Anti-coronavirus compounds

Abstract

The present disclosure relates to new compounds or compositions comprising thereof useful for the treatment or prophylaxis of a disorder mediated by a coronavirus.

Description

[0001] 1

[0002] ANTI-CORONAVIRUS COMPOUNDS FIELD OF THE INVENTION The invention relates to new compounds which are useful for the treatment of 5 coronavirus infections. BACKGROUND OF THE INVENTION In the past two decades, three virulent strains of coronaviruses have emerged from animal reservoirs to cause three outbreaks in 2002 (severe acute respiratory syndrome 10 coronavirus; SARS-CoV), 2012 (Middle East respiratory virus coronavirus; MERS-CoV) and 2019 (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2). With globally over 774 million confirmed cases and seven million deaths reported, the Covid- 19 caused by the SARS-CoV-2 remains a major threat to global health. SARS-CoV-2 belongs to the zoonotic Coronaviridae family with the classification of four15 genera including α, β, γ, δ -CoV. α- and β-CoV are responsible for the infection inmammals while γ- and δ -CoV are responsible for the infection of avian species. BeforeSARS-CoV-2, six coronaviruses had been found to infect humans: HCoV-229E, HCoV- OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV. α-CoVs have less fatal effects causing common cold while β -CoVs such as SARS-CoV, MERS-CoV and SARS-20 CoV-2 can cause severe disease and are potentially lethal. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus with a large genome of about 30,000 nucleotides. In the coronavirus replication cycle, the genomic RNA produces two polyproteins, pp1a and pp1ab which are proteolytically cleaved by two viral cysteine proteases: the main protease or 3CL-protease (nsp5, Mpro, 3CLpro) 25 and the papain-like protease (nsp3, PLpro) to generate 16 nonstructural proteins (nsps), essential for the virus replication. The 3CLpro is a cysteine protease consisting of three domains, active as a homodimer. The substrate-binding site with a catalytic dyad of His41 and Cys145 is located between domains I and domain II. Domain III plays an important role in Mpro dimerization. This30 viral protease was rapidly reported and validated as a promising target to develop broad- spectrum anti-coronavirus compounds because of its crucial role in the viral replication cycle, its high substrate specificity not found in human proteases and the high degree of homology shared with other human coronaviruses, in particular at the level of thecatalytic site. 2

[0003] However, despite the massive vaccination of the population and the development of some antiviral treatments, greatly reducing the risk of death, the high prevalence and intrinsic virulence of SARS-CoV-2 continue to cause severe disease and mortality. The development of new oral anti-coronavirus compounds is still essential to fight SARS- 5 CoV-2, to address some issues with current treatments including drug-drug interactions or potential emerging resistance with the constant spread of new variants of concern, and also to prepare for emerging coronavirus-related epidemics. SUMMARY OF THE INVENTION10 The invention relates to a compound of formula (I) as disclosed herein as well ashydrates, solvates, salts or deuterated analogs thereof and to their use in medicine, in particular for the treatment or prophylaxis of a disorder mediated by a coronavirus.The invention also related to a pharmaceutical or veterinary composition comprising at least one compound of formula (I) as disclosed herein and one or more excipients and15 to its use in medicine, in particular for the treatment or prophylaxis of a disorder mediatedby a coronavirus. Further aspects of the invention are as disclosed herein and in the claims. DESCRIPTION OF THE INVENTION 20 Compounds of formula (I) The present invention relates to compounds of formula (I): 25 (I) wherein: Ais a bicyclic ring system, the bicyclic ring system being: 3

[0004] (i) a 9-membered bicyclic aromatic or partially aromatic ring system consisting of a pyridinyl fused with a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S, and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule 5 via a ring carbon atom of the pyridinyl; or (ii) a 10-membered bicyclic aromatic or partially aromatic ring system consisting of a pyridinyl fused with a 6-membered ring, the 6-membered ring being a phenyl or a ring containing one, two or three heteroatoms, each independently selected from O, S, and N,10 said 10-membered bicyclic aromatic ring being attached to the remainder of the molecule via a ring carbon atom of the pyridinyl; andR is selected from the group consisting of -C1-C6-alkyl; -C1-C6-hydroxalkyl; -C1-C6-haloalkyl; -C1-C6-cyanoalkyl; -O-C1-C6-alkyl; -C(O)ORa wherein Ra is selected from thegroup consisting of hydrogen atom, -C1-C6-alkyl and Li; -C(O)N(Rb)2 wherein Rb is15 independently selected from the group consisting of hydrogen atom and C1-C6-alkyl, orthe two Rb form together a 5- or 6-membered non-aromatic ring containing one, two orthree heteroatoms, each independently selected from O, S, and N; 3- to 6-memberednon-aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, and N; 5- or 6-membered heteroaryl;-C1-C6-alkyl-SRc wherein Rc is20 selected from the group consisting of hydrogen atom and -C(O)-C1-C6-alkyl; -C1-C6-alkyl-O-C1-C6-alkyl; -C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16; -C1-C6-alkyl-N(Rd)2wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and-C(O)O-C1-C6-alkyl; -C1-C6-alkyl-C(O)ORe wherein Re isselected from the group consisting of hydrogen atom, -C1-C6-alkyl and Li; C1-C6-alkyl-25 C(O)-azetidine-(5- or 6-membered heteroaryl); ; C1-C6-alkyl-C(O)-azetine-(5- or 6-membered heteroaryl); -C1-C6-alkyl-C(O)N(Rf)2wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C6-alkyl, -C1-C6-alkyl-O-C1-C6-alkyl, - C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16, C1-C6-alkyl-(5- or6-membered heteroaryl), -C1-C6-alkoxy and C1-C6-alkyl-N(C1-C6-alkyl)2, or the two Rf30 form together a 5- to 6-membered non-aromatic ring containing one, two or threeheteroatoms, each independently selected from O, S (in particular S or SO2), and N; -C1-C6-alkyl-(5- or 6-membered heteroaryl); and -C1-C6-alkyl-NH-C(O)ORg wherein Rg isindependently selected from the group consisting of -C1-C6-alkyl and -C1-C6-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl; wherein said 5- or35 6-membered non-aromatic ring, said 3- to 6-membered non-aromatic ring and said 5- or 4

[0005] 6-membered heteroaryl may be substituted by one or more substituents selected from the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, halogen, hydroxyl, nitro, cyano, =O,=S, =N—CN, and ═N—OH; X1 is independently selected from the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, - 5 C1-C6-haloalkyl, halogen, hydroxyl, nitro, cyano, =O, =S, =N—CN and ═N—OH, preferably X1 is independently selected from the group consisting of -C1-C6-alkyl, -C1-C6- alkoxy, halogen, hydroxyl, nitro, cyano, =O, =S, =N—CN and ═N—OH; X2 is a halogen atom;X3 is a halogen atom; 10 n1 is 0, 1, 2 or 3; n2 is 0 or 1;n3 is 0 or 1;or hydrates, solvates, salts or deuterated analogs thereof.15 Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of formula (I). However, the invention also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention. The term “physiologically acceptable salt" refers to a relatively non-toxic, inorganic or 20 organic acid addition salt of the compound of formula (I). A suitable pharmaceutically acceptable salt of the compound of formula (I) may be, for example, an acid-addition salt of a compound of formula (I), such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, 25 trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3 -hydroxy-2 -naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3- phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethane sulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluene30 sulfonic, methansulfonic, 2- naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example. 5

[0006] Solvates in the context of the invention are described as those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. The present invention includes all possible stereoisomers of the compounds of formula 5 (I) as single stereoisomer, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of formula (I) can be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.10 The term “9-membered bicyclic aromatic ring system” as used herein designates apyridinyl fused with an aromatic 5-membered ring, containing one, two or threeheteroatoms, each independently selected from O, S, and N. The term “9-membered bicyclic partially aromatic ring system” as used herein designates 15 a pyridinyl fused with a non-aromatic (saturated or unsaturated) 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S, and N. When the heteroatoms include a sulphur atom (S), it may be under an oxidized form,such as SO2.20 The term “10-membered bicyclic aromatic ring system” as used herein designates apyridinyl fused with an aromatic 6-membered ring, the 6-membered aromatic ring beinga phenyl or a ring containing one, two or three heteroatoms, each independently selected from O, S, and N. 25 The term “10-membered bicyclic partially aromatic ring system” designates a pyridinyl fused with a non-aromatic (saturated or unsaturated) 6-membered ring, the 6-membered aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, and N. When the heteroatoms include a sulphur atom (S), it may be under an oxidized form, such as SO2. 30 Examples of non-aromatic 3-membered ring to 6-membered ring include but are notlimited to oxiranyl, aziridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, imidazolidinyl, oxadiazolidinyl, thiadiazolidinyl, triazolidinyl, oxadiazolidinyl, 35 thiadiazolidinyl, dihydrofuryl, dihydrothienyl, pyrrolinyl, isoxazolinyl, isothiazolinyl, 6 dihydropyrazolyl, dihydrooxazolyl, piperidinyl, dioxanyl, tetrahydropyranyl, tetrahydrothienyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl andhexahydrotriazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxyde.5 Examples of aromatic 5-membered ring or 6-membered ring containing one, two or threeheteroatoms, together designated as “heteroaryl”, include but are not limited to thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazolyl.10 The terms “aromatic 5-membered ring” and “aromatic 6-membered ring” (designated“heteroaryl”), “non-aromatic 5-membered ring” and “non-aromatic 6-membered ring” areintended to include both substituted and unsubstituted ring. The “aromatic 5-membered ring”, “aromatic 6-membered ring”, “non-aromatic 5-membered ring” and “non-aromatic15 6-membered ring” can be substituted with one or more substituents. The expression “one or more substituents” refers to a number of substituents that ranges from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the conditions of stability and chemical feasibility are met. Suchsubstituents can include, but are not limited to, -C1-C6-alkyl, -C1-C6-alkoxy, halogen,20 hydroxyl, nitro, cyano, =O, =S, =N—CN and ═N—OH. Preferably, the ring is substitutedby a single substituent which is -C1-C6-alkyl, preferably methyl. The term “Cx-Cy” as used herein, e.g. in the context of the definition of “C1-C6-alkyl”,designates a group having a finite number of carbon atoms of x to y, e.g. a C1-C6-alkyl25 has a finite number of carbon atoms of 1 to 6, i.e.1, 2, 3, 4, 5, or 6 carbon atoms.The term “alkyl” as used herein designates a linear or branched alkyl, e.g. methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, pentyl, iso-pentyl, hexyl, and The term “hydroxyalkyl” as used herein designates an alkyl, as defined supra, substituted30 by one or more hydroxyl groups, e.g.2-hydroxy-ethyl, 3-hydroxy-propyl, 4-hydroxy-butyl, 5-hydroxy-pentyl and 6-hydroxy-hexyl. The term “haloalkyl” as used herein designates an alkyl, as defined supra, substitutedby one or more halogen radicals which may be the same or different, e.g. chloromethyl, 7 fluoropropyl, fluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, bromobutyl, trifluoromethyl, iodoethyl, and isomers thereof. The term “cyanoalkyl” as used herein designates an alkyl, as defined supra, substituted5 by one or more cyano groups. The term “halogen” as used herein designates chlorine, bromine, iodine and fluorine. N As used herein, the term “pyridinyl” is to be understood as a group of formula 10 wherein the wavy line designates the point of attachment to the rest of the molecule. The compounds of the present invention are generally present as tautomers. As used herein, the term “tautomers” refers to structural isomers, generally resulting from the relocation of a proton in the molecule. Contrary to stereoisomers in which only spatial 15 arrangement differs, in structural isomers, the molecule has different bonding patterns and atomic organization. For instance, 2-pyridone and 2-hydroxypyridine are tautomeric forms not existing as separate isolatable materials: the two tautomeric forms are interconvertible, and the proportion of each depends on factors such as temperature, solvent, and additional substituents attached to the main ring. 20 . In some embodiments, the term “pyridinyl” is understood as further covering pyridone compounds wherein the nitrogen atom of the amide function is substituted by substituent X1 X1 , so that its tautomeric form is actually a pyridinium . In some embodiments, the term “pyridinyl” is understood as further covering pyridone25 compounds wherein the nitrogen atom of the amide function is unsubstituted. In some embodiments, X2 and X3 are fluorine atoms or chlorine atoms. 8

[0007] In some embodiments, n2=n3= 1 and X2 and X3 are fluorine atoms or chlorine atoms. In some embodiments, n2=0 and n3=1 and X3 is a fluorine atom or a chlorine atom. In some embodiments, n1=0. 5 In some embodiments, the compounds of the invention have the following formula (II): wherein: Bis a phenyl or a 5-membered or 6-membered monocyclic saturated, unsaturated, or10 aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, and N, wherein said phenyl or said aromatic ring may be substituted by one or two substituents selected from the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, halogen, hydroxyl, nitro, cyano, =O, =S, =N—CN and ═N—OH; and R, X2, X3, n2 and n3 are as disclosed herein.15 In some embodiments, the compounds of the invention are compounds of formula (I) or (II) wherein A or B is as disclosed herein, X1, X2, X3, n1, n2 and n3 are as disclosedherein; and Ris selected from the group consisting of -C1-C6-alkyl; -C1-C6-hydroxalkyl; -C1-C6-20 haloalkyl; -C1-C6-cyanoalkyl; -O-C1-C6-alkyl; -C(O)ORawherein Rais selected from the group consisting of hydrogen atom, -C1-C6-alkyl and Li; -C(O)N(Rb)2 wherein Rbis independently selected from the group consisting of hydrogen atom and C1-C6-alkyl, or the two Rb form together a 5- or 6-membered non-aromatic ring containing one, two orthree heteroatoms, each independently selected from O, S, and N; 3- to 6-membered25 non-aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, and N; 5- or 6-membered heteroaryl;-C1-C6-alkyl-SRc wherein Rc isselected from the group consisting of hydrogen atom and -C(O)-C1-C6-alkyl; -C1-C6-alkyl- O-C1-C6-alkyl; -C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16; - 9

[0008] C1-C6-alkyl-N(Rd)2 wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and-C(O)O-C1-C6-alkyl; -C1-C6-alkyl-C(O)ORewherein Reis selected from the group consisting of hydrogen atom, -C1-C6-alkyl and Li; C1-C6-alkyl- C(O)-azetidine-(5- or 6-membered heteroaryl); ; C1-C6-alkyl-C(O)-azetine-(5- or 6-5 membered heteroaryl); -C1-C6-alkyl-C(O)N(Rf)2 wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C6-alkyl, -C1-C6-alkyl-O-C1-C6-alkyl, - C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16, -C1-C6-alkoxy and C1-C6-alkyl-N(C1-C6-alkyl)2, or the two Rf form together a 5- to 6-membered non-aromaticring containing one, two or three heteroatoms, each independently selected from O, S,10 and N; -C1-C6-alkyl-(5- or 6-membered heteroaryl); and -C1-C6-alkyl-NH-C(O)ORgwherein Rgis independently selected from the group consisting of -C1-C6-alkyl and -C1- C6-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl; wherein said5- or 6-membered non-aromatic ring, said 3- to 6-membered non-aromatic ring and said5- or 6-membered heteroaryl may be substituted by one or more substituents selected15 from the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, halogen, hydroxyl, nitro, cyano, =O, =S, =N—CN, and ═N—OH. In some embodiments, the compounds of the invention are compounds of formula (I) or (II) wherein:20 A or B is as disclosed herein;X1, X2, X3, n1, n2and n3are as disclosed herein; and Ris selected from the group consisting of -C1-C6-alkyl; -C1-C3-hydroxalkyl; -C1-C3-haloalkyl; -C1-C3-cyanoalkyl; -C(O)ORa wherein Ra is selected from the group consistingof hydrogen atom, -C1-C3-alkyl and Li; -C(O)N(Rb)2wherein Rbis independently selected25 from the group consisting of hydrogen atom and C1-C3-alkyl, or the two Rb form togethera 5- or 6-membered non-aromatic ring containing one, two or three heteroatoms, eachindependently selected from O, S, and N; 3- to 6-membered non-aromatic ring containingone, two or three heteroatoms, each independently selected from O, S, and N; 5- or 6-membered heteroaryl; -C1-C6-alkyl-SRcwherein Rcis selected from the group consisting30 of hydrogen atom and -C(O)-C1-C3-alkyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1-C3-alkyl-[O-C1- C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 16; -C1-C6-alkyl-N(Rd)2 wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and- C(O)O-C1-C3-alkyl; -C1-C6-alkyl-C(O)ORewherein Reis selected from the group consisting of hydrogen atom, -C1-C3-alkyl and Li, C1-C6-alkyl-C(O)-azetidine-(5- or 6-35 membered heteroaryl); -C1-C6-alkyl-C(O)N(Rf)2 wherein Rfis independently selected 10 from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl, - C1-C3-alkyl-[O-C1-C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 16, C1-C6-alkyl-(5- or6-membered heteroaryl), -C1-C3-alkoxy and C1-C3-alkyl-N(C1-C3-alkyl)2, or the two Rfform together a 4- to 6-membered non-aromatic ring containing one, two or three5 heteroatoms, each independently selected from O, S (in particular S or SO2), and N; -C1-C3-alkyl-NH-C(O)ORgwherein Rgis independently selected from the group consisting of -C1-C4-alkyl and -C1-C3-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-memberedheteroaryl. 10 In some embodiments, the compounds of the invention are compounds of formula (I) or (II) wherein A or B is as disclosed herein, X1, X2, X3, n1, n2 and n3 are as disclosedherein; and Ris selected from the group consisting of -C1-C6-alkyl; -C1-C3-hydroxalkyl; -C1-C3-haloalkyl; -C1-C3-cyanoalkyl; -C(O)ORawherein Rais selected from the group consisting 15 of hydrogen atom, -C1-C3-alkyl and Li; -C(O)N(Rb)2wherein Rbis independently selected from the group consisting of hydrogen atom and C1-C3-alkyl, or the two Rbform together a5- or 6-membered non-aromatic ring containing one, two or three heteroatoms, eachindependently selected from O, S, and N; 3- to 6-membered non-aromatic ring containingone, two or three heteroatoms, each independently selected from O, S, and N; 5- or 6-20 membered heteroaryl; -C1-C6-alkyl-SRcwherein Rcis selected from the group consisting of hydrogen atom and -C(O)-C1-C3-alkyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1-C3-alkyl-[O-C1- C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 16; -C1-C6-alkyl-N(Rd)2wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and- C(O)O-C1-C3-alkyl; -C1-C6-alkyl-C(O)ORewherein Reis selected from the group25 consisting of hydrogen atom, -C1-C3-alkyl and Li, C1-C6-alkyl-C(O)-azetidine-(5- or 6-membered heteroaryl); -C1-C6-alkyl-C(O)N(Rf)2wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl, - C1-C3-alkyl-[O-C1-C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 16, -C1-C3-alkoxy and C1-C3-alkyl-N(C1-C3-alkyl)2, or the two Rf form together a 4- to 6-membered non-aromatic30 ring containing one, two or three heteroatoms, each independently selected from O, S, and N; -C1-C3-alkyl-NH-C(O)ORgwherein Rgis independently selected from the group consisting of -C1-C4-alkyl and -C1-C3-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl. 11 In some embodiments, the compounds of the invention are compounds of any of the following formulas: (Ia) (Ib) (IIa) (IIb)5 wherein A, B, X1, X2, X3, n1, n2and n3and R are as disclosed herein. In some embodiments, the compounds of the invention are compounds of formula (I) as disclosed herein wherein:10 A is selected from the group consisting of:N,N , N *,*,H *, 12 S H N N N N ,,an , wherein * designates the carbon atom linked to the rest of the formula; Amay be substituted or unsubstituted as disclosed herein,X1, X2, X3, n1, n2 and n3 are as disclosed herein; and Ris as disclosed herein.5 Preferably, A is selected from the group consisting of: N,N *,*,*, 13 N O N N N e, , and . wherein * designates the carbon atom linked to the rest of the formula; Amay be substituted or unsubstituted as disclosed herein. 5 In particular, and may be substituted on the NH group of the amide, in particular by a C1-C6alkyl group such as a methyl group. 14 Therefore, in some embodiments, A may represent or . The present invention includes any of the compounds of formula (I) disclosed in the 5“Examples” section (i.e. any of the compounds 1 to 106 disclosed herein as well as theirmixtures). Preferred compounds are compounds 76, 79, 80, 94, 101, 102, 103 and 105(see table 1). The compounds of the present invention may contain stereocenters. Therefore, the present invention further contemplates all stereoisomers or tautomers of the compounds 10 of the present invention. As used herein, the term “stereoisomers” refers to configurational stereoisomers and more particularly to optical isomers. Optical isomers that are not mirror images of one another are thus designated as “diastereoisomers”, and optical isomers, which are non- superimposable mirror images are designated as “enantiomers”. An equimolar mixture15 of two enantiomers is designated as a racemic mixture or racemate. A carbon atom bondto four non-identical substituents is called a “chiral centre”. The compounds of formula (I), including compounds of formula (II), can be prepared byany methods disclosed in the examples section, in particular by appropriate syntheticroutes A to V disclosed in the examples section.20 Therapeutic applications In the following, the expression “a compound of formula (I)” refers to a compound of formula (I) as described herein, including compounds of formula (II) and any compounds of formula (I) disclosed in the “Examples” section, as well as any salts, hydrates, 25 solvates, deuterated analogs, isomers, mixtures of isomers in any ratio and any combinations thereof. Therefore, the term “a compound of formula (I)” may refer to a single compound of formula (I) or a combination of two or more compounds of formula (I) or salts, hydrates, solvates, isomers or mixtures of isomers thereof. 15 The compounds of formula (I) have been found to be efficient inhibitors of 3CL protease (3CLproor Mpro). “Inhibitors” refer to molecules that are able to reduce or suppress the activity of the enzyme. They inhibit coronavirus replication by targeting a key componentof the viral cycle. Resultantly, the compounds of formula (I) may be useful in medicine.5 In particular, the compounds of formula (I) may be useful for the treatment or prophylaxis of disorders in which 3CL protease is implicated, such as disorders mediated bycoronavirus, in particular disorders mediated by SARS-CoV-2. In other terms, thecompounds of formula (I) may be useful for the treatment or prophylaxis of disorders mediated by coronavirus, in particular disorders mediated by SARS-CoV-2. The10 compounds of the present invention exhibit an antiviral activity. The term “disorder” as used herein refers to a disease, condition or illness. The term "treatment" as used herein refers to combating, alleviating, reducing, relieving, suppressing, repelling, healing or improving the condition of a disorder. 15 The terms "prophylaxis" as used herein refers to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disorder. The treatment or prophylaxis of a disorder may be partial or complete. In one aspect, the present invention relates to a compound of formula (I) for use in20 medicine. In another aspect, the present invention relates to a compound of formula (I) for use in the treatment or prophylaxis of a disorder mediated by a coronavirus, in particular a disorder mediated by SARS-CoV-2. In other terms, the present invention relates to acompound of formula (I) for use in the treatment or prophylaxis of a coronavirus infection,25 in particular for use in the treatment or prophylaxis of a SARS-CoV-2 infection. In accordance with a further aspect, the present invention relates a method of treatment or prophylaxis of disorders mediated by a coronavirus, in particular disorders mediatedby SARS-CoV-2, using a therapeutically effective amount of a compound of formula (I).30 In other words, the present invention relates to a method of treating disorders mediatedby a coronavirus, in particular disorders mediated by SARS-CoV-2, comprising the step of administering to a subject in need thereof, that may be human or animal, atherapeutically effective amount of at least one compound of formula (I). A “therapeutically effective amount” as used herein refers to an amount that (i) treats or 35 prevents the particular disorder, (ii) attenuates, ameliorates, or eliminates one or more 16 symptoms of the particular disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disorder described herein. The amount of a compound which constitutes a therapeutically effective amount will vary depending on many factors, such as for instance the compound and its biological activity, the composition used for 5 administration, the route of administration, the type of disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds, and the age, body weight, general health, sex, and diet of the patient. Such an effective amount can be determined routinely by one of ordinary skill in the art having regard to their ownknowledge. 10 In another aspect, the present invention relates to a compound of formula (I) for use in a method of treating disorders mediated by a coronavirus, in particular disorders mediated by SARS-CoV-2. In accordance with a further aspect, the present invention relates to the use of a compound of formula (I) for the preparation of a pharmaceutical composition, preferably 15 a medicament, for the prophylaxis or treatment of disorders mediated by a coronavirus, in particular disorders mediated by SARS-CoV-2 C The present invention also relates to a pharmaceutical or veterinary composition, in20 particular a medicament, comprising a compound of formula (I)as described herein andone or more excipient(s), in particular one or more pharmaceutically or veterinary acceptable excipient(s) and to their uses for the above-mentioned purposes.Said pharmaceutically or veterinary acceptable excipient(s) is / are selected, according tothe desired dosage form and mode of administration, from the typical excipients known25 to persons skilled in the art. In one aspect, the present invention relates to a composition, in particular a medicament, comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically or veterinary acceptable excipient. The compositions may be useful forthe treatment or prophylaxis of disorders mediated by a coronavirus, in particular 30 disorders mediated by SARS-CoV-2 or in methods for treating disorders mediated by coronavirus, in particular disorders mediated by SARS-CoV-2. Pharmaceutically acceptable excipients include fillers and carriers, ointment bases, bases for suppositories, solvents, surfactants, emulsifiers, dispersants or wetting agents, buffers, acids and bases, isotonicity agents, adsorbent, viscosity-increasing agents, gel 35 formers, thickeners and / or binders, disintegrants, coating materials and film formers for 17 films or diffusion membranes, capsule materials, natural or synthetic polymers, plasticizers, penetration enhancers, stabilizers, preservatives, colourants, flavourings, sweeteners, flavour- and / or odour-masking agents.The pharmaceutical or veterinary compositions according to the invention can be 5 administered parenterally (such as intravenously or intradermally), topically, orally or rectally. The term “parenteral” as used herein includes subcutaneous, intravenous or intramuscular techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using 10 suitable dispersing or wetting agents and suspending agents. For therapeutic purposes, formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. Preferably, the compositions of the invention are administered via oral route. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, 15 and granules. In such solid dosage forms, the compound is ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, 20 or magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise 25 adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. In some embodiments, the pharmaceutical or veterinary composition of the invention further comprises one or more further therapeutic compounds. Examples of therapeuticcompounds that may be used in combination with a compound of formula (I) include, but 30 are not limited to, antimicrobial agents (including antivirals, antibiotics, anti-fungal agents), anti-inflammatory agents, PK enhancers (such as ritonavir or cobicistat). Another aspect of the present invention encompasses a combination of a compound of formula (I) as described above, with one or more other therapeutic compounds. 18 The one or more compounds of formula (I) can be administered in therapeutically effective amounts in a combinational therapy with one or more pharmaceutically active agents (pharmaceutical combinations). The compounds can be administered simultaneously (as a single preparation or separate 5 preparation), sequentially or separately. In one aspect of the invention, a compound of formula (I) is administered to prior to administration of one or more other pharmaceutically active agents. In another aspect of the invention, a compound of formula (I) is administered concomitantly with the administration of one or more other pharmaceutically active10 agents. In yet another aspect of the invention, a compound of formula (I) of the invention is administered immediately after administration of one or more other pharmaceutically active agents. The single pharmaceutically active agents (compounds of formula (I) and other15 pharmaceutically active agents) may be packaged in a kit or separately. Embodiments of the present invention will now be described by way of the following examples which are provided for illustrative purposes only, and not intended to limit the scope of the disclosure. 20

[0009] 19 EXAMPLES I. Chemical synthesis Solvents for synthesis, analysis and purification were purchased as analytical grade from commercial suppliers and used directly without further purification. Chemical reagents 5 were purchased as reagent grade and used without further purification. NMR spectra were recorded on a Bruker DRX-300 spectrometer. Chemical shifts are in parts per million (ppm). The assignments were made using one-dimensional (1D)1H and13C spectra and two-dimensional (2D) HSQC, HMBC and COSY spectra. UPLC-MS Waters system was equipped with a UPLC I SMP MGR-FTN sample 10 manager, an ACQUITY UPLC I-Class eK photodiode array detector (210–400 nm) and an ACQUITY QDa (Performance) detector (scan 30–1250). Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 μm, Waters) was used. The injection volume was 0.5 μL. A mixture of water and acetonitrile was used as mobile phase in gradient-elution. The pH of the mobile phase was adjusted with HCOOH and NH4OH to form a buffer solution at pH 3.8. 15 The analysis time was 5 min (at a flow rate at 600 μL / min), 10 min (at a flow rate at 600 μL / min) or 30 min (at a flow rate at 600 μL / min). Purity (%) was determined using UV detection (215 nm), and all final compounds showed purity greater than 95%. HRMS analysis was performed on a LC-MS system equipped with a LCT Premier XE mass spectrometer (Waters), using a XBridge C18 column (50 mm × 4.6 mm, 3.5 μm, Waters). 20 A gradient starting from 98% H2O 5 mM Ammonium Formate pH 3.8 and reaching 100% CH3CN 5 mM Ammonium Formate pH 3.8 within 3 min at a flow rate of 1 mL / min was used. Flash chromatography purifications were performed with a Puriflash® 430 instrument (Interchim) with UV detection at 254 nm and by ELSD, using prepacked columns (Büchi® 25 FlashPure or Macherey-Nagel® Chromabond flash RS SiOH, 15–40 μm). Reverse flash chromatography was performed using a CombiFlash® C18 Rf200 with C18 silica gel cartridges with UV detection at 215 and 254 nm. Preparative HPLC were performed using a Buchi Pure C-830 system with an OmniSphere 10 μm column C18 Dynamax (250 mm × 41.4 mm, Agilent Technologies) 30 with UV detection at 215 and 254 nm. A gradient starting from 10% MeCN / 90% H2O / 0.1% formic acid and reaching 100% MeCN / 0.1% formic acid at a flow rate of 80 mL / min was used. Structures of the synthetized compounds of formula (I) (examples 1 to 88) are presented35 herein below in table 1. 20 Examples 1-3 were synthetized according as follows (synthetic route A):Ex amples 8, 9, 12-15, 17, 24-26, 47-51, 64, 69, 70 were synthetized as follows(synthetic route B): X 5 2CN E d 6 5 and 7 n n= 1 n=2 Step 4 10 21 Examples 16, 18, 19, 29, 32, 45, 46 were synthetized as follows (synthetic route E):p 4 Examples 20-23, 27-28 were synthetized as follows (synthetic route F): ste 8 , n=1 (rac) : 27 5 Examples 30-31 were synthetized as follows (synthetic route G): 22 Examples 33-44 were synthetized as follows (synthetic route H): 11 Example 52 was synthetized as follows (synthetic route I): 5 Examples 53-57, 59-63 were synthetized as follows (synthetic route J): Me, Example 58 was synthetized as follows (synthetic route K): 23 Ex ampes 68, 9 were synt etzed as o ows (synthetic route L): Examples 71, 72 were synthetized as follows (synthetic route M): 5 Examples 55, 56 were synthetized as follows (synthetic route N): 2 (S)-CH2OMe Examples 73-75 were synthetized as follows (synthetic route O): 24 Examples 76-81, 97 were synthetized as follows (synthetic route P): racemic or(R)Example 64 was synthetized as follows (synthetic route Q): 5 25 Examples 66-67 were synthetized as follows (synthetic route R): Me2Example 65 was synthetized as follows (synthetic route S): 2O5 Examples 82-83 were synthetized as follows (synthetic route T): Examples 84-87 were synthetized as follows (synthetic route U): 26 Example 88 was synthetized as follows (synthetic route V): Example 96 was synthetized as follows (synthetic route W): 5 Examples 94-95 & 97-98 were synthetized as follows (synthetic route X): 27 RR'NH.HCl p 5 E Examples 100-102, 104-106 were synthetized as follows (synthetic route Z): 5 Example 1 [(3R)-4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl]-(4-10 isoquinolyl)methanoneStep 1. tert-butyl (3R)-4-benzhydryl-3- (hydroxymethyl)piperazine-1-carboxylate Tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (150 mg, 0.69 mmol, 1.0 eq.) was solubilized in ACN (1.5 mL). [chloro(phenyl)methyl]benzene (250 µL, 1.39 mmol,2.0 eq.) and K2CO3 (190 mg, 1.39 mmol, 2.0 eq.) were added. The reaction mixture was 28 stirred at 50°C overnight. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1). A second purification was performed on silica gel chromatography (cyclohexane / ethyl acetate 100:0 to 80:20 (v / v)) to afford the 5 desired product as a colorless film (50 mg, 17%). MS (ESI+): m / z = 383 [M+H]+Step 2. [(2R)-1-benzhydrylpiperazin-2-yl]methanol;dihydrochlorideTert-butyl (3R)-4-benzhydryl-3-(hydroxymethyl)piperazine-1-carboxylate (50 mg, 0.14 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (1 mL, 4.0 mmol, 28 eq.).The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to 10 give the crude product as a white solid (46 mg, 89%). MS (ESI+): m / z = 283 [M + H]+Step 3. [(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methylisoquinoline-4-carboxylate Isoquinoline-4-carboxylic acid (42 mg, 0.25 mmol, 2.1 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N-Diisopropylethylamine (100 µL, 0.58 mmol, 5.0 15 eq.) and [(2R)-1-benzhydrylpiperazin-2-yl]methanol dihydrochloride (46 mg, 0.12 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and HBTU (93 mg, 0.25 mmol, 2.1 eq.) was added. The reaction mixture was stirred at rt overnight. A saturatedaqueous solution of NaHCO3was added and the product was extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, 20 brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as an off-white solid (32 mg, 45%), MS (ESI+): m / z = 593 [M + H]+Step 4. [(3R)-4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone 25 [(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl isoquinoline-1- carboxylate (32 mg, 0.05, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of MeOH / H2O (500 µL). Sodium hydroxide (6 mg, 0.16 mmol, 3.0 eq) was added. The reaction mixture was stirred at rt for 2 hours. The mixture was diluted with EtOAc and the product was extracted. The combined organic layers were washed with an aqueous solution of 30 saturated NaHCO3, water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as an amorphous white solid (22 mg, 96%). MS (ESI+): m / z = 438 [M+H]+. HRMS-ESI+ (m / z): calcd for C28H28N3O2 [M+H]+: 438.2182; found: 438.2169 29 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.28-9.15 (m, 1H), 8.57-8.36(m, 1H), 8.04-7.96 (m, 1H), 7.96-7.83 (m, 0.7H), 7.83-7.71 (m, 1H+0.3H), 7.70-7.60 (m, 1H), 7.46-7.34 (m, 4H), 7.33-7.10 (m, 6H), 5.19-4.88 (m, 1H), 4.67 (d, J = 13.8Hz, 0.7H),4.53-4.23 (m, 0.3H), 4.06-3.61 (m, 2H), 3.60-3.16 (m, 4H), 3.05-2.70 (m, 1H), 2.69-2.38 5 (m, 1H), 2.23-1.62 (m, 1H). Example 2 (3S)-(4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl)(isoquinolin-4- yl)methanone Step 1. tert-butyl (3S)-4-benzhydryl-3-(hydroxymethyl)piperazine-1-carboxylate 10 Tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (250 mg, 1.16 mmol, 1.0 eq.) was solubilized in ACN (3 mL). [chloro(phenyl)methyl]benzene (410 µL, 2.31 mmol, 2.0eq.) and K2CO3(320 mg, 2.31 mmol, 2.0 eq.) were added. The reaction mixture was stirred at 50°C overnight. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse 15 phase chromatography (H2O / ACN 9:1 to 0:1). A second purification was performed on silica gel chromatography (cyclohexane / EA 100:0 to 80:20 (v / v)) to afford the desired product as a white solid (110 mg, 25%). MS (ESI+): m / z = 383 [M + H]+Step 2. [(2S)-1-benzhydrylpiperazin-2-yl]methanol;dihydrochloride Tert-butyl (3S)-3-(hydroxymethyl)-4-(isoquinoline-4-carbonyl)piperazine-1-carboxylate 20 (110 mg, 0.29 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (2 mL, 8.0 mmol, 28.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the crude product as an off-white solid (100 mg, quant.). MS (ESI+): m / z = 283 [M + H]+Step 3. [(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl25 isoquinoline-4-carboxylate Isoquinoline-4-carboxylic acid (100 mg, 0.59 mmol, 2.1 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. N,N-Diisopropylethylamine (240 µL, 1.41 mmol, 5.0 eq.) and [(2S)-1-benzhydrylpiperazin-2-yl]methanol;dihydrochloride (100 mg, 0.28 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and HBTU (225 mg, 2.59 mmol,30 2.1 eq.) was added. The reaction mixture was stirred at rt overnight. A saturated aqueoussolution of NaHCO3 was added and the product was extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford35 the desired product as an off-white solid (110 mg, 65%). MS (ESI+): m / z = 593 [M + H]+ 30 Step 4. (3S)-(4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl)(isoquinolin-4- yl)methanone [(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl isoquinoline-1- carboxylate (110 mg, 0.18, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of MeOH / H2O 5 (1 mL). Sodium hydroxide (22 mg, 0.55 mmol, 3.0 eq) was added. The reaction mixture was stirred at rt for 2 hours. The mixture was diluted with EtOAc and the product was extracted. The combined organic layers were washed with an aqueous solution of saturated NaHCO3, water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography 10 (H2O / ACN 9:1 to 0:1) to afford the desired product as an amorphous white solid (60 mg, 75%). MS (ESI+): m / z = 438 [M+H]+. HRMS-ESI+ (m / z): calcd for C28H28N3O2 [M+H]+: 438.2182; found: 438.2190. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamer:9.29-9.14 (m, 1H), 8.55-8.38 (m, 1H), 8.04-7.95 (m, 1H), 7.95-7.82 (m, 0.7H), 7.82-7.70 (m, 1H+0.3H), 7.70-7.59 (m, 1H), 7.46-7.34 (m, 4H), 7.33-7.09 (m, 6H), 5.15-4.89 (m,15 1H), 4.68 (d, J = 13.5Hz, 0.7H), 4.50-4.22 (m, 0.3H), 4.03-3.61 (m, 2H), 3.58-3.14 (m,4H), 3.00-2.68 (m, 1H), 2.68-2.41 (m, 1H), 2.21-1.81 (m, 1H). EXAMPLE 3 [4-benzhydryl-3-(2-hydroxyethyl)piperazin-1-yl]-(4- isoquinolyl)methanone 20 Step 1. tert-butyl 4-benzhydryl-3-(2-hydroxyethyl)piperazine-1-carboxylate Tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (150 mg, 0.65 mmol, 1.0 eq.) was solubilized in dry ACN (1.5 mL). [bromo(phenyl)methyl]benzene (193 mg, 0.78 mmol, 1.2 eq.) and triethylamine (110 µL, 0.78 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. The crude product was purified by reverse phase 25 chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a yellow oil (86 mg, 32%). MS (ESI+): m / z = 397 [M+H]+Step 2.2-(1-benzhydrylpiperazin-2-yl)ethanol;dihydrochloride Tert-butyl 4-benzhydryl-3-(2-hydroxyethyl)piperazine-1-carboxylate (86 mg, 0.21 mmol, 1.0 eq.) was solubilized in 4M HCl in dioxane (1.5 mL). The mixture was stirred for 1 hour 30 at rt. Solvents were removed under reduced pressure to afford the desired product as a brown solid (78 mg, 99%). MS (ESI+): m / z = 297 [M + H]+Step 3. 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]ethyl isoquinoline-4-carboxylate 2-(1-benzhydrylpiperazin-2-yl)ethanol;dihydrochloride (86 mg, 0.23 mmol, 1.0 eq.) was 35 solubilized in dry DMF (1.5 mL) under inert atmosphere. Isoquinoline-4-carboxylic acid 31 (96 mg, 0.56 mmol, 2.4 eq.), N,N-Diisopropylethylamine (318 µL, 1.9 mmol, 8.0 eq.) and HBTU (211 mg, 0.56 mmol, 2.4 eq.) were added. The mixture was stirred at rt overnight. The mixture was stirred at rt 3h. The reaction mixture was diluted with EtOAc and washed with 1M aqueous solution of NaOH. The combined organic layers were dried over 5 MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / ACN) to afford the desired product as a white solid (38 mg, 27%). Step 4. [4-benzhydryl-3-(2-hydroxyethyl)piperazin-1-yl]-(4-isoquinolyl)methanone 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]ethyl isoquinoline-4- 10 carboxylate (38 mg, 0.06 mmol, 1.0 eq.) was solubilized in a 5:1 (v / v) mixture of MeOH / H2O (2.4 mL). Lithium;hydroxide;hydrate (14 mg, 0.32 mmol, 5 eq) was added. The reaction mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as an amorphous white solid (20 mg,15 71%).MS (ESI+): m / z = 452 [M+H]+.HRMS-ESI+ (m / z): calcd for C29H30N3O2[M+H]+: 452.2338; found: 452.2332. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers:9.27 (s, 1H), 8.48-8.34 (m, 1H), 8.14-8.06 (m, 1H), 7.96-7.67 (m, 3H), 7.58-7.40 (m, 4H), 7.35-7.10 (m, 6H), 4.95-4.79 (m, 1H), 4.62-4.42 (m, 1H), 3.61-3.03 (m, 5H), 2.85-2.62 (m, 2H), 2.62-2.28 (m, 2H), 1.87-1.69 (m, 1H). 20 EXAMPLE 4 S-[[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2- yl]methyl] ethanethioate [(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl methanesulfonate 25 To a solution of [(3R)-4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl]-(4- isoquinolyl)methanone (100 mg, 0.23 mmol, 1.0 eq.) and TEA (80 µL, 0.57 mL, 2.5 eq.) in anhydrous DCM (2.5 mL) at 0 °C under argon atmosphere, was dropwise added MsCl (20 µL, 0.25 mmol, 1.1 eq.). The mixture was stirred for 1 h, then the cooling bath was removed. After the mixture had stirred at r.t. for 1 h, it was washed with water and the 30 aqueous washings were extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure to give the desired product as a white solid (110 mg, 93%). The product was directly used in the next step without purification. S-[[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl] 35 ethanethioate 32 [(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl methanesulfonate (110 mg, 0.21 mmol, 1.0 eq.) was solubilized in dry DMF (2 mL) and KSAc (74 mg, mmol, 3.0 eq.) was added. The mixture was stirred at 70°C for 4 hours. The reaction mixture was diluted with water and ethyl acetate. The product was extracted with ethyl acetate. 5 The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a pale yellow solid (25 mg, 23%). MS (ESI+): m / z = 496 [M+H]+, HRMS-ESI+ (m / z): calcd for C30H30N3O2S [M+H]+: 496.2059; found: 496.2054. 1H NMR (300 MHz, CDCl3) δ (ppm)10 Mixture of rotamers: 9.26-9.24 (m, 1H), 8.62-8.43 (m, 1H), 8.00 (dd, J = 8.0 Hz and4.5Hz, 1H+0.3H), 7.95-7.69 (m, 1H+0.7H), 7.65 (t, J = 8.0Hz, 1H), 7.49-7.35 (m, 4H),7.34-7.10 (m, 6H), 4.94 (d, J = 5.0Hz, 1H), 4.55 (br t, J = 13.5Hz, 1H), 3.55-2.97 (m,5H+0.3H), 2.90-2.68 (m, 1H+0.7H), 2.68-2.37 (m, 1H), 2.34 (s, 1H+0.3H), 2.18 (br s, 0.7H), 1.86 (br s, 1H). 15 EXAMPLE 5 [(3R)-4-benzhydryl-3-(chloromethyl)piperazin-1-yl]-(4- isoquinolyl)methanone [(3R)-4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone (50 mg, 0.11 mmol, 1.0 eq.) was solubilized in thionyl chloride (500 µL). Few drops of DMF were 20 added and the mixture was stirred at rt for 5 hours. Thionyl chloride was removed under reduced pressure. The residue was taken up with a 1M aqueous solution of NaOH and diluted with EtOAc. The product was extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase25 chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (25mg, 46%). MS (ESI+): m / z = 456 [M+H]+. HRMS-ESI+ (m / z): calcd for C28H26ClN3O [M+H]+: 456.1843; found: 456.1825 1H NMR (300MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.29 (br s, 1H), 8.61-8.38 (m,1H), 8.06 (s, 0.3H), 8.03 (s, 0.7H), 7.88-7.74 (m, 2H), 7.73-7.64 (m, 1H), 7.47-7.13 (m,30 10H), 4.92 (0.3H), 4.85-4.75, 4.63 (d, J = 12.5Hz, 0.7H), 3.82 (d, J = 5.7Hz, 0.7H), 3.76-3.60 (m, 0.3H), 3.58-3.41 (m, 1H+0.3H), 3.40-3.18 (m, 2H+0.7H), 2.92-2.64 (m,2H+0.3H), 2.49 (br s, 0.7H). EXAMPLE 6 S-[[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-35 yl]methyl] ethanethioate 33 step 1. [(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl methanesulfonate To a solution of [(3S)-4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl]-(4- isoquinolyl)methanone (100 mg, 0.23 mmol, 1.0 eq.) and TEA (80 µL, 0.57 mL, 2.5 eq.) 5 in anhydrous DCM (2.5 mL) at 0 °C under argon atmosphere, was dropwise added MsCl (20 µL, 0.25 mmol, 1.1 eq.). The mixture was stirred for 1 h, then the cooling bath was removed. After the mixture had stirred at r.t. for 1 h, it was washed with water and the aqueous phases were extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure to give the desired product as 10 a yellow oil (115 mg, 98%). The product was directly used in the next step without purification. step 2. S-[[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl] ethanethioate [(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl methanesulfonate 15 (115 mg, 0.22 mmol, 1.0 eq.) was solubilized in dry DMF (2 mL) and KSAc (76 mg, 0.67 mmol, 3.0 eq.) was added. The mixture was stirred at 70°C for 4 hours. The reaction mixture was diluted with water and ethyl acetate. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated under recuded pressure. The crude product was purified by20 reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as ayellow solid (20 mg, 18%). MS (ESI+): m / z = 496 [M+H]+, HRMS-ESI+ (m / z): calcd for C30H30N3O2S [M+H]+: 496.2059; found: 496.2045 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.26-9.24 (m, 1H), 8.62-8.43(m, 1H), 8.00 (dd, J = 8.0Hz and 4.5Hz, 1H+0.3H), 7.95-7.69 (m, 1H+0.7H), 7.65 (t, J =25 8.0Hz, 1H), 7.49-7.35 (m, 4H), 7.34-7.10 (m, 6H), 4.94 (d, J = 5.0Hz, 1H), 4.55 (br t, J =13.5Hz, 1H), 3.55-2.97 (m, 5H+0.3H), 2.90-2.68 (m, 1H+0.7H), 2.68-2.37 (m, 1H), 2.34 (s, 1H+0.3H), 2.18 (br s, 0.7H), 1.86 (br s, 1H). EXAMPLE 7 [(3S)-4-benzhydryl-3-(chloromethyl)piperazin-1-yl]-(4-30 isoquinolyl)methanone [(3S)-4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone (40 mg, 0.09 mmol, 1.0 eq.) was solubilized in thionyl chloride (500 µL). Few drops of DMF were added and the mixture was stirred at rt for 5 hours. Thionyl chloride was removed under reduced pressure. The residue was taken up with a 1M aqueous solution of NaOH and 35 diluted with EtOAc. The product was extracted with EtOAc. The combined organic layers 34 were washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (13 mg, 31%). MS (ESI+): m / z = 456 [M + H]+. HRMS-ESI+ (m / z): calcd for C28H27N3OCl 5 [M+H]+: 456.1843; found: 456.1796 1H NMR (CDCl3, 300MHz) δ (ppm) Mixture of rotamers: 9.32 (br s, 1H), 8.63-8.37 (m,1H), 8.09 (s, 0.3H), 8.06 (s, 0.7H), 7.91-7.77 (m, 2H), 7.75-7.66 (m, 1H), 7.48-7.12 (m, 10H), 4.93 (0.3H), 4.88-4.77, 4.63 (d, J = 12.5Hz, 0.7H), 3.83 (d, J = 5.7Hz, 0.7H), 3.75-3.61 (m, 0.3H), 3.59-3.43 (m, 1H+0.3H), 3.42-3.17 (m, 2H+0.7H), 2.93-2.64 (m,10 2H+0.3H), 2.51 (br s, 0.7H). EXAMPLE 8 [(3R)-4-benzhydryl-3(methoxymethyl) piperazin-1-yl]-(4-isoquinolyl) methanone Step 1. Tert-butyl (3R)-4-benzhydryl-3-(methoxymethyl)piperazine-1-carboxylate15 Tert-butyl (3R)-3-(methoxymethyl)piperazine-1-carboxylate (119 mg, 0.517 mmol, 1.0 eq.) was solubilized in dry ACN (1.64 mL). [bromo(phenyl)methyl]benzene (153 mg, 0.620 mmol, 1.2 eq.) and triethylamine (86 µL, 0.620 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 4 hours. Upon completion, solvents were removed under reduced pressure. The crude product was purified by reverse phase20 chromatography (H2O / ACN 9:1 to 0:1) to afford tert-butyl (3R)-4-benzhydryl-3- (methoxymethyl)piperazine-1-carboxylate (134 mg, 65 %). MS (ESI+): m / z = 397 [M+H]+. Step 2. (2R)-1-benzhydryl-2-(methoxymethyl)piperazine dihydrochloride HCl 4M in dioxane (0.704 mL) was added to the tert-butyl (3R)-4-benzhydryl-3- (methoxymethyl)piperazine-1-carboxylate (134 mg, 0.338 mmol) at 0°C and stirred for 25 1h at rt. The solution mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate white solid (120 mg, 96 %). MS (ESI+): m / z = 297[M+H]+. Step 3. [(3R)-4-benzhydryl-3-(methoxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone 30 Isoquinoline-4-carboxylic acid (82 mg, 0.471 mmol, 1.2 eq.) was solubilized in dry DMF (2.3 mL) under inert atmosphere. N,N-Diisopropylethylamine (270 µL, 1.57 mmol, 4.0 eq.), HBTU (179 mg, 0.471 mmol, 1.2 eq.) and (2R)-1-benzhydryl-2- (methoxymethyl)piperazine; dihydrochloride (145 mg, 0.393 mmol, 1.0 eq.) were added. The mixture was stirred at rt overnight. The solution was diluted with EtOAc and washed 35 with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated 35 under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (40 mg, 23 %). MS (ESI+): m / z = 452 [M+H]+. HRMS-ESI+ (m / z): calcd for C29H30N3O2 [M+H]+: 452.2338; found: 452.2327. 51H NMR (300 MHz, DMSO-d6) Mixture of rotamers δ: 9.35 (s, 0.4H), 9.33 (s, 0.6H), 8.45(br s, 0.3H), 8.42 (s, 0.7H), 8.21-8.17 (m, 1H), 7.86 (t, J = 7.2 Hz, 1H+0.3H), 7.79-7.73(m, 1H+0.7H), 7.49-7.42 (m, 4H), 7.32-7.10 (m, 6H+0.3H), 5.02 (s, 0.4H), 4.97 (s, 0.6H), 4.53-4.40 (m, 1H), 3.70 (dd, J = 10.2 Hz and 3.5 Hz, 0.4H), 3.63-3.57 (m, 0.6H), 3.43 (brs, 1H), 3.30 (br s, 0.7H), 3.26 (br s, 0.8H), 3.21 (br s, 1H+0.8H), 3.13 (br s, 0.5H), 3.09 10 (br s, 0.3H), 3.00 (br s, 1H+0.3H), 2.66-2.62 (m, 2H), 2.34 (br s, 0.7H), 2.30-2.26 (m, 0.7H). EXAMPLE 9 [(3S)-4-benzhydryl-3-(methoxymethyl)piperazin-1-yl]-(4- isoquinolyl)methanone15 Step 1. Tert-butyl (3S)-4-benzhydryl-3-(methoxymethyl)piperazine-1-carboxylateTert-butyl (3S)-3-(methoxymethyl)piperazine-1-carboxylate (135 mg, 0.586 mmol, 1.0 eq.) was solubilized in dry ACN (1.86 mL). [bromo(phenyl)methyl]benzene (174 mg, 0.703 mmol, 1.2 eq.) and triethylamine (98 µL, 0.703 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 4 hours. Upon completion, solvents were20 removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product (129 mg, 56 %). MS (ESI+): m / z = 397 [M+H]+. Step 2. (2S)-1-benzhydryl-2-(methoxymethyl)piperazine;dihydrochloride HCl 4M in dioxane (0.673 mL) was added to the Tert-butyl (3S)-4-benzhydryl-3- 25 (methoxymethyl)piperazine-1-carboxylate (128 mg, 0.323 mmol) at 0°C and stirred for 1h at rt. The solution mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate white solid (115 mg, 97 %). MS (ESI+): m / z = 297[M+H]+. Step 3. [(3S)-4-benzhydryl-3-(methoxymethyl)piperazin-1-yl]-(4-30 isoquinolyl)methanone Isoquinoline-4-carboxylic acid (115 mg, 0.311 mmol, 1.2 eq.) was solubilized in dry DMF (2.0 mL) under inert atmosphere. N,N-Diisopropylethylamine (213 µL, 1.25 mmol, 4.0 eq.), HBTU (142 mg, 0.374 mmol, 1.2 eq.) and (2S)-1-benzhydryl-2- (methoxymethyl)piperazine; dihydrochloride (115 mg, 0.311 mmol, 1.0 eq.) were added. 35 The mixture was stirred at rt overnight. The solution was diluted with EtOAc and washed 36 with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (80 mg, 57%). MS (ESI+): m / z = 452 [M+H]+. HRMS-ESI+ (m / z): calcd for C29H30N3O2 5 [M+H]+: 452.2338; found: 452.2331. 1H NMR (300 MHz, DMSO-d6) Mixture of rotamers δ (ppm): 9.35 (s, 0.4H), 8.34 (s,0.6H), 8.44 (br s, 0.4H), 8.41 (s, 0.6H), 8.19 (dd, J = 7.9 Hz and 3.7 Hz, 1H), 7.86 (t, J =7.2 Hz, 1H+0.3H), 7.79-7.72 (m, 1H+0.7H), 7.49-7.43 (m, 4H), 7.32-7.10 (m, 6H+0.3H), 5.02 (s, 0.4H), 4.98 (s, 0.6H), 4.52-4.40 (m, 1H), 3.71 (dd, J = 10.6 Hz and 3.6 Hz, 0.4H),10 3.60 (t, J = 8.5 Hz, 0.6H), 3.44 (br s, 1H), 3.33 (br s, 1H), 3.31 (br s, 0.6H), 3.26 (br s,0.7H), 3.22 (br s, 1H+0.8H), 3.14 (br s, 0.6H), 3.08 (br s, 0.3H), 3.01 (br s, 1H), 2.66- 2.63 (m, 2H), 2.34 (br s, 0.6H), 2.30 (br s, 0.4H). EXAMPLE 10 [(3S)-4-benzhydryl-3-(2-methoxyethoxymethyl)piperazin-1-yl]-(4-15 isoquinolyl)methanone step 1. Synthesis of tert-butyl (3S)-4-benzhydryl-3-(hydroxymethyl)piperazine-1-carboxylate Tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (1.0 g, 4.62 mmol, 1.0 eq.) was solubilized in ACN (0.3 mol / L). [bromo(phenyl)methyl]benzene (1.3g, 5.55 mmol, 20 1.2 eq.) and triethylamine (0.8 mL, 5.55 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 50°C for 3 hours. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel chromatography (cyclohexane / EA 100:0 to 70:30 (v / v)) to afford the desired product as a white solid (926 mg, 52%).25 step 2. tert-butyl (3S)-4-benzhydryl-3-(2-methoxyethoxymethyl)piperazine-1-carboxylate NaH (60 % dispersion in mineral oil, 86 mg, 4.0 eq.) was added cautiously to a stirred solution of tert-butyl (3S)-4-benzhydryl-3-(hydroxymethyl)piperazine-1-carboxylate (214 mg, 0.56 mmol, 1eq) in anhydrous THF (0.02 mol / L) at room temperature. The resulting30 mixture was stirred for 30 min at room temperature, followed by dropwise addition of 1- (2-bromoethoxy)-2-methoxy-ethane (0.25 mL, 2.7 mmol, 4.8 eq.). The mixture was then heated at 50 °C and stirred for 1.5 h. The reaction was not complete. NaH (60 % dispersion in mineral oil, 86 mg, 4.0 eq.) was added cautiously followed by 1- (2-bromoethoxy)-2-methoxy-ethane (0.25mL, 2.7mmol, 4.8 eq.). After 3.5 h stirring at 50 35 °C, the reaction mixture was cooled to room temperature, diluted with EtOAc and washed 37 with water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was used for the next step without purification. [M+H]+: m / z = 441 step 3. [(2S)-1-benzhydrylpiperazin-2-yl]methanol;dihydrochloride5 In a flask, tert-butyl (3S)-4-benzhydryl-3-(2-methoxyethoxymethyl)piperazine-1- carboxylate (0.56 mmol, 1.0 equiv) was introduced then a solution of HCl 4M in dioxane (4 mL, 30 eq.) was added. The solution was then stirred at room temperature for 4 hours. After completion, the mixture was concentrated under reduced pressure. The product was precipitated in Et2O, filtered and washed with Et2O to give the product as a white 10 solid (113 mg, 39%). MS (ESI+) m / z [M+H]+= 341. step 4. [(3S)-4-benzhydryl-3-(2-methoxyethoxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone Isoquinoline-4-carboxylic acid (37mg, 0.22mmol, 1eq) and ((2S)-1-benzhydryl-2-(2- methoxyethoxymethyl)piperazine;dihydrochloride (113mg, 0.27mmol, 1.3q) were 15 solubilized in dry DMF (0.15M) under argon. Then N,N-Diisopropylethylamine (0.13 mL, 0.72 mmol, 3 eq.), and HBTU (100 mg, 0.26 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. The product was diluted with EtOAc and washed with a saturated solution of NaHCO3. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase 20 chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as brown solid (12 mg, 11%). MS (ESI+) m / z [M+H]+= 496. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C31H34N3O3m / z = 496.2600, found: 496.2585. 1H NMR (300 MHz, CD3CN) mixture of rotamers δ (ppm): 9.26 (s, 1H,), 8.40 (s br, 1H),8.10 (d, J = 8.2 Hz, 1H), 8.00-7.76 (m, 2H), 7.75-7.66 (m, 1H), 7.54-7.40 (m, 4H), 7.35-25 7.08 (m, 6H), 5.00 (s, 0.4H), 4.94 (s br, 0.6H), 4.63 (d, J = 13.6 Hz, 0.4 H), 4.52 (d br, J= 11.7 Hz, 0.6 H), 3.90-3.79 (m, 0.4H), 3.76-3.66 (t, J = 9.4Hz, 0.6H), 3.57-3.40 (m, 3H),3.36-3.03 (m, 6H), 2.97-2.80 (m, 1H), 2.80-2.65 (m, 2H), 2.64- 2.41 (m, 1H), 2.41-2.29(m, 1H). 30 EXAMPLE 11 [(3S)-4-benzhydryl-3-[2-(2-methoxyethoxy)ethoxymethyl]piperazin- 1-yl]-(4-isoquinolyl)methanone step 2. tert-butyl (3S)-4-benzhydryl-3-[2-(2-methoxyethoxy)ethoxymethyl]piperazine-1-carboxylate NaH (60 % dispersion in mineral oil, 84 mg, 4.2 eq.) was added cautiously to a stirred 35 solution of tert-butyl (3S)-4-benzhydryl-3-(hydroxymethyl)piperazine-1-carboxylate (200 38 mg, 0.52 mmol, 1eq) in anhydrous THF (0.02 mol / L) at room temperature. The resulting mixture was stirred for 30 min at room temperature, followed by dropwise addition of 1- (2-bromoethoxy)-2-methoxy-ethane (0.5mL, 2.6mmol, 5 eq.). The mixture was stirred at 50 °C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc 5 and washed with water. The organic layer was washed with brine, dried on MgSO4, filtered, and evaporated. The crude product was used for the next step without purification. MS (ESI+) [M+H]+: m / z = 485. step 3. tert-butyl (3S)-4-benzhydryl-3-[2-(2-methoxyethoxy)ethoxymethyl]piperazine-1-carboxylate 10 In a flask, tert-butyl (3S)-4-benzhydryl-3-[2-(2-methoxyethoxy)ethoxymethyl] piperazine- 1-carboxylate (0.52 mmol, 1.0 equiv) was introduced then a solution of HCl 4M in dioxane (4 mL, 30 eq) was added. The solution was stirred at room temperature for 4 hours. After completion, the mixture was concentrated. The product was precipitated in Et2O, filtered and washed with Et2O. The product was obtained as a white solid (206 mg, 87%). MS 15 (ESI+) m / z [M+H]+: 385. step 4. [(3S)-4-benzhydryl-3-[2-(2-methoxyethoxy)ethoxymethyl]piperazin-1-yl]-(4-isoquinolyl)methanone Isoquinoline-4-carboxylic acid (39mg, 0.23mmol, 1eq) and (2S)-1-benzhydryl-2-[2-(2- methoxyethoxy)ethoxymethyl]piperazine dihydrochloride (145 mg, 0.32 mmol, 1.4 20 eq) were solubilized in dry DMF (0.15M) under argon. Then N,N-Diisopropylethylamine (0.14 mL, 0.82 mmol, 3.6 eq.) and HBTU (97 mg, 0.26 mmol, 1.1 eq.) were added. The mixture was stirred at room temp. overnight. The product was diluted with EtOAc and washed with saturated solution of NaHCO3. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by 25 reverse phase chromatography (H2O / ACN 9:1 to 0:1) to give the desired product as brown solid (53 mg, 43%). MS (ESI+) m / z [M+H]+: 540. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C33H38N3O4m / z = 540.2862, found: 540.2888. 1H NMR (300 MHz, CD3CN) Mixture of rotamers δ (ppm): 9.28 (s, 1H), 8.42 (s br, 1H),8.10 (d, J = 8.2 Hz, 1H), 7.90-7.66 (m, 3H), 7.61-7.41 (m, 4H), 7.37-7.11 (m, 6H), 5.0530 (s, 0.4H), 4.98 (s, 0.6H), 4.65 (d, J = 13.0 Hz, 0.4 H), 4.54 (d, J = 13.0 Hz, 0.6 H), 3.95(m, 0.4H), 3.73 (t, J = 8.9 Hz, 0.6 H), 3.62-3.43 (m, 5H), 3.41-3.31 (m, 2H), 3.28 (s, 2H),3.19 (s, 3H), 2.86-2.68 (m, 2H), 2.64-2.19 (m, 4H). EXAMPLE 12 (5-benzhydryl-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)-(4-35 isoquinolyl)methanone 39 step 1. tert-butyl 5-benzhydryl-2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate:Tert-butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate (50 mg, 0.22 mmol, 1.0 eq.) was solubilized in dry ACN (1 mL). Triethylamine (40 µL, 0.29 mmol, 1.3 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (65 mg, 0.26 5 mmol, 1.2 eq.) was added. The mixture was heated at 50°C for 3 hours. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (86.4 mg, 34%). MS (ESI+) m / z [M+H]+= 395.10 step 2.5-benzhydryl-2-oxa-5,8-diazaspiro[3.5]nonane dihydrochloride:HCl 4M in dioxane (0.136 mL) was added to tert-butyl 5-benzhydryl-2-oxa-5,8- diazaspiro[3.5]nonane-8-carboxylate (25.7 mg, 0.07 mmol, 1 eq.) at 0°C and stirred for 1h at rt. Dichloromethane was added and the solution mixture was concentrated under reduced pressure, to afford the desired product as a yellow solid (23.9 mg, 100%).15 MS (ESI+) m / z [M+H]+=295. step 3. (5-benzhydryl-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)-(4-isoquinolyl)methanone Isoquinoline-4-carboxylic acid (11.3 mg, 0.07 mmol, 1.0 eq.) was solubilized in dry DMF (0.17 mL) under inert atmosphere. N,N-Diisopropylethylamine (34 µL, 0.20 mmol, 3.0 20 eq.), 5-benzhydryl-2-oxa-5,8-diazaspiro[3.5]nonane ; dihydrochloride (23.9 mg, 0.07 mmol, 1 eq.) and HBTU (27.1 mg, 0.07 mmol, 1.1 eq.) were added. The mixture was stirred 72 hours at rt. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid25 (13.8 mg, 46%). MS (ESI+) m / z [M+H]+ =450. HRMS (TOF, ES+) m / z [M+H]+: calcd. forC29H28N3O2m / z= 450.2182, found: 450.2196. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers : 9.41 (s, 0.5H), 9.35 (s,0.5H), 8.54 (s, 0.5H), 8.43 (s, 0.5H), 8.25-8.18 (dd, J = 14.0, 7.8 Hz, 1H), 7.90-7.85 (m,1H + 0.5H), 7.81-7.72 (m, 1H + 0.5H), 7.47-7.41 (m, 4H), 7.33-7.20 (m, 6H), 5.59 (s,30 0.5H), 5.56 (s, 0.5H), 4.43 (d, J = 6.3Hz, 1H), 4.26 (br s, 1H), 4.20-4.19 (m, 1H), 3.95 (d,J = 6.3Hz, 1H), 3.77-3.72 (m, 1H), 3.65-3.63 (m, 1H + 0.5H), 3.47-3.41 (m, 0.5H), 3.12(br s, 1H), 2.56-2.59 (m, 1H), 2.34-2.26 (m, 1H). EXAMPLE 13 methyl 1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-35 carboxylate 40 step 1. O1-tert-butyl O3-methyl 4-benzhydrylpiperazine-1,3-dicarboxylateO1-tert-butyl O3-methyl piperazine-1,3-dicarboxylate (200 mg, 0.82 mmol, 1.0 eq.) was solubilized in dry ACN (2 mL) under argon atmosphere. [bromo(phenyl)methyl]benzene (243 mg, 0.98 mmol, 1.2 eq.) and triethylamine (140 µL, 0.98 mmol, 1.2 eq.) were added. 5 The reaction mixture was heated at 50°C for 3 hours. Upon completion, solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (185 mg, 55%). MS (ESI+): m / z = 411 [M+H]+step 2. methyl 1-benzhydrylpiperazine-2-carboxylate;dihydrochloride10 O1-tert-butyl O3-methyl 4-benzhydrylpiperazine-1,3-dicarboxylate (185 mg, 0.45 mmol, 1.0 eq.) was solubilized in 4M HCl in dioxane (2 mL, 8.00 mmol, 18.0 eq). The mixture was stirred for 3 hours at rt. Solvents were removed under reduced pressure to give the crude product as a colorless oil (175 mg, quant.). MS (ESI+): m / z = 311 [M + H]+step 3. methyl 1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate15 Methyl 1-benzhydrylpiperazine-2-carboxylate;dihydrochloride (175 mg, 0.46 mmol, 1.0 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. Isoquinoline-4-carboxylic acid (95 mg, 0.55 mmol, 1.2 eq.), N,N-Diisopropylethylamine (390 µL, 2.28 mmol, 5.0 eq.), and HBTU (210 mg, 0.55 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3was added and the product was 20 extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (160 mg, 75%), MS(ESI+): m / z = 466 [M+H]+. HRMS-ESI+ (m / z): calcd for C29H28N3O3 [M+H]+: 466.2131;25 found: 466.2090 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.24 (s, 1H), 8.52-8.41 (m,0.5H), 8.38 (s, 0.5H), 7.99 (d, J = 8.3 Hz, 1H), 7.96-7.86 (m, 0.5H), 7.86-7.71 (m,1H+0.5H), 7.65 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H),7.39-7.33 (m, 1H), 7.33-7.16 (m, 6H), 7.16-7.07 (m, 1H), 5.24-5.01 (m, 1H+0.5H), 4.86-30 4.70 (m, 0.5H), 3.84-3.50 (m, 3H+0.5H), 3.44-3.05 (m, 4H), 2.87 (d, J = 10.8 Hz, 0.5H),2.74 (br s, 0.5H), 2.57-2.44 (m, 0.5H). EXAMPLE 14 methyl (2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2- carboxylate35 step 1. O1-tert-butyl O3-methyl (3R)-4-benzhydrylpiperazine-1,3-dicarboxylate: 41 O1-tert-butyl O3-methyl (3R)-piperazine-1,3-dicarboxylate (1016 mg, 4.16 mmol, 1.0 eq.) was solubilized in dry ACN (16.6 mL). Triethylamine (2.32 mL, 16.6 mmol, 4.0 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (1206 mg, 4.88 mmol, 1.2 eq.) was added. The mixture was heated at 50°C for 3 hours.5 The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (1192 mg, 70%). MS (ESI+) m / z [M+H]+= 411. step 2. Methyl (2R)-1-benzhydrylpiperazine-2-carboxylate;dihydrochloride:HCl 4M in dioxane (8 eq., 24 mmol, 6 mL) was added to O1-tert-butyl O3-methyl (3R)-4-10 benzhydrylpiperazine-1,3-dicarboxylate (1192 mg, 2.90 mmol, 1 eq.) at 0°C and stirred for one night at rt. Dichloromethane was then added and the solution mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate yellow solid (1306 mg, quantitative). MS (ESI+) m / z [M+H]+ =311.step 3. Methyl (2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-15 carboxylate Isoquinoline-4-carboxylic acid (502 mg, 2.90 mmol, 1.0 eq.) was solubilized in dry DMF (7.50 mL) under inert atmosphere. N,N-Diisopropylethylamine (1.5 mL, 8.70 mmol, 3.0 eq.), methyl (2R)-1-benzhydrylpiperazine-2-carboxylate;dihydrochloride (1110 mg, 2.90 mmol, 1.0 eq.) and HBTU (1210 mg, 3.18 mmol, 1.1 eq.) were added. After 4 hours at rt 20 with stirring, the mixture was diluted with EtOAc and washed with NaHCO3and brine, dried over MgSO4,filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (1120 mg, 83%). MS (ESI+) m / z [M+H]+ =466. HRMS-ESI+ (m / z): calculated for C29H27N3O3[M+H]+= 466.2131 ; found: 466.209025 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.35 (s, 1H), 9.37 (br s, 1H),8.21-8.19 (m, 1H), 7.90-7.73 (m, 3H), 7.52-7.43 (m, 2H), 7.38-7.13 (m, 8H), 5.07-4.96 (m, 1H), 4.88-4.58 (m, 1H), 3.66-3.37 (m, 4H), 3.25-2.95 (m, 3H), 2.74-2.72 (m, 1H + 0.5H), 2.41-2.37 (m, 0.5H). 30 EXAMPLE 15 methyl (2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2- carboxylate step 1. O1-tert-butyl O3-methyl (3S)-4-benzhydrylpiperazine-1,3-dicarboxylateO1-tert-butyl O3-methyl (3S)-piperazine-1,3-dicarboxylate (1000 mg, 4.09 mmol, 1.0 eq.) was solubilized in dry ACN (16.6 mL). Triethylamine (2.28 mL, 16.4 mmol, 4.0 eq.) was 35 added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (1187 42 mg, 4.8 mmol, 1.2 eq.) was added. The mixture was heated at 50°C for 3 hours. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (946 mg, 56%). MS (ESI+) m / z [M+H]+=411. 5step 2. Methyl (2S)-1-benzhydrylpiperazine-2-carboxylate dihydrochlorideHCl 4M in dioxane (8 eq., 19.2 mmol, 4.8 mL) was added to O1-tert-butyl O3-methyl (3S)-4-benzhydrylpiperazine-1,3-dicarboxylate (943 mg, 2.3 mmol, 1eq.) at 0°C and stirred for 1h at rt. Dichloromethane was then added and the solution mixture was concentrated under reduced pressure, to afford the desired product as yellow solid (90310 mg, yield: quantitative). MS (ESI+) m / z [M+H]+ =311.step 3. Methyl (2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate Isoquinoline-4-carboxylic acid (395 mg, 2.28 mmol, 1.0 eq.) was solubilized in dry DMF (6 mL) under inert atmosphere. N,N-Diisopropylethylamine (1.2 mL, 6.84 mmol, 3.0 eq.), 15 methyl (2S)-1-benzhydrylpiperazine-2-carboxylate (707 mg, 2.28 mmol, 1.0 eq.) and HBTU (948 mg, 2.50 mmol, 1.1 eq.) were added. After one night at rt with stirring, the mixture was diluted with EtOAc and washed with NaHCO3and brine, dried over MgSO4,filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product20 as a white solid (938 mg, 88%). MS (ESI+) m / z [M+H]+ =466. HRMS-ESI+ (m / z):calculated for C29H27N3O3[M+H]+= 466.2131 ; found: 466.2090 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.36 (s, 1H), 8.37 (br s, 1H),8.21-8.18 (m, 1H), 7.87-7.73 (m, 3H), 7.52-7.43 (m, 2H), 7.37-7.13 (m, 8H), 5.07 (s, 0.5H), 4.96 (s, 0.5H), 4.88-4.84 (m, 0.5H), 4.58 (br s, 0.5H), 3.66 (s, 2H), 3.56-3.37 (m, 25 2H), 3.25-3.06 (m, 3H), 2.88 (br s, 0.5H), 2.74-2.72 (m, 1H), 2.41-2.38 (m, 0.5H). EXAMPLE 16 lithium;1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2- carboxylate step 4. Methyl 1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate (5030 mg, 0.11 mmol, 1.0 eq.) was solubilized in a 3:1 (v / v) mixture of MeOH / H2O (500 µL). Lithium;hydroxide;hydrate (14 mg, 0.32 mmol, 3.0 eq) was added. The reaction mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (30 mg, 61%). MS (ESI+): m / z = 452 [M+H]+, 43 MS (ESI-): m / z = 450 [M-H]-. HRMS-ESI+ (m / z): calcd for C28H26N3O3 [M+H]+: 452.1974; found: 452.1965 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.31 (s, 0.5H), 9.30 (s, 0.5H),8.60-8.27 (m, 1H), 8.15 (d, J = 8.0Hz, 1H), 7.80 (t, J = 7.5Hz, 1H), 7.75-7.62 (m,5 1H+0.5H), 7.46 (d, J = 7.5Hz, 1H), 7.41-7.04 (m, 9H+0.5H), 5.65 (s, 0.5H), 5.56 (s, 0.5H),4.88-4.39 (m, 0.5H), 4.33-3.74 (m, 0.5H), 3.66 (d, J = 10.0Hz, 0.5H), 3.35-2.96 (4H),2.71 (s, 0.5H), 2.44-2.22 (m, 0.5H), 2.08-1.93 (m, 0.5H). EXAMPLE 171-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxamide10 Step 1. tert-butyl 4-benzhydryl-3-carbamoyl-piperazine-1-carboxylateTert-butyl 3-carbamoylpiperazine-1-carboxylate (150 mg, 0.65 mmol, 1.0 eq.) was solubilized in dry ACN (2 mL). [bromo(phenyl)methyl]benzene (194 mg, 0.79 mmol, 1.2 eq.) and triethylamine (110 µL, 0.79 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, insoluble were filtered and solvent 15 was removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white foam (115mg, 43%). MS (ESI+): m / z = 396 [M+H]+Step 2.1-benzhydrylpiperazine-2-carboxamide;dihydrochloride Tert-butyl 4-benzhydryl-3-carbamoyl-piperazine-1-carboxylate (115 mg, 0.28 mmol, 1.0 20 eq.) was solubilized in a 4M HCl solution in dioxane (1.5 mL, 6.0 mmol, 21.5 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to afford the crude product as an off-white solid (108 mg, quant.). MS (ESI+): m / z = 296 [M + H]+. Step 3.1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxamide 1-benzhydrylpiperazine-2-carboxamide;dihydrochloride (60 mg, 0.28 mmol, 1.0 eq.) was 25 solubilized in dry DMF (1.5 mL) under inert atmosphere. Isoquinoline-4-carboxylic acid (60 mg, 0.33 mmol, 1.2 eq.), N,N-Diisopropylethylamine (190 µL, 1.11 mmol, 4.0 eq.) and HBTU (130 mg, 0.33 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3was added and the product was extracted with EtOAc. The organic layer was washed with a saturated aqueous solution 30 of NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (90 mg, 69%). MS (ESI+): m / z = 451 [M+H]+,HRMS-ESI+ (m / z): calcd for C28H27N4O2 [M+H]+: 451.2134; found: 451.2142 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.24 (s, 1H), 8.63-8.34 (m, 1H),35 8.07-7.89 (m, 1H+0.5H), 7.83-7.69 (m, 1H+0.5H), 7.63 (t, J = 8.0 Hz, 1H), 7.47-7.36 (m, 44 4H), 7.36-7.13 (m, 6H), 6.89 (br s, 0.5H), 6.55 (br s, 0.5H), 6.38-5.65 (m, 1H), 5.25 (s, 0.5H), 5.16 (s, 0.5H), 5.05-4.65 (m, 0.5H), 4.16 (d, J = 13.5 Hz, 0.5H), 3.87-3.51 (m,2H+0.5H), 3.48-3.13 (m, 2H), 3.13-2.93 (m, 0.5H), 2.81 (d, J = 13.5 Hz, 0.5H), 2.47 (d,J = 12.3 Hz, 0.5H).5 EXAMPLE 18 (2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)-N-methyl-piperazine- 2-carboxamide Step 4. Sodium;(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate 10 To a solution of methyl (2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2- carboxylate (250 mg, 0.54 mmol, 1.0 eq.) in THF (4 mL), was added NaOH (25.8 mg,0.64 mmol, 1.2 eq.) in water (1 mL). The mixture was stirred 3 days at 55°C. The aqueous layer was extracted with ethyl acetate three times. Organics layers was mixed, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product15 as a white solid (236 mg, 93%). MS (ESI-) m / z =425 [M-H]-.Step 5. (2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)-N-methyl-piperazine-2-carboxamide Sodium;(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate (80 mg, 0.17 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under argon. N,N- 20 Diisopropylethylamine (150 µL, 0.85 mmol, 5.0 eq.), methanamine;hydrochloride (11.4 mg, 0.17 mmol, 1.0 eq.) and HBTU (70.3 mg, 0.19 mmol, 1.1 eq.) were added. After one night at room temp. the mixture was diluted with EtOAc and washed with NaOH 1N solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:125 to 0:1) to afford the desired product as a white solid (41 mg, 52%). MS (ESI+) m / z [M+H]+=465. HRMS-ESI+ (m / z): calculated for C29H29N4O2[M+H]+= 465.2291 ; found: 465.2298 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.33 (s, 1H), 8.35 (s, 1H),8.19-8.16 (m, 1H), 7.93-7.71 (m, 3H + 0.7H), 7.53-7.44 (m, 4H), 7.31-7.13 (m, 6H), 5.20- 5.13 (m, 1H), 4.69-4.21 (m, 1H), 3.45 (br s, 1H + 0.7H), 3.30-2.98 (m, 3H + 0.4H), 2.73-30 2.54 (m, 3H), 2.30-2.08 (m, 1H). EXAMPLE 19 (2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)-N,N-dimethyl- piperazine-2-carboxamide Step 5. Sodium;(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate35 (50 mg, 0.11 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere. 45 N,N-Diisopropylethylamine (55 µL, 0.32 mmol, 3.0 eq.), N-methylmethanamine 2M in THF (53 µL, 0.11 mmol, 1.0 eq.) and HBTU (48.1 mg, 0.13 mmol, 1.2 eq.) were added. After one night at room temp. the mixture was diluted with EtOAc and washed with NaOH 1N solution and brine, dried over MgSO4, filtered and concentrated under reduced 5 pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (32 mg, 63%). MS(ESI+) m / z =479 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H31N4O2 m / z=479.2447, found m / z= 479.2427. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.32 (s, 1H), 8.37-8.16 (m,10 2H), 8.08-7.71 (m, 3H), 7.52-7.44 (m, 2H), 7.34-7.10 (m, 8H), 4.86-4.81 (m, 1H), 4.56- 4.52 (m, 1H), 3.81-3.42 (m, 3H), 3.23-3.14 (m, 2H), 2.80-2.59 (m, 3H), 2.26 (s, 2H), 1.90- 1.55 (m, 2H). EXAMPLE 20 [(3R)-4-benzhydryl-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperazin-1-yl]- 15 (4-isoquinolyl)methanone Step 1. Sodium;(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate(1 eq., 0.21 mmol, 100 mg), N'-hydroxyacetamidine (1 eq., 0.21 mmol, 15.6 mg) were solubilized in dry ethyl acetate (0.8 mL) with triethylamine (3 eq., 0.64 mmol, 88 µL) and T3P (1.75 eq., 0.37 mmol, 0.5 mL of T3P 50% in ethyl acetate). The mixture was heated 20 at 85°C. After 1 day, 3 equiv. of TEA and and 1.75 equiv. of T3P were added. After 2 days, the crude product has been diluted with ethyl acetate and washed 3 times with NaOH (1M) solution. The combined organic layer was washed with brine, dried over MgSO4and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product25 as a white solid (17 mg, 16%). MS (ESI+) m / z =490 [M+H]+. HRMS (TOF, ES+) m / z[M+H]+: calcd. for C30H28N5O2m / z= 490.2243, found 490.2249. 1H NMR (500 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.35-9.31 (m, 1H), 8.44-8.41 (m, 1H), 8.19 (d, J = 7.3 Hz, 1H), 7.85 (t, J = 7.3 Hz, 1H), 7.76-7.73 (m, 1H), 7.51(d, J = 6.8 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.36-7.12 (m, 9H), 4.83 (br s, 1H), 4.69 (br30 s, 1H), 4.46-4.13 (m, 1H), 3.94-3.37 (m, 2H), 3.30-3.28 (m, 1H), 3.22-2.90 (m, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.53 (br s, 1H), 2.45-2.17 (m, 2H).EXAMPLE 21 [(3S)-4-benzhydryl-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperazin-1-yl]- (4-isoquinolyl)methanone 46 Step 1. Sodium;(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate(1 eq., 0.11 mmol, 50 mg), N'-hydroxyacetamidine (1.2 eq., 0.13 mmol, 9.4 mg) were solubilized in dry DMF (0.36 mL) with DIEA (3 eq., 0.32 mmol, 54 µL) and T3P (2.5 eq., 0.26 mmol, 0.37 mL of T3P 50% in ethyl acetate). The mixture was heated at 85°C. After 5 1 day, 3 equiv. of DIEA and 2.5 equiv. of T3P were added. After 2 days, the crude product has been diluted with ethyl acetate and washed 3 times with NaOH 1N solution. The combined organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1 with 5% pH=3.8 buffer solution) to afford the10 desired product as a white solid (16.3 mg, 32%). MS (ESI+) m / z =490 [M+H]+. HRMS(TOF, ES+) m / z [M+H]+: calcd. for C30H27N5O2 m / z= 490.2243, found m / z= 490.2220. 1H NMR (500 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.27-9.24 (m, 1H), 8.65-8.22(m, 1H + 0.5H), 8.04-7.99 (m, 1H), 7.84-7.65 (m, 3H), 7.50-7.49 (m, 1H), 7.41-7.29 (m, 5H + 0.5H), 7.25-7.10 (m, 5H), 5.10-4.79 (m, 1H + 0.5H), 4.56-4.47 (m, 1H), 4.07-3.83 15 (m, 1H), 3.64-3.27 (m, 3H), 3.02-2.91 (m, 1H), 2.77-2.72 (m, 0.5H), 2.59-2.52 (m, 3H), 2.15 (s, 0.5H). EXAMPLE 22 [(3R)-4-benzhydryl-3-(5-methyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl]- (4-isoquinolyl)methanone20 Step 2. Sodium;(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate(1 eq., 0.15 mmol, 70 mg), acetohydrazide (1.20 eq., 0.18 mmol, 13.1 mg) were solubilized in dry DMF (0.5 mL) with DIEA (2.5 eq., 0.37 mmol, 63 µL) and T3P (2.5 eq., 0.37 mmol, 0.5 mL of 50% in mass T3P solution in ethyl acetate). The mixture was heated at 85°C. After 1 day, 2.5 equivalents of DIEA and T3P were added and the25 reaction temperature was brought up to 110°C. After 2 days, the crude product was diluted with ethyl acetate and washed three times with NaOH 1N solution. The organic phase was then washed with brine, dried over MgSO4and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (20.2 mg, 28%). MS30 (ESI+) m / z = 490 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H28N5O2 m / z=490.2243, found m / z= 490.2238. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.26-9.23 (m, 1H), 8.39 (br s,1H), 8.07-7.53 (m, 4H), 7.44-7.11 (m, 10H), 4.93-4.68 (m, 2H), 4.40-4.01 (m, 1H), 3.87- 2.77 (m, 5H), 2.52-2.46 (m, 2.5H), 1.89 (br s, 0.5H). 35 47 EXAMPLE 23 [(3S)-4-benzhydryl-3-(5-methyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl]- (4-isoquinolyl)methanone Step 2. Sodium;(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carboxylate(1 eq., 0.16 mmol, 75 mg), acetohydrazide (1.20 eq., 0.19 mmol, 14.1 mg) were 5 solubilized in dry DMF (0.54 mL) with DIEA (2.5 eq., 0.40 mmol, 68 µL) and T3P (2.5 eq., 0.40 mmol, 0.55 mL of 50% in mass T3P solution in ethyl acetate). The mixture was heated at 85°C. After 1 day, 2.5 equivalents of DIEA and T3P were added and the reaction temperature was brought up to 110°C. After 2 days, the crude product was diluted with ethyl acetate and washed three times with NaOH 1N solution. The organic10 phase was then washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (28 mg, 36%). MS (ESI+) m / z = 490 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H28N5O2 m / z=490.2243, found m / z= 490.2245.15 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.26-9.23 (m, 1H), 8.39 (br s,1H), 8.10-7.67 (m, 4H), 7.55-7.11 (m, 10H), 4.93-4.68 (m, 2H), 4.40-4.01 (m, 1H), 3.78- 3.34 (m, 3H), 3.21-2.85 (m, 1H), 2.53-2.46 (m, 3H), 2.13 (br s, 1H), 1.89 (br s, 1H). EXAMPLE 24 methyl 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-20 yl]acetate Step 1. tert-butyl 4-benzhydryl-3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate Tert-butyl 3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate;hydrochloride (150 mg, 0.51 mmol, 1.0 eq.) was solubilized in dry ACN (2 mL). [bromo(phenyl)methyl]benzene (150 mg, 0.61 mmol, 1.2 eq.) and triethylamine (156 µL, 2.12 mmol, 2.2 eq.) were added. 25 The reaction mixture was heated at 50°C for 3 hours. Upon completion, insoluble were filtered and solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (65 mg, 30%). MS (ESI+): m / z = 425 [M+H]+. Step 2. methyl 2-(1-benzhydrylpiperazin-2-yl)acetate dihydrochloride 30 Tert-butyl 4-benzhydryl-3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate (65 mg, 0.15 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (1 mL, 4.0 mmol, 26.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the crude product as a beige solid (60 mg, quant.). MS (ESI+): m / z = 325 [M + H]+. 35 Step 3. methyl 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate 48 Methyl 2-(1-benzhydrylpiperazin-2-yl)acetate;dihydrochloride (60 mg, 0.15 mmol, 1.0 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. Isoquinoline-4-carboxylic acid (31 mg, 0.18 mmol, 1.2 eq.), N,N-Diisopropylethylamine (100 µL, 0.60 mmol, 4.0 eq.), and HBTU (70 mg, 0.18 mmol, 1.2 eq.) were added. The mixture was stirred at rt 5 overnight. A saturated aqueous solution of NaHCO3 was addedand the product was extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (63 mg, 86%). MS 10 (ESI+): m / z = 480 [M+H]+, HRMS-ESI+ (m / z): calcd for C30H30N3O3 [M+H]+: 480.2287; found: 480.2264. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.23 (s, 1H), 8.55-8.35 (m, 1H),8.04-7.89 (m, 1H+0.3H), 7.83-7.61 (m, 2H+0.7H), 7.50-7.33 (m, 4H), 7.33-7.23 (m, 2H), 7.23-7.10 (m, 4H), 4.76-4.57 (m, 2H), 3.71-3.51 (m, 2.4H), 3.51-3.29 (m, 1.9H), 3.29-15 3.10 (m, 2H), 2.86-2.66 (m, 2H), 2.65-2.35 (m, 2H+0.7H). EXAMPLE 25 ethyl 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2- yl]acetate Step 1. tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-20 carboxylate Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (1.0 g, 3.49 mmol, 1.0 eq.) was solubilized in dry ACN (13 mL). [bromo(phenyl)methyl]benzene (1.03 g, 4.19 mmol, 1.2 eq.) and triethylamine (580 µL, 4.19 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for one day. The crude product was purified by reverse25 phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a yellowoil (900 mg, 59%). MS (ESI+): m / z = 439 [M+H]+.Step 2. Synthesis of ethyl 2-[(2R)-1-benzhydrylpiperazin-2- yl]acetate;dihydrochloride Tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (150 mg, 30 0.34 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (1.5 mL, 6.0 mmol, 18.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the crude product as an off-white solid (141 mg, quant.). MS (ESI+): m / z = 339 [M + H]+. Step 3. ethyl 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-35 yl]acetate 49 Isoquinoline-4-carboxylic acid (20 mg, 0.11 mmol, 1.2 eq.) was solubilized in dry DMF (400 µL) under inert atmosphere. N,N-Diisopropylethylamine (66 µL, 0.38 mmol, 4.0 eq.) and ethyl 2-[(2R)-1-benzhydrylpiperazin-2-yl]acetate;dihydrochloride (40 mg, 0.10 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and HBTU (43 mg, 0.11 5mmol, 1.2 eq.) was added. The reaction mixture was stirred at rt overnight. A 1Maqueous solution of NaOH was added theproduct was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired 10 product as a white solid (37 mg, 79%). MS (ESI+): m / z = 494 [M + H]+, HRMS-ESI+ (m / z): calcd for C31H32N3O3 [M+H]+: 494.2444; found: 494.2441. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers : 9.27-9.24 (m, 1H), 8.51-8.34(m, 1H), 8.15-8.02 (m, 1H), 8.02-7.75 (m, 2H), 7.75-7.66 (m, 1H), 7.55-7.39 (m, 4H), 7.35-7.10 (m, 6H), 4.82-4.67 (m, 1H), 4.59 (d, J = 12.5Hz, 1H), 4.08 (q, J = 6.8Hz, 1H),15 3.78 (br s, 0.5H), 3.64-2.88 (m, 4.5H), 2.75-2.64 (m, 1.5H), 2.59 (dt, J = 12.3Hz, 3.5Hz,1H), 2.52-2.24 (m, 1.5H), 1.18 (t, J = 6.8Hz, 1.4H), 1.06 (br s, 0.8H), 0.65 (br s, 0.8H).EXAMPLE 26 ethyl 2-[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-20 yl]acetate Step 1. tert-butyl (3S)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1- carboxylate Tert-butyl (3S)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (400 mg, 1.40 mmol, 1.0 eq.) was solubilized in dry ACN (13 mL). [bromo(phenyl)methyl]benzene (415 mg, 25 1.67 mmol, 1.2 eq.) and triethylamine (230 µL, 1.67 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for one day. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as ayellow oil (300 mg, 49%). MS (ESI+): m / z = 439 [M+H]+Step 2. ethyl 2-[(2S)-1-benzhydrylpiperazin-2-yl]acetate;dihydrochloride 30 Tert-butyl (3S)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (150 mg, 0.34 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (1.5 mL, 6.0 mmol, 18.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the crude product as an off-white solid (140 mg, quant.). MS (ESI+): m / z = 339 [M + H]+ 50 Step 3. ethyl 2-[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2- yl]acetate Isoquinoline-4-carboxylic acid (20 mg, 0.11 mmol, 1.2 eq.) was solubilized in dry DMF (400 µL) under inert atmosphere. N,N-Diisopropylethylamine (66 µL, 0.38 mmol, 4.0 eq.) 5 and ethyl 2-[(2S)-1-benzhydrylpiperazin-2-yl]acetate;dihydrochloride (40 mg, 0.10 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and HBTU (43 mg, 0.11 mmol, 1.2 eq.) was added. The reaction mixture was stirred at rt overnight. A 1Maqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried 10 over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (32 mg, 66%). MS (ESI+): m / z = 494 [M+H]+, HRMS-ESI+ (m / z):calcd for C31H32N3O3[M+H]+: 494.2444; found: 494.2426 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.27-9.24 (m, 1H), 8.50-8.3515 (m, 1H), 8.14-8.04 (m, 1H), 8.02-7.76 (m, 2H), 7.76-7.65 (m, 1H), 7.55-7.39 (m, 4H), 7.36-7.10 (m, 6H), 4.80-4.67 (m, 1H), 4.60 (d, J = 12.5Hz, 1H), 4.14-3.97 (m, 1H), 3.79(br s, 0.5H), 3.65-2.90 (m, 4.5H), 2.78-2.64 (m, 1.5H), 2.58 (dt, J = 12.0Hz, 3.5Hz, 1H),2.52-2.22 (m, 1.5H), 1.19 (t, J = 6.8Hz, 1.4H), 1.06 (br s, 0.8H), 0.65 (br s, 0.8H).20 Example 27 [4-benzhydryl-3-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl]- (4-isoquinolyl)methanone Step 2. Sodium 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (1 eq., 0.10 mmol, 50 mg), acetohydrazide (1.20 eq., 0.12 mmol, 9.1 mg) were solubilized in dry DMF (0.4 mL) with DIEA (2.5 eq., 0.26 mmol, 44 µL) and T3P (2.5 eq., 0.27 mmol, 0.36 25 mL of 50% in mass T3P solution in ethyl acetate). The mixture was heated at 85°C. After 1 day, 2.5 equivalents of DIEA and T3P were added and the reaction temperature was brought up to 110°C. After 2 days, the crude product was extracted with ethyl acetate and washed three times with NaOH 1N solution. The organic phase was then rinced with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product 30 was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (18.7 mg, 36%). MS (ESI+) m / z [M+H]+ =504. HRMS(TOF, ES+) m / z [M+H]+: calcd. for C31H30N5O2 m / z= 504.2400, found m / z= 504.2419. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.28-9.20 (m, 1H), 8.51-8.35(m, 1H), 8.12-7.72 (m, 4H), 7.50-7.41 (m, 4H), 7.33-7.13 (m, 6H), 4.87 (br s, 1H), 4.59- 51 4.55 (m, 1H), 3.58 (br s, 1H), 3.35-2.94 (m, 5H), 2.89-2.70 (m, 2H), 2.46-2.28 (m, 2.5H), 1.89-1.85 (m, 0.5H). Example 28 [4-benzhydryl-3-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]piperazin-1-yl]- 5 (4-isoquinolyl)methanone Step 1. Sodium 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (1 eq., 0.21 mmol, 101 mg), N'-hydroxyacetamidine (1.7 eq., 0.36 mmol, 26.3 mg) were solubilized in dry ethyl acetate (0.79 mL) with Et3N (2.5 eq., 0.52 mmol, 75 µL) and T3P (1.75 eq., 0.36 mmol, 0.50 mL of T3P 50% in ethyl acetate). The mixture was heated at 10 85°C. After 1 day, 2.5 and 1.75 equivalents of Et3N and T3P were added. After 2 days, the crude product has been diluted with ethyl acetate and washed 3 times with NaOH 1N solution. The combined organic layer was washed with brine, dried over MgSO4and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid 15 (16.0 mg, 15%). MS (ESI+) m / z [M+H]+= 504. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C31H30N5O2 m / z= 504.2400, found m / z= 504.2401. 1H NMR (500 MHz, CDCl3) δ (ppm)Mixture of rotamers: 9.25 (s, 0.4H), 9.20 (s, 0.6H), 8.52-8.38 (m, 1H), 8.02-7.59 (m, 4H), 7.43-7.41 (m, 1H), 7.31-7.28 (m, 4H), 7.24-7.10 (m, 5H), 4.74-4.70 (m, 2H), 3.81-3.58 (m, 1H), 3.44-3.10 (m, 4H), 2.98-2.53 (m, 3H), 2.35 (s, 1H), 2.13 (s, 1H), 1.78 (s, 1H).20 Example 29 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl- acetamide Step 5. Sodium 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (59.6 mg, 0.11 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under argon. N,N- 25 Diisopropylethylamine (95 µL, 0.54 mmol, 5.0 eq.), methanamine;hydrochloride (7.4 mg, 0.11 mmol, 1.0 eq.) and HBTU (45.4 mg, 0.12 mmol, 1.1 eq.) were added. After one night at rt, the mixture was diluted with EtOAc and washed with NaOH and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the30 desired product as a white solid (32.7 mg, 63%).MS (ESI+) m / z =479 [M+H]+. HRMS-ESI+ (m / z): calculated for C30H31N4O2 [M+H]+= 479.2447 ; found: 479.2432 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.35-9.31 (m, 1H), 8.56-8.47 (m, 1H), 8.21-8.16 (m, 1H), 7.85-7.71 (m, 3H+0.7H), 7.49-7.41 (m, 4H), 7.32-7.10 (m, 6H), 4.83-4.77 (m, 1H), 4.51-4.36 (m, 1H), 3.53-3.38 (m, 1H), 3.28-3.03 (m, 3H), 35 2.85-2.56 (m, 3H), 2.44-2.24 (m, 3H+0.5H), 1.69 (br s, 0.5H). 52 Example 30 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N- methyl-acetamide Step 1. tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1- 5 carboxylate Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (1.0 g, 3.49 mmol, 1.0 eq.) was solubilized in dry ACN (13 mL). [bromo(phenyl)methyl]benzene (1.03 g, 4.19 mmol, 1.2 eq.) and triethylamine (580 µL, 4.19 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for one day. The crude product was purified by reverse 10 phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a yellow oil (900 mg, 59%). MS (ESI+): m / z = 439 [M+H]+.Step 2. Lithium;2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetate Tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (750 mg, 1.68 mmol, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of MeOH / H2O (5 mL). 15 Lithium;hydroxide;hydrate (210 mg, 5.03 mmol, 3.0 eq.) was added. The reaction mixture was stirred at rt for 3 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as an off-white solid (600 mg, 77%). MS (ESI+): m / z = 411 [M+H]+. Step 3. tert-butyl (3R)-4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-20 carboxylate Lithium;2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetate (600 mg, 1.30 mmol, 1.0 eq.) was solubilized in dry DMF (4 mL) under inert atmosphere. N,N- Diisopropylethylamine (560 µL, 3.24 mmol, 2.50 eq.), methanamine;hydrochloride (175 mg, 2.59 mmol, 2.0 eq.) and HBTU (590 mg, 1.56 mmol, 1.20 eq.) were added. The 25 mixture was stirred at rt for 2 hours. A 1M aqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a yellow oil (340 mg, 61%). MS30 (ESI+): m / z = 424 [M+H]+. Step 4.2-[(2R)-(1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride Tert-butyl (3R)-4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate (335 mg, 0.78 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (4.0 mL, 16.0 mmol, 20.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under 53 reduced pressure to give the crude product as an off-white solid (320 mg, quant.). MS (ESI+): m / z = 324 [M + H]+. Step 5. 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl- acetamide 5 Isoquinoline-4-carboxylic acid (26 mg, 0.15 mmol, 1.2 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N-Diisopropylethylamine (87 µL, 0.50 mmol, 4.0 eq.) and 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (50 mg, 0.13 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and HBTU (57 mg, 0.15 mmol, 1.2 eq.) was added. The reaction mixture was stirred at rt overnight. A10 1M aqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (34 mg, 56%). MS (ESI+): m / z = 479 [M + H]+. HRMS-15 ESI+ (m / z): calcd for C30H31N4O2[M+H]+: 479.2447; found: 479.2447 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.28-9.24 (m, 1H), 8.63-8.28(m, 1H), 8.19-8.03 (m, 1H), 8.02-7.76 (m, 2H), 7.76-7.64 (m, 1H), 7.57-7.37 (m, 4H), 7.36-7.07 (m, 6H), 6.85-5.42 (m, 1H), 4.72 (d, J = 7.2Hz, 1H), 4.57 (br d, J = 12.6Hz,1H), 3.63-3.00 (m, 4H), 2.79-2.51 (m, 3H), 2.51-2.28 (m, 3H), 1.77 (br s, 1H). 20 Example 31 2-[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N- methyl-acetamide Step 1. tert-butyl (3S)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1- carboxylate 25 Tert-butyl (3S)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (400 mg, 1.40 mmol, 1.0 eq.) was solubilized in dry ACN (13 mL). [bromo(phenyl)methyl]benzene (415 mg, 1.67 mmol, 1.2 eq.) and triethylamine (230 µL, 1.67 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for one day. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a30 yellow oil (300 mg, 49%). MS (ESI+): m / z = 439 [M+H]+Step 2. lithium;2-[(2S)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetateTert-tert-butyl (3S)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (150 mg, 0.34 mmol, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of MeOH / H2O (1 mL). Lithium;hydroxide;hydrate (45 mg, 1.02 mmol, 3.0 eq.) was added. The reaction mixture 35 was stirred at rt for 3 hours. The mixture was concentrated and the residue was purified 54 by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as an off-white solid (100 mg, 70%). MS (ESI+): m / z = 411 [M+H]+Step 3. tert-butyl (3S)-4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate 5 Lithium;2-[(2S)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetate (100 mg, 0.24 mmol, 1.0 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N- Diisopropylethylamine (100 µL, 0.60 mmol, 2.50 eq.), methanamine;hydrochloride (32 mg, 0.48 mmol, 2.0 eq.) and HBTU (110 mg, 0.29 mmol, 1.20 eq.) were added. The mixture was stirred at rt for 2 hours. A 1M aqueous solution of NaOH was added and the 10 product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (61 mg, 60%). MS(ESI+): m / z = 424 [M+H]+15 Step 4.2-[(2R)-(1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide dihydrochlorideTert-butyl (3S)-4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate (60 mg, 0.14 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (500 µL, 2.0 mmol, 14.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the crude product as a white solid (56.5 mg, quant.). MS (ESI+): 20 m / z = 324 [M + H]+Step 5. 2-[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide Isoquinoline-4-carboxylic acid (13 mg, 0.08 mmol, 1.2 eq.) was solubilized in dry DMF (250 µL) under inert atmosphere. N,N-Diisopropylethylamine (45 µL, 0.25 mmol, 4.0 eq.) 25 and 2-[(2S)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (25 mg, 0.06 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and HBTU (30 mg, 0.08 mmol, 1.2 eq.) was added. The reaction mixture was stirred at rt overnight. A1M aqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine,30 dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (23 mg, 75%). MS (ESI+): m / z = 479 [M + H]+. HRMS- ESI+ (m / z): calcd for C30H31N4O2 [M+H]+: 479.2447; found: 479.2449. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.28-9.24 (m, 1H), 8.57-8.3035 (m, 1H), 8.15-8.04 (m, 1H), 8.03-7.77 (m, 2H), 7.77-7.66 (m, 1H), 7.55-7.41 (m, 4H), 55 7.35-7.10 (m, 6H), 6.80-5.42 (m, 1H), 4.73 (d, J = 7.2Hz, 1H), 4.57 (br d, J = 12.6Hz,1H), 3.63-3.02 (m, 4H), 2.74-2.51 (m, 3H), 2.51-2.27 (m, 3H), 1.77 (br s, 1H). Example 32 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N,N- 5 dimethyl-acetamide step 5. Sodium; 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (62.7mg, 0.11 mmol, 1.0 eq.) was solubilized in dry DMF (0.3 mL) under inert atmosphere. N,N-Diisopropylethylamine (100 µL, 0.57 mmol, 5.0 eq.), N-methylmethanamine (8.0 mg, 0.18 mmol, 1.5 eq.) and HBTU (49.7 mg, 0.13 mmol, 1.1 eq.) were added. After one 10 night at, the mixture was diluted with EtOAc and washed with NaOH 1N solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (25.4 mg, 45%).MS (ESI+) m / z [M+H]+ =493.HRMS-ESI+ (m / z): calculated for C30H33N4O2[M+H]+= 493.2604 ; found: 493.260415 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.36 (m, 1H), 8.50-8.27 (m,1H), 8.21-8.15 (m, 1H), 7.85-7.73 (m, 3H), 7.50-7.41 (m, 4H), 7.32-7.08 (m, 6H), 4.86 (s, 1H), 4.52-4.42 (m, 1H), 3.46 (br s, 1H), 3.26-3.05 (m, 5H), 2.97-2.52 (m, 5H+0.5H), 2.41- 2.27 (m, 1H+0.5H), 1.86 (br s, 1H). 20 Example 33 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-(2- methoxyethyl)acetamide Lithium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (50 mg, 0.11 mmol, 1.0 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. 2- methoxyethanamine (22 µL, 0.25 mmol, 1.2 eq.), N,N-Diisopropylethylamine (54 µL, 1.0 25 mmol, 3.0 eq.) and HBTU (48 mg, 0.13 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with 1M aqueous solution of NaOH. The combined organic layers were dried over MgSO4, filteredand concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (1830 mg, 33%). MS (ESI+): m / z = 523 [M+H]+. HRMS-ESI+ (m / z): calcd for C32H35N4O3[M+H]+: 523.2709; found: 523.2714. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.33-9.20 (m, 1H), 8.61-8.30(m, 1H), 8.15-8.05 (m, 1H), 8.02-7.76 (m, 2H), 7.76-7.66 (m, 1H), 7.55-7.41 (m, 4H), 7.36-7.10 (m, 6H), 6.94-5.73 (m, 1H), 4.76 (s, 1H), 4.64-4.49 (m, 1H), 3.64-3.35 (m, 3H),35 3.35-2.96 (m, 8H), 2.75-2.32 (m, 4H). 56 Example 34 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-(2- methoxyethoxy)ethyl]acetamide Lithium 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (75 mg, 0.16 5 mmol, 1.0 eq.) was solubilized in dry DMF (750 µL) under inert atmosphere. 2-[2-(2- methoxyethoxy)ethoxy]ethanamine (60 µL, 0.48 mmol, 3.0 eq.), N,N- Diisopropylethylamine (41 µL, 0.24 mmol, 1.5 eq.) and HBTU (90 mg, 0.24 mmol, 1.5 eq.) were added. The mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with 1M aqueous solution of NaOH. The combined organic 10 layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (49 mg, 55%). MS (ESI+): m / z = 567 [M+H]+. HRMS- ESI+ (m / z): calcd for C34H39N4O4[M+H]+: 567.2971; found: 523.2985. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.33-9.22 (m, 1H), 8.61-8.3315 (m, 1H), 8.15-8.03 (m, 1H), 8.03-7.76 (m, 2H), 7.76-7.65 (m, 1H), 7.57-7.39 (m, 4H), 7.37-7.08 (m, 6H), 7.06-5.84 (m, 1H), 4.74 (s, 1H), 4.66-4.50 (m, 1H), 3.66-3.49 (m, 2H), 3.49-3.39 (m, 4H), 3.39-3.24 (m, 5H), 3.24-2.91 (m, 3H), 2.74-2.55 (m, 1H), 2.55-2.29 (m, 3H). 20 Example 35 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-[2-(2- methoxyethoxy)ethoxy]ethyl]acetamide Lithium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (75 mg, 0.16 mmol, 1.0 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. 2-[2-(2- methoxyethoxy)ethoxy]ethanamine (80 µL, 0.48 mmol, 3.0 eq.), N,N-25 Diisopropylethylamine (41 µL, 0.24 mmol, 1.5 eq.) and HBTU (90 mg, 0.24 mmol, 1.5 eq.) were added. The mixture was stirred at rt overnight. The reaction mixture was dilutedwith EtOAc and washed with 1M aqueous solution of NaOH. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Theresidue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford30 the desired product as a white solid (45 mg, 46%). MS (ESI+): m / z = 611 [M+H]+. HRMS- ESI+ (m / z): calcd for C36H43N4O5 [M+H]+: 611.3233; found: 611.3257. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.33-9.20 (m, 1H), 8.64-8.31(m, 1H), 8.16-8.04 (m, 1H), 8.04-7.76 (m, 2H), 7.76-7.64 (m, 1H), 7.55-7.38 (m, 4H), 7.38-7.08 (m, 6H), 7.06-5.82 (m, 1H), 4.74 (s, 1H), 4.58 (t, J = 12.5Hz, 1H), 3.61-3.3835 (m, 10H), 3.38-3.24 (m, 5H), 3.24-2.92 (m, 3H), 2.75-2.56 (m, 1H), 2.56-2.27 (m, 4H). 57 Example 36 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-[2-[2- [2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]acetamide Sodium 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (75.1 mg, 5 0.16 mmol, 1.0 eq.) was solubilized in dry DMF (0.4 mL) under inert atmosphere. N,N- Diisopropylethylamine (54 µL, 0.31 mmol, 2.0 eq.), mPEG5-NH2 (116 mg, 0.47 mmol, 3.0 eq.) and HBTU (70.0 mg, 0.19 mmol, 1.2 eq.) were added. After one night at rt, the mixture was diluted with EtOAc and washed with NaOH and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by 10 reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (9.0 mg, 8%). MS (ESI+) m / z =699 [M+H]+. HRMS (TOF, ES+) m / z[M+H]+: calcd. for C40H51N4O7m / z= 699.3758, found m / z= 699.3737. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.28 (s, 0.5H), 9.24 (s, 0.5H),8.53 (br s, 0.3H), 8.41 (br s, 0.7H), 8.13-8.07 (m, 1H), 7.91-7.68 (m, 3H), 7.52-7.43 (m,15 4H), 7.33-7.11 (m, 6H), 6.92 (br s, 0.5H), 4.76 (s, 1H), 4.57 (t, J = 12 Hz, 1H), 3.57-3.43(m, 17H), 3.31-3.05 (m, 8H), 2.83-2.36 (m, 6H). Example 37 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-[2-[2- [2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide 20 Sodium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (82.9 mg, 0.17 mmol, 1.0 eq.) was solubilized in dry DMF (0.4 mL) under inert atmosphere. N,N- Diisopropylethylamine (59 µL, 0.34 mmol, 2.0 eq.), mPEG7-NH2(118 mg, 0.35 mmol, 2.0 eq.) and HBTU (70.0 mg, 0.19 mmol, 1.1 eq.) were added. After one night at rt, the mixture was diluted with EtOAc and washed with NaOH and brine, dried over MgSO4, 25 filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (17.1 mg, 13%). MS (ESI+) m / z =787 [M+H]+. HRMS (TOF, ES+) m / z[M+H]+: calcd. for C44H59N4O9m / z= 787.4282, found m / z= 787.4282. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.28 (s, 0.5H), 9.24 (s, 0.5H),30 8.53 (br s, 0.4H), 8.40 (br s, 0.7H), 8.13-8.07 (m, 1H), 7.84-7.68 (m, 3H), 7.52-7.44 (m, 4H), 7.33-7.13 (m, 6H), 4.76 (s, 1H), 4.61-4.53 (m, 1H), 3.57-3.05 (m, 34H), 2.72-2.36 (m, 5H). Example 38 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-[2-[2-35 [2-[2-[2-[2-[2-(2- 58 methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]aceta mide Sodium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (72.1 mg, 0.15 mmol, 1.0 eq.) was solubilized in dry DMF (0.4 mL) under inert atmosphere. N,N- 5 Diisopropylethylamine (54 µL, 0.30 mmol, 2.0 eq.), mPEG9-NH2 (65.8 mg, 0.15 mmol, 1.0 eq.) and HBTU (70.0 mg, 0.19 mmol, 1.3 eq.) were added. After one night at rt, the mixture was diluted with EtOAc and washed with NaOH and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product10 as a white solid (16 mg, 12%).MS (ESI+) m / z =876 [M+H]+. HRMS (TOF, ES+) m / z[M+H]+: calcd. for C48H67N4O11 m / z= 875.4806, found m / z= 875.4801. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.28 (s, 0.5H), 9.24 (s, 0.5H),8.54 (br s, 0.3H), 8.41 (br s, 0.7H), 8.13-8.07 (m, 1H), 7.84-7.68 (m, 3H), 7.52-7.44 (m, 4H), 7.33-7.13 (m, 6H), 6.94-5.98 (m, 1H), 4.76 (s, 1H), 4.57 (m, 1H), 3.77-3.05 (m, 42H),15 2.72-2.35 (m, 5H). Example 39 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-[2-[2- [2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etho 20 xy]ethyl]acetamide Sodium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (75.0 mg, 0.15 mmol, 1.0 eq.) was solubilized in dry DMF (0.4 mL) under inert atmosphere. N,N- Diisopropylethylamine (54 µL, 0.31 mmol, 2.0 eq.), mPEG11-NH2(79.3 mg, 0.15 mmol, 1.0 eq.) and HBTU (70.0 mg, 0.19 mmol, 1.2 eq.) were added. After one night at rt, the 25 mixture was diluted with EtOAc and washed with NaOH and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (67.1 mg, 45%). MS (ESI+) m / z = 963 [M+H]+. HRMS (TOF, ES+) m / z[M+H]+: calcd. for C52H75N4O13 m / z= 963.5338, found: 963.5331.30 1H NMR (500 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.28 (s, 0.5H), 9.24 (s, 0.5H),8.55 (br s, 0.3H), 8.43 (br s, 0.7H), 8.13-8.07 (m, 1H), 7.84-7.67 (m, 3H), 7.52-7.43 (m, 4H), 7.30-7.13 (m, 6H), 4.74 (s, 1H), 4.61-4.54 (m, 1H), 3.76-3.09 (m, 50H), 2.71-2.34 (m, 5H). 59 Example 40 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-[2-[2- [2-[2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethyl]acetamide 5 Sodium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (54 mg, 0.111 mmol, 1 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. HBTU (52.5 mg, 0.138 mmol, 1.25 eq.), mPEG12-NH2 (64.4 mg, 0.113 mmol, 1 eq.) and N,N- Diisopropylethylamine (44.4 µL, 0.255 mmol, 2.3 eq.) were added. The resulting mixture was stirred at rt overnight and then concentrated under reduced pressure. The crude 10 product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1 with 5% HCOOH / NH4OH pH 3.8 buffer) to afford the desired product as a clear oil (81 mg, 71%). MS (ESI+): m / z =1008 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C54H79N4O14m / z= 1007.5593, found m / z= 1007.5627. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.26 (s, 0.5H), 9.22 (s, 0.4H),15 8.47 (brs, 0.7H), 8.39 (brs, 0.3H), 8.04-7.67 (m, 4H), 7.46-7.34 (m, 4H), 7.31-7.09 (m, 6H), 6.35-5.86 (m, 1H), 4.72 (s, 1H), 4.72-4.58 (m, 1H), 3.65-2.92 (m, 55H), 2.74-2.40 (m, 4H). Example 412-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-[2-[2-20 [2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2- [2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide Sodium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (43 mg, 0.0882 mmol, 1 eq.) was solubilized in dry DMF (0.53 mL) under inert atmosphere. HBTU25 (41.8 mg, 0.11 mmol, 1.25 eq.), mPEG16-NH2(66.2 mg, 0.0882 mmol, 1 eq.) and N,N- Diisopropylethylamine (35.3 µL, 0.203 mmol, 2.3 eq.) were added. The resulting mixture was stirred at rt overnight and then concentrated under reduced pressure. The crude was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1 with 5% HCOOH / NH4OH pH 3.8 buffer) to afford the desired product as a clear oil (47 mg, 45%). 30 MS (ESI+): m / z =1184 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C62H95N4O18 m / z= 1183.6641, found m / z= 1183.6675. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.35 (s, 0.5H), 9.31 (s,0.5H), 8.46 (brs, 0.3H), 8.40 (s, 0.7H), 8.21-8.16 (m, 1H), 7.98-7.75 (m, 3H), 7.49-7.42 (m, 4H), 7.32-7.12 (m, 6H), 6.85-5.32 (m, 1H), 4.85-4.81 (m, 1H), 4.48-4.44 (m, 1H),35 3.73-3.35 (m, 60H), 3.28-2.59 (m, 12H), 2.35-1.98 (m, 3H). 60 Example 42 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-(2- methoxyethyl)-N-methyl-acetamide Lithium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (75 mg, 0.16 5 mmol, 1.0 eq.) was solubilized in dry DMF (750 µL) under inert atmosphere.2-methoxy- N-methyl-ethanamine (52 µL, 0.48 mmol, 3 eq.), N,N-Diisopropylethylamine (82 µL, 0.48 mmol, 3.0 eq.) and HBTU (72 mg, 0.19 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with 1M aqueous solution of NaOH. The combined organic layers were dried over MgSO4, filtered 10 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (51 mg, 60%). MS (ESI+): m / z =537 [M+H]+. HRMS-ESI+ (m / z): calcd for C33H37N4O3[M+H]+: 537.2866; found: 537.2842. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.35-9.18 (m, 1H), 8.57-8.2815 (m, 1H), 8.16-8.07 (m, 1H), 8.00-7.75 (m, 2H), 7.75-7.62 (m, 1H), 7.58-7.36 (m, 4H), 7.36-7.08 (m, 6H), 4.85-4.65 (m, 1H), 4.65-4.48 (m, 1H), 3.73-3.31 (m, 6H), 3.31-3.00 (m, 5H), 3.00-2.78 (m, 2H), 2.78-2.53 (m, 4H), 2.37-2.28 (m, 1H). Example 43 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-(2-20 methoxyethoxy)ethyl]-N-methyl-acetamide Lithium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (75 mg, 0.16 mmol, 1.0 eq.) was solubilized in dry DMF (750 µL) under inert atmosphere. 2-[2-(2- methoxyethoxy)ethoxy]ethanamine (60 µL, 0.48 mmol, 3 eq.), N,N- Diisopropylethylamine (41 µL, 0.24 mmol, 1.5 eq.) and HBTU (90 mg, 0.24 mmol, 1.5 25 eq.) were added. The mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with 1M aqueous solution of NaOH. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (39 mg, 42%). MS (ESI+): m / z =581 [M+H]+. HRMS-30 ESI+ (m / z): calcd for C35H41N4O4 [M+H]+: 581.3128; found: 581.3151. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.31-9.20 (m, 1H), 8.56-8.28(m, 1H), 8.15-8.01 (m, 1H), 8.01-7.75 (m, 2H), 7.75-7.64 (m, 1H), 7.56-7.39 (m, 4H), 7.36-7.08 (m, 6H), 4.83-4.70 (m, 1H), 4.68-4.48 (m, 1H), 3.72-3.41 (m, 7H), 3.41-3.26 (m, 5H), 3.26-2.89 (m, 4H), 2.89-2.57 (m, 4H), 2.57-2.30 (m, 2H). 35 61 Example 44 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-[2-(2- methoxyethoxy)ethoxy]ethyl]-N-methyl-acetamide Lithium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (75 mg, 0.16 mmol, 1.0 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. 2-[2-(2- 5 methoxyethoxy)ethoxy]ethanamine (84 mg, 0.48 mmol, 3 eq.), N,N- Diisopropylethylamine (41 µL, 0.24 mmol, 1.5 eq.) and HBTU (90 mg, 0.24 mmol, 1.5 eq.) were added. The mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with 1M aqueous solution of NaOH. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The 10 residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (45 mg, 46%). MS (ESI+): m / z =451 [M+H]+. HRMS- ESI+ (m / z): calcd for C37H45N4O5[M+H]+: 625.3390; found: 625.3381. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.30-9.20 (m, 1H), 8.53-8.28(m, 1H), 8.15-8.01 (m, 1H), 8.01-7.75 (m, 2H), 7.75-7.64 (m, 1H), 7.58-7.39 (m, 4H), 15 7.34-7.09 (m, 6H), 4.82-4.71 (m, 1H), 4.67-4.49 (m, 1H), 3.72-3.39 (m, 12H), 3.39-3.21 (m, 5H), 3.21-3.02 (m, 3H), 2.89-2.58 (m, 4H), 2.58-2.30 (m, 2H). Example 45 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-1-morpholino-ethanone 20 Step 6. Sodium;2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (75 mg, 0.15 mmol, 1.0 eq.) was solubilized in dry DMF (0.4 mL) under argon. N,N- Diisopropylethylamine (54 µL, 0.31 mmol, 2.0 eq.), morpholine (27 µL, 0.31 mmol, 2.0eq.) and HBTU (70 mg, 0.19 mmol, 1.2 eq.) were added. After one night stirring at rt, the mixture was diluted with EtOAc and washed with NaOH and brine, dried over MgSO4, 25 filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (18.9 mg, 23%). MS (ESI+) m / z =535 [M+H]+. HRMS (TOF, ES+) m / z[M+H]+: calcd. for C33H35N4O3m / z= 535.2709, found m / z= 535.2709. 1H NMR (300 MHz, CD3CN) δ (ppm) Mixture of rotamers: 9.27-9.23 (m, 1H), 8.45-8.4230 (m, 1H), 8.12-8.07 (m, 1H), 7.92-7.69 (m, 3H), 7.53-7.42 (m, 4H), 7.33-7.12 (m, 6H), 4.77 (s, 1H), 4.61-4.57 (d, J = 11.2 Hz, 1H), 3.61-3.05 (m, 10H), 2.83-2.37 (m, 6H).Example 46 lithium 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2- yl]acetate 62 step 4. Methyl 2-[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate,(example 24, 30 mg, 0.06 mmol, 1.0 eq.) was solubilized in a 3:1 (v / v) mixture of MeOH / H2O (500 µL). Lithium;hydroxide;hydrate (8 mg, 0.19 mmol, 3.0 eq) was added. The reaction mixture was stirred at rt overnight. The mixture was concentrated under 5 reduced pressure and the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (22 mg, 75%). MS (ESI+): m / z = 466 [M+H]+, MS (ESI-): m / z =464 [M-H]-, HRMS-ESI+ (m / z): calcd for C29H28N3O3 [M+H]+: 466.2131; found: 466.2120. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.34 (s, 0.6H), 9.28 (s, 0.4H),10 8.41 (s, 0.6H), 8.37 (s, 0.4H), 8.23-8.12 (m, 1H), 7.91-7.79 (m, 1H+0.4H), 7.79-7.67 (m, 1H+0.6H), 7.50-7.34 (m, 4H), 7.32-7.06 (m, 6H, 4.83 (s, 1H), 4.70-4.46 (m, 0.6H), 4.46- 4.24 (m, 0.4H), 3.41-3.13 (m, 3H), 3.13-2.93 (m, 1H), 2.60-2.50 (m, 1H), 2.42-2.25 (m, 1H+0.6H), 2.25-2.09 (m, 1H+0.4H). 15 Example 471-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile step 1. tert-butyl 4-benzhydryl-3-cyano-piperazine-1-carboxylate Tert-butyl 3-cyanopiperazine-1-carboxylate (200 mg, 0.95 mmol, 1.0 eq.) was solubilized in dry ACN (3 mL). [bromo(phenyl)methyl]benzene (280 mg, 1.14 mmol, 1.2 eq.) and triethylamine (160 µL, 1.14 mmol, 1.2 eq.) were added. The reaction mixture was heated 20 at 50°C for 3 hours. Upon completion, solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white foam (175 mg, 49%). step 2.1-benzhydrylpiperazine-2-carbonitrile dihydrochloride Tert-butyl 4-benzhydryl-3-cyano-piperazine-1-carboxylate (175 mg, 0.46 mmol, 1.0 eq.) 25 was solubilized in 4M HCl in dioxanne (2 mL, 8.00 mmol, 17.0 eq). The mixture was stirred for 5 hours at rt under inert atmosphere. Solvents were removed under reduced pressure to give the crude product 1-benzhydrylpiperazine-2-carbonitrile;dihydrochloride as a pale yellow film (163 mg, quant.). MS (ESI+): m / z =278 [M + H]+. step 3.1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile 30 1-benzhydrylpiperazine-2-carbonitrile dihydrochloride (160 mg, 0.46 mmol, 1.0 eq.) was solubilized in dry DMF (1.5 mL) under argon. Isoquinoline-4-carboxylic acid (95 mg, 0.55 mmol, 1.2 eq.), N,N-Diisopropylethylamine (315 µL, 1.83 mmol, 4.0 eq.) and HBTU (210 mg, 0.55 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3 was added and the product was extracted with EtOAc. The 35 combined organic layers were washed with a saturated aqueous solution of NaHCO3, 63 brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (140 mg, 71%). MS (ESI+): m / z =433 [M+H]+, HRMS- ESI+ (m / z): calcd for C28H25N4O [M+H]+: 433.2028; found: 433.2019. 51H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.24 (s, 1H), 8.81-8.49 (m,0.4H), 8.49-8.30 (m, 0.6H), 8.28-8.05 (m, 0.6H), 7.98 (d, J = 8.0 Hz, 1H), 7.89-7.69 (m,1H+0.4H), 7.69-7.70 (m, 1H), 7.51-7.43 (m, 2H), 7.43.-7.29 (m, 4H), 7.29-7.10 (m, 4H), 5.11 (d, J = 13.2 Hz, 0.6H), 4.86 (d, J = 13.2 Hz, 0.4H), 4.50 (s, 1H), 3.94 (s, 0.6H), 3.63-3.49 (m, 0.6H), 3.38-3.19 (1H+0.4H), 3.18-2.97 (m, 1H), 2.77-2.53 (m, 1H), 2.53-2.1710 (m, 1H+0.4H). Example 48 (2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile step 1. tert-butyl (3R) 4-benzhydryl-3-cyano-piperazine-1-carboxylate15 Tert-butyl (3R) 3-cyanopiperazine-1-carboxylate (150 mg, 0.71 mmol, 1.0 eq.) wassolubilized in dry ACN (2 mL). [bromo(phenyl)methyl]benzene (210 mg, 0.85 mmol, 1.2 eq.) and triethylamine (120 µL, 0.85 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, insoluble were filtered and solvent was removed under reduced pressure. The crude product was purified by reverse phase 20 chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (140 mg, 52%). step 2. (2R)-1-benzhydrylpiperazine-2-carbonitrile;dihydrochloride Tert-butyl (3R)-4-benzhydryl-3-cyano-piperazine-1-carboxylate (140 mg, 0.37 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (2 mL, 8.0 mmol, 22.0 eq.). The 25 mixture was stirred for 1h at rt under argon atmosphere. Solvents were removed under reduced pressure to give the crude product as a brown solid (130 mg, quant.). MS (ESI+): m / z =278 [M + H]+. step 3. (2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile (2R)-1-benzhydrylpiperazine-2-carbonitrile;dihydrochloride (130 mg, 0.36 mmol, 1.0 eq.) 30 was solubilized in dry DMF (1 mL) under inert atmosphere. Isoquinoline-4-carboxylic acid (75 mg, 0.44 mmol, 1.2 eq.), N,N-Diisopropylethylamine (250 µL, 1.45 mmol, 4.0 eq.) and HBTU (166 mg, 0.44 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3 was added and the product was extracted with EtOAc. The combined organic layers were washed with a saturated 35 aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under 64 reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to the desired product as a white solid (130 mg, 83%).MS (ESI+): m / z =433 [M+H]+, HRMS-ESI+ (m / z): calcd for C28H25N4O [M+H]+: 433.2028 ; found: 433.2010. 51H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.28 (s, 1H), 8.84-8.49 (m,0.4H), 8.50-8.34 (m, 0.6H), 8.27-8.09 (m, 0.6H), 8.02 (d, J = 8.0 Hz, 1H), 7.93-7.72 (m,1H+0.4H), 7.72-7.64 (m, 1H), 7.52-7.45 (m, 2H), 7.43.-7.31 (m, 4H), 7.31-7.19 (m, 3H), 7.19-7.10 (m, 1H), 5.13 (d, J = 13.2 Hz, 0.6H), 4.88 (d, J = 13.2 Hz, 0.4H), 4.51 (s, 1H),3.95 (s, 0.6H), 3.63-3.54 (m, 0.4H), 3.42-3.20 (1H+0.6H), 3.19-2.99 (m, 1H), 2.75-2.6310 (m, 0.6H), 2.63-2.53 (m, 0.4H), 2.46-2.22 (m, 1H+0.4H). Example 49 (2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2- carbonitrile step 1. tert-butyl (3S) 4-benzhydryl-3-cyano-piperazine-1-carboxylate15 Tert-butyl (3S) 3-cyanopiperazine-1-carboxylate (150 mg, 0.71 mmol, 1.0 eq.) wassolubilized in dry ACN (2 mL). [bromo(phenyl)methyl]benzene (210 mg, 0.85 mmol, 1.2 eq.) and triethylamine (120 µL, 0.85 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, insoluble were filtered and solvent was removed under reduced pressure. The crude product was purified by reverse phase 20 chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (145 mg, 53%). step 2. (2S)-1-benzhydrylpiperazine-2-carbonitrile dihydrochloride Tert-butyl (3S)-4-benzhydryl-3-cyano-piperazine-1-carboxylate (145 mg, 0.38 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (2 mL, 8.0 mmol, 22.0 eq.). The 25 mixture was stirred for 1h at rt under argon atmosphere. Solvents were removed under reduced pressure to give the desired product as a brown solid (133 mg, quant.). MS (ESI+): m / z =278 [M + H]+. step 3. (2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile(2S)-1-benzhydrylpiperazine-2-carbonitrile dihydrochloride (130 mg, 0.36 mmol, 1.0 eq.) 30 was solubilized in dry DMF (1 mL) under inert atmosphere. Isoquinoline-4-carboxylic acid (75 mg, 0.44 mmol, 1.2 eq.), N,N-Diisopropylethylamine (250 µL, 1.45 mmol, 4.0 eq.) and HBTU (166 mg, 0.44 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3 was added and the product was extracted with EtOAc. The combined organic layers were washed with a saturated 35 aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under 65 reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (115 mg, 73%). MS (ESI+): m / z =433 [M+H]+. HRMS-ESI+ (m / z): calcd for C28H25N4O [M+H]+: 433.2028 ; found: 433.2037. 51H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.28 (s, 1H), 8.84-8.49 (m,0.4H), 8.50-8.34 (m, 0.6H), 8.27-8.09 (m, 0.6H), 8.02 (d, J = 8.0 Hz, 1H), 7.93-7.72 (m,1H+0.4H), 7.72-7.64 (m, 1H), 7.52-7.45 (m, 2H), 7.43.-7.31 (m, 4H), 7.31-7.19 (m, 3H), 7.19-7.10 (m, 1H), 5.13 (d, J = 13.2 Hz, 0.6H), 4.88 (d, J = 13.2 Hz, 0.4H), 4.51 (s, 1H),3.95 (s, 0.6H), 3.63-3.54 (m, 0.4H), 3.42-3.20 (1H+0.6H), 3.19-2.99 (m, 1H), 2.75-2.6310 (m, 0.6H), 2.63-2.53 (m, 0.4H), 2.46-2.22 (m, 1H+0.4H). Example 50 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2- yl]acetonitrile Step 1. tert-butyl (3R)-4-benzhydryl-3-(cyanomethyl)piperazine-1-carboxylate 15 Tert-butyl (3R)-3-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.44 mmol, 1.0 eq.) was solubilized in dry ACN (1.5 mL). [bromo(phenyl)methyl]benzene (130 mg, 0.53 mmol, 1.2 eq.) and triethylamine (75 µL, 0.53 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, insoluble were filtered and solvent was removed under reduced pressure. The crude product was purified by 20 reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (100 mg, 58%). Step 2.2-[(2R)-1-benzhydrylpiperazin-2-yl]acetonitrile;dihydrochloride Tert-butyl (3R)-4-benzhydryl-3-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.26 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (1.5 mL, 6.0 mmol, 23.5 25 eq.). The mixture was stirred for 1h at rt under argon atmosphere. Solvents were removed under reduced pressure to give the crude product as a brown solid (95 mg, quant.). MS (ESI+): m / z =292 [M+H]+. Step 3.2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetonitrile 2-[(2R)-1-benzhydrylpiperazin-2-yl]acetonitrile dihydrochloride (95 mg, 0.26 mmol, 1.0 30 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. Isoquinoline-4-carboxylic acid (53 mg, 0.31 mmol, 1.2 eq.), N,N-Diisopropylethylamine (175 µL, 1.02 mmol, 4.0 eq.) and HBTU (117 mg, 0.31 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3 was added and the product was extracted with EtOAc. The combined organic layers were washed with a saturated 35 aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under 66 reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to the desired product as a white solid (45 mg, 39%). MS (ESI+): m / z =447 [M+H]+, HRMS-ESI+ (m / z): calcd for C29H27N4O [M+H]+: 447.2185; found: 447.2199. 51H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.28 (s, 1H), 8.63-8.36 (m, 1H),8.04 (d, J = 8.2 Hz, 1H), 7.99-7.88 (m, 0.4H), 7.88-7.75 (m, 1H+0.6H), 7.75-7.63 (m, 1H),7.47-7.39 (m, 3H), 7.40-7.13 (m, 7H), 4.83 (s, 0.4H), 4.75-4.55 (m, 1H+0.6H), 3.59-3.42 (m, 1H+0.6H), 3.38-3.21 (m, 1H+0.6H), 3.14 (br s, 0.4H), 2.92-2.81 (m, 0.4H), 2.78-2.65 (m, 1H), 2.64-2.51 (m, 1H+0.6H), 2.51-2.32 (m, 1H+0.4H). 10 Example 51 2-[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetonitrile Step 1. tert-butyl (3S)-4-benzhydryl-3-(cyanomethyl)piperazine-1-carboxylate Tert-butyl (3S)-3-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.44 mmol, 1.0 eq.) 15 was solubilized in dry ACN (1.5 mL). [bromo(phenyl)methyl]benzene (130 mg, 0.53 mmol, 1.2 eq.) and triethylamine (75 µL, 0.53 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, insoluble were filtered and solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a20 colorless oil (125 mg, 72%). Step 2.2-[(2S)-1-benzhydrylpiperazin-2-yl]acetonitrile dihydrochloride Tert-butyl (3S)-4-benzhydryl-3-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.32 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (1.5 mL, 6.0 mmol, 19.0 eq.). The mixture was stirred for 1h at rt under argon atmosphere. Solvents were 25 removed under reduced pressure to give the crude product as a brown solid (118 mg, quant.). MS (ESI+): m / z =292 [M+H]+. Step 3.2-[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetonitrile 2-[(2S)-1-benzhydrylpiperazin-2-yl]acetonitrile;dihydrochloride (118 mg, 0.32 mmol, 1.0 eq.) was solubilized in dry DMF (1.5 mL) under inert atmosphere. Isoquinoline-4- 30 carboxylic acid (66 mg, 0.38 mmol, 1.2 eq.), N,N-Diisopropylethylamine (220 µL, 1.27 mmol, 4.0 eq.) and HBTU (145 mg, 0.38 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3 was added and the product was extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and 35 concentrated under reduced pressure. The crude product was purified by reverse phase 67 chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (100 mg, 71%). MS (ESI+): m / z =447 [M+H]+, HRMS-ESI+ (m / z): calcd for C29H27N4O [M+H]+: 447.2185; found: 447.2187. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.28 (s, 1H), 8.63-8.36 (m, 1H),5 8.04 (d, J = 8.2 Hz, 1H), 7.99-7.88 (m, 0.4H), 7.88-7.75 (m, 1H+0.6H), 7.75-7.63 (m, 1H),7.47-7.39 (m, 3H), 7.40-7.13 (m, 7H), 4.83 (s, 0.4H), 4.75-4.55 (m, 1H+0.6H), 3.59-3.42 (m, 1H+0.6H), 3.38-3.21 (m, 1H+0.6H), 3.14 (br s, 0.4H), 2.92-2.81 (m, 0.4H), 2.78-2.65 (m, 1H), 2.64-2.51 (m, 1H+0.6H), 2.51-2.32 (m, 1H+0.4H). 10 Example 52 Tert-butyl N-[[1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2- yl]methyl]carbamate In a tube, 1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile (110 mg, 0.25 mmol, 1 eq.) has been dissolved in dry methanol (9.5 mL) at 0°C. Tert- butoxycarbonyl tert-butyl carbonate (158 mg, 0.72 mmol, 2.9 eq.) and NiCl2(145 mg, 15 1.12 mmol, 4.40 eq.) were added to the reaction mixture at 0°C. Sodium borohydride (21.2 mg, 0.56 mmol, 2.2 eq.) was then added at 0°C. After 15 minutes, sodium borohydride (162 mg, 4.27 mmol, 16.8 eq.) was added by little portion over 10 min at ambient temperature. After total conversion of the starting material, the reaction mixture was exposed to air to let secondary products reoxyde to tert-butyl N-[[1-benzhydryl-4- 20 (isoquinoline-4-carbonyl)piperazin-2-yl]methyl]carbamate. The reaction mixture was concentrated under reduced pressure. The crude product was extracted with EtOAc and washed with NaOH and brine; dried over MgSO4; filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (26.0 mg, 19%).25 MS (ESI+) m / z =537 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C33H37N4O3 m / z=537.2866, found m / z= 537.2889. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.34 (s, 1H), 8.42-8.36 (m,1H), 8.19 (d, J = 8.5 Hz, 1H), 7.87-7.72 (m, 3H), 7.45-7.43 (m, 4H), 7.30-7.13 (m, 6H),6.71-6.35 (m, 1H), 5.12 (s, 1H), 4.31-4.24 (m, 1H), 3.26-3.16 (m, 2H), 3.06-3.02 (m, 2H),30 2.81-2.56 (m, 2H), 2.28-2.23 (m, 1H), 1.39-1.15 (m, 9H). Example 53 [(2R)-4-benzhydryl-2-(hydroxymethyl)piperazin-1-yl]-(4- isoquinolyl)methanone Step 1. Tert-butyl (3R)-3-(hydroxymethyl)-4-(isoquinoline-4-carbonyl)piperazine-1-35 carboxylate 68 Isoquinoline-4-carboxylic acid (170 mg, 0.97 mmol, 2.1 eq.) was solubilized in dry DMF (1.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (240 µL, 1.39 mmol, 3.0 eq.), tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (100 mg, 0.46 mmol, 1.0 eq.) and HBTU (370 mg, 0.97 mmol, 2.10 eq.) were added. The mixture was stirred at rt 5 overnight. A saturated aqueous solution of NaHCO3 was added and the product was extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford [(2R)-4-tert-butoxycarbonyl-1-(isoquinoline-4- 10 carbonyl)piperazin-2-yl]methyl isoquinoline-4-carboxylate as a brown oil (230 mg, 91%). MS (ESI+): m / z =527 [M+H]+. [(2R)-4-tert-butoxycarbonyl-1-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl isoquinoline-4-carboxylate (230 mg, 0.42, 1.0 eq.) was solubilized in a 3:1 (v / v) mixture of MeOH / H2O (2 mL). Sodium hydroxide (50 mg, 1.26 mmol, 3.0 eq) was added. The 15 reaction mixture was stirred at rt for 3 hours. The mixture was diluted with EtOAc and the product was extracted. The combined organic layers were washed with an aqueous solution of saturated NaHCO3, water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product as a colorless oil (110 mg, 71%). MS (ESI+): m / z =372 [M+H]+. 20 Step 2. (2R)-2-(hydroxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone; dihydrochloride [(2R)-4-tert-butoxycarbonyl-1-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl isoquinoline-4-carboxylate (110 mg, 0.30 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (1.5 mL, 6.0 mmol, 20.0 eq.). The mixture was stirred for 2 hours at25 rt. Solvents were removed under reduced pressure to give the crude product as an off- white solid (106 mg, quant.). MS (ESI+): m / z =272 [M + H]+. Step 3. [(2R)-4-benzhydryl-2-(hydroxymethyl)piperazin-1-yl]-(4- isoquinolyl)methanone [(2R)-2-(hydroxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone;dihydrochloride (105 30 mg, 0.31 mmol, 1.0 eq.) was solubilized in dry ACN (1 mL). Triethylamine (170 µL, 1.22, mmol, 4.0 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (90 mg, 0.37 mmol, 1.2 eq.) was added. The mixture was heated at 50°C for 3 hours. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse 35 phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white 69 solid (32 mg, 23%). MS (ESI+): m / z =438 [M + H]+, HRMS-ESI+ (m / z): calcd for C28H28N3O2 [M+H]+: 438.2182; found: 438.2187. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.23 (s, 0.7H), 9.17 (s, 0.3H),8.60-8.33 (m, 1H), 8.07-7.95 (m, 1H+0.3H), 7.95-7.82 (m, 0.7H), 7.82-7.70 (m, 1H), 7.70- 5 7.56 (m, 1H), 7.44-7.37 (m, 2H), 7.36-7.26 (m, 4H), 7.25-7.17 (m, 3H), 7.16-7.09 (m, 1H), 5.04-4.90 (m, 0.7H), 4.79-4.43 (m, 0.3H), 4.41-4.30 (m, 0.3H), 4.27-4.13 (m, 1H), 4.13- 3.92 (m, 1H), 3.82-3.63 (m, 0.7H), 3.63-3.47 (m, 1H), 3.47-3.30 (m, 1H+0.3H), 3.27-3.13 (m, 1H), 3.13-3.02 (m, 0.7H), 2.90-2.63 (m, 1H), 2.38-2.23 (m, 0.7H), 2.22-2.06 (m, 0.6H), 2.05-1.89 (m, 0.7H). 10 Example 54 [(2S)-4-benzhydryl-2-(hydroxymethyl)piperazin-1-yl]-(4- isoquinolyl)methanone step 1. tert-butyl (3S)-3-(hydroxymethyl)-4-(isoquinoline-4-carbonyl)piperazine-1-carboxylate 15 Isoquinoline-4-carboxylic acid (170 mg, 0.97 mmol, 2.1 eq.) was solubilized in dry DMF (1.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (240 µL, 1.39 mmol, 3.0 eq.), tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (100 mg, 0.46 mmol, 1.0 eq.) and HBTU (370 mg, 0.97 mmol, 2.10 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3 was added and the product was20 extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford [(2S)-4-tert-butoxycarbonyl-1-(isoquinoline-4- carbonyl)piperazin-2-yl]methyl isoquinoline-4-carboxylate as a brown oil (220 mg, 88%). 25 MS (ESI+): m / z = 527 [M+H]+[(2S)-4-tert-butoxycarbonyl-1-(isoquinoline-4-carbonyl)piperazin-2-yl]methyl isoquinoline-4-carboxylate (220 mg, 0.41, 1.0 eq.) was solubilized in a 3:1 (v / v) mixture of MeOH / H2O (2 mL). Sodium hydroxide (50 mg, 1.22 mmol, 3.0 eq) was added. The reaction mixture was stirred at rt for 3 hours. The mixture was diluted with EtOAc and 30 the product was extracted. The combined organic layers were washed with an aqueous solution of saturated NaHCO3, water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as a colorless oil (90 mg, 59%). MS (ESI+): m / z =372 [M+H]+. step 2. [(2S)-2-(hydroxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone;35 dihydrochloride 70 Tert-butyl (3S)-3-(hydroxymethyl)-4-(isoquinoline-4-carbonyl)piperazine-1-carboxylate (90 mg, 0.24 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (1.5 mL, 6.0 mmol, 25.0 eq.). The mixture was stirred for 2h at rt. Solvents were removed under reduced pressure to give the crude product as an off-white solid (85 mg, quant.). MS 5 (ESI+): m / z =272 [M + H]+. step 3. (2S)-4-benzhydryl-2-(hydroxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone [(2S)-2-(hydroxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone;dihydrochloride (85 mg, 0.25 mmol, 1.0 eq.) was solubilized in dry ACN (1 mL). Triethylamine (140 µL, 0.99 10 mmol, 4.0 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (75 mg, 0.30 mmol, 1.2 eq.) was added. The mixture was heated at 50°C for 3 hours. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white15 solid (26 mg, 23%). MS (ESI+): m / z =438 [M + H]+. HRMS-ESI+ (m / z): calcd forC28H28N3O2[M+H]+: 438.2182; found: 438.2169. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.24 (s, 0.7H), 9.18 (s, 0.3H),8.62-8.34 (m, 1H), 8.06-7.96 (m, 1H+0.3H), 7.96-7.82 (m, 0.7H), 7.82-7.69 (m, 1H), 7.69- 7.57 (m, 1H), 7.45-7.37 (m, 2H), 7.36-7.26 (m, 4H), 7.25-7.17 (m, 3H), 7.17-7.09 (m, 1H),20 5.02-4.89 (m, 0.7H), 4.82-4.53 (m, 0.3H), 4.43-4.30 (m, 0.3H), 4.29-4.13 (m, 1H), 4.13- 3.92 (m, 1H), 3.82-3.61 (m, 0.7H), 3.60-3.43 (m, 1H), 3.43-3.32 (m, 0.7H), 3.27-3.13 (m, 1H+0.3H), 3.13-3.00 (m, 1H), 2.90-2.64 (m, 1H), 2.36-2.22 (m, 0.7H), 2.22-2.06 (m, 0.6H), 2.05-1.79 (m, 0.7H). 25 Example 55 [(2R)-4-benzhydryl-2(methoxymethyl) piperazin-1-yl]-(4- isoquinolyl)methanone Step 1. Tert-butyl (2R)-4-benzhydryl-2-(methoxymethyl)piperazine-1-carboxylateTert-butyl (2R)-2-(methoxymethyl)piperazine-1-carboxylate (100 mg, 0.434 mmol, 1.0 eq.) was solubilized in dry ACN (1.38 mL). [bromo(phenyl)methyl]benzene (129 mg, 30 0.521 mmol, 1.2 eq.) and triethylamine (73 µL, 0.521 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product (130 mg, 76 %). MS (ESI+): m / z =397 [M+H]+.35 Step 2. (3R)-1-benzhydryl-3-(methoxymethyl)piperazine;dihydrochloride 71 HCl 4M in dioxane (0.610 mL) was added to the Tert-butyl (2R)-4-benzhydryl-2- (methoxymethyl)piperazine-1-carboxylate (116 mg, 0.293 mmol) at 0°C and stirred for 2h at rt. The solution mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate white solid (109 mg, 100 %). MS (ESI+): m / z = 2975 [M+H]+. Step 3. [(2R)-4-benzhydryl-2-(methoxymethyl)piperazin-1-yl]-(4-isoquinolyl)methanone Isoquinoline-4-carboxylic acid (61 mg, 0.354 mmol, 1.2 eq.) was solubilized in dry DMF (1.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (202 µL, 1.18 mmol, 4.010 eq.), HBTU (134 mg, 0.354 mmol, 1.2 eq.) and (3R)-1-benzhydryl-3- (methoxymethyl)piperazine;dihydrochloride (109 mg, 0.295 mmol, 1.0 eq.) were added. The mixture was stirred at rt overnight. The solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase 15 chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (70 mg, 53 %). MS (ESI+): m / z =452 [M+H]+. HRMS-ESI+ (m / z): calcd for C29H30N3O2[M+H]+: 452.2338; found: 452.2348. 1H NMR (300 MHz, DMSO-d6) δ: 9.35 (s, 0.5H), 9.32 (s, 0.5H), 8.42 (br s, 1H), 8.19 (brd, 1H), 7.85 (br d, 2H), 7.77-7.72 (m, 1H), 7.50-7.10 (m, 10H), 4.87 (br d, 0.5H), 4.52 (d,20 J = 12.0 Hz, 0.3H), 4.36 (br s, 0.2H), 4.29 (s, 1H), 4.08 (t, J = 8.8 Hz, 0.3H), 3.88-3.75(m, 1H+0.4H), 3.52 (br s, 0.3H), 3.45 (s, 0.9H), 3.40 (br s, 0.5H), 3.31 (br s, 0.6H), 3.20 (br s, 1H+0.8H), 3.04 (d, J = 12.8 Hz, 0.7H), 2.97-2.89 (m, 1H+0.5H), 2.73-2.52 (m, 1H), 2.28-2.23 (br s, 0.3 H), 2.09 (br d, 1H), 1.87 (br d, 0.6H), 1.72 (br s, 0.2H). 25 Example 56 [(2S)-4-benzhydryl-2 (methoxymethyl)piperazin-1-yl]-(4- isoquinolyl)methanone Step 1. Tert-butyl (2S)-4-benzhydryl-2-(methoxymethyl)piperazine-1-carboxylate Tert-butyl (2S)-2-(methoxymethyl)piperazine-1-carboxylate(100 mg, 0.434 mmol, 1.0 eq.) was solubilized in dry ACN (1.38 mL). [bromo(phenyl)methyl]benzene (129 mg, 30 0.521 mmol, 1.2 eq.) and triethylamine (73 µL, 0.521 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product (138 mg, 80 %). MS(ESI+): m / z =397 [M+H]+. 35 Step 2. (3S)-1-benzhydryl-3-(methoxymethyl)piperazine;dihydrochloride 72 HCl 4M in dioxane (0.641 mL) was added to the Tert-butyl (2S)-4-benzhydryl-2- (methoxymethyl)piperazine-1-carboxylate (122 mg, 0.308 mmol) at 0°C and stirred for 2h at rt. The solution mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate white solid (96 mg, 85 %). MS (ESI+): m / z =297 [M+H]+.5 Step 3. [(2S)-4-benzhydryl-2-(methoxymethyl)piperazin-1-yl]-(4- isoquinolyl)methanone: Isoquinoline-4-carboxylic acid (54 mg, 0.312 mmol, 1.2 eq.) was solubilized in dry DMF (1.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (180 µL, 1.04 mmol, 4.0 eq.), HBTU (118 mg, 0.312 mmol, 1.2 eq.) and (3S)-1-benzhydryl-3-10 (methoxymethyl)piperazine;dihydrochloride (96 mg, 0.26 mmol, 1.0 eq.) were added.The mixture was stirred at rt overnight. The solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (6015 mg, 51 %). MS (ESI+): m / z =452 [M+H]+. HRMS-ESI+ (m / z): calcd for C29H30N3O2[M+H]+: 452.2338; found: 452.2348. 1H NMR (300 MHz, DMSO-d6) δ: 9.35 (s, 0.5H), 9.32 (s, 0.5H), 8.41 (br s, 1H), 8.19 (brd, 1H), 7.85 (br d, 2H), 7.77-7.72 (m, 1H), 7.49-7.09 (m, 10H), 4.88 (br d, 0.5H), 4.52 (d, J= 13.5 Hz, 0.3H), 4.36 (br s, 0.2H), 4.30 (s, 1H), 4.08 (t, J = 9.0 Hz, 0.3H), 3.88-3.7220 (m, 1H+0.5H), 3.51 (br s, 0.3H), 3.45 (br s, 1H), 3.40 (br s, 0.6H), 3.20 (br s, 1H+0.7H), 3.13 (br s, 0.2H), 3.06 (br s, 0.4H), 3.02 (br s, 0.3H), 2.97 (br s, 0.2H), 2.93 (br s, 0.5H), 2.89 (br s, 0.8H), 2.73-2.56 (m, 1H), 2.26-2.21 (m, 0.2H), 2.11-2.07 (m, 1H), 1.88 (br s, 0.5H), 1.73 (br s, 0.2H). 25 Example 57 methyl 4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazine-2- carboxylate step 1. O1-tert-butyl O3-methyl 4-(isoquinoline-4-carbonyl)piperazine-1,3- dicarboxylate Isoquinoline-4-carboxylic acid (170 mg, 0.98 mmol, 1.2 eq.) was solubilized in dry DMF 30 (2 mL) under inert atmosphere. O1-tert-butyl O3-methyl piperazine-1,3-dicarboxylate (200 mg, 0.82 mmol, 1.0 eq.), N,N-Diisopropylethylamine (210 µL, 1.23 mmol, 1.5 eq.) and HBTU (375 mg, 0.98 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3 was added and the product was extracted with EtOAc. The combined organic layers were washed with a saturated 35 aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under 73 reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a yellow oil (170 mg, 51%). MS (ESI+): m / z =400 [M+H]+. step 2. methyl 1-(isoquinoline-4-carbonyl)piperazine-2-carboxylate;2,2,2- 5 trifluoroacetic acid O1-tert-butyl O3-methyl 4-(isoquinoline-4-carbonyl)piperazine-1,3-dicarboxylate (170 mg, 0.42 mmol, 1.0 eq.) was solubilized in DCM (1 mL). TFA (310 µL, 4.17 mmol, 10.0 eq.) was added and the mixture was stirred for 3 hours at rt. Solvents were removed under reduced pressure to give the crude product as a brown oil (225 mg, quant.). MS10 (ESI+): m / z =300 [M + H]+. step 3. methyl 4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazine-2-carboxylate Methyl 1-(isoquinoline-4-carbonyl)piperazine-2-carboxylate;2,2,2-trifluoroacetic acid (225 mg, 0.42 mmol, 1.0 eq.) was solubilized in dry ACN (1 mL). [bromo(phenyl)methyl]benzene (124 mg, 0.50 mmol, 1.2 eq.) and triethylamine (235 µL, 15 1.67 mmol, 4.0 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Insoluble was filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (62 mg, 32%). MS (ESI+): m / z =466 [M+H]+, HRMS- ESI+ (m / z): calcd for C29H28N3O3[M+H]+: 466.2131; found: 466.2136.20 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers : 9.28 (br s, 0.8H), 9.25 (br s,0.2H), 8.68-8.50 (m, 0.8H), 8.50-8.39 (m, 0.2H), 8.30 (d, J = 8.0Hz, 0.5H), 8.01 (d, J =8.0Hz, 1H), 7.94-7.82 (m, 1H), 7.82-7.72 (m, 0.5H), 7.63 (t, J = 7.3Hz, 1H), 7.44-7.36(m, 2H), 7.36-7.29 (m, 4H), 7.28-7.17 (m, 3H), 7.17-7.09 (m, 1H), 5.51 (br s, 0.8H), 4.68 (dd, J = 28.5Hz and 13.5Hz, 0.2H), 4.37-4.21 (m, 1H), 3.99-3.91 (m, 2H+0.6H), 3.82 (br25 s, 0.4H), 3.73-3.40 (m, 2H), 3.37-3.14 (m, 1H), 3.06 (d, J = 11.0Hz, 0.2H), 2.67 (br d, J= 11.0Hz, 0.8H), 2.33 (dd, J = 12.0Hz and 4.0Hz, 1H), 2.29-2.04 (m, 0.2H), 2.04-1.79(m, 0.8H). Example 58 lithium;1-benzhydryl-1-(isoquinoline-4-carbonyl)piperazine-2-30 carboxylate Methyl 4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazine-2-carboxylate (50 mg, 0.11 mmol, 1.0 eq.) was solubilized in a 3:1 (v / v) mixture of MeOH / H2O (500 µL). Lithium;hydroxide;hydrate (14 mg, 0.32 mmol, 3.0 eq) was added. The reaction mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and 74 the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (30 mg, 61%). MS (ESI+): m / z =452 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.30 (s, 0.5H), 9.25 (s,0.5H), 8.83 (d, J = 8.0Hz, 0.5H), 8.57-8.47 (m, 0.5H), 8.40-8.28 (m, 0.5H), 8.14 (d, J =5 8.0Hz, 1H), 7.89-7.76 (m, 1H+0.5H), 7.71 (t, J = 7.4Hz, 1H), 7.49-7.34 (m, 3H), 7.33-7.04 (m, 7H), 4.84 (s, 0.5H), 4.40 (d, J = 12.0Hz, 0.5H), 4.25 (s, 0.5H), 4.22 (s, 0.5H),3.73 (d, J = 11.0Hz, 0.5H), 3.66-3.52 (m, 0.5H), 3.40-3.29 (m, 0.5H), 2.90 (d, J = 12.0Hz,0.5H), 2.78 (d, J = 11.0Hz, 0.5H), 2.43 (d, J = 11.0Hz, 0.5H), 2.08-1.89 (m, 1H), 1.84-1.61 (m, 1H). 10 Example 594-benzhydryl-1-(isoquinoline-4-carbonyl)piperazine-2-carboxamide Step 1. Tert-butyl 3-carbamoyl-4-(isoquinoline-4-carbonyl)piperazine-1- carboxylate Isoquinoline-4-carboxylic acid (63 mg, 0.364 mmol, 1.0 eq.) was solubilized in dry DMF 15 (2.85 mL) under inert atmosphere. N,N-Diisopropylethylamine (187 µL, 1.09 mmol, 3.0 eq.), HBTU (166 mg, 0.437 mmol, 1.2 eq.) and Tert-butyl 3-carbamoylpiperazine-1- carboxylate (100 mg, 0.437 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. The solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The 20 crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (101 mg, 72 %). MS (ESI+): m / z =385 [M+H]+. Step 2.1-(isoquinoline-4-carbonyl)piperazine-2-carboxamide;dihydrochlorideHCl 4M in dioxane (0.509 mL) was added to the Tert-butyl 3-carbamoyl-4-(isoquinoline- 4-carbonyl)piperazine-1-carboxylate (94 mg, 0.245 mmol) at 0°C and stirred for 2h at rt. 25 The solution mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate white solid (59 mg, 68 %). MS (ESI+): m / z =285 [M+H]+.Step 3.4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazine-2-carboxamide 1-(isoquinoline-4-carbonyl)piperazine-2-carboxamide;dihydrochloride (59 mg, 0.165 mmol, 1.0 eq.) was solubilized in dry ACN (0.6 mL). [bromo(phenyl)methyl]benzene (49 30 mg, 0.198 mmol, 1.2 eq.) and triethylamine (92 µL, 0.661 mmol, 4.0 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white powder (20 mg, 27%). MS (ESI+): m / z =451 [M+H]+. 75 1H NMR (500 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.35 (s, 0.6H), 9.34 (s,0.4H), 8.53 (br s, 0.2H), 8.40 (br s, 0.5H), 8.33-8.29 (m, 0.7H), 8.19 (d, J = 8.4 Hz, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.79 (br s, 0.4H), 7.75 (t, J = 7.9 Hz, 1H), 7.45-7.42 (m, 2H), 7.39(d, J = 7.8 Hz, 0.7H), 7.37-7.35 (m, 0.7H), 7.33-7.29 (m, 3H+0.7H), 7.23 -7.18 (m,5 3H+0.7H), 7.14 (br s, 0.2H), 7.11 (t, J = 7.3 Hz, 1H), 5.10 (br s, 0.7H), 4.49 (d, J = 13.4Hz, 0.2H), 4.40 (br s, 0.1H), 4.33 (s, 0.6H), 4.31 (s, 0.4H), 4.08 (br s, 0.1H), 3.67 (br s, 0.2H), 3.58 (t, J = 11.1 Hz, 0.7H), 3.52 (br s, 0.2 H), 3.47 (d, J = 12.1 Hz, 0.5H), 3.42-3.37 (m, 0.2H), 3.18 (d, J = 11.0 Hz, 0.4H), 3.07 (d, J = 12.7 Hz, 0.7H), 2.84 (d, J = 10.6Hz, 0.3H), 2.52-2.51 (m, 0.5H), 2.24 (dd, J = 12.2 and 4.3 Hz, 0.7H), 2.04 (t, J = 11.9 Hz,10 0.4H), 1.95 (d, J = 10.4 Hz, 0.2H), 1.89 (t, J = 11.5 Hz, 0.4H), 1.74 (br s, 0.2H).Example 60 methyl 2-[4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazin-2- yl]acetate Step 1. Tert-butyl 4-(isoquinoline-4-carbonyl)-3-(2-methoxy-2-oxo-15 ethyl)piperazine-1-carboxylate Isoquinoline-4-carboxylic acid (50 mg, 0.289 mmol, 1.0 eq.) was solubilized in dry DMF (2.3 mL) under inert atmosphere. N,N-Diisopropylethylamine (198 µL, 1.15 mmol, 4.0 eq.), HBTU (131 mg, 0.346 mmol, 1.2 eq.) and Tert-butyl 3-(2-methoxy-2-oxo- ethyl)piperazine-1-carboxylate;hydrochloride (102 mg, 0.346 mmol, 1.2 eq.) were added. 20 The mixture was stirred at rt overnight. The solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (75 mg, 63 %). MS (ESI+): m / z =414 [M+H]+. 25 Step 2. Methyl 2-[1-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate dihydrochloride HCl 4M in dioxane (0.378 mL) was added to the Tert-butyl 4-(isoquinoline-4-carbonyl)- 3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate (75 mg, 0.181 mmol) at 0°C and stirred for 1h at rt. The solution mixture was concentrated under reduced pressure, to30 afford the desired product as a white solid (59 mg, 84 %). MS (ESI+): m / z =314 [M+H]+.Step 3. Methyl 2-[4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate Methyl 2-[1-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate;dihydrochloride (76 mg,0.197 mmol, 1.0 eq.) was solubilized in dry ACN (0.6 mL). [bromo(phenyl)methyl]benzene (58 mg, 0.236 mmol, 1.2 eq.) and triethylamine (110 µL, 35 0.787 mmol, 4.0 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. 76 Upon completion, solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white powder (30 mg, 32 %). MS (ESI+): m / z =480 [M+H]+. HRMS- ESI+ (m / z): calcd for C30H30N3O3 [M+H]+: 480.2287; found: 480.2286. 51H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.36 (s, 0.4H), 9.35 (s, 0.6H),8.47 (s, 0.4H), 8.39 (br s, 0.6H), 8.19 (d, J = 8.1 Hz, 1H), 7.89-7.72 (m, 3H), 7.51 (d, J =7.3 Hz, 0.8H), 7.42 (d, J = 7.3 Hz, 2H+0.4H), 7.35-7.10 (m, 7H), 5.09 (br s, 0.6H), 4.54(d, J = 12.7 Hz, 0.4H), 4.31 (s, 1H), 3.63 (s, 1H+0.7H), 3.55 (br s, 0.3H), 3.46 (br s, 0.8H),3.37 (br s, 0.4H), 3.29 (br s, 0.4H), 3.19 (br s, 1H+0.6H), 3.04 (br s, 1H), 2.94-2.84 (m,10 1H+0.4H), 2.57 (d, J = 11.5 Hz, 0.8H), 2.43 (br s, 0.3H), 2.18 (br s, 0.8H), 2.10 (br s,0.4H), 1.89 (br d, 0.6H), 1.75 (br s, 0.3H). Example 614-benzhydryl-1-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile Step 1. tert-butyl 3-cyano-4-(isoquinoline-4-carbonyl)piperazine-1-carboxylate 15 Isoquinoline-4-carboxylic acid (150 mg, 0.85 mmol, 1.2 eq.) was solubilized in dry DMF (2 mL) under inert atmosphere. Tert-butyl 3-cyanopiperazine-1-carboxylate (150 mg, 0.71 mmol, 1.0 eq.), N,N-Diisopropylethylamine (180 µL, 1.07 mmol, 1.5 eq.) and HBTU (320 mg, 0.85 mmol, 1.2 eq.) were added. The mixture was stirred at rt overnight. A saturated aqueous solution of NaHCO3was added and the product was extracted with 20 EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (226 mg, 87%). MS (ESI+): m / z =367 [M+H]+. 25 Step 2.1-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile;dihydrochloride Tert-butyl 3-cyano-4-(isoquinoline-4-carbonyl)piperazine-1-carboxylate (225 mg, 0.61mmol, 1.0 eq.) was solubilized in 4M HCl in dioxane (2.5 mL, 10.0 mmol, 16.0 eq). The mixture was stirred for 2 hours at rt under inert atmosphere. Solvents were removed under reduced pressure to give the crude product as a pale yellow solid (215 mg, quant.).30 MS (ESI+): m / z =267 [M + H]+. Step 3.4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile 1-(isoquinoline-4-carbonyl)piperazine-2-carbonitrile;dihydrochloride (215 mg, 0.62 mmol, 1.0 eq.) was solubilized in dry ACN (1.5 mL). [bromo(phenyl)methyl]benzene (184 mg, 0.75 mmol, 1.2 eq.) and triethylamine (350 µL, 2.48 mmol, 4.0 eq.) were added. The 35 reaction mixture was heated at 50°C for 3 hours. Insoluble was filtered and the solvent 77 was removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as an off-white solid (60 mg, 22%). MS (ESI+): m / z =433 [M+H]+. HRMS-ESI+ (m / z): calcd for C28H25N4O [M+H]+: 433.2028; found: 433.2028. 51H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.26 (s, 1H), 8.67-8.34 (m, 1H),8.50-7.96 (m, 1H), 7.78 (br s, 2H), 7.72-7.60 (m, 1H), 7.53-7.36 (m, 4H), 7.36-7.09 (m, 6H), 5.83 (br s, 1H), 4.36 (br s, 1H), 3.80-3.23 (m, 3H), 3.20-3.05 (m, 0.2H), 3.05-2.91 (m, 0.2H), 2.75 (d, J = 11.4Hz, 0.8H), 2.30 (d, J = 11.4Hz, 0.8H), 2.04-1.79 (m, 1H).10 Example 62 2-[(2R)-4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazin-2- yl]acetonitrile Step 1. tert-butyl (3R)-3-(cyanomethyl)-4-(isoquinoline-4-carbonyl)piperazine-1- carboxylate Isoquinoline-4-carboxylic acid (192.8 mg, 1.11 mmol, 1.0 eq.) was solubilized in dry DMF 15 (3 mL) under inert atmosphere. N,N-Diisopropylethylamine (580 µL, 3.34 mmol, 3.0 eq.), tert-butyl (3R)-3-(cyanomethyl)piperazine-1-carboxylate (253.2 mg, 1.12 mmol, 1.0 eq.) and HBTU (463.3 mg, 1.22 mmol, 1.1 eq.) were added. After 4 hours at rt with stirring, the mixture was diluted with EtOAc and washed with NaOH and brine, dried over MgSO4,filtered and concentrated under reduced pressure to afford the desired product as a white20 solid (404 mg, 57%). MS (ESI) m / z =381 [M+H]+.Step 2. 2-[(2R)-1-(isoquinoline-4-carbonyl)piperazin-2- yl]acetonitrile;dihydrochloride: HCl 4M in dioxane (8 eq., 5.3 mmol, 1.33 mL) was added to tert-butyl (3R)-3-(cyanomethyl)-4-(isoquinoline-4-carbonyl)piperazine-1-carboxylate (404 mg, 0.637 25 mmol) at 0°C and stirred for 1h at rt. Dichloromethane was then added and the solution mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate yellow solid (400 mg). MS (ESI+) m / z =281 [M+H]+.Step 3.2-[(2R)-4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazin-2-yl]acetonitrile 2-[(2R)-1-(isoquinoline-4-carbonyl)piperazin-2-yl]acetonitrile;dihydrochloride (225 mg, 30 0.63 mmol, 1.0 eq.) was solubilized in dry ACN (2.6 mL). Triethylamine (355 µL, 2.55 mmol, 4.0 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (185 mg, 0.747 mmol, 1.2 eq.) was added. The mixture was heated at 50°C for 3 hours. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified by 35 reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product 78 as a white solid (64.8 mg, 22%). MS (ESI+) m / z =447 [M+H]+. HRMS (TOF, ES+) m / z[M+H]+: calcd. for C29H27N4O m / z= 447.2185, found m / z= 447.2167. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.26 (s, 1H), 8.71-8.40 (m, 1H),8.01 (d, J = 7.3 Hz, 1H + 0.5H), 7.79 (s, 1H + 0.5H), 7.69-7.64 (m, 1H), 7.42-7.31 (m,5 7H), 7.24-7.15 (m, 3H), 5.30 (br s, 1H), 4.77 (br s, 0.5H), 4.28 (s, 1H), 3.34 (s, 1H + 0.5H), 3.23 (br s, 1H), 3.08-2.98 (m, 2H), 2.75 (d, J = 12.3 Hz, 1H), 2.33 (dd, J = 12.3,3.5 Hz, 1H), 2.00-1.84 (m, 1H). Example 63 2-[(2S)-4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazin-2-10 yl]acetonitrile Step 1. Tert-butyl (3S)-3-(cyanomethyl)-4-(isoquinoline-4-carbonyl)piperazine-1- carboxylate Isoquinoline-4-carboxylic acid (110 mg, 0.64 mmol, 1.0 eq.) was solubilized in dry DMF (1.6 mL) under inert atmosphere. N,N-Diisopropylethylamine (332 µL, 1.91 mmol, 3.0 15 eq.), tert-butyl (3S)-3-(cyanomethyl)piperazine-1-carboxylate (141.8 mg, 0.63 mmol, 1.0 eq.) and HBTU (263 mg, 0.69 mmol, 1.1 eq.) were added. After stirring at room temp. overnight, the mixture was diluted with EtOAc and washed with NaOH and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the20 desired product as a white solid (171 mg, 71%). MS (ESI+) m / z =381 [M+H]+.Step 2. 2-[(2S)-1-(isoquinoline-4-carbonyl)piperazin-2- yl]acetonitrile;dihydrochloride: HCl 4M in dioxane (9 eq., 4.0 mmol, 1 mL) was added to tert-butyl (3S)-3-(cyanomethyl)- 4-(isoquinoline-4-carbonyl)piperazine-1-carboxylate (171 mg, 0.45 mmol) at 0°C and 25 stirred for 1h at rt. Dichloromethane was then added and the solution mixture was concentrated under reduced pressure, to afford the desired product as yellow solid (164 mg, quantitative). MS (ESI+) m / z =281 [M+H]+.Step 3.2-[(2S)-4-benzhydryl-1-(isoquinoline-4-carbonyl)piperazin-2-yl]acetonitrile 2-[(2S)-1-(isoquinoline-4-carbonyl)piperazin-2-yl]acetonitrile;dihydrochloride (159.0 mg, 30 0.45 mmol, 1.0 eq.) was solubilized in dry ACN (1.8 mL). Triethylamine (250 µL, 1.80 mmol, 4.0 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (130.0 mg, 0.53 mmol, 1.2 eq.) was added. The mixture was heated at 50°C for 3 hours. The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:135 to 0:1) to afford the desired product as a white solid (60.0 mg, 30%). MS (ESI+) m / z = 79 447 [M+H]+. HRMS-ESI+ (m / z): calculated for C29H27N4O [M+H]+ = 447.2185 ; found:447.2224. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.37 (s, 1H), 8.54-8.42 (m,1H), 8.22-8.19 (m, 1H), 7.98-7.73 (m, 3H), 7.56-7.10 (m, 10H), 5.13 (br s, 0.6H), 4.60 (br 5 s, 0.4H), 4.33 (s, 1H), 3.66-3.36 (m, 2H), 2.23-2.72 (m, 3H), 2.61-2.57 (m, 1H), 2.28-2.23 (m, 1H), 1.99-1.75 (m, 1H). Example 64 (2R)-1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazine-2- carbonitrile 10 Step 1. Thieno[2,3-c]pyridine-4-carboxylic acid Pd(OAc)2 (2.52 mg, 0.0112 mmol, 3 mol %) and Xantphos (6.49 mg, 0.0112 mmol, 3 mol %) were added to an oven-dried tube which was then placed under vacuum and refilled with nitrogen three times. A solution of formic acid (99 µL, 2.62 mmol, 7.0 eq.) and organic halide (80 mg, 0.374 mmol, 1.0 eq.) in DMF (1.0 mL) was added to the reaction 15 tube. After DCC (15 mg, 0.075 mmol, 0.2 eq.) and Et3N (104 µL, 0.747 mmol, 2.0 eq.) were added, the tube was sealed and the mixture was stirred at 100 °C for 20 h. After the reaction was completed, the reaction mixture was filtered and concentrated under vacuum. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired compound (22 mg, 33 %). MS (ESI+): m / z =180 [M+H]+.20 Step 2. Tert-butyl (3R)-4-benzhydryl-3-cyano-piperazine-1-carboxylate Tert-butyl (3R)-3-cyanopiperazine-1-carboxylate (132 mg, 0.625 mmol, 1.0 eq.) was solubilized in dry ACN (1.8 mL). [bromo(phenyl)methyl]benzene (185 mg, 0.750 mmol, 1.2 eq.) and triethylamine (105 µL, 0.750 mmol, 1.2 eq.) were added. The reaction mixture was heated at 50°C for 3 hours. Upon completion, insoluble were filtered and 25 solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product (138 mg, 58 %). Step 3. (2R)-1-benzhydrylpiperazine-2-carbonitrile;dihydrochloride HCl 4M in dioxane (0.762 mL) was added to the Tert-butyl (3R)-4-benzhydryl-3-cyano- 30 piperazine-1-carboxylate (138 mg, 0.366 mmol) at 0°C and stirred for 3h at rt. The solution mixture was concentrated under reduced pressure, to afford the desired product as white solid (100 mg, 78 %). MS (ESI+): m / z =278 [M+H]+. Step 4. (2R)-1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazine-2- carbonitrile 80 Thieno[2,3-c]pyridine-4-carboxylic acid (18.6 mg, 0.104 mmol, 1.0 eq.) was solubilized in dry DMF (1.0 mL) under inert atmosphere. N,N-Diisopropylethylamine (71 µL, 0.416 mmol, 4.0 eq.), HBTU (47 mg, 0.125 mmol, 1.2 eq.) and (2R)-1-benzhydrylpiperazine-2- carbonitrile;dihydrochloride (44 mg, 0.125 mmol, 1.2 eq.) were added. The mixture was 5 stirred at rt overnight. The solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (15 mg, 33 %). MS (ESI+) m / z =439 [M+H]+. HRMS-ESI+ (m / z): calculated for C26H23N4OS [M+H]+= 439.1593; found:10 428.1577. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.34 (s, 0.8H), 8.42 (br s, 0.9H), 8.27 (br s, 0.9H),7.50-7.20 (m, 11H), 4.84 (br s, 0.5H), 4.58 (br s, 0.4H), 4.48 (s, 0.9H), 4.09 (br s, 0.6H), 3.78-3.52 (m, 1H+0.4H), 3.28-3.01 (m, 1H+0.7H), 2.91-2.58 (m, 1H+0.4H), 2.36-2.12 (m, 1H+0.2H). 15 Example 65 [(3S)-4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl]-furo[3,2- c]pyridin-7-yl-methanone Step 1. Tert-butyl (3S)-4-benzhydryl-3-(hydroxymethyl)piperazine-1-carboxylateTert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (200 mg, 0.925 mmol, 1.020 eq.) was solubilized in ACN (3 mL). [bromo(phenyl)methyl]benzene (274 mg, 1.11 mmol,1.2 eq.) and triethylamine (155 µL, 1.11 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 50°C for 3 hours. The mixture was filtered to remove insoluble and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel chromatography (cyclohexane / EA 100:0 to 70:30 (v / v)) to afford the desired25 product (180 g, 51%). MS (ESI+): m / z =383 [M + H]+. Step 2. Tert-butyl (3S)-3-(acetoxymethyl)-4-benzhydryl-piperazine-1-carboxylate Tert-butyl (3S)-4-benzhydryl-3-(hydroxymethyl)piperazine-1-carboxylate (180 mg, 0.471 mmol, 1.0 eq.) was solubilized in dry DCM (1.20 mL). Acetic anhydride (53 µL, 0.565 mmol, 1.2 eq.) and pyridine (40 µL, 0.494 mmol, 1.05 eq.) were added. The reaction 30 mixture was stirred at rt for 72h. Upon completion, the reaction mixture was quenched with water and diluted with CH2Cl2. The product was extracted with CH2Cl2. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired compound (157 mg, 77%). MS (ESI+): m / z =425 [M + H]+. 35 Step 3. [(2S)-1-benzhydrylpiperazin-2-yl]methyl acetate;dihydrochloride 81 Tert-butyl (3S)-3-(acetoxymethyl)-4-benzhydryl-piperazine-1-carboxylate (157 mg, 0.366 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (0.763 mL). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the crude product as an off-white solid (144 mg, 99 %). MS (ESI+): m / z =325 [M + H]+.5 Step 4. [(2S)-1-benzhydryl-4-(furo[3,2-c]pyridine-7-carbonyl)piperazin-2-yl]methylacetate Furo[3,2-c]pyridine-7-carboxylic acid (148 mg, 0.372 mmol, 1.2 eq.) was solubilized in dry DMF (2 mL) under inert atmosphere. N,N-Diisopropylethylamine (255 µL, 1.49 mmol, 4.0 eq.) and [(2S)-1-benzhydrylpiperazin-2-yl]methyl acetate;dihydrochloride (148 mg, 10 0.372 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and HBTU (170 mg, 0.447 mmol, 1.2 eq.) was added. The reaction mixture was stirred at rtovernight. The solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to 15 afford the [(2S)-1-benzhydryl-4-(furo[3,2-c]pyridine-7-carbonyl)piperazin-2-yl]methyl acetate. MS (ESI+): m / z =470 [M + H]+.Step 5. [(3S)-4-benzhydryl-3-(hydroxymethyl)piperazin-1-yl]-furo[3,2-c]pyridin-7-yl-methanone To a solution of [(2S)-1-benzhydryl-4-(furo[3,2-c]pyridine-7-carbonyl)piperazin-2-20 yl]methyl acetate (314 mg, 0.669 mmol, 1.0 eq.) in THF (11.0 mL), was added NaOH (32mg, 0.803 mmol, 1.2 eq.) in water (2.8 mL). The mixture was stirred 48 h at r.t. The resulting solution was evaporated under reduced pressure and the crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (100 mg, 35 %). MS (ESI+): m / z =428 [M+H]+. HRMS-ESI+25 (m / z): calculated for C26H26N3O3[M+H]+= 428.1974; found: 428.1983. 1H NMR (500 MHz, 263 K, CDCl3) δ: 8.97 (s, 0.7H), 8.88 (s, 0.3H), 8.59 (s, 0.7H), 8.51(s, 0.3H), 7.72 (d, J = 2.2 Hz, 0.7H), 7.69 (d, J = 2.2 Hz, 0.3H), 7.45-7.41 (m, 4H), 7.30-7.27 (m, 2H+0.6H), 7.25-7.23 (m, 1H+0.2H), 7.22-7.14 (m, 2H), 6.91 (d, J = 2.2 Hz,0.7H), 6.89 (d, J = 2.2 Hz, 0.3H), 5.04 (s, 0.3H), 4.88 (s, 0.8H), 4.83 (br s, 0.3H, OH),30 4.62 (d, J = 13.8 Hz, 0.7H), 4.34 (d, J = 13.8 Hz, 0.3H), 3.88-3.81 (m, 1H+0.4H), 3.78-3.75 (m, 0.3 H), 3.59 (t, J = 9.0 Hz, 0.3H), 3.53-3.48 (m, 1H), 3.42-3.34 (m, 1H+0.3H),3.30 (br s, 0.5H), 3.28 (br s, 0.4H), 3.23 (br s, 0.9H), 2.91-2.85 (m, 0.7H), 2.80-2.76 (m, 0.4H), 2.69-2.65 (m, 0.9H), 2.58 (br s, 0.5H), 2.55 (br s, 0.3H). 82 Example 662-[1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazin-2-yl]-N- methyl-acetamide Step 1. Methyl 2-[1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazin-2-yl]acetate 5 Thieno[2,3-c]pyridine-4-carboxylic acid (161 mg, 0.898 mmol, 1.0 eq.) was solubilized in dry DMF (7 mL) under inert atmosphere. N,N-Diisopropylethylamine ( 615 µL, 3.59 mmol, 4.0 eq.) and methyl 2-(1 benzhydrylpiperazin-2-yl)acetate;dihydrochloride (428 mg, 1.08 mmol, 1.2 eq.) were added. The mixture was stirred at rt for 10 min and HBTU (409 mg, 1.08 mmol, 1.2 eq.) was added. The reaction mixture was stirred at rt overnight. The 10 solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product (335 mg, 77 %). MS (ESI+): m / z =486 [M + H]+. Step 2. Sodium;2-[1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazin-2-15 yl]acetate To a solution of Methyl2-[1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazin-2- yl]acetate (315 mg, 0.649 mmol, 1.0 eq.) in THF (6.0 mL), was added NaOH (130 mg, 3.24 mmol, 5.0 eq.) in water (2.0 mL). The mixture was stirred 72 h at r.t. The resulting solution was concentrated under reduced pressure and the crude product was purified 20 by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product (250 mg, 78 %). MS (ESI+): m / z =472 [M+H]+. Step 3. 2-[1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide Sodium;2-[1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazin-2-yl]acetate (100 25 mg, 0.203 mmol, 1.0 eq.) was solubilized in dry DMF (1.3 mL) under inert atmosphere. N,N-Diisopropylethylamine (104 µL, 0.608 mmol, 3.0 eq.), HBTU (92 mg, 0.243 mmol, 1.2 eq.) and methanamine hydrochloride (27 mg, 0.405 mmol, 2.0 eq.) were added. The mixture was stirred at rt overnight. The solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and concentrated under 30 reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (40 mg, 41 %). MS (ESI+): m / z =485 [M+H]+. HRMS-ESI+ (m / z): calculated for C28H29N4O2S [M+H]+= 485.2011; found: 485.2034. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.31 (s, 0.3H), 9.27 (s, 0.6H),35 8.48 (br s, 0.3H), 8.44 (s, 0.6H), 8.22 (d, J = 5.4 Hz, 1H), 7.77 (br s, 0.3H), 7.59 (br s, 83 0.6H), 7.49-7.43 (m, 5H), 7.32-7.13 (m, 6H), 4.82 (s, 0.3H), 4.76 (s, 0.6H), 4.45 (d, J = 12.5 Hz, 0.6H), 4.31 (d, J = 12.5 Hz, 0.3H), 3.48 (d, J = 12.7 Hz, 0.7H), 3.39 (br s, 0.5H),3.28-3.15 (m, 1H+0.6H), 3.07 (br d, 1H+0.4H), 2.62-2.51 (m, 2H), 2.45 (br s, 0.7H), 2.40 (br s, 0.4H), 2.37-2.32 (m, 1H+0.3H), 2.26 (br s, 0.5H), 2.21 (br s, 0.3H), 2.09 (br d, 5 1H+0.8H). Example 67 2-[1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazin-2-yl]- N,N-dimethyl-acetamide Sodium;2-[1-benzhydryl-4-(thieno[2,3-c]pyridine-4-carbonyl)piperazin-2-yl]acetate (102 10 mg, 0.206 mmol, 1.0 eq.) was solubilized in dry DMF (1.3 mL) under inert atmosphere. N,N-Diisopropylethylamine (106 µL, 0.617 mmol, 3.0 eq.), HBTU (94 mg, 0.247 mmol, 1.2 eq.) and N-methylmethanamine;hydrochloride (34 mg, 0.411 mmol, 2.0 eq.) were added. The mixture was stirred at rt overnight. The solution was diluted with EtOAc and washed with a solution of NaOH (1N) and brine, dried over MgSO4, filtered and 15 concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (50 mg, 49 %). MS (ESI+): m / z =499 [M+H]+. HRMS-ESI+ (m / z): calculated for C29H31N4O2S [M+H]+= 499.2168; found: 499.2193. 1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.32 (br s, 0.3H), 9.25 (s,20 0.7H), 8.47 (br s, 0.3H), 8.28 (br s, 0.6H), 8.23 (d, J = 5.4 Hz, 1H), 7.50-7.42 (m, 5H),7.32-7.09 (m, 6H), 4.85 (s, 1H), 4.46 (d, J = 12.8 Hz, 0.7H), 4.38 (d, J =12.8 Hz, 0.3H),3.49 (br s, 0.4H), 3.45 (br s, 0.6H), 3.37 (br s, 0.8H), 3.26-3.05 (m, 2H), 3.01 (s, 1H), 2.89 (s, 2H), 2.77 (br s, 0.8H), 2.70-2.58 (m, 1H+0.9H), 2.55-2.52 (m, 1H), 2.37 (br s, 1H), 2.32 (br s, 0.5H), 2.26 (s, 2H). 25 Example 68 2-[1-benzhydryl-4-(2-methyl-1H-imidazo[4,5-c]pyridine-7- carbonyl)piperazin-2-yl]-N-methyl-acetamide step 1. ethyl 2-methyl-1H-imidazo[4,5-c]pyridine-7-carboxylate Ethyl 4,5-diaminopyridine-3-carboxylate (80 mg, 0.44 mmol, 1.0 eq.) was solubilized in 30 1,1,1-triethoxyethane (1 mL).4-methylbenzenesulfonic acid;hydrate (9.0 mg, 0.04 mmol, 0.1 eq.) was added. The mixture was stirred under microwave irradiation at 150°C for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (65 mg, 70%). MS (ESI+): m / z =206 [M + H]+.35 Step 2. sodium;2-methyl-1H-imidazo[4,5-c]pyridine-7-carboxylate 84 Ethyl 1H-imidazo[4,5-c]pyridine-7-carboxylate (40.0 mg, 0.21 mmol, 1.0 eq.) was solubilized in MeOH (400 µL) and THF (400 µL). NaOH 3M in water (320 µL, 0.95 mmol, 3.0 eq.) was added. The reaction mixture was stirred at rt overnight. The mixture was neutralized with a 1M aqueous solution of HCl solution until pH=7 and concentrated 5 under reduced pressure to give the desired product as a white solid (63 mg, quant.). The crude product was used in the next without further purification. MS (ESI+): m / z =164 [M+H]+, MS (ESI-): m / z =162 [M-H]-. Step 3. 2-[1-benzhydryl-4-(4-methoxypyridine-3-carbonyl)piperazin-2-yl]-N- methyl-acetamide 10 Sodium;2-methyl-1H-imidazo[4,5-c]pyridine-7-carboxylate (60 mg, 0.30 mmol, 1.2 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. N,N-Diisopropylethylamine (130 µL, 0.76 mmol, 3.0 eq.), 2-(1-benzhydrylpiperazin-2-yl)-N-methyl- acetamide;dihydrochloride (100 mg, 0.25 mmol, 1.0 eq.) and HBTU (115 mg, 0.30 mmol, 1.2 eq.) were added. The reaction mixture was stirred at rt overnight. A 1M aqueous15 solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1). A second purification by flash column chromatography on silica gel in using as eluant (DCM / MeOH 100:0 to 20 90:10) was performed to afford the desired product as a white solid (10 mg, 8%). MS (ESI+): m / z =483 [M + H]+, HRMS-ESI+ (m / z): calcd for C28H31N6O2[M+H]+: 483.2508; found:483.2523. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.75 (br s, 1H), 8.32 (s, 1H), 7.47-7.36 (m, 4H),7.31-7.20 (m, 4H), 7.22-7.10 (m, 2H), 6.66 (br s, 0.5H), 4.64 (s, 1H), 4.56 (br s, 1H),25 3.70-3.49 (m, 1H), 3.49-3.09 (m, 4H), 2.66-2.29 (m, 10H). Example 69 Ethyl 2-[(2R)-1-[(R)-(3-fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]acetate / Ethyl 2-[(2R)-1-[(S)-(3-fluorophenyl)-phenyl- methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate 30 Step 1. Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)-4-[(3-fluorophenyl)-phenyl- methyl]piperazine-1-carboxylate Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (300 mg, 1.05 mmol, 1.0 eq.) was solubilized in dry ACN (4 mL). 1-[bromo(phenyl)methyl]-3-fluoro-benzene (330 mg, 1.24 mmol, 1.2 eq.) and triethylamine (300 µL, 2.09 mmol, 2.0 eq.) were added. 35 The reaction mixture was heated at 50°C for one day. The crude product was purified by 85 reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (200 mg, 41%). MS (ESI+): m / z =457 [M+H]+.Step 2. 2-[(2R)-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2- yl]acetate;dihydrochloride 5 Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)-4-[(3-fluorophenyl)-phenyl-methyl]piperazine-1- carboxylate (50 mg, 0.11 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (500 µL, 2.0 mmol, 19.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the crude product as an off-white solid (47 mg, quant.).MS (ESI+): m / z =357 [M + H]+. 10 Step 3. ethyl 2-[(2R)-1-[(3-fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]acetate Ethyl 2-[(2R)-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2-yl]acetate;dihydrochloride (47 mg, 0.11 mmol, 1.0 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N-Diisopropylethylamine (60 µL, 0.33 mmol, 3.0 eq.), isoquinoline-4-carboxylic acid15 (23 mg, 0.13 mmol, 1.2 eq.) and HBTU (50 mg, 0.13 mmol, 1.2 eq.) were added. Thereaction mixture was stirred at rt overnight. A 1M aqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase 20 chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (30 mg, 54%). MS (ESI+): m / z =512 [M + H]+, HRMS-ESI+ (m / z): calcd for C31H31N3O3F [M+H]+: 512.2349; found: 512.2363. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture ofdiastereoisomers and rotamers: 9.23 (br s, 1H), 8.46 (br s, 1H), 8.06-7.91 (m, 1H), 7.83-7.71 (m, 1H), 7.71-7.58 (m, 1H), 7.47-7.03 (m, 9H), 6.95-6.76 (m, 1H), 4.80-4.54 (m, 2H),25 4.22-4.00 (m, 1H), 3.87 (br s, 0.5H), 3.68-3.49 (m, 1H), 3.49-3.05 (m, 3H+0.5H), 2.82- 2.25 (m, 4H), 1.30-1.17 (m, 1H+0.6H), 1.17-1.00 (m, 1H), 0.69 (br s, 0.4H).19F NMR (282MHz, CDCl3) δ (ppm) Mixture of diastereoisomers and rotamers: -112.3, -112.4.Example 70 ethyl 2-[(2S)-1-[(R)-(3-fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4-30 carbonyl)piperazin-2-yl]acetate / ethyl 2-[(2S)-1-[(S)-(3-fluorophenyl)-phenyl- methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate Step 1. tert-butyl (3S)-3-(2-ethoxy-2-oxo-ethyl)-4-[(3-fluorophenyl)-phenyl-methyl]piperazine-1- carboxylate Tert-butyl (3S)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (300 mg, 1.05 mmol, 35 1.0 eq.) was solubilized in dry ACN (4 mL). 1-[bromo(phenyl)methyl]-3-fluoro-benzene 86 (330 mg, 1.24 mmol, 1.2 eq.) and triethylamine (300 µL, 2.09 mmol, 2.0 eq.) were added. The reaction mixture was heated at 50°C for one day. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a colorless oil (280 mg, 59%). MS (ESI+): m / z =457 [M+H]+.5 Step 2. ethyl 2-[(2S)-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2- yl]acetate;dihydrochloride Tert-butyl (3S)-3-(2-ethoxy-2-oxo-ethyl)-4-[(3-fluorophenyl)-phenyl-methyl]piperazine-1- carboxylate (50 mg, 0.11 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (500 µL, 2.0 mmol, 19.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed10 under reduced pressure to give the crude product as an off-white solid (47 mg, quant.).MS (ESI+): m / z =357 [M + H]+. Step 3. ethyl 2-[(2S)-1-[(3-fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]acetate Ethyl 2-[(2S)-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2-yl]acetate;dihydrochloride 15 (47 mg, 0.11 mmol, 1.0 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N-Diisopropylethylamine (60 µL, 0.33 mmol, 3.0 eq.), isoquinoline-4-carboxylic acid (23 mg, 0.13 mmol, 1.2 eq.) and HBTU (50 mg, 0.13 mmol, 1.2 eq.) were added. Thereaction mixture was stirred at rt overnight. A 1M aqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed 20 with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (30 mg, 53%). MS (ESI+): m / z =512 [M + H]+, HRMS-ESI+ (m / z): calcd for C31H31N3O3F [M+H]+: 512.2349; found: 512.2358. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of25 diastereoisomers and rotamers: 9.23 (br s, 1H), 8.46 (br s, 1H), 8.04-7.91 (m, 1H), 7.84-7.71 (m, 1H), 7.71-7.58 (m, 1H), 7.47-7.05 (m, 9H), 6.95-6.77 (m, 1H), 4.79-4.56 (m, 2H), 4.20-4.03 (m, 1H), 3.87 (br s, 0.5H), 3.67-3.49 (m, 1H), 3.48-3.05 (m, 3H+0.5H), 2.83- 2.23 (m, 4H), 1.30-1.18 (m, 1H+0.6H), 1.17-1.03 (m, 1H), 0.69 (br s, 0.4H). 19F NMR(282 MHz, CDCl3) δ (ppm) Mixture of diastereoisomers and rotamers: -112.3, -112.4.30 Example 71 2-[(2R)-1-[(R)-(3-fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]-N-methyl-acetamide / 2-[(2R)-1-[(S)-(3-fluorophenyl)- phenyl-methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide 87 Step 1. lithium;2-[(2R)-4-tert-butoxycarbonyl-1-[(3-fluorophenyl)-phenyl- methyl]piperazin-2-yl]acetate Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)-4-[(3-fluorophenyl)-phenyl-methyl]piperazine-1- carboxylate (150 mg, 0.32 mmol, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of 5 MeOH / H2O (1 mL). Lithium hydroxide hydrate (40 mg, 0.97 mmol, 3.0 eq.) was added. The reaction mixture was stirred at rt for 3 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (85 mg, 61%). MS (ESI+): m / z =429 [M+H]+. Step 2. tert-butyl (3R)-4-[(3-fluorophenyl)-phenyl-methyl]-3-[2-(methylamino)-2-10 oxo-ethyl]piperazine-1-carboxylate Lithium 2-[(2R)-4-tert-butoxycarbonyl-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2- yl]acetate (80 mg, 0.18 mmol, 1.0 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N-Diisopropylethylamine (130 µL, 0.74 mmol, 3.0 eq.), methanamine;hydrochloride (37 mg, 0.55 mmol, 3.0 eq.) and HBTU (84 mg, 0.22 mmol,15 1.2 eq.) were added. The reaction mixture was stirred at rt overnight. A 1M aqueoussolution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired20 product as a white solid (60 mg, 74%). MS (ESI+): m / z =442 [M + H]+. Step 3. 2-[(2R)-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2-yl]-N-methyl- acetamide; dihydrochloride Tert-butyl (3R)-4-[(3-fluorophenyl)-phenyl-methyl]-3-[2-(methylamino)-2-oxo- ethyl]piperazine-1-carboxylate (60 mg, 0.14 mmol, 1.0 eq.) was solubilized in a 4M HCl 25 solution in dioxane (500 µL, 2.0 mmol, 15.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the desired product as an off- white solid (56 mg, quant.). MS (ESI+): m / z =342 [M + H]+. Step 4. 2-[(2R)-1-[(3-fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]-N-methyl-acetamide 30 Isoquinoline-4-carboxylic acid (25 mg, 0.15 mmol, 1.2 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N-Diisopropylethylamine (84 µL, 0.48 mmol, 4.0 eq.) and 2-[(2R)-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2-yl]-N-methyl-acetamide; dihydrochloride (50 mg, 0.12 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and and HBTU (55 mg, 0.15 mmol, 1.2 eq.) was added. The reaction mixture35 was stirred at rt overnight. A 1M aqueous solution of NaOH was added and the product 88 was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (32 mg, 53%). MS 5 (ESI+): m / z =497 [M + H]+, HRMS-ESI+ (m / z): calcd for C30H30N4O2F [M+H]+: 497.2353; found: 497.2354. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of diastereoisomers androtamers: 9.36-9.17 (m, 1H), 8.60-8.36 (m, 1H), 8.08-7.96 (m, 1H), 7.96-7.73 (m, 2H),7.73-7.60 (m, 1H), 7.48-7.29 (m, 3H), 7.29-7.06 (m, 5H), 6.97-6.76 (m, 1H), 4.80-4.56 (m, 2H), 3.57-3.44 (m, 1H), 3.44-3.15 (m, 3H), 2.85-2.68 (m, 2H+0.6H), 2.65-2.38 (m,10 3H), 2.38-2.12 (m, 1H+0.4H). 19F NMR (282 MHz, CDCl3) δ (ppm) Mixture ofdiastereoisomers and rotamers: -112.2, -112.25, -112.32, -112.4.Example 72 2-[(2S)-1-[(R)-(3-fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide / 2-[(2S)-1-[(S)-(3-15 fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N- methyl-acetamide Step 1. Lithium;2-[(2S)-4-tert-butoxycarbonyl-1-[(3-fluorophenyl)-phenyl- methyl]piperazin-2-yl]acetate Tert-butyl (3S)-3-(2-ethoxy-2-oxo-ethyl)-4-[(3-fluorophenyl)-phenyl-methyl]piperazine-1- 20 carboxylate (230 mg, 0.50 mmol, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of MeOH / H2O (1 mL). Lithium;hydroxide;hydrate (63 mg, 1.50 mmol, 3.0 eq.) was added. The reaction mixture was stirred at rt for 3 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a yellow oil (150 mg, 69%). MS (ESI+): m / z =429 [M+H]+. 25 Step 2. Tert-butyl (3S)-4-[(3-fluorophenyl)-phenyl-methyl]-3-[2-(methylamino)-2- oxo-ethyl]piperazine-1-carboxylate Lithium;2-[(2S)-4-tert-butoxycarbonyl-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2- yl]acetate (150 mg, 0.35 mmol, 1.0 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N-Diisopropylethylamine (240 µL, 1.38 mmol, 3.0 eq.), 30 methanamine;hydrochloride (70 mg, 1.04 mmol, 3.0 eq.) and HBTU (160 mg, 0.41 mmol, 1.2 eq.) were added. The reaction mixture was stirred at rt overnight. A 1M aqueoussolution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was 89 purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (90 mg, 59%). MS (ESI+): m / z =442 [M + H]+. Step 3. 2-[(2S)-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2-yl]-N-methyl- acetamide; dihydrochloride 5 Tert-butyl (3S)-4-[(3-fluorophenyl)-phenyl-methyl]-3-[2-(methylamino)-2-oxo- ethyl]piperazine-1-carboxylate (90 mg, 0.20 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (800 µL, 3.20 mmol, 16.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the desired product as an off- white solid (87 mg, quant.). MS (ESI+): m / z =342 [M + H]+. 10 Step 4. 2-[(2S)-1-[(R)-(3-fluorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]-N-methyl-acetamide / 2-[(2S)-1-[(S)-(3-fluorophenyl)- phenyl-methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide Isoquinoline-4-carboxylic acid (23 mg, 0.13 mmol, 1.2 eq.) was solubilized in dry DMF (500 µL) under inert atmosphere. N,N-Diisopropylethylamine (75 µL, 0.43 mmol, 4.0 eq.)15 and 2-[(2S)-1-[(3-fluorophenyl)-phenyl-methyl]piperazin-2-yl]-N-methyl- acetamide;dihydrochloride (45 mg, 0.11 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and and HBTU (50 mg, 0.13 mmol, 1.2 eq.) was added. Thereaction mixture was stirred at rt overnight. A 1M aqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed20 with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (30 mg, 55%). MS (ESI+): m / z =497 [M + H]+, HRMS-ESI+ (m / z): calcd for C30H30N4O2F [M+H]+: 497.2353; found: 497.2357 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of25 diastereoisomers and rotamers: 9.37-9.18 (m, 1H), 8.59-8.39 (m, 1H), 8.09-7.96 (m, 1H),7.96-7.74 (m, 2H), 7.74-7.62 (m, 1H), 7.48-7.29 (m, 3H), 7.29-7.06 (m, 5H), 6.97-6.76 (m, 1H), 4.80-4.57 (m, 2H), 3.57-3.44 (m, 1H), 3.44-3.14 (m, 3H), 2.86-2.67 (m, 2H+0.6H), 2.67-2.38 (m, 3H), 2.38-2.12 (m, 1H+0.4H). 19F NMR (282 MHz, CDCl3) δ(ppm) Mixture of diastereoisomers and rotamers: -112.2, -112.25, -112.33, -112.4.30 Example 73 2-[(2R)-1-[(R)-(4-chlorophenyl)-phenyl-methyl]-4-(isoquinoline- 4-carbonyl)piperazin-2-yl]-N-methyl-acetamide / 2-[(2R)-1-[(S)-(4- chlorophenyl)-phenyl-methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N- methyl-acetamide 35 Step 1.1-[bromo(phenyl)methyl]-4-chloro-benzene 90 In a dried, argon-flushed 50 mL round bottom flask, (4-chlorophenyl)-phenyl-methanol (1000 mg, 4.48 mmol, 1.0 eq.) and dry DCM (6 mL) were added. The reaction mixture was cooled down at 0°C. Phosphorus tribromide (2.2 mL, 22.4 mmol, 5.0 eq.) in dichloromethane (6 mL) was added dropwise. After the addition of PBr3, the cooling bath 5 was removed and the solution was allowed to reach room temperature. Stirring was continued for 3 h, then crushed ice was added into the mixture, following by DCM. The crude compound was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as a colorless oil (1330 mg, quant.). The crude product was used in10 the next step without further purification. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.39-7.20 (m, 9H), 6.18 (s, 1H).Step 2. Tert-butyl (3R)-4-[(4-chlorophenyl)-phenyl-methyl]-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (600 mg, 2.2 mmol, 1.0 15 eq.) was solubilized in dry ACN (6.3 mL). N,N-Diisopropylethylamine (1.5 mL, 8.8 mmol, 4.0 eq.) was added and the mixture was stirred at rt for 15 min.1-[bromo(phenyl)methyl]- 4-chloro-benzene (1241 mg, 4.4 mmol, 2.0 eq.) was added. The mixture was heated at 30°C overnight and then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the20 desired product as a white lyophilizate (474 mg, 46%). MS (ESI+): m / z =473 [M+H]+. Step 3. Lithium;2-[(2R)-4-tert-butoxycarbonyl-1-[(4-chlorophenyl)-phenyl-methyl]piperazin-2-yl]acetate To a solution of tert-butyl (3R)-4-[(4-chlorophenyl)-phenyl-methyl]-3-(2-ethoxy-2-oxo- ethyl)piperazine-1-carboxylate (464 mg, 0.98 mmol, 1.0 eq.) in MeOH (0.5 mL), was25 added lithium;hydroxide;hydrate (123 mg, 2.94 mmol, 3.0 eq.) in water (0.1 mL). The mixture was stirred for 24h at 35°C. The crude product was concentrated under reduced pressure and purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (314 mg, 71%). MS (ESI+): m / z =445[M+H]+.30 Step 4. Tert-butyl (3R)-4-[(4-chlorophenyl)-phenyl-methyl]-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate Lithium;2-[(2R)-4-tert-butoxycarbonyl-1-[(4-chlorophenyl)-phenyl-methyl]piperazin-2- yl]acetate (300 mg, 0.59 mmol, 1.0 eq.) was solubilized in dry DMF (2.8 mL) under inert atmosphere. N,N-Diisopropylethylamine (310 µL, 1.78 mmol, 3.0 eq.), 35 methanamine;hydrochloride (48.0 mg, 0.71 mmol, 1.2 eq.) and HBTU (247 mg, 0.65 91 mmol, 1.1 eq.) were added. After one night at rt with stirring, the mixture was diluted with EtOAc, washed with NaHCO3 (sat.), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white5 lyophilizate (148 mg, 55%). MS (ESI+): m / z =458 [M+H]+.Step 5. 2-[(2R)-1-[(4-chlorophenyl)-phenyl-methyl]piperazin-2-yl]-N-methyl- acetamide;dihydrochloride HCl 4M in dioxane (8 eq., 2.52 mmol, 0.63 mL) was added to tert-butyl (3R)-4-[(4- chlorophenyl)-phenyl-methyl]-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate 10 (138 mg, 0.301 mmol) at 0°C and stirred overnight at rt. Dichloromethane was then added and the mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate orange solid (142 mg, quant.). MS (ESI+): m / z =358 [M+H]+. Step 6. 2-[(2R)-1-[(4-chlorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]-N-methyl-acetamide 15 2-[(2R)-1-[(4-chlorophenyl)-phenyl-methyl]piperazin-2-yl]-N-methyl- acetamide;dihydrochloride (64.6 mg, 0.15 mmol, 1.0 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (78 µL, 0.45 mmol, 3.0 eq.), isoquinoline-4-carboxylic acid (31.2 mg, 0.18 mmol, 1.2 eq.) and HBTU (62.6 mg, 0.17 mmol, 1.1 eq.) were added. After one night at rt with stirring, the mixture was diluted with 20 EtOAc, washed with NaHCO3(sat.), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a whitelyophilisate (32 mg, 42%). MS (ESI+) m / z: =513 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+:calcd. for C30H30N4O2Cl m / z= 513.2057, found m / z= 513.2078.25 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of diastereoisomers and rotamers: 9.28 (s,0.5H), 9.24 (s, 0.5H), 8.51 (br s, 1H), 8.05-8.02 (m, 1H), 7.89-7.66 (m, 3H), 7.44-7.28 (m, 6H), 7.24-7.10 (m, 4H), 4.74-4.67 (m, 2H), 3.47-3.24 (m, 4H), 2.80-2.73 (m, 3H), 2.53-2.31 (m, 4H). 30 Example 74 2-[1-[bis(4-chlorophenyl)methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]-N-methyl-acetamide Step 1.1-[bromo-(4-chlorophenyl)methyl]-4-chloro-benzene In a dried, argon-flushed 25 mL round bottom flask, bis(4-chlorophenyl)methanol (600 mg, 2.32 mmol, 1.0 eq.) and dry DCM (3.2 mL) were added. The reaction mixture was 35 cooled down at 0°C. Phosphorus tribromide (1.1 mL, 11.6 mmol, 5.0 eq.) in 92 dichloromethane (3.2 mL) was added dropwise. After the addition of PBr3, the cooling bath was removed and the solution was allowed to reach room temperature. Stirring was continued for 3 h, then crushed ice was added into the mixture, following by DCM. The crude compound was extracted with DCM. The combined organic layers were washed 5 with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as a pale yellow oil (855 mg, quant.). The crude product was used in the next step without further purification. Step 2. Tert-butyl 4-[bis(4-chlorophenyl)methyl]-3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate 10 Tert-butyl 3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate (300 mg, 1.2 mmol, 1.0 eq.) was solubilized in dry ACN (3.3 mL). N,N-Diisopropylethylamine (0.8 mL, 4.7 mmol, 4 eq.) was added and the mixture was stirred at rt for 15 min. 1-[bromo-(4- chlorophenyl)methyl]-4-chloro-benzene (734 mg, 2.3 mmol, 2.0 eq.) was added. The mixture was heated at 35°C for a week and was then concentrated under reduced 15 pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (260 mg, 45%). MS (ESI+): m / z =493 [M+H]+. Step 3. Lithium;2-[1-[bis(4-chlorophenyl)methyl]-4-tert-butoxycarbonyl-piperazin- 2-yl]acetate 20 To a solution of tert-butyl 4-[bis(4-chlorophenyl)methyl]-3-(2-methoxy-2-oxo- ethyl)piperazine-1-carboxylate (249 mg, 0.51 mmol, 1.0 eq.) in MeOH (1.0 mL), wasadded lithium;hydroxide;hydrate (63.5 mg, 1.51 mmol, 3.0 eq.) in water (0.2 mL). The mixture was stirred for 24h at 35°C. The crude product was concentrated under reduced pressure and purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to25 afford the desired product as a white lyophilizate (149 mg, 61%). MS (ESI+): m / z =479[M+H]+. Step 4. Tert-butyl 4-[bis(4-chlorophenyl)methyl]-3-[2-(methylamino)-2-oxo- ethyl]piperazine-1-carboxylate Lithium;2-[1-[bis(4-chlorophenyl)methyl]-4-tert-butoxycarbonyl-piperazin-2-yl]acetate 30 (144 mg, 0.30 mmol, 1.0 eq.) was solubilized in dry DMF (1.4 mL) under inert atmosphere. N,N-Diisopropylethylamine (155 µL, 0.89 mmol, 3.0 eq.), methanamine;hydrochloride (24.0 mg, 0.36 mmol, 1.2 eq.) and HBTU (124 mg, 0.33 mmol, 1.1 eq.) were added. After one night at rt with stirring, the mixture was diluted with EtOAc, washed with NaHCO3 (sat.), dried over MgSO4, filtered and concentrated under 93 reduced pressure to afford the desired product as a yellow oil (127 mg, 82%). MS (ESI+):m / z =492 [M+H]+. Step 5. 2-[1-[bis(4-chlorophenyl)methyl]piperazin-2-yl]-N-methyl- acetamide;dihydrochloride 5HCl 4M in dioxane (10 eq., 2.0 mmol, 0.50 mL) was added to tert-butyl 4-[bis(4-chlorophenyl)methyl]-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate (117 mg, 0.2 mmol, 1 eq.) at 0°C and stirred for 24 hours at rt. Dichloromethane was then added and the solution mixture was concentrated under reduced pressure, to afford the desired product as chlorhydrate white solid (114 mg, yield: quant). MS (ESI+): m / z =392 [M+H]+. 10 Step 6. 2-[1-[bis(4-chlorophenyl)methyl]-4-(isoquinoline-4-carbonyl)piperazin-2- yl]-N-methyl-acetamide 2-[1-[bis(4-chlorophenyl)methyl]piperazin-2-yl]-N-methyl-acetamide;dihydrochloride (114.0 mg, 0.24 mmol, 1.0 eq.) was solubilized in dry DMF (1.1 mL) under inert atmosphere. N,N-Diisopropylethylamine (124 µL, 0.71 mmol, 3.0 eq.), isoquinoline-4- 15 carboxylic acid (49.5 mg, 0.29 mmol, 1.2 eq.) and HBTU (99.3 mg, 0.26 mmol, 1.1 eq.) were added. After one night at rt with stirring, the mixture was diluted with EtOAc, washed with NaHCO3(sat.), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (68.0 mg, 52%).20 MS (ESI+): m / z =547 [M+H]+.HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H29N4O2Cl2m / z= 547.1668, found m / z= 547.1666. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.29-9.25 (m, 1H), 8.50 (br s,1H), 8.06-8.03 (m, 1H), 7.89-7.72 (m, 2H), 7.72-7.67 (m, 1H), 7.40-7.18 (m, 8H), 4.73- 4.61 (m, 2H), 3.48-3.17 (m, 4H), 2.80-2.70 (m, 3H), 2.59-2.16 (m, 4H). 25 Example 75 2-[1-[bis(3-chlorophenyl)methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]-N-methyl-acetamide Step 1.1-[bromo-(3-chlorophenyl)methyl]-3-chloro-benzene In a dried, argon-flushed 25 mL round bottom flask, bis(3-chlorophenyl)methanol (600 30 mg, 2.32 mmol, 1.0 eq.) and dry DCM (3.2 mL) were added. The reaction mixture was cooled down at 0°C. Phosphorus tribromide (1.1 mL, 11.6 mmol, 5.0 eq.) in dichloromethane (3.2 mL) was added dropwise. After the addition of PBr3, the cooling bath was removed and the solution was allowed to reach room temperature. Stirring was continued for 3 h, then crushed ice was added into the mixture, following by DCM. The 35 crude compound was extracted with DCM. The combined organic layers were washed 94 with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as a pale yellow oil (765 mg, quant.). The crude product was used in the next step without further purification. Step 2. Tert-butyl 4-[bis(3-chlorophenyl)methyl]-3-(2-methoxy-2-oxo- 5 ethyl)piperazine-1-carboxylate Tert-butyl 3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate (300 mg, 1.2 mmol, 1.0 eq.) was solubilized in dry ACN (3.3 mL). N,N-Diisopropylethylamine (0.5 mL, 2.9 mmol, 2.5 eq.) was added and the mixture was stirred at rt for 15 min. 1-[bromo-(3- chlorophenyl)methyl]-3-chloro-benzene (734 mg, 2.3 mmol, 2.0 eq.) and sodium iodide 10 (34.8 mg, 0.2 mmol, 0.2 eq.) were added. The mixture was heated at 35°C for a week and was then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilisate (300 mg, 45%). MS (ESI+): m / z =493 [M+H]+.Step 3. Lithium;2-[1-[bis(3-chlorophenyl)methyl]-4-tert-butoxycarbonyl-piperazin-15 2-yl]acetate To a solution of tert-butyl 4-[bis(3-chlorophenyl)methyl]-3-(2-methoxy-2-oxo- ethyl)piperazine-1-carboxylate (300 mg, 0.61 mmol, 1.0 eq.) in MeOH (1.2 mL), wasadded lithium;hydroxide;hydrate (76.5 mg, 1.82 mmol, 3.0 eq.) in water (0.2 mL). The mixture was stirred for 24h at 35°C. The crude product was concentrated under reduced20 pressure and purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (127 mg, 43%). MS (ESI+): m / z =479[M+H]+. Step 4. Tert-butyl 4-[bis(3-chlorophenyl)methyl]-3-[2-(methylamino)-2-oxo- ethyl]piperazine-1-carboxylate 25 Lithium;2-[1-[bis(3-chlorophenyl)methyl]-4-tert-butoxycarbonyl-piperazin-2-yl]acetate (122 mg, 0.25 mmol, 1.0 eq.) was solubilized in dry DMF (1.2 mL) under inert atmosphere. N,N-Diisopropylethylamine (131 µL, 0.75 mmol, 3.0 eq.), methanamine;hydrochloride (20.4 mg, 0.11 mmol, 1.2 eq.) and HBTU (45.4 mg, 0.12 mmol, 1.1 eq.) were added. After one night at rt with stirring, the mixture was diluted with 30 EtOAc, washed with NaHCO3 (sat.), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as a yellow oil (110 mg, 86%). MS (ESI+):m / z =492 [M+H]+. Step 5. 2-[1-[bis(3-chlorophenyl)methyl]piperazin-2-yl]-N-methyl- acetamide;dihydrochloride 95 HCl 4M in dioxane (8 eq., 1.68 mmol, 0.42 mL) was added to tert-butyl 4-[bis(3-chlorophenyl)methyl]-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate (100 mg, 0.2 mmol, 1 eq.) at 0°C and stirred overnight at rt. Dichloromethane was then added and the solution mixture was concentrated under reduced pressure, to afford the desired 5 product as chlorhydrate white solid (98 mg, yield: quant.). MS (ESI+): m / z =392 [M+H]+. Step 6. 2-[1-[bis(3-chlorophenyl)methyl]-4-(isoquinoline-4-carbonyl)piperazin-2- yl]-N-methyl-acetamide 2-[1-[bis(3-chlorophenyl)methyl]piperazin-2-yl]-N-methyl-acetamide;dihydrochloride (97.4 mg, 0.20 mmol, 1.0 eq.) was solubilized in dry DMF (1.0 mL) under inert10 atmosphere. N,N-Diisopropylethylamine (106 µL, 0.22 mmol, 3.0 eq.), isoquinoline-4- carboxylic acid (42.2 mg, 0.24 mmol, 1.2 eq.) and HBTU (84.7 mg, 0.22 mmol, 1.1 eq.) were added. After one night at rt with stirring, the mixture was diluted with EtOAc, washed with NaHCO3(sat.), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography15 (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (45.0 mg, 40%).MS (ESI+): m / z =547 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H29N4O2Cl2m / z= 457.1668, found m / z= 547.1664. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.29-9.25 (m, 1H), 8.50 (br s,1H), 8.06-8.03 (m, 1H), 7.89-7.82 (m, 2H), 7.72-7.67 (m, 1H), 7.44-7.11 (m, 8H), 4.74-20 4.59 (m, 2H), 3.48-3.27 (m, 4H), 2.80-2.72 (m, 3H), 2.60-2.22 (m, 4H). EXAMPLE 76: 2-[1-benzhydryl-4-(furo[2,3-c]pyridine-4-carbonyl)piperazin-2-yl]-N- methyl-acetamide Step 1. Tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-25 carboxylate / Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (1000 mg, 3.67 mmol, 1.0 eq.) was solubilized in dry ACN (15.2 mL). DIEA (943 µL, 5.51 mmol, 1.5 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (907 mg, 3.67 mmol, 1.0 eq.) was added. The mixture was heated at 50°C for 10 days.0.2 eq 30 of [bromo(phenyl)methyl]benzene and 0.5 ed of DIEA were added in three times during 7 days. Once the reaction completed, the mixture was diluted with EtOAc and washed with a saturated solution of NaHCO35%. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude obtained was used for the next stage without further purification. 35 Step 2.2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetic acid / 96 Tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (1610 mg, 3.67 mmol, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of MeOH / H2O. Lithium hydroxide hydrate (462 mg, 11.01 mmol, 3.0 eq.) was added. The reaction mixture was stirred at rt for 3 hours. The mixture was concentrated and the residue was purified by 5 reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as an off-white solid (958 mg, 63%). MS (ESI+): m / z =411.36 [M+H]+. Step 3. Tert-butyl (3R)-4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1- carboxylate 2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetic acid (940 mg, 2.2910 mmol, 1.0 eq.) was solubilized in dry DMF (15 mL) under inert atmosphere. N,N- Diisopropylethylamine (1.18mL, 6.870 mmol, 3 eq.), methanamine;hydrochloride (186 mg, 2.75 mmol, 1.2 eq.) and HBTU (955 mg, 2.52 mmol, 1.1 eq.) were added. The mixture was stirred at rt overnight. The mixture was diluted with ethyl acetate and washed with a 1M aqueous solution of NaOH, dried over MgSO4, filtered and concentrated under 15 reduced pressure. The desired product was obtained as a colored oil (1.26 g). The crude obtained was used for the next step without any further purification. MS (ESI+): m / z=424.46 [M+H]+. Step 4.2-[(2R)-(1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloridetert-butyl (3R)-4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate20 (1.02 g 0.78 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (4.0 mL,16.0 mmol, 20.0 eq.). The mixture was stirred for 2h at rt. Solvents were removed under reduced pressure to afford the desired product as a yellow solid (1.2 g, quant.). Step 5.2-[1-benzhydryl-4-(furo[2,3-c]pyridine-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide 25 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (60 mg, 0.18 mmol, 1.0 eq.) was solubilized in dry DMF (1.5 mL) under inert atmosphere. furo[2,3- c]pyridine-4-carboxylic acid (36.3 mg, 0.22 mmol, 1.2 eq.), N,N-Diisopropylethylamine (127 µL, 0.74 mmol, 4 eq.) and HBTU (213 mg, 0.22 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc30 and washed with a saturated solution of NaHCO3. The organic phase was dried overMgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) to afford the desired product as a white powder (18 mg, 23%). MS (ESI+) m / z =469 [M+H]+. HRMS- ESI+ (m / z): calcd for C28H29N4O3 [M+H]+: 469.2240; found: 469.2219. 97 1H NMR (300 MHz, CDCl3) δ (ppm): 8.93 (s, 1H), 8.49 (s, 1H), 7.85 (s, 1H), 7.52-7.27(m, 6.4H), 7.24-7.06 (m, 4.1 H), 6.88 (s, 1H), 4.69 (s, 1H), 4.61-4.47 (m, 1H), 3.67-3.16 (m, 4.2 H), 2.76 (s, 2.6H), 2.61-2.15 (m, 4.6H). 5 EXAMPLE 77 2-[1-benzhydryl-4-(furo[3,2-c]pyridine-7-carbonyl)piperazin-2-yl]-N- methyl-acetamide Step 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochlorideacetamide (60 mg, 0.186 mmol, 1.0 eq.) was solubilized in dry DMF (1.5 mL) under inert atmosphere. Furo[3,2-c]pyridine-7-carboxylic acid (36.3 mg, 10 0.223 mmol, 1.2 eq.), N,N-Diisopropylethylamine (127 µL, 0.742 mmol, 4 eq.) and HBTU (213 mg, 0.223 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with a saturated solution ofNaHCO3. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography 15 (ACN / H2O 10:90 to 100:0) to afford the desired product as a white powder (20 mg, 23%). MS (ESI+) m / z =358 [M+H]+. HRMS-ESI+ (m / z): calcd for C28H29N4O3[M+H]+: 469.2240 ; found: 469.2212.1H NMR (300 MHz, CDCl3) δ (ppm): 9.02-8.92 (m, 1H),8.61-8.52 (m, 1H), 7.72 (s, 1H), 7.53-7.27 (m, 6.5H), 7.25-7.1 (m, 3H), 6.92 (br, 1.7H), 4.81-4.48 (m, 2H), 3.68-3.15 (m, 4H), 2.81-2.71 (m, 2.4 H), 2.68-2.22 (m,20 4.5H). EXAMPLE 78: 2-[(2R)-1-benzhydryl-4-(1H-pyrrolo[3,2-c]pyridine-7- carbonyl)piperazin-2-yl]-N-methyl-acetamide Step 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (100 25 mg, 0.252 mmol, 1.0 eq.) was solubilized in dry DMF (1.7 mL) under inert atmosphere. 1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (45 mg, 0.278 mmol, 1.1 eq.), N,N- Diisopropylethylamine (173 µL, 1.01 mmol, 4 eq.) and HBTU (115 mg, 0.303 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with a saturated solution of NaHCO3. The organic30 phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) to afford the desired product as a white powder (60 mg, 50%). MS (ESI+): m / z =468 [M+H]+. HRMS-ESI+ (m / z): calcd for C27H29N6O2 [M+H]+: 469.2240 ; found: 469.2212. 1H NMR (500MHz, 250K, CDCl3) : rotamers mixture : δ (ppm) 10.86 (s, 0.25H), 10.3335 (s, 0.75H), 8.97 (s, 0.75H), 8.91 (s, 0.25H), 8.38 (s, 0.75H), 8.30 (s, 0.25H), , 7.54-7.39 98 (m, 3.7H), 7.38-7.13 (m, 9.2H), 6.69 (s, 0.75H), 6.62 (s, 0.25H),, 4.61 (s, 075H), 4.54- 4.51 (m, 1H), 4.44-4.43 (m, 0.25H), 3.89 (m, 0.75H), 3.72-3.64 (m, 0.5H), 3.54 (m, 0.75H), 3.39 (m, 0.75H), 3.26 (m, 1H), 3.10 (m, 0.25H), 2.64 (m, 2.5H), 2.58 (m, 1H), 2.45-2.30 (m, 2.5H), 2.24-2.14 (m, 0.5H), 2.01 (m, 0.5) 5 EXAMPLE 79: 2-[(2R)-1-benzhydryl-4-(1H-pyrrolo[2,3-c]pyridine-4- carbonyl)piperazin-2-yl]-N-methyl-acetamide Step 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (70 mg, 0.17 mmol, 1.0 eq.) was solubilized in dry DMF (0.8 mL) under inert atmosphere. 10 1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (33 mg, 0.21 mmol, 1.2 eq.), HBTU (72 mg, 0.19 mmol, 1.1 eq.) and N,N-Diisopropylethylamine (119 µL, 0.69 mmol, 4.0 eq.) were added and the reaction mixture was stirred at rt overnight. The mixture was diluted with EtOAc, washed with NaHCO3 (5%), and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) 15 to afford the desired product as a white lyophilizate (60.5 mg, 76%). MS (ESI+) m / z [M+H]+=468. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C28H30N5O2m / z= 468.2399, found m / z= 468.2384.1H NMR (500 MHz, CD3OD, 250K) δ (ppm) Mixture of rotamers: 8.89 (s, 0.4H), 8.84 (s, 0.6H), 8.29 (s, 0.4H), 8.22 (s, 0.6H), 7.52-7.43 (m, 5H), 7.31-7.11 (m, 6H), 6.77 (d, J = 3.2 Hz, 0.4H), 6.74 (d, J = 3.2 Hz, 0.6H), 4.72 (s, 0.4H), 4.67 (s,20 0.6H), 4.60 (d, J = 12.8Hz, 0.6H), 4.54 (d, J = 12.8Hz, 0.4H), 3.67-3.64 (m, 0.6H), 3.55-3.53 (m, 0.4H), 3.47-3.33 (m, 1.6H), 3.32-3.30 (m, 0.2H), 3.25-3.19 (m, 1.2H), 2.76-2.73 (m, 0.6H), 2.70 (s, 1.2H), 2.60-2.55 (m, 1H), 2.49-2.45 (m, 0.8H), 2.43-2.33 (m, 1.6H), 2.21 (s, 1.8H). 25 EXAMPLE 80: 2-[(2R)-1-benzhydryl-4-(1H-pyrazolo[4,3-c]pyridine-7- carbonyl)piperazin-2-yl]-N-methyl-acetamide Step 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide dihydrochloride (100mg, 0.252 mmol, 1.0 eq.) was solubilized in dry DMF (1.7 mL) under inert atmosphere. 1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (45.3 mg, 0.278 mmol, 1.1 eq.), N,N-30 Diisopropylethylamine (173 µL, 1.01 mmol, 4 eq.) and HBTU (115 mg, 0.303 mmol, 1.2eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with a saturated solution of NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) 99 to afford the desired product as a white powder (60 mg, 51%). MS(ESI+): m / z =469 [M+H]+. HRMS-ESI+ (m / z): calcd for C27H29N6O2 [M+H]+: 469.2352 ; found: 469.2350. 1H NMR (500 MHz, 250K, CDCl3) : rotamers mixture δ (ppm) 13.05 (s, 0.3H), 12.93(s, 0.7H), 9.16-9.13 (m, 1H), 8.48-8.44 (m, 1H), 8.28-8.21 (m, 1H), 7.43-7.40 (m, 3H), 5 7.34-7.26 (m, 3H), 7.25-7.14 (m, 4Hp), 7.00 (m, 0.7H), 6.18 (m, 0.3H), 4.63 (m, 0.7H, CH), 4.58-4.52 (m, 1H, CH2), 4.49 (m, 0.3H, CH), 3.85-3.80 (m, 1H, CH2), 3.72-3.70 (m, 0.3H, CH2), 3.59-3.53 (m, 0.7H, CH2), 3.43 (m, 0.7H , CH), 3.32-3.30 (m, 0.7H, CH2+0.3H, CH), 3.19 (m , 0.3H, CH2), 2.66 (m, 0.3H, CH2), 2.66 (d, J=4.8 Hz, 0.3H CH3),2.58 (m, 0.7H, CH2), 2.57 ( d, J=4.4 Hz, 1.8H, CH3), 2.49-2.22 (m, 1H, CH2 +2H, CH2),10 1.95 (d, J=4.2Hz, 0.9H CH3) EXAMPLE 81: 2-[(2R)-1-benzhydryl-4-(2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-8- carbonyl)piperazin-2-yl]-N-methyl-acetamide Step 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide dihydrochloride (100 15 mg, 0.252 mmol, 1.0 eq.) was solubilized in dry DMF (1.7 mL) under inert atmosphere. 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-8-carboxylic acid (50 mg, 0.278 mmol, 1.1 eq.), N,N-Diisopropylethylamine (173 µL, 1.01 mmol, 4 eq.) and HBTU (115 mg, 0.303 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with a saturated solution of NaHCO3. The organic 20 phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) to afford the desired product as a white powder (56 mg, 45%). MS (ESI+): m / z =469[M+H]+. HRMS-ESI+ (m / z): calcd for C28H32N5O3[M+H]+: 486.2505 ; found: 486.2498. 1H NMR (500 MHz, 250K, CDCl3): δ (ppm) 7.90 (s, 1H), 7.86 (s, 1H), 7.50-7.40 (m, 5H),25 7.37-7.14 (m, 5H), 6.17 (s, 1H, NH), 6.03-5.97(m, 0.3H), 4.62 (s, 1H), 4.42 (m, 1H), 4.21 (m, 2H), 3.80 (m, 1H), 3.56-3.50 (m, 3H), 3.33 (m, 1H), 3.22 (m, 1H), 2.72 (s, 2.7 H), 2.57 (m, 1.2H), 2.45 (m, 1.3H), 2.28 (m, 1.8H) Example 82 3-[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-4H-30 1,2,4-oxadiazol-5-one Step 1. Tert-butyl (3S)-4-benzhydryl-3-[(Z)-N'-hydroxycarbamimidoyl]piperazine-1- carboxylate Tert-butyl (3S)-4-benzhydryl-3-cyano-piperazine-1-carboxylate (270 mg, 0.72 mmol, 1.0 eq.) was solubilized in dry ethanol (1.6 mL) under argon atmosphere. 100 Hydroxylamine;hydrochloride (138 mg, 1.79 mmol, 2.5 eq.) and DIEA (0.6 mL, 3.58 mmol, 5 eq.) were added. The reaction mixture was stirred at 80°C for 4h and then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1 with 5% HCOOH / NH4OH pH 3.8 buffer) to 5afford the desired product as a white lyophilizate (71 mg, 24%). MS (ESI+) : m / z =411[M+H]+. Step 2. Tert-butyl (3S)-4-benzhydryl-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)piperazine-1- carboxylate Tert-butyl (3S)-4-benzhydryl-3-[(Z)-N'-hydroxycarbamimidoyl]piperazine-1-carboxylate 10 (71 mg, 0.17 mmol, 1 eq.) was solubilized in dry 1,4-Dioxane (0.9 mL) under argon atmosphere. CDI (67.3 mg, 0.42 mmol, 2.4 eq.) and DBU (28.5 µL, 0.19 mmol, 1.1 eq.) were added. The resulting mixture was stirred at 110°C for 2h and then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1 with 5% HCOOH / NH4OH pH 3.8 buffer) to afford15 the desired product as a white lyophilizate (108 mg, 90%). MS (ESI-): m / z =435 [M-H]-.Step 3.3-[(2S)-1-benzhydrylpiperazin-2-yl]-4H-1,2,4-oxadiazol-5-one dihydrochloride HCl in 4M 1,4-Dioxane (0.7 mL) was added to tert-butyl (3S)-4-benzhydryl-3-(5-oxo-4H- 1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate (108 mg, 0.156 mmol, 1 eq.) at 0°C. The 20 resulting mixture was stirred at rt for 3h. The mixture was concentrated under reduced pressure. The crude product was engaged in the next step without further purification. MS (ESI+): m / z =335 [M-H]-.Step 4.3-[(2S)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-4H-1,2,4- oxadiazol-5-one 25 3-[(2S)-1-benzhydrylpiperazin-2-yl]-4H-1,2,4-oxadiazol-5-one dihydrochloride (63.9 mg, 0.16 mmol, 1.0 eq.) was solubilized in dry DMF (0,8 mL) under argon atmosphere. Isoquinoline-4-carboxylic acid (33.1 mg, 0.19 mmol, 1.2 eq.), HBTU (65.1 mg, 0.17 mmol, 1.1 eq.) and N,N-diisopropylethylamine (81.5 µL, 0.47 mmol, 3 eq.) were added. The resulting mixture was stirred at rt overnight and then concentrated under reduced 30 pressure. The crude was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1 with 5% HCOOH / NH4OH pH 3.8 buffer) to afford the desired product as a white lyophilisate (35 mg, 45%). MS (ESI+): m / z =492 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+:calcd. for C29H26N5O3 m / z= 492.2036, found m / z= 492.2039. 1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.21 (s, 0.8H), 8.74 (s, 0.2H),35 8.40 (brs, 1H), 8.08-7.67 (m, 4H), 7.47-7.35 (m, 4H), 7.30-7.18 (m, 4H), 7.17-7.10 (m, 101 2H), 5.08 (brs, 0.7H), 4.86 (brs, 1H), 4.78 (s, 0.3H), 4.11 (s, 0.7H), 3.72 (brs, 0.5H), 3.69 (brs, 0.3H), 3.55-3.52 (m, 0.8H), 3.41-3.34 (m, 1.5H), 3.13 (brs, 0.2H), 3.02-2.74 (m, 1.2H), 2.56-2.52 (m, 0.8H). 5 Example 83 3-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-4H- 1,2,4-oxadiazol-5-one Step 1. Tert-butyl (3R)-4-benzhydryl-3-[(Z)-N'-hydroxycarbamimidoyl]piperazine-1-carboxylate Tert-butyl (3R)-4-benzhydryl-3-cyano-piperazine-1-carboxylate (730 mg, 1.74 mmol, 1.0 10 eq.) was solubilized in dry ethanol (3.77 mL) under argon atmosphere. Hydroxylamine hydrochloride (336 mg, 4.35 mmol, 2.5 eq.) and DIEA (1.49 mL, 8.7 mmol, 5.0 eq.) were added. The reaction mixture was stirred at 80°C for 4h and then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1 with 5% HCOOH / NH4OH pH 3.8 buffer) to afford15 the desired product as a white lyophilizate (229 mg, quantitative). MS (ESI+) : m / z =411[M+H]+. Step 2. Tert-butyl (3R)-4-benzhydryl-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate Tert-butyl (3R)-4-benzhydryl-3-[(Z)-N'-hydroxycarbamimidoyl]piperazine-1-carboxylate 20 (240 mg, 0.585 mmol, 1.0 eq.) was solubilized in dry 1,4-Dioxane (2.92 mL) under argon atmosphere. CDI (212 mg, 0.877 mmol, 1.5 eq.) and DBU (96.2 µL, 0.643 mmol, 1.1 eq.) were added. The resulting mixture was stirred at 110°C for 2h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (H2O / ACN 9:1 to 0:1 with 0.1% HCOOH) to afford the desired product as a white lyophilizate (14225 mg, 55%). MS (ESI-): m / z =435 [M-H]-. Step 3.3-[(2R)-1-benzhydrylpiperazin-2-yl]-4H-1,2,4-oxadiazol-5-onedihydrochloride HCl in 4M 1,4-Dioxane (1.02 mL) was added to tert-butyl (3R)-4-benzhydryl-3-(5-oxo- 4H-1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate (136 mg, 0.196 mmol, 1.0 eq.) at 0°C. 30 The resulting mixture was stirred at rt for 3h. The mixture was concentrated under reduced pressure. The crude product was engaged in the next step without further purification. MS (ESI+): m / z =335 [M-H]-. Step 4. 3-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-4H-1,2,4- oxadiazol-5-one 102 3-[(2R)-1-benzhydrylpiperazin-2-yl]-4H-1,2,4-oxadiazol-5-one dihydrochloride (80.2 mg, 0.196 mmol, 1.0 eq.) was solubilized in dry DMF (0.94 mL) under argon atmosphere. Isoquinoline-4-carboxylic acid (41.6 mg, 0.235 mmol, 1.2 eq.), HBTU (81.8 mg, 0.216 mmol, 1.1 eq.) and N,N-diisopropylethylamine (102 µL, 0.588 mmol, 3 eq.) were added. 5 The resulting mixture was stirred at rt overnight and then concentrated under reduced pressure. The crude was purified by preparative HPLC (H2O / ACN 9:1 to 0:1 with 0.1% HCOOH) to afford the desired product as a white lyophilizate (70 mg, 71%). MS (ESI+):m / z =492[M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C29H25N5O3 m / z= 492.2036, found m / z= 492.2050. 101H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.23 (s, 0.8H), 8.62 (s, 0.2H), 8.42 (s, 1H), 8.03-7.90 (m, 1H), 7.80-7.67 (m, 3H), 7.40-7.33 (m, 4H), 7.31-7.21 (m, 4H), 7.19-7.10 (m, 2H), 5.10 (s, 1H), 4.90-4.86 (m, 0.8H), 4.12 (s, 0.7H), 3.75 (br s, 0.5H),3.71 (br s, 0.3H), 3.56-3.52 (m, 1.2H), 3.34 (br s, 1.5H), 2.88-2.56 (m, 2H).15 Example 84 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-1-(4-methylpiperazin-1-yl)ethenone Step 1. Tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (2500 mg, 9.18 mmol, 20 1.0 eq.) was solubilized in dry ACN (28.5 mL). N-ethyl-N-isopropyl-propan-2-amine (2.36 mL, 13.8 mmol, 1.5 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (2269 mg, 9.18 mmol, 1.0 eq.) and sodium;iodide (275 mg, 1.84 mmol, 0.2 eq.) were added. The mixture was heated at 35°C for a week. After 24h, [bromo(phenyl)methyl]benzene (464 mg, 1.84 mmol, 0.2 eq.) and N-ethyl-N- 25 isopropyl-propan-2-amine (0.47 mL, 2.8 mmol, 0.3 eq.) were added. After 99h, [bromo(phenyl)methyl]benzene (227 mg, 0.92 mmol, 0.1 eq.) and N-ethyl-N-isopropyl- propan-2-amine (0.30 mL, 1.8 mmol, 0.2 eq.) were added. After a week (164h), the mixture was concentrated under reduced pressure. The crude product was washed with ethyl acetate and NaHCO3 (saturated solution). The combined organic layer was dried 30 on MgSO4 and concentrated under reduced pressure. The following step was started without purification. MS (ESI+) m / z =439 [M+H]+. Step 2. Ethyl 2-[(2R)-1-benzhydrylpiperazin-2-yl]acetate dihydrochlorideHCl 4M in dioxane (8 eq., 76.0 mmol, 19.1 mL) was added to tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (4026 mg, 9.18 mmol) at 35 0°C and stirred for 7h at rt. The reaction mixture was concentrated under reduced 103 pressure. Few milliliters of dichloromethane were added with 300 mL of cyclohexane to allow precipitation of the product as brown chlorhydrate solid (3690 mg, 95%). MS (ESI+) m / z =339 [M+H]+. Step 3. Ethyl 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-5 yl]acetate Ethyl 2-[(2R)-1-benzhydrylpiperazin-2-yl]acetate;dihydrochloride (600 mg, 1.41 mmol, 1 eq.) was solubilized in dry DMF (3.66 mL) under argon atmosphere. Isoquinoline-4- carboxylic acid (294 mg, 1.70 mmol, 1.2 eq.), HBTU (588 mg, 1.55 mmol, 1.1 eq.) and N,N-Diisopropylethylamine (739 µL, 4.24 mmol, 3 eq.) were added. The resulting mixture 10 was stirred at rt overnight. The mixture was concentrated under reduced pressure then diluted with EtOAc and washed with NaHCO3 (sat.), dried over MgSO4, filtered andconcentrated under reduced pressure to afford the desired product as a brown solid (711mg, 87%). MS (ESI+) m / z =494 [M+H]+.Step 4. Lithium;2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-15 yl]acetate Ethyl 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (711 mg, 1.22 mmol, 1 eq.) was solubilized in MeOH (4.37 mL). Lithium;hydroxide;hydrate 154 mg, 3.67 mmol, 3 eq.) and water (0.655 mL) were added. The resulting mixture was stirred at 35°C for 5h. The mixture was concentrated under reduced pressure then 20 purified by reverse phase flash chromatography with a gradient H2O / ACN 8:2 to 0:1 (with 5% HCOOH / NH4OH pH 3.8 buffer) to afford the desired product as a white lyophilizate (388 mg, 66%). MS (ESI+) m / z =466 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.34 (s, 0.5H), 9.29 (s, 0.5H), 8.46 (s, 1H), 8.44 (br s, 0.6H), 8.37(s, 0.5H), 8.20-8.15 (m, 1H), 7.86-7.72 (m, 3H), 7.49-7.41 (m, 4H), 7.31-7.08 (m, 6H), 25 4.83 (s, 1H), 4.53-4.41 (m, 1H), 3.35-2.93 (m, 4H), 2.54 (m, 1H), 2.45 (m, 1H), 2.39-2.23 (m, 2H). Step 5.2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-1-(4- methylpiperazin-1-yl)ethanone Lithium;2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (70 mg,30 0.15 mmol, 1.0 eq.) was solubilized in dry DMF (0.7 mL) under inert atmsophere. 1- methylpiperazine (19.7 µL, 0.17 mmol, 1.2 eq.), HBTU (70.4 mg, 0.19 mmol, 1.2 eq.) and N,N-Diisopropylethylamine (59.5 µL, 0.34 mmol, 2.3 eq.) were added. After 16h of stirring at rt, 0.2 eq. of HBTU and N,N-Diisopropylethylamine were added. After 20h, 0.2 eq. of HBTU and N,N-Diisopropylethylamine were added again. After 24h, the reaction mixture 35 was diluted with EtOAc and washed with NaHCO3 (sat.), dried over MgSO4, filtered and 104 concentrated under reduced pressure. The crude was purified by preparative HPLC (H2O / ACN 9:1 to 0:1 with 0.1% HCOOH) to afford the desired product as a whitelyophilizate (29.6 mg, 36%). MS (ESI+) m / z =548 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C34H38N5O2 m / z= 548.3026, found m / z= 548.3042.1H NMR (300 MHz, 5 DMSO-d6) δ (ppm) Mixture of rotamers: 9.35 (s, 0.3H), 9.29 (s, 0.7H), 8.49 (br s, 0.3H), 8.32 (br s, 0.7H), 8.21-8.15 (m, 1H), 7.86-7.74 (m, 3H), 7.50-7.40 (m 4H), 7.32-7.10 (m, 6H), 4.88-4.84 (m, 1H), 4.48-4.45 (m, 1H), 3.57-3.43 (m, 3H), 3.26-3.03 (m 5H), 2.73- 2.63 (m, 2H), 2.59 (br s, 0.6H), 2.46-2.40 (m, 1,4H), 2.32-1.97 (m, 7H).10 Example 85 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-(dimethylamino)ethyl]-N-methyl-acetamide Step 1 to step 4 described in example 84. Step 5.2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2- (dimethylamino)ethyl]-N-methyl-acetamide: 15 Lithium;2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (70 mg, 0.148 mmol, 1 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere. N,N',N'- trimethylethane-1,2-diamine (23.3 µL, 0.174 mmol, 1.17 eq.), T3P (66.2 µL, 0.223 mmol, 1.5 eq.) and N,N-Diisopropylethylamine (129 µL, 0.742 mmol, 5 eq.) were added. The reaction mixture was stirred at rt. After 2.5h, 0.5 eq. of T3P were added. After 3.5h, the 20 mixture was concentrated under reduced pressure, diluted with EtOAc and washed with NaHCO3 (5%), dried over MgSO4, filtered and concentrated under reduced pressure toafford the desired product as a yellow oil (22.9mg, 28%). MS (ESI+) m / z =550 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C34H40N5O2m / z= 550.3182, found m / z= 550.3188. 251H NMR (300 MHz, DMSO-d6) δ (ppm) Mixture of rotamers: 9.36 (s, 0.4H), 9.31-9.28 (m, 0.6H), 8.48 (br s, 0.4H), 8.39-8.35 (m, 0.6H), 8.22-8.15 (m, 1H), 7.86-7.73 (m, 3H), 7.51- 7.38 (m, 4H), 7.32-7.10 (m, 6H), 4.88-4.83 (m, 1H), 4.49-4.42, (m, 1H), 3.51-3.23 (m, 7H), 3.15-2.89 (m, 3H), 2.78-2.56 (m, 4H), 2.44-1.91 (m, 7H).30 Example 862-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-1-(1,1-dioxo-1,4-thiazinan-4-yl)ethanone Step 1 to step 4 described in example 84. Step 5. 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-1-(1,1- dioxo-1,4-thiazinan-4-yl)ethanone 105 Lithium;2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (70.0 mg, 0.15 mmol, 1.0 eq.) was solubilized in dry ethyl acetate (0.6 mL) under argon atmosphere.1,4-thiazinane 1,1-dioxide (24.8 mg, 0.18 mmol, 1.2 eq.), T3P (620 µL, 0.45 mmol, 3.0 eq) and N,N-Diisopropylethylamine (129 µL, 0.74 mmol, 5.0 eq.) were added. 5 The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with NaHCO3 (5%), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as a yellow oil (69.2 mg, 80%). MS (ESI+) m / z =583 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C33H34N4O4S m / z= 583.2379, found m / z= 583.2387.1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers:10 9.25 (s, 0.5H), 9.20 (s, 0.5H), 8.42 (s, 0.55H), 8.32 (brs, 0.45H), 8.04-7.98 (m, 1H), 7.82- 7.64 (m, 3H), 7.42-7.32 (m, 4H), 7.30-7.14 (m, 6H), 4.67 (s, 1H), 4.64 (m, 1H), 3.86-3.61 (m, 4H), 3.36-2.69 (m, 9H), 2.66-2.34 (m, 3H). Example 87 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-1-[3-15 (3-methyl-1,2,4-oxadiazol-5-yl)azetidin-1-yl]ethanone Step 1 to step 4 described in example 84. Step 5. 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-1-[3-(3- methyl-1,2,4-oxadiazol-5-yl)azetidin-1-yl]ethanone Lithium;2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (60 mg,20 0.127 mmol, 1,0 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere.5- (azetidin-3-yl)-3-methyl-1,2,4-oxadiazole (24.2 mg, 0.174 mmol, 1.4 eq.), HBTU (96.5 mg, 0.255 mmol, 2,0 eq.) and N,N-Diisopropylethylamine (111 µL, 0.636 mmol, 5,0 eq.) were added. The reaction mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure, diluted with EtOAc and washed with NaHCO325 (sat.), dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by preparative HPLC (H2O / ACN 9:1 to 0:1 with 0.1% HCOOH) to afford the desired product as a white lyophilizate (33 mg, 44%). MS (ESI+) m / z =587 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C35H35N6O3m / z= 587.2771, found m / z= 587.2791. 1H NMR (500 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.25 (s, 0.8H), 9.2030 (s, 0.2H), 8.45 (s, 1H), 8.02-7.95 (m, 1H), 7.82-7.65 (m, 3H), 7.43-7.34 (m, 4H), 7.30- 7.11 (m, 6H), 4.74-4.00 (m, 6.5H), 3.77-3.70 (m, 1H), 3.39-3.17 (m, 3.5H), 2.81-2.20 (m, 7H). 106 Example 88 2-[(2R)-1-[(R)-(3-chlorophenyl)-phenyl-methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide / 2-[(2R)-1-[(S)-(3-chlorophenyl)- phenyl-methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide Step 1.1-[bromo(phenyl)methyl]-3-chloro-benzene: 5 In a dried, argon-flushed 25 mL round bottom flask, (3-chlorophenyl)-phenyl-methanol (500 mg, 2.24 mmol, 1.0 eq.) and dry DCM (6.2 mL) were added. The reaction mixture was cooled down at 0°C. Phosphorus tribromide (1090 µL, 11.2 mmol, 5.0 eq.) in dichloromethane (6.1 mL) was added dropwise. After addition of PBr3, the cooling bath was removed and the solution was allowed to reach room temperature. Stirring was 10 continued for 4 h, then crushed ice was added into the mixture, following by DCM. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as a yellow oil (yield: quant.). The crude product was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.48-7.28 (m, 9H),15 6.25 (s, 1H). Step 2. Tert-butyl (3R)-4-[(3-chlorophenyl)-phenyl-methyl]-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate: Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (250 mg, 0.9 mmol, 1.0 eq.) was solubilized in dry ACN (2.6 mL). N,N-Diisopropylethylamine (0.4 mL, 2.3 mmol,20 2.5 eq.) was added and the mixture was stirred at rt for 15 min.1-[bromo(phenyl)methyl]- 3-chloro-benzene (517 mg, 1.8 mmol, 2.0 eq.) & sodium iodide (27.5 mg, 0.2 mmol, 0.2 eq.) were added. The mixture was heated at 35°C for a week. The reaction progress was monitored by LC / MS. After acetonitrile removal, the crude product was extracted with EtOAc, washed with NaHCO3(sat.), dried on MgSO4and concentrated under reduced 25 pressure. The mixture was engaged in the next step without further purification. MS (ESI+) m / z =473 [M+H]+.Step 3. Ethyl 2-[(2R)-1-[(3-chlorophenyl)-phenyl-methyl]piperazin-2-yl]acetate;dihydrochloride: Tert-butyl (3R)-4-[(3-chlorophenyl)-phenyl-methyl]-3-(2-ethoxy-2-oxo-ethyl)piperazine- 30 1-carboxylate (434 mg, 0.92 mmol, 1.0 eq.) was solubilized in 1,4-Dioxane (6 mL).After 10 minutes, HCl (4M in dioxane, 1.9 mL, 7.6mmol, 8 eq.) was added at 0°C. The mixture was allowed to reach room temperature and was stirred overnight. Upon completion, the mixture was concentrated under reduced pressure. Dichloromethane was added, followed by cyclohexane to induce product precipitation. The mixture was filtrated to 107 afford the desired product as a brown solid (450 mg, quantitative). MS (ESI+) m / z =373 [M+H]+. Step 4. Ethyl 2-[(2R)-1-[(3-chlorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]acetate: 5 Ethyl 2-[(2R)-1-[(3-chlorophenyl)-phenyl-methyl]piperazin-2-yl]acetate;dihydrochloride (409 mg, 0.92 mmol, 1.0 eq.) was solubilized in dry DMF (4.4 mL) under inert atmosphere. N,N-Diisopropylethylamine (640 µL, 3.67 mmol, 4.0 eq.), isoquinoline-4- carboxylic acid (175 mg, 1.01 mmol, 1.1 eq.) and HBTU (383 mg, 1.01 mmol, 1.1 eq.) were added. The reaction progress was monitored by LC / MS. After one night at rt with 10 stirring, the mixture was diluted with EtOAc and washed with NaHCO3 (5%), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (144 mg, 30% over 3 steps). MS (ESI+) m / z =528[M+H]+. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.26 (s, 1H), 8.48 (br s, 1H), 8.02-7.64 (m,15 4H), 7.48-7.34 (m, 5H), 7.26-7.16 (m, 4H), 4.74-4.62 (m, 2H), 4.14-3.91 (m, 1H + 0.5H), 3.59-3.15 (m, 4H + 0.5H), 2.80-2.44 (m, 4H), 1.34-1.16 (m, 3H). Step 5. Lithium;2-[(2R)-1-[(3-chlorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]acetate To a solution of ethyl 2-[(2R)-1-[(3-chlorophenyl)-phenyl-methyl]-4-(isoquinoline-4-20 carbonyl)piperazin-2-yl]acetate (144 mg, 0.27 mmol, 1.0 eq.) in MeOH (0.56 mL), wasadded lithium;hydroxide;hydrate (34.3 mg, 0.82 mmol, 3.0 eq.) in water (84 µL). The mixture was stirred over for 24h at 35°C. The crude product was concentrated under reduced pressure and purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (113 mg, 82%). MS (ESI+) m / z =50025 [M+H]+. Step 6.2-[(2R)-1-[(R)-(3-chlorophenyl)-phenyl-methyl]-4-(isoquinoline-4- carbonyl)piperazin-2-yl]-N-methyl-acetamide / 2-[(2R)-1-[(S)-(3-chlorophenyl)- phenyl-methyl]-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-methyl-acetamide Lithium;2-[(2R)-1-[(3-chlorophenyl)-phenyl-methyl]-4-(isoquinoline-4- 30 carbonyl)piperazin-2-yl]acetate (100 mg, 0.20 mmol, 1.0 eq.) was solubilized in dry DMF (0.95 mL) under inert atmosphere. N,N-Diisopropylethylamine (138 µL, 0.80 mmol, 4.0 eq.), methanamine;hydrochloride (16.0 mg, 0.24 mmol, 1.2 eq.) and HBTU (83 mg, 0.22 mmol, 1.1 eq.) were added. The reaction progress was monitored by LC / MS. After one night at rt with stirring, the mixture was diluted with EtOAc and washed with NaHCO335 (5%), dried over MgSO4, filtered and concentrated under reduced pressure. the crude 108 product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (40 mg, 39%). MS (ESI+) m / z =513 [M+H]+. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H30ClN4O2 m / z= 513.2057, foundm / z= 513.2081. 1H NMR (500 MHz, CDCl3) δ (ppm) Mixture of diastereoisomers and5 rotamers: 9.27-9.24 (m, 1H), 8.53-8.46 (m, 1H), 8.04-7.67 (m, 4H), 7.48-7.32 (m, 5H), 7.23-7.08 (m, 4H), 4.69-4.64 (m, 2H), 3.48-3.24 (m, 4H), 2.78-2.76 (m, 3H), 2.53-2.19 (m, 4H). Example 89 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-1-[3-10 (triazol-1-yl)azetidin-1-yl]ethenone Step 1 to step 4 described in example 84. Lithium;2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (40 mg, 0.08 mmol, 1.0 eq.) was solubilized in dry EtOAc (0.5 mL) under inert atmosphere. 1-(azetidin-3-yl)triazole;hydrochloride (16.9 mg, 0.10 mmol, 1.2 eq.), T3P (354 µL, 0.25 15 mmol, 3.0 eq.) and DIEA (73.9 µL, 0.42 mmol, 5.0 eq.) were added and the reaction mixture was stirred at room temperature. After one night of stirring, 1.0 eq. of T3P, 2.0 eq. of DIEA and 0.15 mL of EtOAc were added. After 20h, 1.0 eq. of 1-(azetidin-3-yl)triazole;hydrochloride was added. After 24h, dry DMF (0.2 mL) was added. After 41h, reaction mixture was concentrated under reduced pressure, diluted with EtOAc and 20 washed with NaHCO3(sat.); dried over MgSO4; filtered and concentrated under reduced pressure. The crude was purified by reverse phase flash chromatography with a gradient H2O / ACN 9:1 to 0:1 to afford the desired product as a white lyophilisate (17.5 mg, 36%). UPLC-MS (ESI) m / z [M+H]+= 572. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C34H34N7O2m / z= 572.2774, found m / z= 572.2770.1H NMR (500 MHz, DMSO-d6) δ (ppm) Mixture of25 rotamers: 9.36-9.35 (m, 0.7H), 9.31 (s, 0.3H), 8.56-7.74 (m, 7H), 7.50-7.44 (m, 4H), 7.31- 7.11 (m, 6H), 5.70-5.23 (m, 1H), 4.96-4.68 (m, 2H), 4.59-3.96 (m, 4H), 3.65-3.46 (m, 1H), 3.27-2.99 (m, 3H), 2.63 (brs, 2H), 2.36-2.29 (m, 2H). Example 90 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N-[2-30 (5-oxo-4H-1,2,4-oxadiazol-3-yl)ethyl]acetamide Step 1 to step 4 described in example 84.Lithium;2-[(2R)-1-benzhydryl-4-(isoquinoline- 4-carbonyl)piperazin-2-yl]acetate (60.0 mg, 0.13 mmol, 1.0 eq.) was solubilized in dry DMF (0.6 mL) under inert atmosphere. N,N-Diisopropylethylamine (89 µL, 0.51 mmol, 4.0 eq.), 3-(2-aminoethyl)-4H-1,2,4-oxadiazol-5-one;hydrochloride (25.3 mg, 0.15 mmol, 35 1.2 eq.) and HBTU (53.1 mg, 0.14 mmol, 1.1 eq.) were added. After one night at rt, the 109 mixture was concentrated under reduced pressure and purified by preparative HPLC to afford the desired product as a white solid (44 mg, 60%). UPLC-MS (ESI+) m / z [M+H]+= 577. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C33H33N6O4 m / z= 577.2563, found m / z= 577.2573. 1H NMR (500 MHz, CDCl3) δ (ppm) Mixture of rotamers: 9.20 (br s, 0.7H),5 9.09 (s, 0.3H), 8.62 (s, 0.5H), 8.47 (s, 0.5H), 8.01-7.59 (m, 4H), 7.44-7.29 (m, 6H), 7.22 (m, 4H), 4.76-4.55 (m, 2H), 3.89 (br s, 0.5H), 3.69 (br s, 1H) 3.39-3.16 (m, 4.5H), 2.70- 2.33 (m, 6H). Example 91 2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]-N,N-10 bis(2-methoxyethyl)acetamide Step 1 to step 4 described in example 84. Lithium;2-[(2R)-1-benzhydryl-4-(isoquinoline-4-carbonyl)piperazin-2-yl]acetate (70.0 mg, 0.15 mmol, 1.0 eq.) was solubilized in dry DMF (0.7) under inert atmosphere (argon). 2-methoxy-N-(2-methoxyethyl)ethanamine (26.5 µL, 0.18 mmol, 1.2 eq.), HBTU (61.9 15 mg, 0.16 mmol, 1.1 eq.) and N,N-Diisopropylethylamine (103 µL, 0.59 mmol, 4.0 eq.) were added and the reaction mixture was stirred at rt. After 20h, 0.3 eq of HBTU and DIEA were added. After 24h, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc ; washed with a saturated solution of NaHCO3; dried over MgSO4; filtered and concentrated under reduced pressure. The crude product was 20 purified by normal phase flash chromatography (DCM / MeOH 1:0 to 96:4) to afford the desired product as a yellow oil (42.6 mg, 49%). UPLC-MS (ESI) m / z [M+H]+=581. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C35H41N4O4m / z= 581.3128, found m / z= 581.3120.1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers : 9.23 (s, 0.4H), 9.20 (s, 0.5H), 8.46(s, 0.4H), 8.38 (s, 0.5H), 8.01-7.59 (m, 4H), 7.45-7.27 (m, 5.5H), 7.24-7.09 (m, 4.5H),25 4.71-7.58 (m, 2H), 3.75-3.24 (m, 18H), 2.79-2.45 (m, 4H). Example 92 2-[(2R)-1-benzhydryl-4-(2-methyl-1H-imidazo[4,5-c]pyridine-7- carbonyl)piperazin-2-yl]-N-methyl-acetamide Step 1 and 2 described in example 68.30 Step 3. 2-[(2R)-1-benzhydryl-4-(2-methyl-1H-imidazo[4,5-c]pyridine-7-carbonyl)piperazin-2-yl]-N-methyl-acetamide: Lithium;2-methyl-1H-imidazo[4,5-c]pyridine-7-carboxylate (40 mg, 0.22 mmol, 1.5 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (0.1 mL, 0.58 mmol, 4.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl- 35 acetamide;dihydrochloride (63.9 mg, 0.15 mmol, 1.0 eq.) and HBTU (61 mg, 0.16 mmol, 110 1.1 eq.) were added. After one night at rt, the mixture was diluted with EtOAc and washed with NaOH (1N) solution, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (10 mg, 14%). UPLC-MS (ESI+) m / z 5 [M+H]+ =483. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C28H31N6O2 m / z= 483.2508, found m / z= 483.2502. 1H NMR (300 MHz, CD3OD) δ (ppm) Mixture of rotamers : 8.76(s, 1H), 8.29 (s, 1H), 7.46 (br s, 4H + 0.5H), 7.27-7.17 (m, 6H + 0.5H), 4.75-4.74 (m, 1H), 4.53 (br s, 1H), 3.65-3.35 (m, 3H), 3.23-3.20 (m, 1H), 2.70-2.29 (m, 10H). 10 Example 93 2-[(2R)-1-benzhydryl-4-(2-tert-butyloxazolo[4,5-c]pyridine-7- carbonyl)piperazin-2-yl]-N-methyl-acetamide 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (70 mg, 0.17 mmol, 1.0 eq.) was solubilized in DCM (0.8 mL) under inert atmosphere (argon).2-tert- butyloxazolo[4,5-c]pyridine-7-carboxylic acid (44 mg, 0.20 mmol, 1.2 eq.), HATU (70 mg, 15 0.19 mmol, 1.1 eq.) and N,N-Diisopropylethylamine (117 µL, 0.67 mmol, 4.0 eq.) were added and the reaction mixture was stirred at rt overnight. The mixture was diluted with DCM, washed with NaHCO3(5%) solution, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white 20 lyophilizate (43 mg, 49%). UPLC-MS (ESI) m / z [M+H]+=526. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C31H36N5O3m / z= 526.2818, found m / z= 526.2813. 1H NMR (500 MHz, CDCl3, 250K) δ (ppm) Mixture of rotamers: 9.04 (s, 0.7H), 8.98 (s, 0.3H), 8.65(s, 0.7H), 8.59 (s, 0.3H), 7.49-7.28 (m, 6H), 7.25-7.13 (m, 4H), 7.07 (br s, 0.7NH), 5.69 (br s, 0.3NH), 4.64-4.54 (m, 2H), 3.56-3.22 (m, 4H), 2.74 (s, 1H + 0.1H), 2.73 (s, 1H + 25 0.2H), 2.57-2.52 (m, 1H + 0.7H), 2.38-2.26 (m, 3H), 1.50 (s, 6H), 1.49 (s, 3H). Example 94 2-[(2R)-1-benzhydryl-4-(2-methyl-1H-imidazo[4,5-c]pyridine-7-carbonyl)piperazin-2-yl]-N,N-dimethyl-acetamide Step 1. Tert-butyl (3R)-4-benzhydryl-3-[2-(dimethylamino)-2-oxo-ethyl]piperazine-30 1-carboxylate: Lithium;2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetate (306 mg, 0.74 mmol, 1.0 eq.) was solubilized in DMF (2.9 mL) under inert atmosphere. N,N- Diisopropylethylamine (0.4 mL, 2.21 mmol, 3.0 eq.), N- methylmethanamine;hydrochloride (71.9 mg, 0.88 mmol, 1.2 eq.) and HBTU (307 mg, 35 0.81 mmol, 1.1 eq.) were added. After one night at rt, the mixture was diluted with EtOAc, 111 washed with NaOH (1N) and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (237 mg, 74%). MS (ESI+): m / z [M+H]+ =438. 1HNMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers : 7.43-7.38 (m, 4H), 7.28 (br s, 1H),5 7.23 (br s, 1H), 7.19-7.14 (m, 2H), 4.65 (s, 1H), 3.90-3.86 (m, 2H), 3.51-3.49 (m, 1H), 3.14-3.10 (m, 1H), 2.99-2.87 (m, 7H), 2.66-2.44 (m, 3H), 2.34-2.29 (m, 1H), 1.41 (s, 9H). NB: 2H aromatic under solvent peak. Step 2.2-[(2R)-1-benzhydrylpiperazin-2-yl]-N,N-dimethyl-acetamide : Tert-butyl (3R)-4-benzhydryl-3-[2-(dimethylamino)-2-oxo-ethyl]piperazine-1-carboxylate 10 (230 mg, 0.484 mmol, 1.0 eq.) was solubilized in 1,4-dioxane (1.77 mL). After 10 minutes, HCl (4M in dioxane, 1 mL, 29 mmol, 60 eq.) was added at 0°C. The mixture was allowed to reach room temperature and was stirred overnight. Upon completion, the mixture was concentrated under reduced pressure to afford the desired product as a white solid (229 mg, q). MS (ESI+): m / z [M+H]+ = 238.15 Step 3. Methyl 2-methyl-1H-imidazo[4,5-c]pyridine-7-carboxylate: Methyl 4,5-diaminopyridine-3-carboxylate (300 mg, 1.62 mmol, 1.0 eq.) was solubilized in dry ethyl acetate (3.4 mL) under inert atmosphere. N,N-Diisopropylethylamine (420 µL, 2.42 mmol, 1.5 eq.), acetic acid (97 mg, 1.62 mmol, 1.0 eq.) and T3P (1030 mg, 1.62 mmol, 1.0 eq.) were added. The tube was sealed and heated at 70°C for 1 hour to allow 20 full solubilization of the reactants. The mixture was then irradiated under microwaves for acombined 1h30 (1h + 30min cycles) at 160°C. Upon completion, the crude mixture wasevaporated and purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) two times to afford the desired product as a white lyophilizate (396 mg, 78%). MS (ESI+):m / z [M+H]+ =192. 1H NMR (300 MHz, CD3OD) δ (ppm): 9.12 (br s, 1H), 8.95 (s, 1H),25 4.08 (s, 3H), 2.74 (s, 3H). Step 4. Lithium;2-methyl-1H-imidazo[4,5-c]pyridine-7-carboxylate: To a solution of methyl 2-methyl-1H-imidazo[4,5-c]pyridine-7-carboxylate (396 mg (61 %pure), 1.26 mmol, 1.0 eq.) in MeOH (6.1 mL), was added lithium;hydroxide;hydrate (159 mg, 2.80 mmol, 3.0 eq.) in water (0.7 mL). The mixture was stirred for 16h at 45°C. The30 crude product was concentrated under reduced pressure to afford the desired compound as a white solid (312 mg, q). MS (ESI+): m / z [M+H]+ =178. Step 5. 2-[(2R)-1-benzhydryl-4-(2-methyl-1H-imidazo[4,5-c]pyridine-7- carbonyl)piperazin-2-yl]-N,N-dimethyl-acetamide: Lithium;2-methyl-1H-imidazo[4,5-c]pyridine-7-carboxylate (55 mg, 0.3 mmol, 1.2 eq.) 35 was solubilized in dry DMF (1.1 mL) under inert atmosphere. N,N-Diisopropylethylamine 112 (174 µL, 1.0 mmol, 4.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N,N-dimethyl- acetamide;dihydrochloride (119 mg, 0.25 mmol, 1.0 eq.) and HBTU (104 mg, 0.28 mmol, 1.1 eq.) were added. After one night at room temperature with stirring, the mixture was diluted with EtOAc and washed with NaHCO3 (5%) and concentrated under reduced 5 pressure. The crude product was purified by normal phase flash chromatography (DCM / MeOH 1:0 to 85:15) to afford the desired product as a white lyophilizate (62 mg; 49%). MS (ESI+): m / z [M+H]+ = 497. 1H NMR (300 MHz, CD3OD) δ (ppm) Mixtureof rotamers : 8.77 (s, 1H), 8.32-8.23 (m, 1H), 7.51-7.43 (m, 4H), 7.27-7.14 (m, 6H), 4.79 (s, 1H), 4.60-4.57 (d, J = 10.5 Hz, 0.8H), 3.70-3.53 (m, 1.5H), 3.44-3.33 (m, 0.9H), 3.28-10 3.14 (m, 1.2H), 2.97-2.44 (m, 13H), 0.6 H under solvent peak. Example 952-[(2R)-1-benzhydryl-4-[2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine- 7-carbonyl]piperazin-2-yl]-N-methyl-acetamide Step 3. Methyl 2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine-7-carboxylate:15 Methyl 4,5-diaminopyridine-3-carboxylate (75mg, 0.40 mmol, 1.0 eq.), T3P (257 mg, 0.40 mmol, 1.0 eq.), 2,2,2-trifluoroacetic (46 mg, 0.40 mmol, 1.0 eq.) were solubilized in dry ethyl acetate (0.9 mL) in a microwave tube. N,N-Diisopropylethylamine (100 µL, 0.61 mmol, 1.5 eq.) was then added and the tube was sealed. For 1h, the reaction mixture was heated at 60°C to allow full solubilization of the reactants. The tube was then 20 irradiated with microwaves at 120°C for 30min. Solvents was evaporated and the crude reaction mixture was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (44 mg, 44%). UPLC-MS (ESI+) m / z [M+H]+ =246. 1H NMR (300 MHz, CD3CN) δ (ppm): 9.29 (s, 1H), 9.06 (s, 1H), 4.06(s, 3H).25 Step 4. Lithium;2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine-7-carboxylate:To a solution of methyl 2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine-7-carboxylate (40mg, 0.16 mmol, 1.0 eq.) in MeOH (0.8 mL), was added lithium;hydroxide;hydrate (40 mg, 0.33 mmol, 2.0 eq.) in water (0.1 mL). The mixture was stirred for 24h at 35°C. The crude product was concentrated under reduced to afford the desired compound as a white solid30 (40 mg, q). UPLC-MS (ESI+) m / z [M+H]+=232. Step 5. 2-[(2R)-1-benzhydryl-4-[2-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine-7-carbonyl]piperazin-2-yl]-N-methyl-acetamide Lithium;2-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine-7-carboxylate (37 mg, 0.16 mmol, 1.0 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. N,N-35 Diisopropylethylamine (111 µL, 0.64 mmol, 4.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]- 113 N-methyl-acetamide;dihydrochloride (70 mg, 0.16 mmol, 1.0 eq.) and HBTU (66 mg, 0.17 mmol, 1.1 eq.) were added. After one night at room temperature with stirring, the mixture was diluted with EtOAc and washed with NaHCO3 (5%), filtered and concentrated under reduced pressure. The product was purified by preparative HPLC (H2O / ACN + 0.1% 5 HCOOH 90:10 to 0:100) to afford the desired product as a lyophilizate (36 mg, 42 %). UPLC-MS (ESI+) m / z [M+H]+ = 537. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C28H28F3N6O2 m / z= 537.2226, found m / z= 537.2217. 1H NMR (300 MHz, CD3OD) δ(ppm) Mixture of rotamers : 9.05 (s, 0.5H), 9.03 (s, 0.5H), 8.32 (s, 0.5H), 8.28 (s, 0.5H),7.51-7.42 (m, 4H), 7.31-7.10 (m, 6H), 4.75 (s, 0.5H), 4.74 (s, 0.5H), 4.56-4.49 (m, 1H), 10 3.62-3.58 (m, 0.5H + 0.5H), 3.46-3.22 (m, 1.5H + 1H), 3.12-3.11 (m, 0.5H), 2.83-2.45(m, 1.7H + 2H + 2H), 2.28 (s, 1.3H). 0.5H under solvent peak.Example 96 2-[(2R)-1-benzhydryl-4-(2-methyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin-2-yl]-N-methyl-acetamide 15 Step 1.2-[(2R)-4-(5-amino-4-hydroxy-pyridine-3-carbonyl)-1-benzhydryl-piperazin- 2-yl]-N-methyl-acetamide: 5-amino-4-hydroxy-pyridine-3-carboxylic acid (58.3 mg, 0.38 mmol, 1.0 eq.) was solubilized in dry DMF (1.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (260 µL, 1.51 mmol, 4.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl- 20 acetamide;dihydrochloride (150 mg, 0.38 mmol, 1.0 eq.) and HBTU (158 mg, 0.42 mmol, 1.1 eq.) were added. After stirring overnight, the mixture was concentrated under reduced pressure and purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired compound as a white lyophilizate (70 mg, 40%). UPLC-MS (ESI+) m / z [M+H]+ =460.25 Step 2. 2-[(2R)-1-benzhydryl-4-(2-methyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin-2-yl]-N-methyl-acetamide: In a microwave tube was solubilized 2-[(2R)-4-(5-amino-4-hydroxy-pyridine-3-carbonyl)- 1-benzhydryl-piperazin-2-yl]-N-methyl-acetamide (70.0 mg, 0.15 mmol, 1.0 eq.) in dry ethyl acetate (0.7 mL). Acetic acid (9.2 mg, 0.15 mmol, 1.0 eq.), DIEA (40 µL, 0.23 mmol, 30 1.5 eq.) and T3P (50% w / w in ethyl acetate) (100 mg, 0.16 mmol, 1.0 eq.) were added. The tube was sealed and heated at 70°C for 45 min to allow full solubilization of the reactant. The mixture was then irradiated for 1h at 160°C under microwaves. T3P (50% w / w in ethyl acetate) (50 mg, 0.08 mmol, 0.5 eq.) was added and the mixture was irradiated at 160°C for another 45 min. The crude product was purified by reverse phase 35 flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white 114 lyophilizate (17 mg, 23%). UPLC-MS (ESI+) m / z [M+H]+ =484. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C28H30N5O3 m / z= 484.2349, found m / z= 484.2336.1H NMR (300 MHz, CD3OD) δ (ppm) Mixture of rotamers : 8.93 (s, 0.4H), 8.92 (s, 0.6H), 8.59 (s,0.4H), 8.52 (s, 0.6H), 7.51-7.43 (m, 4H), 7.30-7.11 (m, 6H), 4.82 (s, 0.4H), 4.74 (s, 0.6H), 5 4.51-4.46 (m, 1H), 3.69-3.64 (m, 0.6H), 3.57-3.35 (m, 2H), 3.26-3.16 (m, 1H + 0.2H), 2.75-2.64 (m, 5H + 0.2H), 2.60-2.33 (m, 3H), 2.30 (s, 1H + 0.8H). Example 97 2-[(2R)-1-benzhydryl-4-(1,6-naphthyridine-8-carbonyl)piperazin-2-yl]-N-methyl-acetamide 10 Step 1 to 4 described in example 76. Step 5. 2-[(2R)-1-benzhydryl-4-(1,6-naphthyridine-8-carbonyl)piperazin-2-yl]-N-methyl-acetamide 1,6-naphthyridine-8-carboxylic acid (37 mg, 0.21 mmol, 1.2 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (123 µL, 0.71 mmol, 15 4.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-Nmethyl-acetamide;dihydrochloride (70 mg, 0.18 mmol, 1.0 eq.) and HBTU (73.7 mg, 0.19 mmol, 1.1 eq.) were added. After one night at room temperature with stirring, the mixture was diluted with EtOAc, washed with NaHCO3(5%) and concentrated under reduced pressure. The crude product was purified by normal phase flash chromatography (DCM / MeOH 100:0 to 97:3) to afford the20 desired product as a white solid (55 mg, 64 %). UPLC-MS (ESI+) m / z [M+H]+ = 480.HRMS (TOF, ES+) m / z [M+H]+: calcd. for C29H30N5O2 m / z= 480,2383, found m / z= 480,2400. 1H NMR (500 MHz, MeOD) δ (ppm) Mixture of rotamers: 9.40 (s, 0.5H), 9.37(s, 0.5H), 9.24-9.23 (m, 0.4H), 9.15-9.14 (m, 0.4H), 9.06 (m, 0.2H), 8.81 (s, 0.2H), 8.69 (s, 0.3H), 8.65 (s, 0.3H), 8.61-8.54 (m, 1.2H), 7.78-7.68 (m, 1H), 7.50-7.46 (m, 2H), 7.43- 25 7.39 (m, 2H), 7.29-7.26 (m, 2H), 7.23-7.16 (m, 3H), 7.13-7.09 (m, 1H), 4.79 (s, 0.2H), 4.73-4.72 (m, 0.9H), 4.64-4.58 (m, 1H), 3.60-3.34 (m,1.6H), 3.29-3.19 (m, 0.8H), 3.08- 2.99 (m, 1.4H), 2.79-2.59 (m, 3.4H), 2.54-2.34 (m, 2.9H) 0.8H under solvent peak. 30 Example 98.2-[(2R)-1-benzhydryl-4-[2-(1-methoxy-1-methyl-ethyl)-1H- imidazo[4,5-c]pyridine-7-carbonyl]piperazin-2-yl]-N,N-dimethyl-acetamide Step 3. Methyl 2-(1-methoxy-1-methyl-ethyl)-1H-imidazo[4,5-c]pyridine-7- carboxylate: Methyl 4,5-diaminopyridine-3-carboxylate (75 mg, 0.40 mmol, 1.0 eq.) was solubilized in 35 dry ethyl acetate (0.9 mL) under inert atmosphere. N,N-Diisopropylethylamine (104 µL, 115 0.61 mmol, 1.5 eq.), 2-methoxy-2-methyl-propanoic acid (48 mg, 0.40 mmol, 1.0 eq.) and T3P (257 mg, 0.40 mmol, 1.0 eq.) were added. The tube was sealed and heated at 70°C for 1 hour to allow full solubilization of the reactants. The mixture was then irradiated under microwaves for 30 min at 160°C. Upon completion, the crude mixture 5 was evaporated and purified by normal phase flash chromatography (DCM / MeOH 1:0 to 9:1 + 0.1% TEA) to afford the desired product as a pale yellow solid (50 mg, 50%). MS(ESI+): m / z [M+H]+ =250.1H NMR (300 MHz, DMSO) δ (ppm): 12.58 (br s, 0.9 NH), 9.09(s, 1H), 8.81 (s, 1H), 3.96 (s, 3H), 3.06 (s, 3H), 1.66 (s, 6H). Step 4. Lithium;2-(1-methoxy-1-methyl-ethyl)-3H-imidazo[4,5-c]pyridine-7-10 carboxylate: To a solution of methyl 2-(1-methoxy-1-methyl-ethyl)-3H-imidazo[4,5-c]pyridine-7- carboxylate (45 mg, 0.18 mmol, 1.0 eq.) in MeOH (0.9 mL), was addedlithium;hydroxide;hydrate (15.2 mg, 0.36 mmol, 2.0 eq.) in water (0.1 mL). The mixture was stirred for 16h at 35°C. The crude product was concentrated under reduced to afford15 the desired compound as a white solid (60 mg, q). MS (ESI+): m / z [M+H]+=236. Step 5. 2-[(2R)-1-benzhydryl-4-[2-(1-methoxy-1-methyl-ethyl)-3H-imidazo[4,5- c]pyridine-7-carbonyl]piperazin-2-yl]-N,N-dimethyl-acetamide: Lithium;2-(1-methoxy-1-methyl-ethyl)-3H-imidazo[4,5-c]pyridine-7-carboxylate (45 mg, 0.19 mmol, 1.2 eq.) was solubilized in dry DMF (0.8 mL) under inert atmosphere. N,N-20 Diisopropylethylamine (80 µL, 0.45 mmol, 3.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]- N,N-dimethyl-acetamide;dihydrochloride (65 mg, 0.15 mmol, 1.0 eq.) and HBTU (69 mg, 0.18 mmol, 1.2 eq.) were added. After one night at rt with stirring, the mixture was diluted with EtOAc and washed with NaHCO3(5%), filtered and concentrated under reduced pressure. The crude product was purified by normal phase flash chromatography 25 (DCM / MeOH 1:0 to 85:15) to afford the desired product as a pale yellow solid (54 mg, 65%). MS (ESI+): m / z [M+H]+=555. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C32H39N6O3 m / z= 555.3084, found m / z= 555.3098..1H NMR (300 MHz, CD3OD) δ (ppm)Mixture of rotamers: 8.84 (br s, 1H), 8.34 (s, 0.5H), 8.26 (s, 0.5H), 7.54-7.44 (m, 4H), 7.32-7.12 (m, 6H), 4.82 (s, 0.5H), 4.79 (s, 0.5H), 4.63-4.57 (m, 1H), 3.71-3.47 (m, 2H),30 3.24 (br s, 5H), 3.08-2.88 (m, 5H), 2.77-2.45 (m, 5H), 1.71 (s, 6H). Example 99. -[(2R)-1-benzhydryl-4-[2-(methoxymethyl)-1H-imidazo[4,5-c]pyridine- 7-carbonyl]piperazin-2-yl]-N,N-dimethyl-acetamide Step 3. Methyl 2-(methoxymethyl)-1H-imidazo[4,5-c]pyridine-7-carboxylate: 116 Methyl 4,5-diaminopyridine-3-carboxylate (75 mg, 0.40 mmol, 1.0 eq.) was solubilized in dry ethyl acetate (0.9 mL) under inert atmosphere. N,N-Diisopropylethylamine (104 µL, 0.61 mmol, 1.5 eq.), 2-methoxyacetic acid (72 mg, 0.33 mmol, 1.0 eq.) and T3P (257 mg, 0.40 mmol, 1.0 eq.) were added. The tube was sealed and heated at 70°C for 1 hour 5 to allow full solubilization of the reactants. The mixture was then irradiated under microwaves for 30 min at 160°C. Upon completion, the crude mixture was evaporatedand purified by normal phase flash chromatography (DCM / MeOH 1:0 to 9:1 + 0.1% TEA) to afford the desired product as a pale yellow solid (72 mg, 81%). MS (ESI+): m / z [M+H]+=222. 1H NMR (300 MHz, DMSO) δ (ppm): 13.02 (br s, 1NH), 9.11 (s, 1H), 8.83 (s, 1H)10 4.70 (s, 2H), 3.97 (s, 3H), 3.37 (s, 3H). Step 4. Lithium;2-(methoxymethyl)-3H-imidazo[4,5-c]pyridine-7-carboxylate: To a solution of methyl 2-(methoxymethyl)-3H-imidazo[4,5-c]pyridine-7-carboxylate (67mg, 0.30 mmol, 1.0 eq.) in MeOH (1.5 mL), was added lithium;hydroxide;hydrate (25.4 mg, 0.61 mmol, 2.0 eq.) in water (0.2 mL). The mixture was stirred for 60h at 35°C. The15 crude mixture was concentrated under reduced to afford the desired compound as awhite solid (99 mg, q). MS (ESI+): m / z [M+H]+=208. Step 5. 2-[(2R)-1-benzhydryl-4-[2-(methoxymethyl)-3H-imidazo[4,5-c]pyridine-7- carbonyl]piperazin-2-yl]-N,N-dimethyl-acetamide: Lithium;2-(methoxymethyl)-3H-imidazo[4,5-c]pyridine-7-carboxylate (65 mg, 0.31 mmol,20 1.8 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. N,N- Diisopropylethylamine (0.1 mL, 0.52 mmol, 3.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]- N,N-dimethyl-acetamide;dihydrochloride (75 mg, 0.17 mmol, 1.0 eq.) and HBTU (79 mg, 0.21 mmol, 1.2 eq.) were added. After one night at rt, the mixture was diluted with EtOAc and washed with NaHCO3(5%), filtered and concentrated under reduced pressure. The 25 crude product was purified by normal phase flash chromatography (DCM / MeOH 1:0 to 85:15) to afford the desired product as a pale yellow solid (36 mg, 39%). MS (ESI+): m / z[M+H]+=527. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H35N6O3m / z= 527.2771, found m / z= 527.2745.1H NMR (300 MHz, CD3OD) δ (ppm) Mixture of rotamers: 8.86 (s,1H), 8.37 (s, 0.4H), 8.27 (s, 0.6H), 7.54-7.44 (m, 4H), 7.30-7.12 (m, 6H), 4.79 (s, 3H), 30 4.63-4.59 (m, 1H + 0.5H), 3.66-3.62 (m, 1H + 0.5H), 3.53 (s, 3H), 3.45-3.37 (m, 0.6H), 3.27-3.24 (m, 1H + 0.4H), 3.05-2.45 (m, 10H). Example 100.2-[(2R)-1-benzhydryl-4-(1H-imidazo[4,5-c]pyridine-7- carbonyl)piperazin-2-yl]-N,N-dimethyl-acetamide 35 Step 1. Methyl 1H-imidazo[4,5-c]pyridine-7-carboxylate: 117 Methyl 4,5-diaminopyridine-3-carboxylate (100 mg, 0.57 mmol, 1.0 eq.) was solubilized in diethoxymethoxyethane (0.3 mL) and formic acid was added (0.4 mL). The mixture was heated at 60°C. After 2 days, diethoxymethoxyethane (0.3 mL) and formic acid were added (0.4 mL). After two additional days, solvents were evaporated under reduced 5 pressure. The crude compound was purified by reverse phase flash chromatography (H2O / ACN 98:2 to 0:1) to afford the desired compound as a white lyophilizate (61 mg, 61%). MS (ESI+): m / z [M+H]+ =178. 1H NMR (300 MHz, DMSO) δ (ppm): 13.08 (br s,0.8NH), 9.17 (s, 1H), 8.85 (s, 1H), 8.49 (s, 1H), 3.96 (s, 3H).Step 2. Lithium;3H-imidazo[4,5-c]pyridine-7-carboxylate:10 To a solution of methyl 3H-imidazo[4,5-c]pyridine-7-carboxylate (37 mg, 0.21 mmol, 1.0eq.) in MeOH (1.0 mL), was added lithium;hydroxide;hydrate (17.5 mg, 0.42 mmol, 2.0 eq.) in water (0.1 mL). The mixture was stirred for 16h at 35°C. The crude product was concentrated under reduced to afford the desired compound as a white solid (51 mg, q). MS (ESI+): m / z [M+H]+=164. 15 Step 3. 2-[(2R)-1-benzhydryl-4-(3H-imidazo[4,5-c]pyridine-7-carbonyl)piperazin-2- yl]-N,N-dimethyl-acetamide: Lithium;3H-imidazo[4,5-c]pyridine-7-carboxylate (35 mg, 0.21 mmol, 1.4 eq.) was solubilized in dry DMF (0.8 mL) under inert atmosphere. N,N-Diisopropylethylamine (80 µL, 0.45 mmol, 3.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N,N-dimethyl- 20 acetamide;dihydrochloride (65 mg, 0.15 mmol, 1.0 eq.) and HBTU (70 mg, 0.18 mmol, 1.2 eq.) were added. After one night at rt, the mixture was diluted with EtOAc and washed with NaHCO3(5%), filtered and concentrated under reduced pressure. The crude product was purified by normal phase flash chromatography (DCM / MeOH 1:0 to 85:15) to afford the desired product as a pale yellow solid (26 mg, 36%). MS (ESI+): m / z [M+H]+25 =483. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C28H31N6O2m / z= 483.2508, found m / z= 483.2492. 1H NMR (500 MHz, CD3OD, 250K) δ (ppm) Mixture of rotamers: 8.95 (br s,1H), 8.59-8.55 (m, 1H), 8.44 (br s, 0.3H), 8.31 (s, 0.7H), 7.55-7.44 (m, 4H), 7.31-7.09 (m, 6H), 5.03 (s, 0.8NH), 4.78-4.76 (m, 1H), 4.65-4.59 (m, 1H), 3.66-3.59 (m, 1.7H), 3.49- 3.39 (m, 0.6H), 3.20 (br s, 1.7H), 3.10-2.94 (m, 3.3H), 2.87-2.86 (m, 1.2H), 2.79-2.77 (m,30 0.9H), 2.71-2.62 (m, 1.8H), 2.51-2.48 (m, 1.2H), 2.42-2.34 (br s, 1.5H). Example 101. 2-[(2R)-1-benzhydryl-4-(1H-pyrazolo[4,5-c]pyridine-7- carbonyl)piperazin-2-yl]-N,N-dimethyl-acetamide Step 1 & 2 described in example 94. Step 3.2-[(2R)-1-benzhydryl-4-(1H-pyrazolo[4,5-c]pyridine-7-carbonyl)piperazin-2-35 yl]-N,N-dimethyl-acetamide:2-[(2R)-1-benzhydrylpiperazin-2-yl]-N,N-dimethyl- 118 acetamide;dihydrochloride (70 mg, 0.17 mmol, 1.0 eq.) was solubilized in DMF (0.8 mL). 1H-pyrazolo[4,5-c]pyridine-7-carboxylic acid (33 mg, 0.21 mmol, 1.2 eq.), HBTU (71 mg, 0.19 mmol, 1.1 eq.) and N,N-Diisopropylethylamine (119 µL, 0.68 mmol, 4.0 eq.) were added and the reaction mixture was stirred at rt. After 24h, 1H-pyrazolo[4,5-c]pyridine- 5 7-carboxylic acid (8 mg, 0.05 mmol, 0.3 eq.), HBTU (32 mg, 0.09 mmol, 0.5 eq.) and N,N-Diisopropylethylamine (60 µL, 0.34 mmol, 2.0 eq.) were added. After 48h, the mixture was diluted with EtOAc, washed with NaHCO3 (5%) and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white 10 lyophilizate (36.1 mg, 44%). MS (ESI+): m / z [M+H]+=483. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C28H31N6O2 m / z= 483.2508, found m / z= 483.2511..1H NMR (500 MHz, CDCl3, 250K) δ (ppm) Mixture of rotamers: 13.42 (s, 0.5H), 13.17 (s, 0.5H), 9.13 (s, 1H), 8.41 (s, 0.5H), 8.36 (s, 0.5H), 8.25 (s, 0.5H), 8.22 (s, 0.5H), 7.44-7.39 (m, 3H), 7.33-7.28 (m, 2H), 7.24-7.09 (m, 5H), 4.64-4.52 (m, 2H), 4.03 (d, J = 12.8 Hz, 0.5H), 3.79 (d, J =15 12.8 Hz, 0.4H), 3.62-3.60 (m, 1H), 3.37-3.35 (m, 1H), 3.26 (d, J = 12.3 Hz, 0.5H), 3.15-3.10 (m, 0.6H), 2.87-2.80 (m, 1.6H), 2.74-2.65 (m, 3.9H), 2.61-2.44 (m, 2.6H), 2.26 (s, 1.9H). Example 102. 2-[(2R)-1-benzhydryl-4-(1H-pyrazolo[4,5-c]pyridine-7-20 carbonyl)piperazin-2-yl]-1-morpholino-ethanone Step 1. Tert-butyl (3R)-4-benzhydryl-3-(2-morpholino-2-oxo-ethyl)piperazine-1-carboxylate :Lithium;2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetate (1.0 g, 2.28 mmol, 1.0 eq.) was solubilized in dry DMF (10 mL) under inert atmosphere. Morpholine25 (0.4 mL, 4.56 mmol, 2.0 eq.), HBTU (952 mg, 2.51 mmol, 1.1 eq.) and N,N- Diisopropylethylamine (1.2 mL, 6.84 mmol, 3.0 eq.) were added and the reaction mixture was stirred at rt overnight. The mixture was diluted with EtOAc, washed with NaHCO3(5%) and concentrated under reduced pressure. The crude was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a30 white lyophilizate (690 mg, 63%). MS (ESI+): m / z [M+H]+ =480. 1H NMR (300 MHz,CDCl3) δ (ppm) Mixture of rotamers: 7.43-7.39 (m, 4H), 7.29-7.24 (m, 4H), 7.20-7.14 (m, 2H), 4.64 (s, 1H), 3.90-3.86 (m, 2H), 3.60-3.46 (m, 7H), 3.26-3.23 (m, 2H), 3.15-3.11 (m, 1H), 2.99-2.92 (m, 1H), 2.65-2.56 (m, 2H), 2.51-2.42 (m, 1H), 2.37-2.32 (m, 1H), 1.42 (s, 9H). 119 Step 2. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-1-morpholino-ethanone;dihydrochloride: Tert-butyl (3R)-4-benzhydryl-3-(2-morpholino-2-oxo-ethyl)piperazine-1-carboxylate (690 mg, 1.44 mmol, 1.0 eq.) was solubilized in 1,4-Dioxane (7 mL). HCL (4M in dioxane, 3.6 5 mL, 14.4 mmol, 10 eq.) was added at 0°C. The reaction mixture was then allowed to reach room temperature. After stirring overnight, the mixture was concentrated under reduced pressure to afford the desired product as a pale brown solid (615 mg, 95%). MS(ESI+): m / z [M+H]+ =380.Step 3.2-[(2R)-1-benzhydryl-4-(1H-pyrazolo[4,5-c]pyridine-7-carbonyl)piperazin-2-10 yl]-1-morpholino-ethanone :2-[(2R)-1-benzhydrylpiperazin-2-yl]-1-morpholino-ethanone;dihydrochloride (70 mg, 0.16 mmol, 1.0 eq.) was solubilized in DMF (0.7 mL). 1H-pyrazolo[4,5-c]pyridine-7- carboxylic acid (30 mg, 0.19 mmol, 1.2 eq.), HBTU (65 mg, 0.17 mmol, 1.1 eq.) and N,N- Diisopropylethylamine (108 µL, 0.62 mmol, 4.0 eq.) were added and the reaction mixture 15 was stirred at rt. After 24h, 1H-pyrazolo[4,5-c]pyridine-7-carboxylic acid (8 mg, 0.05 mmol, 0.3 eq.), HBTU (29 mg, 0.08 mmol, 0.5 eq.) and N,N-Diisopropylethylamine (54 µL, 0.31 mmol, 2.0 eq.) were added. After 48h, the mixture was diluted with EtOAc, washed with NaHCO3(5%) and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to20 afford the desired product as white lyophilizate (36.3 mg, 45%). MS (ESI+): m / z [M+H]+=525. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H33N6O3m / z= 525.2614, found m / z= 525.2617. 1H NMR (500 MHz, CDCl3, 250K) δ (ppm) Mixture of rotamers: 13.31 (br s,0.6NH), 12.97 (br s, 0.4NH), 9.13 (s, 1H), 8.40 (s, 0.6H), 8.38 (s, 0.4H), 8.25 (s, 1H), 7.45-7.30 (m, 5.4H), 7.24-7.16 (m, 3.6H), 4.59 (d, J = 12.4 Hz, 0.9H), 4.55 (s, 1H), 3.9925 (d, J = 12.4 Hz, 0.4H), 3.72-3.53 (m, 3.4H), 3.40-3.37 (m, 3.3H), 3.29-3.27 (m, 1.8H),3.16-3.09 (m, 0.9H), 3.02 (s, 0.8H), 2.88 (br s, 0.9H), 2.82 (br s, 0.6H), 2.74-2.64 (m, 1H), 2.56-2.44 (m, 2.6H), 2.33-2.30 (m, 0.4H). Example 103. 2-[(2R)-1-benzhydryl-4-(1H-pyrazolo[4,5-c]pyridine-7-30 carbonyl)piperazin-2-yl]-1-(1,1-dioxo-1,4-thiazinan-4-yl)ethanone Step 1. Tert-butyl (3R)-4-benzhydryl-3-[2-(1,1-dioxo-1,4-thiazinan-4-yl)-2-oxo-ethyl]piperazine-1-carboxylate: Lithium;2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetate (1.0 g, 2.28 mmol, 1.0 eq.) was solubilized in dry DMF (10mL) under inert atmosphere.1,4-thiazinane35 1,1-dioxide (617 mg, 4.56 mmol, 2.0 eq.), HBTU (952 mg, 2.51 mmol, 1.1 eq.) and N,N- 120 Diisopropylethylamine (1.2 mL, 6.84 mmol, 3.0 eq.) were added and the reaction mixture was stirred at rt overnight. The mixture was then diluted with EtOAc, washed with NaHCO3 (5%) and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the 5desired product as a white lyophilizate (744 mg, 62%). MS (ESI+): m / z [M+H]+ =528. 1HNMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 7.43-7.38 (m, 4H), 7.31-7.25 (m, 4H), 7.23-7.16 (m, 2H), 4.60 (s, 1H), 4.20-3.83 (m, 4H), 3.69-3.52 (m, 3H), 3.12-2.83 (m, 6H), 2.72-7.60 (m, 2H), 2.47-2.34 (m, 2H), 1.42 (s, 9H). Step 2. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-1-(1,1-dioxo-1,4-thiazinan-4-10 yl)ethanone;dihydrochloride: Tert-butyl (3R)-4-benzhydryl-3-[2-(1,1-dioxo-1,4-thiazinan-4-yl)-2-oxo-ethyl]piperazine- 1-carboxylate (744 mg, 1.41 mmol, 1.0 eq.) was solubilized in 1,4-Dioxane (6.9 mL). HCl (4M in dioxane, 3.5 mL, 14.1 mmol, 10 eq.) was added at 0°C. The reaction mixture was then allowed to reach room temperature and stirred over night. Upon completion, the 15 mixture was concentrated under reduced pressure to afford the desired product as a beige solid (731 mg, quant.). MS (ESI+): m / z [M+H]+ =428.Step 3.2-[(2R)-1-benzhydryl-4-(1H-pyrazolo[4,5-c]pyridine-7-carbonyl)piperazin-2-yl]-1-(1,1-dioxo-1,4-thiazinan-4-yl)ethanone: 2-[(2R)-1-benzhydrylpiperazin-2-yl]-1-(1,1-dioxo-1,4-thiazinan-4-yl)ethanone; 20 dihydrochloride (70 mg, 0.14 mmol, 1.0 eq.) was solubilized in DMF (0.6 mL). 1H- pyrazolo[4,5-c]pyridine-7-carboxylic acid (27 mg, 0.17 mmol, 1.2 eq.), HBTU (58 mg, 0.15 mmol, 1.1 eq.) and N,N-Diisopropylethylamine (97 µL, 0.56 mmol, 4.0 eq.) were added and the reaction mixture was stirred at rt. After 18h, 1H-pyrazolo[4,5-c]pyridine- 7-carboxylic acid (7 mg, 0.04 mmol, 0.3 eq.), HBTU (27 mg, 0.07 mmol, 0.5 eq.) and 25 N,N-Diisopropylethylamine (24 µL, 0.14 mmol, 1.0 eq.) were added. After 40h, the mixture was diluted with EtOAc, washed with NaHCO3(5%) and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (47mg, 59%). MS (ESI+): m / z [M+H]+ =573. HRMS (TOF, ES+) m / z [M+H]+:30 calcd. for C30H33N6O4S m / z= 573.2284, found m / z= 573.2307.1H NMR (500 MHz, CDCl3, 250K) δ (ppm) Mixture of rotamers: 13.17 (s, 0.4NH), 12.93 (s, 0.6NH), 9.17 (s, 0.7H), 9.10 (s, 0.3H), 8.50 (s, 0.7H), 8.30 (s, 0.7H), 8.25 (s, 0.6H), 7.44-7.28 (m, 6.5H), 7.25-7.15 (m, 3.5H), 4.61-4.54 (m, 2H), 3.93-3.88 (m, 1.1H), 3.66-3.39 (m, 4.5H), 3.33 (d, J = 12.5Hz, 0.7H), 3.21-3.02 (m, 3.1H), 2.85-2.65 (m, 4.5H), 2.54-2.45 (m, 1.7H),35 2.36 (d, J = 15.2Hz, 0.4H). 121 Example 104. 2-[(2R)-1-benzhydryl-4-(1-methyl-2-oxo-quinoline-4- carbonyl)piperazin-2-yl]-N,N-dimethyl-acetamide Starting directly from commercially available 1-methyl-2-oxo-quinoline-4-carboxylic acid. 5 Step 2. 2-[(2R)-1-benzhydryl-4-(1-methyl-2-oxo-quinoline-4-carbonyl)piperazin-2- yl]-N,N-dimethyl-acetamide 1-methyl-2-oxo-quinoline-4-carboxylic acid (36 mg, 0.18 mmol, 1.2 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (102 µL, 0.59 mmol, 4.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N,N-dimethyl- 10 acetamide;dihydrochloride (70 mg, 0.15 mmol, 1.0 eq.) and HBTU (61 mg, 0.16 mmol, 1.1 eq.) were added. After one night at room temperature with stirring, the mixture was diluted with EtOAc and washed with NaHCO3(5%) and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 80:20 to 0:1) to afford the desired product as a white lyophilizate (59 mg, 7615 %). MS (ESI+): m / z [M+H]+= 523. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C32H35N4O3m / z= 523.2709, found m / z= 523.2714.1H NMR (300 MHz, CD3OD) δ (ppm) Mixture ofrotamers: 7.74-7.66 (m, 1.60H), 7.62-7.58 (0.8H), 7.52-7.42 (m, 4.7H), 7.38-7.33 (m, 1H), 7.30-7.08 (m, 6H), 6.70 (s, 0.2H), 6.60 (s, 0.1H), 6.58 (s, 0.3H), 6.49 (m, 0.4H), 4.8 (s, 1H), 4.55-4.51 (s, 1H), 3.77-3.58 (3.9H), 3.44-3.43 (m, 0.8H), 3.35-3.12 (m, 3.1H),20 3.03(s, 0.5H), 2.99 (s, 0.3H), 2.89-2.48 (m, 7H), 2.18 (s, 0.9H), 0.5H under solvent peak. Example 105. 2-[(2R)-1-benzhydryl-4-(8-fluoro-2-oxo-1H-quinoline-4- carbonyl)piperazin-2-yl]-N,N-dimethyl-acetamide: 25 Step 2. 2-[(2R)-1-benzhydryl-4-(8-fluoro-2-oxo-1H-quinoline-4-carbonyl)piperazin- 2-yl]-N,N-dimethyl-acetamide: 8-fluoro-2-oxo-1H-quinoline-4-carboxylic acid (37 mg, 0.18 mmol, 1.2 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (102 µL, 0.59 mmol, 4.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N,N-dimethyl- 30 acetamide;dihydrochloride (70 mg, 0.15 mmol, 1.0 eq.) and HBTU (61 mg, 0.16 mmol, 1.1 eq.) were added. After stirring overnight at room temperature, the mixture was diluted with EtOAc and washed with NaHCO3 (5%) and concentrated under reduced pressure. The product was purified by reverse phrase chromatography (H2O / ACN 90:10 to 0:1) to afford the desired product as a lyophilizate (63 mg, 80 %). MS (ESI+): m / z [M+H]+= 527. 35 HRMS (TOF, ES+) m / z [M+H]+: calcd. for C31H32FN4O3 m / z= 527.2458, found m / z= 122 527.2463.1H NMR (300 MHz, CD3OD) δ (ppm) Mixture of rotamers: 7.52-7.36 (m, 5.4H),7.30-7.08 (m, 7.6H), 6.68 (s, 0.2H), 6.58 (s, 0.1H), 6.56 (s, 0.3H), 6.48 (s, 0.4H), 4.80 (s, 1H), 4.54-4.49 (m, 1H), 3.79-3.75 (m, 0.3H), 3.68-3.59 (m, 0.6H), 3.44 (s, 0.8H), 3.35- 3.34 (m, 0.4H), 3.28-3.14 (m, 1.2H), 3.11 (s, 1.2H), 3.03 (s, 0.5H), 2.97 (s, 0.4H), 2.88 5 (s, 0.3H), 2.87 (s, 0.6H), 2.83 (s, 0.8H), 2.82-2.48 (m, 5.2H), 2.26 (s, 0.8H), 0.9H under solvent peak. Example 106. 2-[(2R)-1-benzhydryl-4-(1,3-dimethyl-6-oxo-7H-pyrazolo[5,4- b]pyridine-4-carbonyl)piperazin-2-yl]-N,N-dimethyl-acetamide 10 Step 1. Lithium;1,3-dimethyl-6-oxo-7H-pyrazolo[5,4-b]pyridine-4-carboxylate: Ethyl 1,3-dimethyl-6-oxo-7H-pyrazolo[5,4-b]pyridine-4-carboxylate (50 mg, 0.21 mmol, 1.0 eq.) was solubilized in MeOH (0.9 mL). Lithium;hydroxide;hydrate (9 mg, 0.21 mmol, 1.0 eq.) in water (0.1 mL) was added and the reaction mixture was stirred at rt. After one night of stirring, lithium;hydroxide;hydrate (4 mg, 0.11 mmol, 0.5 eq.) was added. Upon 15 completion, the mixture was concentrated under reduced pressure to afford the desired product as a pale orange solid (47.2 mg, quant.). MS (ESI+): m / z [M+H]+=208.1H NMR (300 MHz, DMSO-d6) δ (ppm): 5.95 (s, 1H), 3.59 (s, 3H), 2.29 (s, 3H). Step 2. 2-[(2R)-1-benzhydryl-4-(1,3-dimethyl-6-oxo-7H-pyrazolo[5,4-b]pyridine-4- carbonyl)piperazin-2-yl]-N,N-dimethyl-acetamide: 20 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N,N-dimethyl-acetamide;dihydrochloride (60 mg, 0.15 mmol, 1.0 eq.) was solubilized in DMF (0.7 mL). Lithium;1,3-dimethyl-6-oxo-7H- pyrazolo[5,4-b]pyridine-4-carboxylate (37 mg, 0.18 mmol, 1.2 eq.), HBTU (61 mg, 0.16 mmol, 1.1 eq.) and N,N-Diisopropylethylamine (102 µL, 0.59 mmol, 4.0 eq.) were added and the reaction mixture was stirred at rt. After one night, HBTU (28 mg, 0.07 mmol, 0.5 25 eq.) and N,N-Diisopropylethylamine (51 µL, 0.29 mmol, 2.0 eq.) were added. After 40h, the mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white lyophilizate (22 mg, 28%). MS (ESI+): m / z [M+H]+=527. HRMS (TOF, ES+) m / z [M+H]+: calcd. for C30H35N6O3 m / z= 527.2771, found m / z= 527.2761.1H NMR 30 (500 MHz, CDCl3, 250K) δ (ppm) Mixture of rotamers: 14.11 (br s, 1H), 7.48-7.29 (m, 5.6H), 7.25-7.14 (m, 4.4H), 6.14 (s, 0.3H), 6.07 (s, 0.1H), 6.01 (s, 0.1H), 5.88 (s, 0.5H), 4.73-7.49 (m, 2.7H), 3.92 (br s, 3H), 3.75-3.68 (m, 0.5H), 3.58-3.38 (m, 2.5H), 3.08-2.98 (m, 2.3H), 2.88-2.78 (m, 4.3H), 2.58-2.52 (m, 2.2H), 2.39-2.34 (m, 2.1H), 2.26 (s, 2.4H).35 II. Biological data 123 SARS-CoV-23CLproenzymatic assays. The FRET-based assay was optimized and miniaturized in Corning 384-wells plates (dark, low-binding, low volume). The assay was conducted at room temperature using a 5 reaction volume of 20 µL and a buffer containing 50 mM HEPES, 0.1 mg / mL BSA, 0.01% Triton and 2 mM GSH at pH 7.5. Compounds stored as 10 mM stock solutions in DMSO were dispensed by acoustic nanodispensing with an Echo Liquid Handler (Labcyte).10 µL 3CLprowas added to the tested compounds and preincubated for 30 min before addition of 10 µL FRET-based substrate {Dabcyl}-KTSAVLQSGFRKM-{Glu(Edans)}. 10 Final concentrations were 15 nM and 10 µM for enzyme and substrate respectively. Final concentration of DMSO did not exceed 1%. After 30 min of preincubation, the reaction progress was monitored for 30 minutes to measure the initial velocities used in calculations. The fluorescence intensity was monitored with a Victor 3V instrument (Perkin-Elmer) using excitation and emission wavelengths of 340(25) nm and 535(25) 15 nm. pIC50 values were obtained from concentration-response curves by a nonlinear regression analysis of the data using an equation at four parameters (using XL fitTM5.2.0.0. from IDBS (Guilford, United Kingdom) or GraphPad Prism 7 (San Diego, USA). y 20 A, minimum y value; B, maximum y value; C, LogIC50 value; D, slope factor. pIC50 values were averages of three independent experiments and were given with their standard deviation (SD). IC50 were calculated from the mean pIC50 value Results are presented in table 1. 25 124 (3S)-(4-benzhydryl-3- 125 [(3S)-4-benzhydryl-3-(2- 126 (2R)-1-benzhydryl-4- 1 127 ethyl 2-[(2S)-1-benzhydryl- 6 128 2-[1-benzhydryl-4- mide 129 2-[1-benzhydryl-4- 130 2-[1-benzhydryl-4- 131 tert-butyl N-[[1-benzhydryl- 132 methyl 2-[4-benzhydryl-1- 133 2-[1-benzhydryl-4-(2- methyl-acetamide 134 2-[(2R)-1-[(R)-(4- 135 N 2-[(2R)-1-benzhydryl-4- 136 2-[(2R)-1-benzhydryl-4- 137 2-[(2R)-1-benzhydryl-4- 138 2-[(2R)-1-benzhydryl-4- 139 2-[(2R)-1-benzhydryl-4- 106 5

Claims

1. 140 CLAIMS 1. A compound of formula (I):5wherein: Ais a bicyclic ring system, the bicyclic ring system being:(i) a 9-membered bicyclic aromatic or partially aromatic ring system consisting of 10 a pyridinyl fused with a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S, and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule via a ring carbon atom of the pyridinyl; or (ii) a 10-membered bicyclic aromatic or partially aromatic ring system consisting 15 of a pyridinyl fused with a 6-membered ring, the 6-membered ring being a phenyl or a ring containing one, two or three heteroatoms, each independently selected from O, S, and N, said 10-membered bicyclic aromatic ring being attached to the remainder of the molecule via a ring carbon atom of the pyridinyl; and20 R is selected from the group consisting of -C1-C6-alkyl; -C1-C6-hydroxalkyl; -C1-C6-haloalkyl; -C1-C6-cyanoalkyl; -O-C1-C6-alkyl; -C(O)ORawherein Rais selected from the group consisting of hydrogen atom, -C1-C6-alkyl and Li; -C(O)N(Rb)2 wherein Rbis independently selected from the group consisting of hydrogen atom and C1-C6-alkyl, or the two Rb form together a 5- or 6-membered non-aromatic ring containing one, two or25 three heteroatoms, each independently selected from O, S, and N; 3- to 6-memberednon-aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, and N; 5- or 6-membered heteroaryl;-C1-C6-alkyl-SRc wherein Rc is141 selected from the group consisting of hydrogen atom and -C(O)-C1-C6-alkyl; -C1-C6-alkyl- O-C1-C6-alkyl; -C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16; - C1-C6-alkyl-N(Rd)2 wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and-C(O)O-C1-C6-alkyl; -C1-C6-alkyl-C(O)ORewherein Reis 5 selected from the group consisting of hydrogen atom, -C1-C6-alkyl and Li; C1-C6-alkyl- C(O)-azetidine-(5- or 6-membered heteroaryl); ; C1-C6-alkyl-C(O)-azetine-(5- or 6-membered heteroaryl); -C1-C6-alkyl-C(O)N(Rf)2 wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C6-alkyl, -C1-C6-alkyl-O-C1-C6-alkyl, - C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16, C1-C6-alkyl-(5- or10 6-membered heteroaryl), -C1-C6-alkoxy and C1-C6-alkyl-N(C1-C6-alkyl)2, or the two Rfform together a 5- to 6-membered non-aromatic ring containing one, two or threeheteroatoms, each independently selected from O, S, and N; -C1-C6-alkyl-(5- or 6-membered heteroaryl); and -C1-C6-alkyl-NH-C(O)ORgwherein Rgis independently selected from the group consisting of -C1-C6-alkyl and -C1-C6-alkyl-heteroaryl wherein15 the heteroaryl is a 5- or 6-membered heteroaryl; wherein said 5- or 6-membered non-aromatic ring, said 3- to 6-membered non-aromatic ring and said 5- or 6-memberedheteroaryl may be substituted by one or more substituents selected from the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, halogen, hydroxyl, nitro, cyano, =O, =S, =N— CN, and ═N—OH; 20 X1is independently selected from the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, - C1-C6-haloalkyl, halogen, hydroxyl, nitro, cyano, =O, =S, =N—CN and ═N—OH; X2 is a halogen atom;X3is a halogen atom; n1is 0, 1, 2 or 3; 25 n2is 0 or 1; n3is 0 or 1; or hydrates, solvates, salts or deuterated analogs thereof.

2. The compound according to claim 1, wherein it has the following formula (II):142wherein: Bis a phenyl or a 5-membered or 6-membered monocyclic saturated, insaturated, or5 aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, and N, wherein said phenyl or said aromatic ring may be substituted by one or two substituents selected from the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, halogen, hydroxyl, nitro, cyano, =O, =S, =N—CN and ═N—OH; and R, X2, X3, n2and n3are as recited in claim 1. 10 3. The compound according to claim 1 or 2, wherein R is selected from the groupconsisting of -C1-C6-alkyl; -C1-C3-hydroxalkyl; -C1-C3-haloalkyl; -C1-C3-cyanoalkyl; - C(O)ORawherein Rais selected from the group consisting of hydrogen atom, -C1-C3- alkyl and Li; -C(O)N(Rb)2 wherein Rbis independently selected from the group consisting15 of hydrogen atom and C1-C3-alkyl, or the two Rb form together a 5- or 6-membered non-aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, and N; 3- to 6-membered non-aromatic ring containing one, two or threeheteroatoms, each independently selected from O, S, and N; 5- or 6-memberedheteroaryl; -C1-C6-alkyl-SRcwherein Rcis selected from the group consisting of hydrogen20 atom and -C(O)-C1-C3-alkyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1-C3-alkyl-[O-C1-C3-alkyl]n-O- C1-C3-alkyl with n ranging from 1 to 16; -C1-C6-alkyl-N(Rd)2wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and-C(O)O-C1-C3- alkyl; -C1-C6-alkyl-C(O)ORewherein Reis selected from the group consisting of hydrogen atom, -C1-C3-alkyl and Li, C1-C6-alkyl-C(O)-azetidine-(5- or 6-membered heteroaryl); -25 C1-C6-alkyl-C(O)N(Rf)2wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl, -C1-C3-alkyl-[O-C1-C3-alkyl]n-O- C1-C3-alkyl with n ranging from 1 to 16, C1-C6-alkyl-(5- or 6-membered heteroaryl), -C1-C3-alkoxy and C1-C3-alkyl-N(C1-C3-alkyl)2, or the two Rf form together a 4- to 6-143 membered non-aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, and N; -C1-C3-alkyl-NH-C(O)ORgwherein Rgis independently selected from the group consisting of -C1-C4-alkyl and -C1-C3-alkyl- heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl.5 4. The compound according to any one of claims 1 to 3, wherein it has the followingformula (Ia) or (IIa):10 (Ia) (IIa) with A and B being respectively as recited in claim 1 or 2, X1, X2, X3, n1, n2 and n3 beingas recited in claim 1and R being as recited in claim 1 or 3.

5. The compound according to according to any one of claims 1 to 3, wherein it has15 the following formula (Ib) or (IIb):(Ib) (IIb) with A and B being respectively as recited in claim 1 or 2, X1, X2, X3, n1, n2 and n3 being20 as recited in claim 1and R being as recited in claim 1 or 3.

6. The compound according to any one of claims 1, 3 to 5, wherein A is selectedfrom the group consisting of:144 H N S NN,N , N , N ,,.and .

7. The compound according to any one the preceding claims, which is any ofcompounds 1 to 106, preferably compounds 76, 79, 80, 94, 101, 102, 103 or 105, as145 defined in table 1, or tautomers, stereorisomers, hydrates, solvates, salts or deuteratedanalogs thereof.

8. A pharmaceutical or veterinary composition comprising at least one compound of5 formula (I) according to any one of the preceding claims and one or more excipients.

9. A compound of formula (I) according to any of claims 1 to 7 or a pharmaceuticalcomposition according to claim 8 for use in medicine.10 10. A compound of formula (I) according to any of claims 1 to 7 or a pharmaceuticalcomposition according to claim 8 for use in treatment or prophylaxis of a disordermediated by a coronavirus.

11. A compound of formula (I) or a pharmaceutical composition for its use according15 to claim 10, wherein the coronavirus is SARS-CoV-2.

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