5-[7-(3,4-DIHYDRO-1H-ISOQUINOLINE-2-CARBONYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-6-YL]-1H-PYRROL-3-CARBOXAMIDE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THEIR APPLICATIONS AS PRO-APOPTOTIC AGENTS

Abstract

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

Description

[0001] 5-[7-(3,4-DIHYDRO-1H-ISOQUINOLINE-2-CARBONYL)-1,2,3,4 TETRAHYDROISOQUINOLIN-6-Y L]-1H-PYRROLE-3-CARBOXAMIDE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USES AS PRO-APOPTOTIC AGENTS 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, to pharmaceutical compositions containing them and their uses as pro-apoptotic agents. The compounds of the present invention inhibit the activity of the Bcl-2 protein and may be of interest in the treatment of cancer, immune and autoimmune diseases. BACKGROUND OF THE INVENTION Apoptosis, or programmed cell death, is a physiological process that is crucial for embryonic development and maintenance of tissue homeostasis. Apoptotic-type cell death involves morphological changes such as condensation of the nucleus, DNA fragmentation and also biochemical phenomena such as the activation of caspases which cause damage to key structural components of the cell, so inducing its disassembly and death. Regulation of the process of apoptosis is complex and involves the activation or repression of several intracellular signalling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656). Deregulation of apoptosis is involved in certain pathologies. Accordingly, absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70). The anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies. The involvement of proteins of the Bcl-2 family is described in numerous types of cancer, such as colon cancer, breast cancer, small-cell lung cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia, follicular lymphoma, myeloma, and prostate cancer. Overexpression of the anti-apoptotic proteins of the Bcl-2 family is involved in tumorigenesis, in resistance to chemotherapy and in the clinical prognosis of patients affected by cancer. There is, therefore, a therapeutic need for compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family. Venetoclax (also known as ABT-199) is a selective Bcl-2 inhibitor that counteracts the interaction of Bcl-2 with BH3-only proteins thus inducing apoptosis. Venetoclax is approved (i) to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior treatment and (ii) in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who are 75 years of age or older, or have other medical conditions that prevent the use of standard chemotherapy. However, since a significant number of relapses are observed in CLL, an acquired mechanism of resistance seems to appear. In other high-affinity targeted therapies, target mutations responsible for resistance have been demonstrated (Garraway & Janne, Cancer Discovery 2012, 2, 214-226). In different venetoclax-resistant derived leukemia and lymphoma cell lines, Bcl-2 mutations affecting its hydrophobic groove have been identified (Fresquet et al., Blood 2014, 123, 4111-4119; Tahir et al., BMC Cancer, 17:399). One mutation on Bcl-2 (Glycine substituted by a Valine in position 101: Gly101Val) was recently shown to be clinically relevant since identified in CLL samples from patients resistant to venetoclax. This Gly101Val (also called G101V) mutation was associated with reduced venetoclax binding to the hydrophobic groove of Bcl-2 and resistance to venetoclax (Blombery et al., Cancer Discovery 2019, 9, 342-353). Following the G101V identification, several other mutations in the BCL-2 protein were identified in patients treated with venetoclax in 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 refractory mantle cell lymphoma following sequential venetoclax / zanubutinib monotherapy (Thompson et al., Blood 2022, 25;6(2):503-508). Acquired BCL-2 mutations (D111A) have also been disclosed in multiple myleoma patients treated with venetoclax (Neri et al., Blood, 134 (Supplement_1):572). F104I has also been described 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 new therapeutic agents that can be used to treat cancer patients who carry the BCL-2 mutations following venetoclax treatment, and especially refractory and relapsed patients. The generation of BCL-2–selective inhibitors is complicated by the high degree of similarity within the BH3-binding domains of BCL-2 and BCL-XL (Petros et al., Proc. Natl. Acad. Sci. USA 2001, 98, 3012–3017). Besides, it has been previously established that BCL-XL is also the primary survival factor in 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, hypomorphic mutation, or pharmacologic inhibition of BCL-XL results in reduced platelet half-life and dose-dependent thrombocytopenia in vivo. Using a dual BCL-2 / BCL-XL inhibitor (ABT263, navitoclax), early signs of clinical antitumor activity have been observed 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 the number of circulating platelets. This mechanism-based thrombocytopenia is the dose-limiting toxicity of single-agent navitoclax treatment in patients and limits the ability to drive drug concentrations into a highly efficacious range. Consequently, there is also a need to minimize the BCL-XL affinity in order to design drugs exhibiting an advantageous effectiveness-tolerability profile. Last, drug interactions due to drug metabolism inhibition are frequent since CYP450-mediated metabolism is the major route of elimination for a large number of drugs (Deodhar et al., Pharmaceutics 2020, 4;12(9):846). Among CYP450, CYP3A4 is the most abundant in the human liver (∼40%) and metabolizes more than 50% of clinically used drugs. Thus, drugs inhibiting CYP3A4 may cause severe drug toxicity through the enhanced exposure to co- administered drugs (Zhou et al., Ther Clin Risk Manag 2005, Mar;1(1):3-13). This issue needs also to be addressed during the drug discovery process to mitigate the CYP3A4 drug-drug interaction risk. Here, we claim the discovery of next generation BCL-2 inhibitors that are selective for BCL-2 protein with limited on-target affinity for BCL-XL and platelets loss, highly potent on BCL-2 wild type protein and showing good selectivity profile on the different BCL-2 mutations appearing in clinic following venetoclax treatment. The identified compounds also showed limited inhibition of CYP3A4. SUMMARY OF THE INVENTION The present invention provides potent selective Bcl-2 inhibitors of formula (I) as defined below. We have shown that these compounds have a strong binding affinity on Bcl-2 wild-type receptor as well as on a panel of Bcl-2 mutants. The compounds of the invention demonstrated an overall better on-target affinity for the Bcl-2 proteins ac compared to Bcl-xL protein. We have also shown that the compounds of formula (I) have a cytotoxic profile in cell lines overexpressing Bcl-2 wild-type or Bcl-2 mutants. Furthermore, the compounds of formula (I) are able to induce apoptosis of cancer cells in vivo, triggering tumor regression in mice. Last, we have observed that the platelet loss in animals highly exposed to exemplary compounds is limited. Moreover, exemplary compounds also exhibited a limited inhibitory potential towards CYP3A4. Based on their pro-apoptotic properties, the compounds of the invention could be of interest for the treatment of pathologies involving a deregulation in apoptosis, such as, for example, cancer, auto-immune diseases and diseases of the immune system. In a first aspect, the present invention provides compounds of formula (I): wherein: · Z1 and Z2 represent both a methyl group or they form together with the atoms carrying them a fused piperidine group, · T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, a (C1-C4)alkylene-NR1R2 group, a (C1- C4)alkylene-ORi group, · R1and R2independently of one another represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, or R1 and R2 form with the nitrogen atom carrying them a heterocycloalkyl group, which heterocycloalkyl is optionally substituted by one to three groups selected from: (C1- C6)alkyl group and halogen atom, · R3 represents a group selected from: · R4 represents a group selected from: · R5 represents a hydrogen atom, a halogen atom or a hydroxy group, · R6represents a hydrogen, a linear or branched (C1-C6)alkyl group, or a halogen atom, · Alk represents a linear or branched (C1-C6)alkyl group, · A1represents a C-Y4or a nitrogen atom, · A2 represents a C-H or a nitrogen atom, · Cy1represents a phenyl, a heteroaryl, a cycloalkyl or a heterocycloalkyl group, wherein the phenyl, the heteroaryl, the cycloalkyl and the heterocycloalkyl groups are optionally substituted by one to three groups selected from: linear or branched (C1-C6)alkyl group optionally substituted by 1 to 3 halogen atoms, hydroxy group, cycloalkyl group, and halogen atom and the heterocycloalkyl group is optionally further substituted by an oxo group, · Cy2 represent a phenyl or a heteroaryl group, wherein the phenyl and the heteroaryl groups are optionally substituted by one to three groups selected from: linear or branched (C1-C6)alkyl group optionally substituted by 1 to 3 halogen atoms, hydroxy group, and halogen atom, · X represents a bond, -O-, -S- or NRk, · Y1 and Y5 independently of one another represent a group selected from: hydrogen atom, halogen atom, cyano, linear or branched (C1-C6)alkyl group, and linear or branched (C1-C6)alkoxy group, · Y2 and Y4 independently of one another represent a group selected from: hydrogen atom, halogen atom, linear or branched (C1-C6)alkyl group, linear or branched (C1- C6)alkoxy group, and heterocycloalkyl group optionally substituted by a linear or branched (C1-C6)alkyl group, · Y3 represents a group selected from: hydrogen atom, halogen atom, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkynyl, -(C1-C4)alkylene-ORl, linear or branched (C1-C6)alkoxy group, -O-phenyl, -S-phenyl, -O-(C1-C4)alkylene-Cy3, -O-(C1- C4)alkylene-Cy4, -O-Cy3, -O-(C1-C4)alkylene-NRgRh, -(C1-C4)alkylene-Cy3, -(C1- C4)alkylene-Cy4, Cy3, Cy4,and: , wherein the alkylene moiety of the preceding groups may be linear or branched, · Cy3represents a heterocycloalkyl optionally substituted by one to three groups selected from: linear or branched (C1-C6)alkyl group optionally substituted by 1 to 3 halogen atoms, hydroxy group, cycloalkyl group, heterocycloalkyl group, and halogen atom, · Cy4 represents a cycloalkyl optionally substituted by one to three groups selected from: linear or branched (C1-C6)alkyl group optionally substituted by 1 to 3 halogen atoms, hydroxy group, cycloalkyl group, heterocycloalkyl group, and halogen atom · Raand Rbindependently of one another represent a hydrogen atom or a halogen atom, · Rc represents a group selected from: hydrogen, linear or branched (C1-C6)alkyl group optionally substituted by 1 to 3 halogen atoms, (C1-C6)alkylene-NRdRe, (C1- C6)alkylene-ORj, cycloalkyl, heterocycloalkyl, and (C1-C6)alkylene-heterocycloalkyl group, · R’c and R’’c independently of one another represent a hydrogen atom or a linear or branched (C1-C6)alkyl (preferably a methyl), · Rd and Re independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, a cycloalkyl group or a heterocycloalkyl group, · Rf represents a hydrogen atom, a halogen atom or a cyano group, · R’f represents a hydrogen atom or a halogen atom, · Rgand Rhindependently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, a cycloalkyl group, a heterocycloalkyl group, or a –(C1-C6)alkylene-heterocycloalkyl, · Ri, Rj, and Rkindependently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, or a –(C1-C6)alkylene-cycloalkyl group, · Rlrepresents a hydrogen atom, a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)alkylene-heterocycloalkyl group, · Rm represents a hydrogen or a linear or branched (C1-C6)alkyl group, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. In another aspect, the invention provides compounds of formula (I) as described herein, for use in the treatment of cancer, autoimmune diseases and the disease of immune system. In a further aspect, the invention provides a pharmaceutical composition comprising the compounds of Formula (I) as described herein, and at least one pharmaceutically acceptable excipient. DEFINITIONS Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic 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, methanesulphonic acid, camphoric acid, etc. Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. “heteroaryl” means any monocyclic or fused bicyclic group composed of from 5 to 12 ring members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen. Among the heteroaryl groups, there may be mentioned, without implying any limitation, 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, thienopyrimidinyl, 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, etc. “cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, which may include fused, bridged or spiro ring systems. Among the cycloalkyl groups, there may be mentioned, without implying any limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group, composed of from 3 to 10 ring members, and containing from one to 3 hetero atoms or groups selected from oxygen, sulphur, SO, SO2and nitrogen, wherein the bicyclic group may be fused or spiro type. Heterocycloalkyl group may have one double bond. Among the heterocycloalkyl groups, there may be mentioned, without implying any limitation, 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-1λ⁶-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 called cis-3-azabicyclo[3.1.0]hexanyl), etc. “(C1-C6)alkylene” means a divalent linear or branched, saturated hydrocarbon radical having from 1 to 6 carbon atoms. Among the alkylene radicals, there may be mentioned, without implying any limitation, -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)-, etc. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules. The pharmaceutical compositions according to the invention comprise one or more excipients or carriers selected from diluents (such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol…), lubricants (such as silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol…), binders (such as magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone…), disintegration agents (such as agar, alginic acid and its sodium salt, effervescent mixtures…), stabilizers, preservatives, absorbents, colorants, sweeteners, flavorings, etc. The administration route is preferably the oral route or the intravenous route, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients. Among the combinations of a compound of formula (I) with an anticancer agent according to the invention, there may be mentioned more especially those that are suitable for a simultaneous administration or a sequential administration. The combinations according to the invention comprise a compound of formula (I) combined to anti-cancer agents selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors, protein- protein interaction inhibitors, immunomodulators, E3 ligase inhibitors, chimeric antigen receptor T-cell therapy and antibodies. The compounds of the combination may moreover 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 in admixture. As used herein, the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which 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 a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. Among the cancer treatments envisaged there may be mentioned, without implying any limitation, the treatment of haematological malignancies and solid tumors. Haematological malignancies include myeloma, especially multiple myeloma, lymphoma, especially Non- Hodgkin Lymphoma (NHL) and Diffuse Large B-cell Lymphoma (DLBCL), and leukemia, especially Chronic Lymphocytic Leukemia (CLL), T-cell Acute Lymphoblastic Leukemia (T- ALL), B-cell Acute Lymphoblastic Leukemia (B-ALL) and Acute Myelogenous Leukemia (AML). Solid tumors include the bladder, brain, breast, uterus, œsophagus and liver cancers, colorectal cancer, renal cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer and lung cancer, especially non-small-cell lung cancer and small-cell lung cancer. Among the treatments of autoimmune diseases envisaged there may be mentioned, without implying any limitation, the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon 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 being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A suitable daily dose of a compound of the invention will depend upon the factors described above and may range from 0.01 mg to 2.5 g per day in one or more administration(s). DETAILED DESCRIPTION Advantageously, the compound of the invention has the formula (I-a):

[0002] wherein R3, R4, R5, R6 and T are as defined in claim 1. In a preferred embodiment, R3represents the following group: and Rc represents a group selected from: hydrogen, linear or branched (C1-C6)alkyl group optionally substituted by 1 to 3 halogen atoms, (C1-C6)alkylene-NRdRe, (C1-C6)alkylene-ORj, cycloalkyl, heterocycloalkyl, and (C1-C6)alkylene-heterocycloalkyl group. Preferably, Rcrepresents 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, Rcrepresents a methyl group. In another embodiment, R3 represents the following group: and Rc represents a group selected from: methyl, ethyl, oxanyl, 2-methoxyethyl, 2- methylpropyl, difluoromethyl, and 2-(dimethylamino)ethyl. Even more preferably, Rcrepresents a methyl group. In some embodiments, R4represents the following group: wherein Ra, Rb, X, A1, Y1, Y2, Y3, Y5are as defined in E1. Described below are a number of embodiments of the invention, where for convenience E1 is identical to the first aspect of the invention hereinabove. Further enumerated embodiments (E) of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. E2. The compound according to E1 having the formula (I-b):

[0003] wherein R5, R6, Ra, Rb, Rc, X, A1, Y1, Y2, Y3, Y5and T are as defined in E1. Advantageously, Rc represents a methyl group. E3. The compound according to E1 having the formula (I-c): wherein R5, R6, Ra, Rb, Rc, R’c, R’’c, X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1. E4. The compound according to E1 having the formula (I-d):

[0004] wherein R5, R6, Ra, Rb, X, A1, Y1, Y2, Y3, Y5and T are as defined in E1. E5. The compound according to E1 having the formula (I-e): wherein R5, R6, Ra, Rb, X, A1, A2, Y1, Y2, Y3, Y5 and T are as defined in E1. E6. The compound according to E1 having the formula (I-f): wherein R5, R6, Ra, Rb, Rf, Rm, X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1. Preferably, Rm represents a methyl group. E7. The compound according to E1 having the formula (I-g): wherein R5, R6, Ra, Rb, Rf, X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1. E8. The compound according to E1 having the formula (I-h): wherein R5, R6, Ra, Rb, Rm, X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1. Preferably, Rmrepresents a methyl group. E9. The compound according to E1 having the formula (I-i): wherein R5, R6, Ra, Rb, R’c, R’f, X, A1, Y1, Y2, Y3, Y5and T are as defined in E1. E10. The compound according to E1 having the formula (I-j): wherein R5, R6, Ra, Rb, Rc, R’c, R’’c, X, A1, Y1, Y2, Y3, Y5 and T are as defined in E1. E11. The compound according to any of E2 to E10 wherein X represents a bond. E12. The compound according to any of E2 to E10 wherein A1 represents C-Y4. E13. The compound according to any of E2 to E10 wherein Raand Rbrepresent both a hydrogen atom. E14. The compound according to any of E2 to E10 wherein R5represents a hydrogen atom, a hydroxy group or a fluorine atom, preferably a hydroxy group. E15. The compound according to any of E2 to E10 wherein R6represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom. E16. The compound according to any of E2 to E10 wherein R5 represents a hydroxy group and R6represents a hydrogen atom. E17. The compound according to any of E2 to E10 wherein A1represents C-H and Y2represents a hydrogen atom. E18. The compound according to any of E2 to E10 wherein Y1and Y5represent both a hydrogen atom, or: Y1 and Y5 represent a fluoro atom and a hydrogen atom, respectively. E19. The compound according to any of E2 to E10 wherein Y3 represents a -O-(C1- C4)alkylene-Cy3 group. Preferably, the (C1-C4)alkylene group is ethylene. E20. The compound according to any of E2 to E10 wherein Y3 represents a -O-(C1- C4)alkylene-NRgRh. Preferably, the (C1-C4)alkylene group is ethylene. Even more preferably, Y3represents a group selected from: 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-{methyl[(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. In some embodiments, Y3 represents a group selected from: 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-1λ⁶-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. 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, 2-(4,4-difluoropiperidin-1-yl)ethyl. Another embodiment of the present disclosure relates to the compound of formula (I) wherein the group: In some embodiments, T represents a linear or branched (C1-C6)alkyl group or a (C1- C4)alkylene-NR1R2 group. Advantageously, T represents a group selected from: methyl group, (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 an other embodiment, T represents a group selected from: 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. In some embodiments, T represents a (C1-C4)alkylene-ORi group. Advantageously, T represents a group selected from: methoxymethyl, ethoxymethyl, and cyclopropylmethoxymethyl. 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. The invention relates also to a process for the preparation of a compound of formula (I) characterised in that there is used as starting material the compound of formula (II): which is subjected to peptide coupling with a compound of formula (III): wherein T is as defined in formula (I), wherein T is as defined in formula (I), the carboxybenzyl (Cbz) protecting group of which compound of formula (IV) is then replaced with a tert-butyloxycarbonyl (Boc) group before hydrolising the ester function of the pyrrole moiety to yield the compound of formula (V): wherein T is as defined in formula (I), compound of formula (V) which is coupled with the following amine: wherein R3, R5and R6are as defined in formula (I), to yield the compound of formula (VII): wherein T, R3, R5and R6are as defined in formula (I), which compound of formula (VII) is deprotected and subjected to an amidation or a sulfonylation reaction to yield the compound of formula (I), this latter compound may be purified according to a conventional separation technique, may be converted into its addition salts with a pharmaceutically acceptable acid or base and may be separated into its isomers according to a conventional separation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino) of the starting reagents or of the synthesis intermediates can be protected and subsequently deprotected, as required by the synthesis. In another embodiment, the invention relates to a process for the preparation of a compound of formula (I) characterised in that there is used as starting material the compound of formula (II): the ester function of which compound of formula (II) is hydrolysed to yield the corresponding carboxylic acid, which is then subjected to a reaction with 1,1-di-tert-butoxy-N,N-dimethyl- methanamine to yield the compound of formula (VIII): wherein tBu represents a tert-butyl group, compound of formula (VIII) which is coupled with the amine of formula (VI): wherein R3, R5 and R6 are as defined in formula (I), to yield the compound of formula (IX):

[0005] wherein R3, R5and R6are as defined in formula (I), the carboxybenzyl protecting group of which compound of formula (IX) being removed by a catalytic hydrogenation reaction to yield the compound of formula (X): wherein R3, R5and R6are as defined in formula (I), which compound is subjected to an amidation or a sulfonylation reaction to yield the compound of formula (XI): wherein R3, R4, R5 and R6 are as defined in formula (I), the tert-butyl ester function of which compound of formula (XI) being deprotected, before being subjected to peptide coupling with a compound of formula (III): wherein T is as defined in formula (I), to yield the compound of formula (I), this latter compound may be purified according to a conventional separation technique, may be converted into its addition salts with a pharmaceutically acceptable acid or base and may be separated into its isomers according to a conventional separation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino) of the starting reagents or of the synthesis intermediates can be protected and subsequently deprotected, as required by the synthesis. Pharmacological studies of the compounds of the invention have shown that they have pro- apoptotic properties. The ability to reactivate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancer and of immune and auto-immune diseases. In particular, the compounds according to the invention will be useful in the treatment of chemo- or radio-resistant cancers. In some embodiments of the present disclosure, the compounds of the invention are very potent on the BCL2 wild type protein (i.e. with a EKI_BCL2 wild type value lower than 1 nM in the TR-FRET assay) and on the BCL2 G101V mutant (i.e. with a [EKI BCL2 G101V] / [EKI BCL2 wild type] selectivity ratio lower than 10, more preferably lower than 5) whilst showing a limited on-target affinity for BCL-XL (i.e. with a [EKI BCL-XL] / [EKI BCL2 wild type] selectivity ratio higher than 10). In a further embodiment, the compounds of the invention also exhibit an overall better on-target affinity for the Bcl-2 wild type protein and the Bcl-2 mutants as compared to Bcl-xL protein. In some embodiments, the Bcl-2 mutants (also called BCL2 mutated proteins) are 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. In some embodiments of the present disclosure, the compounds of the invention are highly potent on the BCL2 wild type protein (i.e. with a EKI_BCL2 wild type value lower than 100 pM in the TR-FRET assay) whilst showing a limited on-target affinity for BCL-XL (i.e. with a [EKI BCL-XL] / [EKI BCL2 wild type] selectivity ratio higher than 100). The present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. In particular, these pharmaceutical compositions are interesting for use as anti-apoptotic inhibitors, particularly, in the treatment of cancer (haematological malignancy and solid tumor) and of auto-immune and immune system diseases. Particularly, these pharmaceutical compositions are interesting for use as anti-apoptotic inhibitors in the treatment of cancer chemo-resistant or radio-resistant. Preferably, these pharmaceutical compositions can be used in the treatment of cancer (haematological malignancy and solid tumor) and of auto-immune and immune system diseases selected from myeloma, especially multiple myeloma, lymphoma, especially Non- Hodgkin Lymphoma (NHL) and Diffuse Large B-cell Lymphoma (DLBCL), leukemia, especially Chronic Lymphocytic Leukemia (CLL), T-cell Acute Lymphoblastic Leukemia (T- ALL), B-cell Acute Lymphoblastic Leukemia (B-ALL) and Acute Myelogenous Leukemia (AML), bladder, brain, breast, uterus, œsophagus and liver cancers, colorectal cancer, renal cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer, lung cancer, especially non-small-cell lung cancer and small-cell lung cancer, rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). In some embodiments, the compounds of formula (I) are used in the manufacture of medicaments for use in the treatment of cancer and of auto-immune and immune system diseases. Furthermore, the present invention relates also to the combination of a compound of formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors, protein-protein interaction inhibitors, immunomodulators, E3 ligase inhibitors, chimeric antigen receptor T-cell therapy and antibodies, and also to pharmaceutical compositions comprising that type of combination and their use in the manufacture of medicaments for use in the treatment of cancer, particularly, haematological malignancy and solid tumors selected from myeloma, especially multiple myeloma, lymphoma, especially Non-Hodgkin Lymphoma (NHL) and Diffuse Large B-cell Lymphoma (DLBCL), leukemia, especially Chronic Lymphocytic Leukemia (CLL), T-cell Acute Lymphoblastic Leukemia (T-ALL), B-cell Acute Lymphoblastic Leukemia (B-ALL) and Acute Myelogenous Leukemia (AML), bladder, brain, breast, uterus, œsophagus and liver cancers, colorectal cancer, renal cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer and lung cancer, especially non-small-cell lung cancer and small-cell lung cancer. In another aspect, the compounds of the invention can be used in combination with radiotherapy in the treatment of cancer. Alternatively, the compounds of the invention may be linked to monoclonal antibodies. Antibody Drug Conjugates (ADCs) represent a new class of therapeutics that is formed by chemically linking a cytotoxic drug to a monoclonal antibody through a linker. The monoclonal antibody of an ADC selectively binds to a target antigen of a cell (e.g. cancer cell) and releases the drug into the cell. ADCs have therapeutic potential because they combine the specificity of the antibody and the cytotoxic potential of the drug. Nonetheless, developing ADCs as therapeutic agents has thus far met with limited success owing to a variety of factors such as unfavorable toxicity profiles, low efficacies and poor pharmacological parameters. Accordingly, there is still a need for new ADCs that overcome these problems and can selectively deliver Bcl-2 to target cancer cells. In another aspect, the compounds of the invention may be linked to fragments of monoclonal antibodies or linked to scaffold proteins that can be related or not to monoclonal antibodies. Antibody fragments must be understood as fragments of Fv, scFv, Fab, F(ab')2, F(ab'), scFv- Fc type or diabodies, which generally have the same specificity of binding as the antibody from which they are descended. According to the present invention, antibody fragments of the invention can be obtained starting from antibodies by methods such as digestion by enzymes, such as pepsin or papain, and / or by cleavage of the disulfide bridges by chemical reduction. In another manner, the antibody fragments comprised in the present invention can be obtained by techniques of genetic recombination likewise well known to the person skilled in the art or else by peptide synthesis by means of, for example, automatic peptide synthesizers such as those supplied by the company Applied Biosystems, etc. Scaffold proteins that can be related or not to monoclonal antibodies are understood to mean a protein that contains or not an immunoglobulin fold and that yields a binding capacity similar to a monoclonal antibody. The person skilled in the art knows how to select the protein scaffold. More particularly, it is known that, to be selected, such a scaffold should display several features as follow (Skerra, J. Mol. Recogn. 2000, 13, 167-187): phylogenetically good conservation, robust architecture with a well-known three-dimensional molecular organization (such as, for example, crystallography or NMR), small size, no or only a low degree of post-translational modifications, easy to produce, express and purify. Such a protein scaffold can be, but without limitation, a structure selected from the group consisting in fibronectin and preferentially the tenth fibronectin type III domain (FNfn10), lipocalin, anticalin (Skerra, J. Biotechnol.2001, 74, 257-75), the protein Z derivative from the domain B of staphylococcal protein A, thioredoxin A or any protein with a repeated domain such as an “ankyrin repeat” (Kohl et al. PNAS 2003, 100, 1700-1705), “armadillo repeat”, “leucine-rich repeat” or “tetratricopeptide repeat”. There could also be mentioned a scaffold derivative from toxins (such as, for example, scorpion, insect, plant or mollusc toxins) or protein inhibitors of neuronal nitric oxide synthase (PIN). The following Examples illustrate the invention but do not limit it in any way. All the reagents for preparing Examples are either commercially available or can be obtained by the person skilled in the art using conventional chemical reactions described in the literature.

[0006] GENERAL SYNTHETIC REMARKS All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying. The reactions were monitored using LCMS and GCMS instruments and / or TLC. TLC Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F254 silica-gel. Column Chromatography Automated flash column chromatography was performed on ISCO CombiFlash® Rf 200 or CombiFlash® Rf+ LumenTM using RediSep® Rf Normal-phase Silica Flash Columns (35-70µm, 60 Å), RediSep Rf Gold® Normal-phase Silica High Performance Columns (20-40µm, 60 Å), RediSep® Rf Reversed-phase C18 Columns (40-63 ^m, 60 Å), or RediSep Rf Gold® Reversed- phase C18 High Performance Columns (20-40 ^m, 100 Å). For HILIC RediSep Rf Gold® Normal-phase Silica High Performance Columns (20-40µm, 60 Å) were used. Microwave Reactions Microwave heating was performed with a CEM Discover® SP, or with an Anton Paar Monowave Microwave Reactor. NMR 1H-NMR and 13C-NMR measurements were performed on Bruker Avance III 500 MHz spectrometer, Bruker Avance III 400 MHz spectrometer, Bruker DPX 400 MHz spectrometer and Bruker Avance NEO 400 MHz spectrometer, using DMSO-d6or CDCl3as solvent. 1H NMR data is in the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-d6and 7.26 ppm for CDCl3) as internal standard. Splitting 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), dm (doublet of multiplets). In certain cases ^ due to the complexity ^ only the decisive signals of the carbon spectra were interpreted. Analytical GC-MS Combination gas chromatography and low-resolution mass spectrometry (GC-MS) was performed on Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using 15 m × 0.25 mm column with 0.25 µm HP-5MS coating and helium as carrier gas. Ion source: EI+, 70 eV, 230°C, quadrupole: 150°C, interface: 300°C. Analytical LC-MS The compounds of the present invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) using the following instruments: Agilent HP1200 LC with Agilent MSD 6140 single quadrupole, operating in positive or negative ion electrospray ionisation mode. Molecular weight scan range is 100 to 1350 m / z. Parallel UV detection was done at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in MeCN, or in THF / water (1:1) with 5 µL loop injection. LCMS analyses were performed on 2 instruments, one of which was operated with basic, and the other with acidic eluents. Basic LCMS: Gemini-NX, 3 µm, C18, 50 mm × 3.00 mm i.d. column at 23°C, at a flow rate of 1 mL min-1 using 5 mM aq. NH4HCO3solution (Solvent A) and MeCN (Solvent B) with a gradient starting from 100% Solvent A and finishing at 100% Solvent B over various duration of time. Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 µm, 50 mm × 4.6 mm i.d. column at 40°C, at a flow rate of 1 mL min-1 using 0.02% V / V aq. HCOOH solution (Solvent A) and 0.02% V / V HCOOH solution in MeCN (Solvent B) with a gradient starting from 100% Solvent A and finishing at 100% Solvent B over various duration of time. Agilent HP1260 Infinity II LC with InfinityLab LC / MSD, operating in positive ion electrospray ionisation mode. Molecular weight scan range is 100 to 1350 m / z. Parallel UV detection was done at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in MeCN, or in methanol with 1-5 µL loop injection operated with Kinetex® XB-C18, 2.6 µm, 50 mm × 2.1 mm i.d. column at 40°C, at a flow rate of 1 mL min-1 using 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) with a gradient starting from 100% Solvent A and finishing at 100% Solvent B over various duration of time. Agilent HP1200 LC with Agilent MSD 6120 Quadrupole LC / MS, operating in positive or negative ion electrospray ionisation mode. Molecular weight scan range is 100 to 1350 m / z. Parallel UV detection was done at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in MeCN, or in methanol with 1-5 µL loop injection operated with Gemini® NX-C18, 3 µm, 50 mm × 3 mm i.d. column at 40°C, at a flow rate of 0.8 mL min-1 using 5 mM NH4HCO3solution in 20 / 1 water / MeCN (Solvent A) and MeCN (Solvent B) with a gradient starting from 100% Solvent A and finishing at 90% Solvent B over various duration of time. High-resolution MS Agilent 1200 SL series instrument linked to an Agilent MSD 6140 single quadrupole with an ESI-APCI multimode source or using an Agilent 1290 Infinity II series instrument connected to an Agilent TOF 6230 with an ESI-jet stream source; column: Thermo Accucore 2.6 µm, C18, 50 mm × 2.1 mm at 55°C or Agilent Zorbax Eclipse plus 3.5 µm, C18, 30 mm × 2.1 mm at 35°C; eluents: Solvent A: 10 mM aq. NH4OAc solution + 0.08% (v / v) HCOOH; Solvent B: MeCN + 5% (v / v) Solvent A + 0.08% (v / v) HCCOH, with a gradient starting from 95% Solvent A and finishing at 95% Solvent B over various duration of time; ionisation is recorded in positive mode, negative mode, or positive-negative switching mode. TOF (basic): Agilent 6230 time-of-flight mass spectrometer equipped with a Jet Stream electrospray ion source in positive ion mode. Injections of 0.5μl were directed to the mass spectrometer at a flow rate 0.7 ml / min (5mM ammonium-bicarbonate in water and acetonitrile gradient program), using an Agilent 1290 Infinity HPLC system. Jet Stream parameters: drying gas (N2) flow and temperature: 8.0 l / min and 325 °C, respectively; nebulizer gas (N2) pressure: 30 psi; capillary voltage: 3000 V; sheath gas flow and temperature: 325 °C and 10.0 l / min; TOFMS parameters: fragmentor voltage: 100 V; skimmer potential: 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 by Agilent MassHunter B.08.00 / 10.10 software. 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. Injections of 0.5μl were directed to the mass spectrometer at a flow rate 0.7 ml / min (5mM ammonium-formate in water and acetonitrile gradient program), using an Agilent 1290 Infinity HPLC system. Jet Stream parameters: drying gas (N2) flow and temperature: 10.0 l / min and 300 °C, respectively; nebulizer gas (N2) pressure: 40 psi; capillary voltage: 2500 V; sheath gas flow and temperature: 300 °C and 10.0 l / min; TOFMS parameters: fragmentor voltage: 100 V; skimmer potential: 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 by Agilent MassHunter B.08.00 / 10.10 software. Preparative HPLC Certain compounds of the present invention were purified by high performance liquid chromatography (HPLC) on the following instruments: Armen Spot Prep II Liquid Chromatography or Teledyne CombiFlash EZ Prep system with a Gemini NX® 5 µM C18, 250 mm × 50 mm i.d. column running at a flow rate of 118 mL min- 1 with UV diode array detection (210 – 400 nm) using 25 mM aqueous NH4HCO3 solution and MeCN or 0.1% TFA in water and MeCN as eluents. Waters FractionLynx MS autopurification system, with a Gemini® 5 µm C18(2), 100 mm × 20 mm i.d. column from Phenomenex, running at a flow rate of 20 mL min-1 with UV diode array detection (210–400 nm) and mass-directed collection. The mass spectrometer was a Waters Micromass ZQ2000 spectrometer, operating in positive or negative electrospray ionisation modes, with a molecular weight scan range of 150 to 1000. pH4 eluents: Solvent A: 10 mM aq. NH4OAc solution + 0.08% (v / v) HCOOH; Solvent B: MeCN + 5% (v / v) Solvent A + 0.08% (v / v) HCOOH. pH9 eluents: Solvent A: 10 mM aq. NH4OAc solution + 0.08% (v / v) cc. aq. NH3solution; Solvent B: MeCN + 5% (v / v) Solvent A + 0.08% (v / v) cc. aq. NH3solution. AccQPrep HP125 (Teledyne ISCO) system, with a Gemini® NX 5 µm C18(2), 150 mm × 21.2 mm i.d. column from Phenomenex, running at a flow rate of 20 mL min-1 or Gemini® NX 5 µm C18(2), 250 mm × 30 mm i.d. column from Phenomenex, running at a flow rate of 40 mL min-1 with UV (214 and 254 nm) and ELS detection. pH4 eluents: Solvent A: water + 0.08% (v / v) HCOOH; solvent B: MeCN + 0.08% (v / v) HCOOH. pH9 eluents: Solvent A: water + 0.08% (v / v) cc. aq. NH3solution; solvent B: MeCN + 0.08% (v / v) cc. aq. NH3solution. Neutral eluents: Solvent A: water; Solvent B: MeCN. Chemical naming IUPAC-preferred names were generated using ChemAxon’s ‘Structure to Name’ (s2n) functionality within MarvinSketch or JChem for Excel (JChem versions 16.6.13 – 18.22.3), or with the chemical naming functionality provided by Biovia® Draw 4.2. Abbreviations AcOH acid acetic ACN acetonitrile aq. aqueous BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ - biphenyl)]palladium(II) methanesulfonate Boc or tBu ester tert-butyloxycarbonyl tBuOH tert-butanol Cbz carboxybenzyl cc. concentrated DAST diethylaminosulfur trifluoride DavePhos 2-dicyclohexylphosphino-2’'-(N,N-dimethylamino)biphenyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DIPEA diisopropylethylamine DMF N,N-dimethylformamide DTBAD di-tert-butyl azodicarboxylate ee. enatiomeric excess eq. equivalent EtOAc ethyl acetate Fmoc fluorenylmethoxycarbonyl HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate hu human IPA, i-PrOH or 2-PrOH Isopropyl alcohol MeCN acetonitrile MTBE methyl tert-butyl ether Pd2dba3 tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2DCM [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane PTFE polytetrafluoroethylene PyBop [(1H-benzotriazol-1-yl)oxy][tri(pyrrolidin-1-yl)]phosphonium hexafluorophosphate quant. quantitative rt room temperature sat. saturated TBAF tetrabutyl ammonium fluoride TBDMSCl tert-butyldimethylsilyl chloride TBTU [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl- ammonium, tetrafluoroborate (1:1) TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran THIQ 1,2,3,4-tetrahydroisoquinoline TIPSCl triisopropylsilyl chloride X-Phos 2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl GENERAL PROCEDURES The following are representative experimental procedures that are referred to by name in subsequent Preparations and Examples. General procedure 1a-Buchwald The appropriate aryl bromide (1 eq.), the appropriate aniline (1.1 eq.), 2-di-tert-butylphosphino- 2',4',6'-triisopropylbiphenyl (0.04 eq.) and NaOtBu (2 eq.) were suspended in toluene (3 mL / mmol aryl bromide). The mixture was sparged with N2 and then Pd2(dba)3 (0.04 eq.) was added, and the mixture was heated for 1 h at 110°C under microwave irradiation or at 70°C under a N2atmosphere until complete conversion was observed. The mixture was allowed to cool 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 MgSO4and concentrated in vacuo. The crude material was purified by automated flash chromatography using heptane and EtOAc as eluents. General procedure 1b-Buchwald To a solution of the appropriate aryl bromide (1 eq.) and the appropriate aniline (1 eq.) in THF (4.5 mL / mmol aryl bromide) was added NaOtBu (1 eq.) 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 eq.) and the mixture was stirred at rt under N2until 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 MgSO4 and concentrated in vacuo. The crude material was purified by automated flash chromatography using heptane or MeOH and EtOAc as eluents. General procedure 2a – Amide coupling To a solution of the appropriate acid (1 eq.) in DCE (12 mL / mmol acid) was added 4Å molecular sieves followed by 1-chloro-N,N,2-trimethyl-1-propenylamine (2 eq.) and then the mixture was stirred under N2 at rt for 30 mins. A solution of the appropriate aniline (1.5 eq.) and pyridine (2 eq.) in DCE (2.5 mL / mmol aniline) was added and the mixture stirred at 80°C under N2for 18 h. The mixture was allowed to cool to rt and partitioned between DCM and water. The phases were separated, and the organic phase was washed with sat. aq. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The crude material was purified by automated flash chromatography using heptane and EtOAc or DCM and MeOH as eluents. General procedure 2b – Amide coupling To a solution of the appropriate acid (1 eq.) in DCM (12 mL / mmol acid) was added oxalyl dichloride (1.7 eq.) and then the mixture was stirred under N2 at rt for 30 mins. The solution was concentrated in vacuo at rt then the appropriate aniline (1.2 eq.) in DCE (12 mL / mmol acid) was added and the mixture was stirred at 80°C under N2 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. General procedure 3a- tBu ester deprotection To a solution of the appropriate tBu ester (1 eq.) in 1,4-dioxane (5 mL / mmol) was added a solution of trimethylsilyl trifluoromethanesulfonate (5 eq.) and TEA (5 eq) in 1,4-dioxane (1 mL / mmol TEA) and the mixture stirred at rt for 5-18 h. The reaction mixture was poured into ice-water, stirred for 10 mins, then extracted with EtOAc. The organic phase was dried over MgSO4and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents. General procedure 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 / mmol silyl derivative) and the mixture stirred at rt until complete conversion was observed. The mixture was concentrated in vacuo and then partitioned between DCM and sat. aq. NaHCO3 solution. The phases were separated, and the organic phase was dried over MgSO4and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents or preparative HPLC automated flash chromatography at pH 9 or pH 4, using water and MeCN as eluents. General procedure 3c – TBAF deprotection To a solution of the appropriate silyl-derivative (1 eq.) in THF (50 mL / mmol) under N2was added 1 M TBAF in THF (2 eq.) and the mixture was stirred at rt for 18 h. The mixture was partitioned between DCM and sat. aq. NaHCO3 solution and then the phases were separated. The aqueous phase was extracted with DCM and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by automated flash chromatography using DCM and MeOH as eluents was followed by preparative HPLC automated flash chromatography at pH 4 or pH 9, using water and MeCN as eluents. General procedure 4a – Amide coupling To a solution of the appropriate amine (1 eq.) in DMF (6 mL / mmol 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 dried over MgSO4 and concentrated. Purification by automated flash chromatography using DCM and MeOH as eluents was followed by preparative HPLC automated flash chromatography at pH 9 or pH 4, using water and MeCN as eluents. General procedure 4b – Amide coupling To a solution of the appropriate amine (1 eq.) in DMF (6 mL / mmol 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 dried over MgSO4and 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. General procedure 4c – Consecutive amide coupling and silyl deprotection To a solution of the carboxylic acid (1.5 eq.) in DMF (6 mL / mmol acid) was added TBTU (3 eq.) followed by DIPEA (4 eq.). After stirring for 10 mins the appropriate amine (1 eq.) was added and the mixture was stirred at rt until complete conversion was observed.2M aq. NaOH solution (5 eq.) was added and the reaction mixture was further stirred until complete silyl deprotection was observed. The reaction mixture - after filtration - was directly injected to an RP C18 column and it was purified via preparative reversed phase chromatography. The appropriate fractions were combined, 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 furnish the targeted amide product which was further purified by automated flash chromatography using DCM and MeOH as eluents. General procedure 4d – Consecutive amide coupling and silyl deprotection Modified General procedure 4c: carboxylic acid chloride (1.2 eq.), DIPEA or TEA (2 eq.) in DCM (3 mL / mmol) were used in the place of carboxylic acid (1.5 eq.), DIPEA (4 eq.) and TBTU were omitted. General procedure 5 - THIQ Amide coupling HATU (1.1 eq.) was added portionwise to a stirred solution of the appropriate amine (1.05eq.), Boc-(3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1 eq.), and TEA (2 eq.) in DMF (10mL / mmol) under N2. The mixture was stirred at rt for 12 h, and then partitioned between EtOAc and sat. aq. NaHCO3solution. The phases were separated, and the organic phase was washed with brine, dried over MgSO4and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents. General procedure 5a - THIQ Amide coupling TBTU (1.5 eq.) was added portion-wise to a stirred solution of the Boc or Cbz protected (3S)- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1 eq.) and DIPEA (3 eq.) in DMF / DCM (5 mL / mmol acid) under N2. After stirring for 10 mins the appropriate amine (1.4 eq.) 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. General procedure 6 - THIQ Amide reduction and deprotection To a solution of the appropriate THIQ amide (1 eq.) in THF (5-7 mL / mmol THIQ) was added 1 M BH3.THF solution in THF (5 eq.) dropwise under an atmosphere of N2 at rt. The mixture was then heated to reflux for 5 h. The mixture was allowed to cool to rt, quenched by the slow addition of MeOH and then stirred for 10 min at rt. The mixture was concentrated under reduced pressure and the residue suspended in MeOH (5-7 mL / mmol). Concentrated HCl (4 eq. (12M)) was added and the mixture was refluxed for 1.5 h. The reaction was allowed to cool to rt, concentrated under reduced pressure and azeotroped with toluene. General procedure 6a - THIQ Amide reduction A solution of the appropriate THIQ amide (1 eq.) in DCM (5-10 mL / mmol THIQ) was cooled to 0°C with an ice-water bath, then 1M LiAlH4solution in THF (2 eq.) was added dropwise under an atmosphere of N2. The cooling bath was removed then the mixture was stirred at rt until complete conversion was observed. The mixture was diluted with THF, cooled to 0 °C then quenched by the subsequent addition of water and 15% aq. NaOH solution according Fieser’s workup method. Anhydrous MgSO4 was added (5g / mmol THIQ) then after 15 min stirring 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). General procedure 6b – Cbz deprotection To a N2flushed solution of the appropriate Cbz protected amine in methanol, THF or EtOAc (20 mL / mmol amine) 3-5 m / m % of Pd (10% on carbon) was added. The reaction mixture was hydrogenated at atmospheric pressure (by the aid of a H2 balloon) until complete conversion was observed. The catalyst was filtered out and the filtrate was concentrated under reduced pressure. General procedure 6c – Boc deprotection To a N2 flushed solution of the appropriate Boc protected amine in DCM (2.5-5 mL / mmol amine) HCl (2M solution in diethyl ether, 10 eq.) was added. The reaction mixture was stirred at rt overnight then concentrated in vacuo. General procedure 7a ^ O-Alkylation A stirred suspension of the appropriate phenol (1 eq.) and K2CO3 (5 eq.) in MeCN (5-10 mL / mmol) was heated at 70°C for 20 min. The appropriate alkyl halide (1.6 eq.) was added, and heating continued until complete conversion was observed. The mixture was allowed to cool to rt and filtered, washing 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. General procedure 7b ^ Mitsunobu To a solution of the appropriate phenol (1 eq.) in THF (5-10 mL / mmol) was added the appropriate alcohol (1 eq.) and PPh3 (1.5 eq.) followed by DTBAD (1.5 eq.) and then stirred at rt under N2for 12 h. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO3solution, 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. General procedure 7c ^ Mitsunobu In a pressure relief vial a solution of 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (1 eq.), the appropriate alcohol (2 eq.) and 2-(tributyl-λ5-phosphanylidene)acetonitrile (2 eq.) in toluene (2 mL / mmol) were stirred at 100°C under N2 for 1 h. The mixture was concentrated in vacuo and the residue was purified by automated flash chromatography using heptane and EtOAc or DCM as eluents. General procedure 7d ^ N-Alkylation A stirred suspension of the appropriate ester of 4-(2-bromoethoxy)phenylacetic acid derivative (1 eq.) and K2CO3 / Cs2CO3 (2-7 eq.) in MeCN (4-7 mL / mmol alkyl halide) and the appropriate amine (1.5-3 eq.) were 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. General procedure 8 ^ Ester hydrolysis A solution of the appropriate ester (1 eq.) in MeOH (3-11 mL / mmol) was treated with 2 M aq. NaOH solution (2 eq.) and stirred at rt for 24 h. The MeOH was removed in vacuo and the aqueous residue was neutralised with 2 M aq. HCl solution and then purified by reverse phase automated flash chromatography using water and MeCN as eluents. PREPARATIONS The following experimental details describe the preparation of synthetic intermediates. Preparation I: 2-benzyloxycarbonyl-6-(4-ethoxycarbonyl-1,5-dimethyl-pyrrol-2-yl)-3,4- dihydro-1H-isoquinoline-7-carboxylic acid The synthesis of the title compound is described in WO2015 / 011164 A1, in Example 805 Step B. 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 Step A: (3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride The synthesis of the title compound is described in WO2015 / 011164 A1 at Preparation 2b. Step 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

[0007] To a solution of Preparation I (3 g, 6.3 mmol, 1 eq.) and the product from Step A (1.27 g, 6.93 mmol, 1.1 eq.) in DMF (30 mL) was added DIPEA (3.13 mL, 18.89 mmol, 3 eq.) and PyBop (3.6 g, 6.93 mmol, 1.1 eq.) and the mixture stirred at rt for 12 h. The mixture was diluted with water (120 mL), stirred for 15 mins and the resultant cream precipitate was collected by filtration, washing with water. The filter cake was dissolved in DCM and washed with sat. aq. NaHCO3 solution and water, dried over MgSO4 and concentrated in vacuo to afford the title product (3.7 g, 6.11 mmol, 97%). HRMS calcd for C37H39N3O5: 605.289, found 606.296 [M+H]+ 1H 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). Step 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 To a solution of the product from Step B (3.7 g, 6.11 mmol, 1 eq.) in MeOH (70 mL) and EtOH (20 mL) was added 10% Pd / C (100 mg). The mixture was evacuated and backfilled with N2, then evacuated and flushed with H2 and then shaken at rt for 6 h under an atmosphere of H2. The mixture was filtered through a celite cartridge, washing with EtOH. The solvent was removed in vacuo to afford the title product (2.94 g, quant.). HRMS calcd for C29H33N3O3: 471.252, found 472.259 [M+H]+ 1H 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). Step 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 To a solution of the product from Step C (2.94 g, 6.23 mmol, 1 eq.) in THF (45 mL) and water (6 mL) was added bis(tert-butyl) dicarbonate (1.43 g, 6.55 mmol, 1.05 eq.) followed by TEA (1.73 mL, 12.47 mmol, 2 eq.) and the mixture stirred at rt for 12 h. The solvents were removed in vacuo and the residue partitioned between EtOAc and sat aq. NH4Cl solution. The phases were separated, and the organic phase was washed with sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo to afford the title product (3.39 g, 5.93 mmol, 95%). HRMS calcd for C H N O : 571.305, found 572.315 [M+H + 34 41 3 5 ] 1H 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).

[0008] Step 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 LiOH.H2O (995 mg, 23.72 mmol, 4 eq.) was added to a solution of the product from Step D (3.39 g, 5.93 mmol, 1 eq.) 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 rt and MeOH removed in vacuo. The aqueous residue was acidified with 1 M aq. HCl solution to pH 5, diluted with water (10 mL) and extracted with DCM. The combined organic extracts were dried over MgSO4and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 6% MeOH in DCM afforded the title product (3.1 g, 5.7 mmol, 96%). HRMS calcd for C H N O : 543.273, found 544.283 [M+H + 32 37 3 5 ] 1H 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). 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 Step A: (3S)-3-[(piperidin-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 (5.56 g, 20.05 mmol, 1 eq.) and piperidine (1.99 mL, 20.05 mmol, 1 eq.) as the appropriate amine afforded the title product (6.11 g, 17.74 mmol, 88%). LRMS calcd for C H + 20 28N2O3: 344.2, found 345.2 [M+H] 1H 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). Step B: (3S)-3-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride Using General procedure 6 and the product from Step A (6.09 g, 17.69 mmol, 1 eq.) as the appropriate THIQ amide afforded the title product (5.73 g, quant.). LRMS calcd for C15H22N2: 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). Step 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 To a solution of Preparation I (3 g, 6.3 mmol, 1 eq.) and the product from Step B (2.1 g, 6.93 mmol, 1.1 eq.) in DMF (25 mL) was added DIPEA (4.17 mL, 25.18 mmol, 4 eq.) and PyBop (3.6 g, 6.93 mmol, 1.1 eq.) and the mixture stirred at rt for 3 h. The mixture was diluted with water (40 mL) and sat. aq. NaHCO3 solution (10 mL) and stirred for 15 mins. The resultant cream precipitate was collected by filtration, washing with water. The filter cake was dissolved in EtOAc, washed with sat. aq. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to afford the title product (4.34 g, quant.). LRMS calcd for C42H48N4O5: 688.4, found 689.6 [M+H]+ 1H 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). Step 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 To a solution of the product from Step C (4.34 g, 6.3 mmol, 1 eq.) in MeOH (100 mL) was added 10% Pd / C (100 mg). The mixture was evacuated and backfilled with N2, then evacuated and flushed with H2 and then shaken at rt for 3 h under an atmosphere of H2. The mixture was filtered through a celite cartridge, washing with MeOH. The solvent was removed in vacuo to afford the title product (3.69 g, quant.). LRMS calcd for C + 34H42N4O3: 544.3, found 555.4 [M+H] 1H 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). Step 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 To a solution of the product from Step D (3.6 g, 6.49 mmol, 1 eq.) in THF (45 mL) and water (6 mL) was added bis(tert-butyl) dicarbonate (1.49 g, 6.81 mmol, 1.05 eq.) and TEA (1.8 mL, 12.98 mmol, 2 eq.) and the mixture stirred at rt for 5 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and sat aq. NH4Cl solution. Water was added, the phases were separated, and the organic phase was washed with brine, dried over MgSO4and concentrated in vacuo to afford the title product (4.27 g, quant.). LRMS calcd for C H N O : 654.4 + 39 50 4 5 , found 655.6 [M+H] 1H 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). Step 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 To a heterogenous mixture of the product from Step E (4.27 g, 6.52 mmol, 1 eq.) in MeOH (40 mL) and water (10 mL) was added LiOH.H2O (1.09 g, 26.08 mmol, 4 eq.) and the mixture was refluxed at 100°C for 24 h. The mixture was allowed to cool to rt and MeOH removed in vacuo. The aqueous residue was neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 14% MeOH (1% NH3) in DCM afforded the title product (2.56 g, 4.09 mmol, 63%). LRMS calcd for (C H N O ): 626.3, + 37 46 4 5 found 627.6 [M+H] 1H 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). 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

[0009] Step A: tert-butyl (3S)-3-[(pyrrolidin-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 (4 g, 14.42 mmol, 1 eq.) and pyrrolidine (0.92 mL, 15.14 mmol, 1.05 eq.) as the appropriate amine afforded the title product (4.33 g, 13.1 mmol, 91%). LRMS calcd for C19H26N2O3: 330.2, found 331.0 [M+H]+ 1H 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). Step B: (3S)-3-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride Using General procedure 6 and the product from Step A (4.33 g, 13.1 mmol, 1 eq.) as the appropriate THIQ amide afforded the title product (3.79 g, 13.1 mmol, quant.). LRMS calcd for C14H20N2: 216.2, found 217.0 [M+H]+ 1H 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). Step 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 The title compound was prepared in an analogous fashion to Preparation IIb using the product from Step B in the next step. LRMS calcd for C H N O : 612.3, fou + 36 44 4 5 nd 613.6 [M+H] 1H 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). Preparation IIIa: 4-[(tert-butyldimethylsilyl)oxy]aniline To a solution of imidazole (13.72 g, 201.6 mmol, 2.5 eq.) and 4-aminophenol (8.8 g, 80.64 mmol, 1 eq.) in MeCN (150 mL), cooled to 0°C under N2, was added TBDMSCl (12.76 g, 84.67 mmol, 1.05 eq.). The mixture was allowed to warm to rt 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 MgSO4and concentrated in vacuo. The residue was diluted with heptane (40 mL) and left to stir for 1 h. The precipitate was removed by filtration and the filtrate concentrated in vacuo to afford the title product (19.6 g, quant.). HRMS calcd for (C12H21NOSi): 223.139, found 224.162 [M+H]+ 1H 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). Preparation IIIb: 4-[(triisopropylsilyl)oxy]aniline The title product was prepared in accordance with the method described in Preparation IIIa using 4-aminophenol (10.7 g, 98.05 mmol, 1 eq.) and TIPSCl (22.06 mL, 102.95 mmol, 1.05 eq.). The compound was obtained with a yield of 97% (25.3 g, 95.3 mmol). LRMS calcd for (C15H27NOSi): 265.2, found 266.2 [M+H]+ 1H 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). 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 Step A: 4-bromo-1,5-dimethylpyrrole-2-carbonitrile A solution of Br2 (6.74 mL, 131.08 mmol, 1.05 eq.) in AcOH (70 mL) was added dropwise to a solution of 1,5-dimethylpyrrole-2-carbonitrile (15 g, 124.84 mmol, 1 eq.) in AcOH (250 mL), cooled to 10°C. The mixture was stirred at 10°C for 1 h, and then allowed to warm to rt, and again stirred 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 afford the title product, (23.7 g, 119.07 mmol, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.05 (s, 1H), 3.65 (s, 3H), 2.22 (s, 3H). Step B: 4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethylpyrrole-2-carbonitrile Using General procedure 1a and the product from Step A (6.1 g, 30.65 mmol, 1 eq.) as the appropriate aryl bromide and Preparation IIIa (7.19 g, 32.18 mmol, 1.05 eq.) as the appropriate aniline afforded the title product (8.2 g, 24 mmol, 78%). HRMS calcd for C H N OSi: + 19 27 3 341.192, 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). Step 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 The title compound was prepared according to General procedure 2a using Preparation IIa (2.5 g, 4.6 mmol, 1 eq.) as the appropriate acid and the product from Step B (3.14 g, 9.2 mmol, 2 eq.) as the appropriate aniline. Purification by automated flash chromatography eluting with a gradient of 0 - 6% MeOH in DCM afforded the title product (2.49 g, 2.87 mmol, 62%). HRMS calcd for C + 51H62N6O5Si: 866.455, found 867.465 [M+H] Step 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 A solution of the product from Step C (2.8 g, 3.23 mmol, 1 eq.) in MeOH (5 mL) was treated with 3 M HCl in MeOH (10 mL, 30 mmol) and stirred at rt for 3 h. The solvents were removed in vacuo and then dried under high vacuum to afford the title product (2.53 g, quant.). HRMS calcd for C40H40N6O3: 652.316, found 653.326 [M+H]+ 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 Step 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 The title compound was prepared according to General procedure 2a using Preparation IIb (2.2 g, 3.51 mmol, 1 eq.) as the appropriate acid and the product from Preparation IVa, Step B (1.68 g, 4.91 mmol, 1.4 eq.) as the appropriate aniline. Purification by automated flash chromatography eluting with a gradient of 0 - 10% MeOH (1% NH3) in DCM afforded the title product (2.29 g, 2.4 mmol, 69%). LRMS calcd for C H N O Si: 949.5, found 950.6 [M+H + 56 71 7 5 ] Step 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 A solution of the product from Step A (2.3 g, 2.42 mmol, 1 eq.) in MeOH (10 mL) was treated with 3 M HCl in MeOH (7 mL, 21 mmol) and stirred at rt for 12 h. The solvents were removed in vacuo and the residue was dissolved in 1:1 DCM / MeOH followed by the addition of TEA (1.5 mL, 3 eq.) and then purified by reverse phase automated flash chromatography eluting with a gradient of 20 - 100% MeCN in water. The product was lyophilised to afford the title product (1.18 g, 1.6 mmol, 66%). LRMS calcd for (C H N O ): 735 + 45 49 7 3 .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). 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

[0010] Step 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 The title compound was prepared according to General procedure 2a using Preparation IIc (1.6 g, 2.61 mmol, 1 eq.) as the appropriate acid and the product from Preparation IVa, Step B (1.34 g, 3.92 mmol, 1.5 eq.) as the appropriate aniline. Purification by automated flash chromatography eluting with a gradient of 0 - 8% MeOH in DCM afforded the title product (1.9 g, 2.03 mmol, 78%). LRMS calcd for C55H69N7O5Si: 935.5, found 936.6 [M+H]+ Step 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 A solution of the product from Step A 1.9 g, 2.03 mmol, 1 eq.) in MeOH (19 mL) was treated with 3 M HCl in MeOH (2.28 mL, 6.83 mmol) and stirred at rt for 12 h. The mixture was diluted with DCM and basified by the addition of sat. aq. NaHCO3 solution. The layers were separated, and the aqueous phase was extracted twice more with DCM. The combined organic extracts were dried over MgSO4and concentrated under reduced pressure. Purification by reverse phase automated flash chromatography at pH 4, eluting with a gradient of 20 - 100% MeCN in water afforded the title product (1.05 g, 1.45 mmol, 71%). LRMS calcd for C + 44H47N7O3: 721.4, found 722.6 [M+H] 1H 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). Preparation Va: {4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid Using General procedure 7a and methyl 4-hydroxyphenylacetate (2.5 g, 15.04 mmol, 1 eq.) as the appropriate phenol and 4-(2-chloroethyl)morpholine hydrochloride (4.48 g, 24.07 mmol, 1.6 eq.) as the appropriate alkyl halide afforded the title product (3.24 g, 11.59 mmol, 77%). LRMS calcd for (C15H21NO4): 279.2, found 280.2 [M+H]+ 1H 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). Step B: {4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid The product from Step A (3.26 g, 11.67 mmol, 1 eq.) was hydrolysed using General procedure 8 to afford the title product (3.1 g, 11.63 mmol, quant). LRMS calcd for (C14H19NO4): 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). Preparation Vb: {2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid Step A: methyl 2-(2-fluoro-4-hydroxyphenyl)acetate Concentrated H2SO4 (5 mL) was added dropwise to MeOH (100 mL), cooled to 0 ^C. After addition, 2-fluoro-4-hydroxyphenylacetic acid (5 g, 29.39 mmol, 1 eq.) was added in portions and then the mixture slowly heated to reflux where it was held for 3 h. The mixture was allowed to cool to rt and poured onto 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 afford the title product (6.1 g, 29.15 mmol, 99%). 1H 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). Step B: methyl 2-{2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetate Using General procedure 7a and the product from Step A (4.22 g, 22.91 mmol, 1 eq.) as the appropriate phenol and 4-(2-chloroethyl)morpholine hydrochloride (8.53 g, 45.83 mmol, 2 eq.) as the appropriate alkyl halide afforded the title product (4.99 g, 16.78 mmol, 73%). HRMS calcd for (C H NO + 15 20 4F): 297.138, found 298.154 [M+H] 1H 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). Step C: {2-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}acetic acid The product from Step B (4.99 g, 16.78 mmol) was hydrolysed using General procedure 8 to afford the title product (4.65 g, 16.41 mmol, 99%). LRMS calcd for (C + 14H18NO4F): 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). Preparation Vc: 2-[4-(2-tetrahydropyran-4-ylethoxy)phenyl]acetic acid Step A: methyl 2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetate Using General procedure 7a and methyl 4-hydroxyphenylacetate (2 g, 12.04 mmol, 1 eq.) as the appropriate phenol and 4-(2-bromoethyl)tetrahydro-2H-pyran (2.32 mL, 15.65 mmol, 1.3 eq.) as the appropriate alkyl halide afforded the title product (2.95 g, 10.61 mmol, 88%). 1H 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). Step B: methyl 2-{4-[2-(oxan-4-yl)ethoxy]phenyl}acetate The product from Step A (2.95 g, 10.61 mmol, 1 eq.) was hydrolysed using General procedure 8. Methanol was removed in vacuo and the aqueous residue was acidified with 2 M aq. HCl solution and extracted with DCM. The organic phase was dried over MgSO4 and concentrated in vacuo to afford the title product (2.71 g, 10.27 mmol, 97%). LRMS calcd for C15H20O4: 264.1, found 263.2 [M-H]- 1H 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). 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

[0011] Step A: 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-carboxylic acid hydrochloride A solution of Preparation IIa (3 g, 5.52 mmol, 1 eq.) in MeOH (20 mL) was treated with 3 M HCl in MeOH (20 mL, 60 mmol) and stirred at rt for 3 h. The solvents were removed in vacuo and dried under vacuum to afford the title product (2.71 g, quant.). LRMS calcd for C27H29N3O3: 443.2, found 444.4 [M+H]+ 1H 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).

[0012] Step 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 To a solution of Preparation Va (1 g, 3.77 mmol, 1 eq) in anhydrous DCM (10 mL) under N2, was slowly added 2 M oxalyl chloride solution in DCM (0.43 mL, 4.52 mmol, 1.2 eq.) followed by DMF (1 drop), and the mixture stirred for 1 h. The solvents were removed in vacuo, the acid chloride intermediate 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 eq.) and DIPEA (2.5 mL, 15.08 mmol, 4 eq.) in anhydrous DCM (10 mL) under N2. The mixture was stirred at rt 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 afforded the title product (1.2 g, 1.74 mmol, 46%). LRMS calcd for (C H N O ): 6 + 41 46 4 6 90.3, found 691.6 [M+H] 1H 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). 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

[0013] The title compound was prepared in an analogous fashion to Preparation VIa using Preparation Vc (700 mg, 2.65 mmol, 1 eq.) and the product from Preparation VIa, Step A (1.14 g, 2.38 mmol, 0.9 eq.) to afford the title product (1.04 g, 1.51 mmol, 57%). LRMS calcd for (C42H47N3O6): 689.3, found 690.6 [M+H]+ 1H 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). 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 Step 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 To a solution of Preparation I (10.4 g, 21.8 mmol, 1 eq.) in DMF (60 mL) was added TBTU (7.71 g, 24.0 mmol, 1.1 eq.) followed by DIPEA (11.2 mL, 65.5 mmol, 3 eq.). After stirring for 10 mins the product from Step B of Preparation IIb (7.95 g, 26.2 mmol, 1.2 eq.) was added and the mixture was stirred at rt for 1h then it was poured into water (600 mL) and the precipitates were filtered out, washed with water. This crude intermediate was dissolved in methanol (150 mL) and water (85 mL) then NaOH (9.18 g, 229.6 mmol, 10.5 eq.) was added and mixture was stirred at reflux temperature for 3 days. Evaporated at reduced pressure, then the pH was adjusted to 6 by the addition of cc. aq. 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 afford the title product (10.97 g, 15.83 mmol, 73%). 1H 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]+ calcd for C32H39N4O3: 527.3017, found 527.3011

[0014] Step 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 To the biphasic mixture of the product from Step A (8.63 g, 13.1 mmol, 1 eq.) dissolved in dioxane (75 mL) and NaHCO3 (2.53 g, 30.1 mmol, 2.3 eq.) dissolved in water (75 mL) 9H- fluoren-9-ylmethyl carbonochloridate (3.73 g, 14.4 mmol, 1.1 eq.) was added dropwise and the mixture was stirred at rt for 24 h. To the reaction mixture 2M aq. HCl (131 mL; 262 mmol, 10 eq.) was added dropwise then after stirring for 10 min it was extracted with DCM. The phases were separated, and the organic phase was washed with sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents (1% NH3) to afford the title product (7.33 g, 9.3 mmol, 71%). 1H 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); 13C 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]+ calcd for C47H49N4O5: 749.3697, found 749.3702 Step 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-(1-piperidylmethyl)- 3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate Using General procedure 2a and the product from Step B (5.33 g, 7.12 mmol, 1 eq.) as the appropriate acid, oxalyl dichloride (1.02 mL, 12.1 mmol, 1.7 eq.) and the product from Step B of Preparation IVa (2.92 g, 8.54 mmol, 1.2 eq.) as the appropriate aniline afforded the title product (4.67 g, 3.92 mmol, 55%). 1H 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]+ calcd for C66H74N7O5Si: 1072.5515, found 1072.5531 Step 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 To a solution of the product from Step C (1.84 g, 1.55 mmol, 1 eq.) in DCM (8 mL) morpholine (7.76 mL, 88.2 mmol, 57 eq.) was added then the mixture was stirred at rt 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 sat. aq. NaCl solution, dried over MgSO4and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents (1% NH3) affording the title product as a yellow solid (0.762 g, 0.867 mmol, 56%). 1H 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]+ calcd for C51H64N7O3Si: 850.4834, found 850.4838 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 Step 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 To a solution of Preparation I (45.9 g, 96.3 mmol, 1 eq.) in DMF (240 mL) was added TBTU (34.1 g, 106 mmol, 1.1 eq.) followed by TEA (40.5 mL, 291 mmol, 3 eq.). After stirring for 10 mins the product from Step A of Preparation IIa (18.6 g, 101 mmol, 1.05 eq.) was added and the mixture was stirred at rt for 1h then it was poured into water (1500 mL) and the precipitates were filtered out, washed with water. This crude intermediate was dissolved in methanol (250 mL) and water (25 mL) then NaOH (28 g, 700 mmol, 7.3 eq.) was added and mixture was stirred at reflux temperature for 18 h. Evaporated at reduced pressure, then the pH was adjusted to 6 by the addition of cc. aq. 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 in diethyl ether / acetonitrile. The formed yellow powder was filtered out then dried in vacuo to afford the title product (38.51 g, 86.8 mmol, 90%). 1H 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]+ calcd for C27H30N3O3: 444.2282, found 444.2267 Step 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 To the biphasic mixture of the product from Step A (13.96 g, 28.33 mmol, 1 eq.) dissolved in dioxane (160 mL) and NaHCO3(5.47 g, 65.2 mmol, 2.3 eq.) dissolved in water (160 mL) 9H- fluoren-9-ylmethyl carbonochloridate (8.06 g, 31.2 mmol, 1.1 eq.) was added dropwise and the mixture was stirred at rt for 24 h. To the reaction mixture 2M aq. HCl (42.5 mL; 85 mmol, 3 eq.) was added dropwise then after stirring for 10 min it was extracted with DCM. The phases were separated, and the organic phase was washed with sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and EtOAc as eluents affording 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., 3 H); 13C 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]+ calcd for C42H40N3O5: 666.2962, found 666.2961 Step 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 Using General procedure 2b and the product from Step B (10.67 g, 16.03 mmol, 1 eq.) as the appropriate acid, oxalyl dichloride (2.17 mL, 25.6 mmol, 1.6 eq.) and the product from Step B of Preparation IVa (6.57 g, 19.2 mmol, 1.2 eq.) as the appropriate aniline afforded the title product (8.12 g, 8.21 mmol, 51%). 1H 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]+ calcd for C61H65N6O5Si: 989.4780, found 989.4779 Step 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 To a solution of the product from Step C (8.12 g, 8.21 mmol, 1 eq.) in DCM (41 mL) morpholine (41 mL, 475 mmol, 58 eq.) was added then the mixture was stirred at rt 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 sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and MeOH as eluents to afford 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]+ calcd for C46H55N6O3Si: 767.4099, found 767.4103 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 To the ice-cooled solution of the product from Step A of Preparation VIIb (3.90 g, 8.80 mmol, 1 eq.) in water (13 mL) and NaOH (1.10 g, 26 mmol, 3 eq.) was added dropwise the solution of 2-phenylacetyl chloride (1.40 mL, 10.6 mmol, 1.2 eq.) in DCE (2.6 mL). The reaction mixture was stirred at rt for 2 h then the pH was adjusted to 2 by the addition of 2M aq. HCl. The mixture was diluted with water then it was extracted with DCM. The phases were separated, and the organic phase was washed with sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. The crude material was purified by automated flash chromatography using DCM and EtOAc as eluents to afford 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); 13C 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]+ calcd for C35H36N3O4: 562.2700, found 562.2705 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

[0015] Step A: 2-benzyloxycarbonyl-6-(4-carboxy-1,5-dimethyl-pyrrol-2-yl)-3,4-dihydro-1H- isoquinoline-7-carboxylic acid To a suspension of Preparation I (20.01 g, 41.99 mmol, 1 eq.) in methanol (100 mL) and water (20 mL), NaOH (14.07 g, 352 mmol, 8.4 eq.) was added and mixture was stirred at reflux temperature for 2 days. The pH of the cooled mixture was adjusted to 6 by the addition of cc. aq. HCl then methanol was evaporated at reduced pressure. The resulting slurry was diluted with 2-propanol and the crude product was filtered out. This crude material was dissolved again in the mixture of ice-water (400 mL) and 2M aq. NaOH solution (41 mL, 82 mmol) then a solution of benzyl carbonochloridate (7.1 mL, 50.7 mmol, 1.19 eq.) in diethyl ether (100 mL) was added dropwise. The mixture was stirred for 24h then the pH of the aqueous phase was adjusted to 2 by the addition of 2M aq. 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 eluents to afford the title product as a white solid (15.09 g, 32.2 mmol, 77%). 1H 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); 13C 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]+ calcd for C25H25N2O6: 449.1707, found 449.1708 Step B: 5-(2-benzyloxycarbonyl-7-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6-yl)- 1,2-dimethyl-pyrrole-3-carboxylic acid A solution of the product from Step A (2.50 g, 5.57 mmol, 1 eq.) and 1,1-di-tert-butoxy-N,N- dimethyl-methanamine (13 mL, 55.7 mmol, 10 eq.) in THF (50 mL) was stirred at rt 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%). 1H 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]+ calcd for C29H33N2O6: 505.2333, found 505.2335 Step 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 Using General procedure 2a and the product from Step B (12.70 g, 25.2 mmol, 1 eq.) as the appropriate carboxylic acid and the product from Step B of Preparation IVa (10.30 g, 30.2 mmol, 1.2 eq.) as the appropriate aniline afforded the title product (14.2 g, 17.1 mmol, 68%). 1H 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, 6 H); 13C 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]+ calcd for C48H58N5O6Si: 828.4151, found 828.4163 Step 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 According to General procedure 6b the product from Step C (1.00 g, 1.21 mmol, 1 eq.) in THF (13 mL) was hydrogenated using 26 mg Pd catalyst (10% on charcoal) affording the title product (0.836 g, 1.205 mmol, quant.). 1H 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); 13C 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]+ calcd for C40H52N5O4Si: 694.3783, found 694.3780 Step 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 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 eq.) in DMF (12 mL), TBTU (0.773 g, 2.406 mmol, 2 eq.), DIPEA (0.838 mL, 4.813 mmol, 4 eq.) and the product from Step D (0.835 g, 1.203 mmol, 1 eq.) was stirred at rt for 30 min. The reaction mixture was poured into water (120 mL) and the precipitates were filtered out, washed with water finally dried at 40°C in vacuo to afford the title product as a yellow solid (1.145 g, 1.194 mmol, 99%). 1H 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); 13C 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]+ calcd for C54H68FN6O7Si: 959.4897, found 959.4897 Step 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 According to General Procedure 3a the product from Step E (1.145 g, 1.11 mmol, 1 eq.) in 1,4-dioxane (20 mL), trimethylsilyl trifluoromethanesulfonate (1.00 mL, 5.55 mmol, 5 eq.) and TEA (0.773 mL, 5.55 mmol, 5 eq) in 1,4-dioxane (8 mL) were reacted for 5 h to afford the title product as an orange solid (0.770 g, 0.724 mmol, 65%). 1H 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); 13C 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]+ calcd for C50H60FN6O7Si: 903.4271, found 903.4269 Preparation X: methyl 2-[4-(2-bromoethoxy)-2-fluoro-phenyl]acetate According to General Procedure 7b methyl 2-(2-fluoro-4-hydroxy-phenyl)acetate (2.000 g, 10.86 mmol, 1 eq.), 2-bromoethanol (4.343 g, 34.75 mmol, 3.2 eq.) were reacted to obtain the desired product (3.15 g, 10.8 mmol, quant.). 1H 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); 13C 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. EXAMPLES 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 Using General procedure 4c, starting from 2-(m-tolyl)acetic acid (34.5 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (117 mg, 0.15 mmol) as the appropriate amine, afforded the title compound (51.8 mg, 43%). HRMS-ESI (m / z) [M+H]+ calcd for C49H48N6O4: 785.3737, found 785.3825. 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

[0016] Using General procedure 4d, starting from 2-phenoxyacetyl chloride (37 mg, 1.2 eq.) as the appropriate carboxylic acid chloride and Preparation VIIb (140 mg, 0.18 mmol) as the appropriate amine, afforded the title compound (67 mg, 73%). HRMS-ESI (m / z) [M+H]+ calcd for C48H47N6O5: 787.3608, found 787.3604. 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 Step A: methyl 2-[3-(4-methylpiperazin-1-yl)phenyl]acetate A mixture of methyl 3-bromophenylacetate (536 µL, 3.27 mmol, 1 eq.), 1-methylpiperazine, (545 µL, 4.91 mmol, 1.5 eq.) and Cs2CO3 (2.13 g, 6.55 mmol, 2 eq.) in toluene (20 mL) was sparged with N2. DavePhos (129 mg, 327 µmol, 0.1 eq.) and Pd2(dba)3(150 mg, 163.7 µmol, 0.05 eq.) were added, the mixture was sparged again and then heated at 120°C under N2 for 20 h. The mixture was allowed to cool to rt and filtered through a celite cartridge, washing with EtOAc. The filtrate was washed with sat. aq. NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 7% MeOH in DCM afforded the title product (203 mg, 0.82 mmol, 25%). 1H 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). Step 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 eq.) as the appropriate ester afforded the title product (310 mg, 1.32 mmol, 82%). LRMS calcd for C H18N2O2: + 13 234.1, found 235.0 [M+H] 1H 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). Step 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 eq.) as the appropriate acid and Example 65, Step A (933 mg, 4.41 mmol, 2 eq.) as the appropriate aniline afforded the title product (1.27 g, 1.72 mmol, 78%). LRMS calcd for C + 45H48N6O4: 736.4, found 737.4 [M+H] Step 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 A solution of 3 M HCl in MeOH (15 mL) was added to the product from Step C (1.28 g, 1.74 mmol, 1 eq.) and the mixture stirred at rt for 5 h. The solvent was removed in vacuo and the residue dried to afford the title product, which was used directly in the subsequent step without further purification (1.17 g, 1.74 mmol, quant.). LRMS calcd for C40H40N6O2: 636.3, found 637.3 [M+H]+ Step 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 eq.) as the appropriate amine and the product from Step B (50 mg, 0.21 mmol, 1.2 eq) as the appropriate carboxylic acid afforded the title product (46.2 mg, 0.05 mmol, 30%). HRMS calcd for C + 53H56N8O3: 852.4475, found 853.4550 [M+H] 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 Step A: 4-bromo-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrrole-2-carbonitrile Using the General procedure 7c, starting from the 2-[tert-butyl(dimethyl)silyl]oxyethanol (705 mg, 2.0 eq.) as the appropriate alcohol, afforded the title product (625 mg, 91%). 1H 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); 13C 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]+ calcd for C14H24BrN2OSi: 343.0836, found 343.0843. Step B: 4-anilino-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrrole-2-carbonitrile Using General procedure 1b, starting from the product of Step A (500 mg, 1.46 mmol) as the appropriate aryl bromide and aniline (0.199 mL, 1.5 eq.), afforded the title product (405 mg, 78%). 1H 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]+ calcd for C20H30N3OSi: 356.2153 , found 356.2142. Step 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 the Preparation VIII as the appropriate acid (200 mg, 0.36 mmol) and the product of Step B (152 mg, 1.2 eq.) 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]+ calcd for C49H49N6O4: 785.3810, found 785.3814. 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 Using General procedure 4d, starting from 2-(4-fluorophenyl)acetyl chloride (36 mg, 1.1 eq.) as the appropriate carboxylic acid chloride and Preparation VIIb (145 mg, 0.19 mmol) as the appropriate amine, afforded the title compound (41.6 mg, 28%). HRMS-ESI (m / z) [M+H]+ calcd for C48H46FN6O4: 789.3564, found 789.3560. 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 Step A: methyl 2-[3-(morpholin-4-yl)phenyl]acetate A mixture of methyl 3-bromophenylacetate (0.36 mL, 2.18 mmol, 1 eq.), morpholine (0.29 mL, 3.27 mmol, 1.5 eq.) and Cs2CO3 (1.42 g, 4.37 mmol, 2 eq.) in toluene (10 mL) was sparged with N2. DavePhos (86 mg, 0.22 mmol, 0.1 eq.) and Pd2(dba)3(100 mg, 0.11 mmol, 0.05 eq.) were added, the mixture was sparged again and then heated at 120°C under N2for 20 h. The mixture was allowed to cool to rt and filtered through a celite cartridge, washing with EtOAc. The filtrate was washed with sat. aq. NaHCO3solution and brine, dried over MgSO4and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 50% EtOAc in heptane afforded the title product (359 mg, 1.53 mmol, 70%). LRMS calcd for C H NO : 2 + 13 17 3 35.1, found 236.0 [M+H] 1H 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). Step 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 eq.) as the appropriate ester afforded the title product (174 mg, 0.79 mmol, 52%). LRMS calcd for C12H15NO3: 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). Step 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 eq.) as the appropriate amine and the product from Step B (46 mg, 0.21 mmol, 1.2 eq.) as the appropriate carboxylic acid afforded the title product (61.3 mg, 0.07 mmol, 41%). HRMS calcd for C H N O : + 52 53 7 5 855.4108, found 856.4181 [M+H] 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 Using General procedure 4d, starting from 2-(3-methoxyphenyl)acetyl chloride (45 mg, 1.2 eq.) as the appropriate carboxylic acid chloride and Preparation VIIb (155 mg, 0.20 mmol) as the appropriate amine, afforded the title compound (30 mg, 19%). HRMS-ESI (m / z) [M+H]+ calcd for C49H49N6O5: 801.3764, found 801.3764. 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 Step 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 eq.), (9aS)-octahydropiperazino[2,1- c]morpholine dihydrochloride (704 mg, 3.27 mmol, 1.5 eq.) and Cs2CO3 (2.84 g, 8.73 mmol, 4 eq.) were combined in toluene (10 mL) and the mixture sparged with N2. DavePhos (86 mg, 0.22 mmol, 0.1 eq.) and Pd2dba3(100 mg, 0.11 mmol, 0.05 eq.) were added and the mixture sparged with N2 and then heated at 120°C under microwave irradiation for 1 h. The mixture was allowed to cool to rt and filtered through a celite cartridge, washing with EtOAc. The filtrate was washed with sat. aq. NaHCO3solution and brine solution and then dried over MgSO4 and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 100% EtOAc in heptane and then 0 – 32% MeOH in EtOAc afforded the title product (73 mg, 0.25 mmol, 12%). LRMS calcd for C16H22N2O3: 290.2, found 291.0 [M+H]+ 1H 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). Step 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 eq.) in MeOH (15 mL) was added 2 M aq. NaOH solution (0.25 mL, 0.5 mmol, 2 eq.) and 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, the pH adjusted to 2 using 2 M aq. HCl solution, and then freeze-dried to afford the title product, which was used directly in the subsequent step without further purification (69 mg, 0.25 mmol, 99%). LRMS calcd for C + 15H20N2O3: 276.1, found 277.0 [M+H] 1H 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). Step 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 eq.) as the appropriate amine and the product from Step B (57 mg, 0.21 mmol, 1.4 eq.) as the appropriate carboxylic acid afforded the title product (22.5 mg, 0.03 mmol, 17%). HRMS calcd for C H N + 55 58 8O4: 894.4581, found 895.4669 [M+H] 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 Step A: 4-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-anilino]-1,5-dimethyl-pyrrole-2- carbonitrile Using General procedure 1b, starting from 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 eq.) as the appropriate aniline, afforded the title product (88 mg, 12%). 1H NMR (500 MHz, DMSO-d6) δ ppm 6.67 (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); 13C 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]+ calcd for C20H30N3OSi: 356.2153, found 356.2152. Step 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 as the appropriate acid (120 mg, 0.214 mmol) and the product from Step A (84 mg, 1.1 eq.) 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]+ calcd for C49H49N6O4: 785.3810, found 785.3812. 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 Using General procedure 4c, starting from 2-(4-phenoxyphenyl)acetic acid (70 mg, 2.4 eq.) as the appropriate carboxylic acid and Preparation VIIb (97 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (35 mg, 32%). HRMS-ESI (m / z) [M+H]+ calcd for C54H51N6O5: 863.3915, found 863.3921. 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 Using General procedure 4c, starting from 2,4-difluorophenylacetic acid (33.7 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (60 mg, 57%). HRMS-ESI (m / z) [M+H]+ calcd for C48H45F2N6O4: 807.3465, found 807.3468. 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

[0017] Using General procedure 4c, starting from 2-(2-cyanophenyl)acetic acid (31.5 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (40 mg, 39%). HRMS-ESI (m / z) [M+H]+ calcd for C49H46N7O4: 796.3606, found 796.3609. 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 Step A: 4-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-aniline A solution of tert-butyl-chloro-dimethyl-silane (3.9 g, 1.1 eq.) in THF (7 mL) was added dropwise to the solution of 4-amino-3-fluoro-phenol (3.0 g, 23.6 mmol, 2.33 mL) and imidazole (2.41 g, 1.5 eq.) in THF (30 mL). After the conversion was complete, the volatiles of the reaction mixture were removed by evaporation. Water (20 mL) was added and the mixture was extracted with Et2O (2x20 mL). The combined organic layers were washed with brine, dried over MgSO4then concentrated. The residue was purified by column chromatography (heptane:EtOAc= 9:1) to give the title compound (3.2 g, 55.8 %). 1H NMR (500 MHz, DMSO-d6) δ ppm 6.64 (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]+ calcd for C12H21FNOSi: 242.1371, found 242.1373. Step 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 (430 mg, 2.16 mmol) as the appropriate aryl bromide and product from Step A (625.7 mg, 1.2 eq.) as the appropriate aniline, afforded the title product (95.7 mg, 12%). 1H NMR (500 MHz, DMSO-d6) δ ppm 6.72 (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); 13C 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]+ calcd for C19H27FN3OSi: 360.1902, found 360.1904. Step 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 as the appropriate acid (120 mg, 0.214 mmol) and the product of Step B (84 mg, 1.1 eq.) 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]+ calcd for C48H46FN6O4: 789.3559, found 789.3562. 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

[0018] To a solution of Preparation VIIb (100 mg, 0.13 mmol) in DCE (2 mL) was added DIPEA (37 mg, 2.2 eq.) and phenylmethanesulfonyl chloride (40 mg, 1.6 eq.) and the mixture was stirred until complete conversion was observed. The TBDMS protecting group was removed using 2 M aq. NaOH (according to the protocol described in General procedure 4c) and the desired product was obtained (32 mg, 30%). HRMS-ESI (m / z) [M+H]+ calcd for C47H46N6O5S: 807.3323, found 807.3325. 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 Using General procedure 4c, starting from 1H-indazole-3-carboxylic acid (48 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (150 mg, 0.20 mmol) as the appropriate amine, afforded the title compound (50 mg, 32%). HRMS-ESI (m / z) [M+H]+ calcd for C48H45N8O4: 797.3558, found 797.3560. 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 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, afforded the title compound as a white powder (39.7 mg, 24%). HRMS-ESI (m / z) [M+H]+ calcd for C50H46N7O4S: 840.3326, found 840.3323. 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 Using General procedure 4a and Preparation IVa (110 mg, 0.16 mmol, 1 eq.) as the appropriate amine and 2,2-difluoro-2-phenylacetic acid (27 mg, 0.16 mmol, 1 eq.) as the appropriate carboxylic acid afforded the title product (15.8 mg, 0.02 mmol, 12%). HRMS calcd for C48H44F2N6O4: 806.3392, found 807.3466 [M+H]+ 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 Using General procedure 4c, starting from 2-(4-chloro-2-fluoro-phenyl)acetic acid (50 mg, 2.0 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (40 mg, 37%). HRMS-ESI (m / z) [M+H]+ calcd for C48H45ClFN6O: 823.3169, found 823.3176. 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 Using General procedure 4a and Preparation IVa (120 mg, 0.18 mmol, 1.2 eq.) as the appropriate amine and 2,3-dihydrobenzo[b]furan-2-carboxylic acid (25 mg, 0.15 mmol, 1 eq.) as the appropriate carboxylic acid afforded the title product (75 mg, 0.09 mmol, 63%). HRMS calcd for C49H46N6O5: 798.3530, found 799.3610 [M+H]+ 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 Using General procedure 4c, starting from the product of Preparation Va (80 mg, 2.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, afforded the title compound (59 mg, 63%). HRMS-ESI (m / z) [M+H]+ calcd for C54H51N7O6: 900.4443, found 900.4446. 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

[0019] Step A: 4-bromo-1-[2-[cyclopropyl(methyl)amino]ethyl]-5-methyl-pyrrole-2-carbonitrile Using the General procedure 7c, starting from the 2-[cyclopropyl(methyl)amino]ethanol (1.2 g, 2.0 eq.) as the appropriate alcohol, afforded the title product (690 mg, 45%). 1H 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]+ calcd for C12H17BrN3: 282.1, found 282.0. Step 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 eq.) as the appropriate aniline, afforded the title compound (680 mg, 70%). 1H 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); 13C 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]+ calcd for C24H37N4OSi: 425.2731, found 425.2741. Step 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 eq.) 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]+ calcd for C53H56N7O4: 854.4388, found 854.4385. 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 Step A: 2-[4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]acetic acid To a solution of the methyl 2-(4-bromophenyl)acetate (0.20 mL, 1.4 eq.) and 1-(2,2,2- trifluoroethyl)piperazine (0.40 mL, 1.02 mmol) in 1,4-dioxane (5.0 mL) was added Cs2CO3(439 mg, 1.0 eq.) and [2-(2-aminoethyl)phenyl]-chloro-palladium, dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (1:1) (37 mg, 0.04 eq.), and the mixture was stirred until complete conversion was observed. After filtration, the crude product was hydrolysed using the 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); 13C 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]+ calcd for C14H18F3N2O3: 303.1320, found 303.1315. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (75 mg, 0.10 mmol) as the appropriate amine, afforded the title product (62 mg, 68%). HRMS-ESI (m / z) [M+H]+ calcd for C54H56F3N8O4: 937.4371, found 937.4375. 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 Using General procedure 4c, starting from 2-(4-bromo-2-fluorophenyl)acetic acid (30 mg, 1.3 eq.) as the appropriate carboxylic acid and Preparation VIIb (75 mg, 0.10 mmol, as the appropriate amine, afforded the title compound (41.2 mg, 49%). HRMS-ESI (m / z) [M+H]+ calcd for C48H45BrFN6O4: 867.2664, found 867.2661. 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 Using General procedure 4d, starting from benzoyl chloride (30 mg, 1.6 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (55 mg, 56%). HRMS-ESI (m / z) [M+H]+ calcd for C47H45N6O4: 757.3502, found 757.3494. 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 Step A: ethyl 2-(4-bromophenyl)-2,2-difluoroacetate Ethyl 2-(4-bromophenyl)-2-oxoacetate (3 g, 11.67 mmol, 1 eq.) was cooled to 0°C under N2 followed by the dropwise addition of DAST (3.08 mL, 23.34 mmol, 2 eq.). On complete addition, the mixture was stirred at rt under N2for 2 h. The mixture was poured on to ice with stirring and then extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title product (3.06 g, 10.95 mmol, 94%). 1H 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). Step B: difluoro[4-(4-methylpiperazin-1-yl)phenyl]acetic acid The product from Step A (1 g, 3.58 mmol, 1 eq.), 1-methylpiperazine, (0.6 mL, 5.37 mmol, 1.5 eq.) and Cs2CO3(2.33 g, 7.17 mmol, 2 eq.) were combined in toluene (15 mL) and the mixture sparged with N2. DavePhos (141 mg, 0.36 mmol, 0.1 eq.) and Pd2dba3 (164 mg, 0.18 mmol, 0.05 eq.) were added and the mixture sparged with N2 and then heated at 120°C under microwave irradiation for 1 h. The mixture was allowed to cool to rt and filtered through a celite cartridge, washing with EtOAc. The filtrate was washed with sat. aq. NaHCO3 solution and brine and then dried over MgSO4 and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 100% EtOAc in heptane and then 0 – 90% MeOH in EtOAc afforded the title product, which was used directly in the subsequent step without further purification (0.86 g, 3.18 mmol, 89%). LRMS calcd for C13H16F2N2O2: 270.1, found 270.8 [M+H]+ 1H 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). Step 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 eq.) as the appropriate amine and the product from Step B (102 mg, 0.33 mmol, 1.3 eq.) as the appropriate carboxylic acid afforded the title product (6.7 mg, 0.01 mmol, 3%). HRMS calcd for C H F N O : 904.4236, fou + 53 54 2 8 4 nd 905.4309 [M+H] 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 Using General procedure 4c, starting from Preparation Vc (49 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (94 mg, 0.12 mmol) as the appropriate amine, afforded the title compound (64 mg, 58%). HRMS-ESI (m / z) [M+H]+ calcd for C55H59N6O6: 899.4496, found 899.4498. 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 Step 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 eq.) , 3,6- dihydro-2H-pyridine-1-N-Boc-4-boronic acid, pinacol ester (2.07 g, 6.68 mmol, 1.1 eq.) and K2CO3(2.52 g, 18.21 mmol, 3 eq.) in THF (10 mL) and water (1 mL) was sparged with N2followed by the addition of Pd(dppf)Cl2·DCM (496 mg, 0.61 mmol, 0.1 eq.). 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 rt, 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 afforded the title product (1.52 g, 4.36 mmol, 72%). LRMS calcd for C H FNO : 349.2, found 250.0 [M- + 19 24 4 Boc+H] 1H 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). Step 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 eq.) in MeOH (30 mL) was added 10% Pd / C (catalytic). The mixture was evacuated and backfilled with N2, then evacuated and flushed with H2 and shaken at rt for 16 h under an atmosphere of H2. The mixture was filtered through a celite cartridge, washing with MeOH. The solvent was removed in vacuo to afford the title product (1.36 g, 3.88 mmol, 89%). LRMS calcd for C19H26FNO4: 351.2, found 252.0 [M+H]+ 1H 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). Step 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 eq.) in 3 M HCl in MeOH (30 mL) was stirred at rt for 18 h. The solvents were removed in vacuo and then purified by reverse phase automated flash chromatography (Combiflash Rf, C1843g RediSep column) eluting with a gradient of 0 – 14% MeCN in water to afford the title product (140 mg, 0.49 mmol, 25%). LRMS calcd for C H FNO : 251.1, + 14 18 2 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). Step 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 eq.) in DMF (5 mL), cooled to 0°C, was added TEA (68 µL, 0.49 mmol, 1 eq.) followed by NaH (60% in mineral oil, 23 mg, 0.58 mmol, 1.2 eq.) and the mixture was stirred for 15 mins. 1-Fluoro-2-iodoethane (44 µL, 0.54 mmol, 1.1 eq.) was added and the mixture was allowed to warm to rt. The reaction was stirred for 18 h. The solvent was removed in vacuo to afford an intermediate which was dissolved in MeOH (10 mL) and treated with 2 M aq. NaOH solution (0.49 mL, 0.97 mmol, 2 eq.). The mixture was heated at 80°C under microwave irradiation for 0.5 h. The solvent was removed under reduced pressure and the residue diluted with water and the pH was adjusted to 2 using 2 M aq. HCl solution. Purification by reverse phase automated flash chromatography eluting with a gradient of 0 – 40 % MeCN in water afforded the title product (144 mg, 0.46 mmol, 94%). LRMS calcd for C15H19F2NO2: 283.1, found 284.0 [M+H]+ Step E: 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 Using General procedure 4a and Preparation IVa (200 mg, 0.29 mmol, 1 eq.) as the appropriate amine and the product from Step D (107 mg, 0.38 mmol, 1.3 eq.) as the appropriate carboxylic acid afforded the title product (42.5 mg, 0.05 mmol, 16%). HRMS calcd for C55H57F2N7O4: 917.4440, found 918.4511 [M+H]+ 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 (Diastereoisomer 1) 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 (Diastereoisomer 2) Using General procedure 4c, starting from 2-oxo-1-phenyl-pyrrolidine-3-carboxylic acid (57 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (141 mg, 0.18 mmol) as the appropriate amine, afforded the product 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 eluent to provide Diastereoisomer 1 (39.5 mg, 26%) and Diastereoisomer 2 (40.1 mg, 27%), the title products. HRMS-ESI (m / z) [M+H]+ calcd for C51H50N7O5: 840.3868, found 840.3865 (Diastereosiomer 1) HRMS-ESI (m / z) [M+H]+ calcd for C51H50N7O5: 840.3868, found 840.3868 (Diastereosiomer 2) 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

[0020] Step A: 1-(2-trityloxyethyl)piperidin-4-ol To a solution of 1-(2-hydroxyethyl)piperidin-4-ol (1.0 g, 6.887 mmol, 1 eq.) in DCM (10 mL) were added TEA (1.4 mL, 10.0 mmol, 1.5 eq.) and N,N-dimethylpyridin-4-amine (40 mg, 0.327 mmol, 0.05 eq.). The reaction mixture was stirred at rt for 10 min. At 0°C trityl chloride (2.0 g, 7.174 mmol, 1.04 eq.) was added to the reaction mixture, which was allowed to warm up and was stirred at rt for overnight. The mixture was concentrated in vacuo and the residue was purified by automated flash chromatography using DCM and MeOH as eluents to afford the title product (1.20 g, 45%). 1H 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, 4 H); 13C 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]+ calcd for C26H30NO2: 388.2271, found 388.2278 Step B: tert-butyl-dimethyl-[[1-(2-trityloxyethyl)-4-piperidyl]oxy]silane The product of Step A (1.20 g, 3.100 mmol, 1 eq.) in DCM (6.45 mL / mmol) was treated with imidazole (500 mg, 7.344 mmol, 2.4 eq.) and tert-butyl-chloro-dimethyl-silane (860 mg, 5.706 mmol, 1.8 eq.) at 0°C. The reaction mixture was allowed to warm up and stirred at rt overnight. The mixture was concentrated in vacuo and the residue was purified by automated flash chromatography using DCM and MeOH as eluents to afford the title product (1.40 g, 90%). 1H 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]+ calcd for C32H44NO2Si: 502.3, found 502.2. Step C: 2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]ethanol The product of Step B (1.40 g, 2.800 mmol, 1 eq.) in DCM (3.57 mL / mmol) was treated with acetic acid (20 mL, 349.4 mmol, 30 eq.) and stirred at 100°C for overnight. The mixture was concentrated in vacuo and the residue was dissolved in MeOH, treated with K2CO3 (2.0 g, 14.471 mmol, 5.2 eq.) and stirred at rt for 2 h. The mixture was concentrated in vacuo. The crude product was taken up in H2O (15 mL), extracted with DCM (3 x 10 mL), the combined organic layers were washed with brine (20 mL), dried over sodium sulphate, filtered and evaporated. The crude product was purified by automated flash chromatography using DCM and MeOH as eluents (Visualization on TLC: KMnO4) to afford the title product (380 mg, 52%). 1H 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]+ calcd for C13H30NO2Si: 260.2, found 260.2 Step 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 eq.), methyl 2- (4-hydroxyphenyl)acetate (330 mg, 1.986 mmol, 1.4 eq.), PPh3 (660 mg, 2.516 mmol, 1.7 eq.) and DTBAD (580 mg, 2.519 mmol, 1.7 eq.) in THF (8.0 mL) were stirred at rt for 1 h. The reaction mixture was evaporated. To the crude product was added H2O (15 mL), extracted with DCM (3 x 10 mL), the combined organic layers were washed with brine (20 mL), dried over sodium sulphate, 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 afford 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]+ calcd for C22H38NO4Si: 408.3, found 408.2 Step E: 2-[4-[2-(4-hydroxy-1-piperidyl)ethoxy]phenyl]acetic acid The product of Step D (120 mg, 0.294 mmol, 1 eq.) in 1,4-dioxane (2 mL) was treated with 2M aq. NaOH solution (1.0 mL, 2.0 mmol, 6.8 eq.) and stirred at 90 °C for 1 h. The reaction mixture was acidified with 2M aq. HClsolution (few drops) to pH~3 and evaporated. Toluene was added then the residual water was removed by azeotropic distillation. The compound was isolated (it contains inorganic salts) and used as a crude product in the next coupling step (75 mg, 91%). 1H 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]+ calcd for C15H22NO4: 280.1, found 280.2 Step 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, afforded the title compound (15 mg, 13%). HRMS-ESI (m / z) [M+H]+ calcd for C55H60N7O6: 914.4605, found 914.4599. 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

[0021] Step A: 2-[4-[2-(4-cyclopropylpiperazin-1-yl)ethoxy]phenyl]acetic acid The suspension of 1-cyclopropylpiperazine (164 mg, 1.30 mmol), 2-bromoethanol (0.14 mL, 1.5 eq.), and K2CO3(350 mg, 1.9 eq.) in ethanol (3 mL) were stirred at 100°C until complete conversion was observed. After the reaction mixture was diluted with MTBE, filtered, and concentrated, the residue was reacted according to General procedure 7b, using methyl 2-(4- hydroxyphenyl)acetate (190 mg, 1.1 eq.) as the appropriate phenol. The mixture was further hydrolysed according to the General procedure 8to give the title compound (120 mg, 27%). 1H 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]+ calcd for C17H25N2O3: 305.1865, found 305.1860. Step 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, afforded the title compound (15 mg, 15%). HRMS-ESI (m / z) [M+H]+ calcd for C57H63N8O5: 939.4916, found 939.4925. 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 Step 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 eq), and K2CO3(3 g, 1.9 eq) 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%). 1H 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 ); 13C 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]+ calcd for C11H15O4: 211.0965, found 211.0965. Step 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) was added methanesulfonyl chloride (0.65 ml, 1.5 eq.) dropwise, and the reaction mixture was stirred until the reaction was completed. 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%). 1H 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); 13C 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]- calcd for C12H17O6S: 289.0740, found 289.0743. Step 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 eq.) in 1,4-dioxane (3 mL), the product of Step B (164 mg, 0.57 mmol) and DIPEA (0.15 mL, 1.5 eq.) were added. The mixture was stirred at 100°C until complete conversion was observed, then the product was hydrolysed according to 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); 13C 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]+ calcd for C16H22F3N2O3: 347.1582, found 347.1582. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (72 mg, 56%). HRMS-ESI (m / z) [M+H]+ calcd for C56H60F3N8O5: 981.4633, found 981.4630. 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

[0022] Step A: methyl 2-(2-fluoro-4-methoxyphenyl)acetate Using General procedure 7b and Preparation Vb, Step A (940 mg, 5.1 mmol, 1 eq.) as the appropriate phenol and MeOH (4 mL) as the appropriate alcohol afforded the title product (543 mg, 2.74 mmol, 54%). LRMS calcd for C H FO : 198.1, found 19 + 10 11 3 9.2 [M+H] 1H 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). Step B: 2-(2-fluoro-4-methoxyphenyl)acetic acid To a solution of the product from Step A (543 mg, 2.74 mmol, 1 eq.) in MeOH (5 mL) was added LiOH.H2O (70 mg, 1.66 mmol, 2 eq.) and the mixture was heated at 100°C under microwave irradiation for 30 mins. The mixture was allowed to cool to rt, diluted with DCM and washed with 2 M aq. HCl solution. The phases were separated and the organic phase dried (PTFE phase separator) and concentrated in vacuo to afford the title product (450 mg, 2.44 mmol, 89%). LRMS calcd for C H FO : 184.1 - 9 9 3 , found 183.0 [M-H] 1H 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). Step 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 eq.) as the appropriate amine and the product from Step B (36 mg, 0.19 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (56.7 mg, 0.06 mmol, 36%). HRMS calcd for C H + 54 56FN7O5: 901.4327, found 902.4407 [M+H] 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 Step 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 eq.) in DMF (3 mL) was added 4-(2-bromoethyl)tetrahydropyran (231 mg, 1.19 mmol, 1 eq.) and K2CO3 (330 mg, 2.39 mmol, 2 eq.) and the mixture was stirred at 60°C under N2for 18 h. The mixture was allowed to cool to rt, 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 - 50% EtOAc in heptane afforded the title product (246 mg, 0.83 mmol, 69%). LRMS calcd for C16H21FO4: 296.1, found 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). Step 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 eq.) in MeOH (3 mL) was added LiOH.H2O (70 mg, 1.66 mmol, 2 eq.) and the mixture was heated at 100°C under microwave irradiation for 30 mins. The mixture was allowed to cool to rt and partitioned between DCM and 2 M aq. HCl solution. The phases were separated and the organic phase dried (PTFE phase separator) and concentrated in vacuo to afford the title product (209 mg, 0.74 mmol, 89%). LRMS calcd for C15H19FO4: 282.1, found 281.2 [M-H]- 1H 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). Step 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 eq.) as the appropriate amine and the product from Step B (55 mg, 0.19 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (69.5 mg, 0.07 mmol, 39%). HRMS calcd for C + 60H66FN7O6: 999.5059, found 1000.5136 [M+H] 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

[0023] Step 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 eq.) in DMF (18 mL) was added K2CO3 (3.9 g, 2.0 eq.) and diacetoxypalladium (315 mg, 0.1 eq.) 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%). 1H 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); 13C 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]+ calcd for C28H29N2O5: 473.2072, found 473.2074. Step 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 eq.) in 2- methylpropan-2-ol (36 mL) and THF (24 mL) was added NaH2PO4(4.7 g, 5.0 eq.) in water (31 mL) dropwise. After cooling to 14°C and dropwise addition of NaClO2(2.1 g, 3.0 eq.) in water (31 mL), the mixture was stirred at 20°C until complete conversion was observed. After cooling to 5-10°C, dropwise addition of Na2S2O3 (1.6 g, 1.3 eq.) 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%). 1H 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); 13C 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]+ calcd for C28H29N2O6: 489.2021, found 489.2023. Step 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 Step A of Preparation VIIb, starting from the product of Step B (3.1 g, 6.45 mmol) as the appropriate carboxylic acid and the product from Step A of Preparation IIa (1.4 mg, 1.2 eq.) as the appropriate amine, the title compound was obtained (3.1 g, 83%). 1H 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]+ calcd for C29H32N3O3: 470.2437, found 470.2439. Step 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), NaHCO3(1.5 g, 2.3 eq.) in 1,4-dioxane (30 mL) and water (30 mL) was added 9H-fluoren-9-ylmethyl carbonochloridate (208 mg, 1.1 eq.), and the reaction mixture was stirred until complete conversion was observed. After the addition of a 2 M solution of HCl (53 mL), stirring for 15 min, and dilution 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); 13C 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]+ calcd for C44H42N3O5: 692.3119, found 692.3118. Step 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 from 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 eq.) as the appropriate aniline, the title compound was obtained (2.3 g, 62%). 1H 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]+ calcd for C63H67N6O5Si: 1015.4939, found 1015.4940. Step 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) were 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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 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]+ calcd for C48H57N6O3Si: 793.4255, found 793.4256. Step G: 2-[4-[2-[cyclopropyl(methyl)amino]ethoxy]phenyl]acetic acid Using the General procedures 7d and then General procedure 8, starting from methyl 2-[4- (2-bromoethoxy)phenyl]acetate (250 mg, 0.91 mmol) as the appropriate alkyl halide and N- methylcyclopropanamine (130 mg, 2.0 eq.) as the appropriate amine, the desired product was obtained (190 mg, 59%). 1H 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); 13C 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]+ calcd for C14H20NO3: 250.1438, found 250.1437. Step 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 eq.) 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]+ calcd for C56H60N7O5: 910.4652, found 910.4653. 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 Step 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 the General procedure 7d and then General procedure 8, starting from 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 eq.) as the appropriate amine, the desired product was obtained (90 mg, 25%). 1H 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]+ calcd for C17H25N2O4: 321.1814, found 321.1807. Step 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 from the product of Step A (150 mg, 4.0 eq.) as the appropriate carboxylic acid and Preparation VIIb (90 mg, 0.12 mmol) as the appropriate amine, afforded the title compound (54 mg, 48%). HRMS-ESI (m / z) [M+H]+ calcd for C57H63N8O6: 955.4865, found 955.4858. Example 37: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(2-{2-[4-(2-{1,1-dioxo-1λ⁶-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

[0024] Step A: 2-[4-[2-(1,1-dioxo-1λ^{6}-thia-6-azaspiro[3.3]heptan-6-yl)ethoxy]phenyl]acetic acid To the suspension of 3λ^{6}-thia-6-azaspiro[3.3]heptane 3,3-dioxide, HCl salt (213 mg, 1.7 eq.) in 1,4-dioxane (1 mL), the product of Step B of Example 32 (200 mg, 0.69 mmol) and DIPEA (0.4 mL, 3.0 eq.) were added. The reaction mixture was stirred at 80°C until complete conversion was observed, then the product was hydrolysed according to the General procedure 8, to give the title compound (149 mg, 66%). 1H 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); 13C 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]+ calcd for C15H20NO5S: 326.1062, found 326.1054. Step B: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(2-{2-[4-(2-{1,1-dioxo-1λ⁶-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 eq.) as the appropriate carboxylic acid and Preparation VIIb (90 mg, 0.12 mmol) as the appropriate amine, afforded the title compound (24 mg, 21%). HRMS-ESI (m / z) [M+H]+ calcd for C55H58N7O7S: 960.4113, found 960.4110. 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 Step A: methyl 2-{4-[(E)-2-ethoxyethenyl]phenyl}acetate To a solution of methyl 4-bromophenylacetate (224 mg, 0.98 mmol, 1 eq.), (E)-1-ethoxyethene- 2-boronic acid pinacol ester (213 mg, 1.08 mmol, 1.1 eq.) in THF (4 mL) and water (0.4 mL) was added K2CO3(405 mg, 2.93 mmol, 3 eq.), and the mixture was sparged with N2. Pd(dppf)Cl2 DCM (80 mg, 0.1 mmol, 0.1 eq.) was added and then the reaction was heated at 110°C under microwave irradiation for 1 h. The mixture was allowed to cool to rt 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 afforded the title product (173 mg, 0.79 mmol, 80%). 1H 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). Step 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 eq.) in acetone (5 mL) was added 2 M aq. HCl solution (0.79 mL, 1.57 mmol, 2 eq.) and the mixture was stirred at 45°C for 2 h. The mixture was allowed to cool to rt, diluted with DCM, dried (PTFE phase separator) and concentrated in vacuo to afford an intermediate which was dissolved in DCM (5 mL). Morpholine (82 µL, 0.94 mmol, 1.2 eq.) and NaBH(OAc)3 (331 mg, 1.56 mmol, 2 eq.) were added and the mixture was stirred at rt for 2 h. A mixture of ester and acid was observed. Purification by automated flash chromatography eluting with a gradient of 0 - 20% MeOH in DCM afforded the ester, and then the acid was eluted with MeOH, and the solvent removed in vacuo. The residue was dissolved in DCM and loaded onto a pre-wetted (DCM) SCX-2 cartridge, washing with DCM, MeOH and eluting with 10% NH3 / MeOH in DCM to afford the title product (54 mg, 0.22 mmol, 28%). 1H 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). Step 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 eq.) as the appropriate amine and the product from Step B (65 mg, 0.26 mmol, 1.3 eq.) as the appropriate carboxylic acid afforded the title product (67 mg, 0.08 mmol, 38%). HRMS calcd for C H N O : 883.4421, fo + 54 57 7 5 und 884.4513 [M+H] 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 Step 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 the General procedure 7d, starting from 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 eq.) as the appropriate amine, the desired product was obtained (1.4 g, 90%). 1H 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); 13C 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]+ calcd for C17H26NO4: 308.1856, found 308.1860. Diastereomers of the desired product was separated on a Daicel AS-V chiral column (100*500 mm, 20 μm) using 7:93 i-PrOH-heptane + 0.05% DEA as eluents to give the Diastereomer 1, Diastereomer 2 Enantiomer 1 (99.9% ee) and Diastereomer 2 Enantiomer 2 (99.9% ee). Step B: 2-[4-[2-[cis-2,6-dimethylmorpholin-4-yl]ethoxy]phenyl]acetic acid (from Diastereomer 1) Using the General procedure 8, starting from the Diastereomer 1 of Step A (420 mg, 1.37 mmol), the desired product was obtained (360 mg, 67%). 1H 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); 13C 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]+ calcd for C16H24NO4: 294.1705, found 294.1702. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, afforded the title compound (60 mg, 62%). HRMS-ESI (m / z) [M+H]+ calcd for C56H62N7O6: 928.4761, found 928.4755. 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 Step 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 eq.), (8aS)-7,7-difluoro- octahydropyrrolo[1,2-a]pyrazine dihydrochloride (535 mg, 2.28 mmol, 1.25 eq.) and Cs2CO3 (2.37 g, 7.29 mmol, 4 eq.) were combined in toluene (10 mL) and the mixture was sparged with N2. DavePhos (72 mg, 0.18 mmol, 0.1 eq.) and Pd2dba3(83 mg, 0.09 mmol, 0.05 eq.) were added and the mixture was heated at 130°C under microwave irradiation for 1 h. Further DavePhos (36 mg, 0.09 mmol, 0.05 eq.) and Pd2dba3 (42 mg, 0.045 mmol, 0.025 eq.) were added, the mixture sparged with N2and then heated at 130°C under microwave irradiation for 2 h. The mixture was allowed to cool to rt and partitioned between DCM and sat. aq. NaHCO3 solution. The phases were separated (PTFE phase separator) and the organic phase concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 65% EtOAc in heptane afforded the title product (181 mg, 0.55 mmol, 30%). LRMS calcd for C16H19F3N2O2: 328.1, found 329.2 [M+H]+ 1H 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). Step 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 eq.) in MeOH (4 mL) was added LiOH.H2O (46 mg, 1.1 mmol, 2 eq.) and the mixture was heated at 100°C under microwave irradiation for 30 mins. The mixture was allowed to cool to rt, neutralised with 2 M aq. HCl solution and concentrated in vacuo. Purification by reverse phase automated flash chromatography eluting with a gradient of 10 - 95% MeCN in water afforded the title product (124 mg, 0.39 mmol, 72%). LRMS calcd for C H F N O : 31 + 15 17 3 2 2 4.1, found 315.2 [M+H] 1H 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). Step 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 eq.) as the appropriate amine and the product from Step B (69 mg, 0.22 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (80.3 mg, 0.08 mmol, 42%). HRMS calcd for C55H55F3N8O4: 948.4298, found 949.4376 [M+H]+ 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 Step A: 4-bromo-1-ethyl-5-methyl-pyrrole-2-carbonitrile Using General procedure 7c, starting from 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (500 mg, 2.7 mmol.) and ethanol (0.3 ml, 1.9 eq) as the appropriate alcohol, afforded the title product (500 mg, 87%). GC-MS (m / z) [M+H]+ calcd for C8H10BrN2: 213, found 212 / 215. Step 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 eq.) as the appropriate amine, afforded the title product (570 mg, 85%). 1H 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); 13C 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]+ calcd for C20H30N3OSi: 356.2153 , found 356.2152. Step 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 the amide formation. 1H 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]+ calcd for C47H57N6O3Si: 781.4, found 781.4. Step 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 from Preparation Va as the appropriate acid (65 mg, 2.5 eq.) 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]+ calcd for C55H60N7O6: 914.4600, found 914.4600. 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 Step A: 2-[4-[2-[(2R or S,6R or S)-2,6-dimethylmorpholin-4-yl]ethoxy]phenyl]acetic acid Using the General procedure 8, starting from the Diastereomer 2 Enantiomer 2 of Step A of Example 39 (210 mg, 0.68 mmol), the desired product was obtained (150 mg, 56%). 1H 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); 13C 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]+ calcd for C16H24NO4: 294.1705, found 294.1722. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, afforded the title compound (60 mg, 62%). HRMS-ESI (m / z) [M+H]+ calcd for C56H62N7O6: 928.4762, found 928.4757. 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 Using General procedure 4a and Preparation IVb (130 mg, 0.18 mmol, 1 eq.) as the appropriate amine and Preparation Vb (55 mg, 0.19 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (45.4 mg, 0.05 mmol, 26%). HRMS calcd for C59H65FN8O6: 1000.5011, found 1001.5094 [M+H]+ 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 Using General procedure 4a and Preparation IVb (130 mg, 0.18 mmol, 1 eq.) as the appropriate amine and 4-chloro-2-fluorophenylacetic acid (37 mg, 0.19 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (72.7 mg, 0.08 mmol, 45%). HRMS calcd for C53H53ClFN7O4: 905.3832, found 906.3913 [M+H]+ 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

[0025] Step 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-fluoro-phenyl)acetate (240 mg, 0.8 eq.) 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) were added Cs2CO3 (469 mg, 1.1 eq.) and [2-(2- aminoethyl)phenyl]-chloro-palladium, dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl] phosphane (1:1) (37 mg, 0.04 eq.). The reaction was stirred until complete conversion was observed. After filtration, the crude product was hydrolysed using the General procedure 8, purified, treated with 2 mL of 2 M HCl solution, and freeze dried 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); 13C 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]+ calcd for C15H19FN2O3: 295.1452, found 295.1453. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, afforded the title compound (51 mg, 53%). HRMS-ESI (m / z) [M+H]+ calcd for C55H58FN8O5: 929.4509, found 929.4513. 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 Step A: 2-[2-chloro-4-(2-morpholinoethoxy)phenyl]acetic acid, TEA salt Using General procedure 7b and then General procedure 8, starting from methyl 2-(2- chloro-4-hydroxy-phenyl)acetate (150 mg, 0.75 mmol) as the appropriate phenol and 2- morpholinoethanol (147 mg, 1.5 eq.) as the appropriate alcohol, followed with a purification step by automated flash chromatography using DCM and MeOH (1% TEA) as eluents afforded the TEA salt of the title product (236 mg, 79%). 1H 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); 13C 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]+ calcd for C14H19ClNO4:300.0997, found 300.0998. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (90 mg, 0.12 mmol) as the appropriate amine, afforded the title compound (68.8 mg, 63%). HRMS-ESI (m / z) [M+H]+ calcd for C54H57ClN7O6: 934.4053, found 934.4058. 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 Step 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 from 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 eq) as the appropriate amine, the title product was obtained (145 mg, 76 %). 1H 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]+ calcd for C16H23F2N2O3: 329.1671, found 329.2. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.10 mmol) as the appropriate amine, afforded the title product (38.8 mg, 30%). HRMS-ESI (m / z) [M+H]+ calcd for C56H61F2N8O5: 963.4727, found 963.4729. 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 Step 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 eq.), 3,6-dihydro-2H- pyridine-1-N-Boc-4-boronic acid, pinacol ester (688 mg, 2.23 mmol, 1.1 eq.) and K2CO3(839 mg, 6.07 mmol, 3 eq.) were combined in 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 eq.) was added and the mixture was heated at 110°C under microwave irradiation for 1 h. The mixture was allowed to cool to rt 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 - 31% EtOAc in heptane afforded the title product (707 mg, 2.03 mmol, quant.). LRMS calcd for C19H24FNO4: 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). Step 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 eq.) in MeOH (30 mL) was added 10% Pd / C (25 mg). The mixture was evacuated and backfilled with N2, then evacuated and flushed with H2 and then shaken at rt for 4 h under an atmosphere of H2. The mixture was filtered through a celite cartridge, washing with MeOH and the solvent removed in vacuo to afford the title product (679 mg, 1.93 mmol, 95%). 1H 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). Step 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 eq.) in DCM (10 mL) and the reaction mixture was stirred at rt for 2 h. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. aq. NaHCO3solution. The organic phase was collected (PTFE phase separator) and concentrated in vacuo to afford the title product (488 mg, 1.94 mmol, 100%). LRMS calcd for C14H18FNO2: 251.1, found 252 [M+H]+ 1H 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). Step 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 eq.) was added to a stirred suspension of the product from Step C (240 mg, 0.96 mmol, 1 eq.) and K2CO3 (528 mg, 3.82 mmol, 4 eq.) in DMF (2 mL) under a N2atmosphere and the mixture was heated at 100°C under microwave irradiation for 1 h. The mixture was allowed to cool to rt and partitioned between DCM and sat. aq. NaHCO3 solution. The organic phase was separated (PTFE phase separator) and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 80% EtOAc in heptane afforded the title product (164 mg, 0.52 mmol, 54%). LRMS calcd for C 6H20F3N + 1 O2: 315.1, found 316.2 [M+H] 1H 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). Step 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 eq.) in MeOH (4 mL) was added LiOH.H2O (44 mg, 1.04 mmol, 2 eq.) and the mixture was heated at 100°C under microwave irradiation for 30 mins. The mixture was allowed to cool to rt, neutralised with 2 M aq. HCl solution and concentrated in vacuo. Purification by reverse phase automated flash chromatography eluting with a gradient of 10 - 100% MeCN in water afforded the title product (139 mg, 0.46 mmol, 89%). LRMS calcd for C + 15H18F3NO2: 301.1, found 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). Step 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 eq.) as the appropriate amine and the product from Step E (66 mg, 0.22 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (97.2 mg, 0.1 mmol, 52%). HRMS calcd for C H F N O : 935.4346, found 936.4436 [M + 55 56 3 7 4 +H] 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 Step A: 2-[4-[2-(3-fluoroazetidin-1-yl)ethoxy]phenyl]acetic acid Using General procedure 7d and then General procedure 8, starting from 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 eq) as the appropriate amine, the title product was obtained (108 mg, 77.6 %). 1H 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); 13C 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]+ calcd for C13H17FNO3: 254.1186, found 254.1187. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (70 mg, 0.091 mmol) as the appropriate amine, afforded the title product (40.1 mg, 50%). HRMS-ESI (m / z) [M+H]+ calcd for C53H55FN7O: 888.4243, found 888.4247. 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 Step A: 2-[4-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]phenyl]acetic acid Using General procedure 7d and then General procedure 8, starting from methyl 2-[4-(2- bromoethoxy)phenyl]acetate (150 mg, 0.55 mmol) and 3,3-difluoropyrrolidine hydrochloride (157.7 mg, 2 eq.) as reactants, the title product was obtained (48 mg, 31 %). 1H 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]+ calcd for C14H18F2NO3: 286.1249, found 286.1253. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (50 mg, 0.065 mmol.) as the appropriate amine, afforded the title product (25.1 mg, 42%). HRMS-ESI (m / z) [M+H]+ calcd for C54H56F2N7O5: 920.4306, found 920.4304. 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 Step 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 eq.) in MeOH (5 mL) was added 2 M aq. NaOH solution (0.82 mL, 1.63 mmol, 1 eq.) and the mixture was stirred at rt for 18 h. The mixture was concentrated in vacuo, acidified with 2 M aq. HCl solution and extracted with DCM. The combined organic extracts were dried over MgSO4and concentrated in vacuo to afford the title product (311 mg, 1.51 mmol, 92%). 1H 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). Step 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 eq.) in acetone (5 mL) was added 2 M aq. HCl solution (0.54 mL, 1.08 mmol, 1 eq.) and the mixture stirred at rt for 18 h. The mixture was diluted with DCM and dried over MgSO4and concentrated in vacuo. To a solution of the intermediate in DCM (5 mL) was added 4,4-difluoropiperidine (249 mg, 1.58 mmol, 1.2 eq.) and TEA (220 µL, 1.58 mmol, 1.2 eq.) followed by NaBH(OAc)3 (559 mg, 2.64 mmol, 2 eq.) and the mixture was stirred at rt 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 afford 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). Step 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 eq) as the appropriate amine and the product from Step B (95 mg, 0.34 mmol, 2 eq.) as the appropriate carboxylic acid afforded the title product (23 mg, 0.02 mmol, 15%). HRMS calcd for C + 55H57F2N7O4: 917.4440, found 918.4522 [M+H] 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 Step 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 eq.) in DCM (50 mL) was added TEA (6.14 mL, 44.11 mmol, 3.6 eq.) and di-tert-butyl dicarbonate, (3.15 mL, 14.7 mmol, 1.2 eq.) and the mixture was stirred at rt under N2for 18 h. The mixture was diluted with sat. aq. NaHCO3solution and the organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 100% EtOAc in heptane afforded the title product (2.96 g, 11.23 mmol, 92%). LRMS calcd for C H NO : 263.2, found 164.0 [M- + 15 21 3 Boc+H] 1H 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). Step 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 eq.) in DMF (10 mL), cooled to 0°C, was added NaH (60% dispersion in mineral oil; 100 mg, 2.51 mmol, 1.5 eq.) and the mixture was stirred for 10 mins. Iodomethane (156 µL, 2.51 mmol, 1.5 eq.) was added and the reaction was allowed to warm to rt. Then, it was stirred for 18 h. The mixture was partitioned between EtOAc and sat. aq. NaHCO3, the layers were separated, and the organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title product (450 mg, 1.62 mmol, 97%). LRMS calcd for C16H23NO3: 277.2, found 178.0 [M-Boc+H]+ 1H 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). Step 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 eq.) in THF (10 mL) was added 4 M HCl in dioxane (10 mL) and the mixture was stirred at rt for 18 h. The mixture was concentrated in vacuo and then triturated with Et2O and heptane to afford the title product (257 mg, 1.45 mmol, 89%). LRMS calcd for C H NO + 11 15 : 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). Step 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 eq) as the appropriate carboxylic acid and the product from Step C (222 mg, 1.04 mmol, 1.1 eq.) as the appropriate amine afforded the title product which was used directly in the subsequent step without further purification. LRMS calcd for C H N O : 63 + 38 41 3 6 5.3, found 636.4 [M+H] Step 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 eq.) in MeOH (25 mL) was added 10% Pd / C (25 mg). The mixture was evacuated and backfilled with N2, then evacuated and flushed with H2 and then shaken at rt for 18 h under an atmosphere of H2. The mixture was filtered through a celite cartridge, washing with MeOH. The solvent was removed in vacuo and the residue was loaded onto a pre-washed (MeOH) 10g SCX-2 cartridge, washing with DCM and MeOH and then the product was eluted with 4:1 DCM / 7 M NH3in MeOH. The solvents were removed in vacuo to afford the title product which was used directly in the subsequent step without further purification. LRMS calcd for C + 30H35N3O4: 501.3, found 502.4 [M+H] Step 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 eq.) in THF (10 mL) and water (2 mL) was added di-tert-butyl dicarbonate (0.21 mL, 1 mmol, 1.05 eq.) and TEA (0.27 mL, 1.91 mmol, 2 eq.) and the mixture was stirred at rt for 24 h. The solvent was evaporated under reduced pressure and the residue partitioned between EtOAc and sat. aq. NH4Cl solution. Water was added, the phases were separated, and the organic phase was washed with brine. The organic phase was dried over MgSO4and concentrated in vacuo to afford the title product (476 mg, 0.79 mmol, 83%). LRMS calcd for C + 35H43N3O6: 601.3, found 602.4 [M+H] Step G: 5-[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 eq.) in MeOH (10 mL) and water (2 mL) was added LiOH.H2O (133 mg, 3.16 mmol, 4 eq.) and the mixture was refluxed at 100°C for 48 h. The mixture was allowed to cool to rt and concentrated in vacuo. The aqueous residue was neutralised with 1 M aq. HCl solution and extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 20 - 100% EtOAc in heptane afforded the title product (318 mg, 0.55 mmol, 70%). LRMS calcd for C H N O : 573.3, f + 33 39 3 6 ound 574.4 [M+H] Step 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 eq) and Preparation IIIb (12.79 g, 48.17 mmol, 1.2 eq) as the appropriate aniline afforded the title product (10.68 g, 27.84 mmol, 69%). LRMS calcd for C22H33N3OSi: 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). Step 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 eq.) as the appropriate acid and the product from Step H (321 mg, 0.84 mmol, 1.6 eq.) as the appropriate aniline afforded the title product (318 mg, 0.34 mmol, 65%). LRMS calcd for C55H70N6O6Si: 938.5, found 939.6 [M+H]+ Step 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 eq.) as the appropriate silyl-derivative afforded the title product (176 mg, 0.21 mmol, 62%). LRMS calcd for C + 50H62N6O4Si: 838.5, found 839.6 [M+H] Step 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 eq) as the appropriate amine and the product from Example 34, Step B (36 mg, 0.13 mmol, 1.2 eq.) as the appropriate carboxylic acid afforded the title product (106 mg, 0.1 mmol, 92%). LRMS calcd for C65H79FN6O7Si) 1102.6, found 1103.4 [M+H]+ Step 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 eq.) as the appropriate silyl-derivative afforded the title product (41.7 mg, 0.04 mmol, 46%). HRMS calcd for C56H59FN6O7: 946.4429, found 947.4509 [M+H]+ 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

[0026] Step A: 2-[4-[2-(4-fluoro-1-piperidyl)ethoxy]phenyl]acetic acid Using the General procedure 7d and then General procedure 8, starting from 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 eq.) as the appropriate amine, followed with purification step by automated flash chromatography using DCM and MeOH (1% TEA) as eluents afforded the title product (157 mg, 95%). 1H 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); 13C 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]+ calcd for C15H21FNO3: 282.1499, found 282.1500. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, afforded the title product (69 mg, 72%). HRMS-ESI (m / z) [M+H]+ calcd for C55H59FN7O5: 916.4556, found 916.4561. 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 Step 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 at 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 eq., the synthesis is disclosed in WO2015 / 011164 A1 as Preparation 2d) as the appropriate amine, the title compound was obtained (2.6 g, 69%). 1H 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); 13C 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]+ calcd for C31H37N4O4: 529.2809, found 529.2814. Step 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.), NaHCO3(437 mg, 2.3 eq.) in 1,4-dioxane (13 mL) and water (13 mL) was added 9H-fluoren-9-ylmethyl carbonochloridate (643 mg, 1.1 eq.), and the reaction mixture was stirred until complete conversion was observed. After the addition of a 2 M solution of HCl (23mL) and stirring for 15 min, 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%). 1H 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]+ calcd for C46H47N4O6: 751.3490, found 751.3493. Step 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 from 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 eq.) as the appropriate aniline, the title compound was obtained (1.18 g, 82%). 1H 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]+ calcd for C65H72N7O6Si: 1074.5308, found 1074.5307. Step 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]+ calcd for C50H62N7O4Si: 852.4624, found 852.4619. Step 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 from 2-[2-fluoro-4-(2-tetrahydropyran-4- ylethoxy)phenyl]acetic acid (56 mg, 2.0 eq.) 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]+ calcd for C59H65FN7O7: 1002.4924, found 1002.4926. 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 Step A: methyl 2-[4-(2-thiomorpholinoethoxy)phenyl]acetate Using the General procedure 7d and then General procedure 8, starting from methyl 2-[4- (2-bromoethoxy)phenyl]acetate (121 mg, 0.44 mmol) as the appropriate alkyl halide and thiomorpholine (55 mg, 3.0 eq.) as the appropriate amine, afforded the title product (88 mg, 53%). LCMS-ESI (m / z) [M+H]+ calcd for C14H20NO4S: 282.1, found 282.2. Step 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, staring from the product of Step A (83 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (150 mg, 0.20 mmol) as the appropriate amine, afforded the expected product (115 mg, 64%). HRMS-ESI (m / z) [M+H]+ calcd for C54H58N7O5S: 916.4215, found 916.4216. 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) Step 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 from methyl 2-[4-(2-bromoethoxy)phenyl]acetate (320 mg, 1.17 mmol) as the appropriate alkyl halide and 2-methylmorpholine (355 mg, 3 eq.) as the appropriate amine, the desired product was obtained (351 mg, quant.). 1H 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]+ calcd for C16H24NO4: 294.1700, found 294.1702. 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 eluents to give the Enantiomer 1 and Enantiomer 2. Enantiomer 1 was identified as (R) and Enantiomer 2 was identified as (S) based on the comparison of the products of test reactions starting from (2R)-2-methylmorpholine and (2S)-2-methylmorpholine. Step 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 eq.).The reaction mixture was stirred for 18 h. The THF was removed in vacuo and the aqueous residue was acidified with 2 M aq. HCl solution to pH 5.5 then evaporated. Purification by automated flash chromatography using DCM and MeOH (1% TEA) as eluents afforded the title product (184 mg, quant., 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); 13C 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]+ calcd for C15H22NO4: 280.1543, found 280.1544. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, afforded the desired product (45 mg, 47%). HRMS-ESI (m / z) [M+H]+ calcd for C55H60N7O6: 914.4600, found 914.4600. 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) Step A: 2-[4-[2-[(2S)-2-methylmorpholin-4-yl]ethoxy]phenyl]acetic acid (from Enantiomer 2) Using General procedure 8, starting from Enantiomer 2 product of Example 56, Step A (167 mg, 0.569 mmol) afforded the title product (150 mg, quant., partial TEA salt). HRMS-ESI (m / z) [M+H]+ calcd for C15H22NO4: 280.1543, found 280.1545. Step 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, afforded the title product (72 mg, 76%). HRMS-ESI (m / z) [M+H]+ calcd for C55H60N7O6: 914.4600, found 914.4600. 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 To a solution of Preparation IVa (90 mg, 0.14 mmol, 1 eq.) in DCM (3 mL) was added isoquinoline-3-carboxaldehyde (33 mg, 0.21 mmol, 1.5 eq.) and NaBH(OAc)3(58 mg, 0.28 mmol, 2 eq.) and the mixture was stirred at rt for 18 h. The mixture was partitioned between DCM and water. The phases were separated, and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification by preparative HPLC automated flash chromatography at pH 4 and then at pH 9, eluting with a gradient of 5 - 95% MeCN in water afforded the title product (16.3 mg, 0.02 mmol, 15%). HRMS calcd for C50H47N7O3: 793.3740, found 794.3817 [M+H]+ 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

[0027] Step A: 2-[6-(2-tetrahydropyran-4-ylethoxy)-3-pyridyl]acetic acid To a solution of the 2-(6-chloro-3-pyridyl)acetic acid (163 mg, 0.95 mmol) and 2- tetrahydropyran-4-ylethanol (239 mg, 1.9 eq.) in 1,4-dioxane (1.0 mL) was added sodium tert- butoxide (280 mg, 3.0 eq.). Then the mixture was 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 aq. NH4HCO3 solution as eluent) to give the title compound (158 mg, 63%). 1H 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); 13C 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]+ calcd for C14H20NO4: 266.1387, found 266.1386. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (70.0 mg, 60%). HRMS-ESI (m / z) [M+H]+ calcd for C54H58N7O6: 900.4443, found 900.4444. 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 Step A: 2-[4-[2-[methyl(oxetan-3-yl)amino]ethoxy]phenyl]acetic acid Using the General procedure 7d and then General procedure 8, starting from 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 eq.) as the appropriate amine, the desired product was obtained (180 mg, 90%). 1H 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); 13C 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]+ calcd for C14H20NO4: 266.1387, found 266.1387. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (65.0 mg, 55%). HRMS-ESI (m / z) [M+H]+ calcd for C54H58N7O6: 900.4448, found 900.4436. 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 Step A: 2-[6-[2-[cyclopropyl(methyl)amino]ethoxy]-3-pyridyl]acetic acid To a solution of the 2-(6-chloro-3-pyridyl)acetic acid (193 mg, 1.12 mmol) and 2- [cyclopropyl(methyl)amino]ethanol (666 mg, 5.1 eq.) in 1,4-dioxane (0.5 mL) was added sodium tert-butoxide (288 mg, 2.7 eq.), then the mixture was heated at 150°C under microwave irradiation until complete conversion was observed. The reaction mixture was purified by HILIC chromatography (using ACN:NH4HCO3 as eluent) to give the title compound (120 mg, 43%). 1H 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); 13C 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]+ calcd for C13H18N2O3: 251.1390, found 251.1393. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (100 mg, 0.13 mmol) as the appropriate amine, afforded the title compound (71.0 mg, 62%). HRMS-ESI (m / z) [M+H]+ calcd for C53H57N8O5: 885.4446, found 885.4447. 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 Step 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 eq.) as the appropriate aryl bromide and Preparation IIIa (1.16 g, 5.19 mmol, 1.1 eq.) as the appropriate aniline afforded the title product (732 mg, 2.06 mmol, 44%). LRMS calcd for C H N OSi: 354.2, found 355.2 [ + 19 26 4 M+H] 1H 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). Step 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 eq.) as the appropriate acid and the product from Step A (135 mg, 0.38 mmol, 1.5 eq.) as the appropriate aniline afforded an intermediate which was treated according to General procedure 3b to afford the title product (37.4 mg, 0.04 mmol, 16%). HRMS calcd for C54H56N8O6: 912.4323 found, 913.4403 [M+H]+ 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) Step 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 eq.) in 1,4-dioxane (5 mL / mmol) were added 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 eq.) and Cs2CO3 (996 mg, 2 eq.) and the mixture was stirred at 110°C under N2for 2h. The mixture was allowed to cool to room temperature, was filtered through a pad of Celite and was purified by automated flash chromatography using DCM and methanol as eluents to obtain the racemic product as a brown solid (369 mg, 79%). 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 eluents 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 eluents and freeze-drying with hydrochloric acid afforded the HCl salt of the title product as a brown solid (225 mg, quant.). 1H 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]+ calcd for C16H23N2O3: 291.1703, found 291.1704. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, afforded the title product (64 mg, 66%). HRMS-ESI (m / z) [M+H]+ calcd for C56H61N8O5: 925.4759, found 925.4758. 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

[0028] Step A: 4-bromo-1-isopropyl-5-methyl-pyrrole-2-carbonitrile Using General procedure 7c, starting from 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (70 mg, 0.38 mmol) and propan-2-ol (0.3 ml, 2.2 eq) as the appropriate alcohol, afforded the title product (45 mg, 51%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.12 (s, 1H), 4.61 (sept., 1H), 2.27 (s, 3H), 1.49 (d, 6H); 13C 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]+ calcd for C9H12BrN2: 227, found 226 / 228. Step 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 eq.) as the appropriate aniline, afforded the title product (41 mg, 63%). 1H 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); 13C 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]+ calcd for C21H32N3OSi: 370.2, found 370.2. Step 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 the amide formation. 1H 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]+ calcd for C48H59N6O3Si: 795.4, found 795.4. Step 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 from Preparation Va as the appropriate acid (46 mg, 0.157 mmol, 2.5 eq.) and the product of Step C (50 mg, 0.063 mmol, 1 eq.) as the appropriate amine, the desired product was obtained (24.7 mg, 42%). HRMS-ESI (m / z) [M+H]+ calcd for C56H62N7O6: 928.4756, found 928.4755. 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 Step 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 eq.) as the appropriate aryl bromide and aniline (5.5 mL, 60.29 mmol, 1.2 eq.) afforded the title product (6.36 g, 30.12 mmol, 60%). LRMS calcd for C13H13N3: 211.1, found 212.0 [M+H]+ 1H 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). Step 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 Using General procedure 2a and Preparation VIa (163 mg, 0.24 mmol, 1 eq.) as the appropriate acid and the product from Step A (75 mg, 0.35 mmol, 1.5 eq.) as the appropriate aniline, followed with a purification step by preparative HPLC automated flash chromatography at pH 9 eluting with a gradient of 5 - 95% MeCN in water afforded the title product (10.3 mg, 0.01 mmol, 5%). HRMS calcd for C H N O : 883.4421, found 884.4 + 54 57 7 5 511 [M+H] . 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 Using General procedure 4a and Preparation IVb (142 mg, 0.19 mmol, 1 eq.) as the appropriate amine and Preparation Vc (56 mg, 0.21 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (49.7 mg, 0.05 mmol, 26%). HRMS calcd for C60H67N7O6: 981.5153, found 982.5237 [M+H]+ 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 Using General procedure 4a and Preparation IVb (142 mg, 0.19 mmol, 1 eq.) as the appropriate amine and Preparation Va (56 mg, 0.21 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (71 mg, 0.07 mmol, 37%). HRMS calcd for C H N O : 9 + 59 66 8 6 82.5105, found 983.5185 [M+H] 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

[0029] Step A: 4-bromo-1-(2-methoxyethyl)-5-methyl-pyrrole-2-carbonitrile Using General procedure 7c, starting from 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (100 mg, 0.54 mmol) and 2-methoxyethanol (80 mg, 2 eq) as the appropriate alcohol, afforded the title product (100 mg, 71%). 1H 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); 13C 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]+ calcd for C9H12BrN2O: 243, found 243. Step B: 4-[4-[tert-butyl(dimethyl)silyl]oxyanilino]-1-(2-methoxyethyl)-5-methyl-pyrrole-2- carbonitrile Using General procedure 1b, starting the product of Step A (100 mg, 0.41 mmol) as the appropriate aryl bromide and Preparation IIIa (138 mg, 1.5 eq.) as the appropriate aniline, afforded the title product (120 mg, 76%). 1H 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); 13C 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]+ calcd for C21H32N3O2Si: 386.2259 , found 386.2259. Step 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 the 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]+ calcd for C42H45N6O4: 697.3497, found 697.3496. Step 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 Using General procedure 4c, starting from Preparation Va as the appropriate acid (41 mg, 2.5 eq.) 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]+ calcd for C56H62N7O7: 944.4705, found 944.4706. 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 Step 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 eq.) in THF (250 mL) was placed under N2. A cartridge supplied by OmniFit™ was loaded with zinc granules mesh 300 (12 g excess). A second vessel containing a 0.25 M solution of 4-bromo-2,5-difluoroanisole in THF (200 mL, 49.32 mmol, 1 eq.) was placed under N2. To this solution was added X-Phos (0.59 g, 1.23 mmol, 0.03 eq.) and Pd2dba3 (0.56 g, 0.62 mmol, 0.01 eq.) and the mixture sparged with N2 for 20 mins and then sonicated to form a homogenous mixture. A Syrris Asia Flow Chemistry System™ was set up with a column heater into which the cartridge containing the zinc was mounted and heated to 40°C. The zinc was pre-activated using a procedure analogous to the method according to Berton, M., Huck, L. & Alcázar, J. On- demand synthesis of organozinc halides under continuous flow conditions. Nat Protoc 13, 324– 334 (2018). A T-mixer (head-to-head) was placed prior to the tube reactor and reagent feeds to the Asia pumps were set up under N2in the Asia Reagent Store. A 16 mL fluoropolymer tube reactor was mounted on an Asia heater module and was surrounded by 450 nm (blue) LED lights (18 W). The tube heater was set to 80°C. The system back pressure regulator was set to 2 bar. The solution of ethyl bromoacetate flow rate was set to 250 µL min-1. The 4 -bromo-2,5-difluoroanisole solution flow rate was set at 250 µL min-1 and the resultant combined flow rate in the tube reactor was 500 µL min-1 giving a reaction residence time of 32 mins. The collected crude product solution was passed through a celite cartridge to remove spent palladium and washed through with further THF. The combined filtrate was diluted with EtOAc, washed with sat. aq. NH4Cl solution, brine and then dried over MgSO4and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of heptane - 42% DCM in heptane afforded the title product (10.9 g, 47 mmol, 95%). LRMS calcd for C H F O : + 11 12 2 3 230.1, found 231.2 [M+H] 1H 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). Step B: ethyl 2-(2,5-difluoro-4-hydroxyphenyl)acetate A solution of 1 M BBr3in DCM (14.53 mL, 14.53 mmol, 1.5 eq.) was added dropwise over 15 mins to a suspension of the product from Step A (2.23 g, 9.69 mmol, 1 eq.) in anhydrous DCM (40 mL), cooled to -78°C under N2. The mixture was allowed to warm to rt and stirred for 3 h. 100g of crushed ice was added and the mixture was stirred vigorously for 15 mins. The DCM was removed in vacuo and the aqueous 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 afforded the title product (1.22 g, 5.64 mmol, 58%). LRMS calcd for C H F O : 216.1, fo - 10 10 2 3 und 215.0 [M-H] 1H 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). Step 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 eq.) was added to a mixture of the product from Step B (1.22 g, 6.03 mmol, 1 eq.) and KI (0.1 g, 0.6 mmol, 0.1 eq.) in acetone. K2CO3 (4.17 g, 30.17 mmol, 5 eq.) was added and the mixture was heated at 60°C for 2 days. The mixture was allowed to cool to rt 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 afforded the title product (1.46 g, 4.63 mmol, 77%). 1H 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). Step 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 eq.) as the appropriate ester afforded the title product (621 mg, 2.06 mmol, 45%). LRMS calcd for C14H17F2NO4: 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). Step 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 eq.) as the appropriate amine and the product from Step D (73 mg, 0.24 mmol, 1.2 eq.) as the appropriate carboxylic acid afforded the title product (51 mg, 0.05 mmol, 27%). HRMS calcd for C H F N O : 935.4182, found 936.4 + 54 55 2 7 6 262 [M+H] 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) Step 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 eq.) was added to suspension of trans-2-(4-bromo-3-fluorophenyl)cyclopropan-1-amine hydrochloride (750 mg, 2.81 mmol, 1 eq.) and K2CO3(1.17 g, 8.44 mmol, 3 eq.) in MeCN (10 mL) and the mixture stirred at 60°C under N2 for 18 h. The mixture was allowed to cool to rt 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 - 70% EtOAc in heptane afforded the title product (469 mg, 56%). LRMS calcd for C H 5BrFN + 13 1 O: 299.0, found 300.2 [M+H] 1H 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). Step 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 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 eq.), followed with a purification step by automated flash chromatography eluting with a gradient of 0 – 100% EtOAc in heptane afforded the title product (144 mg, 30%). LRMS calcd for C H FNO : 307.2, found 308.2 + 17 22 3 [M+H] 1H 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). Stereomers 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 eluents to give Stereoisomer 1 and Stereoisomer 2. Step C: 2-[2-fluoro-4-[(1S,2R) or (1R,2S)-2-morpholinocyclopropyl]phenyl]acetic acid (from Stereoisomer 1) Using the General procedure 8, starting from the Enantiomer 1 of Step B (51 mg, 0.166 mmol), 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); 13C 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]+ calcd for C15H19FNO3: 280.1343, found 280.1343. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (79 mg, 0.102 mmol) as the appropriate amine, afforded the title compound (29.0 mg, 20%). HRMS-ESI (m / z) [M+H]+ calcd for C55H57FN7O5: 914.4400, found 914.4408. 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 Step A: 4-bromo-1-cyclopropyl-5-methyl-pyrrole-2-carbonitrile A 4 mL screw-cup vial was charged with 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile (200 mg, 1.08 mmol), bromocyclopropane (326.9 mg, 2.5 eq) and cesium carbonate (2.7 g, 2 eq.) in DMF (2 mL / mmol). The reaction mixture was stirred at 160°C under N2for 24 hours. The volatiles of the reaction mixture were evaporated, the residue was dissolved in DCM (5 mL), and it was concentrated to Celite. Purification via automated flash chromatography, using DCM and EtOAc as eluents afforded the title compound (124 mg, 51 %). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.05 (s, 1H), 3.35 (m, 1H), 1.15-1.00 (m, 4H); 13C 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]+ calcd for C9H11BrN2: 226, found 226. Step 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 eq.) as the appropriate aniline, afforded the title product (102 mg, 52%). 1H 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); 13C 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]+ calcd for C21H30N3OSi: 368.2, found 368.2. Step 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 the amide formation. HPLC-MS-ESI (m / z) [M+H]+ calcd for C48H57N6O3Si: 793.4, found 793.4. Step 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 from Preparation Va as the appropriate acid (45 mg, 2.5 eq.) 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]+ calcd for C56H60N7O6: 926.4600, found 926.4606. 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 Step 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 eq.) as the appropriate aryl bromide and Preparation IIIa (1.14 g, 5.1 mmol, 1.05 eq.) as the appropriate aniline afforded the title product (1.1 g, 3.16 mmol, 65%). LRMS calcd for C H FN O Si: 348.2, found 349.2 [M+H]+ 18 25 2 2 1H 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). Step 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 eq.) as the appropriate acid and the product from Step A (132 mg, 0.38 mmol, 1.5 eq.) as the appropriate aniline afforded an intermediate which was treated according to General procedure 3b to afford the title product (17 mg, 0.02 mmol, 7%). HRMS calcd for C53H55FN6O7: 906.4116, found 907.4208 [M+H]+ 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 Step A: 2-[4-[2-(6-oxa-9-azaspiro[4.5]decan-9-yl)ethoxy]phenyl]acetic acid Using the General procedure 7d and then General procedure 8, starting from 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 eq.) as the appropriate amine, the desired product was obtained (169 mg, 96%). 1H 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]+ calcd for C18H26NO4: 320.1856, found 320.1858. Step 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 from the product of Step A (67.0 mg, 2.0 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.10 mmol) as the appropriate amine, afforded the title compound (70.0 mg, 70%). HRMS-ESI (m / z) [M+H]+ calcd for C58H64N7O6: 954.4918, found 954.4915. 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 Step A: tert-butyl (3S)-3-[2-oxo-2-(1-piperidyl)ethyl]-3,4-dihydro-1H-isoquinoline-2- carboxylate Using General procedure 5a, starting from 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 eq.) as the appropriate amine, followed with a purification step via automated flash chromatography with DCM and methanol as eluents provided the desired compound (332 mg, 90%). 1H 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]+ calcd for C21H31N2O3: 359.2329, found 359.2333. Step B: (3S)-3-[2-(1-piperidyl)ethyl]-1,2,3,4-tetrahydroisoquinoline Using General procedure 6c, the product of Step A (324 mg, 0.90 mmol) was deprotected, then the title product was prepared according to a modified General procedure 6a using MTBE, THF and DCM as solvents. The desired product was obtained (160 mg, 72%). 1H 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]+ calcd for C16H25N2: 245.2012, found 245.2015. Step 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 eq.) as the appropriate amine, the title product was obtained (18.1 mg, 28%). HRMS-ESI (m / z) [M+H]+ calcd for C60H68FN8O6: 1015.5240, found 1015.5241. 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)

[0030] Step 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 the General procedure 7d, starting from Preparation X (500 mg, 1.72 mmol) as the appropriate alkyl halide and 2-methylmorpholine (380 mg, 2.2 eq.) as the appropriate amine, the desired product was obtained (510 mg, 95%). 1H 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); 13C 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]+ calcd for C16H23FNO4: 312.1606, found 312.1608. Enantiomers of the desired product was separated on an AD-3 chiral column (100*500 mm, 20 μm) using 30:70 EtOH-heptane + 0.1% DEA as eluents to give the Enantiomer 1 (99.9% ee) and Enantiomer 2 (99.8% ee). Step B: 2-[2-fluoro-4-[2-((2S or R)-2-methylmorpholin-4-yl)ethoxy]phenyl]acetic acid (from Enantiomer1) Using the General procedure 8, starting from the Enantiomer 1 of Step A (255 mg, 0.82 mmol), the desired product was obtained (146 mg, 60%). 1H 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); 13C 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]+ calcd for C15H21FNO4: 298.1449, found 298.1450. Step 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 eq.) as the appropriate carboxylic acid and Preparation VIIb (80 mg, 0.104 mmol) as the appropriate amine, afforded the title compound (79.0 mg, 81%). HRMS-ESI (m / z) [M+H]+ calcd for C55H59FN7O6: 932.4511, found 932.4505. 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 Using General procedure 4a and Preparation VIIa (150 mg, 0.18 mmol, 1 eq.) as the appropriate amine and the product of Step A in Example 53 (52 mg, 0.18 mmol, 1 eq.) as the appropriate carboxylic acid afforded an intermediate which was treated according to General procedure 3c to afford the title product (67.3 mg, 0.07 mmol, 37%). HRMS calcd for C60H67FN8O5: 998.5218, found 999.5294 [M+H]+ 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 Step 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 eq.) in 1,4-dioxane (85 mL) was added 4-bromo-1-(difluoromethyl)-5-methyl-1H-pyrrole-2-carbonitrile (2 g, 8.51 mmol, 1 eq.) and Cs2CO3 (8.32 g, 25.53 mmol, 3 eq.) and the mixture was sparged with N2. BrettPhos Pd G3 (759 mg, 0.85 mmol, 0.1 eq.) was added and the mixture was sparged with N2 and then stirred at 100°C for 18 h. The mixture was allowed to cool to rt, 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 MgSO4and concentrated in vacuo. Purification by automated flash chromatography eluting with a gradient of 0 - 20% EtOAc in heptane afforded the title product (3.11 g, 7.4 mmol, 87%). LRMS calcd for C H F + 22 31 2N3OSi: 419.2, found 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). Step 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 eq.) as the appropriate acid and the product from Step A (254 mg, 0.61 mmol, 1.5 eq.) as the appropriate aniline afforded the title product (220 mg, 0.21 mmol, 53%). LRMS calcd for C59H75F2N7O5Si: 1027.6, found 1028.6 [M+H]+ Step 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 eq.) as the appropriate silyl-derivative afforded the title product (115 mg, 0.12 mmol, 58%). LRMS calcd for C H F N O Si: 927.5, + 54 67 2 7 3 found 928.6 [M+H] Step 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 eq.) as the appropriate amine and Preparation Va (18 mg, 0.07 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (65 mg, 0.06 mmol, 89%). LRMS calcd for C68H84F2N8O6Si: 1174.6, found 1175.8 [M+H]+ Step 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 eq.) as the appropriate silyl-derivative afforded the title product (13.3 mg, 0.01 mmol, 24%). HRMS calcd for C59H64F2N8O6: 1018.4917, found 1019.4988 [M+H]+ 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 Using General procedure 4a and the product from Example 77, Step C (57.5 mg, 0.06 mmol, 1 eq.) as the appropriate amine and Preparation Vb (19 mg, 0.07 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded an intermediate which was treated according to General procedure 3c to afford the title product (6.1 mg, 0.01 mmol, 10%). HRMS calcd for C59H63F3N8O6: 1036.4823, found 1037.4903 [M+H]+ 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 Step 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 eq.) and (R)-(-)-3-fluoropyrrolidine hydrochloride (1.49 g, 11.9 mmol, 1.1 eq.) as the appropriate amine afforded the title product (3.06 g, 8.78 mmol, 81%). LRMS calcd for C H FN O : 348.2; found 249.2 [M-Boc+H + 19 25 2 3 ] 1H 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). Step 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 eq.) as the appropriate THIQ amide afforded the title product (2.61 g, quant.). LRMS calcd for C H FN : 234.2; fou + 14 19 2 nd 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). Step 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 eq.) as the appropriate amine and Preparation I (4.05 g, 8.5 mmol, 1 eq.) as the appropriate carboxylic acid, followed with a purification step by automated flash chromatography eluting with a gradient of 40 – 100% EtOAc in heptane afforded the title product (2.9 g, 4.19 mmol, 49%). LRMS calcd for C H FN O : 692.3, found 693.4 + 41 45 4 5 [M+H] Step 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 eq.) in MeOH (40 mL) and water (10 mL) was added 5 M aq. NaOH solution (8.37 mL, 41.86 mmol, 10 eq.) and the mixture was refluxed for 2 days. The mixture was allowed to cool to rt and MeOH removed in vacuo. Water was added (90 mL) and the mixture was neutralised 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 MgSO4and concentrated in vacuo. Purification by reverse phase automated flash chromatography eluting with a gradient of 10 - 100% MeCN in water afforded the title product (1.35 g, 2.54 mmol, 61%). LRMS calcd for C H FN O : 530.3, foun + 31 35 4 3 d 531.4 [M+H] Step 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 eq.) in THF (30 mL) and water (3 mL) was added di-tert-butyl dicarbonate (0.54 mL, 2.54 mmol, 1.05 eq.) followed by the dropwise addition of TEA (0.67 mL, 4.84 mmol, 2 eq.). The mixture was stirred at rt for 18 h. THF was removed in vacuo and the residue partitioned between EtOAc and sat. aq. NH4Cl solution. 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 afforded the title product (1.36 g, 2.16 mmol, 89%). LRMS calcd for C36H43FN4O5: 630.3, found 631.6 [M+H]+ Step 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 eq.) as the appropriate acid and Preparation IVa, Step B (1.1 g, 3.23 mmol, 1.5 eq.) as the appropriate aniline afforded the title product (0.61 g, 0.63 mmol, 29%). LRMS calcd for C55H68FN7O5Si: 953.5, found 954.4 [M+H]+ Step 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 eq.) as the appropriate silyl-derivative afforded the title product (520 mg, 100%). LRMS calcd for C + 44H46FN7O3: 739.4, found 740.3 [M+H] Step H: 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 Using General procedure 4a and the product from Step G (161 mg, 0.2 mmol, 1 eq.) as the appropriate amine and Preparation Vc (63 mg, 0.24 mmol, 1.2 eq.) as the appropriate carboxylic acid afforded the title product (39 mg, 0.04 mmol, 20%). HRMS calcd for C H FN O : 985.4902, foun + 59 64 7 6 d 986.4980 [M+H] 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 Using General procedure 4a and the product from Example 79, Step G (159 mg, 0.2 mmol, 1 eq.) as the appropriate amine and Preparation Vb (67 mg, 0.23 mmol, 1.2 eq.) as the appropriate carboxylic acid afforded the title product (43 mg, 0.04 mmol, 22%). HRMS calcd for C58H62F2N8O6: 1004.4760, found 1005.4836 [M+H]+ 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 Step 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 eq.) as the appropriate aryl bromide and Preparation IIIa (188 mg, 0.84 mmol, 1.1 eq.) as the appropriate aniline afforded the title product (140 mg, 0.39 mmol, 52%). LRMS calcd for C20H26N2O2Si: 354.2, found 355.0 [M+H]+ 1H 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). Step B: 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 Using General procedure 2a and Preparation VIa (175 mg, 0.25 mmol, 1 eq.) as the appropriate acid and the product from Step A (135 mg, 0.38 mmol, 1.5 eq.) as the appropriate aniline afforded an intermediate which was treated according to General procedure 3b to afford the title product (12 mg, 0.01 mmol, 5%). HRMS calcd for C + 55H56N6O7: 912.4210, found 913.4286 [M+H] 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 Using General procedure 4a and Preparation IVb (144 mg, 0.19 mmol, 1 eq.) as the appropriate amine and the product of Step A of Example 50 (72 mg, 0.25 mmol, 1.3 eq.) as the appropriate carboxylic acid afforded the title product (34.3 mg, 0.03 mmol, 18%). HRMS calcd for C H F N O : 100 + 59 64 2 8 5 2.4968, found 1003.5047 [M+H] 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 Using General procedure 4a and Preparation IVb (143.5 mg, 0.19 mmol, 1 eq) as the appropriate amine and the product from Example 69, Step D (65 mg, 0.21 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (54.4 mg, 0.05 mmol, 27%). HRMS calcd for C59H64F2N8O6: 1018.4917, found 1019.4992 [M+H]+ 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) Step 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 the General procedure 7c, starting from the tetrahydrofuran-3-ylmethanol (1.0 mL, 2.0 eq.) as the appropriate alcohol, afforded the title compound (1.44 g, 99%). 1H 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); 13C 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]+ calcd for C11H14BrN2O: 286.0549, found 286.0549. Enantiomers of the desired product was separated on an AD chiral column (100*500 mm, 20 μm) using 10:90 EtOH / heptane as eluents to give the Enantiomer 1 (99.9% ee) and Enantiomer 2 (99.2% ee). Step 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 the Enantiomer 2 of Step A (700 mg, 2.60 mmol) as the appropriate aryl-bromide and Preparation IIIa (875 mg, 1.5 eq.) as the appropriate aniline, afforded the title compound (538 mg, 50%). 1H 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); 13C 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]+ calcd for C23H34N3O2Si: 412.2415, found 412.2418. Step 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 the Step B of Preparation VIIb as the appropriate acid (300 mg, 0.45 mmol) and the product of Step B (270 mg, 1.4 eq.) as the appropriate aniline, afforded the title compound (200 mg, 42%). 1H 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]+ calcd for C65H71N6O6Si: 1059.5199, found 1059.5198. Step 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 eq.). The reaction mixture was stirred until the deprotection was completed. The mixture was treated with Preparation Vb (50 mg, 0.18 mmol) as the appropriate acid according to General procedure 4c, the title compound was obtained (45 mg, 40%). HRMS-ESI (m / z) [M+H]+ calcd for C58H63FN7O7: 988.4767, found 988.4770. 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 Step 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 eq.) as the appropriate aryl bromide and Preparation IIIa (1.66 g, 7.45 mmol, 1.2 eq.) as the appropriate aniline afforded the title product (1.23 g, 4.06 mmol, 65%). LRMS calcd for C16H25N3OSi: 303.2, found 304.2 [M+H]+ 1H 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). Step 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 eq.) as the appropriate acid and the product from Step A (115 mg, 0.38 mmol, 1.5 eq.) as the appropriate aniline afforded an intermediate which was treated according to General procedure 3b to afford the title product (92 mg, 0.11 mmol, 42%). HRMS calcd for C52H56N6O6: 860.4261, found 861.4336 [M+H]+ 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 Step A: tert-butyl (3S)-3-(4-fluoropiperidine-1-carbonyl)-3,4-dihydro-1H-isoquinoline-2- carboxylate Using the modified General procedure 5a, starting from (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 eq.) as the appropriate amine in DCM (50 mL), followed with a purification step via automated flash chromatography with heptane and IPA as eluents provided 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]+ calcd for C20H28FN2O3: 363.2078, found 363.2079. Step 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 (12M aq. solution, 1 mL, 6 eq.). The reaction mixture was stirred at rt for 1.5h 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 1M LiAlH4solution in THF (4.05 mL, 2 eq.) according to General procedure 6a. Purification via flash chromatography using heptane and heptane / IPA=3 / 2 (0.25% TEA) as eluents afforded the desired product (345 mg, 66%). 1H 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);13C 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]+ calcd for C15H22FN2: 249.1762, found 249.1763. Step 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-[(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 Using General procedure 4c, starting from Preparation IX (80 mg, 0.09 mmol.) as the appropriate carboxylic acid and the product from Step B (33 mg, 1.5 eq.) as the appropriate amine, afforded the desired compound (62.6 mg, 69%). HRMS-ESI (m / z) [M+H]+ calcd for C59H65F2N8O6: 1019.4990, found 1019.4985. Example 87: N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-5-(2-{2-[4- (methoxymethyl)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 2-[4-(methoxymethyl)phenyl]acetic acid (53 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (150 mg, 0.20 mmol.) as the appropriate amine, afforded the title product (110 mg, 69%). HRMS-ESI (m / z) [M+H]+ calcd for C50H51N6O5: 815.3915, found 815.3913. Example 88: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(4-{2- [cyclopropyl(methyl)amino]ethoxy}-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-(4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Step A: methyl 2-(4-{2-[cyclopropyl(methyl)amino]ethoxy}-2-fluorophenyl)acetate Using General procedure 7b and the product from Preparation Vb, Step A (270 mg, 1.47 mmol, 1 eq.) as the appropriate phenol and 2-[cyclopropyl(methyl)amino]ethan-1-ol (186 mg, 1.61 mmol, 1.1 eq.) as the appropriate alcohol afforded the title product (410.4 mg, 1.46 mmol, 100%). LRMS calcd for C + 15H20FNO3: 281.1, found 282.0 [M+H] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.22 (t, J = 8.7 Hz, 1H), 6.80 (dd, J = 12.0, 2.5 Hz, 1H), 6.76 – 6.71 (m, 1H), 4.07 (t, J = 5.9 Hz, 2H), 3.64 – 3.62 (m, 2H), 3.61 (s, 3H), 2.84 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H), 1.77 – 1.69 (m, 1H), 0.45 – 0.39 (m, 2H), 0.32 – 0.27 (m, 2H). Step B: (4-{2-[cyclopropyl(methyl)amino]ethoxy}-2-fluorophenyl)acetic acid To a solution of the product from Step A (410 mg, 1.46 mmol, 1 eq.) in MeOH (15 mL) was added 2 M aq. NaOH solution (1.46 mL, 2.92 mmol, 2 eq.) and the mixture was stirred at rt for 72 h. The MeOH was removed in vacuo and the aqueous residue was neutralised with 2 M aq. HCl solution and concentrated in vacuo. The residue was stirred in DCM and filtered. The filtrate was concentrated in vacuo to afford the title product which was used directly in the subsequent step without further purification (366.8 mg, 1.37 mmol, 94%). LRMS calcd for C14H18FNO3: 267.1, found 268.0 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.18 – 7.10 (m, 1H), 6.69 – 6.60 (m, 2H), 4.03 (t, J = 5.9 Hz, 2H), 3.20 – 3.17 (m, 2H), 2.83 (t, J = 5.9 Hz, 2H), 2.32 (s, 2H), 0.45 – 0.38 (m, 2H), 0.32 – 0.27 (m, 2H). Step C: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(4-{2- [cyclopropyl(methyl)amino]ethoxy}-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- (4-hydroxyphenyl)-1,2-dimethylpyrrole-3-carboxamide Using General procedure 4a and Preparation IVb (200 mg, 0.27 mmol, 1 eq.) as the appropriate amine and the product from Step B (80 mg, 0.3 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (66.8 mg, 0.07 mmol, 25%). HRMS calcd for C + 59H65FN8O5: 984.5062, found 985.5136 [M+H] Example 89: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(2-fluoro-4-{[(3S)-1-(2- fluoroethyl)pyrrolidin-3-yl]oxy}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 Step A: tert-butyl (3S)-3-[3-fluoro-4-(2-methoxy-2-oxoethyl)phenoxy]pyrrolidine-1- carboxylate Using General procedure 7b and the product from Preparation Vb, Step A (1.61 g, 8.74 mmol, 1 eq.) as the appropriate phenol and (R)-1-N-Boc-3-hydroxypyrrolidine (1.8 g, 9.62 mmol, 1.1 eq.) as the appropriate alcohol afforded the title product (3.11 g, 8.71 mmol, 100%). LRMS calcd for C + 18H24FNO5: 353.2, found 254.0 [M-Boc+H] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.25 (t, J = 8.7 Hz, 1H), 6.85 (dd, J = 12.0, 2.5 Hz, 1H), 6.75 (dd, J = 8.4, 2.5 Hz, 1H), 5.05 – 4.96 (m, 1H), 3.64 (d, J = 1.3 Hz, 2H), 3.61 (s, 3H), 3.59 – 3.49 (m, 1H), 3.46 – 3.25 (m, 3H), 2.21 – 1.96 (m, 2H), 1.45 – 1.33 (m, 9H). Step B: methyl 2-{2-fluoro-4-[(3S)-pyrrolidin-3-yloxy]phenyl}acetate hydrochloride A solution of the product from Step A (3.11 g, 8.8 mmol, 1 eq.) in 3 M HCl in MeOH (29 mL) was stirred at rt for 18 h. The solvent was removed in vacuo and then azeotroped with toluene to afford the title product (2.55 g, 8.8 mmol, 100%). LRMS calcd for C13H16FNO3: 253.1, found 254.0 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.71 – 9.51 (br m, 1H), 9.51 – 9.30 (br m, 1H), 7.32 – 7.24 (m, 1H), 6.92 – 6.85 (m, 1H), 6.82 – 6.76 (m, 1H), 5.18 – 5.11 (m, 1H), 3.68 – 3.64 (m, 2H), 3.61 (s, 3H), 3.51 – 3.40 (m, 1H), 3.37 – 3.18 (m, 3H), 2.25 – 2.06 (m, 2H). Step C: (2-fluoro-4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]oxy}phenyl)acetic acid To a solution of the product from Step B (1.28 g, 4.4 mmol, 1 eq.) in DMF (10 mL), cooled to 0°C, was added TEA (0.61 mL, 4.4 mmol, 1 eq.) followed by NaH (60% dispersion in mineral oil; 0.21 g, 5.28 mmol, 1.2 eq.) and the mixture was stirred at 0°C for 15 mins. 1-Fluoro-2- iodoethane (0.39 mL, 4.84 mmol, 1.1 eq.) was added and the mixture was allowed to warm to rt and stirred for 18 h. The mixture was cooled to 0°C and quenched with MeOH (15mL). The solvent was removed in vacuo to afford an intermediate which was treated according to General procedure 8 to afford the title product (331 mg, 1.16 mmol, 71%). LRMS calcd for C H F NO : + 14 17 2 3 285.1, found 286.2 [M+H] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.33 (br s, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.75 (dd, J = 12.0, 2.5 Hz, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 1H), 4.93 – 4.84 (m, 1H), 4.53 (dt, J = 47.7, 4.9 Hz, 2H), 3.54 – 3.49 (m, 2H), 2.99 – 2.67 (m, 5H), 2.58 – 2.52 (m, 1H), 2.35 – 2.22 (m, 1H) 1.83 – 1.70 (m, 1H). Step D: N-(5-cyano-1,2-dimethylpyrrol-3-yl)-5-{2-[2-(2-fluoro-4-{[(3S)-1-(2- fluoroethyl)pyrrolidin-3-yl]oxy}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 (200 mg, 0.27 mmol, 1 eq.) as the appropriate amine and the product from Step C (85 mg, 0.3 mmol, 1.1 eq.) as the appropriate carboxylic acid afforded the title product (110.7 mg, 0.11 mmol, 41%). HRMS calcd for C + 59H64F2N8O5: 1002.4968, found 1003.5041 [M+H] Example 90: 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-methylindazol-5-yl)pyrrole-3-carboxamide Step A: N-{4-[(tert-butyldimethylsilyl)oxy]phenyl}-1-methylindazol-5-amine Using General procedure 1a and 5-bromo-1-methyl-1H-indazole (400 mg, 1.9 mmol, 1 eq.) as the appropriate aryl bromide and Preparation IIIa (466 mg, 2.08 mmol, 1.1 eq.) as the appropriate aniline afforded the title product (213 mg, 0.6 mmol, 32%). LRMS calcd for C20H27N3OSi: 353.2, found 354.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.82 (d, J = 1.0 Hz, 1H), 7.71 (s, 1H), 7.52 – 7.47 (m, 1H), 7.24 (dd, J = 2.1, 0.8 Hz, 1H), 7.11 (dd, J = 8.9, 2.1 Hz, 1H), 6.97 – 6.90 (m, 2H), 6.76 – 6.70 (m, 2H), 3.98 (s, 3H), 0.95 (s, 9H), 0.16 (s, 6H). Step 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-methylindazol-5-yl)pyrrole-3-carboxamide Using General procedure 2a and Preparation VIa (175 mg, 0.25 mmol, 1 eq) as the appropriate acid and the product from Step A (134 mg, 0.38 mmol, 1.5 eq) as the appropriate aniline afforded an intermediate which was treated according to General procedure 3b to afford the title product (7.5 mg, 0.01 mmol, 3%). HRMS calcd for C H N O : 911.4 + 55 57 7 6 370, found 912.4442 [M+H] Example 91: 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 Step A: tert-butyl (3S)-3-[isopropyl(methyl)carbamoyl]-3,4-dihydro-1H-isoquinoline-2- carboxylate Using the General procedure 5a, starting from (3S)-2-tert-butoxycarbonyl-3,4-dihydro-1H- isoquinoline-3-carboxylic acid (800 mg, 2.88 mmol) as the appropriate carboxylic acid and N- methylpropan-2-amine (0.360 mL, 1.2 eq.) as the appropriate amine, afforded the desired product (450 mg, 44%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.22-7.10 (m, 4H), 5.50-4.00 (brs, 2H), 4.69 / 4.35 (d+d, 2H), 3.30-2.50 (brm, 5H), 1.40 (s, 9H), 1.30-0.80 (brs, 6H). HRMS-ESI (m / z) [M+H]+ calcd for C19H29N2O3: 333.2173, found 333.2174. Step B: N-methyl-N-[[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl]propan-2-amine To a solution of the product of Step A (450 mg, 1.35 mmol) in ACN (20 mL) was added HCl (12M aq. solution, 1.0 mL, 8.8 eq.). The reaction mixture was stirred until the deprotection was complete, then concentrated under reduced pressure and azeotroped with toluene. The residue was dissolved in a mixture of DCM (5 mL) and MTBE (7 mL). This solution was treated with 1M LiAlH4solution in THF (2.7 mL, 2 eq.) following General procedure 6a, affording the title compound (110 mg, 35%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.08 (m, 1H), 7.07 (m, 1H), 7.06 (m, 1H), 7.01 (m, 1H), 3.90 (s, 2H), 2.83 (m, 1H), 2.77 (m, 1H), 2.64 / 2.37 (dd+dd, 2H), 2.35 / 2.31 (dd+dd, 2H), 2.16 (s, 3H), 0.95 (d, 6H); 13C NMR (125 MHz, DMSO-d6) δ ppm 129.4, 126.5, 126.1, 125.8, 58.7, 54.1, 51.6, 48.6, 37.8, 34.2, 18.3 / 17.9. HRMS-ESI (m / z) [M+H]+ calcd for C14H23N2: 219.1856, found 219.1858. Step 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-{[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 Using General procedure 4c, starting from Preparation IX (90 mg, 0.10 mmol) as the appropriate carboxylic acid and the product of Step B (44 mg, 2.0 eq.) as the appropriate amine, afforded the title compound (55 mg, 56%). HRMS-ESI (m / z) [M+H]+ calcd for C58H66FN8O6: 989.5089, found 989.5086. Example 92: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-5-[2-[2-[2-fluoro-4-(2- morpholinoethoxy)phenyl]acetyl]-7-[(3S)-3-(1-piperidylmethyl)-3,4-dihydro-1H- isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethyl-N-phenyl- pyrrole-3-carboxamide Step A: 2-benzyloxycarbonyl-6-[4-[(5-cyano-1,2-dimethyl-pyrrol-3-yl)-phenyl-carbamoyl]- 1,5-dimethyl-pyrrol-2-yl]-3,4-dihydro-1H-isoquinoline-7-carboxylic acid Using General procedure 2b, starting from the product of Step B of Preparation IX (350 mg, 0.69 mmol) as the appropriate acid and the product of Step A of Example 65 (176 mg, 1.2 eq.) as the appropriate amine, afforded the title compound as major product (160 mg, 36%) and O2- benzyl O7-tert-butyl 6-[4-[(5-cyano-1,2-dimethyl-pyrrol-3-yl)-phenyl-carbamoyl]-1,5- dimethyl-pyrrol-2-yl]-3,4-dihydro-1H-isoquinoline-2,7-dicarboxylate (60 mg, 12%) as minor product. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.74 (brs, 1 H), 7.61-6.79 (m, 13 H), 5.15 (s, 1 H), 5.14 (s, 2 H), 4.69-2.78 (m, 6 H), 3.58 / 3.15 (s+s, 6 H), 2.39 / 1.98 (s+s, 6 H); 13C NMR (100 MHz, DMSO-d6) δ ppm 108.1, 66.7, 33.2 / 31.6, 11.9 / 10.1. HPLC-MS-ESI (m / z) [M+H]+ calcd for C38H36N5O5: 642.3, found 642.4. Step B: benzyl 6-[4-[(5-cyano-1,2-dimethyl-pyrrol-3-yl)-phenyl-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 Using a modified General Procedure 4c without the deprotection step, starting from the major carboxylic acid product of Step B (155 mg, 0.24 mmol) as the appropriate acid and the product of Step B of Preparation IIb (109 mg, 1.5 eq.) as the appropriate amine, afforded the title compound (123 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.47-6.82 (m, 16H), 6.78-6.48 (s, 1H), 5.51-5.20 (s, 1H), 5.20-5.01 (s, 2H), 5.10-1.60 (m, 17H), 3.65-3.03 (s, 6H), 2.44-1.79 (s, 6H), 1.58-1.12 (m, 6H). HPLC-ESI-MS (m / z) [M+H]+ calcd for C53H56N7O4: 854.4, found 854.4. Step C: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-1,2-dimethyl-N-phenyl-5-[7-[(3S)-3-(1- piperidylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinolin-6- yl]pyrrole-3-carboxamide Using General procedure 6b, starting from the product of Step C (112 mg. 0.13 mmol) afforded the title product (66 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.24-6.49 (m, 12 H), 5.50-5.20 (s, 1 H), 5.06-1.22 (m, 23 H), 3.60-3.06 (s, 6 H), 2.41-1.82 (s, 6 H). HPLC-MS-ESI (m / z) [M+H]+ calcd for C45H50N7O2: 720.4, found 720.4. Step D: N-(5-cyano-1,2-dimethyl-pyrrol-3-yl)-5-[2-[2-[2-fluoro-4-(2- morpholinoethoxy)phenyl]acetyl]-7-[(3S)-3-(1-piperidylmethyl)-3,4-dihydro-1H- isoquinoline-2-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-1,2-dimethyl-N-phenyl-pyrrole- 3-carboxamide Using a modified General Procedure 4c without the deprotection step, starting from Preparation Vb as the appropriate acid (42 mg, 2 eq.) and the product of Step C (60 mg, 0.083 mmol) as the appropriate amine, the desired product was obtained (22.4 mg, 27%). HRMS-ESI (m / z) [M+H]+ calcd for C59H66FN8O5: 985.5135, found 985.5137. Example 93: 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- oxa-7-azaspiro[2.5]octan-7-yl}ethoxy)phenyl]acetyl}-1,2,3,4-tetrahydroisoquinolin-6-yl}- 1H-pyrrole-3-carboxamide

[0031] Step A: 2-[4-[2-(4-oxa-7-azaspiro[2.5]octan-7-yl)ethoxy]phenyl]acetic acid Using General procedure 7d, then General procedure 8, starting from methyl 2-[4-(2- bromoethoxy)phenyl]acetate (300 mg, 1.1 mmol) and 4-oxa-7-azaspiro[2.5]octane hydrochloride (197 mg, 1.2 eq.) as reactants, afforded the title product (186 mg, 58 %). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.27 / 11.35 (brs, 2H), 7.18 (m, 2H), 6.91 (m, 2H), 4.8- 2.1 (brm, 10H), 3.49 (s, 2H), 1.00-0.30 (brm, 4H). HRMS-ESI (m / z) [M+H]+ calcd for C16H22NO4: 292.1543, found 292.1544. Step 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-{4-oxa-7- azaspiro[2.5]octan-7-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 (85 mg, 1.5 eq.) as the appropriate carboxylic acid and Preparation VIIb (150 mg, 0.20 mmol) as the appropriate amine, afforded the title compound (47 mg, 26%). HRMS-ESI (m / z) [M+H]+ calcd for C56H60N7O6: 926.4600, found 926.4603. Example 94: N-[5-cyano-1-(difluoromethyl)-2-methylpyrrol-3-yl]-5-[2-(2-{2-fluoro-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

[0032] Step A: tert-butyl 6-(4-{[5-cyano-1-(difluoromethyl...

Claims

1. Compound of formula (Ib): where T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted with one to three halogen atoms, a (C1-C4)alkylene-NR1R2 group, a (C1-C4)alkylene-ORi group, R1 and R2 independently of each other represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, or R1 and R2 together with the nitrogen atom bearing them form a heterocycloalkyl group, the heterocycloalkyl being optionally substituted with one to three groups selected from a (C1-C6)alkyl group and a halogen atom, 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, A1 represents C-Y4 or nitrogen atom, X represents a bond, -O-, -S- or NRk, Y1 and Y5 independently of each other represent a group selected from a hydrogen atom, a halogen atom, a cyano, a linear or branched (C1-C6) alkyl group and a linear or branched (C1-C6) alkoxy group, Y2 and Y4 independently of one another 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 group selected from 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, -O-(C1-C4)alkylene-NRgRh, -(C1-C4)alkylene-Cy3, -(C1-C4)alkylene-Cy4, Cy3, Cy4, and where the alkylene fragment of the preceding groups can be linear or branched, Cy3 is a heterocycloalkyl optionally substituted with one to three 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, a heterocycloalkyl group and a halogen atom, Cy4 is cycloalkyl optionally substituted with one to three 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, a heterocycloalkyl group and a halogen atom, Ra and Rb independently of each other represent a hydrogen atom or a halogen atom, Rc is a group selected from hydrogen, a linear or branched (C1-C6)alkyl group optionally substituted with 1-3 halogen atoms, (C1-C6)alkylene-NRdRe, (C1-C6)alkylene-ORj, cycloalkyl, heterocycloalkyl and (C1-C6)alkyleneheterocycloalkyl group, Rd and Re independently represent a hydrogen atom, a linear or branched (C1-C6) alkyl group, a cycloalkyl group or a heterocycloalkyl group, Rg and Rh independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted with one to three halogen atoms, a cycloalkyl group, a heterocycloalkyl group, or -(C1-C6)alkyleneheterocycloalkyl, Ri, Rj and Rk independently of each other represent a hydrogen atom, a linear or branched (C1-C6)alkyl group or a -(C1-C6)alkylenecycloalkyl group, R1 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, or a linear or branched (C1-C6)alkyleneheterocycloalkyl group, its enantiomers, diastereoisomers or their addition salts with a pharmaceutically acceptable acid or base, where cycloalkyl means any mono- or bicyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, which may include fused, bridged or spiro ring systems, heterocycloalkyl means any mono- or bicyclic non-aromatic carbocyclic group consisting of 3 to 10 ring members and containing from one to 3 heteroatoms or groups selected from oxygen, sulfur, SO, SO2 and nitrogen, where the bicyclic group may be fused or spiro-type, (C1-C6)alkylene means a divalent linear or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms.

2. A compound of formula (Ib) according to claim 1, wherein Rc is a methyl group.

3. The compound according to claim 1 or 2, wherein X is a bond.

4. A compound according to any one of claims 1 to 3, wherein A1 is C-Y4.

5. A compound according to any one of claims 1 to 4, wherein Ra and Rb both represent a hydrogen atom.

6. A compound according to any one of claims 1 to 5, wherein R5 is a hydrogen atom, a hydroxy group or a fluorine atom.

7. A compound according to any one of claims 1 to 6, wherein R6 is a hydrogen atom or a fluorine atom.

8. A compound according to any one of claims 1 to 7, wherein R5 is a hydroxy group and R6 is a hydrogen atom.

9. A compound according to any one of claims 1 to 8, wherein A1 is CH and Y2 is a hydrogen atom.

10. A connection according to any one of paragraphs 1-9, where Y1 and Y5 both represent a hydrogen atom, or Y1 and Y5 represent a fluorine atom and a hydrogen atom, respectively.

11. A compound according to any one of claims 1 to 10, wherein Y3 is 1) an -O-(C1-C4)alkylene-Cy3 group; or 2) a group selected from 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-1λ6-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 any one of paragraphs. 1-11, where the group 13. A compound according to any one of claims 1 to 12, wherein T is 1) a linear or branched (C1-C6) alkyl group; 2) a (C1-C4) alkylene-NR1R2 group; or 3) a group selected from 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]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 groups.

14. The compound according to item 1, selected from the following list: 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-dihyde rho-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-d ihydro-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-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-dimethylpyrrole-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-tetrahydroisoquinol in-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-{[(3 S)-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.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

16. Use of the pharmaceutical composition according to paragraph 15 as a pro-apoptotic agent.

17. Use of the pharmaceutical composition according to claim 15 for the treatment of malignant neoplasms treatable by inhibiting the activity of the Bcl-2 protein.

18. The use according to claim 17, wherein the malignant neoplasm is a hematological malignancy.

19. The use according to claim 18, wherein the hematological malignancy is myeloma, in particular multiple myeloma, lymphoma, in particular non-Hodgkin's lymphoma (NHL), or leukemia, in particular chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL) and acute myelocytic leukemia (AML).

20. The use of a compound according to any one of claims 1 to 14 or an addition salt thereof with a pharmaceutically acceptable acid or base for the treatment of a malignant neoplasm selected from myeloma, in particular multiple myeloma, lymphoma, in particular non-Hodgkin's lymphoma (NHL), or leukemia, in particular chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL) and acute myelocytic leukemia (AML).

21. Use of a compound according to any one of claims 1 to 14 for the treatment of malignant neoplasms requiring radiotherapy.

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