diatomaceous earth, and washed with DCM. The filtrate was concentrated, and the residue was purified by dry flash using ethyl acetate in heptane to give the title compound (4.46 g, 94%).

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[0091] Intermediate 39 [ka] 2-Benzylsulfanyl-13-cyclopropyl-12-azatetracyclo[8.4.0.0^{3.8}.0^{4,6}]tetradeca-1(10),2,8,11,13-pentaene-6-carboxylic acid hydrochloride To a solution of intermediate 38 (4.46 g, 11.1 mmol) in THF (50 mL) was added 2 M aqueous LiOH (16.7 mL). The reaction was stirred at 50° C. for 1 hour, then at room temperature for 3 days. The reaction was diluted with water (15 mL) and the THF was removed in vacuo. 1 M aqueous HCl (30 mL) was added to the residue, forming an orange gum. Further 6 M aqueous HCl (1 mL) was added, followed by TBME, which was then removed in vacuo to give a fine suspension in the aqueous layer. The solid was collected by vacuum filtration and washed with 1 M aqueous HCl (30 mL), water (20 mL), and then TBME (30 mL) to give the title compound (4.86 g, quantitative). LCMS [M+H] + 388.00, retention time 1.05 minutes (method 5).

[0092] Intermediate 40 [ka] 2-Chlorosulfonyl-13-cyclopropyl-12-azatetracyclo[8.4.0.0^{3.8}.0^{4,6}]tetradeca-1(10),2,8,11,13-pentaene-6-carboxylic acid Intermediate 39 (97%, 4.86 g, 11.1 mmol) was stirred in MeCN (50 mL) and cooled in an ice bath. Water (1 mL, 55.6 mmol), acetic acid (3.18 mL, 55.6 mmol), and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (4.38 g, 22.2 mmol) were added. The suspension was stirred for 40 minutes while warming to room temperature. The reaction was filtered under vacuum, and the solid was washed with MeCN to give the title compound (3.96 g, 97%). LCMS [M+H] +363.95, retention time 1.16 minutes (method 5).

[0093] Intermediate 41 [ka] 13-Cyclopropyl-2-(2-methylpropylsulfamoyl)-12-azatetracyclo[8.4.0.0^{3.8}.0^{4,6}]tetradeca-1(10),2,8,11,13-pentaene-6-carboxylic acid hydrochloride 2-Methylpropan-1-amine (3.69 mL, 37.1 mmol) was dissolved in DCM (50 mL) and Intermediate 40 (2.7 g, 7.42 mmol) was added portionwise. The reaction was stirred for 5 minutes and then concentrated in vacuo. Water (20 mL) was added to the residue, followed by 1 M aqueous HCl (10 mL). A white gum formed, and additional 6 M aqueous HCl (3 mL) was added, followed by TBME (20 mL). The mixture was partially concentrated under vacuum at 40 °C to remove the TBME, resulting in a pure solid suspension. The solid was collected by vacuum filtration and washed with 1 M aqueous HCl (20 mL), water (20 mL), and TBME (20 mL). The solid was dried in a vacuum oven at 50 °C for 16 hours to give the title compound (2.84 g, 84%).

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[0094] Intermediate 42 [ka] 5-Benzylsulfanyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-amine Intermediate 9 (10 g, 26.6 mmol) was stirred in anhydrous THF (100 mL). Triethylamine (9.28 ml, 66.6 mmol) was added, followed by DPPA (5.74 mL, 26.6 mmol), and the reaction was heated at 75° C. for 2 hours. The reaction was cooled in an ice bath and slowly added to 2 M aqueous NaOH (200 mL) at 0° C. The reaction was stirred for 5 minutes and then extracted with ethyl acetate (2×200 mL). Insoluble material was removed by filtration, and the filtrate was dried over sodium sulfate and concentrated under vacuum. The solid was slurried in DCM, filtered, and the filtrate was concentrated under vacuum to give the title compound (9.4 g), which was used crude in the next step. LCMS [M+H] + 346.9, retention time 0.91 min (method 5).

[0095] Intermediate 43 [ka] Benzyl N-(5-benzylsulfanyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl)carbamate Intermediate 42 (9.4 g, 27.1 mmol) was stirred in DCM (100 mL), triethylamine (9.45 mL, 67.8 mmol) was added, followed by 1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (6.76 g, 27.1 mmol), and the reaction was stirred for 40 minutes. Further 1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (1.2 g, 4.81 mmol) was added, and the reaction was stirred for 15 minutes. The reaction was washed with water (2 × 100 mL), brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography using ethyl acetate in heptane, and the resulting solid was triturated with diethyl ether and then ethyl acetate in heptane. Purification by column chromatography using ethyl acetate in heptane gave the title compound (5.6 g, 43% yield over two steps).

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[0096] Intermediate 44 [ka] Benzyl N-(5-chlorosulfonyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl)carbamate To a suspension of Intermediate 43 (1 g, 2.08 mmol) in acetonitrile (25 mL) was added acetic acid (596 μL, 10.4 mmol) and water (187 μL, 10.4 mmol). The mixture was cooled to 0° C. in an ice bath. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (820 mg, 4.16 mmol) was added and the reaction was stirred at 0° C. for 5 minutes. The bath was removed and the reaction was stirred at room temperature under a nitrogen atmosphere for 40 minutes. The white precipitate was filtered off, washed with acetonitrile, and dried under high vacuum for 30 minutes to give the title compound (960 mg, quantitative). LCMS [M+H] + 457, retention time 1.37 minutes (method 5).

[0097] Intermediate 45 [ka] Benzyl N-[3-cyclopropyl-5-[(3-hydroxyoxetan-3-yl)methylsulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate To a stirred solution of 3-(aminomethyl)oxetan-3-ol (120 mg, 1.16 mmol) and DIPEA (549 μL, 3.15 mmol) in anhydrous DCM (10 mL), Intermediate 44 (480 mg, 1.05 mmol) was added in one portion, and the resulting solution was stirred under a nitrogen atmosphere for 15 h. The reaction mixture was diluted with a mixture of DCM and MeOH (3:1, 20 mL, respectively) and washed with water (10 mL) followed by saturated NH4Cl solution (10 mL). The layers were separated, and the aqueous layer was further extracted with a mixture of DCM and MeOH (3:1, 20 mL, respectively). The combined organics were washed with brine (10 mL), then dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography eluting with a gradient of ethyl acetate in heptane followed by a gradient of methanol in ethyl acetate to give the title compound (403 mg, 73% yield). LCMS [M+H] + 524, retention time 1.75 minutes (method 1).

[0098] Intermediate 46 [ka] 7-Amino-3-cyclopropyl-N-[(3-hydroxyoxetan-3-yl)methyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a stirred suspension of Intermediate 45 (403 mg, 0.77 mmol) in methanol (30 mL) was added 10% palladium on charcoal (50% wet, 230 mg, 0.11 mmol) and the mixture was stirred under 1 atmosphere of hydrogen for 3 hours to give a solution. 10% palladium on charcoal (50% wet, 160 mg, 0.075 mmol) was added and the solution was stirred under 1 atmosphere of hydrogen for an additional 3 hours. The reaction was filtered through Celite, washed with methanol, and the filtrate was concentrated to dryness to give the title compound (284 mg, 95% yield). LCMS [M+H] + 390, retention time 1.25 minutes (method 1).

[0099] Intermediate 47 [ka] 2-Hydroxyimino-3,5,6,7-tetrahydro-s-indacen-1-one To a solution of 3,5,6,7-tetrahydro-2H-s-indacen-1-one (1.00 g, 5.81 mmol) in diethyl ether (18 mL) at +5° C. was introduced hydrogen chloride (0.22 mL of a saturated ethanolic solution), followed by the dropwise addition of ethyl nitrite (5.12 mL of a 15% solution in ethanol, 10.24 mmol). The solution was cooled to 0° C. for 30 minutes, and the resulting precipitate was collected by filtration. The filter cake was washed with diethyl ether and then dried on the filter to give the title product (0.571 g, 46% yield).

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[0100] Intermediate 48 [ka] 1,3-Dichloro-7,8-dihydro-6H-cyclopenta[g]isoquinoline Phosphorus pentachloride (0.67 g, 3.20 mmol) was introduced to a solution of intermediate 47 (0.570 g, 2.67 mmol) in phosphoryl chloride (28 g) at 0° C. under a nitrogen atmosphere. Gaseous hydrogen chloride was then slowly bubbled through the reaction mixture for 5 minutes. The reaction was warmed to 60° C. under a nitrogen atmosphere for 4 hours, then cooled to room temperature and re-treated with phosphorus pentachloride (0.22 g, 1.05 mmol). After warming to 80° C. for 2 hours, the reaction mixture was concentrated in vacuo and the residue was quenched with water (20 mL). The resulting mixture was subjected to sonication and stirring to give a suspension which was filtered. The filter cake was dried on the filter to give the title compound (0.994 g, quantitative, salt form not identified). H(500 MHz, d6-benzene) 7.82 (s, 1H), 7.10 (s, 1H), 6.79 (s, 1H), 2.50 (approximate q, J = 6.8 Hz, 4H), 1.64 (approximate pJ = 7.4 Hz, 2H); LCMS [M+H] + 238 / 240, retention time 2.13 min (Method 1). This material was used in the next synthetic step without further purification.

[0101] Intermediate 49 [ka] 3-chloro-7,8-dihydro-6H-cyclopenta[g]isoquinoline To a solution of intermediate 48 (0.994 g, 2.67 mmol) in glacial acetic acid (3.0 mL) were introduced red phosphorus (0.209 g, 6.75 mmol) and hydrogen iodide (2.10 g of a 57% aqueous solution, 5.50 mmol). The reaction mixture was warmed to 80° C. under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was suspended in water (7 mL). Concentrated aqueous ammonia was introduced until the pH was basic, and the precipitated mass was broken down into a finely suspended solid by sonication. The solid was collected by filtration, and the filter cake was washed with water (3 mL) and dried on a filter. The dried solid was dissolved in dichloromethane (60 mL), the insoluble material was removed by filtration, and the filter cake was washed with dichloromethane (20 mL). The combined filtrate was washed with brine (10 mL) and dried over magnesium sulfate, after which decolorizing carbon (approximately 1 g of powder) was added, and the solution was swirled for 30 seconds before filtering (vacuum filtration) through a shallow bed of diatomaceous earth. The filtrate was concentrated under vacuum to give the title compound (0.899 g, 83% purity, quantitative). H (500 MHz, d-chloroform) 8.96 (s, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.57 (s, 1H), 3.11-3.05 (m, 4H), 2.18 (approximate pJ = 7.4 Hz, 2H); LCMS [M+H] + 204 / 206, retention time 1.94 min (Method 1). This material was used in the next synthetic step without further purification.

[0102] Intermediate 50 [ka] 3-chloro-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonyl chloride A suspension of intermediate 49 (9.290 g, 37.86 mmol, 83% pure) in chlorosulfonic acid was warmed to 80° C. under a nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and quenched by slowly pouring the residual oil onto ice (750 mL) with vigorous stirring. The resulting suspension was filtered (vacuum filtration), the filter cake was resuspended in water (10 mL), and the solid was isolated by filtration. After air-drying on the filter and in a vacuum oven at 40° C., the title compound was isolated as a gray powder (15.79 g, 1 Estimated purity by H NMR: 60%, yield: 83%. LCMS [M+H] + 302 / 304, retention time 2.04 min (Method 1). This material was used in the next synthetic step without further purification.

[0103] Intermediate 51 [ka] 3-Chloro-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 50 (15.8 g, 31.3 mmol, 60% pure) in dichloromethane (500 mL) was added a solution of isobutylamine (16.7 g, 228 mmol) in dichloromethane (50 mL) dropwise under a nitrogen atmosphere. After 2 hours, the reaction mixture was diluted with dichloromethane (500 mL) and washed with water (2 × 200 mL) followed by brine (1 × 100 mL). The organic phase was dried over sodium sulfate and filtered through a shallow bed of diatomaceous earth (vacuum filtration). After concentration of the filtrate in vacuo, the residue was purified by column chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (6.18 g, 56% yield) as a solid.

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[0104] Intermediate 52 [ka] 3-Bromo-5-[(6-methyl-3-pyridyl)sulfanyl]pyridine Nitrogen was bubbled through N-methylpyrrolidone (1.5 mL) for 10 minutes, followed by the introduction of 6-methylpyridine-3-thiol** [100 mg, 0.56 mmol, 70% purity]. A separate pressure tube was charged with 3-bromo-5-iodo-pyridine (380 mg, 2.4 mmol) and potassium tert-butoxide (98 mg, 0.879 mmol). The 6-methylpyridine-3-thiol solution was introduced into the pressure tube, and nitrogen was bubbled through the mixture for an additional 5 minutes. Pd2(dba)3 (73 mg, 0.080 mmol) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (559 mg, 1.038 mmol) were then added. The pressure tube was closed and heated to 90 °C for 70 minutes. The reaction mixture was concentrated under vacuum to a volume of 5 mL, and then dichloromethane (30 mL) was introduced, producing a solution with a precipitate. After removing insoluble material by vacuum filtration, the filtrate was partially purified by column chromatography eluting with a gradient of 0 to 4% (v / v) of 7 M ammonia in methanol in dichloromethane to give the title compound (LCMS-UV 215 5.51 g of 50% purity was obtained. LCMS [M+H] + 281 / 283, retention time 3.36 minutes (method 2). 1 H NMR revealed the presence of 16 molar equivalents of N-methylpyrrolidone. This material was carried on to the next synthetic step without further purification. **Prepared in two steps from 5-bromo-2-methyl-pyridine according to US Patent Application Publication No. 2009 / 156642 and EP Patent Application Publication No. 1806337 (2007).

[0105] Intermediate 53 [ka] 3-chloro-N-(2-hydroxypropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of 1-aminopropan-2-ol (0.058 mL, 0.75 mmol) and triethylamine (0.14 mL, 0.99 mmol) in anhydrous DCM (5 mL) was added Intermediate 50 (150 mg, 0.5 mmol), and the resulting solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was diluted with DCM (15 mL) and washed with saturated NH4Cl (10 mL), water (10 mL), and brine (10 mL), then dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (107 mg, 63% yield).

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[0106] Intermediate 54 [ka] 5-[(5-bromo-3-pyridyl)sulfonyl]-2-methyl-pyridine 16 molar equivalents of intermediate 52 (1.65 g, containing 16 molar equivalents of N-methylpyrrolidone) in dichloromethane (10 mL) at room temperature. LCMS-UV 215 To a solution of 1.65 g of 50% pure benzoic acid (estimated 125 mg, 0.445 mmol) was added 3-chloroperbenzoic acid (410 mg, 75% pure, 1.778 mmol) in one portion. After 24 h, the reaction mixture was re-treated with 3-chloroperbenzoic acid (150 mg, 75% pure, 0.654 mmol) and allowed to continue for another 24 h. Dichloromethane (10 mL) and 10% w / v aqueous sodium sulfite (6 mL) were added, and the biphasic mixture was vigorously stirred for 15 min. The phases were separated, and the aqueous phase was extracted with dichloromethane (10 mL). The pooled dichloromethane extracts were washed with saturated aqueous sodium carbonate (2 × 10 mL) and dried over sodium sulfate. The extracts were then filtered and concentrated in vacuo. The residue was purified by HPLC Method 3 to give the title compound (88.5 mg, estimated 63% yield) as a solid.

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[0107] Intermediate 55 [ka] N-[(2,4-dimethoxyphenyl)methyl]cyclopropanecarboxamide Cyclopropanecarbonyl chloride (5.5 mL, 60.6 mmol) was added to a stirred solution of triethylamine (10 mL, 0.07 mol) in DCM (250 mL) at 0 °C, followed by the dropwise addition of 1-(2,4-dimethoxyphenyl)methanamine (10.4 g, 62.2 mmol). The solution was allowed to warm to room temperature and stirred for 15 min, then diluted with water (50 mL) and washed with saturated aqueous NH4Cl (2 × 100 mL), followed by saturated aqueous NaHCO3 (100 mL), and then brine (50 mL). Drying over MgSO4, filtration, and concentration under reduced pressure gave the title compound (14.6 g, quantitative).

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[0108] Intermediate 56 [ka] N-(cyclopropylmethyl)-1-(2,4-dimethoxyphenyl)methanamine A solution of intermediate 55 (14.3 g, 60.6 mmol) in THF (250 mL) was cooled to 0 °C and 4 M LiAlH in diethyl ether (18.2 mL) was added dropwise. The reaction mixture was stirred at this temperature for 15 min, then allowed to warm to room temperature and stirred for 30 min, before being heated to 75 °C for 20 h. The reaction mixture was then cooled to 0 °C and stirred rapidly while water (2.5 mL) was carefully added dropwise (gas evolution). This was followed by the addition of 15% aqueous NaOH (2.5 mL) and then water (7.5 mL). The white suspension was allowed to warm to room temperature and stirred for 30 min. Diethyl ether (100 mL) was added and the suspension was stirred for a further 15 min before being filtered through Celite and washed with diethyl ether. The filtrate was concentrated under reduced pressure and purified by column chromatography using a gradient of methanol in dichloromethane. The product containing residue was dissolved in DCM (50 mL) and washed with 2M NaOH (2×50 mL) then brine, dried over MgSO, filtered and concentrated under reduced pressure to give the title compound (6.68 g, 50%).

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[0109] Intermediate 57 [ka] tert-Butyl 2-(4-bromopyrazolo[3,4-c]pyridin-1-yl)acetate (57) 4-Bromo-1H-pyrazolo[3,4-c]pyridine (200 mg, 1.01 mmol) was dissolved in THF (5 mL) and tert-butyl bromoacetate (164 μL, 1.11 mmol) was added, followed by 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (322 μL, 1.11 mmol). The reaction mixture was left to stand at room temperature for 4 hours, after which the solvent was removed under a stream of N. The residue was purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (110 mg, 35%).

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[0110] Intermediate 58 [ka] 3-Bromo-5-[(6-methyl-3-pyridyl)oxy]pyridine A mixture of 3-bromo-5-fluoropyridine (200 mg, 1.14 mmol), 6-methylpyridin-3-ol (149 mg, 1.36 mmol), and potassium carbonate (236 mg, 1.71 mmol) in DMF (4 mL) was heated in a microwave reactor at 200 °C for 30 min. The reaction mixture was diluted with 3 M aqueous LiCl (10 mL) and extracted with DCM (3 × 10 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (165 mg, 53% yield).

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[0111] Intermediate 59 [ka] 4-Bromo-2-methyl-pyrazolo[3,4-c]pyridine To NaH (60%, 242 mg, 6.06 mmol) under nitrogen was added anhydrous DMF (8 mL), and the mixture was cooled in an ice bath. 4-Bromo-1H-pyrazolo[3,4-c]pyridine (1 g, 5.05 mmol) was added, and the mixture was stirred while warming to room temperature over 30 minutes. Iodomethane (346 μL, 5.55 mmol) was added, and the resulting orange solution was stirred for 1 hour. Water (40 mL) was carefully added, and the mixture was extracted with a 1:1 mixture of IPA and CHCl3 (4 × 20 mL), dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography to give the title compound (315 mg, 29% yield).

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[0112] Intermediate 60 [ka] Ethyl 5-nitroindan-2-carboxylate Sulfuric acid (5 mL, 93.8 mmol) was added to 5-nitroindan-2-carboxylic acid [synthesized according to the procedure in U.S. Pat. No. 6,262,087, 2001] (20.3 g, 73.4 mmol) in EtOH (220 mL), and the reaction mixture was heated at 70° C. for 3 h. The mixture was then concentrated in vacuo to 20% of its original volume, diluted with DCM (150 mL) and HO (100 mL), and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL), and the combined organics were dried and concentrated in vacuo to give the title compound (25.8 g), which was carried forward without purification. LCMS [M+H] + was not observed (not ionized) at a retention time of 1.10 min (Method 6).

[0113] Intermediate 61 [ka] Ethyl 5-aminoindan-2-carboxylate A stirred solution of intermediate 60 (25.8 g, 82.2 mmol) in EtOH (220 mL) at room temperature was placed under an atmosphere of N. Palladium on carbon (2.5 g, 2.3 mmol) was added and the reaction mixture was placed under an atmosphere of H. After 20 h, the reaction mixture was filtered through Celite (200 mL EtOH wash) and concentrated in vacuo. Purification by column chromatography eluting with 0% to 40% EtOAc in isohexane gave the title compound (14.2 g, 83% yield). LCMS [M+H] + 206, retention time 1.36 minutes (method 7).

[0114] Intermediate 62 [ka] Ethyl 5-amino-6-iodo-indan-2-carboxylate (62) To a stirred solution of Intermediate 61 (14.3 g, 69.3 mmol) in MeOH (300 mL) in an ice bath was added silver sulfate (21.6 g, 69.3 mmol), followed by iodine (17.6 g, 69.3 mmol) in four portions over 5 min. After an additional 5 min, the reaction was warmed to room temperature and stirred for 6 h. The mixture was concentrated in vacuo to 150 mL, filtered (400 mL MeOH wash), and concentrated in vacuo to 50 mL. EtOAc (400 mL) and 10% aqueous NaSO (200 mL) were added to the solution. The aqueous layer was extracted with EtOAc (2 x 200 mL), and the combined organics were dried and concentrated in vacuo. Purification by column chromatography eluting with 0% to 15% EtOAc in isohexane afforded the title compound (17.0 g, 50% yield, 68% purity by LCMS). LCMS [M+H] + 332, retention time 1.13 minutes (method 6).

[0115] Intermediate 63 [ka] Ethyl 5-amino-6-(2-cyclopropylethynyl)indan-2-carboxylate To a stirred solution of intermediate 62 (17.0 g, 34.6 mmol, 68% purity) in THF (200 mL) at room temperature was added cuprous iodide (660 mg, 3.44 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.82 g, 2.59 mmol), and TEA (17 mL, 122 mmol). The reaction was purged with N for 5 minutes, after which cyclopropylacetylene (6.2 mL, 70 mmol) was added. After 17 hours, the reaction mixture was filtered through Celite (washing with EtOAc) and concentrated in vacuo. Purification by column chromatography eluting with 0% to 40% EtOAc in isohexane afforded the title compound (13.9 g, 89% yield, 60% purity by LCMS). LCMS [M+H] + 270, retention time 1.20 minutes (method 6).

[0116] Intermediate 64 [ka] Ethyl 4-bromo-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxylate To a stirred solution of Intermediate 63 (13.9 g, 30.9 mmol, ca. 60% purity) in MeCN (250 mL) was added copper dibromide (70 mg, 0.31 mmol), (1S)-(+)-10-camphorsulfonic acid (9.73 g, 41.9 mmol), and tetrabutylammonium bromide (20.2 g, 62.2 mmol). The solution was immersed in an ice bath, and tert-butyl nitrite (5.3 mL, 40 mmol) was added. After 5 min, the reaction was stirred at room temperature for 1 h, then concentrated in vacuo to 80 mL, filtered through silica (150 mL, wash with 50% EtOAc in isohexane), and concentrated in vacuo. Purification by column chromatography eluting with 0→30% EtOAc in isohexane gave the title compound (5.42 g, 49% yield). LCMS [M{ 79 Br}+H]+ 361, retention time 1.28 minutes (method 6).

[0117] Intermediate 65 [ka] Ethyl 3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxylate To a stirred solution of intermediate 64 (1.43 g, 3.38 mmol) in MeCN (50 mL) was added DIPEA (14 mL) and tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.197 mmol). The resulting mixture was purged with N for 5 minutes and then heated to 100 °C in a sealed vessel for 26 hours. The reaction mixture was diluted with DCM (200 mL) and HO (150 mL) and the phases were separated. The aqueous phase was extracted with DCM (3 × 50 mL) and the combined organic phases were dried and concentrated in vacuo. Purification by column chromatography eluting with 0 → 60% EtOAc in isohexane afforded the title compound (905 mg, 92% yield). LCMS [M+H] + 283, retention time 1.43 minutes (method 7).

[0118] Intermediate 66 [ka] Ethyl 5-bromo-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxylate To a stirred solution of intermediate 65 (3.97 g, 14.1 mmol) in DCM (250 mL) at 0 °C, methanesulfonic acid (170 mL) was slowly added, followed by the dropwise addition of N-bromosuccinimide (2.64 g, 14.1 mmol). After 16 h, the reaction mixture was slowly poured into saturated Na2CO3 solution (400 mL) at 0 °C, followed by the addition of a large amount of Na2CO3. The reaction mixture was diluted with DCM (50 mL) and the phases were separated. The aqueous phase was extracted with DCM (3 × 100 mL), and the combined organic phases were dried and concentrated in vacuo. Purification by basic reverse-phase column chromatography eluting with 0 → 60% MeCN in H2O gave the title compound (1.07 g, 21% yield). LCMS [M{ 79 Br}+H] + 361, retention time 1.23 minutes (method 6).

[0119] Intermediate 67 [ka] Ethyl 5-benzylsulfanyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxylate To a stirred solution of Intermediate 66 (4.41 g, 12.2 mmol) in 1,4-dioxane (80 mL) was added Xantphos Pd G3 (1.80 g, 1.80 mmol) and DIPEA (5.3 mL, 30 mmol). The mixture was purged with N2 for 5 minutes, after which benzyl mercaptan (1.7 mL, 14 mmol) was added. The resulting reaction mixture was then heated to 120 °C in a sealed vessel for 24 hours, then filtered through Celite (200 mL, EtOAc wash) and concentrated in vacuo. Purification by column chromatography eluting with 0 → 40% EtOAc in isohexane afforded the title compound (5.11 g, 96% yield). LCMS [M+H] + 405, retention time 1.38 minutes (method 6).

[0120] Intermediate 68 [ka] 5-Benzylsulfanyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxylic acid hydrochloride To a stirred solution of intermediate 67 (5.19 g, 11.9 mmol) in THF (60 mL) and HO (40 mL) was added lithium hydroxide monohydrate (1.50 g, 35.8 mmol). The reaction mixture was heated at 50° C. for 30 min, then concentrated in vacuo and acidified with 1N HCl (100 mL). The resulting precipitate was collected by filtration and dried in vacuo to give the title compound (3.20 g) as the HCl salt. The filtrate was diluted with EtOAc (350 mL containing a few mL of MeOH) and the phases were separated. The aqueous phase was extracted with EtOAc (3×100 mL containing a few mL of MeOH), and the combined organic phases were dried and concentrated in vacuo to give a second crop of the title compound as the HCl salt (1.24 g). A total of 4.4 g of product was isolated (97% yield). LCMS [M+H] + 377, retention time 1.28 minutes (method 7).

[0121] Intermediate 69 [ka] 3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxylic acid hydrochloride To a suspension of Intermediate 68 (1.00 g, 2.62 mmol) in a mixture of MeCN (20 mL), DCM (20 mL), acetic acid (750 μL, 13.1 mmol), and HO (240 μL, 13.3 mmol) at 0° C. was added 1,3-dichloro-5,5-dimethylhydantoin (875 mg, 4.44 mmol). After 1 h 15 min, additional 1,3-dichloro-5,5-dimethylhydantoin (100 mg, 0.51 mmol) was added. After 25 min, the reaction mixture was cooled to −5° C. and added to a pre-stirred solution of 2-fluoro-2-methylpropan-1-amine HCl (1.34 g, 10.5 mmol) and DIPEA (1.9 mL, 11 mmol) in DCM (40 mL) at 0° C. After 15 min, the reaction mixture was diluted with 2N HCl (50 mL) and H2O (50 mL) and the precipitate was collected by filtration to give the title compound as the HCl salt (388 mg, 35% yield). LCMS [M+H] + 408, retention time 0.67 minutes (method 6).

[0122] Intermediate 70 [ka] 5-Bromo-3-chloro-7,8-dihydro-6H-cyclopenta[g]isoquinoline To a flask containing Intermediate 49 (0.770 g, 3.78 mmol) and N-bromosuccinimide (478 mg, 2.66 mmol) was added sulfuric acid (7.5 mL) at 0 °C under a nitrogen atmosphere. The reaction was stirred for 2.5 h while the ice bath was allowed to warm to room temperature. The reaction was added additional N-bromosuccinimide (278 mg, 1.55 mmol) for 1.5 h. The reaction was slowly added to ice water (ca. 150 mL) and the pH of the solution was adjusted to ca. 9 by the addition of concentrated ammonium hydroxide (ca. 24 mL). The aqueous solution was extracted with DCM (3 × 100 mL), and the combined organic layers were passed through a phase separator, concentrated in vacuo, and purified by column chromatography on silica (gradient elution with 0% to 10% EtOAc in isohexane) to give the title compound (723 mg, 68% yield).

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[0123] Intermediate 71 [ka] 5-Bromo-3-chloro-9-nitro-7,8-dihydro-6H-cyclopenta[g]isoquinoline Potassium nitrate (282 mg, 2.79 mmol) was added to a solution of Intermediate 70 (0.723 g, 2.56 mmol) in sulfuric acid (7.5 mL) at 0 °C under a N atmosphere. The reaction was stirred at 0 °C for 1 hour and 20 minutes. The reaction mixture was slowly added to ice water (ca. 150 mL) and the pH of the solution was adjusted to pH 9 by the addition of concentrated ammonium hydroxide (ca. 22 mL). The aqueous solution was extracted with DCM (3 × 100 mL) and the combined organic layers were passed through a phase separator and concentrated in vacuo to give the title compound (800 mg, 95% yield), which was used without further purification.

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[0124] Intermediate 72 [ka] 5-Benzylsulfanyl-3-chloro-9-nitro-7,8-dihydro-6H-cyclopenta[g]isoquinoline DIPEA (0.85 mL, 4.9 mmol) and benzyl mercaptan (0.30 mL, 2.5 mmol) were added to a solution of Intermediate 71 (760 mg, 2.32 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (84.1 mg, 0.141 mmol), and tris(dibenzylideneacetone)dipalladium(0) (67.9 mg, 0.0741 mmol) in 1,4-dioxane (11.7 mL). The reaction was degassed, placed under nitrogen, and stirred at 100 °C for 40 min. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and washed with saturated aqueous ammonium chloride (50 mL) followed by water (100 mL). The organic layer was passed through a phase separator, concentrated in vacuo and purified by column chromatography on silica (gradient elution 0% to 100% EtOAc in isohexane) to give the title compound (879 mg, quantitative). LCMS [M+H] + 370.8 / 372.8, retention time 1.83 minutes (method 7).

[0125] Intermediate 73 [ka] 3-chloro-N-isobutyl-9-nitro-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Water (0.12 mL) and acetic acid (0.07 mL) were added to a solution of Intermediate 72 (0.837 g, 2.26 mmol) in a mixture of DCM (10 mL) and MeCN (10 mL). The solution was cooled to −10° C. and 1,3-dichloro-5,5-dimethylhydantoin (0.895 g, 4.54 mmol) was added. The reaction was stirred from −10° C. to −5° C. for 0.5 h, after which isobutylamine (1.8 mL, 18 mmol) was added. The reaction was allowed to warm to 15° C. while stirring for an additional 4 h. The reaction was then diluted with DCM (50 mL), washed with saturated aqueous ammonium chloride (50 mL), and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were passed through a phase separator, concentrated in vacuo and purified by column chromatography on silica (gradient elution from 0% to 50% EtOAc in isohexane) to give the title compound (613 mg, 71% yield). LCMS [M+H] + 383.8 / 385.8, retention time 1.64 minutes (method 7).

[0126] Intermediate 74 [ka] 9-Amino-3-chloro-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Ammonium chloride (297 mg, 5.56 mmol) and zinc (377 mg, 5.65 mmol) were added to a solution of Intermediate 73 (202.0 mg, 0.5263 mmol) in a mixture of THF (4.2 mL) and MeOH (4.2 mL) under nitrogen. The reaction was stirred at room temperature for 1 hour, filtered through a pad of Celite, washed with EtOAc (100 mL), and concentrated in vacuo. The resulting solid was suspended in DCM (50 mL), washed with water (25 mL), and passed through a phase separator. The solid remaining in the phase separator was washed with MeOH, and the solution was concentrated in vacuo. The solid remaining in the flask after filtration through Celite was dissolved in EtOAc (50 mL), washed with water (25 mL), passed through a phase separator, combined with the previous extract, and concentrated in vacuo to give the title compound (185 mg, 99% yield), which was used without further purification. LCMS [M+H] + 354.0 / 356.0, retention time 1.46 minutes (method 7).

[0127] Intermediate 75 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[(2-methoxy-4-pyridyl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide formic acid Intermediate 12 (50 mg, 0.13 mmol), 4-bromo-2-methoxypyridine (37.3 mg, 0.199 mmol), sodium tert-butoxide (38.19 mg, 0.39 mmol), Pd(dba) (12.1 mg, 0.013 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (16.5 mg, 0.026 mmol) were heated in anhydrous toluene (1 mL) at 110 °C in a 20 mL pressure tube with stirring for 4 h. Water (15 mL) was added, and the reaction was extracted with DCM (3 × 10 mL). The organics were dried over sodium sulfate and concentrated in vacuo. The brown residue was purified by acidic reverse-phase HPLC to give the title compound as the bisformate salt (35 mg, 46% yield). LCMS [M+H] +485, retention time 1.79 minutes (method 2).

[0128] Intermediate 76 and Intermediate 77 [ka] 2-[(7-Bromoimidazo[4,5-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (76) 2-[(7-Bromoimidazo[4,5-c]pyridin-3-yl)methoxy]ethyl-trimethyl-silane (77) To a solution of 7-bromo-1H-imidazo[4,5-c]pyridine (100 mg, 0.5 mmol) in anhydrous THF (3 mL) was added sodium hydride (24.2 mg, 0.6 mmol) in portions at 0 °C. After stirring at 0 °C for 0.5 h, SEMCl (92.6 mg, 0.55 mmol) was added. The reaction mixture was stirred at room temperature for 5 h, then poured into water and extracted with EtOAc (2 × 30 mL). The organic layer was dried (Na SO ), filtered, and concentrated in vacuo. The crude product was purified by column chromatography using 50% → 100% EtOAc in heptane to give the title compound (90 mg, 54% yield) as a 1:1 mixture of intermediate 76 and intermediate 77. LCMS [M+H] + 328 / 330, retention times 1.81 and 1.85 min (Method 1).

[0129] Intermediate 78 and Intermediate 79 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[[1-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-7-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide (78) 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[[3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-7-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide (79) Prepared by the general procedure from Intermediate 12 (50 mg, 0.13 mmol) and a 1:1 mixture of Intermediate 76 and Intermediate 77 (60.8 mg, 0.18 mmol). The crude was purified by column chromatography using 0% to 10% MeOH in DCM to give the mixture of title compounds (74 mg, 77%). LCMS [M+H] + 625, retention times 1.84 and 1.88 min (Method 1).

[0130] Intermediate 80 and Intermediate 81 [ka] 6-Bromo-3-cyclopropyl-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide 8-Bromo-3-cyclopropyl-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of Intermediate Example 69 (500 mg, 1.452 mmol) in ethyl acetate (28 mL) was introduced AIBN (24 mg, 0.145 mmol) and N-bromosuccinimide (362 mg, 2.032 mmol). The reaction mixture was heated to reflux under a nitrogen atmosphere for 40 minutes. After cooling to room temperature, the reaction mixture was adsorbed onto silica in vacuo, and the dry-loaded material was purified by column chromatography using a gradient of ethyl acetate in heptane to afford the title compound as a 1:1 mixture of regioisomers (339 mg, 46% yield). LCMS [M+H] + 423 / 425, retention time 2.03 minutes (method 1).

[0131] Intermediate 82 [ka] Methyl 3-cyclopropyl-5-iodo-7-(2-trimethylsilylethoxymethyl)-6,8-dihydrocyclopenta[g]isoquinoline-7-carboxylate To a −78° C. solution of intermediate 7 (400 mg, 1.017 mmol) in tetrahydrofuran (20 mL) was added a solution of 1 M LiHMDS in THF (2.03 mL, 2.03 mmol). After 60 min, a solution of SEMCl (509 mg, 3.05 mmol) in THF (3 mL) was introduced dropwise over 5 min. The reaction mixture was stirred at −78° C. for an additional 60 min and then quenched by the addition of saturated aqueous ammonium chloride (2 mL), and the mixture was allowed to warm to room temperature. After concentration in vacuo to remove tetrahydrofuran, the aqueous residue was diluted with ethyl acetate (40 mL). The organic layer was then washed with saturated aqueous ammonium chloride (10 mL), water (2×10 mL), and brine (10 mL). The organic layer was then dried over magnesium sulfate, filtered, and the filtrate was purified by column chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (297 mg, 52% yield).

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[0132] Intermediate 83 [ka] Methyl 5-benzylsulfanyl-3-cyclopropyl-7-(2-trimethylsilylethoxymethyl)-6,8-dihydrocyclopenta[g]isoquinoline-7-carboxylate Nitrogen was bubbled through a solution of Intermediate 82 (330 mg, 0.59 mmol) in anhydrous 1,4-dioxane (5 mL) for 5 min. Separately, nitrogen was bubbled through anhydrous 1,4-dioxane (1 mL) for 5 min, followed by the addition of benzyl mercaptan (117 mg, 0.946 mmol) and diisopropylethylamine (244 mg, 1.89 mmol). Pd2(dba)3 (17 mg, 0.019 mmol), Xantphos (22 mg, 0.038 mmol), the Intermediate 82 solution, and the benzyl mercaptan / diisopropylethylamine solution were added to a pressure tube. The pressure tube was closed under a nitrogen atmosphere and heated to 100 °C for 100 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (3 × 40 mL) followed by brine (20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was purified by column chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (284 mg, 89% yield).

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[0133] Intermediate 84 [ka] 5-Benzylsulfanyl-3-cyclopropyl-7-(2-trimethylsilylethoxymethyl)-6,8-dihydrocyclopenta[g]isoquinoline-7-carboxylic acid hydrochloride To a solution of intermediate 83 (264 mg, 0.49 mmol) in tetrahydrofuran (5 mL) was added 2 M aqueous lithium hydroxide solution (0.38 mL, 0.76 mmol). The reaction mixture was warmed to 40° C. for 11 hours and then treated with additional 2 M aqueous lithium hydroxide solution (0.08 mL, 0.16 mmol), and the reaction was continued at this temperature for an additional 20 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and concentrated in vacuo to remove tetrahydrofuran. The pH of the aqueous residue was adjusted to pH 3 with 1 M aqueous hydrochloric acid and extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were washed with brine (10 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound as the HCl salt (239 mg, 92% yield).

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[0134] Intermediate 85 [ka] 3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7-(2-trimethylsilylethoxymethyl)-6,8-dihydrocyclopenta[g]isoquinoline-7-carboxylic acid hydrochloride To a solution of intermediate 84 (853 mg, 1.60 mmol) in acetonitrile (14 mL) was introduced acetic acid (506 mg, 8.433 mmol), water (152 mg, 8.43 mmol), and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (665 mg, 3.37 mmol). After 30 min, the reaction mixture was treated with additional 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (221 mg, 1.12 mmol) and stirred for 20 min, during which time a solid precipitated. The solid was collected by vacuum filtration, washed on the filter with acetonitrile (5 mL), and air-dried on the filter for 10 min to give the sulfonyl chloride intermediate, which was dissolved in dichloromethane (14 mL). A solution of 2-fluoro-2-methyl-propan-1-amine hydrochloride (236 mg, 1,855 mmol) was added, followed by a solution (5 mL) of diisopropylethylamine (763 mg, 5,903 mmol) in dichloromethane (5 mL). After 90 minutes, the reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate (50 mL), and washed with 1 M aqueous hydrochloric acid (2 × 10 mL), followed by brine (10 mL). The organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound (790 mg, 80% yield over two steps) as the HCl salt. δ H( 500MHz,d6-dmso)9.23(s,1H),8.46(s,1H),8.45(t,J=6.6Hz,1H),8.13(s,1H),3.90(d ,J=18.7Hz,1H),3.59(d,J=8.9Hz,1H),3.54(d,J=9.3Hz,1H),3.50(m,3H),3.41(d,J=1 7.4Hz,1H),3.15(d,J=17.4Hz,1H),3.02-2.86(m,2H),2.33-2.29(m,1H),1.16(d,J=21 .3Hz,3H),1.09(d,J=21.4Hz,3H),1.09-1.07(m,4H),0.84-0.81(m,2H),-0.02(s,9H). δ F( 235MHz, d6-dmso, H-decoupling) - 140.08; LCMS [M+H] + 537, Retention time 2.05 minutes (Method 1).

[0135] Intermediate 86 [ka] 7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-(2-trimethylsilylethoxymethyl)-6,8-dihydrocyclopenta[g]isoquinoline-5-sulfonamide To a solution of Intermediate 85 (737 mg, 1.19 mmol) in anhydrous tetrahydrofuran (22 mL) were introduced triethylamine (347 mg, 3.43 mmol) and diphenylphosphoryl azide (416 mg, 1.51 mmol). The reaction was warmed to 75°C in a pressure vessel for 100 minutes under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into a rapidly stirred mixture of 1 M aqueous sodium hydroxide (40 mL) and tetrahydrofuran (40 mL), and stirring was continued for 15 minutes. The pH of the mixture was adjusted to pH 7 by the addition of acetic acid and then adjusted to pH 8 using a 10:1 mixture of saturated aqueous sodium bicarbonate / 2 M aqueous sodium carbonate. The solution was extracted with ethyl acetate (140 mL). The pH of the aqueous phase was then adjusted to pH 12 with 2 M aqueous sodium carbonate, and the solution was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were washed with 2M aqueous sodium carbonate (50 mL) and brine (50 mL), then dried over sodium sulfate and filtered through a shallow bed of diatomaceous earth. The filtrate was concentrated in vacuo to give an oil. Ethyl acetate (30 mL) was added and the solution was allowed to stand until no further precipitate was observed. The precipitate was removed by vacuum filtration and the filtrate was concentrated in vacuo to give the title compound (854 mg, 97% yield), which was used in the next step without further purification. LCMS [M+H] + 508, retention time 1.82 minutes (method 1).

[0136] Intermediate 87 [ka] 1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7-(2-trimethylsilylethoxymethyl)-6,8-dihydrocyclopenta[g]isoquinolin-7-yl]-3-(3-pyridyl)thiourea Intermediate 86 (425 mg, LCMS-UV) in anhydrous dichloromethane (20 mL) 215 To a solution of 3-isocyanatopyridine (79 mg, 0.577 mmol) in DCM (1 mL) was added diisopropylethylamine (75 mg, 0.577 mmol). After 17 h at room temperature, the reaction mixture was adsorbed onto silica and the dry-loaded material was purified by column chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (305 mg, 79% yield) as a colorless solid.

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[0137] Intermediate 88 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[(4-(3-pyridyl)-1,2,4-triazol-3-yl]amino]-7-(2-trimethylsilylethoxymethyl)-6,8-dihydrocyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 87 (305 mg, 0.45 mmol) in anhydrous DMF (6 mL) were added formic hydrazide (85 mg, 1.421 mmol) and mercury(II) chloride (386 mg, 1.421 mmol). After 5 minutes at room temperature, a solution of triethylamine (144 mg, 1.421 mmol) in DMF (0.5 mL) was introduced, and the reaction mixture was warmed to 90 °C for 60 minutes. After cooling to room temperature, the reaction mixture was poured into a suspension of diatomaceous earth (10 g) in dichloromethane (120 mL) and stirred for 10 minutes. The suspension was then filtered (vacuum filtration) through a shallow bed of diatomaceous earth, and the filter cake was washed with dichloromethane (30 mL). The filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate (100 mL) and then washed with water (2 × 30 mL) and brine (20 mL). The organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound (245 mg, 71% yield).

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[0138] Intermediate 89 and Intermediate 90 [ka] 6-Amino-3-cyclopropyl-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide 8-Amino-3-cyclopropyl-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A 1:1 mixture of intermediate 80 and intermediate 81 ( 1 To a solution of 160 mg (0.303 mmol) of approximately 80% purity by H NMR was added a 0.5 M solution of ammonia in THF (9 mL, 4.50 mmol). The reaction mixture was warmed to 60° C. in a pressure tube for 48 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was dissolved in tetrahydrofuran (5 mL) and concentrated in vacuo to give the title compound (LCMS-UV 215201 mg of 59% purity (quantitative) was obtained. For both regioisomers, LCMS [M+H] + 360, retention time 1.59 min (Method 1). This material was used in the next synthetic step without further purification.

[0139] Intermediate 91 [ka] 7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]cinnoline-5-sulfonamide To a room temperature suspension of Example 65 (75 mg, 0.14 mmol) in DCM (4 mL) was added trifluoroacetic acid (320 μL, 4.23 mmol). After 3 h 30 min, the reaction mixture was concentrated in vacuo and diluted with DCM (20 mL), HO (10 mL), and saturated NaHCO (5 mL). The phases were separated and the aqueous layer was extracted with DCM (4 × 10 mL) containing 10% IPA. The combined organics were dried and concentrated in vacuo to give the title compound (62 mg, quantitative). LCMS [M+H] + 379, retention time 0.79 minutes (method 6).

[0140] Intermediate 92 [ka] 1-[3-cyclopropyl-5-(isobutylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-3-(cyclopropylmethyl)thiourea Intermediate 122 (0.16 g, 0.45 mmol) was stirred in a mixture of DCM (5 mL) and DIPEA (62 μL, 0.45 mmol). (Isothiocyanatomethyl)cyclopropane (62 mg, 0.54 mmol) was added and the reaction was stirred for 16 h. Further (isothiocyanatomethyl)cyclopropane (31 mg, 0.27 mmol) was added and the solution was stirred for 24 h. The reaction was concentrated in vacuo to give a white solid which was triturated with DCM in heptane to give the title compound (162 mg, 76%). LCMS [M+H] + 473.2, retention time 1.90 minutes (method 1).

[0141] Intermediate 93 [ka] tert-Butyl N-[(5-bromopyridin-2-yl)-methyl-oxo-λ6-sulfanylidene]carbamate To a suspension of Intermediate 34 (150 mg, 0.68 mmol), magnesium oxide (110 mg, 2.73 mmol), rhodium(II) acetate dimer (8 mg, 0.017 mmol), and tert-butyl carbamate (163 mg, 1.36 mmol) in DCM (3 mL) was added iodobenzene diacetate (336 mg, 1.02 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction was filtered through Celite and washed with DCM. The solvent was removed in vacuo, and the crude material was purified by column chromatography to give the title compound (149 mg, 65% yield).

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[0142] Intermediate 94 [ka] 7-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-2-(2-nitro-3-pyridyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide A solution of intermediate 27 (100 mg, 0.28 mmol), 3-fluoro-2-nitropyridine (47 mg, 0.33 mmol), and DIPEA (192 μL, 1.10 mmol) in THF (5 mL) was heated to 50 °C in a sealed tube for 5 h. After cooling to room temperature, the solution was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO (10 mL). The aqueous layer was extracted with EtOAc (10 mL), and the combined organic extracts were washed with brine (10 mL), dried over MgSO, filtered, and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (20 mg, 15% yield).

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[0143] Intermediate 95 [ka] 5-Benzylsulfanyl-3-cyclopropyl-N-(2,2-dimethylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide Intermediate 9 (190 mg, 0.51 mmol) was dissolved in DCM (5 mL), and DIPEA (315 μL, 1.81 mmol) was added, followed by HATU (210 mg, 0.55 mmol). The mixture was stirred at room temperature for 10 minutes, and then 2,2-dimethylpropan-1-amine (120 μL, 1.02 mmol) was added. Stirring was continued at room temperature for 1 hour. The solution was then concentrated under reduced pressure and purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (170 mg, 76% yield).

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[0144] Intermediate 96 [ka] 1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl)thiourea A solution of intermediate 12 (85%, 215 mg, 0.44 mmol) and DIPEA (115 μL, 0.66 mmol) in DCM (5 mL) was treated with a solution of 5-isothiocyanato-1,3-dimethyl-1H-pyrazole (82 mg, 0.54 mmol) in DCM (1 mL), and the reaction was stirred at room temperature for 1 h before being concentrated under reduced pressure and purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (255 mg, 87% yield).

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[0145] Intermediate 97 [ka] 3-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1-(cyclopropylmethyl)-1-[(2,4-dimethoxyphenyl)methyl]thiourea Phenylchloromethanethioate (65 μL, 0.47 mmol) was dissolved in DCM (5 mL), and a solution of Intermediate 12 (160 mg, 0.42 mmol) and triethylamine (180 μL, 1.29 mmol) in DCM (2.5 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 45 minutes. Intermediate 56 (140 mg, 0.57 mmol) was then added, and the reaction was stirred at room temperature for 3 days. The reaction mixture was concentrated under a stream of N2 and purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (247 mg, 91% yield). LCMS [M+H] + 641.2, retention time 2.07 minutes (method 2).

[0146] Intermediate 98 [ka] (7R)-7-[[6-[bis(2-trimethylsilylethoxymethyl)sulfamoyl]-3-pyridyl]amino]-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Prepared by general procedure 1 from intermediate 15 (55 mg, 0.14 mmol) and intermediate 99 (87 mg, 0.17 mmol). The crude was purified by column chromatography using 0% to 90% EtOAc in heptane to give the title compound (85 mg, 73% yield). LCMS [M+H] + 794, retention time 2.35 minutes (method 1).

[0147] Intermediate 99 [ka] 5-Bromo-N,N-bis(2-trimethylsilylethoxymethyl)pyridine-2-sulfonamide A solution of 5-bromopyridine-2-sulfonamide (100 mg, 0.42 mmol) in DMF (3 mL) was stirred with sodium hydride (60% dispersion; 37.1 mg, 0.92 mmol) at 20 °C under a nitrogen atmosphere. After 15 min, SEMCl (140.6 mg, 0.84 mmol) was added, and the mixture was stirred at 20 °C for 3 h. Phosphate buffer (pH 6.5, 7 mL) was added, and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (2 × 20 mL), and the combined organic layers were washed with water (2 × 20 mL), followed by brine (20 mL). The solution was dried (NaSO) and evaporated to dryness. Purification by column chromatography using 0% → 20% EtOAc in heptane gave the title compound (109 mg, 52% yield). LCMS [M+Na] + 519 / 521, retention time 2.41 minutes (method 1).

[0148] Intermediate 100 [ka] tert-Butyl N-[[5-[[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]-2-pyridyl]-methyl-oxo-lambda 6-sulfanylidene]carbamate The title compound was prepared by general procedure 1 using intermediate 12 (55 mg, 0.15 mmol), intermediate 93 (146 mg, 0.44 mmol), sodium tert-butoxide (42 mg, 0.44 mmol), tBuXPhos Pd G3 (18 mg, 0.022 mmol) and 1,4-dioxane (1 mL). Purification by column chromatography afforded the title compound (52 mg, 56% yield).

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[0149] Intermediate 101 [ka] tert-Butyl N-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-2-oxide-7,8-dihydro-6H-cyclopenta[g]isoquinolin-2-ium-7-yl]carbamate To an ice-cold solution of intermediate 12 (900 mg, 1.88 mmol) in DCM (25 mL) was added 3-chloroperbenzoic acid (790 mg, 3.20 mmol) and the reaction was stirred for 2 h at 0° C. The reaction was then washed with saturated aqueous NaHCO (40 mL) and the organic layer was dried (NaSO) and concentrated in vacuo to give the title compound (1.01 g, 92% yield).

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[0150] Intermediate 102 [ka] [7-(tert-butoxycarbonylamino)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-1-yl]-trimethyl-ammonium 2,2,2-trifluoroacetate To a stirred solution of Intermediate 101 (1.00 g, 1.7 mmol) in DCM (85 mL) was added a 1 M solution of trimethylamine in THF (12 mmol, 12 mL). The solution was cooled in an ice bath, and then trifluoroacetic anhydride (0.73 mL, 5.2 mmol) was added. The reaction was stirred at 0° C. for 20 minutes, then washed with water, dried, and concentrated in vacuo. The resulting crude was purified by column chromatography to give the title compound (717 mg, 64% yield).

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[0151] Intermediate 103 [ka] tert-Butyl N-[3-cyclopropyl-1-fluoro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate To a solution of intermediate 102 (710 mg, 1.09 mmol) in N,N-dimethylformamide (2.5 mL) was added tetrabutylammonium fluoride 1 M in THF (3.3 mL, 3.3 mmol). The reaction was sealed and heated to 75 °C with stirring for 1.5 h. The reaction was cooled, diluted with EtOAc (10 mL), and washed with water (10 mL). The aqueous layer was extracted with EtOAc (5 mL), and the combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound (413 mg, 76% yield).

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[0152] Intermediate 104 [ka] 7-Amino-3-cyclopropyl-1-fluoro-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a stirred solution of intermediate 103 (410 mg, 0.83 mmol) in DCM (8 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at ambient temperature for 2 h and then concentrated in vacuo. The residue was dissolved in a mixture of IPA (2 mL), DCM (25 mL), and saturated aqueous NaHCO3 (25 mL). The solution was stirred vigorously for 5 min. The organic layer was separated and concentrated in vacuo to give the title compound (295 mg, 84% yield).

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[0153] Intermediate 105 [ka] Methyl 5-[[3-cyclopropyl-1-fluoro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylate The title compound was prepared by general procedure 1 using intermediate 104 (50 mg, 0.13 mmol), methyl 5-bromopyridine-2-carboxylate (59 mg, 0.27 mmol), sodium tert-butoxide (38.2 mg, 0.39 mmol), tBuXPhos Pd G3 (16.3 mg, 0.019 mmol) and anhydrous 1,4-dioxane (3 mL). The reaction was heated to 45° C. for 5 h and then purified by column chromatography to give the title compound (36 mg, 48% yield).

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[0154] Intermediate 106 [ka] 5-[[3-Cyclopropyl-1-fluoro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid To a solution of intermediate 105 (43 mg, 0.081 mmol) in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL) was added lithium hydroxide (3 mg, 0.12 mmol) and the reaction was heated to 50° C. for 6 h. The reaction was acidified to pH 4 with 0.5 M HCl and extracted with EtOAc (2×2 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo to give the title compound (24 mg, 49% yield). LCMS [M+H] + 517, retention time 1.89 minutes (method 4).

[0155] Intermediate 107 [ka] tert-Butyl N-[[7-(tert-butoxycarbonylamino)-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-5-yl]sulfonyl-N-(2-fluoro-2-methyl-propyl)carbamate To a solution of Intermediate 12 (0.3 g, 0.79 mmol) and di-tert-butyl dicarbonate (0.35 g, 1.59 mmol) in anhydrous 1,4-dioxane (5 mL) was added N,N-diisopropylethylamine (0.28 mL, 1.59 mmol), followed by 4-dimethylaminopyridine (10 mg, 0.08 mmol). The reaction was stirred for 30 minutes, then diluted with EtOAc (5 mL) and washed with 0.5 M HCl (5 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give the title compound (483 mg, 63% yield).

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[0156] Intermediate 108 [ka] tert-Butyl N-[[7-(tert-butoxycarbonylamino)-3-cyclopropyl-2-oxide-7,8-dihydro-6H-cyclopenta[g]isoquinolin-2-ium-5-yl]sulfonyl-N-(2-fluoro-2-methyl-propyl)carbamate To an ice-cold solution of intermediate 107 (0.30 g, 0.49 mmol) in DCM (5 mL) was added 3-chloroperbenzoic acid (134 mg, 0.54 mmol). The reaction was stirred at 0 °C for 2.5 h. The reaction was washed with aqueous NaSO (2.5 mL), followed by saturated aqueous NaHCO (2.5 mL). The organic layer was separated, dried, and concentrated in vacuo. Purification by column chromatography afforded the title compound (217 mg, 63% yield).

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[0157] Intermediate 109 [ka] [7-(tert-butoxycarbonylamino)-5-[tert-butoxycarbonyl-(2-fluoro-2-methyl-propyl)sulfamoyl]-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-1-yl]-trimethyl-ammonium;2,2,2-trifluoroacetate The title compound was prepared by the same procedure as described for Intermediate 102 using Intermediate 108 (0.3 g, 0.43 mmol), DCM (15 mL), trimethylamine (2.9 mL, 2.9 mmol) and trifluoroacetic anhydride (0.18 mL, 1.29 mmol). Purification by column chromatography afforded the title compound (184 mg, 57% yield).

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[0158] Intermediate 110 [ka] tert-Butyl N-[[7-(tert-butoxycarbonylamino)-3-cyclopropyl-1-fluoro-7,8-dihydro-6H-cyclopenta[g]isoquinolin-5-yl]sulfonyl-N-(2-fluoro-2-methyl-propyl)carbamate The title compound was prepared using the same procedure described for Intermediate 103, using Intermediate 109 (0.3 g, 0.40 mmol), N,N-dimethylformamide (1 mL), and tetrabutylammonium fluoride 1 M in THF (1.2 mL). Purification by column chromatography afforded the title compound (124 mg, 52% yield).

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[0159] Intermediate 111 and Intermediate 112 [ka] 7-Amino-3-cyclopropyl-1-fluoro-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide (111) 7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-1-methoxy-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide (112) Intermediate 110 (74 mg, 0.12 mmol) was dissolved in DCM (5 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified using an SCX cartridge to give the mixture of title compounds, which was carried on to the next step without further purification. LCMS [M+H] + 396, retention time 1.88 minutes; [M+H] + 408, retention time 2.16 minutes (Method 10).

[0160] Intermediate 113 [ka] tert-Butyl 5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylate The title compound was prepared using general procedure 2 with intermediate 15 (290 mg, 0.77 mmol) and tert-butyl 5-bromopyridine-2-carboxylate (298 mg, 1.15 mmol) with stirring at room temperature for 2 hours. The crude material was purified by flash chromatography eluting with a gradient of ethyl acetate in heptane followed by a gradient of methanol in ethyl acetate to give the title compound (384 mg, 84% yield). LCMS [M+H] + 555, retention time 1.92 minutes (method 1).

[0161] Intermediate 114 [ka] 3-Bromo-5-[(2-methoxy-4-pyridyl)oxy]pyridine A mixture of 3-bromo-5-fluoropyridine (232, 1.3 mmol), 2-methoxypyridin-4-ol (150 mg, 1.2 mmol), and potassium carbonate (249 mg, 1.8 mmol) in DMF (4 mL) was heated in a microwave reactor at 200 °C for 30 min. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (50 mg, 15% yield). LCMS [M+H] + 281 / 283, retention time 1.76 minutes (method 1).

[0162] Intermediate 115 [ka] 3-Cyclopropyl-5-[(3-fluorooxetan-3-yl)methylsulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid To a stirred solution of (3-fluorooxetan-3-yl)methanamine (180 mg, 1.7 mmol) and DIPEA (0.22 mL, 1.28 mmol) in anhydrous DCM (1.5 mL) was added Intermediate 10 (500 mg, 1.42 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with 1 M aqueous HCl (approximately 3 mL), and the formed white precipitate was filtered off to give the title compound (250 mg, 41% yield). The aqueous layer was then extracted with CHCl3 / IPA (3:1, 2 × 15 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography eluting with a gradient of ethyl acetate in heptane followed by a gradient of methanol in ethyl acetate to give a second batch of the title compound (140 mg, 23% yield).

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[0163] Intermediate 116 [ka] 7-Amino-3-cyclopropyl-N-[(3-fluorooxetan-3-yl)methyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a stirred suspension of intermediate 115 (250 mg, 0.6 mmol) in anhydrous THF (10 mL) was added triethylamine (210 μL, 1.49 mmol), followed by DPPA (135 μL, 0.6 mmol), and the resulting mixture was heated to reflux (75° C.) for 2 h. The mixture was cooled, and 1 M aqueous HCl (10 mL) was added. The mixture was stirred at room temperature for 30 min and then washed with ethyl acetate (2×10 mL). The aqueous layer was basified to pH >10 with 1 M NaOH and extracted with ethyl acetate / MeOH (5:1, 3×10 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography using a gradient of ethyl acetate in heptane followed by a gradient of methanol in ethyl acetate afforded the title compound (110 mg, 45% yield). LCMS [M+H] + 392, retention time 1.31 minutes (method 1).

[0164] Intermediate 117 [ka] 3-Cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid 3,3-Difluorocyclobutan-1-amine hydrochloride (1.08 g, 7.50 mmol) and DIPEA (3.27 mL, 18.8 mmol) were dissolved in DCM (40 mL), followed by the addition of Intermediate 10 (2.20 g, 6.25 mmol) in portions. The mixture was stirred at room temperature for 15 minutes. 1M aqueous NaOH (50 mL) and DCM (50 mL) were added, and the layers were separated. The aqueous layer was washed with DCM (50 mL), and the basic aqueous layer was carefully acidified with 3M aqueous HCl and extracted with EtOAc (50 mL), followed by 1:1 IPA / chloroform (4 x 50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (1.59 g, 54% yield). LCMS [M+H] + 423.0, retention time 1.71 minutes (method 1).

[0165] Intermediate 118 [ka] (7S)-7-Amino-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of Intermediate 13 (16 g, 35.5 mmol) in DCM (160 mL) at 0 °C was added trifluoroacetic acid (25.8 mL, 335 mmol). The reaction was stirred at room temperature for 6 h, then cooled to 0 °C and basified to pH 8-9 with 4 M aqueous NaOH (75 mL), followed by saturated aqueous NH4Cl. The suspension was extracted with a 1:1 mixture of CHCl3 and IPA (200 mL, then 2 × 150 mL), and the combined organics were washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. This material was suspended in EtOAc (200 mL), and 1 M aqueous NaOH (100 mL) was added. The layers were separated, and the organic layer was further washed with 1 M aqueous NaOH. The aqueous layers were combined and extracted with EtOAc (100 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, concentrated in vacuo, and dried in a vacuum oven to give the title compound (10.5 g, 83%). LCMS [M+H] + 378.2, retention time 1.46 minutes (method 1).

[0166] Intermediate 119 [ka] 7-Amino-3-cyclopropyl-N-(3,3-difluorocyclobutyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 117 (1.59 g, 3.39 mmol) was stirred in anhydrous THF (20 mL), followed by the addition of triethylamine (1.18 mL, 8.47 mmol) and DPPA (0.73 mL, 3.39 mmol). The reaction was heated at 75 °C for 45 minutes and then cooled to 0 °C in an ice bath. This solution was added to a cooled solution of 3 M aqueous HCl (20 mL), and the biphasic solution was stirred at room temperature for 1 hour. The solution was then extracted with EtOAc (2 × 50 mL), and the aqueous layer was basified with 1 M aqueous NaOH and then extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with 1 M aqueous NaOH, resulting in the formation of a precipitate. The layers were separated, and the aqueous layer was extracted with a 1:1 mixture of IPA and CHCl (2 × 50 mL). The combined organics were dried (MgSO), filtered, and concentrated under reduced pressure. Purification by column chromatography using a gradient of methanol in dichloromethane gave the title compound (516 mg, 39% yield).

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[0167] Intermediate 120 [ka] tert-Butyl N-[3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate Intermediate 119 (0.41 g, 1.02 mmol) was stirred in DCM (10 mL). Triethylamine (0.14 mL, 1.02 mmol) was then added, followed by di-tert-butyl dicarbonate (0.25 g, 1.13 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (20 mL), washed with water (2 × 20 mL), dried over sodium sulfate, and concentrated under vacuum. Addition of diethyl ether and sonication gave a precipitate, which was collected by vacuum filtration and dried to give the title compound (400 mg, 78% yield).

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[0168] Intermediate 121 [ka] 3-Cyclopropyl-5-(isobutylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid; hydrochloride Intermediate 10 (0.6 g, 1.6 mmol) was stirred in MeCN (30 mL) and acetic acid (0.46 mL, 7.99 mmol) and water (0.14 mL, 7.99 mmol) were added, followed by 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.63 g, 3.2 mmol). The reaction was stirred at room temperature for 45 minutes. The solid sulfonyl chloride was collected by vacuum filtration, suspended in DCM (150 mL), and cooled to 0° C. 2-Methylpropan-1-amine (2 mL, 20.1 mmol) was then added, and the solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo, and 1 M aqueous HCl (50 mL) was added and sonicated to afford a white solid that was collected by vacuum filtration and subsequently concentrated in vacuo with MeCN to afford the title compound as the HCl salt (511 mg, 82% yield).

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[0169] Intermediate 122 [ka] 7-Amino-3-cyclopropyl-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 121 (0.51 g, 1.32 mmol) in anhydrous THF (15 mL) was added triethylamine (0.46 mL, 3.29 mmol) and DPPA (0.31 mL, 1.45 mmol). The reaction was heated to 75 °C for 2.5 h, allowed to cool, and then added dropwise to 1 M aqueous HCl (15 mL) and heated at 30 °C for 30 min, then 40 °C for 30 min. Saturated aqueous NaCO (25 mL) was added to the solution, which was then extracted with DCM (50 mL, then 20 mL). The combined organics were washed with saturated aqueous NaCO (2 × 25 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by SCX column using MeOH in DCM followed by column chromatography gave the title compound (326 mg, 63% yield).

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[0170] Intermediate 123 [ka] 1-[3-cyclopropyl-5-(isobutylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-3-(3-pyridyl)thiourea To a solution of intermediate 122 (0.16 g, 0.45 mmol) in DCM (5 mL) was added DIPEA (62 μL, 0.45 mmol), followed by 3-isothiocyanatopyridine (60 μL, 0.54 mmol). The suspension was stirred for 16 h, after which a second portion of 3-isothiocyanatopyridine (30 μL, 0.27 mmol) was added. The reaction mixture was stirred for 2 h. The white suspension was diluted with heptane (5 mL), filtered, and the solid was washed with DCM to give the title compound (210 mg, 93% yield).

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[0171] Intermediate 124 [ka] (7R)-7-Amino-3-cyclopropyl-N-(3,3-difluorocyclobutyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 131 (9.1 g, 18.4 mmol) was dissolved in DCM (70 mL) and TFA (14 mL, 182 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. Ethyl acetate (200 mL) and 1 M aqueous NaOH (200 mL) were added to the resulting oil. The layers were separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic extracts were washed with 1 M aqueous NaOH (50 mL), and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The light brown solid was then triturated with TBME and collected by vacuum filtration to give the title compound (6 g, 79% yield).

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[0172] Intermediate 125 [ka] (7S)-7-Amino-3-cyclopropyl-N-(3,3-difluorocyclobutyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 130 (8.64 g, 17.5 mmol) was dissolved in DCM (70 mL) and TFA (13.6 mL, 178 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. Ethyl acetate (200 mL) and 1 M aqueous NaOH (200 mL) were added to the resulting oil. The layers were separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic extracts were washed with 1 M aqueous NaOH (50 mL) and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a light brown solid which was triturated with TBME and collected by vacuum filtration to give the title compound (6 g, 84% yield).

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[0173] Intermediate 126 and Intermediate 127 [ka] Benzyl N-[(7R)-5-benzylsulfanyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate (126) Benzyl N-[(7S)-5-benzylsulfanyl-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate (127) To a solution of intermediate 9 (10 g, 26.6 mmol) in THF (100 mL) was added triethylamine (9.28 mL, 66.6 mmol), followed by DPPA (5.74 mL, 26.6 mmol). The reaction was heated to 75° C. for 2 h. Benzyl alcohol (8.28 mL, 79.9 mmol) was then added, and the mixture was heated at 75° C. for 6.5 h. Once at room temperature, 1 M aqueous NaOH (100 mL) was added, and the reaction mixture was extracted with ethyl acetate (2×200 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo to give an orange solid, which was triturated twice with diethyl ether to give a white solid. The solid was purified by column chromatography using ethyl acetate in heptane to give the title compound as a racemic compound (1.6 g). The filtrate from the diethyl ether trituration was purified by column chromatography using ethyl acetate in heptane to give a second batch of racemic product (3.2 g). The two batches were combined (5 g, 38% yield).

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[0174] The racemate (8.4 g) [Note: an additional 3.4 grams was obtained from a separate experiment] was purified by supercritical fluid LC using a CHIRALCEL ODI column (50 × 290 mm) eluting with 20% EtOH in CO at 30 °C to give the title compounds as individual isomers.

[0175] Intermediate 126 Chiral retention time** = 2.20 min (4.1 g)

[0176] Intermediate 127 Chiral retention time** = 2.68 min (4.1 g) **Analytical chiral HPLC was performed using a CHIRALPAK IB column (4.6 x 150 mm) eluted with IPA 50% n-heptane 50% DEA 0.1% at 30°C at a rate of 1.5 ml / min.

[0177] Intermediate 128 [ka] Benzyl N-[(7R)-3-cyclopropyl-5-[(3-fluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate Intermediate 126 (0.5 g, 1.04 mmol) was stirred in a mixture of MeCN (10 mL), acetic acid (300 μL, 5.2 mmol), and water (94 μL, 5.2 mmol). The suspension was cooled in an ice bath, and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (410 mg, 2.08 mmol) was added. The reaction was allowed to warm to room temperature, and after 1.5 h, the suspension was filtered under vacuum, and the solid was washed with MeCN to give the sulfonyl chloride as a white solid. This was added to a stirred solution of 3-fluorocyclobutan-1-amine hydrochloride (144 mg, 1.14 mmol) and DIPEA (0.72 mL, 4.16 mmol) in DCM (10 mL). After 1 h, the reaction was concentrated in vacuo and purified by column chromatography using ethyl acetate in heptane to give the title compound (410 mg, 77%). LCMS [M+H] + 510.0, retention time 1.92 minutes (method 2).

[0178] Intermediate 129 [ka] (7R)-7-Amino-3-cyclopropyl-N-(3-fluorocyclobutyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To intermediate 128 (350 mg, 0.69 mmol) and lead-contaminated 5% Pd on CaCO (Lindlar's catalyst, 5%, 439 mg, 0.08 mmol) was added water (4 mL) and THF (12 mL). The reaction was stirred under 1 atmosphere of H for 3 hours. Additional lead-contaminated 5% Pd on CaCO (5%, 200 mg, 0.04 mmol) was added, and the reaction was stirred under 1 atmosphere of H for 2 hours. The reaction was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The yellow oil was purified by column chromatography using MeOH in DCM. The resulting oil was dissolved in DCM, heptane was added, and the solution was concentrated in vacuo to give a solid that was triturated with heptane and collected by vacuum filtration to give the title compound (207 mg, 72%) as a mixture of cis and trans isomers. LCMS [M+H] + 376.2, retention times 1.39 and 1.42 min (Method 2).

[0179] Intermediate 130 and Intermediate 131 [ka] tert-Butyl N-[(7S)-3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate (130) tert-Butyl N-[(7R)-3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamate (131) Intermediate 120 (0.3 g) was separated by chiral SFC using column IF 50 x 250 at 30°C, flow rate of 360 mL / min, collecting at 220 nm, and eluting with 20% MeOH+CO2 to obtain the title compound.

[0180] Intermediate 130 (S isomer, 135 mg) Chiral retention time** = 2.51 min

[0181] Intermediate 131 (R isomer, 138 mg) Chiral retention time** = 3.89 min **Chiral analysis was performed by normal phase using a Chiralpak IF-3 150 x 4.6 mm, 3 μM, flow rate 1.5 mL / min, eluting with 49% dichloromethane:49% n-heptane:2% ethanol (+0.1% diethylamine) on an Agilent 1290 Infinity UV directing system with an 8 minute run time.

[0182] Intermediate 132 [ka] 5-Bromo-N-(3-pyridyl)pyrimidin-4-amine A solution of 1 M potassium bis(trimethylsilyl)amide in THF (1.24 mL, 1.24 mmol) was added to a solution of 3-aminopyridine (127 mg, 1.33 mmol) in THF (4.5 mL) at −78° C. The reaction was stirred for 5 min, after which a solution of 5-bromo-4-chloropyrimidine (220 mg, 1.08 mmol) in THF (0.5 mL) was added. The reaction was stirred at −78° C. for an additional 1.5 h and then quenched by the slow addition of saturated aqueous NH4Cl (20 mL) and DCM (10 mL) at 0° C. The layers were separated, and the aqueous layer was extracted with DCM (2 × 15 mL). The organic layer was passed through a phase separator, concentrated in vacuo and purified by column chromatography on silica (gradient elution with 0% to 100% EtOAc in isohexane, 0% to 20% MeOH in EtOAc) to give the title compound (94.2 mg, 35% yield).

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[0183] Intermediate 133 [ka] 5-Bromo-N-(cyclopropylmethyl)pyrimidin-4-amine Cyclopropylmethylamine (0.12 mL, 1.4 mmol) and DIPEA (0.22 mL, 1.3 mmol) were added to a solution of 5-bromo-4-chloropyrimidine (104 mg, 0.509 mmol) in MeCN (2.5 mL). The reaction was stirred at 120° C. in a microwave for 1 h, concentrated in vacuo, and purified by column chromatography on silica (gradient elution from 0% to 100% EtOAc in isohexane) to give the title compound (116 mg, quantitative). LCMS [M+H] + 228.2 / 230.2, retention time 0.93 minutes (method 6).

[0184] Intermediate 134 [ka] 3-Cyclopropyl-5-iodo-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid To a stirred solution of intermediate 7 (4 g, 8.84 mmol) in THF (40 mL) was added 2 M lithium hydroxide monohydrate (8.84 mL, 17.7 mmol) and the mixture was stirred at 50° C. for 1.5 h. The reaction was diluted with water and the solvent was reduced in vacuo. The remaining aqueous solution was acidified to pH=1 with 1 M HCl. The thick paste that formed was diluted with water, filtered with suction, and then dried overnight under vacuum at 40° C. to give the title compound (3.66 g) as a pale yellow solid. LCMS [M+H] + 380, retention time 1.76 minutes (method 1).

[0185] Intermediate 135 [ka] 3-Cyclopropyl-5-iodo-N-methoxy-N-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide To a stirred suspension of Intermediate 134 (1.8 g, 4.75 mmol) in anhydrous DMF (30 mL) was added N,O-dimethylhydroxylamine hydrochloride (695 mg, 7.12 mmol), followed by triethylamine (2.3 mL, 16.6 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. HATU (2.17 g, 5.7 mmol) was added, and stirring was continued at room temperature for 72 hours. The mixture was diluted with ethyl acetate (70 mL) and washed with 1 M HCl (30 mL), water (30 mL), 1 M NaOH (30 mL), water (30 mL), and brine (30 mL), then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane to give the title compound (1.72 g, 81% yield) as a yellow gum.

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[0186] Intermediate 136 [ka] 1-(3-cyclopropyl-5-iodo-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl)ethenone To a stirred solution of intermediate 135 (1.72 g, 4.1 mmol) in anhydrous THF (20 mL) cooled to −78 °C under nitrogen, methylmagnesium bromide (3.2 M in 2-Me-THF) (2.54 mL, 8.13 mmol) was added dropwise, and the mixture was allowed to reach 0 °C and left stirring for 1 h. Saturated aqueous NH4Cl (10 mL) was added dropwise, and the mixture was allowed to warm to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (2 × 30 mL). The combined organics were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (1.42 g, 89% yield) as a yellow gum that solidified on standing.

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[0187] Intermediate 137 [ka] (E)-1-(3-cyclopropyl-5-iodo-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl)-3-(dimethylamino)prop-2-en-1-one A stirred suspension of intermediate 136 (200 mg, 0.53 mmol) in DMF-DMA (0.7 mL, 5.3 mmol) was heated to 105 °C in a sealed tube for 7 h. The reaction was cooled to room temperature, and the brown solid was dissolved in ethyl acetate (20 mL) and washed with saturated aqueous NH4Cl / water (1:1, 15 mL), water (10 mL), brine (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane, followed by 0% to 30% methanol in ethyl acetate to afford the title compound (152 mg, 66% yield) as a red solid.

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[0188] Intermediate 138 [ka] 5-(3-cyclopropyl-5-iodo-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl)isoxazole A mixture of intermediate 137 (865 mg, 2 mmol) and hydroxylamine hydrochloride (186 mg, 2.1 mmol) in ethanol (15 mL) was stirred under nitrogen at 85° C. for 84 h. The solvent was reduced in vacuo and the residue purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane to afford the title compound (650 mg, 81% yield) as a red solid.

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[0189] Intermediate 139 [ka] Methyl 3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylate Acetyl chloride (130 μL, 1.83 mmol) was added to methanol (80 mL) and stirred for 10 minutes, after which Intermediate 11 (91%, 4 g, 8.96 mmol) was added. The suspension was stirred and heated at 40° C. for 2.5 hours. The solvent was removed, and the residue was dissolved in EtOAc (200 mL), washed with saturated NaHCO (2×100 mL), dried over MgSO, filtered, and concentrated to give the title compound (3.63 g, 91% yield) as a light brown solid.

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[0190] Intermediate 140 [ka] Methyl 3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)-(2-trimethylsilylethoxymethyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylate Intermediate 139 (94%, 3.63 g, 8.11 mmol) was dissolved in DMF (60 mL) and cooled to 0 °C before adding NaH (60%, 380 mg, 9.5 mmol) in portions. The reaction was stirred at 0 °C for 10 min, then 2-(chloromethoxy)ethyl](trimethyl)silane (1.7 mL, 9.61 mmol) was added. The reaction was allowed to warm to room temperature, stirred for 15 min, quenched with water (100 mL), and then extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (100 mL), then brine (50 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 15% to 30% EtOAc / heptane to afford the title compound (3.42 g, 76% yield) as a pale yellow solid.

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[0191] Intermediate 141 [ka] 3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)-(2-trimethylsilylethoxymethyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid Intermediate 140 (105 mg, 0.191 mmol), 2 M aqueous lithium hydroxide (0.28 mL, 0.84 mmol), and THF (3 mL) were heated in a stirred pressure tube under reduced pressure at 40 °C for 3 h. The reaction was neutralized with 1 M aqueous HCl, and then pH 6.5 buffer (3 mL) was added. The mixture was extracted with ethyl acetate (2 × 40 mL), and the combined ethyl acetate extracts were washed with brine (10 mL), dried over MgSO, filtered, and concentrated in vacuo to give the title compound (98.7 mg, 92% yield) as a colorless oil.

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[0192] Intermediate 142 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-(hydroxymethyl)-N-(2-trimethylsilylethoxymethyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 141 (110 mg, 0.20 mmol) was dissolved in THF (2.5 mL) and cooled to 0 °C before adding 1.2 M DIBAL-H in toluene (198 μL). The reaction was stirred at 0 °C for 30 min, and an additional 200 μL of 1.2 M DIBAL-H in toluene was added. After 15 min, the reaction was quenched with water (20 μL), followed by 15% aqueous NaOH (20 μL) and more water (50 μL). After stirring for 15 min, the reaction was diluted with EtOAc (20 mL), washed with an aqueous solution of Rochelle's salt (2 × 20 mL), then brine (20 mL), and dried over MgSO. Removal of the solvent afforded the title compound (110 mg, 94% pure) as a colorless solid. LCMS [M+H] + 523.2, retention time 2.11 minutes (method 1)

[0193] Intermediate 143 [ka] [3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)-(2-trimethylsilylethoxymethyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]methyl methanesulfonate Intermediate 142 (94%, 110 mg, 0.2 mmol) was dissolved in DCM (2 mL) and DIPEA (86 μL, 0.49 mmol), followed by the addition of methanesulfonyl chloride (23 μL, 0.3 mmol). The solution was stirred at room temperature for 15 minutes, concentrated, and purified by silica column chromatography eluting with 30% to 60% EtOAc / heptane to afford the title compound (100 mg, 84% yield) as a colorless oil. LCMS [M+H] + 601.2, retention time 2.18 minutes (method 1)

[0194] Intermediate 144 [ka] 13-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-N-(2-trimethylsilylethoxymethyl)-12-azatetracyclo[8.4.0.03,8.04,6]tetradeca-1(10),2,8,11,13-pentaene-2-sulfonamide Potassium cyanide (12 mg, 0.18 mmol) was added to a mixture of Intermediate 143 (100 mg, 0.17 mmol) and TBAB (11 mg, 0.03 mmol) in DMF / water (2 mL / 0.2 mL). The mixture was stirred and heated at 100° C. for 3 h, diluted with EtOAc (25 mL), washed with water (3×25 mL) and then brine (25 mL), dried over MgSO4, and concentrated. The residue was purified by silica column chromatography eluting with 5% to 25% EtOAc / heptane to afford the title compound (75% yield) as a white solid.

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[0195] Intermediate 145 [ka] 7-[(5-benzyloxy-2-methyl-pyrazol-3-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 12 (45 mg, 0.119 mmol) in anhydrous 1,4-dioxane (1 mL) was added intermediate 188 (38 mg, 0.121 mmol), sodium tert-butoxide (35 mg, 0.364 mmol), and tBuXPhos Pd G3 (15 mg, 0.0183 mmol). The reaction was heated to 100° C. under a nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature, filtered through Celite, the solvent removed, and the residue purified by silica column chromatography eluting with 0% to 100% ethyl acetate in isohexane to give the title compound (78% yield) as a brown oil. LCMS [M+H] + 564.4, retention time 1.26 minutes (method 1)

[0196] Intermediate 146 [ka] 5-Iodo-4-tetrahydropyran-4-yloxy-pyrimidine To tetrahydro-4-pyranol (34 mg, 0.321 mmol) in 1,4-dioxane (1.1 mL) was added 4-chloro-5-iodopyrimidine (53 mg, 0.210 mmol), followed by sodium tert-butoxide (78 mg, 0.813 mmol), and the reaction was stirred under nitrogen at room temperature for 2 hours, then at 80° C. for 45 minutes. This crude solution was used in the next step. LCMS [M+H] + 307.0, retention time 1.33 minutes (method 6).

[0197] Intermediate 147 [ka] (7R)-7-[(2-cyanopyrimidin-5-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 15 (50 mg, 0.133 mmol) was dissolved in 1,4-dioxane (2 mL) and tBuXPhos Pd G3 (16 mg, 0.0195 mmol), sodium tert-butoxide (38 mg, 0.395 mmol) and 5-bromopyrimidine-2-carbonitrile (49 mg, 0.266 mmol) were added, and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc, filtered through Celite, and purified by silica column chromatography eluting with 0% to 100% EtOAc in hexanes to afford the title compound (26 mg, 41% yield) as a yellow oil. LCMS [M+H] + 481.2, retention time 1.08 minutes (method 6).

[0198] Intermediate 148 [ka] (7R)-7-[(6-chloro-4-cyano-3-pyridyl)amino]-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 15 (60 mg, 0.159 mmol) was dissolved in 1,4-dioxane (2 mL) and tBuXPhos Pd G3 (13 mg, 0.0159 mmol), and sodium tert-butoxide (45 mg, 0.468 mmol) and 5-bromo-2-chloro-pyridine-4-carbonitrile (58 mg, 0.2667 mmol) were added. The mixture was heated at 70 °C for 3 h. The reaction was diluted with EtOAc, filtered through Celite, and purified by silica column chromatography eluting with 0% to 100% EtOAc in hexane to give the title compound (30 mg, 37% yield). LCMS [M+H] + 514.1, retention time 1.22 minutes (method 6).

[0199] Intermediate 149 [ka] Methyl 6-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxylate To a suspension of Intermediate 15 (200 mg, 0.53 mmol) and methyl 6-bromopyridazine-3-carboxylate (138 mg, 0.64 mmol) in tert-butanol (8 mL) in a pressure tube was added DIPEA (0.28 mL, 1.59 mmol). The mixture was sealed and heated at 110° C. for 18 h. Removal of the solvent gave a brown oil, which was purified by silica column chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound (144 mg, 52% yield).

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[0200] Intermediate 150 [ka] 6-[[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxylic acid hydrochloride To a solution of intermediate 149 (53 mg, 0.1 mmol) in THF (3 mL) / water (0.75 mL) was added lithium hydroxide hydrate (1:1) (13 mg, 0.31 mmol). The solution was stirred at room temperature for 18 hours. The solvent was removed, 1N HCl (2 mL) was added, and the solvent was removed to quantitatively obtain the title compound as a brown gum. LCMS [M+H] + 500.0, retention time 1.56 minutes (method 1).

[0201] Intermediate 151 [ka] (7R)-7-[(6-(acetamidocarbamoyl)pyridazin-3-yl]amino]-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 150 (51 mg, 0.1 mmol) in DMF (3 mL) was added triethylamine (0.04 mL, 0.31 mmol), acetohydrazide (9.1 mg, 0.12 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (20.8 mg, 0.15 mmol), and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (1:1) (29.4 mg, 0.15 mmol). The solution was stirred for 18 hours, followed by the addition of N-[(dimethylamino)(3H-[1.2.3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (38.8 mg, 0.1 mmol) and stirring for 2 hours. Water (10 mL) and EtOAc (15 mL) were added, the organic layer was separated, washed with water (2 x 5 mL), dried (Na2SO4) and the solvent was removed. The residue was purified by silica column chromatography eluting with 0% to 10% 7M NH3 in methanol / DCM to give the title compound (42 mg, 74% yield). LCMS [M+H] + 556, retention time 1.60 minutes (method 1).

[0202] Intermediate 152 [ka] Methyl 4-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]isoquinoline-1-carboxylate Intermediate 15 (50 mg, 0.133 mmol), methyl 4-bromoisoquinoline-1-carboxylate (109 mg, 0.397 mmol), sodium tert-butoxide (38 mg, 0.397 mmol), and tBuXPhos Pd G3 (16 mg, 0.0199 mmol) were degassed with three vacuum / nitrogen cycles, followed by the addition of anhydrous 1,4-dioxane (2 mL). After another vacuum / nitrogen cycle, the reaction was sealed and stirred at room temperature for 45 minutes, followed by 70 °C for 2.5 hours. The reaction was diluted with water (3 mL) and extracted with EtOAc (3 mL). The organic extract was dried over NaSO, concentrated in vacuo, and purified by silica column chromatography eluting with 0% to 100% EtOAc in isohexane, followed by 0% to 5% MeOH in EtOAc to give the title compound (64 mg, 86% yield).

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[0203] Intermediate 153 [ka] 3-Cyclopropyl-5-[(2,2-dimethylcyclopropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid To a stirred solution of 2,2-dimethylcyclopropanamide hydrochloride (1:1) (42 mg, 0.34 mmol) and DIPEA (0.15 mL, 0.85 mmol) in anhydrous DCM (1 mL) was added Intermediate 10 (100 mg, 0.28 mmol), and the mixture was stirred at room temperature for 4 h. The mixture was diluted with DCM (2 mL) and treated with 1 M aqueous HCl (1 mL). The layers were separated, and the aqueous layer was extracted with DCM / MeOH (10:1, 2 x 10 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound (61 mg, 50%) as a white solid. LCMS [M+H] + 401, retention time 1.75 minutes (method 1).

[0204] Intermediate 154 [ka] 5-[[2-[tert-Butyl(diphenyl)silyl]oxy-2-methyl-propyl]sulfamoyl]-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxylic acid To a stirred solution of intermediate 193 (490 mg, 1.5 mmol) and DIPEA (0.74 mL, 4.3 mmol) in anhydrous DCM (10 mL) was added intermediate 10 (500 mg, 1.4 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM (20 mL), water (10 mL), and 1 M aqueous HCl (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organics were washed with 1 M HCl (10 mL), brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane, followed by 0% to 20% methanol in ethyl acetate to give the title compound (660 mg, 70% yield). LCMS [M+H] + 643, retention time 2.28 minutes (method 1).

[0205] Intermediate 155 [ka] 7-Amino-N-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl]-3-cyclopropyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To intermediate 154 (430 mg, 0.67 mmol) in anhydrous THF (12 mL) was added triethylamine (233 μL, 1.67 mmol), followed by DPPA (144 μL, 0.67 mmol), and the resulting mixture was heated to reflux for 2.5 h. The reaction was allowed to cool to room temperature, and 1 M aqueous HCl (12 mL) was added, and the mixture was stirred at room temperature for 1.5 h. 1 M NaOH was added to pH 10, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified using a 5 g SCX cartridge, washed with DCM (×2), MeOH (×3), and eluted with ammonia (7N in methanol) to give the title compound (340 mg, 64% yield, UV purity 77%) as a pale yellow solid. LCMS [M+H] + 614, retention time 2.06 minutes (method 1).

[0206] Intermediate 156 [ka] N-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl]-3-cyclopropyl-7-[(6-methylpyridazin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of intermediate 155 (100 mg, 0.16 mmol), 3-bromo-6-methylpyridazine (43 mg, 0.24 mmol), tBuXPhos Pd G3 (20 mg, 0.024 mmol), and sodium tert-butoxide (47 mg, 0.29 mmol) in anhydrous dioxane / tBuOH (2:1, 4.5 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organics were washed with saturated aqueous NH4Cl (10 mL), brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane, followed by 0% to 20% methanol in ethyl acetate, to afford the title compound (23% yield) as a yellow film. LCMS [M+H] + 706, retention time 2.19 minutes (method 1).

[0207] Intermediate 157 [ka] 1-[3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-3-(2-methyl-3-pyridyl)thiourea To a solution of Intermediate 12 (300 mg, 0.8 mmol) in anhydrous DCM (10 mL) was added a solution of 3-isothiocyanato-2-methylpyridine (120 mg, 0.8 mmol) in DCM (1 mL), and the resulting solution was stirred at room temperature under a nitrogen atmosphere overnight. The white precipitate that formed was filtered off and washed with DCM to give the title compound (326 mg, 75% yield) as a white solid. LCMS [M+H] + 528, retention time 1.68 minutes (method 1).

[0208] Intermediate 158 and Intermediate 159 [ka] 2-[(4-bromopyrazolo[3,4-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane 2-[(4-bromopyrazolo[3,4-c]pyridin-2-yl)methoxy]ethyl-trimethyl-silane NaH (60%, 24 mg, 0.61 mmol) was stirred in anhydrous DMF (3 mL) and cooled in an ice bath. 4-Bromo-1H-pyrazolo[3,4-c]pyridine (100 mg, 0.5 mmol) was added, and the mixture was allowed to warm to room temperature with stirring for 20 minutes. [2-(chloromethoxy)ethyl](trimethyl)silane (98 μL, 0.56 mmol) was added, and the reaction was stirred for 2 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (30 mL). The organics were washed with saturated aqueous NH4Cl (10 mL), water (10 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica column chromatography eluting with 0% to 60% ethyl acetate in heptane to give a 65:35 mixture of the two title compounds (120 mg, 72% yield) as a yellow oil. LCMS [M+H] + 328.0 / 330.0, retention time 1.99 min / 2.06 min (method 1).

[0209] Intermediate 160 and Intermediate 161 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[[1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[[2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A 65:35 isomeric mixture of Intermediate 12 (50 mg, 0.132 mmol), Intermediate 158 and Intermediate 159 (43 mg, 0.132 mmol), sodium tert-butoxide (38 mg, 0.397 mmol), and tBuXPhos Pd G3 (11 mg, 0.013 mmol) in dioxane (3 mL) and tBuOH (1.5 mL) in a 20 mL pressure tube was flushed with nitrogen, sealed, and heated to 110 °C with stirring for 3 h. Water (10 mL) was added, and the reaction was extracted with DCM (3 × 10 mL). The organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0% to 10% MeOH in DCM to give the title compound in two batches. Batch 1: 49 mg, 44% yield as individual isomers, and batch 2: 27 mg, 22% yield as a mixture of both title compound isomers (21% and 57%). Batch 1: LCMS [M+H] + 625.2, retention time 1.94 minutes (93%) (method 1) Batch 2: LCMS [M+H] + 625.2, retention time 1.94 minutes (21%), 625.2, retention time 1.90 minutes (57%) (method 1)

[0210] Intermediate 162 [ka] Methyl 5-[[3-cyclopropyl-5-(isobutylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylate Intermediate 122 (50 mg, 0.14 mmol), methyl 5-bromopyridine-2-carboxylate (45 mg, 0.21 mmol), sodium tert-butoxide (27 mg, 0.28 mmol), and tBuXPhos Pd G3 (11 mg, 0.01 mmol) in dioxane (3 mL) and tBuOH (1.5 mL) were heated with stirring in a sealed tube at 110 °C for 1 h 45 min. The reaction was allowed to cool, concentrated in vacuo, and purified by silica column chromatography eluting with 0% → 20% MeOH in DCM followed by preparative basic reverse-phase HPLC to afford the title compound (28 mg, 41% yield) as a white solid. LCMS [M+H] + 495.2, retention time 1.82 minutes (method 1).

[0211] Intermediate 163 [ka] Methyl 6-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxylate Intermediate 15 (300 mg, 0.79 mmol), methyl 6-bromopyridazine-3-carboxylate (207 mg, 0.95 mmol), and DIPEA (415 μL, 2.38 mmol) were heated in a sealed tube in tBuOH (10 mL) with stirring at 110° C. for 16 hours. The reaction was concentrated in vacuo, and the residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane to give a brown solid, which was dissolved in DCM and precipitated with heptane. The solid was collected by filtration to give the title compound (152 mg, 37% yield) as a gray solid.

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[0212] Intermediate 164 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-(3-pyridyl)-N-(2-trimethylsilylethoxymethyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Solution A: To intermediate 141 (25 mg, 0.047 mmol) was introduced a solution of HATU (18 mg, 0.047 mmol in 0.2 mL of anhydrous DMF) at room temperature under a nitrogen atmosphere. Then, a solution of trimethylamine (5 mg, 0.047 mmol in 0.1 mL of anhydrous DMF) was added and the reaction mixture was stirred for 1 h. Solution B: Isopropylmagnesium chloride lithium chloride complex (1.18 mL of a 1.3 M solution in tetrahydrofuran, 1.53 mmol) was diluted with anhydrous tetrahydrofuran (1.2 mL) and cooled to 0 °C under a nitrogen atmosphere. 3-Bromopyridine (220 mg, 1.39 mmol) was then introduced dropwise and stirring was continued at 0 °C for 30 min. Zinc(II) chloride (1.67 mL of a 1.0 M solution in anhydrous tetrahydrofuran, 1.67 mmol) was then added. Separately, a flask was charged with nickel(II) chloride glyme complex (2 mg, 0.009 mmol) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (5 mg, 0.019 mmol). Anhydrous DMF (0.2 mL) was introduced, followed by solution A at room temperature under a nitrogen atmosphere. After 5 minutes, solution B (0.52 mL, 0.093 mmol) was introduced, and the reaction mixture was diluted with anhydrous THF (0.2 mL). After 20 hours, the reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate (20 mL). The solution was washed with water (3 × 15 mL), and the organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (LCMS-UV NMR (MS / MS) δ 1.04-1.04 (2.04), ... 215 Purity 27%, [M+H] + A crude residue containing 570, retention time 4.87 min (Method 9) was obtained and used in the next synthetic step without purification.

[0213] Intermediate 165 [ka] 3-Cyclopropyl-N-(3,3-difluorocyclobutyl)-7-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of Intermediate 117 (500 mg, 1.184 mmol) and Meldrum's acid (188 mg, 1.302 mmol) in anhydrous dichloromethane (10 mL) was introduced 4-dimethylaminopyridine (217 mg, 1.775 mmol). After cooling to 0 °C under a nitrogen atmosphere, EDC·HCl (318 mg, 1.657 mmol) was added in portions over 20 min, and the reaction mixture was then allowed to warm to room temperature. After 24 h, the reaction mixture was concentrated in vacuo to give the crude title compound (LCMS-UV NMR (MS) δ 1.07-1.08, 1.07-1.08). 215 649 mg with 67% purity was obtained, which was used in the next synthetic step without further purification. LCMS [M+H] + 549, retention time 1.81 minutes (method 1).

[0214] Intermediate 166 [ka] Ethyl 3-[3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-3-oxo-propanoate A solution of intermediate 165 (649 mg, 67% purity) in ethanol was heated to reflux under a nitrogen atmosphere for 48 hours. The pH of the reaction mixture was adjusted to pH 1 with 10% trifluoroacetic acid in ethanol and refluxing was continued for another 4 hours. The reaction mixture was concentrated in vacuo, ethyl acetate (40 mL) was introduced to the residue and the solution was washed with 0.1 M aqueous hydrochloric acid (5 mL), water (2×5 mL) and brine (5 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (LCMS-UV 215716 mg with 83% purity was obtained, which was used in the next synthetic step without further purification. LCMS [M+H] + 493, retention time 3.16 minutes (method 2).

[0215] Intermediate 167 [ka] (7R)-7-[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazolo[3,4-c]pyridin-4-yl]amino]-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 15 (50 mg, 0.13 mmol), Intermediate 191 (65 mg, 0.18 mmol), sodium tert-butoxide (38 mg, 0.4 mmol), and tBuXPhos Pd G3 (11 mg, 13.25 μmol) were dissolved in dioxane (3 mL) and tBuOH (1.5 mL) and stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite, concentrated, and purified by silica column chromatography eluting with 0% to 10% MeOH / DCM to give the title compound (20 mg, 23% yield) as a yellow oil. LCMS [M+2H] 2+ 327.2, retention time 1.96 minutes (method 1)

[0216] Intermediate 168 [ka] (7R)-7-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazolo[3,4-c]pyridin-4-yl]amino]-3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 15 (50 mg, 0.13 mmol), Intermediate 192 (65 mg, 0.18 mmol), sodium tert-butoxide (38 mg, 0.4 mmol), and tBuXPhos Pd G3 (11 mg, 13.25 μmol) were dissolved in dioxane (3 mL) and tBuOH (1.5 mL) and stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite, concentrated, and purified by silica column chromatography eluting with 0% to 100% EtOAc / heptane, then 0% to 5% MeOH / DCM to afford the title compound (30 mg, 35% yield) as a yellow oil. LCMS [M+2H] 2+ 327.2, retention time 1.94 minutes (method 1)

[0217] Intermediate 169 [ka] Methyl 6-[[(7R)-3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxylate Intermediate 124 (100 mg, 0.25 mmol) and methyl 6-bromopyridazine-3-carboxylate (66 mg, 0.30 mmol) were heated in a sealed tube in tert-butanol (6 mL) containing DIPEA (133 μL, 0.76 mmol) at 110° C. for 16 h. The reaction was concentrated and purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane to give the title compound (64 mg, 39% yield, 82% purity) as a brown oil. LCMS [M+H] + 530.1, retention time 1.74 minutes (method 1).

[0218] Intermediate 170 [ka] 9-Bromo-7-chloro-N-isobutyl-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-sulfonamide To Intermediate 22 (33 mg, 0.11 mmol) in DCM (3 mL) was added DIPEA (41 μL, 0.23 mmol) and 2-methylpropyl)sulfamoyl chloride (23.9 mg, 0.14 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 1 h, then diluted with DCM (30 mL) and saturated NaHCO (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (20 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 20% to 70% EtOAc in heptane to afford the title compound (40 mg, 82% yield) as a white solid. LCMS [M+H] + 418 / 420, retention time 2.01 min (method 1).

[0219] Intermediate 171 [ka] 9-Benzylsulfanyl-7-chloro-N-isobutyl-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-sulfonamide To Intermediate 170 (40 mg, 0.096 mmol) in dioxane (2 mL) was added phenylmethanethiol (12.3 μL, 0.10 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (2.6 mg, 0.006 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) (1.71 mg, 0.003 mmol), and DIPEA (33.2 μL, 0.19 mmol). The mixture was degassed with nitrogen for 20 minutes and heated at 90° C. for 6 hours. The solvent was removed, DCM and water were added, and the organic layer was separated, washed with brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 20% to 60% EtOAc in heptane to give the title compound as an off-white solid (47 mg, 91% yield, 86% purity). LCMS [M+H] + 462, retention time 2.10 minutes (method 1).

[0220] Intermediate 172 [ka] 7-Chloro-2-(isobutylsulfamoyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonyl chloride Intermediate 171 (47 mg, 0.10 mmol) was dissolved in acetonitrile (2 mL) and cooled to 0° C. Water (10 μL) and acetic acid (29 μL) were added, followed by 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (40 mg, 0.20 mmol), and stirring was continued for 5 minutes at 0° C. and for 1 hour at room temperature. The white solid was filtered off and washed with cold acetonitrile to give the title compound (22 mg, 45% yield, 91% purity) as a white solid. LCMS [M+H] in MeOH + 438, retention time 2.01 min (+ methyl ester) (Method 1).

[0221] Intermediate 173 [ka] 7-chloro-N9-(2-fluoro-2-methyl-propyl)-N2-isobutyl-1,3-dihydropyrrolo[3,4-g]isoquinoline-2,9-disulfonamide To a solution of intermediate 172 (20 mg, 0.046 mmol, 91% purity) in DCM (2 mL) was added dropwise a premixed solution of 2-fluoro-2-methylpropan-1-amine hydrochloride (7.0 mg, 0.05 mmol) and DIPEA (19.8 μL, 0.11 mmol) in DCM (1 mL) at 0° C., and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (20 mL), washed with water, and the combined organic layers were dried over MgSO and concentrated under reduced pressure to give the crude product, which was purified by silica column chromatography eluting with 25% to 60% EtOAc in heptane to give the title compound (20 mg, 89% yield).

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[0222] Intermediate 174 [ka] 6,7-bis(bromomethyl)-3-chloro-isoquinoline Intermediate 18 (750 mg, 3.91 mmol) was dissolved in EtOAc (40 mL) and NBS (1.46 g, 8.21 mmol) was added, followed by AIBN (64.2 mg, 0.39 mmol). The reaction mixture was divided into two large microwave vials and heated at 100 °C for 30 min. The reactions were combined, diluted with EtOAc, washed with aqueous NaSO, water, and brine, dried over MgSO, and concentrated to give the crude product, which was purified by silica column chromatography eluting with 0% to 40% EtOAc in heptane to give the title compound (320 mg, 21% yield) as an off-white solid.

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[0223] Intermediate 175 [ka] 7-Chloro-2-trityl-1,3-dihydropyrrolo[3,4-g]isoquinoline Intermediate 174 (100 mg, 0.28 mmol), tritylamine (74 mg, 0.28 mmol), and N,N-diisopropylethylamine (0.12 mL, 0.71 mmol) in anhydrous DMF (2 mL) were stirred at 60 °C under nitrogen for 2 h, followed by the addition of another 0.5 equivalents of tritylamine and stirring at 60 °C for an additional 3 h. The solvent was removed, and the residue was diluted to 15 mL with ethyl acetate, washed with water and brine, dried over anhydrous MgSO, and the solvent was removed. The residue was purified by silica column chromatography eluting with hexane / EtOAc (9:1) to give the title compound (127 mg, 99% yield) as a pale yellow solid.

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[0224] Intermediate 176 [ka] 7-Chloro-2,3-dihydro-1H-pyrrolo[3,4-g]isoquinoline; 2,2,2-trifluoroacetic acid Intermediate 175 (127 mg, 0.28 mmol) in 10% trifluoroacetic acid in dichloromethane (10 mL) was stirred under nitrogen at room temperature for 30 minutes, then diluted to 5 mL with ethanol and stirred for an additional 15 minutes. The solvent was removed and the residue (95 mg, 87% yield) was used without further purification. LCMS [M+H] + 205.2, retention time 0.47 minutes (method 1).

[0225] Intermediate 177 [ka] 7-Chloro-N-ethyl-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-carboxamide To a solution of intermediate 176 (90 mg, 0.28 mmol) in DCM (6 mL) was added isocyanatoethane (24.5 μL, 0.031 mmol), followed by DIPEA (123 μL, 0.70 mmol). The reaction was stirred at room temperature for 1 h, and the resulting solid was filtered off and washed with DCM to give the title compound (41 mg, 53% yield) as an off-white solid. LCMS [M+H] + 276.2, retention time 1.67 minutes (method 1).

[0226] Intermediate 178 [ka] 9-Bromo-7-chloro-N-ethyl-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-carboxamide Intermediate 177 (25 mg, 0.091 mmol) was added batchwise to sulfuric acid (141 μL) in DCM (3 mL) at 0° C. The reaction mixture was cooled to −10° C., and N-bromosuccinamide (17.7 mg, 0.1 mmol) was added portionwise. The reaction was maintained at −10° C. for 2 hours and then at room temperature for 16 hours. An additional equivalent of N-bromosuccinamide was added and stirred at room temperature for 6 hours. The reaction mixture was diluted with 20 mL of ice water, and the pH of the solution was adjusted to 8–10 with concentrated ammonium hydroxide. The resulting solution was extracted with DCM (2×15 mL), dried (sodium sulfate), and concentrated. The residue was purified by silica column chromatography eluting with 50% to 100% EtOAc in heptane, followed by 1% to 10% MeOH in DCM to give the title compound (22 mg, 55% yield, 80% purity) as a white solid.

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[0227] Intermediate 179 [ka] 9-Benzylsulfanyl-7-chloro-N-ethyl-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-carboxamide To a sealed tube was added Intermediate 178 (22 mg, 0.05 mmol, 80% pure), phenylmethanethiol (6.39 μL, 0.055 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (1.72 mg, 0.003 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) (1.36 mg, 0.001 mmol), and DIPEA (17.2 μL, 0.099 mmol) in dioxane (1 mL). The mixture was degassed with nitrogen for 20 minutes, sealed, and heated at 85° C. for 18 hours. The solvent was removed, DCM and water were added, and the organic layer was separated, washed with brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 50%→100% EtOAc followed by 0%→10% MeOH in DCM to give the title compound (25 mg, 72% yield, 57% purity) as a white solid. LCMS [M+H] + 398.2, retention time 1.82 minutes (method 1).

[0228] Intermediate 180 [ka] 7-Chloro-N-ethyl-9-(isobutylsulfamoyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-carboxamide Intermediate 179 (25 mg, 0.044 mmol) was dissolved in DCM (2 mL) and cooled to 0 °C. Water (4.5 μL), acetic acid (12.1 μL), and thionyl chloride (17.8 μL, 0.22 mmol) were added, and stirring was continued at 0 °C for 5 min and at room temperature for 1 h. The reaction mixture was cooled to 0 °C, isobutylamine (34.9 μL, 0.35 mmol) was added, and the reaction was stirred at room temperature for 1 h. The reaction was diluted with water (10 mL), the aqueous phase was extracted with DCM (2 × 10 mL), and the combined organics were washed with water, dried (NaSO), filtered, and concentrated to give the crude product, which was purified by silica column chromatography eluting with 50% to 100% EtOAc in heptane, followed by 0% to 10% MeOH in DCM to give the title compound (20 mg, 62% yield, 56% purity) as a white solid. LCMS [M+H] + 411.2, retention time 1.73 minutes (method 1).

[0229] Intermediate 181 [ka] N-[(5-bromo-2-pyridyl)sulfonyl]-N-(2-trimethylsilylethoxymethyl)acetamide A solution of N-[(5-bromopyridin-2-yl)sulfonyl]acetamide (85 mg, 0.30 mmol) in DMF (3 mL) was stirred with sodium hydride (60% oil dispersion, 13.4 mg, 0.33 mmol) at 0° C. and then warmed to 20° C. under nitrogen. After 15 min, the reaction was cooled to 0° C., 2-(chloromethoxy)ethyl-trimethyl-silane (50.7 mg, 0.30 mmol) was added, and the mixture was stirred at 20° C. for 3 h. Phosphate buffer (pH 6.5, 6 mL) was added, and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with water (2×20 mL), followed by brine (20 mL). The solution was dried (NaSO) and evaporated to dryness. The residue was purified by silica column chromatography eluting with 0% to 20% EtOAc in heptane to afford the title compound (71 mg, 57% yield) as a colorless oil.

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[0230] Intermediate 182 and Intermediate 183 [ka] 5-Bromo-2-(4-methyltriazol-1-yl)pyridine and 5-Bromo-2-(4-methyltriazol-2-yl)pyridine In a 30 mL ChemGlass vessel under a nitrogen atmosphere, 5-bromo-2-chloropyridine (500 mg, 2.47 mmol) and cesium carbonate (1770 mg, 5.43 mmol) were suspended in N,N-dimethylacetamide (5 mL). To this mixture was added 4-methyl-1H-1,2,3-triazole (325 mg, 3.72 mmol), and the resulting suspension was heated at 130° C. for 3 hours. The reaction was poured into water (25 mL), and the solid was filtered off, washed with water (×3), and dried under vacuum overnight to give 421 mg of a 57:39 mixture of Intermediate 182 and Intermediate 183 as a white solid. LCMS [M+H] +239 / 241, retention times 0.88 min (Intermediate 182) and 0.91 min (Intermediate 183) (Method 6)

[0231] Intermediate 184 [ka] 2-chloro-4-(cyclopropylmethoxy)-5-iodo-pyridine To cyclopropanemethanol (45 μL, 0.569 mmol) in DMF (1.5 mL) in a pressure-tested, capped 8 mL vial under nitrogen was added potassium tert-butoxide (72 mg, 0.629 mmol). After 10 min, 2,4-dichloro-5-iodopyridine (150 mg, 0.520 mmol) was added and stirred at room temperature for 18 h. The reaction was quenched with 10% aqueous ammonium chloride (2 mL) and extracted with DCM (2 × 3 mL). The DCM layer was filtered through a phase separator, the solvent removed, and the residue purified by silica column chromatography eluting with 0% to 15% EtOAc / DCM, then 40% EtOAc / DCM to give the title compound (68 mg, 41% yield) as a white solid.

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[0232] Intermediate 185 [ka] 3-Bromo-4-(1-methylpyrazol-3-yl)oxy-pyridine 1-Methyl-1H-pyrazol-3-ol (114 mg, 1.120 mmol), 3-bromo-4-chloropyridine (200 mg, 1.019 mmol), and cesium carbonate (498 mg, 1.527 mmol) were suspended in DMF (7 mL) and the mixture was sealed and heated to 80° C. for 2.5 h. The reaction was diluted with water (10 mL), extracted with EtOAc (2×10 mL), the organics dried (NaSO), concentrated, and purified by silica column chromatography eluting with a 0% to 100% gradient of EtOAc in isohexane to afford the title compound (117 mg, 45% yield) as a colorless liquid.

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[0233] Intermediate 186 [ka] 5-Bromo-2-methylsulfinyl-pyridine Sodium periodate (4.2 g, 20 mmol) was added as a slurry in water (4 mL) to a stirred solution of 5-bromo-2-methylthiopyridine (1 g, 4.8 mmol) in acetic acid (25 mL) at 0 °C. Once the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 3.5 h. The reaction was treated with water (50 mL), basified by the addition of solid potassium carbonate powder, and extracted with EtOAc (3 × 50 mL). The combined organic phases were then washed with 10% aqueous sodium thiosulfate solution (50 mL), dried over NaSO, and the solvent removed. The resulting crude oil was purified by silica column chromatography eluting with 0% → 100% EtOAc in heptane to afford the title compound (838 mg, 80% yield) as a colorless oil that crystallized on standing.

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[0234] Intermediate 187 [ka] 2-(5-Bromopyrimidin-2-yl)-5-methyl-1,3,4-oxadiazole To a suspension of 5-bromopyrimidine-2-carbohydrazide (1 g, 4.6 mmol), triethylamine (700 mg, 6.9 mmol), and DCM (15 mL) was added acetic anhydride (520 mg, 5.1 mmol). Acetonitrile (10 mL) was added, and the reaction was stirred at room temperature for 45 minutes. The mixture was concentrated, suspended in DCM (5 mL), sonicated for 3 minutes, and the precipitate was collected and dried. The crude precipitate was suspended in acetonitrile (10 mL), and triethylamine (2.80 g, 28 mmol) was added. p-Toluenesulfonyl chloride (1300 mg, 6.9 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated, dissolved in water (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with a gradient of 0% to 10% MeOH in DCM to give the title compound as a pale brown solid. 1 H NMR (300 MHz, DMSO-d6) δ H 9.24(s,2H),2.63(s,3H).

[0235] Intermediate 188 [ka] 3-Benzyloxy-5-iodo-1-methyl-pyrazole To a colorless solution of 3-benzyloxy-1-methyl-pyrazole (246 mg, 1.31 mmol) in anhydrous THF (5 mL) at −78° C. was added n-butyllithium. After 30 min, a 5 mL solution of iodine in anhydrous THF was added and allowed to warm to room temperature overnight. The reaction was quenched with 2 mL of saturated NH4Cl (aq) and 2 mL of 1 M Na2SO5 (aq), diluted with 20 mL of 1.5 M Na2CO3 (aq), extracted into 3×30 mL of DCM, dried, and concentrated. The residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate followed by reverse-phase basic C18 column chromatography eluting with 0% to 100% MeCN in water to give the title compound (54.5 mg, 11.5% yield). LCMS [M+H] + 315.0, retention time 1.19 minutes (method 1).

[0236] Intermediate 189 [ka] 4-Bromo-1-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-one 4-Bromopyridin-2-ol (59 mg, 0.33 mmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (50 mg, 0.30 mmol) in DMF (2.0 mL) was flushed with nitrogen, then potassium carbonate (84 mg, 0.61 mmol) was added and stirring was continued for 1.5 h in a microwave at 90 °C. The mixture was partitioned between water and EtOAc, the organic layer was dried (MgSO) and evaporated, and the residue was purified by silica column chromatography eluting with 40% → 100% EtOAc in n-heptane to give the title compound (36 mg, 40% yield with 88% purity) as a white solid.

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[0237] Intermediate 190 [ka] tert-Butyl N-[(5-bromo-2-pyridyl)sulfonyl]-N-methyl-carbamate To a solution of tert-butyl N-[(5-bromo-2-pyridyl)sulfonyl]carbamate (30 mg, 0.089 mmol) in anhydrous DMF (3 mL) was added sodium hydride (4.6 mg, 0.11 mmol) at 0 °C. After stirring at 0 °C for 0.5 h, iodomethane (6.6 μL, 0.10 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (10 mL), EtOAc (25 mL) was added, and the EtOAc layer was washed with water (2 × 10 mL). The organic layer was dried (Na SO ), filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0% → 30% EtOAc in heptane to afford the title compound (26 mg, 83% yield) as a white solid.

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[0238] Intermediate 191 and Intermediate 192 [ka] 2-(4-Bromopyrazolo[3,4-c]pyridin-1-yl)ethoxy-tert-butyl-dimethyl-silane and 2-(4-Bromopyrazolo[3,4-c]pyridin-2-yl)ethoxy-tert-butyl-dimethyl-silane 4-Bromo-1H-pyrazolo[3,4-c]pyridine (220 mg, 1.11 mmol) was dissolved in THF (5 mL) and (2-bromoethoxy)(tert-butyl)dimethylsilane (262 μL, 1.22 mmol) was added, followed by BEMP (354 μL, 1.22 mmol). The reaction mixture was heated to 40° C. with stirring for 8 h and then allowed to stand at room temperature for 16 h. The reaction was concentrated and the residue was purified by silica column chromatography eluting with 15% to 40% EtOAc / heptane to give 200 mg of intermediate 191 and 139 mg of intermediate 192 as a white solid.

[0239] Intermediate 191:

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[0240] Intermediate 192:

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[0241] Intermediate 193 [ka] 2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propan-1-amine To a stirred solution of 1-amino-2-methylpropan-2-ol (300 mg, 3.37 mmol) in dichloromethane (5 mL) was added 1H-imidazole (687 mg, 10 mmol), followed by tert-butyl(chloro)diphenylsilane (1.2 g, 4.38 mmol), and the resulting solution was stirred at room temperature for 22 hours. The mixture was partitioned between DCM (20 mL) and water (15 mL). The layers were separated, and the aqueous phase was extracted with DCM (15 mL). The combined organics were then washed with brine (15 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane, followed by 0% to 20% methanol in ethyl acetate to afford the title compound (875 mg, 79% yield) as a colorless oil.

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[0242] Example 1 [ka] (7R)-3-Cyclopropyl-N-(3-fluorocyclobutyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide General Procedure 2 using Intermediate 129 (110 mg, 0.26 mmol) and 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (95 mg, 0.4 mmol) was used at room temperature to give the title compound. Purification by column chromatography followed by reverse-phase HPLC (acidic conditions) afforded the title compound (33 mg, 23%) as a mixture of cis / trans isomers.

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[0243] Example 2 [ka] 13-Cyclopropyl- ~ {N}-(2-methylpropyl)-6-(5-pyridin-3-yl-1- ~ {H}-imidazol-2-yl)-12-azatetracyclo[8.4.0.0^{3,8}.0^{4,6}]tetradeca-1,3(8),9,11,13-pentaene-2-sulfonamide To a solution of Intermediate 41 (100 mg, 0.25 mmol) in anhydrous MeCN (3 mL) was added DIPEA (174 μL, 1.0 mmol), followed by 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (70 mg, 0.25 mmol). The reaction was stirred at room temperature for 2 hours. 2-Bromo-1-(pyridin-3-yl)ethanone hydrobromide (20 mg, 0.07 mmol) and DIPEA (100 μL, 0.57 mmol) were added, and the reaction was stirred for an additional hour. 2-Bromo-1-(pyridin-3-yl)ethanone hydrobromide (35 mg, 0.12 mmol) was added, and the reaction was stirred for 1 hour. The orange solution was diluted with ethyl acetate (40 mL), washed with saturated aqueous NaHCO3 (2 x 20 mL), brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was suspended in anhydrous toluene (3 mL), and ammonium acetate (95 mg, 1.25 mmol) was added. The mixture was then heated in a pressure tube at 110 °C for 16 h. The reaction was diluted with ethyl acetate (50 mL) and MeOH (5 mL) and washed with saturated aqueous NaHCO3 (30 mL). The aqueous layer was further extracted with 10% MeOH in EtOAc (20 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The orange residue was purified by column chromatography, then triturated with ethyl acetate and washed with a 1:1 mixture of ethyl acetate and heptane, followed by heptane, to give the title compound (20 mg, 16% yield).

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[0244] Example 3 [ka] (7R*)-3-Cyclopropyl-N-(2-methylpropyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide[* or S] General procedure 3 using intermediate 123 (210 mg, 0.42 mmol) was used to give the title compound. Purification by column chromatography using MeOH in DCM followed by chiral HPLC separation gave the title compound as a single isomer (18.7 mg, 9% yield). Chiral retention time** = 4.68.

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[0245] Example 4 [ka] 3-Cyclopropyl-N-(2-methylpropyl)-7-[(3-oxocyclopenten-1-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of intermediate 122 (40 mg, 0.11 mmol), cyclopentane-1,3-dione (11 mg, 0.11 mmol), and acetic acid (6.36 μL, 0.11 mmol) in 1,2-dichloroethane (4 mL) containing 4 Å molecular sieves was heated in a pressure tube at 90 °C for 3.5 h. The reaction mixture was washed with saturated NaHCO (2 mL) and extracted with DCM (2 × 3 mL). The organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using MeOH in DCM to give the title compound (28 mg, 57% yield).

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[0246] Example 5 [ka] 3-Cyclopropyl-7-[[4-(cyclopropylmethyl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide General procedure 3 was used with intermediate 92 (184 mg, 0.39 mmol) to give the title compound. Column chromatography with MeOH in DCM followed by purification by reverse-phase HPLC (basic conditions) gave the title compound (68 mg, 36% yield).

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[0247] Example 6 [ka] N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]pyridine-3-carboxamide Intermediate 12 (30 mg, 0.08 mmol) was dissolved in DCM (3 mL) and DIPEA (42 μL, 0.24 mmol) was added, followed by pyridine-3-carbonyl chloride hydrochloride (17 mg, 0.10 mmol). The reaction was stirred at room temperature for 30 minutes. Additional pyridine-3-carbonyl chloride hydrochloride (10 mg, 0.06 mmol) was added and the suspension was stirred for 30 minutes. One drop of DIPEA was added and the suspension was stirred for 1 hour. The solid was collected by filtration, washed with DCM, and dried in a vacuum oven to give the title compound (20 mg, 52% yield).

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[0248] Example 7 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(3-oxocyclohexen-1-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of intermediate 12 (45 mg, 0.12 mmol) and cyclohexane-1,3-dione (18 mg, 0.16 mmol) in 1,2-dichloroethane (4 mL) containing acetic acid (6.8 μL, 0.12 mmol) and 4 Å molecular sieves was heated to 90° C. for 3 h. The reaction was purified by SCX followed by trituration with ethanol to give the title compound (40 mg, 70% yield).

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[0249] Example 8 [ka] Ethyl 5-amino-1-[[7S)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]imidazole-4-carboxylate A mixture of ethyl 2-amino-2-cyano-acetate* (197 mg, 1.06 mmol, 69% purity) and triethyl orthoformate (176 μL, 1.06 mmol) in MeCN (10 mL) was heated in a pressure tube at 90 °C for 1 h to give a green solution. Once at room temperature, Intermediate 118 (400 mg, 1.06 mmol) was added and the reaction was stirred at room temperature for 1 h. The solid precipitate that formed was collected by vacuum filtration (washing with diethyl ether and MeCN) and dried in a vacuum oven to give the title compound (442 mg, 81% yield).

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[0250] Example 9 [ka] 3-Cyclopropyl-5-[(3-methyloxetan-3-yl)methylsulfamoyl]-N-pyridin-3-yl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide Intermediate 10 (97%, 70 mg, 0.19 mmol) was added portionwise to a mixture of (3-methyloxetan-3-yl)methanamine (20 mg, 0.19 mmol) and DIPEA (100 μL, 0.58 mmol) in DMF (1 mL). The reaction was stirred for 1 h. DIPEA (67 μL, 0.39 mmol), pyridin-3-amine (27 mg, 0.29 mmol), and HATU (88 mg, 0.23 mmol) were then added, and the mixture was stirred for 1 h. The reaction was diluted with DCM (3 mL) and washed with water (2 mL), saturated aqueous NH4Cl (2 mL), and water (2 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography afforded the title compound (9 mg, 9% yield).

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[0251] Example 10 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-(6-methylpyridin-3-yl)oxypyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide General procedure 2 using intermediate 15 (50 mg, 0.13 mmol) and intermediate 58 (53 mg, 0.2 mmol) at 80° C. for 2 hours gave the title compound. The reaction mixture was concentrated to dryness and the crude was purified by HPLC method 2 to give the title compound (41 mg, 55% yield).

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[0252] Example 11 [ka] 5-[[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxamide To a solution of Example 15 (30 mg, 0.06 mmol) in anhydrous DMF (0.5 mL) was added HATU (28 mg, 0.072 mmol), DIPEA (31 μL, 0.18 mmol), and ammonium chloride (32 mg, 0.6 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by HPLC method 2 to give the title compound (14 mg, 48% yield).

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[0253] Example 12 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(hydroxymethyl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide General procedure 2 using intermediate 15 (50 mg, 0.13 mmol) and (5-bromopyridin-2-yl)methanol (37 mg, 0.2 mmol) at 110° C. for 3 hours gave the title compound. Purification by column chromatography followed by HPLC method 2 gave the title compound (57 mg, 44% yield).

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[0254] Example 13 [ka] 3-Cyclopropyl-N-[(3-fluorooxetan-3-yl)methyl]-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide General procedure 2 using intermediate 116 (65 mg, 0.17 mmol) and 5-bromo-2-(2-methyltetrazol-5-yl)pyridine (60 mg, 0.25 mmol) at room temperature for 18 hours afforded the title compound. The reaction mixture was concentrated to dryness and the crude was purified by HPLC method 1 to afford the title compound (34.5 mg, 38% yield).

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[0255] Example 14 [ka] 3-Cyclopropyl-N-[(3-hydroxyoxetan-3-yl)methyl]-7-[(2-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide General procedure 2 using intermediate 46 (135 mg, 0.35 mmol) and intermediate 59 (110 mg, 0.52 mmol) at 80° C. for 2 hours gave the title compound, which was purified by column chromatography to give the title compound (32 mg, 18% yield).

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[0256] Example 15 [ka] 5-[[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid To a stirred solution of intermediate 113 (384 mg, 0.69 mmol) in DCM (10 mL) was added trifluoroacetic acid (1 mL, 13.9 mmol), and the resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 60 h. Trifluoroacetic acid (0.5 mL, 16.5 mmol) was added, and stirring was continued for a total of 84 h. The solution was concentrated in vacuo, and the residue was purified on an SCX cartridge (eluted with methanol and 7N ammonia in methanol) followed by HPLC method 2 to give the title compound (21.6 mg).

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[0257] Example 16 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-(2-methoxypyridin-4-yl)oxypyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide General procedure 2 using intermediate 15 (50 mg, 0.13 mmol) and intermediate 114 (50 mg, 0.18 mmol) at 80° C. for 2 hours gave the title compound. The reaction mixture was concentrated to dryness and the crude was purified by HPLC method 2 to give the title compound (11 mg, 14% yield).

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[0258] Example 17 [ka] 3-Cyclopropyl-N-(2-hydroxypropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of Intermediate 53 (105 mg, 0.3 mmol), cyclopropylboronic acid (79 mg, 0.92 mmol), and 2 M potassium carbonate (0.62 mL, 1.24 mmol) in 1,4-dioxane (3 mL) was degassed by sonication under a stream of nitrogen for 5 minutes. Bedford Catalyst (33 mg, 0.031 mmol) was added, and the mixture was heated to 120 °C in a microwave reactor for 2 hours. Cyclopropylboronic acid (79 mg, 0.92 mmol) was added, and the mixture was degassed by sonication under a stream of nitrogen for 5 minutes. Bedford Catalyst (33 mg, 0.031 mmol) was added, and the mixture was heated in a microwave at 120 °C for an additional hour. The mixture was partitioned between ethyl acetate (15 mL) and water (10 mL), the layers were separated, and the aqueous layer was further extracted with ethyl acetate (10 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography eluting with a gradient of ethyl acetate in heptane afforded the title compound (32 mg, 30% yield).

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[0259] Example 18 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(pyridin-3-ylamino)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 12 (49.2 mg, 0.13 mmol), Intermediate 132 (48.6 mg, 0.19 mmol), tBuXPhos Pd G3 (16.1 mg, 0.019 mmol), and sodium tert-butoxide (39.2 mg, 0.408 mmol) were placed under a N2 atmosphere and suspended in 1,4-dioxane (1.30 mL). The vial was flushed with nitrogen and the reaction was stirred at 100 °C for 10 min. tert-butyl alcohol (0.40 mL) was added and the reaction was stirred at 100 °C for an additional 40 min. Additional tBuXPhos Pd G3 (65.1 mg, 0.079 mmol) was added and the reaction was stirred at room temperature for 1 h, then at 70 °C for an additional 1.5 h. The reaction was diluted with DCM (20 mL) and washed with saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 15 mL). The combined organic layers were passed through a phase separator, concentrated in vacuo, and purified by column chromatography on silica (gradient elution with 0% to 100% EtOAc in isohexane, 0% to 20% MeOH in EtOAc) followed by basic preparative HPLC to give the title compound (1 mg, 1% yield).

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[0260] Example 19 [ka] 3-Cyclopropyl-7-[[4-(cyclopropylmethylamino)pyrimidin-5-yl]amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 12 (48.7 mg, 0.13 mmol), Intermediate 133 (39.7 mg, 0.174 mmol), tBuXPhos Pd G3 (14.5 mg, 0.0177 mmol), and sodium tert-butoxide (36.9 mg, 0.384 mmol) were placed under a N atmosphere and suspended in 1,4-dioxane (1.30 mL). The reaction was stirred at room temperature for 3 h, then diluted with DCM (20 mL) and washed with saturated aqueous NaHCO3 (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layer was passed through a phase separator, concentrated in vacuo, and purified by column chromatography on silica (gradient elution using 0% to 100% EtOAc in isohexane, 0% to 20% MeOH in EtOAc) to give the title compound (42 mg, 62% yield).

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[0261] Example 20 [ka] 7-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Hydrochloric acid (4 mol / L) in 1,4-dioxane (0.040 mL, 0.16 mmol) was added to a microwave vial containing Intermediate 12 (57 mg, 0.15 mmol), 2-chlorobenzimidazole (37.4 mg, 0.245 mmol), and 1-butanol (2.3 mL) under nitrogen. The reaction was stirred in a microwave at 150 °C for 0.5 h, concentrated in vacuo, dissolved in DCM (20 mL), and washed with saturated aqueous NaHCO (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were passed through a phase separator, concentrated in vacuo, and purified by basic preparative HPLC to give the title compound (3 mg, 4% yield).

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[0262] Example 21 [ka] 9-Amino-3-cyclopropyl-N-(2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide 1,4-Dioxane (1.5 mL) was dissolved in Intermediate 74 (61 mg, 0.17 mmol), cyclopropylboronic acid (48.3 mg, 0.53 mmol), cesium carbonate (139 mg, 0.42 mmol) and chloro(η 2 To a flask containing 1,4-dicyclohexyl-2,4-tris(2,4-di-tert-butylphenyl)phosphite (tricyclohexylphosphine)palladium(II) (9.1 mg, 0.008 mmol) was added under nitrogen. The reaction was degassed, placed under nitrogen, and then stirred in a microwave at 120 °C for 3 h. Additional cyclopropylboronic acid (48.6 mg, 0.54 mmol), chloro(η 2 -P,C-Tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II) (19.1 mg, 0.018 mmol), cesium carbonate (340 mg, 1.03 mmol), and 1,4-dioxane (1 mL) were added, and the reaction was degassed, placed under nitrogen again, and stirred in a microwave at 120 °C for a further 3 h. The reaction was diluted with DCM (30 mL) and washed with water (25 mL). The aqueous layer was extracted with DCM (2 × 25 mL), and the combined organic layers were passed through a phase separator, concentrated in vacuo, and purified by column chromatography on silica (gradient elution with 0% to 100% EtOAc in isohexane) to give the title compound (30.2 mg, 49% yield).

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[0263] Example 22 [ka] N-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-9-yl]acetamide Pyridine (11.0 μL, 0.136 mmol) followed by acetic anhydride were added to a suspension of Intermediate 74 (45 mg, 0.127 mmol) in DCM (2 mL) under nitrogen. The reaction was stirred at room temperature for 24.5 hours, then at 40° C. for 1.5 hours, then at room temperature for an additional 1.5 hours. The reaction was stirred for 6.5 hours before 4-dimethylaminopyridine (1.7 mg, 0.014 mmol) was added. The reaction was stirred for 8.5 hours before additional DCM (2 mL), pyridine (36.0 μL, 0.445 mmol), and acetic anhydride (36.8 μL, 0.38 mmol) were added. The reaction was stirred for 26 hours before additional acetic anhydride (0.19 mL, 2.0 mmol) and triethylamine (0.32 mL, 2.3 mmol) were added. After a total of 27.5 h, the reaction was diluted with DCM (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 × 10 mL) and the combined organic layers were passed through a phase separator and concentrated in vacuo. The resulting liquid was diluted with DCM (15 mL), washed with 1 M aqueous HCl (10 mL), passed through a phase separator, and concentrated in vacuo to give a solid (47.7 mg) containing a mixture of acetylated products.

[0264] The solid was dissolved in DCM (2.0 mL) under a nitrogen atmosphere and triethylamine (0.24 mL, 1.7 mmol) was added, followed by acetic anhydride (0.13 mL, 1.3 mmol). The reaction was stirred at room temperature for 20 hours. After stirring the reaction for 3 hours, 4-dimethylaminopyridine (6.0 mg, 0.049 mmol) was added. After stirring the reaction for 20 hours, the reaction was diluted with DCM (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 × 10 mL), and the combined organic layers were washed with 1 M aqueous HCl (10 mL), passed through a phase separator, and concentrated in vacuo to give the crude acetylated material (70.0 mg).

[0265] Cyclopropylboronic acid (52.1 mg, 0.576 mmol), palladium(II) acetate (8.5 mg, 0.038 mmol), tricyclohexylphosphonium tetrafluoroborate (18.3 mg, 0.0482 mmol), and tribasic potassium phosphate (97.0 mg, 0.457 mmol) were added to the crude acetylated material in a mixture (8.3 mmol) of toluene (1.5 mL) and water (0.15 mL). The reaction was degassed, placed under nitrogen, and stirred in a microwave at 120 °C for 3 h. The reaction was diluted with DCM (40 mL), washed with water (15 mL), and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were passed through a phase separator, concentrated in vacuo and purified by column chromatography on silica (gradient elution with 0%→100% EtOAc in isohexane then 0%→10% MeOH in EtOAc) to give a mixture of products (28.3 mg).

[0266] The product mixture was dissolved in MeOH (6 mL). Aqueous sodium hydroxide (2 mL, 1 mol / L) was added and the reaction was stirred for 3 days. The reaction was neutralized by the addition of 1 M aqueous HCl (2 mL, 2 mmol) and then concentrated in vacuo. The residue was dissolved in DCM (30 mL) and washed with water (15 mL). The aqueous layer was extracted with DCM (2 × 20 mL) and the combined organic layers were passed through a phase separator, concentrated in vacuo, and purified by column chromatography followed by basic preparative HPLC to give the title compound (3 mg, 6% yield).

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[0267] Examples 23 and 24 [ka] 5-[[3-Cyclopropyl-1-fluoro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxamide (23) Methyl 5-[[3-cyclopropyl-1-fluoro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylate (24) To a solution of intermediate 106 (24 mg, 0.04 mmol) in tetrahydrofuran (1 mL), HATU (19 mg, 0.05 mmol), ammonium chloride (10 mg, 0.20 mmol), and then N,N-diisopropylethylamine (17 μL, 0.10 mmol) were added, and the reaction was stirred at ambient temperature for 1.5 hours. The reaction was diluted with water (1 mL) and extracted with EtOAc (2×1 mL). The organic layer was dried over NaSO and concentrated in vacuo. The product was purified using column chromatography to give the title compound;

[0268] Example 23 (1.9 mg, 9.3% yield)

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[0269] Example 24 (0.5 mg, 2% yield)

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[0270] Examples 25 and 26 [ka] 3-Cyclopropyl-1-fluoro-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide (25) 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-1-methoxy-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide (26) The title compound was prepared by general procedure 1 using intermediate 111 and intermediate 112 (40 mg, approximately 80 μmol), sodium tert-butoxide (12 mg, 0.12 mmol), tBuXPhos Pd G3 (5 mg, 0.006 mmol), 3-(5-bromo-2-pyridyl)oxetan-3-ol (28 mg, 0.12 mmol) and 1,4-dioxane (0.5 mL). The product was purified by reverse-phase HPLC (basic conditions) to give:

[0271] Example 25 (1 mg, 5% yield)

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[0272] Example 26 (4 mg, 18% yield)

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[0273] Example 27 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide The title compound was prepared by general procedure 1 using intermediate 12 (50 mg, 0.13 mmol), 1-(5-bromo-2-pyridyl)-3-methyl-acetidin-3-ol (121 mg, 0.40 mmol), sodium tert-butoxide (28 mg, 0.40 mmol), tBuXPhos Pd G3 (16 mg, 0.02 mmol) and 1,4-dioxane (5 mL). Purification by column chromatography afforded the title compound (24 mg, 34% yield).

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[0274] Example 28 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-methoxypyridazin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide The title compound was prepared by general procedure 1 using intermediate 12 (120 mg, 0.32 mmol), 3-bromo-6-methoxypyridazine (158 mg, 0.80 mmol), sodium tert-butoxide (92 mg, 0.95 mmol), tBuXPhos Pd G3 (39 mg, 0.048 mmol) and 1,4-dioxane (5 mL). Purification by column chromatography afforded the title compound (98 mg, 63% yield).

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[0275] Example 29 [ka] 3-Cyclopropyl-1-fluoro-N-(2-fluoro-2-methyl-propyl)-7-[(1-methyl-6-oxo-pyridazin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide The title compound was prepared by general procedure 1 using intermediate 104 (50 mg, 0.13 mmol), 5-iodo-2-methyl-pyridazin-3-one (78 mg, 0.33 mmol), sodium tert-butoxide (38 mg, 0.40 mmol), tBuXPhos Pd G3 (16 mg, 0.02 mmol) and 1,4-dioxane (0.5 mL). Purification by column chromatography afforded the title compound (5.9 mg, 9% yield).

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[0276] Example 30 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(3-hydroxyoxetan-3-yl)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide The title compound was prepared by general procedure 1 using intermediate 15 (68 mg, 0.18), sodium tert-butoxide (52 mg, 0.54 mmol), tBuXPhos Pd G3 (22 mg, 0.027 mmol), 3-(5-bromopyrimidin-2-yl)oxetan-3-ol (104 mg, 0.45 mmol), and 1,4-dioxane (5 mL). Purification by column chromatography afforded the title compound (42 mg, 45% yield).

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[0277] Example 31 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide The title compound was prepared by general procedure 1 using intermediate 15 (50 mg, 0.13 mmol), 3-(5-bromo-2-pyridyl)-5-methyl-1,2,4-oxadiazole (95 mg, 0.40 mmol), sodium tert-butoxide (38 mg, 0.40 mmol), tBuXPhos Pd G3 (1.6 mg, 0.020 mmol) and 1,4-dioxane (2 mL). Purification by column chromatography afforded the title compound (28 mg, 39% yield).

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[0278] Example 32 [ka] (7R)-7-[(6-chloropyridin-3-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide The title compound was prepared by general procedure 1 using intermediate 15 (50 mg, 0.13 mmol), 5-bromo-2-chloropyridine (40 mg, 0.2 mmol), sodium tert-butoxide (38 mg, 0.40 mmol), tBuXPhos Pd G3 (16 mg, 0.02 mmol) and 1,4-dioxane (2.5 mL). Purification by column chromatography afforded the title compound (60 mg, 83% yield).

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[0279] Example 33 [ka] N-[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-6-methyl-1H-indole-3-carboxamide General procedure 4 using intermediate 15 (20 mg, 0.053 mmol) and 6-methyl-1H-indole-3-carboxylic acid was used to give the title compound, which was purified by column chromatography to give the title compound (7 mg, 25% yield).

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[0280] Example 34 [ka] N-[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1H-benzotriazole-5-carboxamide The title compound was prepared by general procedure 4 using intermediate 15 (20 mg, 0.053 mmol), benzotriazole-5-carboxylic acid, HATU (1.5 equiv.) instead of HBTU, DIPEA (3 equiv.), and DMF (1 mL). Purification by column chromatography afforded the title compound (10 mg, 37% yield).

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[0281] Example 35 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(methylsulfonimidoyl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 100 (45 mg, 0.071 mmol) in DCM (0.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred at ambient temperature overnight, concentrated in vacuo, and purified by basic reverse-phase column chromatography to give the title compound (21 mg, 59% yield).

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[0282] Example 36 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a mixture of Intermediate 15 (50 mg, 0.13 mmol), sodium tert-butoxide (38 mg, 0.40 mmol), tBuXPhos Pd G3 (17 mg, 0.021 mmol), and 5-(5-bromo-2-pyridyl)-3-methyl-1,2,4-oxadiazole (42 mg, 0.17 mmol) was added 1,4-dioxane (1 mL). After 64 h, the mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organics were purified by flash chromatography. Lyophilization afforded the title compound as an off-white solid (8 mg, 11% yield).

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[0283] Example 37 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a mixture of Intermediate 15 (710 mg, 1.88 mmol), sodium tert-butoxide (535 mg, 5.56 mmol), tBuXPhos Pd G3 (228 mg, 0.278 mmol), and 2-(5-bromo-2-pyridyl)-5-methyl-1,3,4-oxadiazole (670 mg, 2.79 mmol) was added 1,4-dioxane (12 mL). After 30 min, the mixture was diluted with dichloromethane (30 mL) and water (20 mL). The organics were purified by flash chromatography. Lyophilization afforded the title compound as an off-white solid (730 mg, 72% yield).

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[0284] Example 38 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a mixture of Intermediate 15 (520 mg, 1.38 mmol), sodium tert-butoxide (400 mg, 4.16 mmol), tBuXPhos Pd G3 (170 mg, 0.21 mmol), and 3-(5-bromo-2-pyridyl)oxetan-3-ol (480 mg, 2.1 mmol) was added 1,4-dioxane (10 mL). The mixture was heated to 100 °C for 90 min, then cooled and partitioned between dichloromethane (20 mL) and water (20 mL). The aqueous layer was extracted with dichloromethane (2 × 10 mL) and ethyl acetate (2 × 10 mL). The organics were concentrated under reduced pressure and purified by reverse-phase flash chromatography. Lyophilization afforded the title compound as an off-white solid (402 mg, 55% yield).

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[0285] Example 39 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-hydroxypropan-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a mixture of Intermediate 15 (50 mg, 0.13 mmol), sodium tert-butoxide (38 mg, 0.40 mmol), and tBuXPhos Pd G3 (16 mg, 0.019 mmol), a solution of 2-(5-bromo-2-pyridyl)propan-2-ol (43 mg, 0.20 mmol) in 1,4-dioxane (1 mL) was added, and the mixture was heated to 100 °C for 1 h, then cooled and partitioned between dichloromethane (3 mL) and water (1.5 mL). The organics were purified by reverse-phase flash chromatography. Lyophilization afforded the title compound as an off-white solid (48 mg, 71% yield).

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[0286] Example 40 [ka] 3-Cyclopropyl-7-[(1,1-dioxo-2,3-dihydrothiophen-4-yl)amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a suspension of 1,1-dioxothiolan-3-one (21 mg, 0.16 mmol) in tetrahydrofuran (0.5 mL) was added N,N-diisopropylethylamine (14 μL, 0.08 mmol) and Intermediate 12 (30 mg, 0.08 mmol). After 2.5 h, the mixture was concentrated under nitrogen and purified by flash chromatography. Lyophilization afforded the title compound as an off-white solid (2 mg, 5% yield).

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[0287] Example 41 [ka] (7R)-3-Cyclopropyl-N-(3,3-difluorocyclobutyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 124 (30 mg, 0.076 mmol) in 1,4-dioxane (1.5 mL, 18 mmol), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)-pyridine (28 mg, 1.10 mmol), tBuXPhos Pd G3 (10 mg, 0.012 mmol), and sodium tert-butoxide (23 mg, 0.24 mmol) were added. After 1 h at room temperature, the mixture was filtered through Celite. Concentration in vacuo followed by purification by flash column chromatography (elution with 0% to 100% EtOAc in hexanes, followed by 0% to 5% MeOH in DCM) afforded the title compound (25 mg, 59% yield).

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[0288] Example 42 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 15 (800 mg, 2.11 mmol) in 1,4-dioxane (30 mL) was added sodium tert-butoxide (600 mg, 6.23 mmol), tBuXPhos Pd G3 (260 mg, 0.31 mmol), and 5-bromo-2-(2-methyl-2h-tetrazol-5-yl)-pyridine (1 g, 4.16 mmol). The reaction mixture was flushed with nitrogen and stirred at room temperature for an additional 1.5 h. The mixture was diluted with EtOAc, filtered through Celite, and concentrated. The residue was purified by column chromatography (eluting with 0% to 100% EtOAc in hexanes, followed by 0% to 5% MeOH in DCM) to give the product as a light brown solid (0.9 g). This was suspended in a mixture of MeCN (5 mL) and water (1 mL). Filtration then afforded the title compound as a white solid (675 mg, 59% yield).

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[0289] Example 43 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-(6-methylpyridin-3-yl)sulfonylpyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 54 (99 mg, 0.315 mmol), sodium tert-butoxide (51 mg, 0.525 mmol), tBuXPhos Pd G3 (21 mg, 0.026 mmol), and tBuXPhos (11 mg, 0.026 mmol) were introduced into a pressure tube. Separately, nitrogen was bubbled through a solution of intermediate 15 (99 mg, 0.262 mmol) in a mixture of anhydrous 1,4-dioxane (2.0 mL) and tert-butanol (1.0 mL) for 10 minutes. The solution was transferred to a pressure tube, which was closed under a nitrogen atmosphere and warmed to 100 °C for 60 minutes. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was dissolved in dichloromethane and adsorbed onto silica in vacuo. The dry loaded material was purified by column chromatography eluting with a 0% to 4% by volume solution of methanolic ammonia (7M ammonia in methanol) in dichloromethane to give the title compound (175 mg, 90% yield).

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[0290] Example 44 [ka] 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-3-ethylurea Intermediate 122 (LCMS-UV) in anhydrous dichloromethane (2 mL) at 0 °C under nitrogen atmosphere 215 To a solution of 42 mg (0.062 mmol) of 53% purity was added a solution of ethyl isocyanate (8.3 mg, 0.117 mmol) in DCM (0.1 mL). The reaction mixture was allowed to warm to room temperature. After 50 min, the reaction mixture was concentrated in vacuo, and the residue was purified by high pH preparative liquid chromatography to give the title compound (13.9 mg, 52% yield).

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[0291] Examples 45 and 46 [ka] 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-3-ethylurea (45) 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-6-yl]-3-ethylurea (46) Intermediate 89 and Intermediate 90 (LCMS-UV) in dichloromethane (6 mL) at room temperature 215 To a solution of a 1:1 mixture of 200 mg (estimated 0.330 mmol) of 59% pure methylisopropylamine (36 mg, 0.278 mmol) and ethyl isocyanate (40 mg, 0.556 mmol) was introduced. After 24 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC (acidic conditions) afforded the title compound.

[0292] Example 45 (9.7 mg, 7% yield)

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[0293] Example 46 (10.5 mg, 7% yield)

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[0294] Examples 47 and 48 [ka] 3-Cyclopropyl-8-hydroxy-N-(2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide (47) 3-Cyclopropyl-6-hydroxy-N-(2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide (48) A 1:1 mixture of intermediate 80 and intermediate 81 ( 1 A sample of 80 mg (0.160 mmol) of 1H NMR purity 85% was dissolved in a mixture of 1,2-dimethoxyethane (4.0 mL) and water (1.2 mL). Silver(I) carbonate (156 mg, 0.566 mmol) was added to the solution, and the reaction mixture was warmed to 40 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL), the aqueous phase was separated, and the organic phase was dried over sodium sulfate. The dried organic extract was filtered through a shallow bed of diatomaceous earth (vacuum filtration), and the filtrate was concentrated under vacuum. Purification of the residue by preparative HPLC (acidic conditions) afforded the title compound.

[0295] Example 47 (6.1 mg, 10% yield)

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[0296] Example 48 (8.2 mg, 14% yield)

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[0297] Example 49 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-2-oxospiro[1,3-oxazolidine-4,7'-6,8-dihydrocyclopenta[g]isoquinoline-5'-sulfonamide Intermediate 85 (LCMS-UV) in anhydrous tetrahydrofuran (1.8 mL) 215To a solution of 53 mg (0.084 mmol) of 85% pure methylcellulose (III) was added triethylamine (25 mg, 0.247 mmol) and diphenylphosphoryl azide (30 mg, 0.109 mmol). The reaction was warmed to 75°C in a pressure vessel for 90 minutes under a nitrogen atmosphere. After cooling to 0°C, 1 M aqueous hydrochloric acid (3 mL) was added dropwise at 0°C. The reaction was then allowed to warm to room temperature. To the acidic solution was introduced additional tetrahydrofuran (1.5 mL). After 45 minutes at room temperature, the solution was concentrated in vacuo to remove tetrahydrofuran, and the pH of the aqueous residue was adjusted to pH 7.5 by the addition of saturated aqueous sodium bicarbonate. The basic aqueous solution was extracted with ethyl acetate (10 mL), and the pH of the aqueous solution was then adjusted to pH 12 with 1 M aqueous sodium carbonate and extracted again with ethyl acetate (10 mL). The pooled ethyl acetate extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. This residue was purified by preparative HPLC (basic conditions) to give the title compound (20.80 mg, 57% yield) as a colorless solid.

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[0298] Example 50 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(hydroxymethyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-6,8-dihydrocyclopenta[g]isoquinoline-5-sulfonamide Intermediate 88 (LCMS-UV) in dichloromethane (5 mL) at room temperature 215 To a solution of 50 mg (0.066 mmol) of 86% pure methylcellulose (2.5 mL) was added in portions. After 4 h, the reaction mixture was concentrated in vacuo, dissolved in dichloromethane (5 mL), and concentrated in vacuo. The residue was purified by preparative HPLC (basic conditions) to give the title compound (19.5 mg, 54% yield) as a colorless solid.

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[0299] Example 51 [ka] 2-(2-aminopyridin-3-yl)-7-cyclopropyl-N-(2-fluoro-2-methylpropyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide Intermediate 94 (20 mg, 0.04 mmol) was suspended in a 4:1 mixture of ethanol and water (2 mL) in a sealable tube. Ammonium chloride (11 mg, 0.21 mmol) was added, followed by iron powder (9.2 mg, 0.16 mmol). The tube was sealed and heated to 90 °C with stirring for 1.5 h. After cooling to room temperature, the mixture was filtered through Celite and washed with ethanol. The solution was concentrated under reduced pressure, dissolved in EtOAc (20 mL), and then washed with saturated aqueous NaHCO (20 mL), followed by brine (20 mL). The organic layer was dried over MgSO and concentrated under reduced pressure. Purification by column chromatography using a gradient of ethyl acetate in heptane afforded the title compound (3.1 mg, 16% yield).

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[0300] Example 52 [ka] 2-[4-[[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyrazolo[3,4-c]pyridin-1-yl]acetic acid Intermediate 15 (50 mg, 0.13 mmol), Intermediate 57 (50 mg, 0.16 mmol), sodium tert-butoxide (38 mg, 0.40 mmol), andt BuXPhos Pd G3 (11 mg, 13.3 μmol) was dissolved in THF (3 mL) and t The resulting mixture was dissolved in a mixture of 1.5 mL of HCl and 100 mL of HCl. The reaction mixture was stirred at room temperature for 6 hours, then filtered through Celite and concentrated under reduced pressure. Purification by column chromatography using a gradient of methanol in dichloromethane followed by reverse-phase HPLC (basic conditions) afforded the title compound (6.3 mg, 8% yield).

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[0301] Example 53 [ka] 3-Cyclopropyl-7-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 122 (30 mg, 0.08 mmol) in ethanol (1 mL) was added DIPEA (20 μL, 0.11 mmol) and 3,4-diethoxycyclobut-3-ene-1,2-dione (17 μL, 0.11 mmol). The solution was stirred at room temperature for 1 hour. 2 M ethylamine in THF (60 μL) was then added, and the solution was left standing at room temperature for 16 hours. After this time, 2 M ethylamine in THF (100 μL) was added. After standing at room temperature for 2 hours, a white precipitate formed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (basic conditions) to give the title compound (2.4 mg, 7% yield).

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[0302] Example 54 [ka] 3-Cyclopropyl-N-(2,2-dimethylpropyl)-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide Intermediate 95 (170 mg, 0.38 mmol) was dissolved in a mixture of DCM (10 mL) and water (46 μL, 2.55 mmol). Acetic acid (107 μL, 1.87 mmol) and sulfuryl dichloride (152 μL, 1.88 mmol) were then added, and the reaction mixture was stirred at room temperature for 1 h. Water (10 mL) and DCM (20 mL) were added, and the mixture was passed through a hydrophobic frit. The solution was then treated with 2-methylpropan-1-amine (136 μL, 1.37 mmol) and allowed to stand at room temperature for 15 min. The solution was concentrated under reduced pressure and purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (45 mg, 68% yield).

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[0303] Example 55 [ka] 3-Cyclopropyl-7-(methanesulfonamido)-N-(2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 122 (30 mg, 0.08 mmol) was dissolved in DCM (1 mL) and DIPEA (33 μL, 0.19 mmol), followed by the addition of methanesulfonyl chloride (7 μL, 0.09 mmol). The solution was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was purified by column chromatography using a gradient of ethyl acetate in heptane to give the title compound (13 mg, 38% yield).

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[0304] Example 56 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(3H-imidazo[4,5-c]pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 11 (100 mg, 0.22 mmol) was dissolved in DMF (1 mL) and DIPEA (0.09 mL, 0.52 mmol) was added, followed by HATU (95 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then pyridine-3,4-diamine (25 mg, 0.23 mmol) was added. After stirring at room temperature for 1 hour, the solution was diluted with EtOAc (20 mL) and washed with water (2 × 10 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was dissolved in acetic acid (1 mL) and heated to 60 °C for 1 hour. Once at room temperature, the solution was diluted with EtOAc (20 mL), and saturated aqueous NaHCO was added to form an emulsion, which was filtered. The collected white solid was washed with EtOAc and water and dried under vacuum to give the title compound (30 mg, 27% yield).

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[0305] Example 57 [ka] 3-Cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide General procedure 3 using intermediate 96 (215 mg, 0.34 mmol, 85% purity) was used to give the title compound. Column chromatography followed by purification by SCX cartridge and reverse-phase HPLC (acidic conditions) gave the title compound (2 mg, 1 yield).

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[0306] Example 58 [ka] 3-Cyclopropyl-7-[2-(cyclopropylmethylamino)imidazol-1-yl]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 97 (247 mg, 0.39 mmol) was stirred in DMF (5 mL) and 2,2-diethoxyethanamine (170 μL, 1.17 mmol) was added, followed by mercury dichloride (315 mg, 1.16 mmol). After stirring the reaction mixture at room temperature for 5 minutes, triethylamine (160 μL, 1.15 mmol) was added, and the mixture was heated at 90° C. with stirring for 30 minutes. p-Toluenesulfonic acid monohydrate (440 mg, 2.31 mmol) was added, and stirring was continued at 90° C. for 2.5 hours before cooling to room temperature. The reaction mixture was diluted with DCM and Celite was added. The mixture was filtered through a Celite plug and washed with DCM. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL), washed with water (2×20 mL) and brine, dried over MgSO4, and concentrated under reduced pressure. Purification by column chromatography using a gradient of methanol in dichloromethane followed by reverse phase HPLC (acidic conditions) afforded the title compound (2.8 mg, 1% yield).

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[0307] Example 59 [ka] 2-[7-cyclopropyl-9-(2-methylpropylsulfamoyl)-1,3-dihydropyrrolo[3,4-g]isoquinolin-2-yl]-N-ethylacetamide To a solution of Example 60 (20 mg, 0.06 mmol) in MeCN (2 mL) was added KCO (20 mg, 0.14 mmol) and 2-bromo-N-ethylacetamide (11.5 mg, 0.07 mmol). The solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was diluted with DCM (20 mL) and water. The organic layer was dried over MgSO, concentrated under reduced pressure, and purified by column chromatography eluting with 50 to 100% EtOAc / heptane to give the title compound (8 mg, 32% yield).

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[0308] Example 60 [ka] 7-Cyclopropyl-N-(2-methylpropyl)-2,3-dihydro-1H-pyrrolo[3,4-g]isoquinoline-9-sulfonamide Intermediate 29 (13 mg, 0.29 mmol) was dissolved in MeOH (0.5 mL) and 1 M aqueous KCO solution (0.14 mL) was added. The solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was diluted with DCM (10 mL) and water. The organic layer was dried over MgSO, concentrated under reduced pressure, and purified by column chromatography eluting with 0 to 20% MeOH in DCM to give the title compound (2.5 mg, 25% yield).

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[0309] Example 61 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-sulfamoylpyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 98 (85 mg, 0.10 mmol) was dissolved in DCM (3 mL) and cooled to 0° C. TFA (0.41 mL, 5.3 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 16 h. The solvent was removed, and the residue was dissolved in a mixture of AcOH (6 mL) and water (3 mL) and heated at 70° C. for 2 h. The solvent was removed, and the brown residue was purified by acidic reverse-phase HPLC to give the title compound (22 mg, 38% yield).

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[0310] Example 62 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(3H-imidazo[4,5-c]pyridin-7-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of intermediate 78 and intermediate 79 (74 mg, 0.11 mmol) was dissolved in DCM (3 mL) and cooled to 0 °C. TFA (0.45 mL, 5.9 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was then diluted with DCM (15 mL), and the solution was washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with DCM (3 × 10 mL), and the organics were combined, dried over sodium sulfate, and concentrated in vacuo. Purification by basic reverse-phase HPLC afforded the title compound (10.5 mg, 18% yield).

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[0311] Example 63 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(2-oxo-1H-pyridin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of intermediate 75 (30 mg, 0.062 mmol) and lithium iodide (166 mg, 1.23 mmol) was dissolved in N-methyl-2-pyrrolidone (1.5 mL) and stirred at 200 °C for 30 min under microwave irradiation. Water (10 mL) was added, and the reaction mixture was extracted with DCM (3 × 10 mL). The organics were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by acidic reverse-phase HPLC to give the title compound (1.4 mg, 5% yield).

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[0312] Example 64 [ka] Ethyl 5-[[7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]-1,3,4-thiadiazole-2-carboxylate To a solution of Intermediate 15 (50 mg, 0.13 mmol) in DMF (4 mL) was added ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate (30.6 mg, 0.16 mmol) and DIPEA (0.09 mL, 0.53 mmol). The solution was heated at 90° C. for 6 h. Water (10 mL) and EtOAc (15 mL) were added to the mixture. The organic layer was separated, washed with brine (5 mL), and then passed through a phase separator frit. Removal of the solvent gave a brown oil. The oil was purified by flash column chromatography eluting with a gradient of 0 to 100% EtOAc in heptane to give the title compound as a brown oil (62 mg, 88% yield).

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[0313] Example 65 [ka] tert-Butyl N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]cinnolin-7-yl]carbamate To a suspension of intermediate 69 (160 mg, 0.29 mmol) in tert-butyl alcohol (10 mL) was added DIPEA (130 μL, 0.75 mmol) and diphenylphosphoryl azide (70 μL, 0.32 mmol). The resulting mixture was heated in a sealed vessel at 85° C. for 4 h 40 min. The reaction mixture was diluted with DCM (30 mL) and saturated NaHCO (30 mL), and the phases were separated. The aqueous layer was extracted with DCM (2×20 mL), and the combined organics were dried and concentrated in vacuo. Purification by column chromatography eluting with 0→50% EtOAc in isohexane afforded the title compound (43 mg, 26% yield).

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[0314] Example 66 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]cinnoline-5-sulfonamide The title compound was obtained by following general procedure 1 using intermediate 91 (72 mg, 0.16 mmol), 2-(5-bromo-2-pyridyl)-5-methyl-1,3,4-oxadiazole (78 mg, 0.32 mmol), dioxane (2 mL), tBuXPhos (20 mg, 0.02 mmol), and sodium tert-butoxide (47 mg, 0.49 mmol). Purification by column chromatography eluting with 0% to 30% MeOH in EtOAc afforded the title compound (63 mg, 68% yield).

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[0315] Example 67 [ka] 3-Cyclopropyl-1-methyl-N-(2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of Example 69 (7 mg, 0.020 mmol) and [Ir[dF(CF3)ppy]2(dtbpy)]PF6 (1.3 mg, 0.0012 mmol) was dissolved in a mixture of MeCN (100 μL) and TFA (100 μL). The reaction mixture was flushed with argon and treated with tert-butyl peroxyacetate (19 μL, 0.059 mmol). Under an argon atmosphere, the reaction was irradiated with an array of LED lights (120 mW, wavelength 470 nm) for 18 hours. The mixture was purified by reverse-phase HPLC to give the title compound (926 μg, 13% yield).

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[0316] Example 68 [ka] 7-Cyclopropyl-N-(2-methylpropyl)-[1,3]dioxolo[4,5-g]isoquinoline-9-sulfonamide Intermediate 33 (34 mg, 0.16 mmol) was dissolved in DCM (2 mL) and chlorosulfonic acid (37 mg, 0.32 mmol) was added. The solution was stirred at room temperature for 15 min and then heated at 40° C. for 20 min. The mixture was added dropwise to a stirred biphasic solution of DCM (10 mL) and ice water (10 mL). After 2 min of stirring, the organic layer was separated. The aqueous phase was further extracted with DCM (2×5 mL). The combined organic layers were passed through a phase separator and excess isobutylamine (93 mg, 1.28 mmol) was added. The solution was stirred for 18 h and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with a 0→60% EtOAc gradient in heptane to afford the title compound as a brown solid (6.3 mg, 13% yield).

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[0317] Example 69 [ka] 3-Cyclopropyl-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Nitrogen was bubbled through a mixture of 1,4-dioxane (6.0 mL) and 2 M aqueous potassium carbonate (0.44 mL, 0.88 mmol) for 10 min, then Intermediate 51 (100 mg, 0.295 mmol), cyclopropaneboronic acid (51 mg, 0.590 mmol), and Bedford's catalyst (32 mg, 0.030 mmol) were introduced. After nitrogen was bubbled through for an additional 5 min, the reaction vessel was closed and warmed to 120 °C for 2 h. The reaction mixture was treated with additional cyclopropaneboronic acid (51 mg, 0.590 mmol) and Bedford's catalyst (32 mg, 0.030 mmol) and then warmed to 120 °C for an additional 2 h. After cooling, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (2 × 5 mL) and brine (1 × 5 mL). The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. Purification of the residue by preparative HPLC (acidic conditions) afforded the title compound (62 mg, 61% yield) as a colorless solid.

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[0318] Example 70 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[4-(5-methyl-1,3,4-oxadiazol-2-yl)anilino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 15 (25 mg, 0.066 mmol) in 1,4-dioxane (2 mL) was added 2-(4-bromophenyl)-5-1,3,4-oxadiazole (24 mg, 0.10 mmol) and sodium tert-butoxide (19 mg, 0.20 mmol). The mixture was degassed (vacuum / nitrogen cycles (×3)) and tBuXPhos palladium G3 (8 mg, 0.01 mmol) was added. The mixture was again degassed (vacuum / nitrogen cycles (×3)) and then stirred at 75 °C for 2 h and then at room temperature overnight. The solution was filtered through Celite and washed with dioxane (×3). The filtrate was then evaporated to leave a yellow gum, which was purified by column chromatography eluting with 10% to 100% EtOAc in isohexane to give the title compound (24 mg, 67% yield).

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[0319] Example 71 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(4-oxo-1,5-dihydroimidazo[4,5-c]pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 11 (100 mg, 0.25 mmol), 2-methoxypyridine-3,4-diamine (35 mg, 0.25 mmol), DBU (147 μL, 0.98 mmol), and T3P (50% in DMF) (435 μL, 0.74 mmol) in DMF (1 mL) were heated in a microwave at 180 °C for 10 min. The reaction was diluted with ethyl acetate (10 mL) and washed with saturated NaHCO3 (10 mL), the layers were separated, and the aqueous layer was extracted with more ethyl acetate (10 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by acidic preparative HPLC to afford the title compound (5 mg, 4% yield) as a beige solid.

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[0320] Example 72 [ka] 7-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-2-(2-pyridin-3-ylacetyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide To Intermediate 27 (30 mg, 0.083 mmol) in anhydrous DCM (2 mL) was added pyridin-3-ylacetic acid hydrochloride (1:1) (17 mg, 0.099 mmol), DIPEA (43 μL, 0.248 mmol), and HATU (38 mg, 0.099 mmol), and the resulting mixture was stirred at room temperature under nitrogen for 1 hour. The mixture was diluted with DCM (15 mL) and washed with saturated aqueous NH4Cl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), then dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by acidic preparative HPLC to afford the title compound (4.7 mg, 12% yield) as an off-white solid.

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[0321] Example 73 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-fluoropyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of intermediate 15 (30 mg, 0.079 mmol), 5-bromo-2-fluoropyridine (21 mg, 0.12 mmol), tBuXPhos Pd G3 (9.5 mg, 0.012 mmol), and sodium tert-butoxide (23 mg, 0.24 mmol) in anhydrous dioxane / tBuOH (2:1, 1.5 mL) was stirred at room temperature for 2 h. The solvent was removed, and the residue was purified by acidic preparative HPLC to give the title compound (5.9 mg, 16% yield) as a beige solid.

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[0322] Example 74 [ka] 3-Cyclopropyl-N-(3,3-difluorocyclobutyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To Intermediate 119 (205 mg, 0.52 mmol) was added 3-(5-bromopyridin-2-yl)oxetan-3-ol (180 mg, 0.78 mmol), tBuXPhos Pd G3 (63 mg, 0.08 mmol), and sodium tert-butoxide (152 mg, 1.58 mmol), followed by a 2:1 mixture of anhydrous dioxane / tBuOH (15 mL). The reaction mixture was sonicated under a stream of nitrogen for 5 minutes and then stirred at 100 °C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (15 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with saturated aqueous NH4Cl (10 mL), brine (10 mL), dried over magnesium sulfate, concentrated, and the residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane followed by 0% to 20% methanol in ethyl acetate to afford the title compound (160 mg, 57% yield) as a pale yellow solid.

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[0323] Example 75 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-[(2-oxo-1H-pyridin-4-yl)oxy]pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a suspension of Example 16 (30 mg, 0.052 mmol) and sodium iodide (39 mg, 0.26 mmol) in anhydrous acetonitrile (3 mL) was added TMSCl (13 μL, 0.11 mmol) and the mixture was stirred at 60° C. More TMSCl (13 μL, 0.11 mmol) was added and stirring was continued at 60° C. for 3 h. The reaction was filtered through Celite, washed with ethyl acetate, and collected by washing the Celite with methanol, and the solvent was removed. The residue was purified by acidic preparative HPLC to give the title compound (3 mg, 10%) as an off-white solid.

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[0324] Example 76 [ka] 3-Cyclopropyl-N-[(3-hydroxyoxetan-3-yl)methyl]-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A mixture of Intermediate 46 (145 mg, 0.37 mmol), 5-bromo-2-(2-methyltetrazol-5-yl)pyridine (134 mg, 0.36 mmol), tBuXPhos Pd G3 (44 mg, 0.056 mmol), and sodium tert-butoxide (107 mg, 1.12 mmol) in anhydrous dioxane / tBuOH (2:1, 4.5 mL) was stirred at room temperature for 1.5 h. The reaction mixture was diluted with ethyl acetate / methanol (4:1, 20 mL) and treated with saturated aqueous NH4Cl (5 mL) and water (5 mL). The layers were separated, and the aqueous layer was extracted with more ethyl acetate (10 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate, and the solvent was removed. The residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane followed by 0% to 20% methanol in ethyl acetate to afford the title compound (85 mg, 42% yield) as a white solid.

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[0325] Example 77 [ka] 5-[[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]-N-propan-2-ylpyridine-2-carboxamide To a stirred solution of Example 15 (20 mg, 0.04 mmol) in anhydrous DMF (0.5 mL) was added HATU (18 mg, 0.048 mmol), DIPEA (21 μL, 0.12 mmol), and isopropylamine (5.2 μL, 0.06 mmol), and the resulting mixture was stirred at room temperature for 1 h. The reaction was concentrated, and the residue was purified by acidic preparative HPLC to afford the title compound (9.8 mg, 45% yield) as a pale yellow solid.

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[0326] Example 78 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(2-methylpyridin-3-yl)-1,2,4-triazol-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a stirred solution of intermediate 157 (326 mg, 0.62 mmol) in anhydrous DMF (5 mL) was added formic hydrazide (111 mg, 1.85 mmol), followed by mercuric dichloride (503 mg, 1.85 mmol). The reaction was stirred at room temperature for 5 minutes, then triethylamine (258 μL, 1.85 mmol) was added and the reaction was heated to 90° C. for 1 hour. The reaction was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NH4Cl (15 mL), water (15 mL), NH4Cl (15 mL), water (15 mL), brine (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 0% to 100% ethyl acetate in heptane followed by 0% to 50% methanol in ethyl acetate to give a crude mixture which was further purified by preparative HPLC to give the title compound (98 mg, 30% yield).

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[0327] Example 79 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(1,2-oxazol-5-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A tube was charged with Intermediate 138 (100 mg, 0.25 mmol), potassium metabisulfite (111 mg, 0.5 mmol), tetrabutylammonium bromide (88 mg, 0.27 mmol), sodium formate (37 mg, 0.55 mmol), palladium acetate (3 mg, 0.012 mmol), triphenylphosphine (10 mg, 0.037 mmol), 1,10-phenanthroline (7 mg, 0.037 mmol), and anhydrous DMSO (1 mL). The mixture was degassed by sonication under a stream of nitrogen for 10 minutes, then the tube was sealed and the mixture was stirred at 70 °C. After 2 h, a suspension of fluoroisobutylamine hydrochloride (64 mg, 0.5 mmol) and triethylamine (69 μL, 0.5 mmol) in anhydrous THF (1 mL) and DMSO (0.5 mL) was added, and the reaction mixture was cooled to 0 °C in an ice bath. A solution of NBS (89 mg, 0.5 mmol) in anhydrous THF (1 mL) was added dropwise, after which the ice bath was removed and the mixture was allowed to reach room temperature. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine (5 mL) and water (5 mL). The aqueous layer was extracted with more ethyl acetate (15 mL), and the combined organics were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography eluting with 0% to 50% ethyl acetate in heptane, followed by further purification by preparative HPLC to afford the title compound (9.4 mg, 9% yield) as a white solid.

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[0328] Example 80 [ka] 3-Cyclopropyl-N-(2-hydroxy-2-methylpropyl)-7-[(6-methylpyridazin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a stirred solution of intermediate 156 (32 mg, 0.045 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (1 M in THF) (68 μL, 0.1068 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was purified by acidic preparative HPLC to give the title compound (8.4 mg, 39% yield) as a red-orange solid.

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[0329] Example 81 [ka] 3-Cyclopropyl-5-[(2,2-dimethylcyclopropyl)sulfamoyl]-N-pyridin-3-yl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide To a stirred solution of intermediate 153 (55 mg, 0.14 mmol) in anhydrous DMF (1 mL) were added DIPEA (72 μL, 0.41 mmol), HATU (63 mg, 0.17 mmol), and pyridin-3-amine (20 mg, 0.21 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. The mixture was diluted with ethyl acetate (15 mL), water (5 mL), and saturated aqueous NH4Cl (5 mL). The layers were separated, and the aqueous layer was extracted with more ethyl acetate (15 mL). The combined organics were washed with water (10 mL), saturated aqueous NH4Cl (10 mL), brine (10 mL), then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by acidic preparative HPLC to afford the title compound (29 mg, 44% yield) as an off-white solid.

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[0330] Example 82 [ka] 6-[[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxamide Intermediate 163 (30 mg, 0.06 mmol) in 7 M NH in MeOH (1.5 mL) was heated in a microwave at 100 °C for 1 h. The reaction was concentrated and purified by preparative reverse-phase acidic HPLC to afford the title compound (11 mg, 38%) as a white solid.

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[0331] Example 83 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-(1H-pyrazolo[3,4-c]pyridin-4-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide, formate To both batch 1 (47 mg (93% pure), 0.070 mmol) and batch 2 (27 mg (78% pure), 0.034 mmol) of Intermediate 160 and Intermediate 161), DCM (1.75 mL) and TFA (0.25 mL) were added and the reaction was stirred at room temperature for 16 hours. The reactions were combined, quenched with saturated NaHCO3 (15 mL) and extracted with DCM (3 x 10 mL). The organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0% to 10% MeOH in DCM to give the title compound, which was further purified by acidic reverse-phase preparative HPLC to give the title compound (5.5 mg, 10% yield) as a white solid.

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[0332] Example 84 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 12 (40 mg, 0.106 mmol), 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (34 mg, 0.159 mmol), sodium tert-butoxide (31 mg, 0.318 mmol), and tBuXPhos Pd G3 (8.4 mg, 0.011 mmol) in dioxane (3 mL) and tBuOH (1.5 mL) in a 20 mL pressure tube was flushed with nitrogen, sealed, and heated to 110 °C for 2 h, followed by stirring at room temperature for 16 h. Water (10 mL) was added, extracted with DCM (3 × 10 mL), and the organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0% to 10% MeOH in DCM, followed by preparative acidic reverse-phase HPLC to give the title compound (24 mg) as a yellow solid.

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[0333] Example 85 [ka] tert-Butyl 5-[[(7R)-3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylate Intermediate 124 (80 mg, 0.2 mmol), tert-butyl 5-bromopyridine-2-carboxylate (79 mg, 0.3 mmol), sodium tert-butoxide (39 mg, 0.41 mmol), and tBuXPhos Pd G3 (16 mg, 0.02 mmol) were stirred in anhydrous dioxane (3 mL) and tBuOH (1.5 mL) under nitrogen for 17 hours. Water (10 mL) was added, extracted with DCM (3 × 10 mL), and the organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0% to 10% MeOH in DCM, followed by further purification by silica column chromatography eluting with 100% ethyl acetate in heptane to give the title compound (90 mg, 74% yield) as a yellow solid.

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[0334] Example 86 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(pyridin-3-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 12 (40 mg, 0.11 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), tBuXPhos (9 mg, 0.02 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), and 3-bromopyridine (25 mg, 0.16 mmol) were heated in anhydrous toluene (3 mL) at 110 °C in a 20 mL pressure tube with stirring for 1.5 h. The reaction was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0% to 20% MeOH in DCM, followed by preparative reverse-phase basic HPLC to afford the title compound (24 mg) as a white solid.

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[0335] Example 87 [ka] N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-2-phenylacetamide Intermediate 12 (30 mg, 0.08 mmol) was dissolved in DCM (3 mL) and DIPEA (42 μL, 0.24 mmol), followed by the addition of phenylacetyl chloride (12.62 μL, 0.1 mmol). The reaction was stirred at room temperature for 30 minutes, washed with saturated aqueous NaHCO (2 × 1 mL), brine, dried over sodium sulfate, and concentrated in vacuo. The residue was further purified by silica column chromatography using 0% to 100% ethyl acetate in heptane, followed by preparative basic HPLC to afford the title compound (16 mg, 41% yield) as a white solid.

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[0336] Example 88 [ka] 5-[[3-Cyclopropyl-5-(isobutylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid; hydrochloride Intermediate 162 (28 mg, 0.06 mmol) was added to THF (1 mL) and 2 M aqueous LiOH (85 μL). The reaction was stirred at 50 °C for 2 h. THF was removed by evaporation, and 3 M aqueous HCl (1 mL) was added to the remaining aqueous solution. The resulting precipitate was collected by vacuum filtration and washed with water followed by diethyl ether to give the title compound (22 mg, 75% yield) as a yellow solid.

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[0337] Example 89 [ka] 5-[[3-Cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid Intermediate 119 (50 mg, 0.13 mmol), methyl 5-bromopyridine-2-carboxylate (41 mg, 0.19 mmol), sodium tert-butoxide (24 mg, 0.25 mmol), and tBuXPhos Pd G3 (10 mg, 0.01 mmol) in dioxane (3 mL) and tBuOH (1.5 mL) in a sealed tube were heated with stirring at 110 °C for 2.5 h. The reaction was concentrated in vacuo, and THF (2 mL) and 2 M aqueous LiOH (0.19 mL) were added. The reaction was heated to 50 °C with stirring for 45 min. The reaction was concentrated in vacuo, and the residue was purified by preparative reverse-phase acidic HPLC to afford the title compound (12 mg, 17%) as a dark yellow solid.

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[0338] Example 90 [ka] 5-Amino-1-[(7S)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]imidazole-4-carboxamide 2-Amino-2-cyanoacetamide (92%, 28 mg, 0.26 mmol) was stirred in anhydrous MeCN (3 mL) in a 20 mL pressure tube. Triethyl orthoformate (44 μL, 0.26 mmol) was added, and the reaction was sealed and heated at 90° C. for 1 h. The reaction was allowed to cool to room temperature, and Intermediate 118 (100 mg, 0.26 mmol) was added. The reaction was heated to 90° C. with stirring for 1 h, then concentrated in vacuo and purified by silica column chromatography eluting with 0% to 15% MeOH in DCM to give the title compound (42 mg, 32% yield) as a white solid.

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[0339] Example 91 [ka] 7-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-2-(3-pyridylmethyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide; Formic acid Intermediate 27 hydrochloride (20 mg, 0.052 mmol) was dissolved in MeCN (2 mL). KCO (29 mg, 0.20 mmol) and 3-(bromomethyl)pyridine hydrobromide (1:1) (14.6 mg, 0.058 mmol) were added. The solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, diluted with DCM (20 mL) washed with water, and the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 50% to 100% EtOAc / heptane, then 0 to 10% MeOH in DCM, followed by acidic preparative HPLC to give the title compound (6.8 mg, 27% yield).

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[0340] Example 92 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxopyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 15 (22 mg, 0.058 mmol), Intermediate 189 (16.4 mg, 0.064 mmol), sodium tert-butoxide (11.2 mg, 0.11 mmol), and tBuXPhos Pd G3 (6.9 mg, 0.009 mmol) were stirred at room temperature in anhydrous dioxane (3 mL) for 4 h. The reaction mixture was partitioned between water and DCM, the organic layer was dried (MgSO4), evaporated, and the residue was purified by acidic preparative HPLC to give the title compound (3.2 mg, 10% yield) as a white solid.

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[0341] Example 93 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(methylsulfamoyl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 15 (30 mg, 0.079 mmol), Intermediate 190 (27.9 mg, 0.079 mmol), sodium tert-butoxide (22.9 mg, 0.23 mmol), and tBuXPhos Pd G3 (9.4 mg, 0.012 mmol) were heated in anhydrous dioxane / tBuOH (3 mL and 1 mL) at 65 °C in a 20 mL pressure tube with stirring for 2 h. The solvent was removed, water (10 mL) was added, and the reaction was extracted with DCM (3 × 10 mL). The organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 50% to 100% EtOAc in heptane, then 0 to 10% MeOH in DCM, followed by acidic preparative HPLC to afford the title compound (9 mg, 20% yield) as a white solid.

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[0342] Example 94 [ka] 6-[[(7R)-3-Cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxamide Intermediate 169 (64 mg, 0.099 mmol, 82% purity) in 7 M NH in MeOH (2.0 mL) was heated in a microwave at 100 °C for 1 h. The reaction was concentrated and the resulting residue was purified by acidic preparative HPLC to afford the title compound (25 mg, 49% yield) as a gray solid.

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[0343] Example 95 [ka] N-[5-[[(7R)-3-Cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridin-2-yl]sulfonylacetamide Intermediate 15 (50 mg, 0.13 mmol), Intermediate 181 (70.4 mg, 0.17 mmol), sodium tert-butoxide (38 mg, 0.39 mmol), and tBuXPhos Pd G3 (15.7 mg, 0.02 mmol) were heated in anhydrous dioxane / tert-butanol (4 mL and 1 mL) at 60 °C in a 20 mL pressure tube with stirring for 2 h. The solvent was removed, and the residue was redissolved in DCM (5 mL). TFA (0.2 mL) was added and stirred at room temperature for 16 h. The solvent was removed. Water (10 mL) was added, and the reaction was extracted with DCM (3 × 10 mL) followed by IPA / chloroform (1:1) (2 × 10 mL). The organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 20% to 100% EtOAc in heptane, then 0 to 10% MeOH in DCM, followed by acidic preparative HPLC to afford the title compound (1.5 mg, 2% yield) as an off-white solid.

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[0344] Example 96 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[(1-methyl-2-oxo-4-pyridyl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; Formate Intermediate 12 (40 mg, 0.10 mmol), 4-bromo-1-methyl-1,2-dihydropyridin-2-one (29.8 mg, 0.15 mmol), sodium tert-butoxide (30.5 mg, 0.31 mmol), Pd(dba) (9.7 mg, 0.011 mmol), and tBuXPhos (9.0 mg, 0.021 mmol) were heated with stirring in anhydrous dioxane / tert-butanol (3 mL and 1.5 mL) in a 20 mL pressure tube at 110 °C for 4 h. Water (15 mL) was added, the reaction was extracted with DCM (3 × 10 mL), and the organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0% to 20% MeOH in DCM followed by acidic preparative HPLC to afford the title compound (25 mg, 44% yield) as an off-white solid.

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[0345] Example 97 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 12 (50 mg, 0.13 mmol), 2-bromo-5-methyl-1,3,4-oxadiazole (30 mg, 0.18 mmol), and DIPEA (46.1 mL, 0.26 mmol) were heated in anhydrous DMF (5 mL) at 90 °C in a 20 mL pressure tube with stirring for 16 h. The solvent was removed, water (10 mL) was added, and the reaction was extracted with DCM (3 × 10 mL). The organics were dried over sodium sulfate and concentrated in vacuo, and the residue was purified by silica column chromatography eluting with 50% to 100% EtOAc in heptane, then 0 to 15% MeOH in DCM, followed by acidic preparative HPLC to give the title compound (22 mg, 36% yield).

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[0346] Example 98 [ka] 3-Cyclopropyl-7-[(4,4-dimethyl-3-oxocyclobuten-1-yl)amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To intermediate 12 (50 mg, 0.13 mmol) in THF (2 mL) was added DIPEA (34.6 μL, 0.199 mmol), followed by 2,2-dimethylcyclobutane-1,3-dione (22.2 mg, 0.199 mmol). The mixture was stirred at 70° C. for 18 h. The solvent was removed, and the residue was purified by acidic preparative HPLC to give the title compound (32 mg, 50% yield) as a white solid.

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[0347] Example 99 [ka] 7-Cyclopropyl-9-N-(2-fluoro-2-methylpropyl)-2-N-(2-methylpropyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-2,9-disulfonamide A mixture of intermediate 173 (20 mg, 0.041 mmol), cyclopropylboronic acid (8.7 mg, 0.10 mmol), Pd(OAc) (0.45 mg, 2.0 μmol), P(Cy) HBF (2.2 mg, 6.0 μmol), and KPO (21.5 mg, 0.10 mmol) in toluene (1 mL) / water (0.05 mL) was stirred and heated to reflux at 120 °C for 3 h. The reaction was diluted with DCM (5 mL), dried over MgSO, filtered through Celite, and concentrated under reduced pressure to give the crude product, which was purified by silica column chromatography eluting with 20% to 60% EtOAc / heptane to give the title compound (6 mg, 30% yield) as a white solid.

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[0348] Example 100 [ka] 7-Cyclopropyl-N-ethyl-9-(2-methylpropylsulfamoyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-carboxamide Intermediate 180 (20 mg, 0.049 mmol) and cyclopropylboronic acid (8.4 mg, 0.097 mmol) were dissolved in degassed dioxane (2 mL) and 2 M KCO (73.0 μL, 0.14 mmol). Under a nitrogen atmosphere, (2-{[bis(2,4-di-tert-butylphenoxy)phosphanyl]oxy}-3,5-di-tert-butylphenyl)(chloro)palladium and tricyclohexylphosphane (1:1) (Bedford Catalyst) (5.19 mg, 0.005 mmol) were added. The mixture was stirred at 120° C. in a microwave for 3 h, after which the dioxane was removed, the reaction diluted with DCM (10 mL), washed with water, and the combined organic layers dried over MgSO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with 50% to 100% EtOAc in heptane followed by preparative HPLC to give the title compound (2 mg, 10% yield) as a white solid.

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[0349] Example 101 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide A suspension of intermediate 151 (20 mg, 0.04 mmol) in POCl (1 mL) was heated at 70 °C for 4 h. The solvent was removed, and ice, followed by EtOAc (10 mL), was added to the flask. The aqueous layer was basified to pH 10 with saturated NaHCO solution and then extracted with EtOAc (2 × 10 mL). The organic layer was dried (NaSO), the solvent was removed, and the residue was purified by silica column chromatography eluting with 0% to 100% 7 M NH in MeOH / DCM, followed by preparative basic reverse-phase HPLC to afford the title compound (5 mg, 26% yield) as a white solid.

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[0350] Example 102 [ka] 7-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-2-(1H-pyrazol-5-ylmethyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide To intermediate 27 in THF (1 mL) was added 1H-pyrazole-5-carbaldehyde (14 mg, 0.15 mmol) and Ti(IV) isopropoxide (67 μL, 0.23 mmol). The reaction was stirred at room temperature for 3 h, followed by the addition of sodium triacetoxyborohydride (53 mg, 0.25 mmol) and an additional 16 h at room temperature. The reaction was quenched with NaHCO (10 mL), diluted with EtOAc (10 mL), the layers separated, and the aqueous layer extracted with EtOAc (10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO, concentrated under reduced pressure, and purified by acidic preparative HPLC to afford the title compound (5 mg, 9% yield) as a red solid.

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[0351] Example 103 [ka] 3-Cyclopropyl-N-isobutyl-7-(pyridazin-4-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; Formic acid Intermediate 122 (50 mg, 0.14 mmol), sodium tert-butoxide (40 mg, 417 μmol), Xantphos (16 mg, 28 μmol), and 4-bromopyridazine hydrobromide (1:1) (50 mg, 0.21 mmol) were combined in 2:1 dioxane / tBuOH (4.5 mL) in a sealable tube and degassed with nitrogen. Pd2(dba)3 (12.7 mg, 13.9 μmol) was added, and the sealed tube was heated with stirring at 110 °C for 1.5 h. The reaction was diluted with EtOAc (5 mL), filtered through Celite, and concentrated. The residue was purified by silica column chromatography eluting with 0% to 20% MeOH / DCM followed by acidic preparative HPLC to afford the title compound (8.4 mg, 12% yield) as a white solid.

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[0352] Example 104 [ka] N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-2-methylpyrazole-3-carboxamide 1-Methyl-1H-pyrazole-5-carboxylic acid (8.02 mg, 0.06 mmol) and DIPEA (19.3 μL, 0.12 mmol) were dissolved in DMF (0.5 mL) and HATU (22.2 mg, 0.06 mmol) was added. After stirring for 10 min, Intermediate 12 (20 mg, 0.05 mmol) was added, and the solution was stirred at room temperature for 15 min. The solution was diluted with 1:1 MeCN / water (1 mL) and purified by acidic preparative HPLC to give the title compound (21 mg, 78% yield) as a white solid.

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[0353] Example 105 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[1-(2-hydroxyethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 167 (20 mg, 0.03 mmol) was dissolved in THF (1 mL) and 1 M TBAF in THF (61 μL) was added. The solution was left standing at room temperature for 2 hours, and the reaction was concentrated and purified by silica column chromatography eluting with 5% to 20% MeOH / DCM, then using an SCX-2 cartridge eluting with methanol followed by 3.5 N ammonia in methanol to give the title compound (9.9 mg, 59% yield) as a pale yellow solid.

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[0354] Example 106 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(2-hydroxyethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 168 (30 mg, 0.05 mmol) was dissolved in THF (1 mL) and 1 M TBAF in THF (92 μL) was added. The solution was left standing at room temperature for 2 hours. Water (5 mL) was added, extracted with EtOAc (2 × 10 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 0% → 20% MeOH / DCM to give the title compound (6.9 mg, 28% yield) as a yellow solid.

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[0355] Example 107 [ka] 13-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-12-azatetracyclo[8.4.0.03,8.04,6]tetradeca-1(10),2,8,11,13-pentaene-2-sulfonamide Intermediate 144 (60 mg, 0.12 mmol) was dissolved in DCM (5 mL) and TFA (0.5 mL) was added. The reaction was stirred at room temperature for 4.5 hours, the solvent was removed, and the residue was purified by silica column chromatography eluting with 30% to 100% EtOAc / heptane followed by passage through a 2 g SCX-2 cartridge eluting with 3.5 N ammonia in MeOH to give the title compound (29 mg, 62% yield) as a white solid.

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[0356] Example 108 [ka] (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(1-methylpyrazol-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 15 (100 mg, 0.265 mmol), 5-bromo-2-(1-methylpyrazol-3-yl)pyridine (82 mg, 0.344 mmol), sodium tert-butoxide (51 mg, 0.525 mmol), tBuXPhos Pd G3 (21 mg, 0.026 mmol), and tBuXPhos (11 mg, 0.026 mmol) were introduced into a pressure tube. Nitrogen was bubbled through a mixture of anhydrous 1,4-dioxane (2.0 mL) and tert-butanol (1.0 mL) for 10 min and then transferred to the pressure tube. After bubbling nitrogen through the reaction mixture for an additional 2 min, the tube was closed under a nitrogen atmosphere and heated to 110 °C for 90 min. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate (30 mL) and then washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic phase was dried over sodium sulfate, filtered, and the filtrate was adsorbed onto silica in vacuo. Purification by column chromatography eluting with a gradient of ethyl acetate in heptane, then ethanol in ethyl acetate, followed by basic reverse-phase preparative HPLC afforded the title compound (78.5 mg, 54% yield) as a solid.

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[0357] Example 109 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(imidazo[1,2-a]pyrazin-5-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 12 (50 mg, 0.132 mmol), 5-bromoimidazo[1,2-a]pyrazine (39 mg, 0.199 mmol), sodium tert-butoxide (25 mg, 0.265 mmol), Pd(dba) (17 mg, 0.019 mmol), and tBuXPhos (16 mg, 0.037 mmol) were introduced into a pressure tube. Nitrogen was bubbled through a mixture of anhydrous 1,4-dioxane (2.0 mL) and tert-butanol (1.0 mL) for 10 min and then transferred to the pressure tube. After bubbling nitrogen through the reaction mixture for an additional 2 min, the tube was closed under a nitrogen atmosphere and warmed to 110 °C for 2.5 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica and purified by column chromatography eluting with a gradient of methanol in dichloromethane. Further purification by acidic preparative HPLC afforded the title compound (2.4 mg, 4% yield) as a colorless solid.

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[0358] Example 110 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-pyridin-3-yl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide Intermediate 164 (LCMS-UV) in dichloromethane (2 mL) 215 To a solution of 27% pure trifluoroacetic acid (1 mL, dropwise) was introduced trifluoroacetic acid. After 30 min, the reaction mixture was concentrated in vacuo and the residue was purified by basic preparative HPLC to give the title compound (2.6 mg, 13% yield over two steps).

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[0359] Example 111 [ka] 3-Cyclopropyl-N-(3,3-difluorocyclobutyl)-7-(3-oxo-2-pyridin-3-yl-1H-pyrazol-5-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a solution of intermediate 166 (50 mg, 0.084 mmol, 83% pure) in ethanol (1 mL) were introduced acetic acid (12 mg, 0.203 mmol) and 3-pyridylhydrazine hydrochloride (22 mg, 0.152 mmol). The reaction mixture was warmed to 50°C for 60 minutes. Potassium carbonate (100 mg) was introduced, and heating was continued at 50°C for an additional 30 minutes. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with ethanol (1 mL). The combined filtrates were concentrated in vacuo, and the residue was suspended in a pH 6.5 aqueous (phosphate) buffer solution, which was extracted with ethyl acetate (2 x 8 mL). Sodium chloride was then introduced to saturate the buffer, and the solution was extracted with tetrahydrofuran (5 mL). The pooled ethyl acetate and tetrahydrofuran extracts were combined and concentrated under vacuum, and the residue was purified by acidic preparative HPLC followed by further purification by silica column chromatography using a gradient of methanol in dichloromethane to afford the title compound (7.0 mg, 16% yield) as an oil.

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[0360] Example 112 [ka] 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-hydroxy-2-methylpyrazol-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide To a stirred solution of intermediate 145 (55 mg, 0.0976 mmol) in absolute ethanol (2 mL) was added palladium on carbon (5 mg). The reaction was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was filtered through Celite, the solvent removed, and the residue purified by C18 reverse-phase column chromatography eluting with 0% to 100% MeCN in HO (pH 3, formic acid) to give the title compound (7.0 mg, 13% yield).

number

[0361] Example 113 [ka] 3-Cyclopropyl-N-(2,2-dimethylpropyl)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxamide To a solution of intermediate 69 (10 mg, 0.0245 mmol) in anhydrous DMF (1 mL) at room temperature was added N,N-diisopropylethylamine (20 μL, 0.115 mmol). To the resulting solution was added HATU (14 mg, 0.0357 mmol), followed a few minutes later by a few drops of neopentylamine. The reaction was stirred overnight, dil...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 wherein X and Y independently represent C or N; V and W independently represent C or O; When either V or W represents O, Y represents C; When Y represents N, R1' is absent; When V represents O, R2 is absent; When W represents O, R7 is absent; R1 is as follows: hydrogen; C(O)NH—C1-6-alkyl; C(O)NH-heteroaryl; optionally one or more of oxo, hydroxy, amino, C(O)NH ２ , C(O)O—C1-6-alkyl, heteroaryl, NH—C1-6-alkyl, NH—C1-6-alkyl-C3-6-cycloalkyl, or optionally one or more R1 ａ heteroaryl substituted with NH-heteroaryl substituted with; C1-6-alkyl-C(O)-C1-6-alkylamino; C1-6-alkyl-heteroaryl; C(O)—C1-6-alkyl-heteroaryl; optionally one or more R1 ａ NHC(O)-heteroaryl substituted with; optionally one or more R1 ａ NH-C3-8-cycloalkyl substituted with; optionally one or more R1 ａ NH-C3-8-heterocycloalkyl substituted with; NHC(O)-C1-6-alkyl optionally substituted with one or more aryl or heteroaryl; NHC(O)—NH—C1-6-alkyl; NHC(O)O—C1-6-alkyl; NH-aryl optionally substituted with one or more C1-6-alkyl, C(O)—C1-6-alkyl or heteroaryl optionally substituted with one or more C1-6-alkyl; SO ２ -C1-6-alkyl; SO ２ -NH-C1-6-alkyl; NH-SO ２ -C1-6-alkyl; NHC(O)—C(O)-heteroaryl optionally substituted with one or more halogen or C1-6-alkyl; or -NH-heteroaryl, hydrogen; R1 ｂ ; Hydroxy; halogen; oxo; C1-6-alkyl; C1-6-alkoxy; C1-6-hydroxyalkyl; C1-6-haloalkyl; C1-6-alkyl-C(O)OH; C(O)NH ２ ; SO ２ NH ２ ; S(O)—C1-6-alkyl; SO ２ -C1-6-alkyl; SO ２ NHC(O)-C1-6-alkyl; SO ２ -C1-6-alkylamino; S(O)(NH)-C1-6-alkyl; C1-6-alkyl-C3-8-cycloalkyl; C3-8-cycloalkyl-C1-6-alkyl; C1-6-alkoxy-C3-8-cycloalkyl; C3-8-cycloalkyl-C1-6-alkoxy; C1-6-alkylamino-C3-8-cycloalkyl; C3-8-cycloalkyl-C1-6-alkylamino; C(O)OH; C(O)O—C1-6-alkyl; C(O)NH—C1-6-alkyl; NHC(O)-C1-6-alkyl; Cyano; C3-8-heterocycloalkyl optionally substituted by one or more hydroxy, oxo, C1-6-alkyl, or cyano; heterocycloalkyloxy optionally substituted by one or more hydroxy, oxo, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl-C1-6-alkoxy, C(O)NH—C1-6-alkyl, or NHSO2—C1-6-alkyl; heteroaryloxy optionally substituted by one or more hydroxy, oxo, C1-6-alkyl, or C1-6-alkoxy; heteroarylamino optionally substituted with one or more hydroxy, oxo, C1-6-alkyl, or C1-6-alkoxy; or SO optionally substituted with one or more C1-3-alkyl or oxo ２ -heteroaryl -NH-heteroaryl substituted with one or more groups selected from represents a group selected from R1 a is the following hydrogen; halogen; Hydroxy; oxo; amino; C1-6-alkyl; C1-6-alkoxy; C(O)O—C1-6-alkyl; C1-6-alkylamino; Cyano; C1-6-haloalkyl; C1-6-haloalkoxy; C(O)OH; or C3-8-cycloalkyl represents a group selected from R1 ｂ but, optionally one or more halogen, hydroxy, oxo, C1-6-alkyl, C1-6-alkanediyl-C(O)OH, C(O)NH ２ a group selected from heteroaryl substituted with carbamoyl, C(O)O—C1-6-alkyl, S(O)NH—C1-6-alkyl, C3-8-cycloalkyl, heteroarylamino, C1-6-alkoxy, cyano, C1-6-haloalkyl, C1-6-haloalkoxy or C(O)OH; represents R1' is hydrogen; C1-3-alkyl; or C1-3-hydroxyalkyl represents R2 is as follows: hydrogen; C1-3-hydroxyalkyl; NHC(O)NH—C1-6-alkyl; or Hydroxy represents a group selected from R1′ and R2 together can form a cyclopropyl ring incorporating V and Y. R1 and R1' together can form a heterocycloalkyl ring optionally substituted with one or more oxo, halogen, or C1-6 alkyl; R3 is as follows: In some cases, R3 ａ C1-6-alkyl substituted with one or more groups selected from: optionally one or more R3 ａ C1-3-alkanediyl-C3-6-cycloalkyl substituted with; optionally one or more R3 ａ C1-3-alkanediyl-C3-6-heterocycloalkyl substituted with optionally one or more R3 ａ C3-6-heterocycloalkyl substituted with; or optionally one or more R3 ａ C3-6-cycloalkyl substituted with represents a group selected from R3 ａ but, hydrogen; halogen; C1-2-alkyl; Hydroxy; or C1-2-alkoxy represents a group selected from R4 is as follows: optionally one or more R4 ａ C3-6-cycloalkyl substituted by a group; optionally one or more R4 ａ C1-6-alkanediyl-C3-6-cycloalkyl substituted with a group; or optionally one or more R4 ａ C1-6-alkanediyl-C3-6-heterocycloalkyl substituted with a group represents a group selected from R4 ａ but, Hydroxy; halogen; or C1-2-alkyl represents a group selected from R5 is the following hydrogen; Hydroxy, halogen; C1-3-alkyl optionally substituted with one or more halogens; or C1-3-alkoxy represents a group selected from R6 is as follows: hydrogen; halogen; amino; NHC(O)C1-6-alkyl; C1-3-alkyl optionally substituted with one or more halogens; or C1-3-alkoxy represents a group selected from R7 is as follows hydrogen; NHC(O)NH-C1-6-alkyl; halogen; or Hydroxy represents a group selected from R1′ and R7 together can form a cyclopropyl ring incorporating W and Y; R8, hydrogen; halogen; Hydroxy; C1-3-alkyl; or Cyclopropyl Represents, A compound of the above formula (I) or a pharmaceutically acceptable salt thereof.

2. R1 is as follows: hydrogen; C(O)NH—C1-6-alkyl; C(O)NH-heteroaryl; optionally one or more of oxo, hydroxy, amino, C(O)NH ２ , C(O)O—C1-6-alkyl, heteroaryl, NH—C1-6-alkyl, NH—C1-6-alkyl-C3-6-cycloalkyl, or optionally one or more R1 ａ heteroaryl substituted with NH-heteroaryl substituted with; C1-6-alkyl-C(O)-C1-6-alkylamino; C1-6-alkyl-heteroaryl; C(O)—C1-6-alkyl-heteroaryl; optionally one or more R1 ａ NHC(O)-heteroaryl substituted with; optionally one or more R1 ａ NH-C3-8-cycloalkyl substituted with; optionally one or more R1 ａ NH-C3-8-heterocycloalkyl substituted with; NHC(O)-C1-6-alkyl optionally substituted with one or more aryl or heteroaryl; NHC(O)—NH—C1-6-alkyl; NHC(O)O—C1-6-alkyl; NH-aryl optionally substituted with one or more C1-6-alkyl, C(O)—C1-6-alkyl or heteroaryl optionally substituted with one or more C1-6-alkyl; SO ２ -C1-6-alkyl; SO ２ -NH-C1-6-alkyl; NH-SO ２ -C1-6-alkyl; or NHC(O)-C(O)-heteroaryl optionally substituted with one or more halogen or C1-6-alkyl represents a group selected from R1 ａ But the following hydrogen; halogen; Hydroxy; oxo; amino; C1-6-alkyl; C1-6-alkoxy; C(O)O—C1-6-alkyl; C1-6-alkylamino; Cyano; C1-6-haloalkyl; C1-6-haloalkoxy; C(O)OH; or C3-8-cycloalkyl represents a group selected from 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R1 is —NH-heteroaryl, hydrogen; R1 ｂ ; Hydroxy; halogen; oxo; C1-6-alkyl; C1-6-alkoxy; C1-6-hydroxyalkyl; C1-6-haloalkyl; C1-6-alkyl-C(O)OH; C(O)NH ２ ; SO ２ NH ２ ; S(O)—C1-6-alkyl; SO ２ -C1-6-alkyl; SO ２ NHC(O)-C1-6-alkyl; SO ２ -C1-6-alkylamino; S(O)(NH)-C1-6-alkyl; C1-6-alkyl-C3-8-cycloalkyl; C3-8-cycloalkyl-C1-6-alkyl; C1-6-alkoxy-C3-8-cycloalkyl; C3-8-cycloalkyl-C1-6-alkoxy; C1-6-alkylamino-C3-8-cycloalkyl; C3-8-cycloalkyl-C1-6-alkylamino; C(O)OH; C(O)O—C1-6-alkyl; C(O)NH—C1-6-alkyl; NHC(O)-C1-6-alkyl; Cyano; C3-8-heterocycloalkyl optionally substituted by one or more hydroxy, oxo, C1-6-alkyl, or cyano; heterocycloalkyloxy optionally substituted by one or more hydroxy, oxo, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl-C1-6-alkoxy, C(O)NH—C1-6-alkyl or NHSO2-C1-6-alkyl; heteroaryloxy optionally substituted by one or more hydroxy, oxo, C1-6-alkyl, or C1-6-alkoxy; heteroarylamino optionally substituted with one or more hydroxy, oxo, C1-6-alkyl, or C1-6-alkoxy; or SO optionally substituted with one or more C1-3-alkyl or oxo ２ -heteroaryl represents —NH-heteroaryl substituted with one or more groups selected from R1 ｂ but, optionally one or more halogen, hydroxy, oxo, C1-6-alkyl, C1-6-alkanediyl-C(O)OH, C(O)NH ２ , carbamoyl, C(O)O—C1-6-alkyl, S(O)NH—C1-6-alkyl, C3-8-cycloalkyl, heteroarylamino, C1-6-alkoxy, cyano, C1-6-haloalkyl, C1-6-haloalkoxy or C(O)OH substituted heteroaryl group. represents a group selected from 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R4 is optionally Hydroxy, Chloro, fluoro, bromo, or Methyl or a pharmaceutically acceptable salt thereof.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein R represents cyclopropyl optionally substituted with one or more groups independently selected from:

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R4 is cyclopropyl.

6. A compound of formula (I) according to claim 1 selected from the following: (7R)-3-cyclopropyl-N-(3-fluorocyclobutyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 13-cyclopropyl- ～ {N}-(2-methylpropyl)-6-(5-pyridin-3-yl-1- ～ {H}-imidazol-2-yl)-12-azatetracyclo[8.4.0.0^{3,8}.0^{4,6}]tetradeca-1,3(8),9,11,13-pentaene-2-sulfonamide; (7R*)-3-cyclopropyl-N-(2-methylpropyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide[* or S]; 3-cyclopropyl-N-(2-methylpropyl)-7-[(3-oxocyclopenten-1-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[[4-(cyclopropylmethyl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]pyridine-3-carboxamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(3-oxocyclohexen-1-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; Ethyl 5-amino-1-[[7S)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]imidazole-4-carboxylate; 3-cyclopropyl-5-[(3-methyloxetan-3-yl)methylsulfamoyl]-N-pyridin-3-yl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-(6-methylpyridin-3-yl)oxypyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(hydroxymethyl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-[(3-fluorooxetan-3-yl)methyl]-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-[(3-hydroxyoxetan-3-yl)methyl]-7-[(2-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-(2-methoxypyridin-4-yl)oxypyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-hydroxypropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(pyridin-3-ylamino)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[[4-(cyclopropylmethylamino)pyrimidin-5-yl]amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 7-(1H-benzimidazol-2-ylamino)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 9-amino-3-cyclopropyl-N-(2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-9-yl]acetamide; 5-[[3-cyclopropyl-1-fluoro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxamide; Methyl 5-[[3-cyclopropyl-1-fluoro-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylate; 3-cyclopropyl-1-fluoro-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-1-methoxy-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-methoxypyridazin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-1-fluoro-N-(2-fluoro-2-methyl-propyl)-7-[(1-methyl-6-oxo-pyridazin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(3-hydroxyoxetan-3-yl)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-7-[(6-chloropyridin-3-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-6-methyl-1H-indole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1H-benzotriazole-5-carboxamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(methylsulfonimidoyl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-hydroxypropan-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[(1,1-dioxo-2,3-dihydrothiophen-4-yl)amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(3,3-difluorocyclobutyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-(6-methylpyridin-3-yl)sulfonylpyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-3-ethylurea; 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-3-ethylurea; 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-6-yl]-3-ethylurea; 3-cyclopropyl-8-hydroxy-N-(2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-6-hydroxy-N-(2-methyl-propyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3'-cyclopropyl-N-(2-fluoro-2-methylpropyl)-2-oxospiro[1,3-oxazolidine-4,7'-6,8-dihydrocyclopenta[g]isoquinoline-5'-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(hydroxymethyl)-7-[(4-pyridin-3-yl-1,2,4-triazol-3-yl)amino]-6,8-dihydrocyclopenta[g]isoquinoline-5-sulfonamide; 2-(2-aminopyridin-3-yl)-7-cyclopropyl-N-(2-fluoro-2-methylpropyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide; 2-[4-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyrazolo[3,4-c]pyridin-1-yl]acetic acid; 3-cyclopropyl-7-[[2-(ethylamino)-3,4-dioxocyclobuten-1-yl]amino]-N-(2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2,2-dimethylpropyl)-5-(2-methylpropylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide; 3-cyclopropyl-7-(methanesulfonamido)-N-(2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(3H-imidazo[4,5-c]pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[2-(cyclopropylmethylamino)imidazol-1-yl]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 2-[7-cyclopropyl-9-(2-methylpropylsulfamoyl)-1,3-dihydropyrrolo[3,4-g]isoquinolin-2-yl]-N-ethylacetamide; 7-Cyclopropyl-N-(2-methylpropyl)-2,3-dihydro-1H-pyrrolo[3,4-g]isoquinoline-9-sulfonamide: (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-sulfamoylpyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(3H-imidazo[4,5-c]pyridin-7-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(2-oxo-1H-pyridin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; Ethyl 5-[[7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]-1,3,4-thiadiazole-2-carboxylate; tert-butyl N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]cinnolin-7-yl]carbamate; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]cinnoline-5-sulfonamide; 3-cyclopropyl-1-methyl-N-(2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 7-cyclopropyl-N-(2-methylpropyl)-[1,3]dioxolo[4,5-g]isoquinoline-9-sulfonamide; 3-cyclopropyl-N-isobutyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[4-(5-methyl-1,3,4-oxadiazol-2-yl)anilino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(4-oxo-1,5-dihydroimidazo[4,5-c]pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 7-cyclopropyl-N-(2-fluoro-2-methylpropyl)-2-(2-pyridin-3-ylacetyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-fluoropyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(3,3-difluorocyclobutyl)-7-[[6-(3-hydroxyoxetan-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-[(2-oxo-1H-pyridin-4-yl)oxy]pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-[(3-hydroxyoxetan-3-yl)methyl]-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]-N-propan-2-ylpyridine-2-carboxamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(2-methylpyridin-3-yl)-1,2,4-triazol-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(1,2-oxazol-5-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-hydroxy-2-methylpropyl)-7-[(6-methylpyridazin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-5-[(2,2-dimethylcyclopropyl)sulfamoyl]-N-pyridin-3-yl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-7-carboxamide; 6-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxamide; 3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-(1H-pyrazolo[3,4-c]pyridin-4-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide, formate; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; tert-butyl 5-[[(7R)-3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylate; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(pyridin-3-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-2-phenylacetamide; 5-[[3-cyclopropyl-5-(isobutylsulfamoyl)-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid, hydrochloride; 5-[[3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridine-2-carboxylic acid; 5-amino-1-[(7S)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]imidazole-4-carboxamide; 7-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-2-(3-pyridylmethyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide, formic acid; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxopyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(methylsulfamoyl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 6-[[(7R)-3-cyclopropyl-5-[(3,3-difluorocyclobutyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxamide; N-[5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridin-2-yl]sulfonylacetamide; 3-cyclopropyl-N-(2-fluoro-2-methyl-propyl)-7-[(1-methyl-2-oxo-4-pyridyl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide, formate; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-7-[(4,4-dimethyl-3-oxocyclobuten-1-yl)amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 7-cyclopropyl-9-N-(2-fluoro-2-methylpropyl)-2-N-(2-methylpropyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-2,9-disulfonamide; 7-cyclopropyl-N-ethyl-9-(2-methylpropylsulfamoyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-2-carboxamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 7-cyclopropyl-N-(2-fluoro-2-methylpropyl)-2-(1H-pyrazol-5-ylmethyl)-1,3-dihydropyrrolo[3,4-g]isoquinoline-9-sulfonamide; 3-cyclopropyl-N-isobutyl-7-(pyridazin-4-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide, formic acid; N-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-2-methylpyrazole-3-carboxamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[1-(2-hydroxyethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(2-hydroxyethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 13-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-12-azatetracyclo[8.4.0.03,8.04,6]tetradeca-1(10),2,8,11,13-pentaene-2-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(1-methylpyrazol-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(imidazo[1,2-a]pyrazin-5-ylamino)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-pyridin-3-yl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(3,3-difluorocyclobutyl)-7-(3-oxo-2-pyridin-3-yl-1H-pyrazol-5-yl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-hydroxy-2-methylpyrazol-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2,2-dimethylpropyl)-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]cinnoline-7-carboxamide; (7R)-7-(4-acetylanilino)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(4-methyltriazol-1-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(4-methyltriazol-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(1,2,4-triazol-1-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-7-[[6-(difluoromethyl)pyridin-3-yl]amino]-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-7-[[6-chloro-4-(cyclopropylmethoxy)pyridin-3-yl]amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(oxan-4-yloxy)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[5-[[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridin-3-yl]acetamide; 7-[(5-cyanopyridin-3-yl)amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-methylsulfonylpyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(1H-tetrazol-5-yl)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[4-(2-methyltetrazol-5-yl)anilino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-7-[[6-chloro-4-(1H-tetrazol-5-yl)pyridin-3-yl]amino]-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-oxo-2H-pyran-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(1-methylpyrazol-3-yl)oxypyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[2-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1H-indole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-5-fluoro-1H-indole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1-methylindole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-6-methoxy-1H-indole-3-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-4-methyl-1,3-thiazole-5-carboxamide; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]isoquinoline-1-carboxamide; tert-butyl 5-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]carbamoyl]-1,3-dihydroisoindole-2-carboxylate; N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-2-(1-methylpyrazol-4-yl)-2-oxoacetamide; Lithium; 4-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methyl-propyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]isoquinoline-1-carboxylate; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(6-methylsulfinylpyridin-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methyl-6-oxopyridazin-4-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 6-bromo-N-[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]-1H-indazole-3-carboxamide; or 3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(5-oxo-2H-furan-3-yl)amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide.

7. A compound of formula (I) according to claim 1 selected from the following: (7R)-3-cyclopropyl-N-(3-fluorocyclobutyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-(6-methylpyridin-3-yl)oxypyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[4-(pyridin-3-ylamino)pyrimidin-5-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(3,3-difluorocyclobutyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 2-[4-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyrazolo[3,4-c]pyridin-1-yl]acetic acid; 3-cyclopropyl-N-[(3-hydroxyoxetan-3-yl)methyl]-7-[[6-(2-methyltetrazol-5-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; 6-[[(7R)-3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-7-yl]amino]pyridazine-3-carboxamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[1-(2-hydroxyethyl)pyrazolo[3,4-c]pyridin-4-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(4-methyltriazol-1-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; (7R)-3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(4-methyltriazol-2-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide; or (7R)-3-Cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(1,2,4-triazol-1-yl)pyridin-3-yl]amino]-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-sulfonamide.

8. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in therapy.

9. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in a method for the treatment or prevention of disorders caused by IgE.

10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in a method for the treatment or prevention of allergy, non-allergic mast cell response, type 1 hypersensitivity, urticaria, or sinusitis.

11. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically 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.

12. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in a method for the treatment or prevention of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), aspirin-exacerbated respiratory disease, or cutaneous T-cell lymphoma.

13. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

15. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of disorders caused by IgE.

16. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of allergy, non-allergic mast cell response, type 1 hypersensitivity, urticaria, or sinusitis.

17. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment or prevention of allergy, non-allergic mast cell response, type 1 hypersensitivity, urticaria, sinusitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), aspirin-exacerbated respiratory disease, or cutaneous T-cell lymphoma, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a patient in a therapeutically effective amount.

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