5-[7-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1H-pyrrole-3-carboxamide derivatives, pharmaceutical compositions containing same and their use as apoptosis promoters

Abstract

A compound of formula (I): (I) wherein R3, R4, R5, R6, Z1, Z2 and T are as defined in the present description. TIFF2025508803000375.tif93170

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to 5-[7-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1H-pyrrole-3-carboxamide derivatives, pharmaceutical compositions containing them, and their use as pro-apoptotic agents. The compounds of the present invention inhibit the activity of Bcl-2 protein and may be of interest in the treatment of cancer, immune disorders, and autoimmune diseases.

[0002] Background of the Invention Apoptosis, or programmed cell death, is a physiological process important for embryonic development and the maintenance of tissue homeostasis. Apoptotic cell death involves not only morphological changes, such as nuclear condensation and DNA fragmentation, but also biochemical events, such as caspase activation, which damages important structural components of the cell, leading to its degradation and death. Regulation of the apoptotic process is complex and involves the activation or suppression of multiple intracellular signaling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656). Deregulation of apoptosis is involved in certain pathologies. Therefore, lack of apoptosis is one of the phenotypic characteristics of cancer (Hanahan D. et al., Cell 2000, 100, 57-70). Anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies. The involvement of Bcl-2 family proteins has been described in numerous types of cancer, including colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, follicular lymphoma, myeloma, and prostate cancer. Overexpression of anti-apoptotic proteins of the Bcl-2 family is associated with tumorigenesis, resistance to chemotherapy, and poor clinical prognosis in cancer-affected patients. Therefore, there is a therapeutic need for compounds that inhibit the anti-apoptotic activity of Bcl-2 family proteins. Venetoclax (also known as ABT-199) is a selective Bcl-2 inhibitor that disrupts the interaction of Bcl-2 with BH3-only proteins, thereby inducing apoptosis. Venetoclax is approved in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of (i) adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with or without 17p deletion who have received at least one prior therapy and (ii) adults aged 75 years or older with newly diagnosed acute myeloid leukemia (AML) or who have other medical conditions that prevent the use of standard chemotherapy.However, a significant number of relapses are observed in CLL, suggesting the emergence of acquired resistance mechanisms. Target mutations have been shown to cause resistance in other high-affinity targeted therapies (Garraway & Janne, Cancer Discovery 2012, 2, 214-226). Mutations in Bcl-2 affecting its hydrophobic groove have been identified in various venetoclax-resistant leukemia and lymphoma cell lines (Fresquet et al., Blood 2014, 123, 4111-4119; Tahir et al., BMC Cancer 17:399). Recently, a single mutation in Bcl-2 (a substitution of glycine at position 101 with valine: Gly101Val) was identified in CLL samples from patients resistant to venetoclax and therefore demonstrated clinical relevance. This Gly101Val (also called G101V) mutation has been associated with reduced binding of venetoclax to the hydrophobic groove of Bcl-2 and resistance to venetoclax (Blombery et al., Cancer Discovery 2019, 9, 342-353). Following the identification of G101V, multiple other mutations in the BCL-2 protein were identified in patients treated with venetoclax for CLL (e.g., D103Y, D103V, D103E, F104I, F104L, D111A, A113G, R129L, V156D; Blombery et al., Blood 2020, 5;135(10):773-777). D103E and V156D have also been detected in relapsed and refractory mantle cell lymphoma after sequential venetoclax / zanubrutinib monotherapy (Thompson et al., Blood 2022, 25;6(2):503-508). An acquired BCL-2 mutation (D111A) has also been reported in a patient with multiple myeloma treated with venetoclax (Neri et al., Blood, 134 (Supplement_1):572). F104I has also been reported in a patient with follicular lymphoma (Blombery et al., Br J Hematol 2019, 186, pp. e188-e191).Based on these clinical data, there is a need to identify novel therapeutic agents that can be used to treat patients with cancers that harbor BCL-2 mutations after treatment with venetoclax, particularly those who are refractory and relapsed.

[0003] The development of BCL-2-selective inhibitors is complicated by the high similarity between BCL-2 and BCL-XL within the BH3-binding domain (Petros et al., Proc. Natl. Acad. Sci. USA 2001, 98, 3012-3017). In addition, BCL-XL has previously been established as a key survival factor for platelets (Zhang et al., Cell Death Diff 2007, May;14(5):943-51; Mason et al., Cell 2007, 23;128(6):1173-86). Genetic ablation, hypomutation, or pharmacological inhibition of BCL-XL results in a shortened platelet half-life and dose-dependent thrombocytopenia in vivo. Early signs of clinical antitumor activity have been observed with the dual BCL-2 / BCL-XL inhibitor (ABT263, navitoclax) in lymphoid malignancies thought to be dependent on BCL-2 for survival (Wilson et al., Lancet Oncol 2010, Dec;11(12):1149-59). As predicted by preclinical data, inhibition of BCL-XL by navitoclax induces a rapid, concentration-dependent decrease in circulating platelet counts. This mechanism-based thrombocytopenia is a dose-limiting toxicity of navitoclax monotherapy in patients, limiting the ability to increase drug concentrations to highly effective ranges. Consequently, minimizing BCL-XL affinity is also necessary to design drugs with favorable efficacy and tolerability profiles.

[0004] Finally, CYP450-mediated metabolism is the primary excretion pathway for many drugs, leading to frequent drug interactions due to inhibition of drug metabolism (Deodhar et al., Pharmaceutics 2020, 4;12(9):846). Among CYP450s, CYP3A4 is the most abundant in the human liver (approximately 40%) and metabolizes over 50% of clinically used drugs. Therefore, drugs that inhibit CYP3A4 may increase the exposure of co-administered drugs, potentially causing serious drug toxicity (Zhou et al., Ther Clin Risk Manag 2005, Mar;1(1):3-13). This issue must also be addressed in the drug discovery process to mitigate the risk of CYP3A4-mediated drug-drug interactions.

[0005] Here, we claim the discovery of next-generation BCL-2 inhibitors that are selective for BCL-2 protein and have limited on-target affinity for BCL-XL and thrombocytopenia, but are highly active against wild-type BCL-2 protein and exhibit a favorable selectivity profile against various BCL-2 mutations that emerge clinically following venetoclax treatment. The identified compounds also demonstrated limited inhibition of CYP3A4.

[0006] Summary of the Invention The present invention provides potent, selective Bcl-2 inhibitors represented by Formula (I), as defined below. The inventors have demonstrated that these compounds have strong binding affinity to the Bcl-2 wild-type receptor and a panel of Bcl-2 mutants. The compounds of the present invention demonstrate overall better on-target affinity for Bcl-2 proteins compared to Bcl-xL proteins. The inventors have also demonstrated that compounds represented by Formula (I) have a cytotoxic profile in cell lines overexpressing Bcl-2 wild-type or Bcl-2 mutants. Furthermore, compounds represented by Formula (I) can induce apoptosis in cancer cells in vivo and trigger tumor regression in mice. Finally, limited platelet reduction was observed in animals highly exposed to the exemplary compounds. Furthermore, the exemplary compounds also demonstrated limited inhibitory potential against CYP3A4. Based on their pro-apoptotic properties, the compounds of the present invention can be used to treat conditions involving deregulation of apoptosis, such as cancer, autoimmune diseases, and immune system disorders.

[0007] In a first aspect, the present invention provides a compound of formula (I): [ka] [In the formula, Z1 and Z2 both represent a methyl group or they together with the atom carrying them form a fused piperidine group, T is a hydrogen atom, a linear or branched (C1-C6) alkyl group optionally substituted with 1 to 3 halogen atoms, a (C1-C4) alkylene-NR1R2 group, a (C1-C4) alkylene-OR i represents a group, R1 and R2 each independently represent a hydrogen atom or a linear or branched (C1-C6) alkyl group; R1 and R2 together with the nitrogen atom carrying them form a heterocycloalkyl group, which is optionally substituted with 1 to 3 groups selected from a (C1-C6) alkyl group and a halogen atom; R3 is as follows: [ka] represents a group selected from R4 is as follows: [ka] represents a group selected from R5 represents a hydrogen atom, a halogen atom, or a hydroxy group; R6 represents hydrogen, a linear or branched (C1-C6) alkyl group, or a halogen atom; Alk represents a linear or branched (C1-C6) alkyl group; A1 represents C-Y4 or a nitrogen atom; A2 represents CH or a nitrogen atom; Cy1 represents a phenyl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, wherein the phenyl group, the heteroaryl group, the cycloalkyl group, and the heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from a linear or branched (C1-C6) alkyl group optionally substituted with 1 to 3 halogen atoms, a hydroxy group, a cycloalkyl group, and a halogen atom, and the heterocycloalkyl group is optionally further substituted with an oxo group; Cy2 represents a phenyl group or a heteroaryl group, wherein the phenyl group and the heteroaryl group are optionally substituted with 1 to 3 groups selected from a linear or branched (C1-C6) alkyl group optionally substituted with 1 to 3 halogen atoms, a hydroxy group, and a halogen atom; X is a bond, —O—, —S—, or NR k represents Y1 and Y5 each independently represent a group selected from a hydrogen atom, a halogen atom, cyano, a linear or branched chain (C1-C6) alkyl group, and a linear or branched chain (C1-C6) alkoxy group; Y2 and Y4 each independently represent a group selected from a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group, and a heterocycloalkyl group optionally substituted with a linear or branched (C1-C6) alkyl group; Y3 is a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl, a linear or branched (C1-C6) alkynyl, -(C1-C4) alkylene-OR1, a linear or branched (C1-C6) alkoxy group, -O-phenyl, -S-phenyl, -O-(C1-C4) alkylene-Cy3, -O-(C1-C4) alkylene-Cy4, -O-Cy3, or -O-(C1-C4) alkylene-NR g R h , -(C1-C4) alkylene-Cy3, -(C1-C4) alkylene-Cy4, Cy3, Cy4 and [ka] wherein the alkylene portion of the preceding group may be straight or branched; Cy3 represents a linear or branched (C1-C6) alkyl group optionally substituted with 1 to 3 halogen atoms, a hydroxy group, a cycloalkyl group, a heterocycloalkyl group, and a heterocycloalkyl group optionally substituted with 1 to 3 groups selected from a halogen atom; Cy4 represents a linear or branched (C1-C6) alkyl group optionally substituted with 1 to 3 halogen atoms, a hydroxy group, a cycloalkyl group, a heterocycloalkyl group, and a cycloalkyl group optionally substituted with 1 to 3 groups selected from a halogen atom; R a and R b each independently represents a hydrogen atom or a halogen atom, R crepresents hydrogen, a straight or branched chain (C1-C6) alkyl group optionally substituted with 1 to 3 halogen atoms, (C1-C6) alkylene-NR d R e , (C1-C6) alkylene-OR j represents a group selected from cycloalkyl, heterocycloalkyl, and (C1-C6) alkylene-heterocycloalkyl groups; R' c and R'' c each independently represents a hydrogen atom or a linear or branched (C1-C6) alkyl (preferably methyl), R d and R e each independently represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, a cycloalkyl group, or a heterocycloalkyl group; R f represents a hydrogen atom, a halogen atom or a cyano group, R' f represents a hydrogen atom or a halogen atom, R g and R h each independently represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, a cycloalkyl group, a heterocycloalkyl group, or a -(C1-C6) alkylene-heterocycloalkyl group optionally substituted with 1 to 3 halogen atoms, R i , R j and R k each independently represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, or a -(C1-C6) alkylene-cycloalkyl group, R l represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, or a linear or branched (C1-C6) alkylene-heterocycloalkyl group, R m represents hydrogen or a linear or branched (C1-C6) alkyl group] The present invention provides a compound of the formula: and its enantiomers and diastereoisomers and addition salts with pharmaceutically acceptable acids or bases.

[0008] In another aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

[0009] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and at least one pharmaceutically acceptable excipient.

[0010] definition Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, etc.

[0011] Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.

[0012] "Heteroaryl" means any monocyclic or fused bicyclic group of 5 to 12 ring members having at least one aromatic moiety and containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. Among the heteroaryl groups are furyl, thienyl, thiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridinyl (also known as pyridyl), pyrimidinyl, indolyl, dihydroindolyl, indazolyl, tetrahydroindazolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzopyranyl, benzodioxolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroquinazolinyl, pyrrolopyridinyl, thiazole, thiazolyl ... Mention may be made, but is not limited to, enopyrimidinyl, furopyridinyl, benzothiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazinyl, pyridazinyl, dihydroisoindolyl, benzothienyl, tetrahydrobenzothienyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, dihydroquinoxalinyl, 4H,5H,6H,7H-pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-b]pyridinyl and the like.

[0013] "Cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members, and may include fused, bridged, or spiro ring systems. Among cycloalkyl groups, mention may be made, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0014] "Heterocycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group consisting of 3 to 10 ring members and containing 1 to 3 heteroatoms or groups selected from oxygen, sulfur, SO, SO, and nitrogen, wherein the bicyclic group may be fused or spiro. A heterocycloalkyl group may have one double bond. Among the heterocycloalkyl groups, azetidinyl, tetrahydrofuranyl, tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxanyl (also called tetrahydropyranyl), 1,4-dioxanyl, oxetanyl, azepanyl, 1,4-diazepanyl, (9aS)-hexahydro-1H-piperazino[2,1-c]morpholinyl (also called (9aS)-octahydropyrazino[2,1-c][1,4]oxazinyl), 1,1-dioxo-1λ 6 -thia-6-azaspiro[3.3]heptanyl, (8aS)-hexahydropyrrolo[1,2-a]piperazinyl, 6-oxa-9-azaspiro[4.5]decanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 5-azaspiro[2.3]hexanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, (1RS,5SR)-3-azabicyclo[3.1.0]hexanyl (also referred to as cis-3-azabicyclo[3.1.0]hexanyl), and the like may be mentioned, but are not limited to these.

[0015] "(C1-C6) alkylene" means a divalent, straight- or branched-chain saturated hydrocarbon radical having from 1 to 6 carbon atoms. Among alkylene radicals, mention may be made, but is not limited to, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH(CH3)-, -CH2-CH(CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-CH2-, -CH2-CH(CH2-CH3)-CH2-, -CH2-CH[CH(CH3)2]-CH2-, -CH2-C(CH3)2-CH2-, -CH2-CH(CH3)-CH(CH3)-, and the like.

[0016] Among the pharmaceutical compositions according to the invention, mention may be made especially of those suitable for oral, parenteral, nasal, percutaneous or transcutaneous, rectal, sublingual, ocular or respiratory administration, in particular tablets or dragees, sublingual tablets, sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, skin gels and drinkable or injectable ampoules. The pharmaceutical composition of the present invention comprises one or more excipients or carriers selected from diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol...), lubricants (e.g., silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol...), binders (e.g., magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone...), disintegrants (e.g., agar, alginic acid and its sodium salt, effervescent mixture...), stabilizers, preservatives, absorbents, colorants, sweeteners, flavors, etc. The route of administration is preferably oral or intravenous, and the corresponding pharmaceutical composition may allow immediate or delayed release of the active ingredient.

[0017] Among the inventive combinations of a compound of formula (I) and an anti-cancer agent, mention may be made particularly of those suitable for simultaneous or sequential administration. The inventive combination comprises a compound of formula (I) combined with an anti-cancer agent selected from genotoxic agents, mitotic toxins, antimetabolites, proteasome inhibitors, kinase inhibitors, protein-protein interaction inhibitors, immune modulators, E3 ligase inhibitors, chimeric antigen receptor T-cell therapy, and antibodies. The compounds of the combination may further be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition in which the active ingredients are mixed.

[0018] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer, in one embodiment, to ameliorating the disease or disorder (i.e., slowing or halting or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to modulating the disease or disorder either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both.

[0019] Among the cancer treatments envisioned, mention may be made of, but not limited to, hematological malignancies and solid tumors. Hematological malignancies include myeloma, in particular multiple myeloma, lymphoma, in particular non-Hodgkin's lymphoma (NHL) and diffuse large B-cell lymphoma (DLBCL), and leukemia, in particular chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), and acute myeloid leukemia (AML). Solid tumors include bladder, brain, breast, uterine, esophageal, and liver cancer, colorectal cancer, kidney cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer, and lung cancer, in particular non-small cell lung cancer and small cell lung cancer.

[0020] Among the possible treatments of autoimmune diseases, mention may be made, without limitation, of the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

[0021] The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to provide an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient. The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts. A suitable daily dose of a compound of the present invention will depend on the factors described above and can range from 0.01 mg to 2.5 g per day, in one or more administrations.

[0022] Detailed Description Advantageously, the compounds of the present invention have the formula (Ia): [ka] wherein R3, R4, R5, R6 and T are as defined in claim 1. It has.

[0023] In a preferred embodiment, R3 is the following group: [ka] represents R c represents hydrogen, a straight or branched chain (C1-C6) alkyl group optionally substituted with 1 to 3 halogen atoms, (C1-C6) alkylene-NR d R e , (C1-C6) alkylene-OR j , cycloalkyl, heterocycloalkyl, and (C1-C6) alkylene-heterocycloalkyl groups. Preferably, R crepresents a group selected from methyl, 2-hydroxyethyl, 2-[cyclopropyl(methyl)amino]ethyl, ethyl, isopropyl, 2-methoxyethyl, cyclopropyl, difluoromethyl and tetrahydrofuran-3-ylmethyl. Even more preferably, R c represents a methyl group.

[0024] In another embodiment, R3 is the following group: [ka] represents R c represents a group selected from methyl, ethyl, oxanyl, 2-methoxyethyl, 2-methylpropyl, difluoromethyl and 2-(dimethylamino)ethyl. Even more preferably, R c represents a methyl group.

[0025] In some embodiments, R4 is the following group: [ka] [In the formula, R a , R b , X, A1, Y1, Y2, Y3, Y5 are as defined in E1] Represents.

[0026] Below, a number of embodiments of the invention are described, with E1 being the same as the first aspect of the invention above for convenience. Further enumerated embodiments (E) of the invention are described herein. It will be recognized that the features specified in each embodiment can be combined with other specified features to provide further embodiments of the invention.

[0027] E2. Formula (Ib): [ka] [In the formula, R5, R6, R a , R b , Rc , X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0028] Advantageously, R c represents a methyl group.

[0029] E3. Formula (Ic): [ka] [In the formula, R5, R6, R a , R b , R c , R' c , R'' c , X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0030] E4. Formula (Id): [ka] [In the formula, R5, R6, R a , R b , X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0031] E5. Formula (Ie): [ka] [In the formula, R5, R6, R a , R b , X, A1, A2, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0032] E6. Expression (If): [ka] [In the formula, R5, R6, R a , R b , R f , R m , X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0033] Preferably, R m represents a methyl group.

[0034] E7. Formula (Ig): [ka] [In the formula, R5, R6, R a , R b , R f , X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0035] E8. Formula (Ih): [ka] [In the formula, R5, R6, R a , R b , R m , X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0036] Preferably, R m represents a methyl group.

[0037] E9. Formula (Ii): [ka] [In the formula, R5, R6, R a , R b , R' c , R' f , X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0038] E10. Formula (Ij): [ka] [In the formula, R5, R6, R a , R b , R c , R' c , R'' c , X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1] The compound according to E1, having the formula:

[0039] E11. The compound according to any one of E2 to E10, wherein X represents a bond.

[0040] E12. The compound according to any one of E2 to E10, wherein A1 represents C-Y4.

[0041] E13. R a and R b The compound according to any one of E2 to E10, wherein both represent hydrogen atoms.

[0042] E14. The compound according to any one of E2 to E10, wherein R5 represents a hydrogen atom, a hydroxy group or a fluorine atom, preferably a hydroxy group.

[0043] E15. The compound according to any one of E2 to E10, wherein R6 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom.

[0044] E16. The compound according to any one of E2 to E10, wherein R5 represents a hydroxy group and R6 represents a hydrogen atom.

[0045] E17. The compound according to any one of E2 to E10, wherein A1 represents CH and Y2 represents a hydrogen atom.

[0046] E18. The compound according to any one of E2 to E10, wherein Y1 and Y5 both represent a hydrogen atom, or Y1 and Y5 represent a fluorine atom and a hydrogen atom, respectively.

[0047] E19. The compound according to any one of E2 to E10, wherein Y3 represents an -O-(C1-C4)alkylene-Cy3 group, preferably the (C1-C4)alkylene group is ethylene.

[0048] E20. Y3 is -O-(C1-C4)alkylene-NR g R h The compound according to any one of E2 to E10, wherein the (C1-C4) alkylene group is preferably ethylene.

[0049] Even more preferably, Y3 is 2-(morpholin-4-yl)ethoxy, 2-[4-(2,2-difluoroethyl)piperazin-1-yl]ethoxy, 2-(3-fluoroazetidin-1-yl)ethoxy, 2-(3,3-difluoropyrrolidin-1-yl)ethoxy, 2-(oxan-4-yl)ethoxy, 2-(4-fluoropiperidin-1-yl)ethoxy, 2 -(thiomorpholin-4-yl)ethoxy, 2-(2-methylmorpholin-4-yl)ethoxy, 2-{6-oxa-9-azaspiro[4.5]decan-9-yl}ethoxy, 2-{4-oxa-7-azaspiro[2.5]octan-7-yl}ethoxy, 2,6-dimethylmorpholin-4-yl]ethoxy, 2-[cyclopropyl(methyl)amino]ethoxy, 2-{methylmorpholin-4-yl]ethoxy, ethyl[(oxetan-3-yl)methyl]amino}ethoxy, 2-[methyl(oxetan-3-yl)amino]ethoxy, 2-(4-fluoropiperidin-1-yl)ethoxy, 2-[(2-fluoroethyl)(methyl)amino]ethoxy, 2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(2,2-dimethylmorpholin-4-yl)ethoxy, 2-(morpholin-4-yl)propoxy, 2-(4,4-difluoropiperidin-1-yl)ethyl, [2-methyl-1-(morpholin-4-yl)propan-2-yl]oxy, 2-(3,3-dimethylmorpholin-4-yl)ethoxy and [(oxan-4-yl)methoxy]methyl.

[0050] In some embodiments, Y3 is 2-(morpholin-4-yl)ethoxy, 2-(oxan-4-yl)ethoxy, 2-(4-hydroxypiperidin-1-yl)ethoxy, 2-(4-cyclopropylpiperazin-1-yl)ethoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy, 2-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]ethoxy, 2-{2-[4-(2-{1,1-dioxo-1λ 6-thia-6-azaspiro[3.3]heptan-6-yl}ethoxy, 2-[2,6-dimethylmorpholin-4-yl]ethoxy, 2-[4-(2,2-difluoroethyl)piperazin-1-yl]ethoxy, 2-(3-fluoroazetidin-1-yl)ethoxy, 2-(3,3-difluoropyrrolidin-1-yl)ethoxy, 2-(4-fluoropiperidin-1-yl)ethoxy, 2-(thiomorpholin-4-yl)ethoxy, 2-(2-methylmorpholin-4-yl)ethoxy, 2-{6-oxa-9-azaspiro[4.5]decan-9-yl}ethoxy, 2-{4 -oxa-7-azaspiro[2.5]octan-7-yl}ethoxy, 2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(2,2-dimethylmorpholin-4-yl)ethoxy, 2-(morpholin-4-yl)propoxy, [2-methyl-1-(morpholin-4-yl)propan-2-yl]oxy, 2-(3,3-dimethylmorpholin-4-yl)ethoxy, 2-(3-methylmorpholin-4-yl)ethoxy, and 2-(1,4-dioxan-2-yl)ethoxy.

[0051] In some other embodiments, Y3 represents a group selected from 2-[cyclopropyl(methyl)amino]ethoxy, 2-[methyl(oxetan-3-yl)amino]ethoxy, 2-{methyl[(oxetan-3-yl)methyl]amino}ethoxy, 2-[(2-fluoroethyl)(methyl)amino]ethoxy, 2-(dimethylamino)ethoxy, 2-(morpholin-4-yl)ethyl, and 2-(4,4-difluoropiperidin-1-yl)ethyl.

[0052] Another embodiment of the present disclosure is the group: [ka] but [ka] The present invention relates to compounds of formula (I) which represent:

[0053] In some embodiments, T represents a linear or branched (C1-C6) alkyl group or a (C1-C4) alkylene -NR1R2 group. Advantageously, T is selected from the group consisting of methyl, (piperidin-1-yl)methyl, (morpholin-4-yl)methyl, [(3R)-3-fluoropyrrolidin-1-yl]methyl, [methyl(propan-2-yl)amino]methyl, (azepan-1-yl)methyl, (pyrrolidin-1-yl)methyl, [(3S)-3-methylpiperidin-1-yl]methyl, [(3R)-3-methylpiperidin-1-yl]methyl, [(1RS,5SR)-3-azabicyclo[3.1. 0]hexan-3-yl]methyl, [(2S)-2-methylpiperidin-1-yl]methyl, {6-azaspiro[2.5]octan-6-yl}methyl, (4,4-difluoropiperidin-1-yl)methyl, (4-methylpiperidin-1-yl)methyl, [ethyl(propan-2-yl)amino]methyl, [(3R)-3-methylpyrrolidin-1-yl]methyl and [(3S)-3-methylpyrrolidin-1-yl]methyl.In other embodiments, T is selected from the group consisting of methyl, (piperidin-1-yl)methyl, (morpholin-4-yl)methyl, (piperidin-1-yl)ethyl, [(3R)-3-fluoropyrrolidin-1-yl]methyl, (4-fluoropiperidin-1-yl)methyl, [methyl(propan-2-yl)amino]methyl, (azepan-1-yl)methyl, (pyrrolidin-1-yl)methyl, [(3S)-3-methylpiperidin-1-yl]methyl, [(3R)-3-methylpiperidin-1-yl]methyl, [(1RS,5SR)-3-azabicyclo[3.1.0]hexan-3-yl]methyl, [(2S)-2-methylpiperidin-1-yl]methyl, {6-azaspiro[2.5]octan-6-yl}methyl, ( 4,4-difluoropiperidin-1-yl)methyl, (diethylamino)methyl, (4-methylpiperidin-1-yl)methyl, [ethyl(propan-2-yl)amino]methyl, {5-azaspiro[2.3]hexane-5-yl}methyl, (3,3-dimethylpyrrolidin-1-yl)methyl, (diisopropylamino)methyl, [ethyl(isopropyl)amino]methyl, [(3R)-3-methylpyrrolidin-1-yl]methyl, [(3S)-3-methylpyrrolidin-1-yl]methyl, [(2S)-2-methylpyrrolidin-1-yl]methyl, 5-azaspiro[2.4]heptan-5-ylmethyl, 2-azaspiro[3.3]heptan-2-ylmethyl, and a group selected from aminomethyl.

[0054] In some embodiments, T is (C1-C4) alkylene-OR i Advantageously, T represents a group chosen from methoxymethyl, ethoxymethyl and cyclopropylmethoxymethyl.

[0055] Preferably, the compound according to E1 is selected from the following list: - 5-[2-benzylsulfonyl-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{3-fluoro-4-[1-(2-fluoroethyl)piperidin-4-yl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(2-fluoro-4-methoxyphenyl)acetyl]-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-{2-[cis-2,6-dimethylmorpholin-4-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, - 5-[2-(2-{4-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-fluorophenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-5-[2-[2-[2-fluoro-4-(2-tetrahydropyran-4-ylethoxy)phenyl]acetyl]-7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(thiomorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-((2R)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide. - 5-{2-benzoyl-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide, - N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide, - N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-{[methyl(propan-2-yl)amino]methyl}-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(4-{2-[cyclopropyl(methyl)amino]ethoxy}-2-fluorophenyl)acetyl]-7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-((2R or S)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-[(piperidin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, - N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{4-[2-(4,4-difluoropiperidin-1-yl)ethyl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, -N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(4-fluoropiperidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-{[(3S)-3-methylpiperidin-1-yl]methyl}-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide. is selected from.

[0056] The present invention also provides a compound of formula (II): [ka] and converting the compound represented by formula (III): [ka] wherein T is as defined in formula (I). to obtain a compound of formula (IV): [ka] wherein T is as defined in formula (I). to produce a compound represented by the formula The carboxybenzyl (Cbz) protecting group of the compound of formula (IV) is then replaced with a tert-butyloxycarbonyl (Boc) group, followed by hydrolysis of the ester functionality of the pyrrole moiety to give a compound of formula (V): [ka] wherein T is as defined in formula (I). to produce a compound represented by the formula The compound of formula (V) can be reacted with the following amine: [ka] wherein R3, R5 and R6 are as defined in formula (I). to form a compound of formula (VII): [ka] wherein T, R3, R5 and R6 are as defined in formula (I). to produce a compound represented by the formula the compound of formula (VII) is deprotected and subjected to an amidation or sulfonylation reaction to produce a compound of formula (I), which latter compound can be purified according to conventional separation techniques, can be converted into its addition salt with a pharmaceutically acceptable acid or base, and can be separated into its isomers according to conventional separation techniques; It is understood that at any time during the course of the above-described process, some groups (hydroxy, amino) of the starting reagents or synthetic intermediates may be protected as needed for synthesis and then deprotected. The present invention relates to a process for preparing a compound of formula (I).

[0057] In another embodiment, the present invention provides a compound of formula (II): [ka] to hydrolyze the ester functionality of the compound of formula (II) to produce the corresponding carboxylic acid, which is then reacted with 1,1-di-tert-butoxy-N,N-dimethyl-methanamine to produce the compound of formula (VIII): [ka] [wherein tBu represents a tert-butyl group] to produce a compound represented by the formula The compound represented by formula (VIII) is reacted with a compound represented by formula (VI): [ka] wherein R3, R5 and R6 are as defined in formula (I). to form an amine of formula (IX): [ka] wherein R3, R5 and R6 are as defined in formula (I). to produce a compound represented by the formula The carboxybenzyl protecting group of the compound of formula (IX) is removed by catalytic hydrogenation to give a compound of formula (X): [ka] wherein R3, R5 and R6 are as defined in formula (I). to produce a compound represented by the formula This compound is subjected to an amidation reaction or a sulfonylation reaction to give a compound of formula (XI): [ka] wherein R3, R4, R5 and R6 are as defined in formula (I). to produce a compound represented by the formula The tert-butyl ester functionality of the compound of formula (XI) is deprotected, and then the compound of formula (III): [ka] wherein T is as defined in formula (I). to produce a compound of formula (I), which latter compound can be purified according to conventional separation techniques, converted into its addition salt with a pharmaceutically acceptable acid or base, and separated into its isomers according to conventional separation techniques, It is understood that at any time during the course of the above-described process, some groups (hydroxy, amino) of the starting reagents or synthetic intermediates may be protected as needed for synthesis and then deprotected. The present invention relates to a process for preparing a compound of formula (I).

[0058] Pharmacological studies of the compounds of the present invention have shown that they have proapoptotic properties. The ability to reactivate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancer and immune and autoimmune diseases. In particular, the compounds of the present invention will be useful in the treatment of chemotherapy-resistant or radioresistant cancers.

[0059] In some embodiments of the present disclosure, compounds of the present invention are highly active against BCL2 wild-type protein (i.e., values ​​below 1 nM in a TR-FRET assay for EKI_BCL2 wild-type) and highly active against BCL2 G101V mutant (i.e., an [EKI BCL2 G101V] / [EKI BCL2 wild-type] selectivity ratio of less than 10, more preferably less than 5), while exhibiting limited on-target affinity for BCL-XL (i.e., an [EKI BCL-XL] / [EKI BCL2 wild-type] selectivity ratio of greater than 10). In further embodiments, compounds of the present invention also exhibit overall better on-target affinity for Bcl-2 wild-type protein and Bcl-2 mutants compared to Bcl-xL protein. In some embodiments, the Bcl-2 mutant (also referred to as a BCL2 mutein) is selected from the following group: BCL2 G101V, BCL2 D103Y, BCL2 F104I, BCL2 D111A, BCL2 D103E, BCL2 A113G, BCL2 R129L, BCL2 V156D, BCL2 D103V, and BCL2 F104L.

[0060] In some embodiments of the present disclosure, compounds of the present invention are highly active against BCL2 wild-type protein (i.e., values ​​less than 100 pM in the TR-FRET assay for EKI_BCL2 wild-type), while exhibiting limited on-target affinity for BCL-XL (i.e., [EKI_BCL-XL] / [EKI_BCL2 wild-type] selectivity ratio greater than 100).

[0061] The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) or its addition salt with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients. In particular, these pharmaceutical compositions are of interest as anti-apoptosis inhibitors, especially for the treatment of cancer (hematological malignancies and solid tumors) and autoimmune and immune system diseases. In particular, these pharmaceutical compositions are of interest as anti-apoptosis inhibitors in the treatment of cancer chemotherapy resistance or radioresistance. Preferably, these pharmaceutical compositions can be used for the treatment of cancers (hematological malignancies and solid tumors) selected from myeloma, in particular multiple myeloma, lymphoma, in particular non-Hodgkin's lymphoma (NHL) and diffuse large B-cell lymphoma (DLBCL), leukemia, in particular chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML), cancer of the bladder, brain, breast, uterus, esophagus and liver, colorectal cancer, kidney cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer, lung cancer, in particular non-small cell lung cancer and small cell lung cancer, rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), as well as autoimmune diseases and diseases of the immune system. In some embodiments, the compounds of Formula (I) are used in the manufacture of medicaments for use in the treatment of cancer and autoimmune and immune system diseases.

[0062] Still further, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) in combination with an anti-cancer agent selected from genotoxic agents, mitotic toxins, antimetabolites, proteasome inhibitors, kinase inhibitors, protein-protein interaction inhibitors, immune modulators, E3 ligase inhibitors, chimeric antigen receptor T cell therapy and antibodies, as well as to a method for treating cancer, in particular myeloma, in particular multiple myeloma, lymphoma, in particular non-Hodgkin's lymphoma (NHL) and diffuse large B-cell lymphoma. and its use in the manufacture of a medicament for use in the treatment of hematological malignancies and solid tumors selected from lymphoma (DLBCL), leukemia, in particular chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML), cancer of the bladder, brain, breast, uterus, esophagus and liver, colorectal cancer, kidney cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer and lung cancer, in particular non-small cell lung cancer and small cell lung cancer.

[0063] In another embodiment, the compounds of the present invention can be used in combination with radiation therapy in the treatment of cancer.

[0064] Alternatively, the compounds of the present invention can be linked to a monoclonal antibody. Antibody-drug conjugates (ADCs) represent a new class of therapeutic agents formed by chemically linking a cytotoxic drug to a monoclonal antibody via a linker. The monoclonal antibody of an ADC selectively binds to a target antigen in a cell (e.g., a cancer cell) and releases the drug intracellularly. ADCs have therapeutic potential because they combine the specificity of an antibody with the cytotoxicity of a drug. Nevertheless, to date, the development of ADCs as therapeutic agents has met with limited success due to various factors, such as unfavorable toxicity profiles, low efficacy, and poor pharmacological parameters. Therefore, there remains a need for novel ADCs that can overcome these problems and selectively deliver Bcl-2 to target cancer cells.

[0065] In another embodiment, the compounds of the present invention can be linked to fragments of monoclonal antibodies or to scaffold proteins that may or may not be related to monoclonal antibodies. Antibody fragments are understood to be fragments of the Fv, scFv, Fab, F(ab')2, F(ab'), scFv-Fc type or diabodies, which generally have the same binding specificity as the antibody from which they are derived. According to the present invention, antibody fragments of the present invention can be obtained starting from antibodies by cleavage of disulfide bridges by methods such as digestion with enzymes, for example, pepsin or papain, and / or chemical reduction. Alternatively, antibody fragments encompassed by the present invention can be obtained by genetic recombination techniques also well known to those skilled in the art or by other methods, such as peptide synthesis using automated peptide synthesizers, for example those supplied by Applied Biosystems.

[0066] Scaffold proteins, which may or may not be related to monoclonal antibodies, are understood to mean proteins that may or may not contain an immunoglobulin fold and that provide binding capacities similar to those of monoclonal antibodies. Those skilled in the art know how to select protein scaffolds. It is known, inter alia, that such scaffolds to be selected should exhibit several characteristics (Skerra, J. Mol. Recogn. 2000, 13, 167-187): good phylogenetic conservation, a robust structure with a known three-dimensional molecular organization (e.g., crystallography or NMR), small size, no or only few post-translational modifications, and ease of production, expression, and purification. Such protein scaffolds may be structures selected from the group consisting of, but are not limited to, fibronectin and preferentially the tenth fibronectin type III domain (FNfn10), lipocalins, anticalins (Skerra, J. Biotechnol. 2001, 74, 257-75), protein Z derivatives derived from domain B of staphylococcal protein A, thioredoxin A, or any protein with a repeat domain, such as ankyrin repeats (Kohl et al., PNAS 2003, 100, 1700-1705), armadillo repeats, leucine-rich repeats, or tetratricopeptide repeats. Mention may also be made of scaffold derivatives derived from venoms (such as those of scorpions, insects, plants, or mollusks) or protein inhibitors of neuronal nitric oxide synthase (PIN).

[0067] The following examples are intended to illustrate but not limit the present invention, and all reagents for preparing the examples are either commercially available or can be obtained by one skilled in the art using conventional chemistry described in the literature.

[0068] General notes on synthesis All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

[0069] Reactions were monitored using LCMS and GCMS instruments and / or TLC.

[0070] TLC Thin layer chromatography was performed using a Merck Type 60 F 254 The assay was carried out on silica gel-coated 5 x 10 cm plates.

[0071] Column chromatography Automated flash column chromatography was performed on an ISCO CombiFlash® Rf 200 or CombiFlash® Rf+ Lumen™ using a RediSep® Rf Normal-phase Silica Flash Column (35–70 μm, 60 Å), a RediSep® Rf Gold® Normal-phase Silica High Performance Column (20–40 μm, 60 Å), a RediSep® Rf Reversed-phase C18 Column (40–63 μm, 60 Å), or a RediSep® Rf Gold® Reversed-phase C18 High Performance Column (20–40 μm, 100 Å). For HILIC, a RediSep® Rf Gold® Normal-phase Silica High Performance Column (20–40 μm, 60 Å) was used.

[0072] Microwave Reaction Microwave heating was performed in a CEM Discover® SP or Anton Paar MonoWave microwave reactor.

[0073] NMR 1 H-NMR and 13C-NMR measurements were performed on a Bruker Avance III 500 MHz spectrometer, a Bruker Avance III 400 MHz spectrometer, a Bruker DPX 400 MHz spectrometer, and a Bruker Avance NEO 400 MHz spectrometer using DMSO-d6 or CDCl3 as the solvent. 1 H NMR data are given in parts per million (ppm) in the form of delta values, using the residual peaks of the solvent (2.50 ppm for DMSO-d6 and 7.26 ppm for CDCl3) as internal standards. Separation patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), br s (broad singlet), br d (broad doublet), br t (broad triplet), br m (broad multiplet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), qd (quartet of doublets), ddd (doublet of doublet of doublets), and dm (doublet of multiplets). In certain cases, due to the complexity, only definitive signals in the carbon spectra were interpreted.

[0074] Analytical GC-MS Gas chromatography coupled with low-resolution mass spectrometry (GC-MS) was performed on an Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using a 15 m × 0.25 mm column with a 0.25 μm HP-5MS coating and helium as the carrier gas: ion source: EI+, 70 eV, 230 °C, quadrupole: 150 °C, interface: 300 °C.

[0075] Analytical LC-MS The compounds of the present invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) using the following instruments:

[0076] An Agilent HP1200 LC was equipped with one Agilent MSD 6140 quadrupole and operated in positive or negative electrospray ionization mode. The molecular weight scan range was 100–1350 m / z. Parallel UV detection was performed at 210 nm and 254 nm. Samples were delivered as 1 mM solutions in MeCN or THF / water (1:1) via a 5 μL loop injection. LCMS analysis was performed on two instruments, one operated with a basic eluent and the other with an acidic eluent.

[0077] Basic LCMS: Gemini-NX, 3 μm, C18, 50 mm × 3.00 mm (inner diameter) column, 23 °C, flow rate 1 mL min -1 A gradient of 5 mM aqueous NH4HCO3 (solvent A) and MeCN (solvent B) was used starting with 100% solvent A and ending with 100% solvent B over various time periods.

[0078] Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 μm, 50 mm x 4.6 mm (inner diameter) column, 40°C, flow rate 1 mL min. -1 , 0.02% V / V HCOOH in water (solvent A) and 0.02% V / V HCOOH in MeCN (solvent B) were used in a gradient starting from 100% solvent A and ending at 100% solvent B over various time periods.

[0079] An Agilent HP1260 Infinity II LC equipped with an InfinityLab LC / MSD was operated in positive electrospray ionization mode. The molecular weight scan range was 100–1350 m / z. Parallel UV detection was performed at 210 nm and 254 nm. Samples were delivered as 1 mM solutions in MeCN or methanol via loop injection of 1–5 μL, and analyzed on a Kinetex® XB-C18, 2.6 μm, 50 mm × 2.1 mm (id) column at 40°C with a flow rate of 1 mL min . -1The column was run using a gradient of 0.05% V / V TFA solution in 20 / 1 water / MeCN (solvent A) and 0.05% V / V TFA solution in 1 / 20 water / MeCN (solvent B) starting at 100% solvent A and ending at 100% solvent B over various time periods.

[0080] An Agilent HP1200 LC equipped with an Agilent MSD 6120 quadrupole LC / MS was operated in positive or negative electrospray ionization mode. The molecular weight scan range was 100–1350 m / z. Parallel UV detection was performed at 210 nm and 254 nm. Samples were delivered as 1 mM solutions in MeCN or methanol via loop injection of 1–5 μL and analyzed on a Gemini® NX-C18, 3 μm, 50 mm × 3 mm (id) column at 40°C with a flow rate of 0.8 mL min . -1 The column was run using a gradient of 5 mM NH4HCO3 in 20 / 1 water / MeCN (solvent A) and MeCN (solvent B) starting at 100% solvent A and ending at 90% solvent B over various time periods.

[0081] High resolution MS An Agilent 1200 SL series instrument equipped with an ESI-APCI multimode source and coupled to one Agilent MSD 6140 quadrupole or an Agilent 1290 Infinity II series instrument equipped with an ESI-Jetstream source and connected to an Agilent TOF 6230 was used; columns: Thermo Accucore 2.6 μm, C18, 50 mm × 2.1 mm (55 °C) or Agilent Zorbax Eclipse plus 3.5 μm, C18, 30 mm × 2.1 mm (35 °C); eluents: Solvent A: 10 mM aqueous NHOAc + 0.08% (v / v) HCOOH; Solvent B: MeCN + 5% (v / v) solvent A + 0.08% (v / v) HCOOH, starting from 95% solvent A and increasing over various time periods. Gradient ending with solvent B; ionization is recorded in positive mode, negative mode or positive-negative switching mode.

[0082] TOF (basic): Agilent 6230 time-of-flight mass spectrometer equipped with a Jet Stream electrospray ion source in positive ion mode. A 0.5 μl injection was introduced into the mass spectrometer using an Agilent 1290 Infinity HPLC system at a flow rate of 0.7 ml / min (gradient program of 5 mM ammonium bicarbonate in water and acetonitrile). Jet Stream parameters: Drying gas (N2) flow rate and temperature: 8.0 l / min and 325 °C, respectively; Nebulizer gas (N2) pressure: 30 psi; Capillary voltage: 3000 V; Sheath gas flow rate and temperature: 325 °C and 10.0 l / min; TOFMS parameters: Fragmenter voltage: 100 V; Skimmer voltage: 60 V; OCT 1 RF Vpp: 750 V. Full-scan mass spectra were acquired over the m / z range 105–1700 at an acquisition rate of 995.6 ms / spectrum and processed with Agilent MassHunter B.08.00 / 10.10 software.

[0083] Q-TOF (neutral): Agilent 6545 quadrupole time-of-flight mass spectrometer equipped with a Duo-Jet Stream electrospray ion source in positive or negative ion mode. A 0.5 μl injection was introduced into the mass spectrometer using an Agilent 1290 Infinity HPLC system at a flow rate of 0.7 ml / min (gradient program of 5 mM ammonium formate in water and acetonitrile). Jet Stream parameters: Drying gas (N2) flow rate and temperature: 10.0 l / min and 300 °C, respectively; Nebulizer gas (N2) pressure: 40 psi; Capillary voltage: 2500 V; Sheath gas flow rate and temperature: 300 °C and 10.0 l / min; TOFMS parameters: Fragmenter voltage: 100 V; Skimmer voltage: 65 V; OCT 1 RF Vpp: 750 V. Full-scan mass spectra were acquired over the m / z range 105–1700 at an acquisition rate of 1000.0 ms / spectrum and processed with Agilent MassHunter B.08.00 / 10.10 software.

[0084] Preparative HPLC Certain compounds of the present invention were purified by high performance liquid chromatography (HPLC) on the following equipment:

[0085] Gemini NX® 5 μm C18, 250 mm × 50 mm (id) column with a flow rate of 118 mL min -1 The assay was run on an Armen Spot Prep II Liquid Chromatography or Teledyne CombiFlash EZ Prep system with detection by a UV diode array (210-400 nm) and using 25 mM aqueous NH4HCO3 and MeCN or 0.1% TFA and MeCN in water as eluents.

[0086] A Gemini® 5 μm C18(2), 100 mm × 20 mm (id) column (Phenomenex) was used, with a flow rate of 20 mL min -1 The samples were run on a Waters FractionLynx MS automated purification system with direct mass collection and UV diode array detection (210–400 nm). The mass spectrometer was a Waters Micromass ZQ2000 spectrometer operating in positive or negative electrospray ionization mode. The molecular weight scan range was 150–1000. pH 4 eluent: Solvent A: 10 mM aqueous NHOAc + 0.08% (v / v) HCOOH; Solvent B: MeCN + 5% (v / v) solvent A + 0.08% (v / v) HCOOH. pH 9 eluent: Solvent A: 10 mM aqueous NHOAc + 0.08% (v / v) concentrated NH; Solvent B: MeCN + 5% (v / v) solvent A + 0.08% (v / v) concentrated NH.

[0087] The column was equipped with a Gemini® NX 5 μm C18(2), 150 mm × 21.2 mm (inner diameter) column (Phenomenex), and the flow rate was 20 mL min -1 The column was run at 400 rpm or equipped with a Gemini® NX 5 μm C18(2), 250 mm × 30 mm (id) column (Phenomenex) at a flow rate of 40 mL min -1The eluate was run on an AccQPrep HP125 (Teledyne ISCO) system with UV (214 and 254 nm) and ELS detection. pH 4 eluate: Solvent A: water + 0.08% (v / v) HCOOH; Solvent B: MeCN + 0.08% (v / v) HCOOH. pH 9 eluate: Solvent A: water + 0.08% (v / v) concentrated NH3 in water; Solvent B: MeCN + 0.08% (v / v) concentrated NH3 in water. Neutral eluate: Solvent A: water; Solvent B: MeCN.

[0088] compound naming IUPAC recommended names were generated using the ChemAxon "Structure to Name" (s2n) function within MarvinSketch or JChem for Excel (JChem versions 16.6.13-18.22.3) or the compound naming functionality provided by Biovia® Draw 4.2.

[0089] Abbreviation [Table 1] TIFF2025508803000035.tif232170 TIFF2025508803000036.tif101170

[0090] General method The following are representative experimental procedures, which are referred to by name in the subsequent "Preparations" and "Examples".

[0091] General method 1a Buchwald The appropriate aryl bromide (1 equivalent), the appropriate aniline (1.1 equivalents), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.04 equivalents), and NaO tBu (2 equiv.) was suspended in toluene (3 mL / 1 mmol of aryl bromide). The mixture was sparged with N2, then Pd2(dba)3 (0.04 equiv.) was added, and the mixture was heated at 110 °C under microwave irradiation or at 70 °C under N2 atmosphere for 1 h until complete conversion was observed. The mixture was cooled to rt, diluted with water, and filtered through a Celite cartridge. The filtrate was partitioned between EtOAc and water. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude material was purified by automated flash chromatography using heptane and EtOAc as eluents.

[0092] General method 1b Buchwald To a solution of the appropriate aryl bromide (1 equiv.) and the appropriate aniline (1 equiv.) in THF (4.5 mL / 1 mmol of aryl bromide) was added NaO t Bu (1 equiv.) and chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) [t-BuXPhos Palladacycle Gen. 1] (0.04 equiv.) were added, and the mixture was stirred under N at rt until complete conversion was observed. The mixture was diluted with water, and the organic layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO, and concentrated in vacuo. The crude material was purified by automated flash chromatography using heptane or MeOH and EtOAc as eluents.

[0093] General Method 2a Amide Coupling To a solution of the appropriate acid (1 equiv.) in DCE (12 mL / 1 mmol of acid) was added 4A molecular sieves, followed by 1-chloro-N,N,2-trimethyl-1-propenylamine (2 equiv.), and the mixture was then stirred at rt under N for 30 min. A solution of the appropriate aniline (1.5 equiv.) and pyridine (2 equiv.) in DCE (2.5 mL / 1 mmol of aniline) was added, and the mixture was stirred at 80 °C under N for 18 h. The mixture was cooled to rt and partitioned between DCM and water. The phases were separated, and the organic phase was washed with saturated aqueous NaHCO, dried over MgSO, and concentrated in vacuo. The crude material was purified by automated flash chromatography using heptane and EtOAc or DCM and MeOH as eluents.

[0094] General Method 2b Amide Coupling To a solution of the appropriate acid (1 equiv) in DCM (12 mL / 1 mmol of acid) was added oxalyl dichloride (1.7 equiv), and the mixture was then stirred at rt under N for 30 min. The solution was concentrated in vacuo at rt, and then the appropriate aniline (1.2 equiv) in DCE (12 mL / 1 mmol of acid) was added, and the mixture was stirred at 80 °C under N for 4-18 h. The reaction mixture was concentrated in vacuo, and the crude material was purified by automated flash chromatography using DCM and MeOH as eluents.

[0095] General Method 3a tBu Ester Deprotection To a solution of the appropriate tBu ester (1 equiv.) in 1,4-dioxane (5 mL / mmol) was added a solution of trimethylsilyl trifluoromethanesulfonate (5 equiv.) and TEA (5 equiv.) in 1,4-dioxane (1 mL / 1 mmol of TEA), and the mixture was stirred at rt for 5-18 h. The reaction mixture was poured into ice water, stirred for 10 min, and then extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents.

[0096] General method 3b HCl deprotection To a solution of the appropriate silyl derivative in MeOH (5 mL / mmol) was added a solution of 3 M HCl in MeOH (5 mL / 1 mmol of silyl derivative), and the mixture was stirred at rt until complete conversion was observed. The mixture was concentrated in vacuo and then partitioned between DCM and saturated aqueous NaHCO. The phases were separated, and the organic phase was dried over MgSO and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents or by preparative HPLC automated flash chromatography using water and MeCN as eluents at pH 9 or pH 4.

[0097] General method 3c TBAF deprotection To a solution of the appropriate silyl derivative (1 equiv.) in THF (50 mL / mmol) under N2, 1 M TBAF in THF (2 equiv.) was added, and the mixture was stirred at rt for 18 h. The mixture was partitioned between DCM and saturated aqueous NaHCO3, and the phases were then separated. The aqueous phase was extracted with DCM, and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification was performed by automated flash chromatography using DCM and MeOH as eluents, followed by preparative HPLC automated flash chromatography at pH 4 or pH 9 using water and MeCN as eluents.

[0098] General Method 4a: Amide Coupling To a solution of the appropriate amine (1 eq) in DMF (6 mL / 1 mmol of amine) was added the appropriate carboxylic acid (1.5 eq), followed by DIPEA (2 eq) and HATU (1 eq), and the mixture was stirred at rt until complete conversion was observed. The reaction mixture was partitioned between DCM and water. The phases were separated, and the organic phase was dried over MgSO4 and concentrated. Purification was performed by automated flash chromatography using DCM and MeOH as eluents, followed by preparative HPLC automated flash chromatography at pH 9 or pH 4 using water and MeCN as eluents.

[0099] General Method 4b Amide Coupling To a solution of the appropriate amine (1 eq) in DMF (6 mL / 1 mmol of amine) was added the appropriate carboxylic acid (1.2 eq), followed by DIPEA (4 eq) and PyBop (1.2 eq), and the mixture was stirred at rt until complete conversion was observed. DMF was removed in vacuo, and the residue was partitioned between DCM and water. The phases were separated, and the organic phase was dried over MgSO4 and concentrated in vacuo. The crude material was purified by preparative HPLC automated flash chromatography at pH 9 or pH 4 using water and MeCN as eluents.

[0100] General Method 4c: Sequential Amide Coupling and Silyl Deprotection To a solution of carboxylic acid (1.5 equiv) in DMF (6 mL / 1 mmol of acid) was added TBTU (3 equiv), followed by DIPEA (4 equiv). After stirring for 10 min, the appropriate amine (1 equiv) was added, and the mixture was stirred at rt until complete conversion was observed. 2 M aqueous NaOH (5 equiv) was added, and the reaction mixture was further stirred until complete silyl deprotection was observed. The reaction mixture was filtered and then loaded directly onto a RP C18 column and purified by preparative reverse-phase chromatography. The appropriate fractions were combined and concentrated under reduced pressure to approximately 25 mL, then extracted with DCM (2 × 20 mL). The combined organic extracts were dried over Na2SO4 and concentrated to give the target amide product, which was further purified by automated flash chromatography using DCM and MeOH as eluents.

[0101] General Method 4d: Sequential Amide Coupling and Silyl Deprotection Modified general procedure 4c: Carboxylic acid chloride (1.2 equiv.), DIPEA or TEA (2 equiv.) in DCM (3 mL / mmol) was used instead of carboxylic acid (1.5 equiv.), DIPEA (4 equiv.), and TBTU was omitted.

[0102] General Method 5: THIQ Amide Coupling HATU (1.1 equiv.) was added portionwise to a stirred solution of the appropriate amine (1.05 equiv.), Boc-(3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1 equiv.), and TEA (2 equiv.) in DMF (10 mL / mmol) under N. The mixture was stirred at rt for 12 h and then partitioned between EtOAc and saturated aqueous NaHCO. The phases were separated, and the organic phase was washed with brine, dried over MgSO, and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents.

[0103] General Method 5a THIQ Amide Coupling TBTU (1.5 equiv.) was added in small portions to a stirred solution of Boc- or Cbz-protected (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1 equiv.) and DIPEA (3 equiv.) in DMF / DCM (5 mL / 1 mmol of acid) under N2. After stirring for 10 min, the appropriate amine (1.4 equiv.) was added, and the mixture was stirred at rt until complete conversion was observed. The mixture was then partitioned between EtOAc and water. The phases were separated, and the organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents.

[0104] General Method 6 THIQ Amide Reduction and Deprotection To a solution of the appropriate THIQ amide (1 equiv.) in THF (5-7 mL / 1 mmol of THIQ) was added 1 M BH3. The THF solution (5 equiv.) was added dropwise at rt under a N2 atmosphere. The mixture was then heated to reflux for 5 h. The mixture was cooled to rt and quenched by the slow addition of MeOH, then stirred at rt for 10 min. The mixture was concentrated under reduced pressure, and the residue was suspended in MeOH (5-7 mL / mmol). Concentrated HCl (4 equiv. (12 M)) was added, and the mixture was refluxed for 1.5 h. The reaction was cooled to rt, concentrated under reduced pressure, and azeotroped with toluene.

[0105] General Method 6a THIQ Amide Reduction A solution of the appropriate THIQ amide (1 equiv.) in DCM (5–10 mL / 1 mmol of THIQ) was cooled to 0°C in an ice-water bath, and then a 1 M solution of LiAlH4 in THF (2 equiv.) was added dropwise under a N2 atmosphere. The cooling bath was removed, and the mixture was stirred at rt until complete conversion was observed. The mixture was diluted with THF, cooled to 0°C, and then quenched by the subsequent addition of water and 15% aqueous NaOH according to the Fieser workup procedure. Anhydrous MgSO4 (5 g / 1 mmol of THIQ) was added, followed by stirring for 15 min, after which the salts were removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by automated flash chromatography using heptane and IPA or DCM and MeOH as eluents (1% NH3).

[0106] General method 6b Cbz deprotection To an N2-flushed solution of the appropriate Cbz-protected amine in methanol, THF, or EtOAc (20 mL / 1 mmol of amine), 3-5 m / m% Pd (10% on carbon) was added. The reaction mixture was hydrogenated at atmospheric pressure (with the aid of a H2 balloon) until complete conversion was observed. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure.

[0107] General method 6c Boc deprotection To an N2-flushed solution of the appropriate Boc-protected amine in DCM (2.5-5 mL / 1 mmol of amine) was added HCl (2 M solution in diethyl ether, 10 equiv.) The reaction mixture was stirred at rt overnight and then concentrated in vacuo.

[0108] General Method 7a O-Alkylation A stirred suspension of the appropriate phenol (1 equiv.) and K2CO3 (5 equiv.) in MeCN (5-10 mL / mmol) was heated at 70 °C for 20 min. The appropriate alkyl halide (1.6 equiv.) was added and heating continued until complete conversion was observed. The mixture was cooled to rt, filtered, and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by automated flash chromatography using heptane and EtOAc or DCM and MeOH as eluents.

[0109] General method 7b Mitsunobu To a solution of the appropriate phenol (1 equiv.) in THF (5–10 mL / mmol) was added the appropriate alcohol (1 equiv.) and PPh3 (1.5 equiv.), followed by DTBAD (1.5 equiv.), then stirred at rt under N2 for 12 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was purified by automated flash chromatography using heptane and EtOAc or DCM and MeOH as eluents.

[0110] General method 7c Mitsunobu In a pressure-release vial, 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (1 equiv.), the appropriate alcohol (2 equiv.), and 2-(tributyl-λ5-phosphanylidene)acetonitrile (2 equiv.) in toluene (2 mL / mmol) were stirred under N for 1 h at 100° C. The mixture was concentrated in vacuo, and the residue was purified by automated flash chromatography using heptane and EtOAc or DCM as eluents.

[0111] General Method 7d N-Alkylation A stirred suspension of the appropriate ester of the 4-(2-bromoethoxy)phenylacetic acid derivative (1 equiv.) and KCO / CsCO (2-7 equiv.) in MeCN (4-7 mL / 1 mmol of alkyl halide) and the appropriate amine (1.5-3 equiv.) was heated at 80 °C until complete conversion was observed. The reaction mixture was concentrated in vacuo, and the residue was purified by automated flash chromatography using heptane and EtOAc or DCM and MeOH as eluents.

[0112] General Method 8 Ester Hydrolysis A solution of the appropriate ester (1 equiv.) in MeOH (3-11 mL / mmol) was treated with 2 M aqueous NaOH (2 equiv.) and stirred at rt for 24 h. The MeOH was removed in vacuo, and the aqueous residue was neutralized with 2 M aqueous HCl and then purified by reverse-phase automated flash chromatography using water and MeCN as eluents.

[0113] preparation The experimental details below describe the preparation of synthetic intermediates.

[0114] Preparation I: 2-Benzyloxycarbonyl-6-(4-ethoxycarbonyl-1,5-dimethyl-pyrrol-2-yl)-3,4-dihydro-1H-isoquinoline-7-carboxylic acid [ka] The synthesis of the title compound is described in WO2015 / 011164 A1, Example 805, Step B.

[0115] Preparation IIa 5-[2-(tert-butoxycarbonyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxylic acid [ka]

[0116] Process A (3R)-3-Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [ka] The synthesis of the title compound is described in Preparation 2b of WO2015 / 011164 A1.

[0117] Process B Benzyl 6-[4-(ethoxycarbonyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] To a solution of Preparation I (3 g, 6.3 mmol, 1 equiv.) and the product from Step A (1.27 g, 6.93 mmol, 1.1 equiv.) in DMF (30 mL) was added DIPEA (3.13 mL, 18.89 mmol, 3 equiv.) and PyBop (3.6 g, 6.93 mmol, 1.1 equiv.), and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (120 mL), stirred for 15 minutes, and the resulting cream-colored precipitate was collected by filtration and washed with water. The filter cake was dissolved in DCM, washed with saturated aqueous NaHCO3 and water, dried over MgSO4, and concentrated in vacuo to give the title product (3.7 g, 6.11 mmol, 97%). HRMS C 37 H 39 Calculated for N3O5: 605.289, Found: 606.296 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.52 - 6.75 (m, 11H), 6.43 - 6.00 (m, 1H), 5.39 - 1.95 (m, 21H), 1.31 - 0.49 (m, 6H).

[0118] Process C : Ethyl 1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxylate [ka] To a solution of the product from step B (3.7 g, 6.11 mmol, 1 equiv) in MeOH (70 mL) and EtOH (20 mL) was added 10% Pd / C (100 mg). The mixture was evacuated and back-filled with N, then evacuated and flushed with H, and then shaken under an H atmosphere at room temperature for 6 h. The mixture was filtered through a Celite cartridge and washed with EtOH. The solvent was removed in vacuo to give the title product (2.94 g, quantitative). HRMS C 29 H 33 Calculated for N3O3: 471.252, Found: 472.259 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.24 - 6.81 (m, 6H), 6.40 - 5.99 (m, 1H), 5.34 - 1.93 (m, 19H), 1.30 - 0.52 (m, 7H).

[0119] Process D tert-Butyl 6-[4-(ethoxycarbonyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] To a solution of the product from Step C (2.94 g, 6.23 mmol, 1 equiv.) in THF (45 mL) and water (6 mL) was added bis(tert-butyl)dicarbonate (1.43 g, 6.55 mmol, 1.05 equiv.), followed by TEA (1.73 mL, 12.47 mmol, 2 equiv.), and the mixture was stirred at room temperature for 12 h. The solvent was removed in vacuo, and the residue was partitioned between EtOAc and saturated aqueous NH4Cl. The phases were separated, and the organic phase was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo to give the title product (3.39 g, 5.93 mmol, 95%). HRMS C 34 H 41 Calculated for N3O5: 571.305, Found: 572.315 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.33 - 6.79 (m, 6H), 6.41 - 6.00 (m, 1H), 5.34 - 1.99 (m, 19H), 1.51 - 1.37 (m, 9H), 1.28 - 0.52 (m, 6H).

[0120] Process E 5-[2-(tert-butoxycarbonyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxylic acid [ka] LiOH·HO (995 mg, 23.72 mmol, 4 equiv) was added to a solution of the product from step D (3.39 g, 5.93 mmol, 1 equiv) in a mixture of MeOH (40 mL) and water (20 mL) and heated at 100 °C for 24 h. The mixture was allowed to cool to room temperature, and the MeOH was removed in vacuo. The aqueous residue was acidified to pH 5 with 1 M aqueous HCl, diluted with water (10 mL), and extracted with DCM. The combined organic extracts were dried over MgSO and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0–6% MeOH in DCM gave the title product (3.1 g, 5.7 mmol, 96%). HRMS C 32 H 37 Calculated for N3O5: 543.273, Found: 544.283 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.53 (s, 1H), 7.32 - 6.80 (m, 6H), 6.38 - 6.06 (m, 1H), 5.37 - 1.89 (m, 17H), 1.50 - 1.38 (m, 9H), 1.08 - 0.50 (m, 3H).

[0121] Preparation IIb 5-[2-(tert-butoxycarbonyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxylic acid [ka]

[0122] Process A (3S)-3-[(piperidin-1-yl)carbonyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] Using general procedure 5 and Boc-(3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (5.56 g, 20.05 mmol, 1 equiv.) and piperidine (1.99 mL, 20.05 mmol, 1 equiv.) as the appropriate amine, gave the title product (6.11 g, 17.74 mmol, 88%). LRMS C 20 H 28 Calculated for N2O3: 344.2, Found: 345.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.31 -7.04 (m, 4H), 5.25 - 4.87 (m, 1H), 4.72 - 4.58 (m, 1H), 4.47 - 4.25 (.m, 1H), 3.64 - 3.01 (m, 5H), 2.94 - 2.73 (m, 1H), 1.71 - 1.28 (m, 15H).

[0123] Process B (3S)-3-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride [ka] Using general procedure 6 and the product from step A (6.09 g, 17.69 mmol, 1 equiv) as the appropriate THIQ amide gave the title product (5.73 g, quantitative). LRMS C 15 H 22 Calculated N2: 230.2, Found 231.0 [M+H] + 1H NMR (400 MHz, D2O) δ ppm: 7.43 - 7.24 (m, 4H), 4.54 (s, 2H), 4.32 - 4.21 (m, 1H), 3.78 - 3.54 (m, 4H), 3.36 (dd, J = 17.3, 4.9 Hz, 1H), 3.20 - 3.02 (m, 3H), 2.09 - 1.73 (m, 5H), 1.63 - 1.44 (m, 1H).

[0124] Process C Benzyl 6-[4-(ethoxycarbonyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] To a solution of Preparation I (3 g, 6.3 mmol, 1 equiv.) and the product from Step B (2.1 g, 6.93 mmol, 1.1 equiv.) in DMF (25 mL) was added DIPEA (4.17 mL, 25.18 mmol, 4 equiv.) and PyBop (3.6 g, 6.93 mmol, 1.1 equiv.), and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water (40 mL) and saturated aqueous NaHCO3 (10 mL) and stirred for 15 min. The resulting cream-colored precipitate was collected by filtration and washed with water. The filter cake was dissolved in EtOAc, washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo to give the title product (4.34 g, quantitative). LRMS C 42 H 48 Calculated for N4O5: 688.4, Found: 689.6 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.47 - 6.82 (m, 11H), 6.37 - 6.05 (m, 1H), 5.22 - 1.82 (m, 27H), 1.61 - 1.03 (m, 9H).

[0125] Process D : Ethyl 1,2-dimethyl-5-(7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxylate [ka] To a solution of the product from step C (4.34 g, 6.3 mmol, 1 equiv) in MeOH (100 mL) was added 10% Pd / C (100 mg). The mixture was evacuated and back-filled with N, then evacuated and flushed with H, and then shaken under an H atmosphere at room temperature for 3 h. The mixture was filtered through a Celite cartridge and washed with MeOH. The solvent was removed in vacuo to give the title product (3.69 g, quantitative). LRMS C 34 H 42 Calculated for N4O3: 544.3, Found: 555.4 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.22 - 6.81 (m, 6H), 6.36 - 6.01 (m, 1H), 5.14 - 1.65 (m, 25H), 1.57 - 1.05 (m, 10H).

[0126] Process E tert-Butyl 6-[4-(ethoxycarbonyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] To a solution of the product from step D (3.6 g, 6.49 mmol, 1 equiv.) in THF (45 mL) and water (6 mL) was added bis(tert-butyl)dicarbonate (1.49 g, 6.81 mmol, 1.05 equiv.) and TEA (1.8 mL, 12.98 mmol, 2 equiv.), and the mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo, and the residue was partitioned between EtOAc and saturated aqueous NH4Cl. Water was added, the phases were separated, and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title product (4.27 g, quantitative). LRMS C 39 H 50 Calculated for N4O5: 654.4, Found: 655.6 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.31 - 6.81 (m, 6H), 6.37 - 6.03 (m, 1H), 5.24 - 1.65 (m, 25H), 1.59 - 1.06 (m, 18H).

[0127] Process F 5-[2-(tert-butoxycarbonyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxylic acid [ka] To a heterogeneous mixture of the product from step E (4.27 g, 6.52 mmol, 1 equiv) in MeOH (40 mL) and water (10 mL), LiOH·HO (1.09 g, 26.08 mmol, 4 equiv) was added, and the mixture was refluxed at 100 °C for 24 h. The mixture was allowed to cool to room temperature, and MeOH was removed in vacuo. The aqueous residue was neutralized with 2 M aqueous HCl and extracted with DCM. The combined organic extracts were dried over MgSO and concentrated in vacuo. Purification by automated flash chromatography, eluting with a gradient of 0–14% MeOH (1% NH) in DCM, gave the title product (2.56 g, 4.09 mmol, 63%). LRMS (C 37 H 46 N4O5) Calculated: 626.3, Found: 627.6 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.29 (br s, 1H), 7.32 - 6.79 (m, 6H), 6.38 - 6.07 (m, 1H), 5.14 - 1.68 (m, 23H), 1.57 - 1.19 (m, 15H).

[0128] Preparation IIc 5-[2-(tert-butoxycarbonyl)-7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxylic acid [ka]

[0129] Process A : tert-Butyl (3S)-3-[(pyrrolidin-1-yl)carbonyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] Using general procedure 5 and Boc-(3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (4 g, 14.42 mmol, 1 equiv) and pyrrolidine (0.92 mL, 15.14 mmol, 1.05 equiv) as the appropriate amine, gave the title product (4.33 g, 13.1 mmol, 91%). LRMS C 19 H 26 Calculated N2O3: 330.2, Found: 331.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.29 - 7.08 (m, 4H), 4.96 - 4.18 (m, 3H), 3.60 - 2.76 (m, 6H), 2.01 - 1.67 (m, 4H), 1.51 - 1.24 (m, 9H).

[0130] Process B (3S)-3-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride [ka] Using general procedure 6 and the product from step A (4.33 g, 13.1 mmol, 1 equiv.) as the appropriate THIQ amide gave the title product (3.79 g, 13.1 mmol, quantitative). LRMS C 14 H 20 Calculated N2: 216.2, Found 217.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.03 - 10.76 (br m, 1H), 10.26 - 9.84 (br m, 2H), 7.35 - 7.16 (m, 4H), 4.50 - 4.35 (m, 2H), 4.13 - 4.00 (m, 1H), 3.91 - 2.95 (m, 8H), 2.14 - 1.80 (m, 4H).

[0131] Process C 5-[2-(tert-butoxycarbonyl)-7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxylic acid [ka] In the next step, the title compound was prepared by a method similar to Preparation IIb using the product from Step B. LRMS C 36 H 44 Calculated for N4O5: 612.3, Found: 613.6 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.50 (br s, 1H), 7.30 - 6.79 (m, 6H), 6.38 - 6.08 (m, 1H), 5.24 - 1.27 (m, 36H).

[0132] Preparation IIIa : 4-[(tert-butyldimethylsilyl)oxy]aniline [ka] To a solution of imidazole (13.72 g, 201.6 mmol, 2.5 equiv) and 4-aminophenol (8.8 g, 80.64 mmol, 1 equiv) in MeCN (150 mL) cooled to 0 °C with N was added TBDMSCl (12.76 g, 84.67 mmol, 1.05 equiv). The mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was partitioned between EtOAc and water. The phases were separated, and the organic phase was washed with brine, dried over MgSO and concentrated in vacuo. The residue was diluted with heptane (40 mL) and stirred for 1 h. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give the title product (19.6 g, quantitative). HRMS (C 12 H 21NOSi) calculated: 223.139, found: 224.162 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 6.56 - 6.48 (m, 2H), 6.48 - 6.40 (m, 2H), 4.87 (br s, 2H), 0.92 (s, 9H), 0.10 (s, 6H).

[0133] Preparation IIIb : 4-[(triisopropylsilyl)oxy]aniline [ka] The title product was prepared according to the procedure described in Preparation IIIa using 4-aminophenol (10.7 g, 98.05 mmol, 1 equiv.) and TIPSCl (22.06 mL, 102.95 mmol, 1.05 equiv.) The compound was obtained in 97% yield (25.3 g, 95.3 mmol). LRMS (C 15 H 27 NOSi) calculated: 265.2, found: 266.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 6.62 - 6.51 (m, 2H), 6.49 - 6.41 (m, 2H), 4.60 (s, 2H), 1.22 - 1.09 (m, 3H), 1.04 (d, J = 7.1 Hz, 18H).

[0134] Preparation IVa N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxamide hydrochloride [ka]

[0135] Process A : 4-Bromo-1,5-dimethylpyrrole-2-carbonitrile [ka] A solution of Br2 (6.74 mL, 131.08 mmol, 1.05 equiv) in AcOH (70 mL) was added dropwise to a solution of 1,5-dimethylpyrrole-2-carbonitrile (15 g, 124.84 mmol, 1 equiv) in AcOH (250 mL) cooled to 10 °C. The mixture was stirred at 10 °C for 1 h, then allowed to warm to room temperature and stirred again for 3 h. The mixture was poured into ice water (500 mL), and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give the title product (23.7 g, 119.07 mmol, 95%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.05 (s, 1H), 3.65 (s, 3H), 2.22 (s, 3H).

[0136] Process B 4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethylpyrrole-2-carbonitrile [ka] Using general procedure 1a and the product from step A (6.1 g, 30.65 mmol, 1 equiv.) as the appropriate aryl bromide and preparation IIIa (7.19 g, 32.18 mmol, 1.05 equiv.) as the appropriate aniline, the title product was obtained (8.2 g, 24 mmol, 78%). HRMS C 19 H 27 Calculated for N3OSi: 341.192, Found: 342.207 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 6.87 (s, 1H), 6.73 (s, 1H), 6.64 - 6.56 (m, 2H), 6.54 - 6.46 (m, 2H), 3.61 (s, 3H), 2.09 (s, 3H), 0.92 (s, 9H), 0.12 (s, 6H).

[0137] Process C tert-Butyl 6-[4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}(5-cyano-1,2-dimethylpyrrol-3-yl)carbamoyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] The title compound was prepared by general procedure 2a using preparation IIa (2.5 g, 4.6 mmol, 1 equiv.) as the appropriate acid and the product from step B (3.14 g, 9.2 mmol, 2 equiv.) as the appropriate aniline. Purification by automated flash chromatography eluting with a gradient of 0 to 6% MeOH in DCM gave the title product (2.49 g, 2.87 mmol, 62%). HRMS C 51 H 62 Calculated for N6O5Si: 866.455, Found: 867.465 [M+H] +

[0138] Process D N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxamide hydrochloride [ka] A solution of the product from step C (2.8 g, 3.23 mmol, 1 equiv.) in MeOH (5 mL) was treated with 3 M HCl in MeOH (10 mL, 30 mmol) and stirred at room temperature for 3 h. The solvent was removed in vacuo and then dried under high vacuum to give the title product (2.53 g, quantitative). HRMS C 40 H 40 Calculated for N6O3: 652.316, Found: 653.326 [M+H] +

[0139] Preparation IVb N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxamide [ka]

[0140] Process A 6-[4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}(5-cyano-1,2-dimethylpyrrol-3-yl)carbamoyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] The title compound was prepared by general procedure 2a using preparation IIb (2.2 g, 3.51 mmol, 1 equiv.) as the appropriate acid and the product from preparation IVa, step B (1.68 g, 4.91 mmol, 1.4 equiv.) as the appropriate aniline. Purification by automated flash chromatography eluting with a gradient of 0 to 10% MeOH (1% NH) in DCM gave the title product (2.29 g, 2.4 mmol, 69%). LRMS C 56 H 71 Calculated for N7O5Si: 949.5, Found: 950.6 [M+H] +

[0141] Process B N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxamide [ka] A solution of the product from Step A (2.3 g, 2.42 mmol, 1 equiv) in MeOH (10 mL) was treated with 3 M HCl in MeOH (7 mL, 21 mmol) and stirred at room temperature for 12 h. The solvent was removed in vacuo, and the residue was dissolved in 1:1 DCM / MeOH followed by the addition of TEA (1.5 mL, 3 equiv), and then purified by reverse-phase automated flash chromatography eluting with a gradient of 20 to 100% MeCN in water. The product was lyophilized to give the title product (1.18 g, 1.6 mmol, 66%). LRMS (C 45 H 49 N7O3) Calculated: 735.4, Found: 736.6 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.42 - 9.27 (m, 1H), 7.25 - 6.39 (m, 11H), 5.46 - 5.09 (m, 1H), 5.09 - 1.66 (m, 27H), 1.60 - 1.20 (m, 6H).

[0142] Preparation IVc: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxamide [ka]

[0143] Process A tert-Butyl 6-[4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}(5-cyano-1,2-dimethylpyrrol-3-yl)carbamoyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] The title compound was prepared according to general procedure 2a using preparation IIc (1.6 g, 2.61 mmol, 1 equiv.) as the appropriate acid and the product from preparation IVa, step B (1.34 g, 3.92 mmol, 1.5 equiv.) as the appropriate aniline. Purification by automated flash chromatography eluting with a gradient of 0 to 8% MeOH in DCM gave the title product (1.9 g, 2.03 mmol, 78%). LRMS C 55 H 69 Calculated for N7O5Si: 935.5, Found: 936.6 [M+H] +

[0144] Process B N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxamide [ka] A solution of the product from Step A (1.9 g, 2.03 mmol, 1 equiv) in MeOH (19 mL) was treated with 3 M HCl in MeOH (2.28 mL, 6.83 mmol) and stirred at room temperature for 12 h. The mixture was diluted with DCM and basified by the addition of saturated aqueous NaHCO3. The layers were separated, and the aqueous phase was extracted twice more with DCM. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Purification by reverse-phase automated flash chromatography (at pH 4) eluting with a gradient of 20–100% MeCN in water gave the title product (1.05 g, 1.45 mmol, 71%). LRMS C 44 H 47 Calculated for N7O3: 721.4, Found: 722.6 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.41 - 9.28 (m, 1H), 7.26 - 6.42 (m, 11H), 5.45 - 5.11 (m, 1H), 5.03 - 1.91 (m, 29H), 1.86 - 1.47 (m, 4H).

[0145] Preparation Va : {4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid [ka]

[0146] Process A : Methyl 2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetate [ka] Using general procedure 7a and methyl 4-hydroxyphenylacetate (2.5 g, 15.04 mmol, 1 equiv) as the appropriate phenol and 4-(2-chloroethyl)morpholine hydrochloride (4.48 g, 24.07 mmol, 1.6 equiv) as the appropriate alkyl halide gave the title product (3.24 g, 11.59 mmol, 77%). LRMS (C 15 H 21 NO4) Calculated: 279.2, Found: 280.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.20 - 7.12 (m, 2H), 6.93 - 6.85 (m, 2H), 4.06 (t, J = 5.8 Hz, 2H), 3.60 (s, 3H), 3.59 (s, 2H), 3.59 - 3.56 (m, 4H), 2.68 (t, J= 5.8 Hz, 2H), 2.50 - 2.43 (m, 4H).

[0147] Process B : {4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid [ka] The product from Step A (3.26 g, 11.67 mmol, 1 equiv.) was hydrolyzed using general procedure 8 to give the title product (3.1 g, 11.63 mmol, quantitative). LRMS (C 14 H 19 NO4) Calculated: 265.1, Found: 266.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.15 - 7.09 (m, 2H), 6.87 - 6.79 (m, 2H), 4.04 (t, J = 5.8 Hz, 2H), 3.60 - 3.54 (m, 4H), 3.34 (s, 2H), 2.66 (t, J = 5.8 Hz, 2H), 2.49 - 2.42 (m, 4H).

[0148] Preparation Vb {2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid [ka]

[0149] Process A : Methyl 2-(2-fluoro-4-hydroxyphenyl)acetate [ka] Concentrated H2SO4 (5 mL) was added dropwise to MeOH (100 mL) cooled to 0 °C. After the addition, 2-fluoro-4-hydroxyphenylacetic acid (5 g, 29.39 mmol, 1 equiv.) was added portionwise, and the mixture was then slowly heated to reflux and held for 3 h. The mixture was allowed to cool to room temperature and poured into a mixture of ice / water (200 mL) with stirring. The mixture was extracted with DCM, and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to give the title product (6.1 g, 29.15 mmol, 99%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.80 (s, 1H), 7.10 (t, J= 8.8 Hz, 1H), 6.60 - 6.50 (m, 2H), 3.60 (s, 3H), 3.57 (s, 2H).

[0150] Process B : Methyl 2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetate [ka] Using general procedure 7a and the product from step A (4.22 g, 22.91 mmol, 1 equiv) as the appropriate phenol and 4-(2-chloroethyl)morpholine hydrochloride (8.53 g, 45.83 mmol, 2 equiv) as the appropriate alkyl halide gave the title product (4.99 g, 16.78 mmol, 73%). HRMS (C 15 H 20 NO4F) Calculated: 297.138, Found: 298.154 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.22 (t, J = 8.7 Hz, 1H), 6.83 (dd, J = 12.0, 2.5 Hz, 1H), 6.78 - 6.71 (m, 1H), 4.08 (t, J = 5.7 Hz, 2H), 3.63 (d, J= 1.3 Hz, 2H), 3.61 (s, 3H), 3.59 - 3.55 (m, 4H), 2.67 (t, J = 5.7 Hz, 2H), 2.49 - 2.42 (m, 4H).

[0151] Process C {2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid [ka] The product from Step B (4.99 g, 16.78 mmol) was hydrolyzed using general procedure 8 to give the title product (4.65 g, 16.41 mmol, 99%). LRMS (C 14 H 18 NO4F) Calculated: 283.1, Found: 284.0 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.17 (t, J = 8.7 Hz, 1H), 6.75 (dd, J = 12.0, 2.5 Hz, 1H), 6.72 - 6.67 (m, 1H), 4.06 (t, J = 5.8 Hz, 2H), 3.60 - 3.53 (m, 4H), 3.37 (s, 2H), 2.68 - 2.65 (m, 2H), 2.49 - 2.42 (m, 4H).

[0152] Preparation Vc: 2-[4-(2-tetrahydropyran-4-ylethoxy)phenyl]acetic acid [ka]

[0153] Process A : Methyl 2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetate [ka] Using general procedure 7a and methyl 4-hydroxyphenylacetate (2 g, 12.04 mmol, 1 equiv) as the appropriate phenol and 4-(2-bromoethyl)tetrahydro-2H-pyran (2.32 mL, 15.65 mmol, 1.3 equiv) as the appropriate alkyl halide, the title product was obtained (2.95 g, 10.61 mmol, 88%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.19 - 7.11(m, 2H), 6.91 - 6.83 (m, 2H), 3.98 (t, J = 6.3 Hz, 2H), 3.87 - 3.78 (m, 2H), 3.59 (s, 3H), 3.58 (s, 2H), 3.28 (td, J= 11.8, 2.1 Hz, 2H), 1.77 - 1.56 (m, 5H), 1.29 - 1.14 (m, 2H).

[0154] Process B: Methyl 2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetate [ka] The product from Step A (2.95 g, 10.61 mmol, 1 equiv.) was hydrolyzed using General Procedure 8. Methanol was removed in vacuo, and the aqueous residue was acidified with 2 M aqueous HCl and extracted with DCM. The organic phase was dried over MgSO and concentrated in vacuo to give the title product (2.71 g, 10.27 mmol, 97%). LRMS C 15 H 20 Calculated O4: 264.1, Measured: 263.2 [MH] - 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.21 (s, 1H), 7.18 - 7.10 (m, 2H), 6.90 - 6.82 (m, 2H), 3.98 (t, J = 6.4 Hz, 2H), 3.87 - 3.78 (m, 2H), 3.47 (s, 2H), 3.28 (td, J= 11.8, 2.1 Hz, 2H), 1.77 - 1.56 (m, 5H), 1.29 - 1.12 (m, 2H).

[0155] Preparation VIa 1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxylic acid [ka]

[0156] Process A1,2-Dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrole-3-carboxylic acid hydrochloride [ka] A solution of Preparation IIa (3 g, 5.52 mmol, 1 eq) in MeOH (20 mL) was treated with 3M HCl in MeOH (20 mL, 60 mmol) and stirred at room temperature for 3 hours. The solvent was removed in vacuo and dried in vacuo to give the title product (2.71 g, quantitative). LRMS C 27 H 29 Calculated for N3O3: 443.2, Found: 444.4 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.79 - 9.40 (br m, 2H), 7.42 - 6.79 (m, 6H), 6.43 - 6.04 (m, 1H), 5.37 - 1.87 (m, 17H), 1.14 - 0.46 (m, 3H).

[0157] Process B 1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxylic acid [ka] To a solution of Preparation Va (1 g, 3.77 mmol, 1 equiv.) in anhydrous DCM (10 mL) under N2, 2 M oxalyl chloride solution in DCM (0.43 mL, 4.52 mmol, 1.2 equiv.) was slowly added, followed by DMF (1 drop), and the mixture was stirred for 1 h. The solvent was removed in vacuo, and the intermediate acid chloride was dissolved in anhydrous DCM (7 mL) and added dropwise to a stirred solution of the product from Step A (1.63 g, 3.39 mmol, 0.9 equiv.) and DIPEA (2.5 mL, 15.08 mmol, 4 equiv.) in anhydrous DCM (10 mL) under N2. The mixture was stirred at room temperature for 2 h, then quenched with MeOH (5 mL) and concentrated in vacuo. Purification by automated flash chromatography, eluting with a gradient of 0–8% MeOH in DCM, gave the title product (1.2 g, 1.74 mmol, 46%). LRMS (C 41 H 46 N4O6) Calculated: 690.3, Found: 691.6 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.53 (s, 1H), 7.32 - 6.78 (m, 10H), 6.39 - 6.05 (m, 1H), 5.35 - 1.88 (m, 31H), 1.11 - 0.48 (m, 3H).

[0158] Preparation VIb 1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxylic acid [ka] The title compound was prepared in a manner similar to Preparation VIa using Preparation Vc (700 mg, 2.65 mmol, 1 equiv.) and the product from Preparation VIa, Step A (1.14 g, 2.38 mmol, 0.9 equiv.) to give the title product (1.04 g, 1.51 mmol, 57%). LRMS (C 42 H 47 N3O6) Calculated: 689.3, Found: 690.6 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.52 (s, 1H), 7.32 - 6.77 (m, 10H), 6.39 - 6.07 (m, 1H), 5.35 - 1.90 (m, 25H), 1.78 - 1.53 (m, 5H), 1.30 - 1.12 (m, 2H), 1.10 - 0.49 (m, 3H).

[0159] Preparation VIIa N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide [ka]

[0160] Process A : 1,2-dimethyl-5-[7-[(3S)-3-(1-piperidylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxylic acid [ka] To a solution of Preparation I (10.4 g, 21.8 mmol, 1 equiv.) in DMF (60 mL) was added TBTU (7.71 g, 24.0 mmol, 1.1 equiv.), followed by DIPEA (11.2 mL, 65.5 mmol, 3 equiv.). After stirring for 10 min, the product from Preparation IIb, Step B (7.95 g, 26.2 mmol, 1.2 equiv.) was added, and the mixture was stirred at room temperature for 1 h. It was then poured into water (600 mL), and the precipitate was filtered off and washed with water. This crude intermediate was dissolved in methanol (150 mL) and water (85 mL). NaOH (9.18 g, 229.6 mmol, 10.5 equiv.) was then added, and the mixture was stirred at reflux for 3 days. The mixture was evaporated under reduced pressure, and the pH was adjusted to 6 by the addition of concentrated aqueous HCl. The product was extracted with DCM / IPA (3 / 1) (3 × 100 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title product (10.97 g, 15.83 mmol, 73%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.22-6.83 (m, 6 H), 6.38-6.14 (s, 1 H), 5.31-1.17 (m, 23 H), 3.44-3.15 (s, 3 H), 2.51-1.97 (s, 3 H). HRMS-ESI (m / z) [M+H] + C 32 H 39 Calculated N4O3: 527.3017, Measured: 527.3011

[0161] Process B 5-[2-(9H-fluoren-9-ylmethoxycarbonyl)-7-[(3S)-3-(1-piperidylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethyl-pyrrole-3-carboxylic acid hydrochloride [ka] To a biphasic mixture of the product from Step A (8.63 g, 13.1 mmol, 1 equiv.) dissolved in dioxane (75 mL) and NaHCO3 (2.53 g, 30.1 mmol, 2.3 equiv.) dissolved in water (75 mL), 9H-fluoren-9-ylmethyl carbonochloridate (3.73 g, 14.4 mmol, 1.1 equiv.) was added dropwise, and the mixture was stirred at room temperature for 24 h. 2 M aqueous HCl (131 mL; 262 mmol, 10 equiv.) was added dropwise to the reaction mixture, which was then stirred for 10 min before being extracted with DCM. The phases were separated, and the organic phase was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH (1% NH3) as eluent to give the title product (7.33 g, 9.3 mmol, 71%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br., 1 H), 8.05-6.77 (m, 14 H), 6.38-6.05 (br., 1 H), 5.34 (br., 1 H), 4.71-3.37 (br., 12 H), 4.57-4.28 (br., 2 H), 4.33 (t, 1 H), 3.11 (br., 3 H), 2.89-2.69 (br., 2 H), 2.76 / 2.44 (br+d, 2 H), 2.06-1.14 (br., 6 H), 1.93 (s, 3 H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 67.2, 47.3, 42.4, 31.8, 30, 28.2, 11.1. HRMS-ESI (m / z) [M+H] + C 47 H 49 Calculated value of N4O5: 749.3697, Found value: 749.3702

[0162] Process C9H-Fluoren-9-ylmethyl 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-7-[(3S)-3-(1-piperidylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] Using general procedure 2a and the product from step B (5.33 g, 7.12 mmol, 1 equiv.) as the appropriate acid, oxalyl dichloride (1.02 mL, 12.1 mmol, 1.7 equiv.) and the product from step B of preparation IVa (2.92 g, 8.54 mmol, 1.2 equiv.) as the appropriate aniline, gave the title product (4.67 g, 3.92 mmol, 55%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.31 (brs, 1 H), 8.06-6.4 (m, 19 H), 5.5-1.1 (m, 26 H), 5.14-4.9 (s, 1 H), 3.7-2.98 (s, 6 H), 2.44-1.72 (s, 6 H), 0.88-0.76 (s, 9 H), 0.11-0.04 (s, 6 H). HRMS-ESI (m / z) [M+H] + C 66 H 74 Calculated value for N7O5Si: 1072.5515, Found value: 1072.5531

[0163] Process D N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-1,2-dimethyl-5-[7-[(3S)-3-(1-piperidylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide [ka] To a solution of the product from Step C (1.84 g, 1.55 mmol, 1 equiv.) in DCM (8 mL) was added morpholine (7.76 mL, 88.2 mmol, 57 equiv.), and the mixture was then stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated, and the organic phase was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH (1% NH3) as eluents to give the title product as a yellow solid (0.762 g, 0.867 mmol, 56%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.22-6.46 (m, 11 H), 5.41-5.02 (s, 1 H), 5.05-1.25 (m, 22 H), 3.6-3.06 (s, 6 H), 2.4-1.76 (s, 6 H), 0.91-0.84 (s, 9 H), 0.13-0.08 (s, 6 H). HRMS-ESI (m / z) [M+H] + C 51 H 64 Calculated value for N7O3Si: 850.4834, Found value: 850.4838

[0164] Preparation VIIb N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide [ka]

[0165] Process A: 1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxylic acid [ka] To a solution of Preparation I (45.9 g, 96.3 mmol, 1 equiv.) in DMF (240 mL) was added TBTU (34.1 g, 106 mmol, 1.1 equiv.), followed by TEA (40.5 mL, 291 mmol, 3 equiv.). After stirring for 10 min, the product from Preparation IIa, Step A (18.6 g, 101 mmol, 1.05 equiv.) was added, and the mixture was stirred at room temperature for 1 h. It was then poured into water (1500 mL), and the precipitate was filtered off and washed with water. This crude intermediate was dissolved in methanol (250 mL) and water (25 mL). NaOH (28 g, 700 mmol, 7.3 equiv.) was then added, and the mixture was stirred at reflux for 18 h. The mixture was evaporated under reduced pressure, and the pH was adjusted to 6 by the addition of concentrated aqueous HCl. The product was extracted with DCM / IPA (3 / 1) (3 × 400 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was triturated with diethyl ether / acetonitrile. The yellow powder formed was filtered off and then dried in vacuo to give the title product (38.51 g, 86.8 mmol, 90%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.35-6.8 (m, 6 H), 6.35 / 6.28 / 6.13 (s / s / s, 1 H), 5.34-3.23 (m, 6 H), 5.01 / 4.88 / 3.78 (m / m / m, 1 H), 3.46 / 3.43 / 3.38 / 3.15 (s / s / s / s, 3 H), 3.12-2.98 (m, 2 H), 3.02-2.05 (m, 2 H), 2.49 / 2.41 / 1.96 (s / s / s, 3 H), 1.03 / 0.85 / 0.74 / 0.56 (d / d / d / d, 3 H); 13C NMR (125 MHz, DMSO-d6) δ ppm 168.9 / 168.4 / 168.2, 166.5 / 166.3 / 166.2, 111.3 / 111.2 / 110.8, 48.3 / 48.1 / 43 / 42.2, 34.4 / 34.2 / 34 / 32.6, 32.2 / 32.1 / 31.9, 25.4, 18.6 / 16.8 / 16.4, 11.8 / 11.7 / 11.2. HRMS-ESI (m / z) [M+H] + C 27 H 30 Calculated N3O3: 444.2282, Measured: 444.2267

[0166] Process B 5-[2-(9H-fluoren-9-ylmethoxycarbonyl)-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethyl-pyrrole-3-carboxylic acid [ka] To a biphasic mixture of the product from Step A (13.96 g, 28.33 mmol, 1 equiv.) dissolved in dioxane (160 mL) and NaHCO (5.47 g, 65.2 mmol, 2.3 equiv.) dissolved in water (160 mL), 9H-fluoren-9-ylmethyl carbonochloridate (8.06 g, 31.2 mmol, 1.1 equiv.) was added dropwise, and the mixture was stirred at room temperature for 24 h. 2 M aqueous HCl (42.5 mL; 85 mmol, 3 equiv.) was added dropwise to the reaction mixture, which was then stirred for 10 min before being extracted with DCM. The phases were separated, and the organic phase was washed with saturated aqueous NaCl, dried over MgSO, and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and EtOAc as eluents to give the title product (14.77 g, 22.2 mmol, 78%). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.18 (br., 1 H), 7.95-7.26 (br., 8 H), 7.26-6.8 (br., 6 H), 6.52-6.06 (br., 1 H), 5.09-3.74 (br., 3 H), 4.54 (br., 2 H), 4.47 (d, 2 H), 4.31 (t, 1 H), 3.59 (br., 2 H), 3.5-3.19 (br., 3 H), 2.8 (t, 2 H), 2.55-1.93 (br., 3 H), 2.45 (br., 2 H), 1.2-0.41 (br., 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 111.1, 67.2, 47.5, 45.7, 41.6, 34.6, 32, 28.3, 16.8, 11.6. HRMS-ESI (m / z) [M+H] + C 42 H 40 Calculated value of N3O5: 666.2962, Measured value: 666.2961

[0167] Process C 9H-Fluoren-9-ylmethyl 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] Using general procedure 2b and the product from step B (10.67 g, 16.03 mmol, 1 equiv.) as the appropriate acid, oxalyl dichloride (2.17 mL, 25.6 mmol, 1.6 equiv.) and the product from step B of preparation IVa (6.57 g, 19.2 mmol, 1.2 equiv.) as the appropriate aniline, gave the title product (8.12 g, 8.21 mmol, 51%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.05-6.43 (m, 19 H), 5.7-4.95 (s, 1 H), 5.12-2.26 (m, 14 H), 3.71-3 (s, 6 H), 2.48-1.75 (s, 6 H), 1.13-0.44 (d, 3 H), 0.92-0.77 (s, 9 H), 0.15-0.05 (s, 6 H). HRMS-ESI (m / z) [M+H] + C 61 H 65 Calculated value for N6O5Si: 989.4780, Found value: 989.4779

[0168] Process D N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide [ka] To a solution of the product from Step C (8.12 g, 8.21 mmol, 1 equiv.) in DCM (41 mL) was added morpholine (41 mL, 475 mmol, 58 equiv.), and the mixture was then stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated, and the organic phase was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents to give the title product (4.51 g, 5.88 mmol, 72%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.36-6.35 (m, 11 H), 5.55-4.91 (s, 1 H), 5.37-1.97 (m, 12 H), 3.72-2.96 (s, 6 H), 2.48-1.75 (s, 6 H), 1.16-0.39 (d, 3 H), 1-0.76 (s, 9 H), 0.17-0 (s, 6 H). HRMS-ESI (m / z) [M+H] + C 46 H 55 Calculated value of N6O3Si: 767.4099, Found value: 767.4103

[0169] Preparation VIII 1,2-Dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-(2-phenylacetyl)-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxylic acid [ka] To an ice-cooled solution of the product from Step A of Preparation VIIb (3.90 g, 8.80 mmol, 1 equiv.) in water (13 mL) and NaOH (1.10 g, 26 mmol, 3 equiv.) was added dropwise a solution of 2-phenylacetyl chloride (1.40 mL, 10.6 mmol, 1.2 equiv.) in DCE (2.6 mL). The reaction mixture was stirred at room temperature for 2 h, and then the pH was adjusted to 2 by the addition of 2 M aqueous HCl. The mixture was diluted with water, which was then extracted with DCM. The phases were separated, and the organic phase was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and EtOAc as eluents to give the title product (3.14 g, 5.59 mmol, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.90-11.35 (br, 1 H), 7.38-6.81 (m, 11 H), 6.40-6.05 (m, 1 H), 5.36-3.55 (m, 7 H), 3.52-1.88 (m. 12H), 1.06-0.49 (m, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 169.8, 168.4, 166.5 / 166.2, 131.0-124.8. 111.0 / 110.6, 48.2 / 42.9, 47.1, 44.0 / 43.3, 40.3 / 39.6, 34.3, 32.6, 32.1 / 31.8, 29.1 / 28.2, 18.6-16.4, 11.7 / 11.2. HRMS-ESI (m / z) [M+H] + C 35 H 36 Calculated N3O4 value: 562.2700, Measured value: 562.2705

[0170] Preparation IX 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-2-[2-[2-fluoro-4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinoline-7-carboxylic acid [ka]

[0171] Process A : 2-benzyloxycarbonyl-6-(4-carboxy-1,5-dimethyl-pyrrol-2-yl)-3,4-dihydro-1H-isoquinoline-7-carboxylic acid [ka] To a suspension of Preparation I (20.01 g, 41.99 mmol, 1 equiv.) in methanol (100 mL) and water (20 mL), NaOH (14.07 g, 352 mmol, 8.4 equiv.) was added, and the mixture was stirred at reflux for 2 days. The pH of the cooled mixture was adjusted to 6 by the addition of concentrated aqueous HCl, and then the methanol was evaporated under reduced pressure. The resulting slurry was diluted with 2-propanol, and the crude product was filtered off. This crude material was redissolved in a mixture of ice water (400 mL) and 2 M aqueous NaOH (41 mL, 82 mmol), and then a solution of benzyl carbonochloridate (7.1 mL, 50.7 mmol, 1.19 equiv.) in diethyl ether (100 mL) was added dropwise. The mixture was stirred for 24 h, then the pH of the aqueous phase was adjusted to 2 by the addition of 2 M aqueous HCl, and the resulting white precipitate was filtered off, washed with water, and dried. The crude material was purified by automated flash chromatography using DCM and MeOH (1% NH3) as eluent to afford the title product as a white solid (15.09 g, 32.2 mmol, 77%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.71 (s, 1 H), 7.44-7.11 (m, 5 H), 7.16 (s, 1 H), 6.19 (s, 1 H), 5.14 (s, 2 H), 4.71 / 4.65 (br / br., 2 H), 3.67 (br., 2 H), 3.21 (s, 3 H), 2.86 (t, 2 H), 2.48 (s, 3 H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 168.5, 166.7, 155.1, 133.1, 128.2, 109.2, 66.8, 45.5, 41.4 / 41.1, 31.7, 28.6 / 28.4, 11.7. HRMS-ESI (m / z) [M+H] + C 25 H 25 Calculated N2O6: 449.1707, Found: 449.1708

[0172] Process B: 5-(2-benzyloxycarbonyl-7-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6-yl)-1,2-dimethyl-pyrrole-3-carboxylic acid [ka] A solution of the product from Step A (2.50 g, 5.57 mmol, 1 equiv.) and 1,1-di-tert-butoxy-N,N-dimethyl-methanamine (13 mL, 55.7 mmol, 10 equiv.) in THF (50 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the crude material was purified by automated flash chromatography using heptane and EtOAc as eluents. The title product was isolated as a white solid (1.62 g, 3.21 mmol, 58%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.58 (s, 1 H), 7.62 (s, 3 H), 7.45-7.29 (m, 5 H), 7.16 (s, 1 H), 6.16 (s, 1 H), 5.14 (s, 2 H), 4.71 / 4.64 (brs, 2 H), 3.67 (brm, 2 H), 3.2 (s, 3 H), 2.86 (t, 2 H), 2.49 (s, 3 H), 1.25 (s, 9 H). HRMS-ESI (m / z) [M+H] + C 29 H 33 Calculated N2O6: 505.2333, Measured: 505.2335

[0173] Process C : O2-Benzyl O7-tert-butyl 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-3,4-dihydro-1H-isoquinoline-2,7-dicarboxylate [ka] Using general procedure 2a and the product from step B (12.70 g, 25.2 mmol, 1 equiv.) as the appropriate carboxylic acid and the product from step B of preparation IVa (10.30 g, 30.2 mmol, 1.2 equiv.) as the appropriate aniline, the title product was obtained (14.2 g, 17.1 mmol, 68%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (s, 1 H), 7.45-7.28 (m, 5 H), 7.01 (dm, 2 H), 6.9 (s, 1 H), 6.76 (s, 1 H), 6.73 (dm, 2 H), 5.12 (s, 2 H), 5.09 (s, 1 H), 4.67 / 4.6 (br / br., 2 H), 3.63 (br., 2 H), 3.59 (s, 3 H), 3.14 (s, 3 H), 2.8 (t, 2 H), 2.41 (s, 3 H), 2.05 (s, 3 H), 1.27 (s, 9 H), 0.84 (s, 9 H), 0.08 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 166.4, 155.1, 135.6, 133, 132.7, 130.8, 128.5, 128, 126.6, 120.5, 117.6, 114.4, 114, 108.6, 100.7, 66.8, 45.5, 41.4 / 41.1, 33.2, 31.4, 28.6 / 28.4, 27.8, 26, 12.1, 10.1, -4.2. HRMS-ESI (m / z) [M+H] + C 48 H 58 Calculated value for N5O6Si: 828.4151, Found value: 828.4163

[0174] Process D : tert-Butyl 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylate [ka] Following general procedure 6b, the product from step C (1.00 g, 1.21 mmol, 1 equiv) in THF (13 mL) was hydrogenated using 26 mg of Pd catalyst (10% on carbon) to give the title product (0.836 g, 1.205 mmol, quantitative). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.46 / 7.44 (s / s, 1 H), 7.01 (d, 2 H), 6.81 (s, 1 H), 6.77 (s, 1 H), 6.74 / 6.73 (d / d, 2 H), 5.1 (s, 1 H), 3.97 (s, 2 H), 3.59 (s, 3 H), 3.13 / 3.12 (s / s, 3 H), 3.03 (t, 2 H), 2.74 (t, 2 H), 2.42 / 2.41 (s / s, 3 H), 2.05 / 2.04 (s / s, 3 H), 1.26 (s, 9 H), 0.87 (s, 9 H), 0.1 (s, 6 H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 133.1, 128.4, 128, 120.5, 117.6, 108.3, 46.7, 42.6, 33.2, 31.4, 28, 27.8, 26, 12.1, 10.1, -4.2. HRMS-ESI (m / z) [M+H] + C 40 H 52 Calculated value of N5O4Si: 694.3783, Measured value: 694.3780

[0175] Process E tert-Butyl 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-2-[2-[2-fluoro-4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinoline-7-carboxylate [ka] According to the amide coupling step of General Procedure 4c, the product from Step C of Preparation Vb (0.511 g, 1.805 mmol, 1.5 equiv), TBTU (0.773 g, 2.406 mmol, 2 equiv), DIPEA (0.838 mL, 4.813 mmol, 4 equiv), and the product from Step D (0.835 g, 1.203 mmol, 1 equiv) in DMF (12 mL) were stirred at room temperature for 30 minutes. The reaction mixture was poured into water (120 mL), and the precipitate was filtered, washed with water, and finally dried in vacuo at 40 °C to give the title product as a yellow solid (1.145 g, 1.194 mmol, 99%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.62-6.68 (m, 9 H), 6.77 (s, 1 H), 5.11 / 5.1 (s, 1 H), 4.81 / 4.66 (s / s, 2 H), 4.07 (t, 2 H), 3.76 / 3.68 (t / t, 2 H), 3.74 (s, 2 H), 3.6 / 3.15 / 3.14 (s, 6 H), 3.57 (br., 4 H), 2.83 / 2.77 (t / t, 2 H), 2.67 (t, 2 H), 2.45 (br., 4 H), 2.42 / 2.05 (s, 6 H), 1.29 / 1.28 (s, 9 H), 0.86 / 0.85 (s, 9 H), 0.09 (s, 6 H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 166.4, 117.6, 108.5, 66.6, 66.2, 57.4, 54.1, 46.7 / 43.9, 42.9 / 39.4, 33.4 / 33, 33.2 / 31.4, 29.1 / 28.3, 27.8, 26, 12.1 / 10.1, -4.2. HRMS-ESI (m / z) [M+H] + C 54 H 68 Calculated value for FN6O7Si: 959.4897, Found value: 959.4897

[0176] Process F 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-2-[2-[2-fluoro-4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinoline-7-carboxylic acid [ka] According to general procedure 3a, the product from step E (1.145 g, 1.11 mmol, 1 equiv.) in 1,4-dioxane (20 mL), trimethylsilyl trifluoromethanesulfonate (1.00 mL, 5.55 mmol, 5 equiv.) and TEA (0.773 mL, 5.55 mmol, 5 equiv.) in 1,4-dioxane (8 mL) were reacted for 5 h to give the title product as an orange solid (0.770 g, 0.724 mmol, 65%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.71-6.61 (m, 9 H), 6.77 (s, 1 H), 5.11 / 5.1 (s, 1 H), 4.81 / 4.66 (s / s, 2 H), 4.07 (t, 2 H), 3.76 / 3.68 (t / t, 2 H), 3.74 (s, 2 H), 3.57 (br., 4 H), 3.56 / 3.15 / 3.14 (s, 6 H), 2.83 / 2.77 (t / t, 2 H), 2.67 (t, 2 H), 2.45 (br., 4 H), 2.38 / 1.99 (s, 6 H), 0.86 / 0.85 (s, 9 H), 0.09 (s, 6 H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 168.3, 117.6, 108.5, 66.6, 66.2, 57.4, 54.1, 46.7 / 43.9, 42.9 / 39.4, 33.4 / 33, 33.2 / 31.4, 29.1 / 28.3, 26, 11.9 / 10.1, -4.2. HRMS-ESI (m / z) [M+H] + C50 H 60 Calculated value for FN6O7Si: 903.4271, Found value: 903.4269

[0177] Preparation : Methyl 2-[4-(2-bromoethoxy)-2-fluoro-phenyl]acetate [ka] According to general procedure 7b, methyl 2-(2-fluoro-4-hydroxy-phenyl)acetate (2.000 g, 10.86 mmol, 1 equiv.) and 2-bromoethanol (4.343 g, 34.75 mmol, 3.2 equiv.) were reacted to give the desired product (3.15 g, 10.8 mmol, quantitative). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.25 (t, 1 H), 6.86 (dd, 1 H), 6.77 (dd, 1 H), 4.33 (t, 2 H), 3.8 (t, 2 H), 3.65 (s, 2 H), 3.61 (s, 3 H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 171.4, 161.5, 158.8, 132.8, 114.3, 111.2, 102.6, 68.6, 52.3, 33.6, 31.7.

[0178] Example Example 1: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-[2-(3-methylphenyl)acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting with 2-(m-tolyl)acetic acid (34.5 mg, 1.5 equiv) as the appropriate carboxylic acid and preparation VIIb (117 mg, 0.15 mmol) as the appropriate amine, gave the title compound (51.8 mg, 43%). HRMS-ESI (m / z) [M+H] + C 49 H 48 Calculated value of N6O4: 785.3737, Found value 785.3825.

[0179] Example 2: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka] Using general procedure 4d, starting with 2-phenoxyacetyl chloride (37 mg, 1.2 equiv.) as the appropriate carboxylic acid chloride and preparation VIIb (140 mg, 0.18 mmol) as the appropriate amine, gave the title compound (67 mg, 73%). HRMS-ESI (m / z) [M+H] + C 48 H 47 Calculated value for N6O5: 787.3608, Found value: 787.3604.

[0180] Example 3: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-{2-[3-(4-methylpiperazin-1-yl)phenyl]acetyl}-3,4-dihydro-1H-isoquinolin-6-yl)-N-phenylpyrrole-3-carboxamide [ka]

[0181] Process A : Methyl 2-[3-(4-methylpiperazin-1-yl)phenyl]acetate A mixture of methyl 3-bromophenylacetate (536 μL, 3.27 mmol, 1 equiv.), 1-methylpiperazine (545 μL, 4.91 mmol, 1.5 equiv.), and CsCO (2.13 g, 6.55 mmol, 2 equiv.) in toluene (20 mL) was sparged with N. DavePhos (129 mg, 327 μmol, 0.1 equiv.) and Pd(dba) (150 mg, 163.7 μmol, 0.05 equiv.) were added, and the mixture was sparged again and then heated at 120 °C under N for 20 h. The mixture was allowed to cool to room temperature, filtered through a Celite cartridge, and washed with EtOAc. The filtrate was washed with saturated aqueous NaHCO and brine, dried over MgSO, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0-7% MeOH in DCM gave the title product (203 mg, 0.82 mmol, 25%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.17 - 7.10 (m, 1H), 6.84 - 6.78 (m, 2H), 6.68 - 6.63 (m, 1H), 3.60 (s, 3H), 3.59 (s, 2H), 3.14 - 3.07 (m, 4H), 2.47 - 2.40 (m, 4H), 2.22 (s, 3H).

[0182] Process B : 2-[3-(4-methylpiperazin-1-yl)phenyl]acetic acid Using general procedure 8 and the product from step A (400 mg, 1.61 mmol, 1 equiv) as the appropriate ester gave the title product (310 mg, 1.32 mmol, 82%). LRMS C 13 H 18 Calculated N2O2: 234.1, Found 235.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.14 - 7.07 (m, 1H), 6.83 - 6.79 (m, 1H), 6.79 - 6.74 (m, 1H), 6.68 - 6.63 (m, 1H), 3.41 (s, 2H), 3.13 - 3.05 (m, 4H), 2.47 - 2.39 (m, 4H), 2.21 (s, 3H).

[0183] Process C tert-Butyl 6-{4-[(5-cyano-1,2-dimethylpyrrol-3-yl)(phenyl)carbamoyl]-1,5-dimethylpyrrol-2-yl}-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 2a and preparation IIa (1.2 g, 2.21 mmol, 1 equiv.) as the appropriate acid and Example 65, Step A (933 mg, 4.41 mmol, 2 equiv.) as the appropriate aniline, gave the title product (1.27 g, 1.72 mmol, 78%). LRMS C 45 H 48 Calculated for N6O4: 736.4, Found: 737.4 [M+H] +

[0184] Process D N-(5-cyano-1,2-dimethylpyrrol-3-yl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-phenylpyrrole-3-carboxamide hydrochloride To a solution of 3M HCl in MeOH (15 mL) was added the product from step C (1.28 g, 1.74 mmol, 1 equiv.) and the mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue was dried to give the title product, which was used directly in the subsequent step without further purification (1.17 g, 1.74 mmol, quantitative). LRMS C 40H 40 Calculated for N6O2: 636.3, Found: 637.3 [M+H] +

[0185] Process E N-(5-cyano-1,2-dimethylpyrrol-3-yl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-{2-[3-(4-methylpiperazin-1-yl)phenyl]acetyl}-3,4-dihydro-1H-isoquinolin-6-yl)-N-phenylpyrrole-3-carboxamide Using general procedure 4b and the product from step D (120 mg, 0.18 mmol, 1 equiv) as the appropriate amine and the product from step B (50 mg, 0.21 mmol, 1.2 equiv) as the appropriate carboxylic acid gave the title product (46.2 mg, 0.05 mmol, 30%). HRMS C 53 H 56 Calculated value for N8O3: 852.4475, Found value: 853.4550 [M+H] +

[0186] Example 4: N-[5-cyano-1-(2-hydroxyethyl)-2-methyl-pyrrol-3-yl]-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-(2-phenylacetyl)-3,4-dihydro-1H-isoquinolin-6-yl]-N-phenyl-pyrrole-3-carboxamide [ka]

[0187] Process A: 4-Bromo-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrrole-2-carbonitrile Using general procedure 7c, starting with 2-[tert-butyl(dimethyl)silyl]oxyethanol (705 mg, 2.0 equiv.) as the appropriate alcohol, gave the title product (625 mg, 91%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.07 (s, 1H), 4.15 (t, 2H), 3.81 (t, 2H), 2.24 (s, 3H), 0.78 (s, 9H), -0.11 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 135.1, 120.6, 113.9, 103.5, 95.7, 62.1, 49.5, 26.1, 18.4, 11.3, -5.4. HRMS-ESI (m / z) [M+H] + C 14 H 24 Calculated value of BrN2OSi: 343.0836, found value 343.0843.

[0188] Process B: 4-Anilino-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrrole-2-carbonitrile Using general procedure 1b, starting with the product of Step A (500 mg, 1.46 mmol) and aniline (0.199 mL, 1.5 equiv) as the appropriate aryl bromide, gave the title product (405 mg, 78%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.17 (s, 1H), 7.05 (t, 2H), 6.78 (s, 1H), 6.57 (m, 2H), 6.57 (m, 1H), 4.12 (t, 2H), 3.85 (t, 2H), 2.10 (s, 3H), 0.82 (s, 9H), -0.05 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ ppm 148.3, 131.5, 129.3, 123.6, 117.1, 116.5, 114.9, 113.1, 100.6, 62.4, 48.7, 26.2, 18.4, 10.0, -5.3. HRMS-ESI (m / z) [M+H] + C 20 H 30 Calculated N3OSi value: 356.2153, measured value 356.2142.

[0189] Process C: N-[5-cyano-1-(2-hydroxyethyl)-2-methyl-pyrrol-3-yl]-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-(2-phenylacetyl)-3,4-dihydro-1H-isoquinolin-6-yl]-N-phenyl-pyrrole-3-carboxamide Using general procedure 2b, starting from preparation VIII (200 mg, 0.36 mmol) as the appropriate acid and the product of step B (152 mg, 1.2 equiv.) as the appropriate aniline, followed by general procedure 3c for silyl deprotection, the title compound was obtained (25 mg, 9%). HRMS-ESI (m / z) [M+H] + C 49 H 49 Calculated value of N6O4: 785.3810, Found value 785.3814.

[0190] Example 5: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-fluorophenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Using general procedure 4d, starting from 2-(4-fluorophenyl)acetyl chloride (36 mg, 1.1 equiv.) as the appropriate carboxylic acid chloride and preparation VIIb (145 mg, 0.19 mmol) as the appropriate amine, gave the title compound (41.6 mg, 28%). HRMS-ESI (m / z) [M+H] + C 48 H 46 Calculated value for FN6O4: 789.3564, Found value: 789.3560.

[0191] Example 6: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-{2-[3-(morpholin-4-yl)phenyl]acetyl}-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxamide [ka]

[0192] Process A : Methyl 2-[3-(morpholin-4-yl)phenyl]acetate A mixture of methyl 3-bromophenylacetate (0.36 mL, 2.18 mmol, 1 equiv.), morpholine (0.29 mL, 3.27 mmol, 1.5 equiv.), and CsCO (1.42 g, 4.37 mmol, 2 equiv.) in toluene (10 mL) was sparged with N. DavePhos (86 mg, 0.22 mmol, 0.1 equiv.) and Pd(dba) (100 mg, 0.11 mmol, 0.05 equiv.) were added, and the mixture was sparged again and then heated at 120 °C under N for 20 h. The mixture was allowed to cool to room temperature, filtered through a Celite cartridge, and washed with EtOAc. The filtrate was washed with saturated aqueous NaHCO and brine, dried over MgSO, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0-50% EtOAc in heptane gave the title product (359 mg, 1.53 mmol, 70%). LRMS C 13 H 17 NO3 calculated: 235.1, found: 236.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.19 - 7.13 (m, 1H), 6.85 - 6.80 (m, 2H), 6.71 - 6.67 (m, 1H), 3.75 - 3.68 (m, 4H), 3.60 (s, 3H), 3.60 (s, 2H), 3.11 - 3.05 (m, 4H).

[0193] Process B : 2-[3-(morpholin-4-yl)phenyl]acetic acid Using general procedure 8 and the product from step A (359 mg, 1.53 mmol, 1 equiv) as the appropriate ester gave the title product (174 mg, 0.79 mmol, 52%). LRMS C 12 H 15 NO3 calculated: 221.1, found: 222.0 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.30 - 7.20 (m, 1H), 7.13 - 6.96 (m, 2H), 6.94 - 6.80 (m, 1H), 3.85 - 3.77 (m, 4H), 3.53 (s, 2H), 3.25 - 3.15 (m, 4H).

[0194] Process C N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-{2-[3-(morpholin-4-yl)phenyl]acetyl}-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxamide Using general procedure 4b and preparation IVa (120 mg, 0.17 mmol, 1 equiv.) as the appropriate amine and the product from step B (46 mg, 0.21 mmol, 1.2 equiv.) as the appropriate carboxylic acid, gave the title product (61.3 mg, 0.07 mmol, 41%). HRMS C 52 H 53 Calculated for N7O5: 855.4108, Found: 856.4181 [M+H] +

[0195] Example 7: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-5-{2-[2-(3-methoxyphenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Using general procedure 4d, starting with 2-(3-methoxyphenyl)acetyl chloride (45 mg, 1.2 equiv.) as the appropriate carboxylic acid chloride and preparation VIIb (155 mg, 0.20 mmol) as the appropriate amine, gave the title compound (30 mg, 19%). HRMS-ESI (m / z) [M+H] + C 49 H 49 Calculated value of N6O5: 801.3764, Found value 801.3764.

[0196] Example 8: 5-[2-(2-{3-[(9aS)-hexahydro-1H-piperazino[2,1-c]morpholin-8-yl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(5-cyano-1,2-dimethylpyrrol-3-yl)-1,2-dimethyl-N-phenylpyrrole-3-carboxamide [ka]

[0197] Process A : Methyl 2-{3-[(9aS)-hexahydro-1H-piperazino[2,1-c]morpholin-8-yl]phenyl}acetate Methyl 3-bromophenylacetate (500 mg, 2.18 mmol, 1 equiv.), (9aS)-octahydropiperazino[2,1-c]morpholine dihydrochloride (704 mg, 3.27 mmol, 1.5 equiv.), and CsCO (2.84 g, 8.73 mmol, 4 equiv.) were combined in toluene (10 mL) and the mixture was sparged with N. DavePhos (86 mg, 0.22 mmol, 0.1 equiv.) and Pddba (100 mg, 0.11 mmol, 0.05 equiv.) were added, and the mixture was sparged with N and then heated at 120 °C under microwave irradiation for 1 h. The mixture was allowed to cool to room temperature, filtered through a Celite cartridge, and washed with EtOAc. The filtrate was washed with saturated aqueous NaHCO and brine solutions, then dried over MgSO, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0-100% EtOAc in heptane, then 0-32% MeOH in EtOAc gave the title product (73 mg, 0.25 mmol, 12%). LRMS C 16 H 22 Calculated N2O3: 290.2, Found: 291.0 [M+H] + 1 H NMR (400 MHz, MeOD) δ ppm: 7.21 - 7.14 (m, 1H), 6.88 - 6.82 (m, 2H), 6.77 - 6.73 (m, 1H), 3.87 - 3.81 (m, 1H), 3.80 - 3.74 (m, 1H), 3.71 - 3.63 (m, 4H), 3.63 - 3.55 (m, 3H), 3.47 - 3.41 (m, 1H), 3.32 - 3.24 (m, 1H), 2.90 - 2.81 (m, 2H), 2.77 - 2.69 (m, 1H), 2.49 - 2.32 (m, 4H).

[0198] Process B : 2-{3-[(9aS)-hexahydro-1H-piperazino[2,1-c]morpholin-8-yl]phenyl}acetic acid To a solution of the product from step A (73 mg, 0.25 mmol, 1 equiv) in MeOH (15 mL) was added 2 M aqueous NaOH (0.25 mL, 0.5 mmol, 2 equiv) and the mixture was heated under microwave irradiation at 80° C. for 0.5 h. The solvent was removed under reduced pressure and the residue was diluted with water, the pH adjusted to 2 with 2 M aqueous HCl, and then lyophilized to give the title product, which was used directly in the subsequent step without further purification (69 mg, 0.25 mmol, 99%). LRMS C 15 H 20 Calculated N2O3: 276.1, Found 277.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.40 (br s, 1H), 7.23 - 7.15 (m, 1H), 6.93 - 6.84 (m, 2H), 6.80 - 6.72 (m, 1H), 4.07 - 3.92 (m, 3H), 3.87 - 3.68 (m, 3H), 3.56 - 3.39 (m, 4H), 3.39 - 3.07 (m, 4H), 2.98 - 2.87 (m, 1H).

[0199] Process C 5-[2-(2-{3-[(9aS)-hexahydro-1H-piperazino[2,1-c]morpholin-8-yl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(5-cyano-1,2-dimethylpyrrol-3-yl)-1,2-dimethyl-N-phenylpyrrole-3-carboxamide Using general procedure 4b and Example 3, step D (100 mg, 0.15 mmol, 1 equiv) as the appropriate amine and the product from step B (57 mg, 0.21 mmol, 1.4 equiv) as the appropriate carboxylic acid gave the title product (22.5 mg, 0.03 mmol, 17%). HRMS C 55 H 58Calculated for N8O4: 894.4581, Found: 895.4669 [M+H] +

[0200] Example 9: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxy-2-methylphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka]

[0201] Process A: 4-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-anilino]-1,5-dimethyl-pyrrole-2-carbonitrile Using general procedure 1b, starting with 4-bromo-1,5-dimethyl-pyrrole-2-carbonitrile (430 mg, 2.16 mmol) as the appropriate aryl bromide and 4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-aniline (615 mg, 1.2 equiv.) as the appropriate aniline, gave the title product (88 mg, 12%). 1 H NMR (500 MHz, DMSO-d6) δ ppm6.67 (s, 1H), 6.55 (d, 1H), 6.42 (dd, 1H), 6.22 (d, 1H), 6.06 (s, 1H), 3.62 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H), 0.92 (s, 9H), 0.11 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 146.9, 140.6, 131.6, 125.1, 124.6, 122.1, 117.6, 116.3, 115.0, 113.2, 99.9, 33.2, 26.1, 18.3, 9.9, -4.0. HRMS-ESI (m / z) [M+H]+ C 20 H 30 Calculated N3OSi value: 356.2153, measured value 356.2152.

[0202] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxy-2-methylphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide Using general procedure 2b, starting from preparation VIII (120 mg, 0.214 mmol) as the appropriate acid and the product from step A (84 mg, 1.1 equiv.) as the appropriate amine, followed by general procedure 3c for silyl deprotection, the title compound was obtained (20 mg, 12%). HRMS-ESI (m / z) [M+H] + C 49 H 49 Calculated value of N6O4: 785.3810, Found value 785.3812.

[0203] Example 10: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-[2-(4-phenoxyphenyl)acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting with 2-(4-phenoxyphenyl)acetic acid (70 mg, 2.4 equiv) as the appropriate carboxylic acid and preparation VIIb (97 mg, 0.13 mmol) as the appropriate amine, gave the title compound (35 mg, 32%). HRMS-ESI (m / z) [M+H] + C54 H 51 Calculated value for N6O5: 863.3915, Found value: 863.3921.

[0204] Example 11: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(2,4-difluorophenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting with 2,4-difluorophenylacetic acid (33.7 mg, 1.5 equiv) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, gave the title compound (60 mg, 57%). HRMS-ESI (m / z) [M+H] + C 48 H 45 Calculated value for F2N6O4: 807.3465, Found value: 807.3468.

[0205] Example 12: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(2-cyanophenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting with 2-(2-cyanophenyl)acetic acid (31.5 mg, 1.5 equiv) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, gave the title compound (40 mg, 39%). HRMS-ESI (m / z) [M+H] + C 49 H 46 Calculated value for N7O4: 796.3606, Found value: 796.3609.

[0206] Example 13: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(2-fluoro-4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka]

[0207] Process A: 4-[tert-butyl(dimethyl)silyl]oxy-2-fluoroaniline A solution of tert-butyl-chloro-dimethyl-silane (3.9 g, 1.1 equiv.) in THF (7 mL) was added dropwise to a solution of 4-amino-3-fluoro-phenol (3.0 g, 23.6 mmol, 2.33 mL) and imidazole (2.41 g, 1.5 equiv.) in THF (30 mL). After complete conversion, the volatiles of the reaction mixture were removed by evaporation. Water (20 mL) was added, and the mixture was extracted with EtO (2 × 20 mL). The combined organic layers were washed with brine, dried over MgSO, and then concentrated. The residue was purified by column chromatography (heptane: EtOAc = 9:1) to give the title compound (3.2 g, 55.8%). 1 H NMR (500 MHz, DMSO-d6) δ ppm6.64 (dd, 1H), 6.52 (dd, 1H), 6.42 (ddd, 1H), 4.65 (s, 2H), 0.92 (s, 9H), 0.12 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ ppm 150.8, 145.8, 130.9, 117, 116.1, 107.8, 26.1, -4.2. HRMS-ESI (m / z) [M+H] + C 12 H 21 FNOSi calculated value: 242.1371, measured value 242.1373.

[0208] Process B: 4-[4-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-anilino]-1,5-dimethyl-pyrrole-2-carbonitrile Using general procedure 1b, starting from the product from step A of preparation IVa as the appropriate aryl bromide (430 mg, 2.16 mmol) and the product from step A as the appropriate aniline (625.7 mg, 1.2 equiv.), gave the title product (95.7 mg, 12%). 1 H NMR (500 MHz, DMSO-d6) δ ppm6.72 (s, 1H), 6.70 (br., 1H), 6.62 (dd, 1H), 6.44 (dd, 1H), 6.39 (t, 1H), 3.62 (s, 3H), 2.07 (s, 3H), 0.92 (s, 9H), 0.14 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 151.5, 146.6, 131.8, 130.6, 123.6, 116.2, 116, 114.8, 114.5, 108.0, 100.1, 33.2, 26, 9.9, -4.2. HRMS-ESI (m / z) [M+H] + C 19 H 27 FN3OSi calculated value: 360.1902, measured value 360.1904.

[0209] Process C:N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(2-fluoro-4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide Using general procedure 2b, starting from preparation VIII (120 mg, 0.214 mmol) as the appropriate acid and the product of step B (84 mg, 1.1 equiv.) as the appropriate amine, followed by general procedure 3c for silyl deprotection, the desired product was obtained (20 mg, 14%). HRMS-ESI (m / z) [M+H] + C 48 H 46 Calculated value for FN6O4: 789.3559, Found value 789.3562.

[0210] Example 14: 5-[2-Benzylsulfonyl-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide [ka] To a solution of Preparation VIIb (100 mg, 0.13 mmol) in DCE (2 mL) was added DIPEA (37 mg, 2.2 equiv.) and phenylmethanesulfonyl chloride (40 mg, 1.6 equiv.), and the mixture was stirred until complete conversion was observed. The TBDMS protecting group was removed using 2 M aqueous NaOH (according to the protocol described in General Procedure 4c) to give the desired product (32 mg, 30%). HRMS-ESI (m / z) [M+H] + C 47 H 46 Calculated value for N6O5S: 807.3323, Found value: 807.3325.

[0211] Example 15: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-5-[2-(1H-indazole-3-carbonyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting with 1H-indazole-3-carboxylic acid (48 mg, 1.5 equiv) as the appropriate carboxylic acid and preparation VIIb (150 mg, 0.20 mmol) as the appropriate amine, gave the title compound (50 mg, 32%). HRMS-ESI (m / z) [M+H] + C 48 H 45 Calculated value of N8O4: 797.3558, Found value 797.3560.

[0212] Example 17: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenyl-1,3-thiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting from 2-phenylthiazole-5-carboxylic acid (60 mg, 1.5 eq) as the appropriate carboxylic acid and preparation VIIb (150 mg, 0.20 mmol) as the appropriate amine, gave the title compound as a white powder (39.7 mg, 24%). HRMS-ESI (m / z) [M+H] + C 50 H46 Calculated value for N7O4S: 840.3326, Found value: 840.3323.

[0213] Example 18: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2,2-difluoro-2-phenylacetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and preparation IVa (110 mg, 0.16 mmol, 1 equiv.) as the appropriate amine and 2,2-difluoro-2-phenylacetic acid (27 mg, 0.16 mmol, 1 equiv.) as the appropriate carboxylic acid, the title product was obtained (15.8 mg, 0.02 mmol, 12%). HRMS C 48 H 44 Calculated for F2N6O4: 806.3392, Found: 807.3466 [M+H] +

[0214] Example 19: 5-{2-[2-(4-chloro-2-fluorophenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting with 2-(4-chloro-2-fluoro-phenyl)acetic acid (50 mg, 2.0 equiv.) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, gave the title compound (40 mg, 37%). HRMS-ESI (m / z) [M+H] + C 48 H 45 Calculated value for ClFNO: 823.3169, found 823.3176.

[0215] Example 20: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[(2,3-dihydro-1-benzofuran-2-yl)carbonyl]-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and preparation IVa (120 mg, 0.18 mmol, 1.2 equiv) as the appropriate amine and 2,3-dihydrobenzo[b]furan-2-carboxylic acid (25 mg, 0.15 mmol, 1 equiv) as the appropriate carboxylic acid, the title product was obtained (75 mg, 0.09 mmol, 63%). HRMS C 49 H 46 Calculated for N6O5: 798.3530, Found: 799.3610 [M+H] +

[0216] Example 21: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting from the product of preparation Va (80 mg, 2.5 equiv.) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the title compound (59 mg, 63%). HRMS-ESI (m / z) [M+H] + C 54 H 51 Calculated value for N7O6: 900.4443, Found: 900.4446.

[0217] Example 22: N-[5-cyano-1-[2-[cyclopropyl(methyl)amino]ethyl]-2-methyl-pyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-(2-phenylacetyl)-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide [ka]

[0218] Process A: 4-Bromo-1-[2-[cyclopropyl(methyl)amino]ethyl]-5-methyl-pyrrole-2-carbonitrile Using general procedure 7c, starting with 2-[cyclopropyl(methyl)amino]ethanol (1.2 g, 2.0 equiv) as the appropriate alcohol, gave the title product (690 mg, 45%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.05 (s, 1H), 4.06 (t, 2H), 2.74 (t, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 1.78 (qn, 1H), 0.34 (m, 2h), -0.02 (m, 2H). LRMS (m / z) [M+H] + C 12 H 17 Calculated value for BrN3: 282.1, Found value: 282.0.

[0219] Process B 4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-1-[2-[cyclopropyl(methyl)amino]ethyl]-5-methyl-pyrrole-2-carbonitrile Using general procedure 1b, starting from the product of step A (640 mg, 2.27 mmol) as the appropriate aryl bromide and preparation IIIa (760 mg, 1.5 equiv) as the appropriate aniline, gave the title compound (680 mg, 70%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.87 (s, 1H), 6.72 (s, 1H), 6.59 (m, 2H), 6.46 (m, 2H), 4.02 (t, 2H), 2.77 (t, 2H), 2.33 (s, 3H), 2.07 (s, 3H), 1.79 (m, 1H), 0.92 (s, 9H), 0.37 / 0.06 (m+m, 4H), 0.12 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 130.7, 124.6, 120.6, 115.9, 114.9, 114.1, 99.9, 57.8, 44.8, 42.3, 39.0, 26.1, 9.9, 7.3, -4.1. HRMS-ESI (m / z) [M+H] + C 24 H 37 N4OSi calculated value: 425.2731, measured value 425.2741.

[0220] Process C: N-[5-cyano-1-[2-[cyclopropyl(methyl)amino]ethyl]-2-methyl-pyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-(2-phenylacetyl)-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide Using general procedure 2b, starting from preparation VIII (210 mg, 0.37 mmol) as the appropriate acid and the product of step B (230 mg, 1.4 equiv.) as the appropriate aniline, followed by general procedure 3c for silyl deprotection, the title compound was obtained (75 mg, 23%). HRMS-ESI (m / z) [M+H] + C 53 H 56 Calculated value for N7O4: 854.4388, Found value: 854.4385.

[0221] Example 23: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka]

[0222] Process A: 2-[4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]acetic acid To a solution of methyl 2-(4-bromophenyl)acetate (0.20 mL, 1.4 equiv.) and 1-(2,2,2-trifluoroethyl)piperazine (0.40 mL, 1.02 mmol) in 1,4-dioxane (5.0 mL), CsCO (439 mg, 1.0 equiv.) and [2-(2-aminoethyl)phenyl]chloropalladium, dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (1:1) (37 mg, 0.04 equiv.) were added, and the mixture was stirred until complete conversion was observed. After filtration, the crude product was hydrolyzed using General Procedure 8 to give the desired product (314 mg, 74%). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.05 (brs, 1H), 7.08 (d, 2H), 6.86 (d, 2H), 3.40 (s, 2H), 3.23 (q, 2H), 3.10 (t, 4H), 2.74 (t, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.6, 150.1, 130.3, 126.5, 126.4, 115.9, 57.3, 53.5, 49, 40.7. HRMS-ESI (m / z) [M+H] + C 14 H 18 Calculated value of F3N2O3: 303.1320, Found value: 303.1315.

[0223] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (100 mg, 3.4 equiv.) as the appropriate carboxylic acid and preparation VIIb (75 mg, 0.10 mmol) as the appropriate amine, gave the title product (62 mg, 68%). HRMS-ESI (m / z) [M+H] + C 54 H 56 Calculated value for F3N8O4: 937.4371, Found value: 937.4375.

[0224] Example 24:5-{2-[2-(4-bromo-2-fluorophenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting with 2-(4-bromo-2-fluorophenyl)acetic acid (30 mg, 1.3 equiv.) as the appropriate carboxylic acid and preparation VIIb (75 mg, 0.10 mmol) as the appropriate amine, gave the title compound (41.2 mg, 49%). HRMS-ESI (m / z) [M+H] + C 48 H 45 Calculated value for BrFN6O4: 867.2664, found value: 867.2661.

[0225] Example 25: 5-{2-Benzoyl-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Using general procedure 4d, starting with benzoyl chloride (30 mg, 1.6 equiv) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, gave the title compound (55 mg, 56%). HRMS-ESI (m / z) [M+H] + C 47 H 45 Calculated value of N6O4: 757.3502, Found value 757.3494.

[0226] Example 26: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-(2-{2,2-difluoro-2-[4-(4-methylpiperazin-1-yl)phenyl]acetyl}-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl)-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0227] Process A : Ethyl 2-(4-bromophenyl)-2,2-difluoroacetate Ethyl 2-(4-bromophenyl)-2-oxoacetate (3 g, 11.67 mmol, 1 equiv.) was cooled to 0 °C under N2, followed by the dropwise addition of DAST (3.08 mL, 23.34 mmol, 2 equiv.). Upon complete addition, the mixture was stirred at room temperature under N2 for 2 h. The mixture was poured onto ice with stirring and then extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title product (3.06 g, 10.95 mmol, 94%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.80 - 7.73 (m, 2H), 7.58 - 7.51 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0228] Process B : Difluoro[4-(4-methylpiperazin-1-yl)phenyl]acetic acid The product from Step A (1 g, 3.58 mmol, 1 equiv.), 1-methylpiperazine (0.6 mL, 5.37 mmol, 1.5 equiv.), and CsCO (2.33 g, 7.17 mmol, 2 equiv.) were combined in toluene (15 mL), and the mixture was sparged with N. DavePhos (141 mg, 0.36 mmol, 0.1 equiv.) and Pddba (164 mg, 0.18 mmol, 0.05 equiv.) were added, and the mixture was sparged with N and then heated at 120 °C under microwave irradiation for 1 h. The mixture was allowed to cool to room temperature, filtered through a Celite cartridge, and washed with EtOAc. The filtrate was washed with saturated aqueous NaHCO and brine, then dried over MgSO, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0-100% EtOAc in heptane, then 0-90% MeOH in EtOAc gave the title product, which was used directly in the subsequent step without further purification (0.86 g, 3.18 mmol, 89%). LRMS C 13 H 16 Calculated value for F2N2O2: 270.1, Found value: 270.8 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.36 - 7.28 (m, 2H), 6.93 - 6.86 (m, 2H), 3.19 - 3.11 (m, 4H), 2.47 - 2.41 (m, 4H), 2.21 (s, 3H).

[0229] Process C N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-(2-{2,2-difluoro-2-[4-(4-methylpiperazin-1-yl)phenyl]acetyl}-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl)-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and preparation IVa (200 mg, 0.29 mmol, 1.1 equiv) as the appropriate amine and the product from step B (102 mg, 0.33 mmol, 1.3 equiv) as the appropriate carboxylic acid, gave the title product (6.7 mg, 0.01 mmol, 3%). HRMS C 53 H 54 Calculated for F2N8O4: 904.4236, Found: 905.4309 [M+H] +

[0230] Example 27: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka] Using general procedure 4c, starting from preparation Vc (49 mg, 1.5 equiv) as the appropriate carboxylic acid and preparation VIIb (94 mg, 0.12 mmol) as the appropriate amine, gave the title compound (64 mg, 58%). HRMS-ESI (m / z) [M+H] + C 55 H 59 Calculated N6O6: 899.4496, Found: 899.4498.

[0231] Example 28: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{3-fluoro-4-[1-(2-fluoroethyl)piperidin-4-yl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0232] Process A : tert-Butyl 4-[2-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate A solution of methyl 2-(4-bromo-3-fluorophenyl)acetate (1.5 g, 6.07 mmol, 1 equiv.), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid, pinacol ester (2.07 g, 6.68 mmol, 1.1 equiv.), and K2CO3 (2.52 g, 18.21 mmol, 3 equiv.) in THF (10 mL) and water (1 mL) was sparged with N2, followed by the addition of Pd(dppf)Cl2·DCM (496 mg, 0.61 mmol, 0.1 equiv.). The mixture was sparged with N2 and then heated at 110 °C under microwave irradiation for 1 h. The mixture was allowed to cool to room temperature, diluted with DCM, and washed with water. The phases were separated, and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0-35% EtOAc in heptane gave the title product (1.52 g, 4.36 mmol, 72%). LRMS C 19 H 24 Calculated value for FNO4: 349.2, Found value: 250.0 [M-Boc+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.29 (t, J = 8.1 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.01 - 5.92 (m, 1H), 3.98 (d, J = 3.4 Hz, 2H), 3.71 (s, 2H), 3.62 (s, 3H), 3.52 (t, J = 5.7 Hz, 2H), 2.45 - 2.37 (m, 2H), 1.43 (s, 9H).

[0233] Process B: tert-Butyl 4-[2-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]piperidine-1-carboxylate To a solution of the product from Step A (1.52 g, 4.36 mmol, 1 equiv) in MeOH (30 mL) was added 10% Pd / C (catalytic). The mixture was evacuated and back-filled with N, then evacuated, flushed with H, and shaken under an H atmosphere at room temperature for 16 h. The mixture was filtered through a Celite cartridge and washed with MeOH. The solvent was removed in vacuo to give the title product (1.36 g, 3.88 mmol, 89%). LRMS C 19 H 26 Calculated value for FNO4: 351.2, Found value: 252.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.27 (t, J = 8.1 Hz, 1H), 7.10 - 7.01 (m, 2H), 4.12 - 3.96 (m, 2H), 3.67 (s, 2H), 3.61 (s, 3H), 3.00 - 2.68 (m, 3H), 1.75 - 1.64 (m, 2H), 1.60 - 1.45 (m, 2H), 1.41 (s, 9H).

[0234] Process C : Methyl 2-[3-fluoro-4-(piperidin-4-yl)phenyl]acetate hydrochloride A solution of the product from step B (682 mg, 1.94 mmol, 1 equiv) in 3 M HCl in MeOH (30 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo, followed by purification by reverse-phase automated flash chromatography (Combiflash Rf, C18 43 g RediSep column) eluting with a gradient of 0 to 14% MeCN in water to give the title product (140 mg, 0.49 mmol, 25%). LRMS C 14 H 18 Calculated FNO2: 251.1, Found 252.0 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (br s, 2H), 7.13 - 7.06 (m, 2H), 7.09 (s, 1H), 3.69 (s, 2H), 3.62 (s, 3H), 3.39 - 3.31 (m, 2H), 3.18 - 2.95 (m, 3H), 1.98 - 1.80 (m, 4H).

[0235] Process D {3-fluoro-4-[1-(2-fluoroethyl)piperidin-4-yl]phenyl}acetic acid To a solution of the product from Step C (140 mg, 0.49 mmol, 1 equiv.) in DMF (5 mL) cooled to 0 °C, TEA (68 μL, 0.49 mmol, 1 equiv.) was added, followed by NaH (60% in mineral oil, 23 mg, 0.58 mmol, 1.2 equiv.), and the mixture was stirred for 15 min. 1-Fluoro-2-iodoethane (44 μL, 0.54 mmol, 1.1 equiv.) was added, and the mixture was allowed to warm to room temperature. The reaction was stirred for 18 h. The solvent was removed in vacuo to give the intermediate, which was dissolved in MeOH (10 mL) and treated with 2 M aqueous NaOH (0.49 mL, 0.97 mmol, 2 equiv.). The mixture was heated at 80 °C under microwave irradiation for 0.5 h. The solvent was removed under reduced pressure, and the residue was diluted with water and the pH adjusted to 2 with 2 M aqueous HCl. Purification by reverse-phase automated flash chromatography eluting with a gradient of 0-40% MeCN in water gave the title product (144 mg, 0.46 mmol, 94%). LRMS C 15 H 19 Calculated value for F2NO2: 283.1, Found value: 284.0 [M+H] +

[0236] Process EN-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{3-fluoro-4-[1-(2-fluoroethyl)piperidin-4-yl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and preparation IVa (200 mg, 0.29 mmol, 1 equiv.) as the appropriate amine and the product from step D (107 mg, 0.38 mmol, 1.3 equiv.) as the appropriate carboxylic acid, gave the title product (42.5 mg, 0.05 mmol, 16%). HRMS C 55 H 57 Calculated for F2N7O4: 917.4440, Found: 918.4511 [M+H] +

[0237] Example 29-a: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-((3R or S)-2-oxo-1-phenylpyrrolidine-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide (diastereomer 1)

[0238] Example 29-b: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-((3S or R)-2-oxo-1-phenylpyrrolidine-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide (diastereomer 2) [ka] Using general procedure 4c, starting with 2-oxo-1-phenyl-pyrrolidine-3-carboxylic acid (57 mg, 1.5 equivalents) as the appropriate carboxylic acid and preparation VIIb (141 mg, 0.18 mmol) as the appropriate amine, the product was obtained as a mixture of diastereoisomers as a white powder (89.4 mg, 58%). The diastereoisomers of the desired product were separated on an AD-3 chiral column (50 × 500 mm, 20 μm) using EtOH as the eluent to give the title product, diastereomer 1 (39.5 mg, 26%) and diastereomer 2 (40.1 mg, 27%). HRMS-ESI (m / z) [M+H] + C 51 H 50 Calculated for N7O5: 840.3868, Found: 840.3865 (Diastereomer 1) HRMS-ESI (m / z) [M+H] + C 51 H 50 Calculated for N7O5: 840.3868, Found: 840.3868 (Diastereomer 2)

[0239] Example 30: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-5-[2-(2-{4-[2-(4-hydroxypiperidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0240] Process A: 1-(2-trityloxyethyl)piperidin-4-ol To a solution of 1-(2-hydroxyethyl)piperidin-4-ol (1.0 g, 6.887 mmol, 1 equiv.) in DCM (10 mL) was added TEA (1.4 mL, 10.0 mmol, 1.5 equiv.) and N,N-dimethylpyridin-4-amine (40 mg, 0.327 mmol, 0.05 equiv.). The reaction mixture was stirred at room temperature for 10 minutes. At 0° C., trityl chloride (2.0 g, 7.174 mmol, 1.04 equiv.) was added to the reaction mixture, which was allowed to warm and stir at room temperature overnight. The mixture was concentrated in vacuo, and the residue was purified by automated flash chromatography using DCM and MeOH as eluents to give the title product (1.20 g, 45%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.44-7.21 (m, 15 H), 4.52 (d, 1 H), 3.39 (m, 1 H), 3.01 (t, 2 H), 2.64 / 2.01 (m+m, 4 H), 2.49 (m, 2 H), 1.67 / 1.35 (m+m, 4H); 13 C NMR (500 MHz, DMSO-d6) δ ppm 144.5, 86.4, 66.7, 62.2, 57.9, 52.1, 35.0. HRMS-ESI (m / z) [M+H] + C 26 H 30 Calculated NO2: 388.2271, Measured: 388.2278

[0241] Process B: tert-Butyl-dimethyl-[[1-(2-trityloxyethyl)-4-piperidyl]oxy]silane The product of Step A (1.20 g, 3.100 mmol, 1 equiv) in DCM (6.45 mL / mmol) was treated with imidazole (500 mg, 7.344 mmol, 2.4 equiv) and tert-butyl-chloro-dimethyl-silane (860 mg, 5.706 mmol, 1.8 equiv) at 0 °C. The reaction mixture was allowed to warm and stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by automated flash chromatography using DCM and MeOH as eluents to give the title product (1.40 g, 90%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.44-7.22 (m, 15 H), 3.66 (m, 1 H), 3.03 (t, 2 H), 2.61 (br, 2 H), 2.12 (t, 2H), 1.66 (m, 2 H), 1.41 (m, 2 H), 0.86 (s, 9 H), 0.03 (s, 6 H). HPLC-MS (m / z) [M+H] + C 32 H 44 Calculated NO2Si: 502.3, measured 502.2.

[0242] Process C: 2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]ethanol The product of Step B (1.40 g, 2.800 mmol, 1 equiv.) in DCM (3.57 mL / mmol) was treated with acetic acid (20 mL, 349.4 mmol, 30 equiv.) and stirred at 100 °C overnight. The mixture was concentrated in vacuo, and the residue was dissolved in MeOH, treated with KCO (2.0 g, 14.471 mmol, 5.2 equiv.), and stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The crude product was dissolved in HO (15 mL), extracted with DCM (3 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated. The crude product was purified by automated flash chromatography (TLC visualization: KMnO) using DCM and MeOH as eluents to give the title product (380 mg, 52%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.34 (t, 1 H), 3.65 (m, 1 H), 3.45 (m, 2 H), 2.64 (m, 2 H), 2.34 (t, 2 H), 2.13 (t, 2 H), 1.66 (m, 2 H), 1.39 (m, 2 H), 0.86 (s, 9 H), 0.04 (s, 6 H). HPLC-MS (m / z) [M+H] + C 13 H 30 Calculated NO2Si: 260.2, Measured: 260.2

[0243] Process D: Methyl 2-[4-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]ethoxy]phenyl]acetate Using general procedure 7b, the product of Step C (380 mg, 1.464 mmol, 1.0 equiv.), methyl 2-(4-hydroxyphenyl)acetate (330 mg, 1.986 mmol, 1.4 equiv.), PPh3 (660 mg, 2.516 mmol, 1.7 equiv.), and DTBAD (580 mg, 2.519 mmol, 1.7 equiv.) in THF (8.0 mL) were stirred at room temperature for 1 h. The reaction mixture was evaporated. HO (15 mL) was added to the crude product, extracted with DCM (3 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated. The crude product was triturated with MeCN. The precipitate was filtered. The mother liquor was concentrated in vacuo, and the residue was purified by reverse-phase automated flash chromatography using MeCN and water as eluents to give the title product (140 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15 (m, 2 H), 6.87 (m, 2 H), 4.01 (t, 2 H), 3.69 (m, 1 H), 3.60 (s, 3 H), 3.59 (s, 2 H), 2.72 (m, 2 H), 2.66 (t, 2 H). 2.23 (t, 2 H), 1.70 (m, 2 H), 1.42 (m, 2 H), 0.86 (s, 9 H), 0.04 (s, 6 H). HPLC-MS (m / z) [M+H] + C 22 H 38 NO4Si calculated: 408.3, measured: 408.2

[0244] Process E: 2-[4-[2-(4-hydroxy-1-piperidyl)ethoxy]phenyl]acetic acid The product of Step D (120 mg, 0.294 mmol, 1 equiv.) in 1,4-dioxane (2 mL) was treated with 2 M aqueous NaOH (1.0 mL, 2.0 mmol, 6.8 equiv.) and stirred at 90 °C for 1 h. The reaction mixture was acidified to pH ∼3 with 2 M aqueous HCl (a few drops) and evaporated. Toluene was added, and then residual water was removed by azeotropic distillation. The compound was isolated (containing inorganic salts) and used crude in the next coupling step (75 mg, 91%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.33 (br, 1 H), 10.95 (brs, 1 H), 7.19 (m, 2 H), 6.94 (m, 2 H), 4.40 (t, 2 H), 3.93 (m, 1 H), 3.63 (m, 2 H), 3.51 (s, 2 H), 3.25 (m, 2 H), 3.05 (m, 2 H), 2.11-1.67 (m, 4 H). HPLC-MS (m / z) [M+H] + C 15 H 22 NO4 calculated: 280.1, measured: 280.2

[0245] Process F: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-5-[2-(2-{4-[2-(4-hydroxypiperidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of step E (75 mg, 2.2 eq) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.12 mmol) as the appropriate amine, gave the title compound (15 mg, 13%). HRMS-ESI (m / z) [M+H] + C 55 H 60 Calculated value for N7O6: 914.4605, Found value: 914.4599.

[0246] Example 31: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(4-cyclopropylpiperazin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0247] Process A: 2-[4-[2-(4-cyclopropylpiperazin-1-yl)ethoxy]phenyl]acetic acid A suspension of 1-cyclopropylpiperazine (164 mg, 1.30 mmol), 2-bromoethanol (0.14 mL, 1.5 equiv.), and KCO (350 mg, 1.9 equiv.) in ethanol (3 mL) was stirred at 100 °C until complete conversion was observed. The reaction mixture was diluted with MTBE, filtered, concentrated, and the residue was reacted with methyl 2-(4-hydroxyphenyl)acetate (190 mg, 1.1 equiv.) as the appropriate phenol according to General Procedure 7b. The mixture was then hydrolyzed according to General Procedure 8 to give the title compound (120 mg, 27%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.20 (m, 2H), 6.94 (m, 2H), 4.40 (brt, 2H), 3.90-3.00 (brs, 11H), 3.50 (s, 2H), 0.93 / 0.69 (brs+m, 2H). HRMS-ESI (m / z) [M+H] + C 17 H 25 Calculated N2O3: 305.1865, Measured: 305.1860.

[0248] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(4-cyclopropylpiperazin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of step A (100 mg, 2.8 eq) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the title compound (15 mg, 15%). HRMS-ESI (m / z) [M+H] + C 57 H 63 Calculated value for N8O5: 939.4916, Found value: 939.4925.

[0249] Example 32: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-[2-(4-{2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy}phenyl)acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka]

[0250] Process A: Methyl 2-[4-(2-hydroxyethoxy)phenyl]acetate A suspension of methyl 2-(4-hydroxyphenyl)acetate (1.9 g, 11.0 mmol), 2-bromoethanol (1.2 mL, 1.5 equiv.) and KCO (3 g, 1.9 equiv.) in DMF (10 mL) was stirred at 100° C. until complete conversion was observed. The reaction mixture was concentrated and the residue was purified by flash chromatography using DCM and MeOH as eluents to give the title compound (1.2 g, 50%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.16 (m, 2H), 6.88 (m, 2H), 3.95 (t, 2H), 3.69 (t, 2H), 3.59 (s, 3H), 3.59 (s, 2 ); 13 C NMR (125 MHz, DMSO-d6) δ ppm 172.4, 158.1, 130.8, 126.6, 114.8, 69.9, 60.0, 52.1, 39.7. HRMS-ESI (m / z) [M+H] + C 11 H 15 Calculated O4: 211.0965, Measured 211.0965.

[0251] Process B: Methyl 2-[4-(2-methylsulfonyloxyethoxy)phenyl]acetate To the product of Step A (1.18 g, 5.6 mmol) and DIPEA (1.76 mL, 1.8 equiv.) in THF (20 mL), methanesulfonyl chloride (0.65 mL, 1.5 equiv.) was added dropwise, and the reaction mixture was stirred until the reaction was complete. After dilution with DCM (50 mL), the organic phase was washed with water (20 mL) and brine (20 mL), dried, and concentrated to give the desired product (1.52 g, 94%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.19 (d, 2H), 6.92 (d, 2H), 4.52 (t, 2H), 4.23 (t, 2H), 3.61 (s, 2H), 3.60 (s, 3H), 3.23 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 172.3, 157.3, 131.0, 127.3, 114.9, 69.2, 66.2, 52.1, 39.7, 37.3. HRMS-ESI (m / z) [M−H] - C 12 H 17 Calculated O6S value: 289.0740, Measured 289.0743.

[0252] Process C: 2-[4-[2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy]phenyl]acetic acid To a suspension of 1-(2,2,2-trifluoroethyl)piperazine (247 mg, 2.6 equiv.) in 1,4-dioxane (3 mL) was added the product of Step B (164 mg, 0.57 mmol) and DIPEA (0.15 mL, 1.5 equiv.). The mixture was stirred at 100° C. until complete conversion was observed, and the product was then hydrolyzed by General Procedure 8 to give the title compound (150 mg, 76%). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.83 (brs, 1H), 7.16 (m, 2H), 6.87 (m, 2H), 4.06 (t, 2H), 3.47 (s, 2H), 3.12 (q, 2H), 2.69 (t, 2H), 2.63 (m, 4H), 2.51 (m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.1, 130.7, 126.5, 115.0, 66.4, 57.6, 57.0, 53.6, 53.4, 40.4. HRMS-ESI (m / z) [M+H] + C 16 H 22 Calculated value of F3N2O3: 347.1582, Found value: 347.1582.

[0253] Process D: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-[2-(4-{2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy}phenyl)acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of step C (150 mg, 3.3 equiv) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, gave the title compound (72 mg, 56%). HRMS-ESI (m / z) [M+H] + C 56 H 60 Calculated value for F3N8O5: 981.4633, Found value: 981.4630.

[0254] Example 33:N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(2-fluoro-4-methoxyphenyl)acetyl]-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0255] Process A : Methyl 2-(2-fluoro-4-methoxyphenyl)acetate Using general procedure 7b and preparation Vb, step A (940 mg, 5.1 mmol, 1 equiv) as the appropriate phenol and MeOH (4 mL) as the appropriate alcohol gave the title product (543 mg, 2.74 mmol, 54%). LRMS C 10 H 11 FO3 calculated value: 198.1, measured value: 199.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.27 - 7.21 (m, 1H), 6.81 (dd, J = 12.0, 2.6 Hz, 1H), 6.74 (ddd, J = 8.4, 2.6, 0.7 Hz, 1H), 3.75 (s, 3H), 3.65 - 3.62 (m, 2H), 3.61 (s, 3H).

[0256] Process B : 2-(2-fluoro-4-methoxyphenyl)acetic acid To a solution of the product from step A (543 mg, 2.74 mmol, 1 equiv) in MeOH (5 mL) was added LiOH·HO (70 mg, 1.66 mmol, 2 equiv) and the mixture was heated at 100 °C under microwave irradiation for 30 min. The mixture was allowed to cool to room temperature, diluted with DCM, and washed with 2 M aqueous HCl. The phases were separated and the organic phase was dried (PTFE phase separator) and concentrated in vacuo to give the title product (450 mg, 2.44 mmol, 89%). LRMS calculated value for C9H9FO3: 184.1, found value 183.0 [MH] - 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.35 (s, 1H), 7.25 - 7.19 (m, 1H), 6.79 (dd, J = 12.0, 2.6 Hz, 1H), 6.73 (ddd, J = 8.4, 2.6, 0.7 Hz, 1H), 3.75 (s, 3H), 3.54 - 3.50 (m, 2H).

[0257] Process C N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(2-fluoro-4-methoxyphenyl)acetyl]-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and preparation IVb (130 mg, 0.18 mmol, 1 equiv.) as the appropriate amine and the product from step B (36 mg, 0.19 mmol, 1.1 equiv.) as the appropriate carboxylic acid, gave the title product (56.7 mg, 0.06 mmol, 36%). HRMS C 54 H 56 Calculated for FN7O5: 901.4327, Found: 902.4407 [M+H] +

[0258] Example 34:N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0259] Process A : Methyl 2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetate To a solution of Preparation Vb, Step A (220 mg, 1.19 mmol, 1 equiv.) in DMF (3 mL) was added 4-(2-bromoethyl)tetrahydropyran (231 mg, 1.19 mmol, 1 equiv.) and K2CO3 (330 mg, 2.39 mmol, 2 equiv.), and the mixture was stirred at 60 °C under N2 for 18 h. The mixture was allowed to cool to room temperature, diluted with DCM, and washed with water. The phases were separated, and the organic phase was dried (PTFE phase separator) and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 to 50% EtOAc in heptane gave the title product (246 mg, 0.83 mmol, 69%). LRMS C 16 H 21 FO4 calculated value: 296.1, measured value: 297.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.22 (t, J = 8.7 Hz, 1H), 6.81 (dd, J = 12.1, 2.5 Hz, 1H), 6.75 - 6.71 (m, 1H), 4.01 (t, J = 6.3 Hz, 2H), 3.86 - 3.78 (m, 2H), 3.64 - 3.62 (m, 2H), 3.61 (s, 3H), 3.28 (td, J = 11.8, 2.1 Hz, 2H), 1.76 - 1.56 (m, 5H), 1.28 - 1.12 (m, 2H).

[0260] Process B : 2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetic acid To a solution of the product from step A (246 mg, 0.83 mmol, 1 equiv) in MeOH (3 mL) was added LiOH·HO (70 mg, 1.66 mmol, 2 equiv) and the mixture was heated under microwave irradiation at 100 °C for 30 min. The mixture was allowed to cool to room temperature and partitioned between DCM and 2 M aqueous HCl. The phases were separated and the organic phase was dried (PTFE phase separator) and concentrated in vacuo to give the title product (209 mg, 0.74 mmol, 89%). LRMS C 15 H 19 FO4 calculated value: 282.1, measured value: 281.2 [MH] - 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.38 (s, 1H), 7.23 - 7.16 (m, 1H), 6.79 (dd, J = 12.0, 2.5 Hz, 1H), 6.72 (dd, J = 8.4, 2.5 Hz, 1H), 4.01 (t, J = 6.3 Hz, 2H), 3.86 - 3.78 (m, 2H), 3.54 - 3.48 (m, 2H), 3.28 (td, J= 11.7, 2.1 Hz, 2H), 1.76 - 1.56 (m, 5H), 1.28 - 1.14 (m, 2H).

[0261] Process C N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and preparation IVb (130 mg, 0.18 mmol, 1 equiv.) as the appropriate amine and the product from step B (55 mg, 0.19 mmol, 1.1 equiv.) as the appropriate carboxylic acid, gave the title product (69.5 mg, 0.07 mmol, 39%). HRMS C 60 H 66 Calculated for FN7O6: 999.5059, Found: 1000.5136 [M+H] +

[0262] Example 35: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-3-[2-[2-[4-[2-[cyclopropyl(methyl)amino]ethoxy]phenyl]acetyl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide [ka]

[0263] Process A: Benzyl 7-formyl-6-(1-methoxycarbonyl-5,6,7,8-tetrahydroindolizin-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate To benzyl 6-bromo-7-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (5.2 g, 14.03 mmol) and methyl 5,6,7,8-tetrahydroindolizine-1-carboxylate (3.8 g, 1.5 equiv.) in DMF (18 mL) was added KCO (3.9 g, 2.0 equiv.) and diacetoxypalladium (315 mg, 0.1 equiv.), and the mixture was stirred at 100° C. until complete conversion was observed. The reaction mixture was concentrated and purified by flash chromatography using heptane and EtOAc as eluents to give the title compound (3.7 g, 56%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 7.76 (s, 1H), 7.44-7.28 (m, 5H), 7.37 (s, 2H), 6.41 (s, 1H), 5.14 (s, 2H), 4.86 / 4.75 (brs, 2H), 3.69 (s, 3H), 3.68 (brm, 2H), 3.68 (brm, 2H), 3.04 (t, 2H), 2.92 (t, 2H), 1.90-1.74 (m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 191.8, 165.0, 138.1, 132.5, 127.3, 126.2, 112.7, 110.2, 66.9, 50.9, 45.6, 44.6, 41.2, 28.9, 24.2. HRMS-ESI (m / z) [M+H] + C 28 H 29 Calculated N2O5: 473.2072, Found: 473.2074.

[0264] Process B: 2-Benzyloxycarbonyl-6-(1-methoxycarbonyl-5,6,7,8-tetrahydroindolizin-3-yl)-3,4-dihydro-1H-isoquinoline-7-carboxylic acid To the product of Step A (3.7 g, 7.87 mmol), 2-methylbut-2-ene (6.3 mL, 7.5 equiv.) in 2-methylpropan-2-ol (36 mL) and THF (24 mL) was added NaHPO (4.7 g, 5.0 equiv.) in water (31 mL) dropwise. After cooling to 14 °C and dropwise addition of NaClO (2.1 g, 3.0 equiv.) in water (31 mL), the mixture was stirred at 20 °C until complete conversion was observed. After cooling to 5-10 °C and dropwise addition of NaSO (1.6 g, 1.3 equiv.) in water (24 mL), and dilution with MTBE (150 mL), the organic phase was washed with brine (150 mL), dried, concentrated, and purified by flash chromatography using heptane and EtOAc as eluents to give the title compound (2.5 g, 64%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.71 (s, 1H), 7.69 (s, 1H), 7.45-7.28 (m, 5H), 7.18 (s, 1H), 6.22 (s, 1H), 5.14 (s, 2H), 4.70 / 4.64 (brs / brs., 2H), 3.67 (s, 3H), 3.67 (br., 2H), 3.54 (t, 2H), 3.00 (t, 2H), 2.86 (t, 2H), 1.85-1.67 (m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 168.6, 165.2, 155.1, 137.4, 136.4, 134.0, 133.1, 131.5, 131.3, 128.1, 109.6, 108.8, 66.8, 50.8, 45.5, 44.1, 41.3, 28.4, 24.1, 22.9 / 19.9. HRMS-ESI (m / z) [M+H] + C 28 H 29 Calculated N2O6: 489.2021, measured 489.2023.

[0265] Process C:3-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-5,6,7,8-tetrahydroindolizine-1-carboxylic acid Using the procedure described in Preparation VIIb, Step A, starting from the product of Step B (3.1 g, 6.45 mmol) as the appropriate carboxylic acid and the product of Preparation IIa, Step A (1.4 mg, 1.2 equiv.) as the appropriate amine, the title compound was obtained (3.1 g, 83%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.85 (brs, 2H), 7.36-6.87 (m, 6H), 6.39-6.18 (s, 1H), 5.32-1.33 (m, 19H), 1.04-0.54 (d, 3H). HRMS-ESI (m / z) [M+H] + C 29 H 32 Calculated N3O3: 470.2437, Found 470.2439.

[0266] Process D: 3-[2-(9H-Fluoren-9-ylmethoxycarbonyl)-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-5,6,7,8-tetrahydroindolizine-1-carboxylic acid To the product of step C (3.1 g, 5.3 mmol), NaHCO (1.5 g, 2.3 equiv.) in 1,4-dioxane (30 mL) and water (30 mL) was added 9H-fluoren-9-ylmethyl carbonochloridate (208 mg, 1.1 equiv.), and the reaction mixture was stirred until complete conversion was observed. After adding 2 M HCl solution (53 mL), stirring for 15 min, and diluting with DCM (150 mL), the organic phase was washed with brine (150 ml), dried, concentrated, and purified by flash chromatography using DCM and MeOH as eluents to give the title compound (3.0 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01-6.85 (m, 14H), 6.44-6.14 (br., 1H), 5.42-3.31 (br., 9H), 4.53-4.29 (br., 2H), 4.32 (br., 1H), 3.14-1.27 (br., 10H), 1.04 / 0.86 / 0.75 / 0.54 (br / br / br / d, 3H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 111.2, 67.2, 47.3, 18.6 / 16.9 / 16.7 / 16.3. HRMS-ESI (m / z) [M+H] + C 44 H 42 Calculated value of N3O5: 692.3119, Found value 692.3118.

[0267] Process E: 9H-Fluoren-9-ylmethyl 6-[1-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 2b, starting with the product of step D (2.5 g, 3.6 mmol) as the appropriate acid and 4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-1,5-dimethyl-pyrrole-2-carbonitrile (1.5 g, 1.2 equiv.) as the appropriate aniline, the title compound was obtained (2.3 g, 62%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.93-6.56 (m, 19H), 5.41-5.15 (s, 1H), 5.03-1.42 (m, 22H), 3.67-3.54 (s, 3H), 2.16-1.81 (s, 3H), 1.11-0.45 (d, 3H), 0.90-0.83 (s, 9H), 0.14-0.08 (s, 6H). HRMS-ESI (m / z) [M+H] + C 63 H 67 Calculated value for N6O5Si: 1015.4939, Found value: 1015.4940.

[0268] Process F: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-3-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-5,6,7,8-tetrahydroindolizine-1-carboxamide The product of Step E (2.26 g, 2.23 mmol) in morpholine (11 mL) and DCM (11 mL) was stirred until complete conversion was observed. The reaction mixture was concentrated and purified by flash chromatography using DCM and MeOH as eluents to give the title compound (1.7 g, 97%). 1 H NMR (400 MHz, DMSO-d6) δppm 7.31-6.53 (m, 11H), 5.41-4.98 (s, 1H), 5.38-1.20 (m, 20H), 3.71-3.51 (s, 3H), 2.18-1.77 (s, 3H), 1.07-0.43 (d, 3H), 0.92-0.87 (s, 9H), 0.16-0.10 (s, 6H). HRMS-ESI (m / z) [M+H] + C 48 H 57 Calculated value for N6O3Si: 793.4255, Found value: 793.4256.

[0269] Process G: 2-[4-[2-[cyclopropyl(methyl)amino]ethoxy]phenyl]acetic acid Using general procedure 7d and then general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (250 mg, 0.91 mmol) as the appropriate alkyl halide and N-methylcyclopropanamine (130 mg, 2.0 equiv.) as the appropriate amine, the desired product was obtained (190 mg, 59%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.85(brs, 1H), 7.10(dd, 1H), 7.09(t, 1H), 6.99(dm, 1H), 4.11(t, 2H), 3.51 (s, 2H), 2.87 (t, 2H), 2.34 (s, 3H), 1.75 (m, 1H), 0.42 / 0.30 (m+m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 126.0, 117.5, 115.1, 67.2, 56.4, 43.3, 39.9, 38.7, 7.1. HRMS-ESI (m / z) [M+H] + C 14 H 20 Calculated NO3: 250.1438, Measured: 250.1437.

[0270] Process H: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-3-[2-[2-[4-[2-[cyclopropyl(methyl)amino]ethoxy]phenyl]acetyl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide Using general procedure 4c, starting from the product of Step G (65 mg, 2.0 equiv) as the appropriate carboxylic acid and the product of Step F (100 mg, 0.13 mmol) as the appropriate amine, the title compound was obtained (58 mg, 50%). HRMS-ESI (m / z) [M+H] + C 56 H 60Calculated value for N7O5: 910.4652, Found value: 910.4653.

[0271] Example 36: 5-{2-[2-(4-{2-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0272] Process A: 2-[4-[2-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]ethoxy]phenyl]acetic acid Using general procedure 7d followed by general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (317 mg, 1.16 mmol) as the appropriate alkyl halide and (9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (250 mg, 1.0 equiv.) as the appropriate amine, the desired product was obtained (90 mg, 25%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.12 (dm, 2H), 6.82 (dm, 2H), 4.01 (t, 2H), 3.71 / 3.47 (brd+m, 2H), 3.57 / 3.05 (m+m, 2H), 3.35 (s, 2H), 2.84 / 2.19 (d+m, 2H), 2.69 / 1.73 (dm+t, 2H), 2.65 (t, 2H), 2.63 / 2.18 (m+m, 2H), 2.57 / 2.15 (m+m, 2H), 2.09 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ ppm 173.8, 157.2, 130.7, 129.3, 114.5, 68.9, 66.8, 65.8, 60.0, 57.2, 54.5, 54.1, 54.0, 53.4, 42.1. HRMS-ESI (m / z) [M+H] + C 17 H 25 Calculated N2O4: 321.1814, Measured 321.1807.

[0273] Process B: 5-{2-[2-(4-{2-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting with the product of Step A (150 mg, 4.0 equiv) as the appropriate carboxylic acid and preparation VIIb (90 mg, 0.12 mmol) as the appropriate amine, gave the title compound (54 mg, 48%). HRMS-ESI (m / z) [M+H] + C 57 H 63 Calculated value of N8O6: 955.4865, Found value: 955.4858.

[0274] Example 37: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(2-{2-[4-(2-{1,1-dioxo-1λ 6 -thia-6-azaspiro[3.3]heptan-6-yl}ethoxy)phenyl]acetyl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0275] Process A: 2-[4-[2-(1,1-dioxo-1λ^{6}-thia-6-azaspiro[3.3]heptan-6-yl)ethoxy]phenyl]acetic acid To a suspension of 3λ^{6}-thia-6-azaspiro[3.3]heptane 3,3-dioxide, HCl salt (213 mg, 1.7 equiv.) in 1,4-dioxane (1 mL) was added the product of Step B of Example 32 (200 mg, 0.69 mmol) and DIPEA (0.4 mL, 3.0 equiv.). The reaction mixture was stirred at 80° C. until complete conversion was observed, and the product was then hydrolyzed by General Procedure 8 to give the title compound (149 mg, 66%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.84 (brs, 1H), 7.15 (d, 2H), 6.84 (d, 2H), 3.99 (t, 2H), 3.92 (t, 2H), 3.82 / 3.34 (brm+brm, 4H), 3.50 (brs, 2H), 2.76 (brm, 2H), 2.21 (t, 2H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 172.4, 157.5, 130.9, 127.7, 114.6, 78.8, 67.0, 62.4, 60.7, 57.0, 40.5, 17.7. HRMS-ESI (m / z) [M+H] + C 15 H 20 Calculated NO5S value: 326.1062, Measured value: 326.1054.

[0276] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(2-{2-[4-(2-{1,1-dioxo-1λ 6-thia-6-azaspiro[3.3]heptan-6-yl}ethoxy)phenyl]acetyl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (120 mg, 3.1 equiv.) as the appropriate carboxylic acid and preparation VIIb (90 mg, 0.12 mmol) as the appropriate amine, gave the title compound (24 mg, 21%). HRMS-ESI (m / z) [M+H] + C 55 H 58 Calculated value for N7O7S: 960.4113, Found: 960.4110.

[0277] Example 38: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethyl]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxamide [ka]

[0278] Process A : Methyl 2-{4-[(E)-2-ethoxyethenyl]phenyl}acetate To a solution of methyl 4-bromophenylacetate (224 mg, 0.98 mmol, 1 equiv.), (E)-1-ethoxyethene-2-boronic acid pinacol ester (213 mg, 1.08 mmol, 1.1 equiv.) in THF (4 mL) and water (0.4 mL), K2CO3 (405 mg, 2.93 mmol, 3 equiv.) was added, and the mixture was sparged with N2. Pd(dppf)Cl2DCM (80 mg, 0.1 mmol, 0.1 equiv.) was added, and the reaction was then heated at 110 °C under microwave irradiation for 1 h. The mixture was allowed to cool to room temperature and partitioned between EtOAc and water. The phases were separated, and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0-36% EtOAc in heptane gave the title product (173 mg, 0.79 mmol, 80%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.24 - 7.16 (m, 3H), 7.15 - 7.10 (m, 2H), 5.80 (d, J = 13.0 Hz, 1H), 3.88 (q, J = 7.0 Hz, 2H), 3.63 - 3.58 (m, 5H), 1.25 (t, J = 7.0 Hz, 3H).

[0279] Process B : 2-{4-[2-(morpholin-4-yl)ethyl]phenyl}acetic acid To a solution of the product from Step A (173 mg, 0.79 mmol, 1 equiv.) in acetone (5 mL) was added 2 M aqueous HCl (0.79 mL, 1.57 mmol, 2 equiv.), and the mixture was stirred at 45 °C for 2 h. The mixture was allowed to cool to room temperature, diluted with DCM, dried (PTFE phase separator), and concentrated in vacuo to give the intermediate, which was dissolved in DCM (5 mL). Morpholine (82 μL, 0.94 mmol, 1.2 equiv.) and NaBH(OAc) (331 mg, 1.56 mmol, 2 equiv.) were added, and the mixture was stirred at room temperature for 2 h. A mixture of the ester and acid was observed. Purification by automated flash chromatography, eluting with a gradient of 0–20% MeOH in DCM, gave the ester; the acid was then eluted with MeOH, and the solvent was removed in vacuo. The residue was dissolved in DCM and loaded onto a pre-wetted (DCM) SCX-2 cartridge, washed with DCM, MeOH and eluted with 10% NH3 / MeOH in DCM to give the title product (54 mg, 0.22 mmol, 28%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.13 (s, 4H), 3.59 - 3.54 (m, 4H), 3.45 (s, 2H), 2.73 - 2.65 (m, 2H), 2.50 - 2.45 (m, 2H), 2.44 - 2.68 (m, 4H).

[0280] Process C N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethyl]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxamide Using general procedure 4a and preparation IVa (130 mg, 0.2 mmol, 1 equiv.) as the appropriate amine and the product from step B (65 mg, 0.26 mmol, 1.3 equiv.) as the appropriate carboxylic acid, the title product was obtained (67 mg, 0.08 mmol, 38%). HRMS C54 H 57 Calculated for N7O5: 883.4421, Found: 884.4513 [M+H] +

[0281] Example 39: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-{2-[cis-2,6-dimethylmorpholin-4-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0282] Process A: Methyl 2-[4-[2-(cis-2,6-dimethylmorpholin-4-yl)ethoxy]phenyl]acetate, methyl 2-[4-[2-((2R,6R)-2,6-dimethylmorpholin-4-yl)ethoxy]phenyl]acetate and methyl 2-[4-[2-((2S,6S)-2,6-dimethylmorpholin-4-yl)ethoxy]phenyl]acetate (mixture of diastereomers) Using general procedure 7d, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (1.4 g, 5.10 mmol) as the appropriate alkyl halide and 2,6-dimethylmorpholine (1.8 g, 3.0 equiv.) as the appropriate amine, the desired product was obtained (1.4 g, 90%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.15 (dm, 2H), 6.88 (dm, 2H), 4.04 (t, 2H), 3.88 / 3.54 (m / m, 2H), 3.59 (s, 3H), 2.81 / 2.49 / 2.17 / 1.70 (m+dd / m+dd, 4H), 2.65 (t, 2H), 2.59 (s, 2H), 1.11 / 1.03 (d / d, 6H);13 C NMR (500 MHz, DMSO-d6) δ ppm 172.4, 157.9 / 157.8, 130.8, 126.7, 114.9 / 114.8, 71.4 / 66.2, 65.8 / 65.6, 59.8 / 59.2, 57.4 / 57.1, 52.1, 39.7, 19.5 / 18.6. HRMS-ESI (m / z) [M+H] + C 17 H 26 Calculated NO4: 308.1856, Measured: 308.1860.

[0283] The diastereomers of the desired products were separated on a Daicel AS-V chiral column (100*500 mm, 20 μm) using 7:93 i-PrOH-heptane+0.05% DEA as the eluent to give Diastereomer 1, Diastereomer 2 Enantiomer 1 (99.9% ee) and Diastereomer 2 Enantiomer 2 (99.9% ee).

[0284] Process B: 2-[4-[2-[cis-2,6-dimethylmorpholin-4-yl]ethoxy]phenyl]acetic acid (from diastereomer 1) Using general procedure 8, starting from diastereomer 1 (420 mg, 1.37 mmol) from step A, the desired product was obtained (360 mg, 67%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.14 (d, 2H), 6.85 (d, 2H), 4.04 (t, 2H), 3.55 (m, 2H), 3.42 (s, 2H), 2.81 / 1.71 (dt+dd, 4H), 2.65 (t, 2H), 1.03 (d, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.8, 157.6, 130.8, 128.2, 114.6, 71.4, 65.6, 59.8, 57.1, 41.0, 19.5. HRMS-ESI (m / z) [M+H] + C16 H 24 Calculated NO4: 294.1705, Measured: 294.1702.

[0285] Process C: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-{2-[cis-2,6-dimethylmorpholin-4-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of step B (141 mg, 4.8 equiv) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the title compound (60 mg, 62%). HRMS-ESI (m / z) [M+H] + C 56 H 62 Calculated value for N7O6: 928.4761, Found value: 928.4755.

[0286] Example 40: 5-[2-(2-{4-[(8aS)-7,7-difluoro-hexahydropyrrolo[1,2-a]piperazin-2-yl]-2-fluorophenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0287] Process A : Methyl 2-{4-[(8aS)-7,7-difluoro-hexahydropyrrolo[1,2-a]piperazin-2-yl]-2-fluorophenyl}acetate Methyl 2-(4-bromo-2-fluorophenyl)acetate (0.3 mL, 1.82 mmol, 1 equiv.), (8aS)-7,7-difluoro-octahydropyrrolo[1,2-a]pyrazine dihydrochloride (535 mg, 2.28 mmol, 1.25 equiv.) and CsCO 3( The mixture (2.37 g, 7.29 mmol, 4 equiv.) was combined with toluene (10 mL) and the mixture was sparged with N2. DavePhos (72 mg, 0.18 mmol, 0.1 equiv.) and Pd2dba3 (83 mg, 0.09 mmol, 0.05 equiv.) were added, and the mixture was heated under microwave irradiation at 130 °C for 1 h. Additional DavePhos (36 mg, 0.09 mmol, 0.05 equiv.) and Pd2dba3 (42 mg, 0.045 mmol, 0.025 equiv.) were added, and the mixture was sparged with N2 and then heated under microwave irradiation at 130 °C for 2 h. The mixture was allowed to cool to room temperature and partitioned between DCM and saturated aqueous NaHCO3. The phases were separated (PTFE phase separator), and the organic phase was concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0-65% EtOAc in heptane gave the title product (181 mg, 0.55 mmol, 30%). LRMS calculated value C 16 H 19 F3N2O2: 328.1, Measured 329.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.16 - 7.10 (m, 1H), 6.79 - 6.69 (m, 2H), 3.86 - 3.76 (m, 1H), 3.71 - 3.64 (m, 1H), 3.60 (s, 3H), 3.59 - 3.57 (m, 2H), 3.47 - 3.37 (m, 1H), 3.04 - 2.96 (m, 1H), 2.79 (td, J= 11.8, 3.3 Hz, 1H), 2.63 - 2.28 (m, 5H), 2.06 - 1.87 (m, 1H).

[0288] Process B: {4-[(8aS)-7,7-difluoro-hexahydropyrrolo[1,2-a]piperazin-2-yl]-2-fluorophenyl}acetic acid To a solution of the product from Step A (181 mg, 0.55 mmol, 1 equiv) in MeOH (4 mL) was added LiOH·HO (46 mg, 1.1 mmol, 2 equiv) and the mixture was heated at 100 °C under microwave irradiation for 30 min. The mixture was allowed to cool to room temperature, neutralized with 2 M aqueous HCl, and concentrated in vacuo. Purification by reverse-phase automated flash chromatography eluting with a gradient of 10–95% MeCN in water gave the title product (124 mg, 0.39 mmol, 72%). LRMS C 15 H 17 Calculated value for F3N2O2: 314.1, Found value: 315.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.14 - 7.05 (m, 1H), 6.74 - 6.64 (m, 2H), 3.83 - 3.73 (m, 1H), 3.69 - 3.61 (m, 1H), 3.48 - 3.33 (m, 3H), 3.03 - 2.96 (m, 1H), 2.77 (td, J = 11.8, 3.3 Hz, 1H), 2.63 - 2.45 (m, 3H), 2.43 - 2.28 (m, 2H), 2.06 - 1.86 (m, 1H).

[0289] Process C 5-[2-(2-{4-[(8aS)-7,7-difluoro-hexahydropyrrolo[1,2-a]piperazin-2-yl]-2-fluorophenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and preparation IVa (130 mg, 0.2 mmol, 1 equiv.) as the appropriate amine and the product from step B (69 mg, 0.22 mmol, 1.1 equiv.) as the appropriate carboxylic acid, the title product was obtained (80.3 mg, 0.08 mmol, 42%). HRMS C 55 H 55 Calculated for F3N8O4: 948.4298, Found: 949.4376 [M+H] +

[0290] Example 41: N-(5-cyano-1-ethyl-2-methyl-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-[2-[4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide [ka]

[0291] Process A: 4-Bromo-1-ethyl-5-methyl-pyrrole-2-carbonitrile Using general procedure 7c, starting with 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (500 mg, 2.7 mmol.) and ethanol (0.3 ml, 1.9 equiv.) as the appropriate alcohol, gave the title product (500 mg, 87%). GC-MS (m / z) [M+H] + C8H 10 Calculated value of BrN2: 213, Found value: 212 / 215.

[0292] Process B: 4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-1-ethyl-5-methyl-pyrrole-2-carbonitrile Using general procedure 1b, starting from the product of step A (400 mg, 1.87 mmol) as the appropriate aryl bromide and preparation IIIa (629 mg, 1.5 equiv) as the appropriate amine, gave the title product (570 mg, 85%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.87 (s, 1H), 6.75 (s, 1H), 6.60 (m, 2H), 6.50 (m, 2H), 4.02 (q, 2H), 1.28 (t, 3H), 0.92 (s, 9H), 0.12 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 129.9, 124.9, 120.6, 115.7, 114.9, 114.2, 98.7, 41.3, 26.1, 16.5, -4.1. HRMS-ESI (m / z) [M+H] + C 20 H 30 Calculated N3OSi value: 356.2153, measured value 356.2152.

[0293] Process C: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-N-(5-cyano-1-ethyl-2-methyl-pyrrol-3-yl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide The title compound was obtained using the method described in Preparation VIIb and the product from Step B as the appropriate aniline for amide formation. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.40-6.32 (m, 11H), 5.54-4.89 (s, 1H), 5.35-2.08 (m, 14H), 3.41-3 (s, 3H), 2.44-1.81 (s, 6H), 1.36-0.44 (m, 6H), 0.88 (s, 9H), 0.12 (s, 6H). HPLC-MS-ESI: (m / z) [M+H] + C 47 H 57 Calculated value of N6O3Si: 781.4, Found value 781.4.

[0294] Process D: N-(5-cyano-1-ethyl-2-methyl-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-[2-[4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide Using general procedure 4c, starting with preparation Va (65 mg, 2.5 equiv.) as the appropriate acid and the product of step C (90 mg, 0.097 mmol) as the appropriate amine, the desired product was obtained (15.4 mg, 17%). HRMS-ESI (m / z) [M+H] + C 55 H 60 Calculated value of N7O6: 914.4600, Found value: 914.4600.

[0295] Example 42: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-{2-[(2R or S,6R or S)-2,6-dimethylmorpholin-4-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0296] Process A: 2-[4-[2-[(2R or S, 6R or S)-2,6-dimethylmorpholin-4-yl]ethoxy]phenyl]acetic acid Using general procedure 8 and starting from diastereomer 2 enantiomer 2 (210 mg, 0.68 mmol) from step A of example 39, the desired product was obtained (150 mg, 56%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.90 (brs, 1H), 7.15 (d, 2H), 6.87 (d, 2H), 4.04 (t, 2H), 3.88 (m, 2H), 3.47 (s, 2H), 2.61 (m, 2H), 2.49 / 2.17 (dd+dd, 4H), 1.12 (d, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.5, 157.7, 130.8, 127.5, 114.8, 66.2, 65.8, 59.2, 57.4, 40.3, 18.6. HRMS-ESI (m / z) [M+H] + C 16 H 24 Calculated NO4: 294.1705, Measured: 294.1722.

[0297] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-{2-[(2R or S,6R or S)-2,6-dimethylmorpholin-4-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (111 mg, 3.6 equiv) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the title compound (60 mg, 62%). HRMS-ESI (m / z) [M+H] + C 56 H 62 Calculated value for N7O6: 928.4762, Found value: 928.4757.

[0298] Example 43: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and preparation IVb (130 mg, 0.18 mmol, 1 equiv) as the appropriate amine and preparation Vb (55 mg, 0.19 mmol, 1.1 equiv) as the appropriate carboxylic acid gave the title product (45.4 mg, 0.05 mmol, 26%). HRMS C 59 H 65 Calculated for FN8O6: 1000.5011, Found: 1001.5094 [M+H] +

[0299] Example 44: 5-{2-[2-(4-chloro-2-fluorophenyl)acetyl]-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl}-N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and preparation IVb (130 mg, 0.18 mmol, 1 equiv.) as the appropriate amine and 4-chloro-2-fluorophenylacetic acid (37 mg, 0.19 mmol, 1.1 equiv.) as the appropriate carboxylic acid, the title product was obtained (72.7 mg, 0.08 mmol, 45%). HRMS C 53H 53 Calculated for ClFN7O4: 905.3832, Found: 906.3913 [M+H] +

[0300] Example 45: 5-[2-(2-{4-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-fluorophenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0301] Process A: 2-[4-[(9aS)-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-fluoro-phenyl]acetic acid hydrochloride To a mixture of methyl 2-(4-bromo-2-fluorophenyl)acetate (240 mg, 0.8 equiv.) and (9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine, hydrogen chloride (1:2) (225 mg, 1.26 mmol) in 1,4-dioxane (5.0 mL), CsCO (469 mg, 1.1 equiv.) and [2-(2-aminoethyl)phenyl]chloropalladium, dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (1:1) (37 mg, 0.04 equiv.) was added. The reaction was stirred until complete conversion was observed. After filtration, the crude product was hydrolyzed and purified using general procedure 8, treated with 2 mL of 2 M HCl solution, and lyophilized to give the title compound (279 mg, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.19 (brs, 1H), 7.18 (t, 1H), 6.84 (dd, 1H), 6.76 (dd, 1H), 4.00 / 3.70 (dd+dd, 2H), 3.97 (dd, 2H), 3.90 / 3.30 (dt+dd, 2H), 3.85 / 2.94 (dt+dd, 2H), 3.50 (s, 2H), 3.48 (brm, 1H), 3.43 / 3.22 (dd+dd, 2H), 3.35 / 3.20 (dd+dd, 2H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 172.5, 161.8, 150.5, 132.6, 113.3, 111.5, 103.0, 65.5, 63.9, 60.2, 51.7, 51.4, 46.3, 45.4, 34.0. HRMS-ESI (m / z) [M+H] + C 15 H 19 Calculated value of FN2O3: 295.1452, Found value: 295.1453.

[0302] Process B: 5-[2-(2-{4-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-fluorophenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (150 mg, 4.3 equiv) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the title compound (51 mg, 53%). HRMS-ESI (m / z) [M+H] + C 55 H 58 Calculated value for FN8O5: 929.4509, Found value: 929.4513.

[0303] Example 46: 5-[2-(2-{2-chloro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0304] Process A: 2-[2-chloro-4-(2-morpholinoethoxy)phenyl]acetic acid, TEA salt Using general procedure 7b, then general procedure 8, starting with methyl 2-(2-chloro-4-hydroxy-phenyl)acetate (150 mg, 0.75 mmol) as the appropriate phenol and 2-morpholinoethanol (147 mg, 1.5 equiv.) as the appropriate alcohol, followed by a purification step by automated flash chromatography using DCM and MeOH (1% TEA) as eluents gave the TEA salt of the title product (236 mg, 79%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.24 (brs, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.88 (dd, 1H), 4.09 (t, 2H), 3.62 (s, 2H), 3.57 (m, 4H), 2.67 (t, 2H), 2.6-2.3 (brs, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 133.1, 115.3, 114.2, 66.6, 66.2, 57.3, 54, 38.2. HRMS-ESI (m / z) [M+H] + C 14 H 19 Calculated value for ClNO4: 300.0997, Found value: 300.0998.

[0305] Process B: 5-[2-(2-{2-chloro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (122 mg, 2.6 equiv) as the appropriate carboxylic acid and preparation VIIb (90 mg, 0.12 mmol) as the appropriate amine, gave the title compound (68.8 mg, 63%). HRMS-ESI (m / z) [M+H] + C 54 H 57 Calculated value for ClN7O6: 934.4053, found 934.4058.

[0306] Example 47: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-{2-[4-(2,2-difluoroethyl)piperazin-1-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0307] Process A: 2-[4-[2-[4-(2,2-difluoroethyl)piperazin-1-yl]ethoxy]phenyl]acetic acid Using general procedure 7d and then general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (160 mg, 0.58 mmol) as the appropriate alkyl halide and 1-(2,2-difluoroethyl)piperazine (245 mg, 1.2 equiv.) as the appropriate amine, the title product was obtained (145 mg, 76%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.2 (brs, 1H), 7.16 (d, J = 8.5 Hz, 2H), 8.87 (d, 8.5 Hz, 2H), 6.27 (t, J = 4.2 Hz, 0.25H), 6.13 (t, J = 4.2 Hz, 0.5H), 5.99 (t, J = 4.2 Hz, 0.25H), 4.05 (t, J = 5.6 Hz, 2H), 3.34 (s, 8H), 2.70 (m+m, 4H), 2.53 (m, 2H). HPLC-MS-ESI (m / z) [M+H] + C 16 H 23 Calculated value of F2N2O3: 329.1671, Found value: 329.2.

[0308] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-{2-[4-(2,2-difluoroethyl)piperazin-1-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (60 mg, 1.5 equiv.) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.10 mmol) as the appropriate amine, gave the title product (38.8 mg, 30%). HRMS-ESI (m / z) [M+H] + C 56 H 61Calculated value for F2N8O5: 963.4727, Found: 963.4729.

[0309] Example 48: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{4-[1-(2,2-difluoroethyl)piperidin-4-yl]-2-fluorophenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0310] Process A : tert-Butyl 4-[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate Methyl 2-(4-bromo-2-fluorophenyl)acetate (0.33 mL, 2.02 mmol, 1 equiv.), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid, pinacol ester (688 mg, 2.23 mmol, 1.1 equiv.) and KCO 3( Pd(dppf)Cl (839 mg, 6.07 mmol, 3 equiv.) was combined with THF (10 mL) and water (1 mL), and the mixture was sparged with N2. Pd(dppf)Cl2 DCM (83 mg, 0.1 mmol, 0.05 equiv.) was added, and the mixture was heated at 110 °C under microwave irradiation for 1 h. The mixture was allowed to cool to room temperature and partitioned between DCM and brine. The phases were separated, and the organic phase was dried (PTFE phase separator) and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 to 31% EtOAc in heptane gave the title product (707 mg, 2.03 mmol, quantitative). LRMS C 19 H 24 Calculated for FNO4: 349.2, Found: 250.1 [M-Boc+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.36 - 7.20 (m, 3H), 6.28 - 6.18 (m, 1H), 4.06 - 3.94 (m, 2H), 3.73 - 3.70 (m, 2H), 3.62 (s, 3H), 3.53 (t, J = 5.7 Hz, 2H), 2.48 - 2.42 (m, 2H), 1.42 (s, 9H).

[0311] Process B : tert-Butyl 4-[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]piperidine-1-carboxylate To a solution of the product from step A (707 mg, 2.02 mmol, 1 equiv) in MeOH (30 mL) was added 10% Pd / C (25 mg). The mixture was evacuated and back-filled with N, then evacuated and flushed with H, and then shaken under an atmosphere of H at room temperature for 4 h. The mixture was filtered through a Celite cartridge, washed with MeOH, and the solvent was removed in vacuo to give the title product (679 mg, 1.93 mmol, 95%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.25 (t, J = 7.9 Hz, 1H), 7.11 - 7.02 (m, 2H), 4.13 - 3.99 (m, 2H), 3.70 - 3.65 (m, 2H), 3.61 (s, 3H), 2.92 - 2.63 (m, 3H), 1.79 - 1.70 (m, 2H), 1.54 - 1.37 (m, 11H).

[0312] Process C : Methyl 2-[2-fluoro-4-(piperidin-4-yl)phenyl]acetate TFA (3 mL) was added to a solution of the product from Step B (679 mg, 1.93 mmol, 1 equiv.) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, and the residue was partitioned between DCM and saturated aqueous NaHCO3. The organic phase was collected (PTFE phase separator) and concentrated in vacuo to give the title product (488 mg, 1.94 mmol, 100%). LRMS C 14 H 18 Calculated FNO2: 251.1, Found 252 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.25 (t, J = 8.1 Hz, 1H), 7.07 - 6.99 (m, 2H), 3.69 - 3.66 (m, 2H), 3.62 (s, 3H), 3.07 - 2.99 (m, 2H), 2.65 - 2.54 (m, 3H), 1.73 - 1.65 (m, 2H), 1.56 - 1.43 (m, 2H).

[0313] Process D : Methyl 2-{4-[1-(2,2-difluoroethyl)piperidin-4-yl]-2-fluorophenyl}acetate 2-Bromo-1,1-difluoroethane (90 μL, 1.05 mmol, 1.1 equiv.) was dissolved in the product from Step C (240 mg, 0.96 mmol, 1 equiv.) and KCO in DMF (2 mL) under a N atmosphere. 3( To a stirred suspension of 1,2-dimethyl-3,4-dichloro-2 ... LRMS C 16 H 20 Calculated value for F3NO2: 315.1, Found value: 316.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.24 (t, J = 8.1 Hz, 1H), 7.10 - 7.01 (m, 2H), 6.31 - 5.98 (m, 1H), 3.70 - 3.65 (m, 2H), 3.61 (s, 3H), 3.03 - 2.95 (m, 2H), 2.74 (td, J= 15.7, 4.4 Hz, 2H), 2.56 - 2.44 (m, 1H), 2.29 - 2.20 (m, 2H), 1.77 - 1.69 (m, 2H), 1.69 - 1.56 (m, 2H).

[0314] Process E {4-[1-(2,2-difluoroethyl)piperidin-4-yl]-2-fluorophenyl}acetic acid To a solution of the product from step D (164 mg, 0.52 mmol, 1 equiv) in MeOH (4 mL) was added LiOH·HO (44 mg, 1.04 mmol, 2 equiv) and the mixture was heated at 100 °C under microwave irradiation for 30 min. The mixture was allowed to cool to room temperature, neutralized with 2 M aqueous HCl, and concentrated in vacuo. Purification by reverse-phase automated flash chromatography eluting with a gradient of 10 to 100% MeCN in water gave the title product (139 mg, 0.46 mmol, 89%). LRMS C 15 H 18 Calculated value for F3NO2: 301.1, Found value: 302.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.42 (s, 1H), 7.23 (t, J= 8.1 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.15 (tt, J = 55.8, 4.3 Hz, 1H), 3.58 - 3.54 (m, 2H), 3.03 - 2.95 (m, 2H), 2.74 (td, J = 15.7, 4.4 Hz, 2H), 2.55 - 2.45 (m, 1H), 2.29 - 2.20 (m, 2H), 1.77 - 1.57 (m, 4H).

[0315] Process F N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{4-[1-(2,2-difluoroethyl)piperidin-4-yl]-2-fluorophenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and preparation IVa (130 mg, 0.2 mmol, 1 equiv.) as the appropriate amine and the product from step E (66 mg, 0.22 mmol, 1.1 equiv.) as the appropriate carboxylic acid, the title product was obtained (97.2 mg, 0.1 mmol, 52%). HRMS C 55 H 56 Calculated for F3N7O4: 935.4346, Found: 936.4436 [M+H] +

[0316] Example 49: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(3-fluoroazetidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0317] Process A: 2-[4-[2-(3-fluoroazetidin-1-yl)ethoxy]phenyl]acetic acid Using general procedure 7d and then general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (150 mg, 0.55 mmol) as the appropriate alkyl halide and 3-fluoroazetidine hydrochloride (122.5 mg, 2 equiv.) as the appropriate amine, the title product was obtained (108 mg, 77.6%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.88 (brs, 1H), 7.13 (m, 2H), 6.81 (m, 2H), 5.14 (dm, 1H), 3.91 (t, 2H), 3.61 / 3.17 (m+m, 2H), 3.39 (s, 2H), 2.79 (t, 2H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.8, 130.8, 114.5, 83.4, 66.8, 62.1, 57.9, 41.4. HRMS-ESI (m / z) [M+H] + C 13 H 17 Calculated FNO3: 254.1186, measured 254.1187.

[0318] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(3-fluoroazetidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (64 mg, 2.5 equiv.) as the appropriate carboxylic acid and preparation VIIb (70 mg, 0.091 mmol) as the appropriate amine, gave the title product (40.1 mg, 50%). HRMS-ESI (m / z) [M+H] + C 53 H 55 Calculated value for FN7O: 888.4243, Measured value: 888.4247.

[0319] Example 50: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0320] Process A: 2-[4-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]phenyl]acetic acid Using general procedure 7d and then general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (150 mg, 0.55 mmol) and 3,3-difluoropyrrolidine hydrochloride (157.7 mg, 2 equivalents) as reactants, the title product was obtained (48 mg, 31%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.26 (brs, 1H), 7.15 (m, 2H), 6.87 (m, 2H), 4.04 (t, 2H), 3.47 (s, 2H), 2.97 (t, 2H), 2.81 (t, 2H), 2.78 (t, 2H), 2.23 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ ppm 173.5, 131.1, 130.9, 114.7, 66.6, 62.1, 54, 52.6, 40.3, 35.7. HRMS-ESI (m / z) [M+H] + C 14 H 18 Calculated value of F2NO3: 286.1249, Found value: 286.1253.

[0321] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of step A (52 mg, 2.5 equiv.) as the appropriate carboxylic acid and preparation VIIb (50 mg, 0.065 mmol.) as the appropriate amine, gave the title product (25.1 mg, 42%). HRMS-ESI (m / z) [M+H] + C 54 H 56 Calculated value for F2N7O5: 920.4306, Found value: 920.4304.

[0322] Example 51: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{4-[2-(4,4-difluoropiperidin-1-yl)ethyl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0323] Process A : {4-[(E)-2-ethoxyethenyl]phenyl}acetic acid To a solution of the product from Example 38, Step A (360 mg, 1.63 mmol, 1 equiv.) in MeOH (5 mL) was added 2 M aqueous NaOH (0.82 mL, 1.63 mmol, 1 equiv.), and the mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo, acidified with 2 M aqueous HCl, and extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the title product (311 mg, 1.51 mmol, 92%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.24 - 7.14 (m, 3H), 7.14 - 7.08 (m, 2H), 5.80 (d, J = 13.0 Hz, 1H), 3.87 (q, J = 7.0 Hz, 2H), 3.48 (s, 2H), 1.24 (t, J = 7.0 Hz, 3H).

[0324] Process B {4-[2-(4,4-difluoropiperidin-1-yl)ethyl]phenyl}acetic acid To a solution of the product from Step A (222 mg, 1.08 mmol, 1 equiv.) in acetone (5 mL) was added 2 M aqueous HCl (0.54 mL, 1.08 mmol, 1 equiv.), and the mixture was stirred at room temperature for 18 h. The mixture was diluted with DCM, dried over MgSO4, and concentrated in vacuo. To a solution of the intermediate in DCM (5 mL) were added 4,4-difluoropiperidine (249 mg, 1.58 mmol, 1.2 equiv.) and TEA (220 μL, 1.58 mmol, 1.2 equiv.), followed by NaBH(OAc)3 (559 mg, 2.64 mmol, 2 equiv.), and the mixture was stirred at room temperature for 18 h. The mixture was quenched with MeOH, concentrated in vacuo, and purified by reverse-phase automated flash chromatography eluting with a gradient of 10–100% MeCN in water to give the title product (183 mg, 0.65 mmol, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.15 - 7.08 (m, 4H), 3.36 (s, 2H), 2.72 - 2.65 (m, 2H), 2.59 - 2.52 (m, 6H), 2.00 - 1.87 (m, 4H).

[0325] Process C N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{4-[2-(4,4-difluoropiperidin-1-yl)ethyl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and preparation IVa (110 mg, 0.17 mmol, 1 equiv.) as the appropriate amine and the product from step B (95 mg, 0.34 mmol, 2 equiv.) as the appropriate carboxylic acid, the title product was obtained (23 mg, 0.02 mmol, 15%). HRMS C 55 H 57 Calculated for F2N7O4: 917.4440, Found: 918.4522 [M+H] +

[0326] Example 52: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0327] Process A: tert-Butyl (3S)-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate To a solution of (S)-1,2,3,4-tetrahydroisoquinoline-3-methanol (2 g, 12.25 mmol, 1 equiv.) in DCM (50 mL) was added TEA (6.14 mL, 44.11 mmol, 3.6 equiv.) and di-tert-butyl dicarbonate (3.15 mL, 14.7 mmol, 1.2 equiv.), and the mixture was stirred at room temperature under N for 18 h. The mixture was diluted with saturated aqueous NaHCO. The organic layer was separated, washed with brine, dried over MgSO, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 to 100% EtOAc in heptane gave the title product (2.96 g, 11.23 mmol, 92%). LRMS C 15 H 21 Calculated NO3: 263.2, Found 164.0 [M-Boc+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.21 - 7.12 (m, 4H), 4.77 (t, J = 5.4 Hz, 1H), 4.61 (d, J= 16.7 Hz, 1H), 4.37 - 4.08 (br m, 2H), 3.38 - 3.24 (br m, 1H), 3.18 - 3.06 (br m, 1H), 2.93 - 2.79 (m, 2H), 1.43 (s, 9H).

[0328] Process B : tert-Butyl (3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate To a solution of the product from Step A (440 mg, 1.67 mmol, 1 equiv) in DMF (10 mL) cooled to 0 °C, NaH (60% dispersion in mineral oil; 100 mg, 2.51 mmol, 1.5 equiv) was added and the mixture was stirred for 10 min. Iodomethane (156 μL, 2.51 mmol, 1.5 equiv) was added and the reaction was allowed to warm to room temperature. It was then stirred for 18 h. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3, the layers were separated, and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title product (450 mg, 1.62 mmol, 97%). LRMS C 16 H 23 Calculated NO3: 277.2, Found 178.0 [M-Boc+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.20 - 7.13 (m, 4H), 4.62 (d, J = 16.8 Hz, 1H), 4.56 - 4.33 (br m, 1H), 4.28 - 4.08 (br m, 1H), 3.29 -3.17 (m, 4H), 3.13 - 3.04 (m, 1H), 3.00 - 2.89 (m, 1H), 2.80 - 2.71 (m, 1H), 1.43 (s, 9H).

[0329] Process C (3S)-3-(Methoxymethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride To a solution of the product from Step B (450 mg, 1.62 mmol, 1 equiv) in THF (10 mL) was added 4 M HCl in dioxane (10 mL) and the mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and then triturated with EtO and heptane to give the title product (257 mg, 1.45 mmol, 89%). LRMS C 11 H 15 Calculated NO: 177.1, Found 178.0 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.85 - 9.37 (br m, 2H), 7.30 - 7.18 (m, 4H), 4.36 - 4.17 (m, 2H), 3.75 - 3.59 (m, 3H), 3.38 (s, 3H), 3.03 - 2.89 (m, 2H).

[0330] Process D Benzyl 6-[4-(ethoxycarbonyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 4b and preparation I (450 mg, 0.94 mmol, 1 equiv) as the appropriate carboxylic acid and the product from step C (222 mg, 1.04 mmol, 1.1 equiv) as the appropriate amine, gave the title product, which was used directly in the subsequent step without further purification. LRMS C 38 H 41 Calculated for N3O6: 635.3, Found: 636.4 [M+H] +

[0331] Process E : Ethyl 5-(7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2-dimethylpyrrole-3-carboxylate To a solution of the product from step D (600 mg, 0.94 mmol, 1 equiv) in MeOH (25 mL) was added 10% Pd / C (25 mg). The mixture was evacuated and back-filled with N, then evacuated and flushed with H, and then shaken under an atmosphere of H for 18 h at room temperature. The mixture was filtered through a Celite cartridge and washed with MeOH. The solvent was removed in vacuo, and the residue was loaded onto a pre-washed (MeOH) 10 g SCX-2 cartridge, washed with DCM and MeOH, and the product was then eluted with 4:1 DCM / 7M NH in MeOH. The solvent was removed in vacuo to give the title product, which was used directly in the subsequent step without further purification. LRMS C 30 H 35 Calculated for N3O4: 501.3, Found: 502.4 [M+H] +

[0332] Process F tert-Butyl 6-[4-(ethoxycarbonyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate To a solution of the product from step E (480 mg, 0.96 mmol, 1 equiv.) in THF (10 mL) and water (2 mL), di-tert-butyl dicarbonate (0.21 mL, 1 mmol, 1.05 equiv.) and TEA (0.27 mL, 1.91 mmol, 2 equiv.) were added, and the mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, and the residue was partitioned between EtOAc and saturated aqueous NH4Cl. Water was added, the phases were separated, and the organic phase was washed with brine. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title product (476 mg, 0.79 mmol, 83%). LRMS C 35 H 43 Calculated for N3O6: 601.3, Found: 602.4 [M+H] +

[0333] Process G5-[2-(tert-butoxycarbonyl)-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxylic acid To a solution of the product from step F (476 mg, 0.79 mmol, 1 equiv) in MeOH (10 mL) and water (2 mL) was added LiOH·HO (133 mg, 3.16 mmol, 4 equiv), and the mixture was refluxed at 100 °C for 48 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The aqueous residue was neutralized with 1 M aqueous HCl and extracted with DCM. The combined organic extracts were dried over MgSO and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 20 to 100% EtOAc in heptane gave the title product (318 mg, 0.55 mmol, 70%). LRMS C 33 H 39 Calculated for N3O6: 573.3, Found: 574.4 [M+H] +

[0334] Process H : 1,5-dimethyl-4-({4-[(triisopropylsilyl)oxy]phenyl}amino)pyrrole-2-carbonitrile Using general procedure 1a and the product from preparation IVa, step A (7.99 g, 40.14 mmol, 1 equiv.) and preparation IIIb (12.79 g, 48.17 mmol, 1.2 equiv.) as the appropriate aniline, gave the title product (10.68 g, 27.84 mmol, 69%). LRMS C 22 H 33 Calculated for N3OSi: 383.2, Found: 384.4 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 6.86 (s, 1H), 6.72 (s, 1H), 6.67 - 6.58 (m, 2H), 6.55 - 6.46 (m, 2H), 3.61 (s, 3H), 2.08 (s, 3H), 1.26 - 1.10 (m, 3H), 1.04 (d, J = 7.2 Hz, 18H).

[0335] Process I tert-Butyl 6-{4-[(5-cyano-1,2-dimethylpyrrol-3-yl)({4-[(triisopropylsilyl)oxy]phenyl})carbamoyl]-1,5-dimethylpyrrol-2-yl}-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 2a and the product from step G (300 mg, 0.52 mmol, 1 equiv) as the appropriate acid and the product from step H (321 mg, 0.84 mmol, 1.6 equiv) as the appropriate aniline, gave the title product (318 mg, 0.34 mmol, 65%). LRMS C 55 H 70 Calculated for N6O6Si: 938.5, Found: 939.6 [M+H] +

[0336] Process J N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-(7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2-dimethyl-N-{4-[(triisopropylsilyl)oxy]phenyl}pyrrole-3-carboxamide Using general procedure 3b and the product from step I (318 mg, 0.34 mmol, 1 equiv) as the appropriate silyl-derivative gave the title product (176 mg, 0.21 mmol, 62%). LRMS C 50 H 62Calculated for N6O4Si: 838.5, Found: 839.6 [M+H] +

[0337] Process K N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethyl-N-{4-[(triisopropylsilyl)oxy]phenyl}pyrrole-3-carboxamide Using general procedure 4a and the product from step J (88 mg, 0.1 mmol, 1 equiv) as the appropriate amine and the product from example 34, step B (36 mg, 0.13 mmol, 1.2 equiv) as the appropriate carboxylic acid gave the title product (106 mg, 0.1 mmol, 92%). LRMS C 65 H 79 FN6O7Si) calculated 1102.6, found 1103.4 [M+H] +

[0338] Process L N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 3c and the product from step K (106 mg, 0.1 mmol, 1 equiv) as the appropriate silyl-derivative gave the title product (41.7 mg, 0.04 mmol, 46%). HRMS C 56 H 59 Calculated for FN6O7: 946.4429, Found: 947.4509 [M+H] +

[0339] Example 53: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(4-fluoropiperidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0340] Process A: 2-[4-[2-(4-fluoro-1-piperidyl)ethoxy]phenyl]acetic acid Using general procedure 7d and then general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (160 mg, 0.59 mmol) as the appropriate alkyl halide and 4-fluoropiperidine hydrochloride (245 mg, 3.0 equiv.) as the appropriate amine, followed by an automated flash chromatographic purification step using DCM and MeOH (1% TEA) as eluents gave the title product (157 mg, 95%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.07 (br., 1H), 7.15 (dm, 2H), 6.87 (dm, 2H), 4.67 (m, 1H), 4.04 (t, 2H), 3.47 (s, 2H), 2.70 (t, 2H), 2.63 / 2.41 (br+br., 4H), 1.85 / 1.70 (m+m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.5, 157.7, 130.8, 127.5, 114.7, 88.9, 66, 56.8, 50.1, 40.2, 31.6. HRMS-ESI (m / z) [M+H] + C 15 H 21Calculated FNO3: 282.1499, measured 282.1500.

[0341] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(4-fluoropiperidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (73 mg, 2.5 equiv.) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the title product (69 mg, 72%). HRMS-ESI (m / z) [M+H] + C 55 H 59 Calculated value for FN7O5: 916.4556, Found value: 916.4561.

[0342] Example 54: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-5-[2-[2-[2-fluoro-4-(2-tetrahydropyran-4-ylethoxy)phenyl]acetyl]-7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide [ka]

[0343] Process A : 1,2-Dimethyl-5-[7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxylic acid hydrochloride Using the procedure described in Step A of Preparation VIIa, starting from Preparation I (3.0 g, 6.3 mmol) as the appropriate carboxylic acid and 4-[[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl]morpholine dihydrochloride (2.3 g, 1.2 equivalents, the synthesis of which is disclosed in WO2015 / 011164 A1 as Preparation 2d) as the appropriate amine, the title compound was obtained (2.6 g, 69%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.54 / 11.44 (br / br., 1H), 9.67 / 9.55 (br+br., 2H), 7.66 (s, 1H), 7.33 / 7.22 (br / s, 1H), 7.13-6.85 (m, 4H), 6.32 / 6.11 (br / s, 1H), 5.38 (m, 1H), 4.65 / 4.05 (d+d, 2H), 4.39 / 4.25 (dm+dm, 2H), 4.11-3.78 (m, 4H), 3.76-2.94 (m, 4H), 3.46 / 3.09 (s / s, 3H), 3.40 (m, 2H), 3.30 / 3.13 (m+m, 2H), 3.15-2.99 (m, 2H), 2.77 / 2.41 (dd+d, 2H), 1.92 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 131.5 / 129.9, 127.6, 111.1, 63.1, 55.3, 52.6 / 50.4, 44.4, 43.8, 41.7, 40.8, 32.2 / 31.8, 29.8, 25.1, 11.1. HRMS-ESI (m / z) [M+H] + C 31 H 37 Calculated N4O4: 529.2809, Found 529.2814.

[0344] Process B: 5-[2-(9H-fluoren-9-ylmethoxycarbonyl)-7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethyl-pyrrole-3-carboxylic acid To the product of Step A (1.36 g, 2.3 mmol), NaHCO (437 mg, 2.3 equiv.) in 1,4-dioxane (13 mL) and water (13 mL) was added 9H-fluoren-9-ylmethyl carbonochloridate (643 mg, 1.1 equiv.), and the reaction mixture was stirred until complete conversion was observed. 2 M HCl solution (23 mL) was added, and after stirring for 15 minutes, the reaction mixture was diluted with DCM (100 mL). The organic phase was washed with brine (100 ml), dried, concentrated, and purified by flash chromatography using DCM and MeOH as eluents to give the title compound (1.1 g, 65%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.54 (brs, 1H), 11.07 (brd, 1H), 7.96-6.85 (m, 14H), 6.38-6.08 (s, 1H), 5.44-2.39 (m, 24H), 3.18-3.08 (s, 3H), 2.45-1.90 (s, 3H). HRMS-ESI (m / z) [M+H] + C 46 H 47 Calculated value of N4O6: 751.3490, Found value 751.3493.

[0345] Process C 9H-Fluoren-9-ylmethyl 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-(5-cyano-1,2-dimethyl-pyrrol-3-yl)carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 2b, starting with the product of step B (1.0 g, 1.3 mmol) as the appropriate acid and 4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-1,5-dimethyl-pyrrole-2-carbonitrile (548 mg, 1.2 equiv.) as the appropriate aniline, the title compound was obtained (1.18 g, 82%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (brs, 1H), 8.01-6.45 (m, 19H), 5.45-1.86 (m, 24H), 5.16-4.91 (s, 1H), 3.67-2.96 (s, 6H), 2.46-1.67 (s, 6H), 0.82 (s, 9H), 0.13-0.04 (s, 6H). HRMS-ESI (m / z) [M+H] + C 65 H 72 Calculated value for N7O6Si: 1074.5308, Found value: 1074.5307.

[0346] Process D N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-1,2-dimethyl-5-[7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide The product of step C (1.1 g, 1.0 mmol) in morpholine (5 mL) and DCM (5 mL) was stirred until complete conversion was observed. The reaction mixture was concentrated and purified by flash chromatography using DCM and MeOH as eluents to give the title compound (847 mg, 97%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.25-6.43 (m, 11H), 5.42-4.98 (s, 1H), 5.13-1.83 (m, 12H), 3.65-3.38 (m, 4H), 3.62-3.02 (s, 6H), 2.57-1.67 (m, 6H), 2.42-1.74 (s, 6H), 0.94-0.79 (s, 9H), 0.16-0.05 (s, 6H). HRMS-ESI (m / z) [M+H] + C 50 H 62 Calculated value for N7O4Si: 852.4624, Found value: 852.4619.

[0347] Process E: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-5-[2-[2-[2-fluoro-4-(2-tetrahydropyran-4-ylethoxy)phenyl]acetyl]-7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide Using general procedure 4c, starting with 2-[2-fluoro-4-(2-tetrahydropyran-4-ylethoxy)phenyl]acetic acid (56 mg, 2.0 equiv.) as the appropriate carboxylic acid and the product of step D (85 mg, 0.10 mmol) as the appropriate amine, the title compound was obtained (37 mg, 37%). HRMS-ESI (m / z) [M+H] + C 59 H 65 Calculated value for FN7O7: 1002.4924, Found: 1002.4926.

[0348] Example 55:N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(thiomorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka]

[0349] Process A: Methyl 2-[4-(2-thiomorpholinoethoxy)phenyl]acetate Using general procedure 7d and then general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (121 mg, 0.44 mmol) as the appropriate alkyl halide and thiomorpholine (55 mg, 3.0 equiv.) as the appropriate amine, gave the title product (88 mg, 53%). LCMS-ESI (m / z) [M+H] + C 14 H 20 Calculated NO4S: 282.1, Measured: 282.2.

[0350] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(thiomorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of step A (83 mg, 1.5 equiv.) as the appropriate carboxylic acid and preparation VIIb (150 mg, 0.20 mmol) as the appropriate amine, gave the expected product (115 mg, 64%). HRMS-ESI (m / z) [M+H] + C54 H 58 Calculated value for N7O5S: 916.4215, Found value: 916.4216.

[0351] Example 56: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-((2R)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide (diastereomer 1) [ka]

[0352] Process A: Methyl 2-[4-[2-((2R)-2-methylmorpholin-4-yl)ethoxy]phenyl]acetate and Methyl 2-[4-[2-((2S)-2-methylmorpholin-4-yl)ethoxy]phenyl]acetate Using general procedure 7d, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (320 mg, 1.17 mmol) as the appropriate alkyl halide and 2-methylmorpholine (355 mg, 3 equiv.) as the appropriate amine, the desired product was obtained (351 mg, quantitative). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.15 (dm, 2H), 6.88 (dm, 2H), 4.05 (t, 2H), 3.72 / 3.48 (dm+td, 2H), 3.59 (s, 3H), 3.59 (s, 2H), 3.49 (m, 1H), 2.81 / 1.78 (d+t, 2H), 2.74 / 2.08 (d+td, 2H), 2.66 (t, 2H), 1.03 (d, 3H); 13C NMR (125 MHz, DMSO-d6) δ ppm 172.4, 157.8, 130.8, 126.8, 114.8, 71.5, 66.3, 65.7, 60.5, 57.3, 53.4, 52.1, 39.7, 19.5. HRMS-ESI (m / z) [M+H] + C 16 H 24 Calculated NO4: 294.1700, Measured: 294.1702.

[0353] The enantiomers of the desired product were separated on an AD-3 chiral column (50 × 500 mm, 20 μm) using 50:50 EtOH-heptane + 0.05% DEA as the eluent to give Enantiomer 1 and Enantiomer 2. Starting with (2R)-2-methylmorpholine and (2S)-2-methylmorpholine, Enantiomer 1 was identified as (R) and Enantiomer 2 was identified as (S) based on comparison of the products of test reactions.

[0354] Process B: 2-[4-[2-[(2R)-2-methylmorpholin-4-yl]ethoxy]phenyl]acetic acid (from enantiomer 1) A solution of Enantiomer 1 (product of Step A) (160 mg, 0.545 mmol) in THF (5.5 mL) and water (2.7 mL) was treated with lithium hydroxide (46 mg, 2 equiv.). The reaction mixture was stirred for 18 h. The THF was removed in vacuo, and the aqueous residue was acidified to pH 5.5 with 2 M aqueous HCl and then evaporated. Purification by automated flash chromatography using DCM and MeOH (1% TEA) as eluent gave the title product (184 mg, quantitative, partial TEA salt). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.21 (brs, 1H), 7.16 (d, 2H), 6.88 (d, 2H), 4.09 (br, 2H), 3.75 / 3.51 (m+m, 2H), 3.54 (m, 1H), 3.48 (s, 2H), 2.83 / 2.72 (m+m, 4H), 2.12 / 1.81 (m+m, 2H), 1.05 (d, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 130.9, 114.8, 71.6, 66.2, 65.5, 57.4, 56.7, 40.2, 19.3. HRMS-ESI (m / z) [M+H] + C 15 H 22 Calculated NO4: 280.1543, Measured: 280.1544.

[0355] Process C: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-((2R)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide (diastereomer 1) Using general procedure 4c, starting from the product of step B (79 mg, 2 equiv.) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the desired product (45 mg, 47%). HRMS-ESI (m / z) [M+H] + C 55 H 60 Calculated value of N7O6: 914.4600, Found value: 914.4600.

[0356] Example 57:N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-((2S)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide (diastereomer 2) [ka]

[0357] Process A: 2-[4-[2-[(2S)-2-methylmorpholin-4-yl]ethoxy]phenyl]acetic acid (from enantiomer 2) Using general procedure 8, starting from the product of Example 56, Step A, Enantiomer 2 (167 mg, 0.569 mmol), gave the title product (150 mg, quantitative, partial TEA salt). HRMS-ESI (m / z) [M+H] + C 15 H 22 Calculated NO4: 280.1543, Measured: 280.1545.

[0358] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-((2S)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide (diastereomer 2) Using general procedure 4c, starting from the product of step A (85 mg, 2 eq.) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol.) as the appropriate amine, gave the title product (72 mg, 76%). HRMS-ESI (m / z) [M+H] + C55 H 60 Calculated value of N7O6: 914.4600, Found value: 914.4600.

[0359] Example 58: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-5-[2-(isoquinolin-3-ylmethyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxamide [ka] To a solution of Preparation IVa (90 mg, 0.14 mmol, 1 equiv.) in DCM (3 mL) was added isoquinoline-3-carboxaldehyde (33 mg, 0.21 mmol, 1.5 equiv.) and NaBH(OAc) (58 mg, 0.28 mmol, 2 equiv.), and the mixture was stirred at room temperature for 18 h. The mixture was partitioned between DCM and water. The phases were separated, and the organic phase was dried over MgSO and concentrated in vacuo. Purification by preparative HPLC automated flash chromatography (pH 4, then pH 9) eluting with a gradient of 5–95% MeCN in water gave the title product (16.3 mg, 0.02 mmol, 15%). HRMS C 50 H 47 Calculated value for N7O3: 793.3740, Found value: 794.3817 [M+H] +

[0360] Example 59: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{6-[2-(oxan-4-yl)ethoxy]pyridin-3-yl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka]

[0361] Process A: 2-[6-(2-tetrahydropyran-4-ylethoxy)-3-pyridyl]acetic acid To a solution of 2-(6-chloro-3-pyridyl)acetic acid (163 mg, 0.95 mmol) and 2-tetrahydropyran-4-ylethanol (239 mg, 1.9 equiv.) in 1,4-dioxane (1.0 mL) was added sodium tert-butoxide (280 mg, 3.0 equiv.). The mixture was then heated to 150 °C and stirred under microwave irradiation until complete conversion was observed. The reaction mixture was purified by HILIC chromatography (using ACN and 5 mM aqueous NH4HCO3 as eluents) to give the title compound (158 mg, 63%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (d, 1H), 7.57 (dd, 1H), 6.74 (d, 1H), 4.27 (t, 2H), 3.81 / 3.27 (dd+td, 4H), 3.51 (s, 2H), 1.65 (m, 1H), 1.64 (q, 2H), 1.60 / 1.20 (d+dd, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.2, 162.7, 147.4, 140.9, 124.3, 110.5, 67.5, 63.3, 37.3, 35.9, 33.1, 32.0. HRMS-ESI (m / z) [M+H] + C 14 H 20 Calculated NO4: 266.1387, Measured: 266.1386.

[0362] Process B:N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{6-[2-(oxan-4-yl)ethoxy]pyridin-3-yl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (150.0 mg, 4.3 equiv) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, gave the title compound (70.0 mg, 60%). HRMS-ESI (m / z) [M+H] + C 54 H 58 Calculated value for N7O6: 900.4443, Found value: 900.4444.

[0363] Example 60: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{2-[2-(4-{2-[methyl(oxetan-3-yl)amino]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka]

[0364] Process A: 2-[4-[2-[methyl(oxetan-3-yl)amino]ethoxy]phenyl]acetic acid Using general procedure 7d and then general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (250 mg, 0.91 mmol) as the appropriate alkyl halide and N-methyloxetan-3-amine (250 mg, 3.1 equiv.) as the appropriate amine, the desired product was obtained (180 mg, 90%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.08(br., 1H), 7.16(m, 2H), 6.87(m, 2H), 4.53 / 4.42 (t+t, 4H), 4.00 (t, 2H), 3.65 (br., 1H), 3.48 (s, 2H), 2.63 (br., 2H), 2.17 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.5, 130.9, 114.7, 75.3, 65.7, 59.1, 53.3, 40.2, 38.7. HRMS-ESI (m / z) [M+H] + C 14 H 20 NO4 calculated: 266.1387, found: 266.1387.

[0365] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{2-[2-(4-{2-[methyl(oxetan-3-yl)amino]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (170.0 mg, 4.9 equiv) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, gave the title compound (65.0 mg, 55%). HRMS-ESI (m / z) [M+H] + C 54 H 58 Calculated value for N7O6: 900.4448, Found value: 900.4436.

[0366] Example 61:N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(6-{2-[cyclopropyl(methyl)amino]ethoxy}pyridin-3-yl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0367] Process A: 2-[6-[2-[cyclopropyl(methyl)amino]ethoxy]-3-pyridyl]acetic acid To a solution of 2-(6-chloro-3-pyridyl)acetic acid (193 mg, 1.12 mmol) and 2-[cyclopropyl(methyl)amino]ethanol (666 mg, 5.1 equiv.) in 1,4-dioxane (0.5 mL) was added sodium tert-butoxide (288 mg, 2.7 equiv.), and the mixture was then heated at 150° C. under microwave irradiation until complete conversion was observed. The reaction mixture was purified by HILIC chromatography (using ACN:NHHCO as the eluent) to give the title compound (120 mg, 43%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.97 (d, 1H), 7.56 (dd, 1H), 6.71 (d, 1H), 4.32 (t, 2H), 3.45 (s, 2H), 2.83 (t, 2H), 2.32 (s, 3H), 1.71 (m, 1H), 0.41 / 0.28 (m+m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 173.4, 162.3, 147.3, 140.8, 125.1, 110.5, 63.5, 56.5, 43.3, 38.7, 38.0, 7.1. HRMS-ESI (m / z) [M+H] + C 13 H 18Calculated N2O3: 251.1390, Measured 251.1393.

[0368] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(6-{2-[cyclopropyl(methyl)amino]ethoxy}pyridin-3-yl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from the product of Step A (150.0 mg, 4.6 equiv) as the appropriate carboxylic acid and preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, gave the title compound (71.0 mg, 62%). HRMS-ESI (m / z) [M+H] + C 53 H 57 Calculated value of N8O5: 885.4446, Found value: 885.4447.

[0369] Example 62: N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)-N-{1-methylpyrazolo[3,4-b]pyridin-5-yl}pyrrole-3-carboxamide [ka]

[0370] Process A N-{4-[(tert-butyldimethylsilyl)oxy]phenyl}-1-methylpyrazolo[3,4-b]pyridin-5-amine Using general procedure 1a and 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (1 g, 4.72 mmol, 1 equiv.) as the appropriate aryl bromide and preparation IIIa (1.16 g, 5.19 mmol, 1.1 equiv.) as the appropriate aniline, the title product was obtained (732 mg, 2.06 mmol, 44%). LRMS C 19 H 26 Calculated N4OSi: 354.2, Found 355.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.32 (d, J = 2.5 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 6.99 - 6.92 (m, 2H), 6.79 - 6.73 (m, 2H), 4.01 (s, 3H), 0.95 (s, 9H), 0.17 (s, 6H).

[0371] Process B N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)-N-{1-methylpyrazolo[3,4-b]pyridin-5-yl}pyrrole-3-carboxamide Using general procedure 2a and preparation VIa (175 mg, 0.25 mmol, 1 equiv.) as the appropriate acid and the product from step A (135 mg, 0.38 mmol, 1.5 equiv.) as the appropriate aniline, gave the intermediate which was treated according to general procedure 3b to give the title product (37.4 mg, 0.04 mmol, 16%). HRMS C 54 H 56 Calculated for N8O6: 912.4323 Found, 913.4403 [M+H] +

[0372] Example 63:N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[(3R or S)-3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide (diastereomer 1) [ka]

[0373] Process A: 2-[4-((3R or S)-3-morpholinopyrrolidin-1-yl)phenyl]acetic acid (enantiomer 1) To a degassed solution of methyl 2-(4-bromophenyl)acetate (350 mg, 1.53 mmol) and 4-pyrrolin-3-ylmorpholine (358 mg, 1.5 equiv.) in 1,4-dioxane (5 mL / mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) [XPhos Palladacycle Gen. 1] (113 mg, 0.1 equiv.) and CsCO (996 mg, 2 equiv.) were added, and the mixture was stirred under N at 110 °C for 2 h. The mixture was allowed to cool to room temperature, filtered through a Celite pad, and purified by automated flash chromatography using DCM and methanol as eluents to give the racemic product as a brown solid (369 mg, 79%). The enantiomers of the desired product were separated on a Daicel OD chiral column (50 × 500 mm, 20 μm) using 15:85 IPA-heptane + 0.05% DEA as eluent to give Enantiomer 1 and Enantiomer 2. Enantiomer 1 was deprotected using general procedure 8. Purification by automated flash chromatography using DCM and MeOH (1% TEA) as eluent and lyophilization with hydrochloric acid gave the HCl salt of the title product as a brown solid (225 mg, quantitative). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.91 (brs, 1H), 7.05 (m, 2H), 6.5 (m, 2H), 3.64 (brs, 4H), 3.44 / 3.34 / 3.22 / 3.09 (brm, 4H), 3.40 (s, 2H), 2.98 (brs, 1H), 2.49 (brs, 4H), 2.18 / 1.88 (brs, 2H). HRMS-ESI (m / z) [M+H] + C 16 H 23 Calculated N2O3: 291.1703, Measured 291.1704.

[0374] Process B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[(3R or S)-3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide (diastereomer 1) Using general procedure 4c, starting from the product of Step A (85 mg, 2.5 equiv.) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the title product (64 mg, 66%). HRMS-ESI (m / z) [M+H] + C 56 H 61 Calculated value for N8O5: 925.4759, Found value: 925.4758.

[0375] Example 64:N-(5-cyano-1-isopropyl-2-methyl-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-[2-[4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide [ka]

[0376] Process A: 4-Bromo-1-isopropyl-5-methyl-pyrrole-2-carbonitrile Using general procedure 7c, starting with 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (70 mg, 0.38 mmol) and propan-2-ol (0.3 ml, 2.2 equiv) as the appropriate alcohol, gave the title product (45 mg, 51%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.12 (s, 1H), 4.61 (sept., 1H), 2.27 (s, 3H), 1.49 (d, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 134.1, 122.6, 114.7, 99.7, 95.3, 50.8, 22.3, 11.5. GC-MS (m / z) [M+H] + C9H 12 Calculated BrN2: 227, Measured 226 / 228.

[0377] Process B: 4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-1-isopropyl-5-methyl-pyrrole-2-carbonitrile Using general procedure 1b, starting from the product of step A (40 mg, 0.18 mmol) as the appropriate aryl bromide and preparation IIIa (59 mg, 1.5 equiv) as the appropriate aniline, gave the title product (41 mg, 63%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.83 (s, 1H), 6.78 (s, 1H), 6.60 (d, 2H), 6.49 (d, 2H), 4.56 (m, 1H), 2.12 (s, 3H), 1.51 (d, 6H), 0.92 (s, 9H), 0.11 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 146.7, 142.6, 130.2, 124.5, 120.6, 117.7, 116, 114.3, 96.5, 49.5, 26.1, 22.5, 18.4, 10.2, -4.0. HPLC-MS-ESI [M+H] + C 21 H 32 Calculated N3OSi: 370.2, Measured 370.2.

[0378] Process C: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-N-(5-cyano-1-isopropyl-2-methyl-pyrrol-3-yl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide The title compound was obtained using the method described in Preparation VIIb and the product from Step B as the appropriate aniline for amide formation. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.30-6.36 (m, 11H), 5.51-4.89 (s, 1H), 5.40-1.80 (m, 12H), 4.50 (brm, 1H), 3.50-2.99 (s, 3H), 2.44-1.80 (s, 6H), 1.46 (brd, 6H), 1.08-0.44 (d, 3H), 0.84 (s, 9H), -0.04 (s, 6H). HPLC-ESI-MS (m / z) [M+H] + C 48 H 59Calculated N6O3Si: 795.4, Found 795.4.

[0379] Process D: N-(5-cyano-1-isopropyl-2-methyl-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-[2-[4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide Using general procedure 4c, starting with preparation Va (46 mg, 0.157 mmol, 2.5 equiv) as the appropriate acid and the product of step C (50 mg, 0.063 mmol, 1 equiv) as the appropriate amine, the desired product was obtained (24.7 mg, 42%). HRMS-ESI (m / z) [M+H] + C 56 H 62 Calculated value for N7O6: 928.4756, Found value: 928.4755.

[0380] Example 65: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)-N-phenylpyrrole-3-carboxamide [ka]

[0381] Process A : 1,5-dimethyl-4-(phenylamino)pyrrole-2-carbonitrile Using general procedure 1a and the product from preparation IVa, step A (10 g, 50.24 mmol, 1 equiv.) and aniline (5.5 mL, 60.29 mmol, 1.2 equiv.) as the appropriate aryl bromide gave the title product (6.36 g, 30.12 mmol, 60%). LRMS C 13 H 13 N3 calculated: 211.1, found: 212.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.17 (s, 1H), 7.10 - 7.02 (m, 2H), 6.77 (s, 1H), 6.61 - 6.54 (m, 3H), 3.63 (s, 3H), 2.09 (s, 3H).

[0382] Process B N-(5-cyano-1,2-dimethylpyrrol-3-yl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)-N-phenylpyrrole-3-carboxamide General procedure 2a and purification by preparative HPLC automated flash chromatography (at pH 9) using preparation VIa (163 mg, 0.24 mmol, 1 equiv.) as the appropriate acid and the product from step A (75 mg, 0.35 mmol, 1.5 equiv.) as the appropriate aniline, eluting with a gradient of 5 to 95% MeCN in water, gave the title product (10.3 mg, 0.01 mmol, 5%). HRMS C 54 H 57 Calculated for N7O5: 883.4421, Found: 884.4511 [M+H] + .

[0383] Example 66: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide [ka] Using general procedure 4a and preparation IVb (142 mg, 0.19 mmol, 1 equiv) as the appropriate amine and preparation Vc (56 mg, 0.21 mmol, 1.1 equiv) as the appropriate carboxylic acid gave the title product (49.7 mg, 0.05 mmol, 26%). HRMS C 60 H 67 Calculated for N7O6: 981.5153, Found: 982.5237 [M+H] +

[0384] Example 67: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide [ka] Using general procedure 4a and preparation IVb (142 mg, 0.19 mmol, 1 equiv) as the appropriate amine and preparation Va (56 mg, 0.21 mmol, 1.1 equiv) as the appropriate carboxylic acid gave the title product (71 mg, 0.07 mmol, 37%). HRMS C 59 H 66 Calculated for N8O6: 982.5105, Found: 983.5185 [M+H] +

[0385] Example 68:N-[5-cyano-1-(2-methoxyethyl)-2-methyl-pyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-[2-[4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide [ka]

[0386] Process A: 4-Bromo-1-(2-methoxyethyl)-5-methyl-pyrrole-2-carbonitrile Using general procedure 7c, starting with 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (100 mg, 0.54 mmol) and 2-methoxyethanol (80 mg, 2 equiv.) as the appropriate alcohol, gave the title product (100 mg, 71%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.07 (s, 1H), 4.20 (t, 2H), 3.56 (t, 2H), 3.22 (s, 3H), 2.24 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 134.8, 120.8, 113.7, 103.4, 95.4, 71.1, 58.8, 47.2, 11.2. GC-MS (m / z) [M+H] + C9H 12 Calculated for BrNO: 243, Found: 243.

[0387] Process B: 4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-1-(2-methoxyethyl)-5-methyl-pyrrole-2-carbonitrile Using general procedure 1b, starting from the product of step A (100 mg, 0.41 mmol) as the appropriate aryl bromide and preparation IIIa (138 mg, 1.5 equiv) as the appropriate aniline, gave the title product (120 mg, 76%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.88 (s, 1H), 6.75 (s, 1H), 6.60 (dm, 2H), 6.49 (dm, 2H), 4.15 (t, 2H), 3.59 (t, 2H), 3.24 (s, 3H), 2.10 (s, 3H), 0.92 (s, 9H), 0.12 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 146.7, 142.5, 130.7, 124.8, 120.6, 115.8, 114.9, 114.2, 100.1, 71.4, 58.8, 46.2, 26.1, 9.9, -4.1. HRMS-ESI (m / z) [M+H] + C 21 H 32 Calculated value of N3O2Si: 386.2259, Found value: 386.2259.

[0388] Process C: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-N-[5-cyano-1-(2-methoxyethyl)-2-methyl-pyrrol-3-yl]-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide The title compound was obtained using the method described in Preparation VIIb and the product from Step B as the appropriate aniline for amide formation. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.47-9.27 (s, 1H), 7.28-6.40 (m, 11H), 5.54-5.09 (s, 1H), 5.35-1.95 (m, 16H), 3.41-3.01 (s, 3H), 3.12-3.02 (s, 3H), 2.45-1.80 (s, 6H), 1.09-0.42 (d, 3H). HRMS-ESI (m / z) [M+H] + C 42 H 45 Calculated value of N6O4: 697.3497, Found value 697.3496.

[0389] Process D: N-[5-cyano-1-(2-methoxyethyl)-2-methyl-pyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-[2-[4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide

[0390] Using general procedure 4c, starting with preparation Va (41 mg, 2.5 equiv) as the appropriate acid and the product of step C (45 mg, 0.06 mmol) as the appropriate amine, the desired product was obtained (15 mg, 29%). HRMS-ESI (m / z) [M+H] + C 56 H 62 Calculated value for N7O7: 944.4705, Found value: 944.4706.

[0391] Example 69:N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2,5-difluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0392] Process A : Ethyl 2-(2,5-difluoro-4-methoxyphenyl)acetate A vessel containing a 0.6 M solution of ethyl bromoacetate (17.1 mL, 154 mmol, 3 equiv) in THF (250 mL) was placed under N2.

[0393] Cartridges supplied by OmniFit™ were loaded with zinc granules mesh 300 (12 g excess).

[0394] A second vessel containing a 0.25 M solution of 4-bromo-2,5-difluoroanisole in THF (200 mL, 49.32 mmol, 1 equiv.) was placed under N. To this solution was added X-Phos (0.59 g, 1.23 mmol, 0.03 equiv.) and Pd2dba3 (0.56 g, 0.62 mmol, 0.01 equiv.), and the mixture was sparged with N for 20 min and then sonicated to form a homogeneous mixture.

[0395] A Syrris Asia Flow Chemistry System™ was equipped with a column heater, to which a zinc-containing cartridge was attached and heated to 40°C. The zinc was pre-activated using a procedure similar to that described by Berton, M., Huck, L. & Alczar, J. On-Demand Synthesis of Organozinc Halides under Continuous Flow Conditions. Nat Protoc 13, 324-334 (2018).

[0396] A T-mixer (one-to-one) was placed in front of the tube reactor, and the reagent feed to the Asia pumps was set up under N2 from the Asia Reagent Store. The 16 mL fluoropolymer tube reactor was attached to an Asis heater module and surrounded by a 450 nm (blue) LED light (18 W). The tube heater was set to 80 °C.

[0397] The system backpressure regulator was set to 2 bar. The flow rate of the ethyl bromoacetate solution was 250 μL min -1 The flow rate of the 4-bromo-2,5-difluoroanisole solution was set to 250 μL min -1 The resulting total flow rate in the tube reactor was set to 500 μL min -1 giving a reaction residence time of 32 minutes.

[0398] The collected crude product solution was passed through a Celite cartridge to remove spent palladium and further washed with THF. The combined filtrate was diluted with EtOAc, washed with saturated aqueous NH4Cl, brine, then dried over MgSO4, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of heptane-42% DCM in heptane gave the title product (10.9 g, 47 mmol, 95%). LRMS C 11 H 12 Calculated F2O3: 230.1, Found: 231.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.24 (dd, J = 11.8, 7.1 Hz, 1H), 7.11 (dd, J = 11.2, 7.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.63 (d, J = 1.5 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H).

[0399] Process B : Ethyl 2-(2,5-difluoro-4-hydroxyphenyl)acetate A solution of 1M BBr3 in DCM (14.53 mL, 14.53 mmol, 1.5 equiv) was added dropwise over 15 min to a suspension of the product from Step A (2.23 g, 9.69 mmol, 1 equiv) in anhydrous DCM (40 mL) and cooled to −78 °C under N2. The mixture was allowed to warm to room temperature and stirred for 3 h. 100 g of crushed ice was added, and the mixture was stirred vigorously for 15 min. The DCM was removed in vacuo, and the aqueous solution was extracted with EtOAc. The organic phase was washed with water, brine, dried over MgSO4, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0–50% EtOAc in heptane gave the title product (1.22 g, 5.64 mmol, 58%). LRMS C 10 H 10 Calculated F2O3: 216.1, Measured: 215.0 [MH] - 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.28 (s, 1H), 7.15 (dd, J= 11.5, 7.2 Hz, 1H), 6.74 (dd, J= 10.8, 7.4 Hz, 1H), 4.08 (q, J= 7.1 Hz, 2H), 3.57 (d, J = 1.4 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H).

[0400] Process C : Ethyl 2-{2,5-difluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetate 4-(2-Chloroethyl)morpholine hydrochloride (2.25 g, 12.07 mmol, 2 equiv.) was added to a mixture of the product from Step B (1.22 g, 6.03 mmol, 1 equiv.) and KI (0.1 g, 0.6 mmol, 0.1 equiv.) in acetone. K2CO3 (4.17 g, 30.17 mmol, 5 equiv.) was added, and the mixture was heated at 60 °C for 2 days. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The phases were separated, and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0–9% MeOH in DCM gave the title product (1.46 g, 4.63 mmol, 77%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.23 (dd, J = 11.7, 7.1 Hz, 1H), 7.15 (dd, J= 11.3, 7.3 Hz, 1H), 4.16 (t, J= 5.7 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.62 (d, J = 1.4 Hz, 2H), 3.59 - 3.52 (m, 4H), 2.70 (t, J= 5.7 Hz, 2H), 2.49 - 2.44 (m, 4H), 1.18 (t, J = 7.1 Hz, 3H).

[0401] Process D {2,5-difluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid Using general procedure 8 and the product from step C (1.46 g, 4.63 mmol, 1 equiv) as the appropriate ester gave the title product (621 mg, 2.06 mmol, 45%). LRMS C 14 H 17 Calculated for F2NO4: 301.1, Found: 302.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm:7.12 (dd, J = 12.1, 7.1 Hz, 1H), 7.00 (dd, J = 11.1, 7.4 Hz, 1H), 4.12 (t, J = 5.7 Hz, 2H), 3.60 - 3.53 (m, 4H), 3.20 (d, J = 1.5 Hz, 2H), 2.68 (t, J= 5.7 Hz, 2H), 2.49 - 2.43 (m, 4H).

[0402] Process E N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2,5-difluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and preparation IVa (132 mg, 0.2 mmol, 1 equiv.) as the appropriate amine and the product from step D (73 mg, 0.24 mmol, 1.2 equiv.) as the appropriate carboxylic acid, the title product was obtained (51 mg, 0.05 mmol, 27%). HRMS C 54 H 55 Calculated for F2N7O6: 935.4182, Found: 936.4262 [M+H] +

[0403] Example 70: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-5-[2-[2-[2-fluoro-4-[(1S,2R) or (1R,2S)-2-morpholinocyclopropyl]phenyl]acetyl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide (diastereomer 1) [ka]

[0404] Process A trans-4-[2-(4-bromo-3-fluorophenyl)cyclopropyl]morpholine (mixture of (1S,2R) and (1R,2S) stereoisomers) 1-Bromo-2-(2-bromoethoxy)ethane (0.39 mL, 3.1 mmol, 1.1 equiv) was added to a suspension of trans-2-(4-bromo-3-fluorophenyl)cyclopropan-1-amine hydrochloride (750 mg, 2.81 mmol, 1 equiv) and K2CO3 (1.17 g, 8.44 mmol, 3 equiv) in MeCN (10 mL), and the mixture was stirred at 60 °C under N2 for 18 h. The mixture was allowed to cool to room temperature and partitioned between DCM and brine. The phases were separated, and the organic phase was dried (PTFE phase separator) and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 to 70% EtOAc in heptane gave the title product (469 mg, 56%). LRMS C 13 H 15 BrFNO calculated: 299.0, found: 300.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.53 (dd, J = 8.3, 7.6 Hz, 1H), 7.11 (dd, J = 10.5, 2.1 Hz, 1H), 6.92 (dd, J= 8.3, 2.1 Hz, 1H), 3.60 - 3.47 (m, 4H), 2.58 - 2.47 (m, 4H), 2.04 - 1.96 (m, 1H), 1.91 - 1.84 (m, 1H), 1.12 - 1.01 (m, 2H).

[0405] Process B : Ethyl 2-{2-fluoro-4-[(1S,2R)-2-(morpholin-4-yl)cyclopropyl]phenyl}acetate and Ethyl 2-{2-fluoro-4-[(1R,2S)-2-(morpholin-4-yl)cyclopropyl]phenyl}acetate Purification by automated flash chromatography using the procedure described in Example 69, Step A, and a solution of the product from Step A in THF (0.25 M, 6.22 mL, 1.56 mmol, 1 equiv) followed by a gradient of 0 to 100% EtOAc in heptane gave the title product (144 mg, 30%). LRMS C 17 H 22 Calculated FNO3: 307.2, Found 308.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.21 - 7.15 (m, 1H), 6.93 - 6.86 (m, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.65 - 3.61 (m, 2H), 3.59 - 3.48 (m, 4H), 2.59 - 2.49 (m, 4H), 2.01 - 1.92 (m, 1H), 1.90 - 1.82 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H), 1.09 - 0.96 (m, 2H).

[0406] The stereoisomers of the desired product were separated on an OD chiral column (50×500 mm, 20 μm) using 15:85 2-propanol / heptane+0.05% DEA as eluent to give Stereoisomers 1 and 2.

[0407] Process C: 2-[2-fluoro-4-[(1S,2R) or (1R,2S)-2-morpholinocyclopropyl]phenyl]acetic acid (from stereoisomer 1) Using general procedure 8, starting from enantiomer 1 (51 mg, 0.166 mmol) from step B, the desired product was obtained (44 mg, 95%). 1H NMR (500 MHz, DMSO-d6) δ ppm 12 (brs, 1H), 7.15 (t, 1H), 6.87 (dd, 1H), 6.86 (m, 1H), 3.53 (m, 4H), 3.49 (s, 2H), 2.54 (m, 4H), 1.95 (m, 1H), 1.84 (m, 1H), 1.04 / 1 (m+m, 2H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 172.5, 132, 121.9, 112.6, 66.6, 53.3, 49.8, 34.9, 23.7, 16.5. HRMS-ESI (m / z) [M+H] + C 15 H 19 Calculated FNO3: 280.1343, Measured 280.1343.

[0408] Process D: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-5-[2-[2-[2-fluoro-4-[(1S,2R) or (1R,2S)-2-morpholinocyclopropyl]phenyl]acetyl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide (diastereomer 1) Using general procedure 4c, starting from the product of Step C (44 mg, 1.5 equiv.) as the appropriate carboxylic acid and preparation VIIb (79 mg, 0.102 mmol) as the appropriate amine, gave the title compound (29.0 mg, 20%). HRMS-ESI (m / z) [M+H] + C 55 H 57 Calculated value for FN7O5: 914.4400, Found value: 914.4408.

[0409] Example 71:N-(5-cyano-1-cyclopropyl-2-methyl-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-[2-[4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide [ka]

[0410] Process A: 4-Bromo-1-cyclopropyl-5-methyl-pyrrole-2-carbonitrile A 4 mL screw-cap vial was charged with 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (200 mg, 1.08 mmol), bromocyclopropane (326.9 mg, 2.5 equiv.), and cesium carbonate (2.7 g, 2 equiv.) in DMF (2 mL / mmol). The reaction mixture was stirred at 160 °C under N for 24 h. The volatiles of the reaction mixture were evaporated, and the residue was dissolved in DCM (5 mL) and concentrated onto Celite. Purification by automated flash chromatography using DCM and EtOAc as eluents gave the title compound (124 mg, 51%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.05 (s, 1H), 3.35 (m, 1H), 1.15-1.00 (m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 136.8, 121.1, 113.8, 104.3, 95.3, 28.7, 11.7, 7.5. GC-MS (m / z) [M+2H] + C9H 11 Calculated value for BrN2: 226, Found value: 226.

[0411] Process B:4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-1-cyclopropyl-5-methyl-pyrrole-2-carbonitrile Using general procedure 1b and the product of step A (120 mg, 0.533 mmol) as the appropriate aryl bromide and preparation IIIa (178 mg, 1.5 equiv) as the appropriate aniline gave the title product (102 mg, 52%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.87 (s, 1H), 6.72 (s, 1H), 6.60 (d, 2H), 6.51 (d, 2H), 3.29 (m, 1H), 2.15 (s, 3H), 1.09 / 1.02 (m+m, 4H), 0.92 (s, 9H), 0.11 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 146.7, 142.4, 132.3, 124.8, 120.6, 116.1, 115.1, 114.3, 101.2, 27.9, 26.1, 18.4, 10.4, 7.4, -4.0. HPLC-MS-ESI (m / z) [M+H] + C 21 H 30 Calculated N3OSi: 368.2, Measured 368.2.

[0412] Process C: N-[4-[tert-butyl (dimethyl)silyl]oxyphenyl]-N-(5-cyano-1-cyclopropyl-2-methyl-pyrrol-3-yl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]pyrrole-3-carboxamide The title compound was obtained using the method described in Preparation VIIb and the product from Step B as the appropriate aniline for amide formation. HPLC-MS-ESI (m / z) [M+H] + C 48 H 57Calculated value of N6O3Si: 793.4, Found value 793.4.

[0413] Process D: N-(5-cyano-1-cyclopropyl-2-methyl-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-[2-[4-(2-morpholinoethoxy)phenyl]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide Using general procedure 4c, starting with preparation Va (45 mg, 2.5 equiv.) as the appropriate acid and the product of step C (48 mg, 0.06 mmol) as the appropriate amine, the desired product was obtained (8 mg, 14%). HRMS-ESI (m / z) [M+H] + C 56 H 60 Calculated value for N7O6: 926.4600, Found value: 926.4606.

[0414] Example 72: N-(5-Fluoro-6-methoxypyridin-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxamide [ka]

[0415] Process A N-{4-[(tert-butyldimethylsilyl)oxy]phenyl}-5-fluoro-6-methoxypyridin-3-amine Using general procedure 1a and 5-bromo-3-fluoro-2-methoxypyridine (1 g, 4.85 mmol, 1 equiv.) as the appropriate aryl bromide and preparation IIIa (1.14 g, 5.1 mmol, 1.05 equiv.) as the appropriate aniline, the title product was obtained (1.1 g, 3.16 mmol, 65%). LRMS C 18 H 25 Calculated for FN2O2Si: 348.2, Found: 349.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.87 (s, 1H), 7.67 (d, J= 2.4 Hz, 1H), 7.30 (dd, J = 12.4, 2.4 Hz, 1H), 6.95 - 6.88 (m, 2H), 6.78 - 6.71 (m, 2H), 3.86 (s, 3H), 0.94 (s, 9H), 0.16 (s, 6H).

[0416] Process B N-(5-fluoro-6-methoxypyridin-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxamide Using general procedure 2a and preparation VIa (175 mg, 0.25 mmol, 1 equiv.) as the appropriate acid and the product from step A (132 mg, 0.38 mmol, 1.5 equiv.) as the appropriate aniline, gave the intermediate which was treated according to general procedure 3b to give the title product (17 mg, 0.02 mmol, 7%). HRMS C 53 H 55 Calculated for FN6O7: 906.4116, Found: 907.4208 [M+H] +

[0417] Example 73:N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-{2-[4-(2-{6-oxa-9-azaspiro[4.5]decan-9-yl}ethoxy)phenyl]acetyl}-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide [ka]

[0418] Process A: 2-[4-[2-(6-oxa-9-azaspiro[4.5]decan-9-yl)ethoxy]phenyl]acetic acid Using general procedure 7d and then general procedure 8, starting with methyl 2-[4-(2-bromoethoxy)phenyl]acetate (150 mg, 0.55 mmol) as the appropriate alkyl halide and 6-oxa-9-azaspiro[4.5]decane (155 mg, 2.0 equiv.) as the appropriate amine, the desired product was obtained (169 mg, 96%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.97 (brs, 1H), 7.17 (m, 2H), 6.89 (m, 2H), 4.08 (brs, 2H), 3.58 (brs, 2H), 3.48 (s, 2H), 2.66 (brs, 2H), 2.43 (brs, 2H), 2.36 (brs, 2H), 1.80-1.42 (brm, 8H). HRMS-ESI (m / z) [M+H] + C 18 H 26 Calculated NO4: 320.1856, Measured: 320.1858.

[0419] Process B:N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-{2-[4-(2-{6-oxa-9-azaspiro[4.5]decan-9-yl}ethoxy)phenyl]acetyl}-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide Using general procedure 4c, starting with the product of Step A (67.0 mg, 2.0 equiv) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, gave the title compound (70.0 mg, 70%). HRMS-ESI (m / z) [M+H] + C 58 H 64 Calculated value for N7O6: 954.4918, Found value: 954.4915.

[0420] Example 74: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-[2-(piperidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0421] Process A: tert-Butyl (3S)-3-[2-oxo-2-(1-piperidyl)ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 5a, starting with 2-[(3S)-2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-3-yl]acetic acid (300 mg, 1.03 mmol) as the appropriate carboxylic acid and piperidine (123 mg, 1.4 equiv.) as the appropriate amine, followed by an automated flash chromatographic purification step using DCM and methanol as eluents gave the desired compound (332 mg, 90%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.25-7.09 (m, 4H), 4.79-4.59 (br., 1H), 4.70-3.20 (br., 6H), 2.99 / 2.72 (dd+d, 2H), 2.46-2.20 (br., 2H), 1.66-1.31 (br., 6H), 1.42 (s, 9H). HRMS-ESI (m / z) [M+H] + C 21 H 31 Calculated N2O3: 359.2329, Measured 359.2333.

[0422] Process B: (3S)-3-[2-(1-piperidyl)ethyl]-1,2,3,4-tetrahydroisoquinoline The product of step A (324 mg, 0.90 mmol) was deprotected using general procedure 6c, and the title product was then prepared by a modified general procedure 6a using MTBE, THF, and DCM as solvents to give the desired product (160 mg, 72%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.07 (m, 1H), 7.06 (m, 1H), 7.03 (m, 1H), 6.99 (m, 1H), 3.86 (s, 2H), 2.73 (m, 1H), 2.68 / 2.41 (dd+dd, 2H), 2.43 / 2.32 (m+m, 2H), 2.33 / 2.29 (m+m, 4H), 1.59 / 1.53 (m+m, 2H), 1.48 (qn, 4H), 1.37 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ ppm 136.7, 135.5, 129.3, 126.3, 126, 125.8, 56.4, 54.7, 52.7, 48.3, 35.6, 33.7, 26.1, 24.7. HRMS-ESI (m / z) [M+H] + C 16 H 25 Calculated N2: 245.2012, measured: 245.2015.

[0423] Process C: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-[2-(piperidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide Using general procedure 4c, starting from preparation IX (50 mg, 0.064 mmol) as the appropriate carboxylic acid and the product of step B (35 mg, 1.4 equiv) as the appropriate amine, the title product was obtained (18.1 mg, 28%). HRMS-ESI (m / z) [M+H] + C 60 H 68 Calculated value for FN8O6: 1015.5240, found value 1015.5241.

[0424] Example 75: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-((2S or R)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (diastereomer 1) [ka]

[0425] Process A: Methyl 2-[2-fluoro-4-[2-((2S)-2-methylmorpholin-4-yl)ethoxy]phenyl]acetate and Methyl 2-[2-fluoro-4-[2-((2R)-2-methylmorpholin-4-yl)ethoxy]phenyl]acetate Using general procedure 7d, starting with preparation X (500 mg, 1.72 mmol) as the appropriate alkyl halide and 2-methylmorpholine (380 mg, 2.2 equiv) as the appropriate amine, the desired product was obtained (510 mg, 95%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.22 (t, 1H), 6.83 (dd, 1H), 6.75 (t, 2H), 6.75 (dd, 1H), 3.72 / 3.48 (dm+td, 2H), 3.63 (s, 2H), 3.61 (s, 3H), 3.49 (m, 1H), 2.81 / 1.78 (dm+dd, 2H), 2.74 / 2.08 (dm+td, 2H), 2.66 (t, 2H), 1.03 (d, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 171.5, 161.5, 159.5, 132.7, 113.7, 111.1, 102.3, 71.5, 66.3, 66.1, 60.5, 57.1, 53.3, 52.3, 33.6, 19.5. HRMS-ESI (m / z) [M+H] + C 16 H 23 Calculated FNO4 value: 312.1606, measured value 312.1608.

[0426] The enantiomers of the desired product were separated on an AD-3 chiral column (100*500 mm, 20 μm) using 30:70 EtOH-heptane+0.1% DEA as the eluent to give Enantiomer 1 (99.9% ee) and Enantiomer 2 (99.8% ee).

[0427] Process B: 2-[2-fluoro-4-[2-((2S or R)-2-methylmorpholin-4-yl)ethoxy]phenyl]acetic acid (from enantiomer 1) Using general procedure 8, starting from enantiomer 1 (255 mg, 0.82 mmol) from step A, the desired product was obtained (146 mg, 60%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.38 (br., 1H), 7.20 (t, 1H), 6.81 (dd, 1H), 6.73 (dd, 1H), 4.07 (t, 2H), 3.72 / 3.48 (dm+td, 2H), 3.52 (s, 2H), 3.50 (m, 1H), 2.81 / 1.78 (dm+dd, 2H), 2.74 / 2.08 (dm+td, 2H), 2.66 (t, 2H), 1.03 (d, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 172.5, 161.6, 159.3, 132.7, 114.5, 111.0, 102.2, 71.5, 66.3, 66.1, 60.5, 57.1, 53.3, 34, 19.5. HRMS-ESI (m / z) [M+H] + C 15 H 21 Calculated FNO4 value: 298.1449, measured value 298.1450.

[0428] Process C: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-((2S or R)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (diastereomer 1) Using general procedure 4c, starting from the product of Step B (140.0 mg, 4.5 equiv) as the appropriate carboxylic acid and preparation VIIb (80 mg, 0.104 mmol) as the appropriate amine, gave the title compound (79.0 mg, 81%). HRMS-ESI (m / z) [M+H] + C 55 H 59 Calculated value for FN7O6: 932.4511, Found value: 932.4505.

[0429] Example 76: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{4-[2-(4-fluoropiperidin-1-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and preparation VIIa (150 mg, 0.18 mmol, 1 equiv.) as the appropriate amine and the product of step A in example 53 (52 mg, 0.18 mmol, 1 equiv.) as the appropriate carboxylic acid, gave an intermediate which was treated by general procedure 3c to give the title product (67.3 mg, 0.07 mmol, 37%). HRMS C 60 H 67 Calculated value for FN8O5: 998.5218, Found value: 999.5294 [M+H] +

[0430] Example 77:N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide [ka]

[0431] Process A 1-(Difluoromethyl)-5-methyl-4-({4-[(triisopropylsilyl)oxy]phenyl}amino)pyrrole-2-carbonitrile To a solution of Preparation IIIb (4.52 g, 17.02 mmol, 2 equiv.) in 1,4-dioxane (85 mL) were added 4-bromo-1-(difluoromethyl)-5-methyl-1H-pyrrole-2-carbonitrile (2 g, 8.51 mmol, 1 equiv.) and CsCO (8.32 g, 25.53 mmol, 3 equiv.), and the mixture was sparged with N. BrettPhos Pd G (759 mg, 0.85 mmol, 0.1 equiv.) was added, and the mixture was sparged with N and then stirred at 100 °C for 18 h. The mixture was allowed to cool to room temperature, diluted with DCM and water, and then filtered through a Celite cartridge, washing with DCM and water. The filtrate layers were separated by the addition of brine. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0-20% EtOAc in heptane gave the title product (3.11 g, 7.4 mmol, 87%). LRMS C 22 H 31 Calculated value for F2N3OSi: 419.2, Found value: 420.4 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.79 (t, J = 57.5 Hz, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.70 - 6.63 (m, 2H), 6.60 - 6.53 (m, 2H), 2.24 (s, 3H), 1.25 - 1.13 (m, 3H), 1.04 (d, J = 7.3 Hz, 18H).

[0432] Process B tert-Butyl 6-(4-{[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]({4-[(triisopropylsilyl)oxy]phenyl})carbamoyl}-1,5-dimethylpyrrol-2-yl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 2a and preparation IIb (253 mg, 0.4 mmol, 1 equiv.) as the appropriate acid and the product from step A (254 mg, 0.61 mmol, 1.5 equiv.) as the appropriate aniline, the title product was obtained (220 mg, 0.21 mmol, 53%). LRMS C 59 H 75 Calculated value for F2N7O5Si: 1027.6, Found value: 1028.6 [M+H] +

[0433] Process C N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-1,2-dimethyl-5-(7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-{4-[(triisopropylsilyl)oxy]phenyl}pyrrole-3-carboxamide Using general procedure 3b and the product from step B (220 mg, 0.21 mmol, 1 equiv) as the appropriate silyl-derivative gave the title product (115 mg, 0.12 mmol, 58%). LRMS C 54 H 67 Calculated for F2N7O3Si: 927.5, Found: 928.6 [M+H] +

[0434] Process D N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-1,2-dimethyl-5-[2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-{4-[(triisopropylsilyl)oxy]phenyl}pyrrole-3-carboxamide Using general procedure 4a and the product from step C (57.5 mg, 0.06 mmol, 1 equiv.) as the appropriate amine and preparation Va (18 mg, 0.07 mmol, 1.1 equiv.) as the appropriate carboxylic acid, the title product was obtained (65 mg, 0.06 mmol, 89%). LRMS C 68 H 84 Calculated for F2N8O6Si: 1174.6, Found: 1175.8 [M+H] +

[0435] Process E N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide Using general procedure 3c and the product from step D (65 mg, 0.06 mmol, 1 equiv) as the appropriate silyl-derivative gave the title product (13.3 mg, 0.01 mmol, 24%). HRMS C 59 H 64Calculated value for F2N8O6: 1018.4917, Found value: 1019.4988 [M+H] +

[0436] Example 78: N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and the product from Example 77, step C (57.5 mg, 0.06 mmol, 1 equiv.) as the appropriate amine and preparation Vb (19 mg, 0.07 mmol, 1.1 equiv.) as the appropriate carboxylic acid, gave the intermediate which was treated by general procedure 3c to give the title product (6.1 mg, 0.01 mmol, 10%). HRMS C 59 H 63 Calculated for F3N8O6: 1036.4823, Found: 1037.4903 [M+H] +

[0437] Example 79: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-(7-{[(3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka]

[0438] Process A tert-Butyl (3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 5 and Boc-(3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3 g, 10.82 mmol, 1 equiv.) and (R)-(−)-3-fluoropyrrolidine hydrochloride (1.49 g, 11.9 mmol, 1.1 equiv.) as the appropriate amine, gave the title product (3.06 g, 8.78 mmol, 81%). LRMS C 19 H 25 Calculated for FN2O3: 348.2; Found 249.2 [M-Boc+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.24 - 7.15 (m, 4H), 5.52 - 5.18 (m, 1H), 5.00 - 4.20 (m, 3H), 3.96 - 2.75 (m, 6H), 2.34 - 1.86 (m, 2H), 1.47 - 1.29 (m, 9H).

[0439] Process B (3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-1,2,3,4-tetrahydroisoquinoline dihydrochloride Using general procedure 6 and the product from step A (2.96 g, 8.5 mmol, 1 equiv) as the appropriate THIQ amide gave the title product (2.61 g, quantitative). LRMS C 14 H 19 Calculated FN2: 234.2; Found 235.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.94 -9.38 (br m, 3H), 7.36 - 7.10 (m, 4H), 5.63 - 5.29 (m, 1H), 4.71 - 3.01 (m, 11H), 2.60 - 1.94 (m, 2H).

[0440] Process C Benzyl 6-[4-(ethoxycarbonyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 4b and the product from step B (2.61 g, 8.5 mmol, 1 equiv.) as the appropriate amine and preparation I (4.05 g, 8.5 mmol, 1 equiv.) as the appropriate carboxylic acid, followed by a purification step by automated flash chromatography eluting with a gradient of 40 to 100% EtOAc in heptane gave the title product (2.9 g, 4.19 mmol, 49%). LRMS C 41 H 45 Calculated for FN4O5: 692.3, Found: 693.4 [M+H] +

[0441] Process D 5-(7-{[(3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2-dimethylpyrrole-3-carboxylic acid To a solution of the product from step C (2.9 g, 4.19 mmol, 1 equiv) in MeOH (40 mL) and water (10 mL) was added 5 M aqueous NaOH (8.37 mL, 41.86 mmol, 10 equiv), and the mixture was refluxed for 2 days. The mixture was allowed to cool to room temperature, and the MeOH was removed in vacuo. Water was added (90 mL), the mixture was neutralized, and extracted with 3:1 DCM:IPA. The pH was adjusted to pH 5 and extracted again with 3:1 DCM:IPA. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by reverse-phase automated flash chromatography, eluting with a gradient of 10–100% MeCN in water, gave the title product (1.35 g, 2.54 mmol, 61%). LRMS C 31 H 35 Calculated for FN4O3: 530.3, Found: 531.4 [M+H] +

[0442] Process E 5-[2-(tert-butoxycarbonyl)-7-{[(3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethylpyrrole-3-carboxylic acid To a solution of the product from step D (1.29 g, 2.42 mmol, 1 equiv.) in THF (30 mL) and water (3 mL) was added di-tert-butyl dicarbonate (0.54 mL, 2.54 mmol, 1.05 equiv.), followed by the dropwise addition of TEA (0.67 mL, 4.84 mmol, 2 equiv.). The mixture was stirred at room temperature for 18 h. The THF was removed in vacuo, and the residue was partitioned between EtOAc and saturated aqueous NH4Cl. The phases were separated, and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by automated flash chromatography, eluting with a gradient of 0–10% MeOH in DCM, gave the title product (1.36 g, 2.16 mmol, 89%). LRMS C 36 H 43 Calculated for FN4O5: 630.3, Found: 631.6 [M+H] +

[0443] Process F tert-Butyl 6-[4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}(5-cyano-1,2-dimethylpyrrol-3-yl)carbamoyl)-1,5-dimethylpyrrol-2-yl]-7-{[(3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylate Using general procedure 2a and the product from step E (1.36 g, 2.16 mmol, 1 equiv.) as the appropriate acid and preparation IVa, step B (1.1 g, 3.23 mmol, 1.5 equiv.) as the appropriate aniline, gave the title product (0.61 g, 0.63 mmol, 29%). LRMS C 55 H 68 Calculated for FN7O5Si: 953.5, Found: 954.4 [M+H] +

[0444] Process G N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-(7-{[(3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide dihydrochloride Using general procedure 3b and the product from step F (605 mg, 0.63 mmol, 1 equiv) as the appropriate silyl-derivative gave the title product (520 mg, 100%). LRMS C 44 H 46 Calculated for FN7O3: 739.4, Found: 740.3 [M+H] +

[0445] Process HN-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-(7-{[(3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using general procedure 4a and the product from step G (161 mg, 0.2 mmol, 1 equiv.) as the appropriate amine and preparation Vc (63 mg, 0.24 mmol, 1.2 equiv.) as the appropriate carboxylic acid, the title product was obtained (39 mg, 0.04 mmol, 20%). HRMS C 59 H 64 Calculated for FN7O6: 985.4902, Found: 986.4980 [M+H] +

[0446] Example 80: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and the product from Example 79, step G (159 mg, 0.2 mmol, 1 equiv.) as the appropriate amine and preparation Vb (67 mg, 0.23 mmol, 1.2 equiv.) as the appropriate carboxylic acid, gave the title product (43 mg, 0.04 mmol, 22%). HRMS C 58 H 62 Calculated for F2N8O6: 1004.4760, Found: 1005.4836 [M+H]+

[0447] Example 81: N-(3-cyano-4-methoxyphenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxamide [ka]

[0448] Process A 5-({4-[(tert-butyldimethylsilyl)oxy]phenyl}amino)-2-methoxybenzonitrile Using general procedure 1a and 5-bromo-2-methoxybenzonitrile (162 mg, 0.76 mmol, 1 equiv.) as the appropriate aryl bromide and preparation IIIa (188 mg, 0.84 mmol, 1.1 equiv.) as the appropriate aniline, the title product was obtained (140 mg, 0.39 mmol, 52%). LRMS C 20 H 26 Calculated value for N2O2Si: 354.2, Found value: 355.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.87 (s, 1H), 7.24 (dd, J= 9.1, 2.9 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.95 - 6.89 (m, 2H), 6.79 - 6.73 (m, 2H), 3.83 (s, 3H), 0.95 (s, 9H), 0.16 (s, 6H).

[0449] Process BN-(3-cyano-4-methoxyphenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)pyrrole-3-carboxamide Using general procedure 2a and preparation VIa (175 mg, 0.25 mmol, 1 equiv.) as the appropriate acid and the product from step A (135 mg, 0.38 mmol, 1.5 equiv.) as the appropriate aniline, gave the intermediate which was treated according to general procedure 3b to give the title product (12 mg, 0.01 mmol, 5%). HRMS C 55 H 56 Calculated for N6O7: 912.4210, Found: 913.4286 [M+H] +

[0450] Example 82: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{4-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and preparation IVb (144 mg, 0.19 mmol, 1 equiv.) as the appropriate amine and the product of step A of example 50 (72 mg, 0.25 mmol, 1.3 equiv.) as the appropriate carboxylic acid, the title product was obtained (34.3 mg, 0.03 mmol, 18%). HRMS C 59 H 64 Calculated value for F2N8O5: 1002.4968, Found value: 1003.5047 [M+H] +

[0451] Example 83: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2,5-difluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide [ka] Using general procedure 4a and preparation IVb (143.5 mg, 0.19 mmol, 1 equiv.) as the appropriate amine and the product from Example 69, Step D (65 mg, 0.21 mmol, 1.1 equiv.) as the appropriate carboxylic acid, gave the title product (54.4 mg, 0.05 mmol, 27%). HRMS C 59 H 64 Calculated value for F2N8O6: 1018.4917, Found value: 1019.4992 [M+H] +

[0452] Example 84: N-[5-cyano-2-methyl-1-((3S or R)-tetrahydrofuran-3-ylmethyl)pyrrol-3-yl]-5-[2-[2-[2-fluoro-4-(2-morpholinoethoxy)phenyl]acetyl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide (diastereomer 2) [ka]

[0453] Process A:4-Bromo-5-methyl-1-((3S)-tetrahydrofuran-3-ylmethyl)pyrrole-2-carbonitrile and 4-Bromo-5-methyl-1-((3R)-tetrahydrofuran-3-ylmethyl)pyrrole-2-carbonitrile Using general procedure 7c, starting with tetrahydrofuran-3-ylmethanol (1.0 mL, 2.0 equiv) as the appropriate alcohol, gave the title compound (1.44 g, 99%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.12 (q, 1H), 4.07 / 4.01 (dd+dd, 2H), 3.82 / 3.65 (m+m, 2H), 3.62 / 3.42 (dd+dd, 2H), 2.64 (m, 1H), 2.27 (d, 3H), 1.91 / 1.58 (m+m, 2H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 134.7, 121.0, 113.8, 103.0, 95.8, 70.0, 67.1, 49.2, 40.1, 29.3, 11.3. HRMS-ESI (m / z) [M+NH4] + C 11 H 14 Calculated for BrNO: 286.0549, Found: 286.0549.

[0454] The enantiomers of the desired product were separated on an AD chiral column (100*500 mm, 20 μm) using 10:90 EtOH / heptane as the eluent to give Enantiomer 1 (99.9% ee) and Enantiomer 2 (99.2% ee).

[0455] Process B: 4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-5-methyl-1-((3S or R)-tetrahydrofuran-3-ylmethyl)pyrrole-2-carbonitrile (from enantiomer 2) Using general procedure 1b, starting from enantiomer 2 of step A (700 mg, 2.60 mmol) as the appropriate aryl bromide and preparation IIIa (875 mg, 1.5 equiv) as the appropriate aniline, gave the title compound (538 mg, 50%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.89 (s, 1H), 6.78 (s, 1H), 6.61 (dm, 2H), 6.50 (dm, 2H), 4.01 / 3.96 (dd+dd, 2H), 3.84 / 3.67 (m+m, 2H), 3.63 / 3.44 (dd+dd, 2H), 2.66 (m, 1H), 2.12 (s, 3H), 1.93 / 1.61 (m+m, 2H), 0.92 (s, 9H), 0.12 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 146.8, 142.4, 130.4, 125.1, 120.6, 115.9, 115.1, 114.3, 99.8, 70.1, 67.1, 48.3, 40.3, 29.3, 26.1, 10.0, -4.1. HRMS-ESI (m / z) [M+H] + C 23 H 34 Calculated value of N3O2Si: 412.2415, Measured value: 412.2418.

[0456] Process C: 9H-Fluoren-9-ylmethyl 6-[4-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-[5-cyano-2-methyl-1-((3S or R)-tetrahydrofuran-3-ylmethyl)pyrrol-3-yl]carbamoyl]-1,5-dimethyl-pyrrol-2-yl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (diastereomer 2) Using general procedure 2b, starting from Step B of Preparation VIIb (300 mg, 0.45 mmol) as the appropriate acid and the product of Step B (270 mg, 1.4 equiv) as the appropriate aniline, gave the title compound (200 mg, 42%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.05-6.21 (m, 19H), 5.57-5.00 (s, 1H), 5.36-1.29 (m, 23H), 3.48-3.06 (s, 3H), 2.45-1.86 (s, 6H), 1.12-0.47 (brd, 3H), 0.88 (s, 9H), 0.13 (s, 6H). HRMS-ESI (m / z) [M+H] + C 65 H 71 Calculated value for N6O6Si: 1059.5199, Found value: 1059.5198.

[0457] Process D: N-[5-cyano-2-methyl-1-((3S or R)-tetrahydrofuran-3-ylmethyl)pyrrol-3-yl]-5-[2-[2-[2-fluoro-4-(2-morpholinoethoxy)phenyl]acetyl]-7-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide (diastereomer 2) To the product of Step C (120 mg, 0.11 mmol) in DMF (1 mL) was added DBU (0.003 mL, 0.2 equiv.). The reaction mixture was stirred until deprotection was complete. The mixture was treated with Preparation Vb (50 mg, 0.18 mmol) as the appropriate acid according to General Procedure 4c to give the title compound (45 mg, 40%). HRMS-ESI (m / z) [M+H] + C 58 H 63 Calculated value for FN7O7: 988.4767, Found: 988.4770.

[0458] Example 85:N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)-N-(1-methylpyrazol-4-yl)pyrrole-3-carboxamide [ka]

[0459] Process A N-{4-[(tert-butyldimethylsilyl)oxy]phenyl}-1-methylpyrazol-4-amine Using general procedure 1a and 4-bromo-1-methyl-1H-pyrazole (0.64 mL, 6.21 mmol, 1 equiv.) as the appropriate aryl bromide and preparation IIIa (1.66 g, 7.45 mmol, 1.2 equiv.) as the appropriate aniline, the title product was obtained (1.23 g, 4.06 mmol, 65%). LRMS C 16 H 25 Calculated for N3OSi: 303.2, Found: 304.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.55 (d, J = 0.9 Hz, 1H), 7.23 (d, J = 0.9 Hz, 1H), 7.19 (s, 1H), 6.69 - 6.60 (m, 4H), 3.77 (s, 3H), 0.93 (s, 9H), 0.12 (s, 6H).

[0460] Process B N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-3,4-dihydro-1H-isoquinolin-6-yl)-N-(1-methylpyrazol-4-yl)pyrrole-3-carboxamide Using general procedure 2a and preparation VIb (175 mg, 0.25 mmol, 1 equiv.) as the appropriate acid and the product from step A (115 mg, 0.38 mmol, 1.5 equiv.) as the appropriate aniline, gave the intermediate which was treated according to general procedure 3b to give the title product (92 mg, 0.11 mmol, 42%). HRMS C 52 H 56 Calculated for N6O6: 860.4261, Found: 861.4336 [M+H] +

[0461] Example 86: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-[(4-fluoropiperidin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0462] Process A: tert-Butyl (3S)-3-(4-fluoropiperidine-1-carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate Using a modified general procedure 5a, starting with (3S)-2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid (800 mg, 2.885 mmol) as the appropriate carboxylic acid and 4-fluoropiperidine hydrochloride (484 mg, 1.2 equiv.) as the appropriate amine in DCM (50 mL), followed by a purification step by automated flash chromatography using heptane and IPA as eluents gave the desired compound (735 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.26-7.07 (m, 4H), 5.20 / 4.95 (dd, 1H), 4.89 (dm, 1H), 4.67 / 4.64 / 4.39 / 4.32 (d+d, 2H), 3.81-3.14 (m, 4H), 3.12 / 3.08 / 2.88 / 2.81 (dd+dd, 2H), 2.12-1.46 (m, 4H), 1.43 / 1.36 (brs, 9H). HRMS-ESI (m / z) [M+H] + C 20 H 28 Calculated value of FN2O3: 363.2078, Found value: 363.2079.

[0463] Process B: (3S)-3-[(4-fluoro-1-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline To a solution of the product of Step A (735 mg, 2.03 mmol) in ACN (20 mL) was added HCl (12 M aqueous solution, 1 mL, 6 equiv.). The reaction mixture was stirred at room temperature for 1.5 h, then concentrated under reduced pressure and azeotroped with toluene. The residue was dissolved in a mixture of DCM (6 mL) and THF (40 mL). This solution was treated with a 1 M solution of LiAlH4 in THF (4.05 mL, 2 equiv.) according to general procedure 6a. Purification by flash chromatography using heptane and heptane / IPA 3 / 2 (0.25% TEA) as eluents gave the desired product (345 mg, 66%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.13-6.95 (m, 4H), 4.68 (dm, 1H), 3.90 (s, 2H), 2.92 (m, 1H), 2.65-2.22 (br., 4H), 2.65 / 2.37 (dd+m, 2H), 2.32 (m, 2H), 1.94-1.65 (m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 136.7, 135.2, 89.2, 63.8, 51, 50.3, 48.4, 34.1, 31.8. HRMS-ESI (m / z) [M+H] + C 15 H 22 Calculated FN2: 249.1762, measured 249.1763.

[0464] Process C: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-y...

Claims

1. Formula (Ib): 【Chemistry 1】 [In the formula, T is a hydrogen atom, a straight or branched chain (C １ ~C ６ ) alkyl group, (C １ ~C ４ ) alkylene-NR １ R ２ Group, (C １ ~C ４ ) alkylene-OR ｉ represents a group, R １ and R ２ are each independently a hydrogen atom or a straight or branched chain (C １ ~C ６ ) represents an alkyl group, or R １ and R ２ together with the nitrogen atom carrying them form a heterocycloalkyl group, and this heterocycloalkyl is １ ~C ６ ) optionally substituted with 1 to 3 groups selected from alkyl groups and halogen atoms; R ５ represents a hydrogen atom, a halogen atom or a hydroxy group, R ６ is hydrogen, straight or branched chain (C １ ~C ６ ) represents an alkyl group or a halogen atom; A １ is C-Y ４ or a nitrogen atom, X is a bond, —O—, —S—, or NR ｋ represents Y １ and Y ５ are each independently a hydrogen atom, a halogen atom, a cyano, a straight-chain or branched-chain (C １ ~C ６ ) alkyl group and straight or branched chain (C １ ~C ６ ) alkoxy groups, Y ２ and Y ４ are each independently a hydrogen atom, a halogen atom, a straight-chain or branched-chain (C １ ~C ６ ) alkyl group, straight or branched chain (C １ ~C ６ ) alkoxy groups and straight or branched chain (C １ ~C ６ ) heterocycloalkyl groups optionally substituted by alkyl groups; Y ３ is a hydrogen atom, a halogen atom, a straight-chain or branched-chain (C １ ~C ６ ) alkyl, straight or branched chain (C １ ~C ６ ) alkynyl, -(C １ ~C ４ ) alkylene-OR １ , linear or branched chain (C １ ~C ６ ) alkoxy group, —O-phenyl, —S-phenyl, —O—(C １ ~C ４ ) Alkylene-Cy ３ , —O—(C １ ~C ４ ) Alkylene-Cy ４ , —O—Cy ３ , —O—(C １ ~C ４ ) alkylene-NR ｇ R ｈ , -(C １ ~C ４ ) Alkylene-Cy ３ , -(C １ ~C ４ ) Alkylene-Cy ４ , Cy ３ , Cy ４ and 【Chemistry 2】 wherein the alkylene portion of said group may be linear or branched; Cy ３ is a straight or branched chain (C １ ~C ６ ) heterocycloalkyl optionally substituted with 1 to 3 groups selected from alkyl, hydroxy, cycloalkyl, heterocycloalkyl, and halogen atoms; Cy ４ is a straight or branched chain (C １ ~C ６ ) represents a cycloalkyl optionally substituted with 1 to 3 groups selected from an alkyl group, a hydroxy group, a cycloalkyl group, a heterocycloalkyl group, and a halogen atom; R ａ and R ｂ each independently represents a hydrogen atom or a halogen atom, R ｃ is a straight or branched chain (C １ ~C ６ ) alkyl group, (C １ ~C ６ ) alkylene-NR ｄ R ｅ , (C １ ~C ６ ) alkylene-OR ｊ , cycloalkyl, heterocycloalkyl and (C １ ~C ６ ) alkylene-heterocycloalkyl groups, R ｄ and R ｅ are each independently a hydrogen atom, a straight chain or branched chain (C １ ~C ６ ) represents an alkyl group, a cycloalkyl group, or a heterocycloalkyl group; R ｇ and R ｈ are each independently a hydrogen atom, a straight or branched chain optionally substituted with 1 to 3 halogen atoms (C １ ~C ６ ) alkyl group, cycloalkyl group, heterocycloalkyl group or -(C １ ~C ６ ) represents an alkylene-heterocycloalkyl group; R ｉ , R ｊ and R ｋ are each independently a hydrogen atom, a straight chain or branched chain (C １ ~C ６ ) alkyl group or -(C １ ~C ６ ) represents an alkylene-cycloalkyl group. or an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

2. R ｃ 2. The compound according to claim 1, wherein represents a methyl group, its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base.

3. The compound of claim 1, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, wherein X represents a bond.

4. A １ But C-Y ４ 2. The compound of claim 1, wherein the compound represents an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

5. R ａ and R ｂ 2. The compound according to claim 1, wherein both represent a hydrogen atom, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

6. R ５ 2. The compound according to claim 1, its enantiomers or diastereoisomers, or its addition salts with a pharmaceutically acceptable acid or base, wherein represents a hydrogen atom, a hydroxy group or a fluorine atom.

7. R ６ 2. The compound according to claim 1, its enantiomers or diastereoisomers, or its addition salts with a pharmaceutically acceptable acid or base, wherein represents a hydrogen atom or a fluorine atom.

8. R ５ represents a hydroxy group, and R ６ 2. The compound according to claim 1, wherein represents a hydrogen atom, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

9. A １ represents C—H, and Y ２ 2. The compound according to claim 1, wherein represents a hydrogen atom, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

10. Y １ and Y ５ both represent hydrogen atoms, or Y １ and Y ５ 2. The compound according to claim 1, its enantiomers or diastereoisomers, or its addition salts with a pharmaceutically acceptable acid or base, wherein: represent a fluorine atom and a hydrogen atom, respectively.

11. Y ３ But -O-(C １ ~C ４ ) Alkylene-Cy ３ 2. The compound of claim 1, wherein R represents a group, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

12. Y ３ But the following: 2-(morpholin-4-yl)ethoxy, 2-(oxan-4-yl)ethoxy, 2-(4-hydroxypiperidin-1-yl)ethoxy, 2-(4-cyclopropylpiperazin-1-yl)ethoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy, 2-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]ethoxy, 2-{2-[4-(2-{1,1-dioxo-1λ ６ -thia-6-azaspiro[3.3]heptan-6-yl}ethoxy, 2-[2,6-dimethylmorpholin-4-yl]ethoxy, 2-[4-(2,2-difluoroethyl)piperazin-1-yl]ethoxy, 2-(3-fluoroazetidin-1-yl)ethoxy, 2-(3,3-difluoropyrrolidin-1-yl)ethoxy, 2-(4-fluoropiperidin-1-yl)ethoxy, 2-(thiomorpholin-4-yl)ethoxy, 2-(2-methylmorpholin-4-yl)ethoxy, 2-{6-oxa-9-azaspiro[4.5]decan-9-yl}ethoxy , 2-{4-oxa-7-azaspiro[2.5]octan-7-yl}ethoxy, 2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(2,2-dimethylmorpholin-4-yl)ethoxy, 2-(morpholin-4-yl)propoxy, [2-methyl-1-(morpholin-4-yl)propan-2-yl]oxy, 2-(3,3-dimethylmorpholin-4-yl)ethoxy, 2-(3-methylmorpholin-4-yl)ethoxy, 2-(1,4-dioxan-2-yl)ethoxy 12. The compound according to claim 11, its enantiomers or diastereoisomers, or its addition salts with a pharmaceutically acceptable acid or base, wherein R represents a group selected from:

13. Group: 【Transformation 3】 but, 【Chemistry 4】 2. The compound of claim 1, wherein the compound represents an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

14. T is a straight chain or branched chain (C １ ~C ６ ) alkyl group or (C １ ~C ４ ) alkylene-NR １ R ２ 2. The compound of claim 1, wherein R represents a group, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

15. T is one of the following: Methyl group, (piperidin-1-yl)methyl, (morpholin-4-yl)methyl, (piperidin-1-yl)ethyl, [(3R)-3-fluoropyrrolidin-1-yl]methyl, (4-fluoropiperidin-1-yl)methyl, [methyl(propan-2-yl)amino]methyl, (azepan-1-yl)methyl, (pyrrolidin-1-yl)methyl, [(3S)-3-methylpiperidin-1-yl]methyl, [(3R)-3-methylpiperidin-1-yl]methyl, [(1RS,5SR)-3-azabicyclo[3.1.0]hexan-3-yl]methyl, [(2S)-2-methylpiperidin-1-yl]methyl, {6-azaspiro[2.5]octan-6-yl}methyl, ( 4,4-difluoropiperidin-1-yl)methyl, (diethylamino)methyl, (4-methylpiperidin-1-yl)methyl, [ethyl(propan-2-yl)amino]methyl, {5-azaspiro[2.3]hexan-5-yl}methyl, (3,3-dimethylpyrrolidin-1-yl)methyl, (diisopropylamino)methyl, [ethyl(isopropyl)amino]methyl, [(3R)-3-methylpyrrolidin-1-yl]methyl, [(3S)-3-methylpyrrolidin-1-yl]methyl, [(2S)-2-methylpyrrolidin-1-yl]methyl, 5-azaspiro[2.4]heptan-5-ylmethyl, 2-azaspiro[3.3]heptan-2-ylmethyl, and aminomethyl 15. The compound of claim 14, its enantiomers or diastereoisomers, or its addition salts with a pharmaceutically acceptable acid or base, wherein R represents a group selected from:

16. the below described: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{3-fluoro-4-[1-(2-fluoroethyl)piperidin-4-yl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(2-fluoro-4-methoxyphenyl)acetyl]-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-{2-[2-(4-{2-[cis-2,6-dimethylmorpholin-4-yl]ethoxy}phenyl)acetyl]-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, - 5-[2-(2-{4-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-fluorophenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-5-[2-[2-[2-fluoro-4-(2-tetrahydropyran-4-ylethoxy)phenyl]acetyl]-7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-(thiomorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-{7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[2-((2R)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide, N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide, N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-{[methyl(propan-2-yl)amino]methyl}-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(4-{2-[cyclopropyl(methyl)amino]ethoxy}-2-fluorophenyl)acetyl]-7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl}-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-((2R or S)-2-methylmorpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-[(piperidin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, - N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-[2-(2-{4-[2-(4,4-difluoropiperidin-1-yl)ethyl]phenyl}acetyl)-7-{[(3R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide, N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{4-[2-(4-fluoropiperidin-1-yl)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, N-(5-cyano-1,2-dimethylpyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-[2-(2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetyl)-7-{[(3S)-3-(piperidin-1-ylmethyl)-3,4-dihydro-1H-isoquinolin-2-yl]carbonyl}-3,4-dihydro-1H-isoquinolin-6-yl]pyrrole-3-carboxamide, - N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-[2-(2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetyl)-7-[(3S)-3-{[(3S)-3-methylpiperidin-1-yl]methyl}-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide 2. The compound of claim 1, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, selected from:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

18. 18. The pharmaceutical composition of claim 17 for use as an apoptosis promoter.

19. 18. A pharmaceutical composition according to claim 17 for use in the treatment of cancer, an autoimmune disease or an immune system disease.

20. 20. The pharmaceutical composition of claim 19, wherein the cancer is a hematological malignancy or a solid tumor.

21. 21. The pharmaceutical composition of claim 20, wherein the hematological malignancy is selected from myeloma, multiple myeloma, lymphoma, non-Hodgkin's lymphoma (NHL), leukemia, chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), and acute myeloid leukemia (AML).

22. 21. The pharmaceutical composition of claim 20, wherein the solid tumor is selected from bladder, brain, breast, uterine, esophageal and liver cancer, colorectal cancer, kidney cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer and lung cancer.

23. The pharmaceutical composition of claim 17 for use in treating a cancer selected from non-small cell lung cancer and small cell lung cancer.

24. 18. The pharmaceutical composition of claim 17 for use in combination with an anti-cancer agent selected from genotoxic agents, mitotic toxins, antimetabolites, proteasome inhibitors, kinase inhibitors and antibodies.

25. A compound according to any one of claims 1 to 16, its enantiomer or diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base; an anti-cancer agent selected from a genotoxic agent, a mitotic toxin, an antimetabolite, a proteasome inhibitor, a kinase inhibitor, and an antibody; A pharmaceutical composition comprising:

26. 25. The pharmaceutical composition of claim 24 for use in the treatment of cancer.

27. 18. The pharmaceutical composition according to claim 17, for use in the treatment of cancer requiring radiotherapy.

Images