OA17896A

OA17896A - New compounds Isoindoline or Isoquinoline, process for their preparation and pharmaceutical compositions containing them.

Info

Publication number: OA17896A
Application number: OA1201600041
Authority: OA
Inventors: James Edward Paul Davidson; James Brooke Murray; l-Jen CHEN; Claire Walmsley; Mark Dodsworth; Johannes W.G. Meissner; Paul Brough; Imre Fejes; Janos Tatai; Miklos S NYERGES; Andras Kotschy; Zoltan Szlavik; Olivier Geneste; Tiran Arnaud Le; Diguarher Thierry Le; Jean-Michel Henlin; Jérôme-Benoît Starck; Anne-Françoise Guillouzic; Nanteuil Guillaume De
Original assignee: Les Laboratoires Servier; Vernalis (R&D) Limited
Priority date: 2013-07-23
Filing date: 2014-07-22
Publication date: 2018-02-27

Abstract

Compounds of formula (I) wherein Het, R3, R4, R5, R7, R8, R9 T, p, p', q, and q' are as defined in the description.Compounds of formula (I) wherein Het, R3, R4, R5, R7, R8, R9 T, p, p ', q, and q' are as defined in the description.

Description

The présent invention relates to new isoindoline or isoquinoline compounds, to a process for their préparation and to pharmaceutical compositions containing them.

The compounds of the présent invention are new and hâve very valuable pharmacological characteristics in the field of apoptosis and cancerology.

Apoptosis, or programmed cell death, is a physiological process that is crucial for embryonic development and maintenance of tissue homeostasis.

Apoptotic-type cell death involves morphological changes such as condensation of the nucléus, DNA fragmentation and also biochemical phenomena such as the activation of caspases which cause damage to key structural components of the cell, so inducing its F disassembly and death. Régulation of the process of apoptosis is complex and involves the activation or repression of several intracellular signalling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).

Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and ischaemia. Conversely, déficits in the implémentation of apoptosis play a significant rôle in the development of cancers and their chemoresistance, in auto-immune diseases, inflammatory diseases and viral infections. Accordingly, absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70).

The anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies.

The involvement of proteins of the Bcl-2 family is described in numerous types of cancer, such as colon cancer, breast cancer, small-cell lung cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia, follicular lymphoma, myeloma, etc. Overexpression of the anti-apoptotic proteins of the Bcl-2 family is involved in tumorigenesis, in résistance to chemotherapy and in the clinical prognosis of patients affected by cancer. There is, therefore, a therapeutic need for compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.

In addition to being new, the compounds of the présent invention hâve pro-apoptotic properties making it possible to use them in pathologies involving a defect in apoptosis,

-2such as, for example, in the treatment of cancer and of auto-immune and immune System diseases.

The présent invention relates more especially to compounds of formula (I):

r₃

wherein:

♦ Het represents a heteroaryl group, ♦ T represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group optionally substituted by one to three halogen atoms, an alkyl(Ci-C4)-NRiR2 group or an alkyl(Ci-C4)-ORô group, ♦ Ri and R2 independently of one another represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group, or Ri and R2 form with the nitrogen atom carrying them a heterocycloalkyl group, ♦ R3 represents a linear or branched (Ci-Cô)alkyl group, a linear or branched (C2-Ce)alkenyl group, a linear or branched (C2-Cô)alkynyl group, a cycloalkyl group, a (C3-Cio)cycloalkyl-(Ci-C6)alkyl group wherein the alkyl group may be linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated, ♦ R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (Ci-C6)alkyl group, it being understood that one or more carbon atoms of the groups defined

4/ &/ £

-3hereinbefore, or carbon atoms of their possible substituents, may be deuterated, ♦ R₅ represents a hydrogen atom or a halogen atom, a linear or branched (Ci-C&)alkyl group, or a linear or branched (Ci-Côjalkoxy group, ♦ Rê represents a hydrogen atom or a linear or branched (Ci-Côjalkyl group, ♦ R? represents a group selected from R’₇, R’₇-CO-, R’₇-O-CO-, NR’₇R”₇-CO-, R’₇-SC>2-, R’₇-NR”₇-SO2- wherein R’₇ and R”₇ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl, a heterocycloalkyl, an aryl group, or a heteroaryl, ♦ Rg and R9 represent, independently of one another, an oxo group or a halogen atom, ♦ p and p’ are, independently of one another, integers equal to 0, 1, 2, 3 or 4, ♦ q and q’ are, independently of one another, integers equal to 1, 2 or 3, it being understood that when compound of formula (I) contains a hydroxy group, this latter group may be optionally substituted by one of the following groups: -PO(OM)(OM’), -ΡΟ(ΟΜ)(ΟΜι⁺), -ΡΟ(ΟΜΓ)(ΟΜ2⁺), -PO(O)(O)M₃ ²⁺,

-PO(OM)(O[CH₂CH₂O]_nCH₃), or -PO(O‘M₁ ⁺)(O[CH2CH2O]nCH3), wherein M and M’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cg)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl or a heterocycloalkyl, both of them being composed of from 5 to 6 ring members, while Mi⁺ and M2⁺ independently of one another represent a pharmaceutically acceptable monovalent cation, M₃ ²⁺ represents a pharmaceutically acceptable divalent cation and n is an integer comprised between 1 to 5, it also being understood that:

- aryl means a phenyl, naphthyl, biphenyl or indenyl group,

- heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quatemary nitrogens),

- cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, which may include fused, bridged or spiro ring Systems,

I

I “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group, | composed of from 3 to 10 ring members, and containing from one to 3 hetero atoms selected from oxygen, sulphur, SO, SO₂ and nitrogen, it being understood that bicyclic group may be fused or spiro type,

I

I it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 3 groups selected from: optionally substituted linear or branched (Ci-C6)alkyl ; optionally substituted linear or branched (C₂-Cô)alkenyl group; optionally substituted linear or branched (C₂-C6)alkynyl group; (Cj-Côjspiro; optionally substituted linear or branched (Ci-Célalkoxy; (Ci-Cô)alkyl-S-; hydroxyl; oxo (or A-oxide where appropriate); nitro; cyano; -COOR'; -OCOR'; -NR'R; R’CONR”-; NR’R”CO-; linear or branched (Ci-Cô)polyhaloalkyl; trifluoromethoxy; (Ci-C₆)alkylsulphonyl; halogen; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted aryloxy; optionally substituted arylthio; optionally substituted cycloalkyl or optionally substituted heterocycloalkyl, it being understood that R' and R independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Cé)alkyl group or an aryl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

More preferably, the présent invention relates to compounds of formula (IA):

I

(ΙΑ) wherein:

I I

I

I I

I

I I

W represents a C-A3 group or a nitrogen atom,

X, Y and Z represent a carbon atom or a nitrogen atom, it being understood that only one of them represent a nitrogen atom, while the two others represent carbon atoms,

Ai, A2 and A3 independently of one another represent a hydrogen atom or a halogen atom, a linear or branched (Cj-Cô/polyhaloalkyl group, a linear or branched (Ci-Cô)alkyl group or a cycloalkyl group, or A3 represents a hydrogen atom (when W represents a C-A3 group) while Ai and A₂ form together with the atoms carrying them an optionally substituted aromatic or non-aromatic ring Cy, composed of 5, 6 or 7 ring members, which may contain from one to 4 hetero atoms selected independently from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-Côjalkyl group or a group -C(O)-O-Alk wherein Alk is a linear or branched (Ci-Celaikyl group, or W represents a nitrogen atom while Ai and A₂ form together with the atoms carrying them an optionally substituted aromatic or non-aromatic ring Cy, composed of 5, 6 or 7 ring members, which may contain from one to 4 hetero atoms selected independently from oxygen, sulphur and nitrogen, it being

I

- 6 understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-Côlalkyl group or a group -C(O)-O-Alk wherein Alk is a linear or branched (Ci-Ce)alkyl group, ♦ T represents a hydrogen atom, a linear or branched (Cj-Côlalkyl group optionally substituted by one to three halogen atoms, an alkyl(Ci-C4)-NRiR₂, group or an alkyl(Ci-C4)-OR6 group, ♦ Ri and R₂ independently of one another represent a hydrogen atom or a linear or branched (Ci-Cô)alkyl group, or Ri and R₂ form with the nitrogen atom carrying them a heterocycloalkyl,

R₃ represents a linear or branched (Ci-C6)alkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl group, a (C₃-Cio)cycloalkyl-(Ci-C6)alkyl group wherein the alkyl group may be linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated, ♦ R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (Ci-Cô)alkyl group, it being understood that one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated, ♦ R5 represents a hydrogen atom or a halogen atom, a linear or branched (Ci-Cô)alkyl group, or a linear or branched (Ci-C6)alkoxy group, ♦ Rô represents a hydrogen atom or a linear or branched (Ci-Cg)alkyl group, ♦ R7 represents a group selected from R’₇, R’₇-CO-, R’₇-O-CO-, NR’₇R”₇-CO-, R’₇-SO₂-, R’₇-NR”₇-SO₂- wherein R’₇ and R”₇ independently of one another represent a hydrogen atom, a linear or branched (Ci-Côlalkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl, a heterocycloalkyl, an aryl group, or a heteroaryl, ♦ Rg and R9 represent, independently of one another, an oxo group or a halogen atom, ♦ p and p’ are, independently of one another, integers equal to 0, 1, 2, 3 or 4, ♦ q and q’ are, independently of one another, integers equal to 1, 2 or 3, it being understood that when compound of formula (I) contains a hydroxy group, this latter group may be optionally substituted by one of the following groups:

I

-7-P0(0M)(0M’), -PO(OM)(O-Mf), -PO(O-Mj⁺)(O’M2⁺), -PO(O-)(O’)M3²⁺,

-PO(OM)(O[CH₂CH₂O]_nCH₃), or -PO(O’M₁ ⁺)(O[CH2CH2O]nCH3), wherein M and M’ independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl or a heterocycloalkyl, both of them being composed of from 5 to 6 ring members, while M/ and M2⁺ independently of one another represent a pharmaceutically acceptable monovalent cation, M3²⁺ représente a pharmaceutically acceptable divalent cation and n is an integer comprised between 1 to 5, it also being understood that:

- aryl means a phenyl, naphthyl, biphenyl or indenyl group,

- “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group, composed of from 3 to 10 ring members, and containing from one to 3 hetero atoms selected from oxygen, sulphur, S O, SO2 and nitrogen, it being understood that bicyclic group may be fused or spiro type, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 3 groups selected from: optionally substituted linear or branched (Ci-Ce)alkyl ; optionally substituted linear or branched (C2-Cô)alkenyl group; optionally substituted linear or branched (C2-Cô)alkynyl group ; (C₃-C6)spiro; optionally substituted linear or branched (Ci-Cô)alkoxy; (Ci-C6)alkyl-S-; hydroxyl; oxo (or N-oxide where appropriate); nitro; cyano; -COOR'; -OCOR'; -NR'R; R’CONR”-; NR’R’OO-; linear or branched (Ci-C₆)polyhaloalkyl; trifluoromethoxy; (Ci-Cô)alkylsulphonyl; halogen; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted aryloxy; optionally substituted arylthio; optionally substituted cycloalkyl or optionally substituted heterocycloalkyl, it being

I

-8understood that R' and R independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Cô)alkyl group or an aryl group, it being possible for the Cy moiety defined in formula (IA) to be substituted by from 1 to 3 groups selected from linear or branched (Ci-Côfalkyl, linear or branched (Ci-Côjpolyhaloalkyl, hydroxy, linear or branched (Ci-Côjalkoxy, COOH, NRi'Rj and halogen, it being understood that Rf and Rj hâve the same définitions than the groups R' and R mentioned hereinbefore, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

Compounds of formula (IA-1), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base, are more preferred:

wherein X, Y, W, Ai, A2, R3, R4, R5, R7, Rs, R9, T, p, p’, q and q’ are as defined for formula (IA).

Compounds of formula (IA-2), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base, are even more preferred:

^R7 wherein Ai, A₂, R3, R4, R7 and T are as defined for formula (IA).

Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, rert-butylamine etc.

In a preferred embodiment of the invention, R4 represents a phenyl substituted at the para position by a group of formula -OPO(OM)(OM’), -OPO(OM)(O’Mi⁺), -ΟΡΟ(ΟΜΓ)(ΟΜ2⁺), -OPO(O)(O)M3²⁺, -OPO(OM)(O[CH2CH2O]nCH3), or -OPO(O‘Mi⁺)(O[CH2CH₂O]nCH₃), wherein M and M’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Côjalkyl group, a linear or branched (C₂-Cg)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl or a heterocycloalkyl, both of them being composed of from 5 to 6 ring members, while Mi⁺and M2⁺ independently of one another represent a pharmaceutically acceptable monovalent cation, M3²⁺ represents a pharmaceutically acceptable divalent cation and n is an integer comprised between 1 to 5, it being understood that the phenyl group may be optionally substituted by one or more halogen atoms.

I

I I I

I

I I

I

The group Het advantageously represents one of the following groups:

tetrahydroindolizine, indolizine or l,2-dimethyl-1 //-pyrrole. The group 1,2-dimethyl-l//pyrrole is more especially preferred. Altematively, the group 5,6,7,8-tetrahydroindolizine is more preferred.

In the preferred compounds of the invention, q=l and q’=l. Altematively, q=2 and q’=l.

Preferably, T represents a hydrogen atom, a methyl group, a (morpholin-4-yl)alkyl group, a dimethylaminomethyl group, or an (alkylpiperazin-l-yl)alkyl group. More preferably, T represents a methyl group, a (morpholin-4-yl)methyl group, a 3-(morpholin-4-yl)propyl group or a (4-methylpiperazin-l-yl)methyl group. Even more preferably, T represents a methyl group. Altematively, T represents more preferably a (morpholin-4-yl)methyl group.

In preferred compounds of the invention, R3 represents a linear or branched (Ci-Cô)alkyl group, an aryl group or a heteroaryl group. More specifically, R3 is a group selected from phenyl, methyl, elhyl, propyl, butyl, 1-methyl-lH-pyrrolo[2,3-b]pyridine or 5-cyano-l,2dimethyl- l//-pyrrole. More preferably, R3 represents a methyl, propyl or butyl group. Even more preferably, R3 represents a methyl group.

Preferably, R4 represents a linear or branched (Ci-C6)alkyl group (more especially a butyl) or an aryl group. R4 represents advantageously a phenyl group optionally substituted.

Preference is given to the R4 group being a 4-hydroxyphenyl.

Advantageously, R7 represents a group RVCO- or RVO-CO-.

In preferred compounds of the invention, R’7 represents an aryl optionally substituted, a cycloalkyl optionally substituted or an alkyl optionally substituted. More preferably, R’7 represents an optionally substituted naphthalene, phenyl or indole group. The most preferred substitutions for the phenyl group are alkyl optionally substituted, cyano, alkynyl, halogen, alkoxy optionally substituted, or -NR’R”. Even more preferably

- Il preferred substitutions for the phenyl group are methyl, ethyl, methoxy, chloro, bromo, cyano, 2-dimethylaminoethylamino, ethynyl, 2-dimethylaminoethoxy,

2-(dimethylamino)ethyl(methyl)amino, dimethylcarbamoylethyl.

In a preferred embodiment, p=p’=0.

More particularly, the invention relates to the following compounds:

• 2V-(4-Hydroxyphenyl)-/V-methyl-3-{7-[(37?)-3-methyl-l,2,3,4-tetrahydro isoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl}5,6,7,8-tetrahydroindolizine-l-carboxamide;

• Phenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3yl}-7-[(37?)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydro isoquinoline-2-carboxylate;

• Phenyl 6- {4- [(4-hydroxyphenyl)(methyl)carbamoylJ -1,5-dimethyl-177-pyrrol-2-yl} 7-[(37?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydro isoquinoline-2-carboxylate;

• Phenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3yl}-7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;

• Phenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl-l/Z-pyrrol-2-yl}7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonylJ-

1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;

• 4-Methylphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S')-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;

• 2-Methylphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl} -7- [(35)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Methoxyphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetr ahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Chlorophenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro

- 12indolizin-3-yl}-7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Ethylphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Cyanophenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl} -7- [(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 2-Methoxyphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Methylphenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-177pyrrol-2-yl} -7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Chlorophenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l ,5-dimethyl-177- pyrrol-2-yl}-7-[(3S)-3-(moipholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl ]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Cyanophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-177pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Cyanophenyl 6- {4- [(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-177- pyrrol-2-yl}-7-[(37?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate;

• 4-{[2-(Dimethylamino)ethyl]amino}phenyl 6-{ l-[(4-hydroxyphenyl)(methyl) carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl} -7-[(37?)-3-methyl-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• Phenyl 6- {4- [(4-hydroxyphenyl)(propyl)carbamoyl]-1,5-dimethyl- 177-pyrrol-2-yl} 7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• Phenyl 6-{4-[butyl(4-hydroxyphenyl)carbamoylJ-1,5-dimethyl- 177-pyrrol-2-yl}-Ί[(35)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonylJ-1,2,3,4tetrahydroisoquinoline-2-carboxylate;

- B - • Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lZ/-pyrrol-2-yl}7-[(35)-3-i(4-methylpiperazin-l-yl)methyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• N-Butyl-Æ-(4-hydroxyphenyl)-l,2-dimethyl-5-{7-[(3S)-3-(morpholin-4-ylmethyl)- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl} - l//-pyrrole-3-carboxamide;

• 3-[2-(Dimethylamino)ethoxy]phenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoyl]-

1,5-dimethyl- l//-pyrrol-2-yl }-7-[(37?)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-{ [2-(Dimethylamino)ethyl](methyl)amino}phenyl 6-{4-[(4-hydroxyphenyl) (methyl)carbamoyl]-1,5-dimethyl- lH-pyrrol-2-yl} -7- [(3Æ)-3-methyl-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Ethynylphenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl-lH- pyrrol-2-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonylj-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• Naphthalen-2-yl 6- {4- [(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-177- pyrrol-2-yl}-7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• l//-Indol-5-yl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl- IH- pyrrol-2-yl} -7 - [(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 3-[2-(Dimethylcarbamoyl)ethÿl]phènyl 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-1,5-dimethyl- l/7-pyrrol-2-yl} -7- [(37?)-3-methyl-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Bromophenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl- IH- pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• (1 r,4r)-4- {[(ieri-Butoxy)carbonylJamino} cyclohexyl 6- {4- [(4-hydroxyphenyl) (methyl)carbamoylj-1,5-dimethyl- 1 H-pyrrol-2-yl} -7- [(32?)-3-methyl-1,2,3,4tetrahydroisoquinoline-2-parbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-[2-(Dimethylcarbamoyl)ethyl]phenyl 6- {4- [ (4-hydroxyphenyl) (methyl) carbamoyl]-1,5-dimethyl-1 H-py rroI-2-y 1}-7-[(37?)-3-mcthyl-1,2,3,4-tetrahydro

. ]4_ isoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• Cyclohexyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l/7-pyrrol2-yl}-7-[(3R)-3-[3-(morpholin-4-yl)propyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate.

The invention relates also to a process for the préparation of compounds of formula (I) characterised in that there is used as starting material the compound of formula (II):

r₃

wherein Het, R3, R4, Rs, R9, p, p’, q and q’ are as defined for formula (I) and Alk represents a linear or branched (Cj-Cô) alkyl group, the ester function of which compound of formula (II) is hydrolysed to yield the corresponding carboxylic acid which is then subjected to peptide coupling with a compound of formula (III):

wherein R₅ and T are as defined for formula (I), to yield the compound of formula (IV):

R₃

wherein Het, R₃, R4, R5, Rg, R9, T, p, p’, q and q’ are as defined for formula (I), compound of formula (IV) which is deprotected and subjected to an acylation or a sulfonylation reaction, and which can optionally be subjected to the action of a pyrophosphate or a phosphonate dérivative in basic conditions, to yield the compound of formula (I),

- 16which compound of formula (I) may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected and subsequently deprotected, as required by the synthesis.

More specifîcally, the invention relates also to a process for the préparation of compounds of formula (IA-1) characterised in that there is used as starting material the compound of formula (V):

Alk \

wherein X, Y, W, Ai and A2 are as defined for formula (IA) and Alk represents a linear or branched (C|-C₆) alkyl group, the ester function of which compound of formula (V) is hydrolysed to yield the carboxylic acid or the corresponding carboxylate, which may be converted into an acid dérivative such as acyl chloride or the corresponding anhydride before being coupled with an amine NHR3R4 wherein R3 and R4 hâve the same meanings as for formula (IA), to yield the compound of formula (VI):

- 17 r₃

(VI) wherein X, Y, W, Aj, A2, R3 and R4 are as defined for formula (IA), compound of formula (VI) which is then halogenated and further converted into the corresponding borohydride dérivative of formula (VII) :

(VII) wherein X, Y, W, Ai, A2, R3 and R4 are as defined for formula (IA), and

Rbi and Rb2 represent a hydrogen, a linear or branched (Ci-Cô) alkyl group, or Rbi and Rb2 form with the oxygen atoms carrying them an optionally methylated ring, which compound of formula (VII) is further subjected to coupling with a compound of formula (VIII):

(VIII) wherein Rg, R9, p, p’, q and q’ are as defined for formula (IA), and Alk’ represents a linear or branched (Ci-Cô) alkyl group, and L represents a leaving group selected from halogen or sulfonate, to yield the compound of formula (IIA-1) :

wherein X, Y, W, Ai, A2, R3, R4, Rg, R9, p, p’, q, and q’ are as defined for formula (IA) and Alk’ is as defined previously, the ester function of which compound of formula (IIA-1) is hydrolysed to yield the

I

corresponding carboxylic acid which is then subjected to peptide coupling with a compound of formula (III) :

wherein R5 and T are as defined for formula (IA),

wherein X, Y, W, Ai, A₂, R3, R4, R5, Rs, R9, T, p, p’, q, q’ are as defined for formula (IA), compound of formula (IVA-1) which is deprotected and subjected to an acylation or a * sulfonylation reaction, and which can optionally be subjected to the action of a pyrophosphate or a phosphonate dérivative in basic conditions, to yield the compound of formula (IA-1):

I

(IA-1) wherein X, Y, W, Ai, A₂, R3, R4, R5, R7, Rs, R9, T, p, p’, q and q’ are as defmed for formula (IA), which compound of formula (IA-1) may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of 10 the synthesis intermediates can be protected and subsequently deprotected, as required by the synthesis.

More particularly, when one of the groups R3 or R4 of the amine NHR3R4 is substituted by a hydroxy function, the latter may be subjected beforehand to a protection reaction prior to coupling with the carboxylic acid formed from the compound of formula (V), or with a 15 corresponding acid dérivative thereof, the resulting protected function subsequently undergoes a deprotection reaction in the last stage of the process.

- 2l The compounds of formulae (III), (V), (VIII) and the amine NHR3R4 are either commercially available or can be obtained by the person skilled in the art using conventional chemical reactions described in the literature.

Pharmacological study of the compounds of the invention has shown that they hâve proapoptotic properties. The ability to reactivate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancers and of auto-immune and immune System diseases.

More especially, the compounds according to the invention will be useful in the treatment of chemo- or radio-resistant cancers, and in malignant haemopathies and small-cell lung cancer.

Among the cancer treatments envisaged there may be mentioned, without implying any limitation, treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, nonHodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer. Among nonHodgkin lymphomas, there may be mentioned preferably follicular lymphomas, mantle cell lymphomas, diffuse large B-cell lymphomas, small lymphocytic lymphomas and marginal zone B-cell lymphomas.

The présent invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parentéral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.

-22The dosage varies according to the sex, âge and weight of the patient, the administration route, the nature of the therapeutic indication, or of any associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.

Furthermore, the présent invention relates also to the association of a compound of formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, protéasome inhibitors, kinase inhibitors and antibodies, and also to pharmaceutical compositions comprising that type of association and their use in the manufacture of médicaments for use in the treatment of cancer.

The compounds of the invention may also be used in association with radiotherapy in the treatment of cancer.

Finally, the compounds of the invention may be linked to monoclonal antibodies or fragments thereof or linked to scaffold proteins that can be related or not to monoclonal antibodies.

Antibody fragments must be understood as fragments of Fv, scFv, Fab, F(ab')2, F(ab'), scFv-Fc type or diabodies, which generally hâve the same specifïcity of binding as the antibody from which they are descended. According to the présent invention, antibody fragments of the invention can be obtained starting from antibodies by methods such as digestion by enzymes, such as pepsin or papain, and/or by cleavage of the disulfide bridges by chemical réduction. In another manner, the antibody fragments comprised in the présent invention can be obtained by techniques of genetic recombination likewise well known to the person skilled in the art or else by peptide synthesis by means of, for example, automatic peptide synthesizers such as those supplied by the company Applied Biosystems, etc.

Scaffold proteins that can be related or not to monoclonal antibodies are understood to mean a protein that contains or not an immunoglobulin fold and that yields a binding capacity similar to a monoclonal antibody. The man skilled in the art knows how to select the protein scaffold. More particularly, it is known that, to be selected, such a scaffold should display several features as follow (Skerra A., J. Mol. Recogn., 13, 2000, 167-187): phylogenetically good conservation, robust architecture with a well-known three17896

-23dimensional molecular organization (such as, for example, crystallography or NMR), small size, no or only a low degree of post-translational modifications, easy to produce, express and purify. Such a protein scaffold can be, but without limitation, a structure selected from the group consisüng in fibronectin and preferentially the tenth fibronectin type III domain (FNfnlO), lipocalin, anticalin (Skerra A., J. Biotechnol., 2001, 74(4):257-75), the protein Z dérivative from the domain B of staphylococcal protein A, thioredoxin A or any protein with a repeated domain such as an ankyrin repeat (Kohl et al., PNAS, 2003, vol. 100, No.4, 1700-1705), armadillo repeat, leucine-rich repeat or tetratricopeptide repeat. There could also be mentioned a scaffold dérivative from toxins (such as, for example, scorpion, insect, plant or mollusc toxins) or protein inhibitors of neuronal nitric oxide synthase (PIN).

The following Préparations and Examples illustrate the invention but do not limit it in any way.

General Procedures

Ail reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying. Flash chromatography was performed on ISCO CombiFlash Rf 200i with prepacked silica-gel cartridges (SiliaSep™ F60 (40-63μιη, 60Â). Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F254 silica-gel. Microwave heating was performed with a CEM Discover® SP instrument.

Analytical LC-MS

The compounds of the présent invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) on either an Agilent HP1200 Rapid Resolution Mass detector 6140 multi mode source m/z range 150 to 1000 amu or an Agilent HP1100 Mass detector 1946D ESI source m/z range 150 to 1000 amu. The conditions and methods listed below are identical for both machines.

UV détection at 230, 254 and 270 nm.

Détection:

	-24-
Injection Volume:	2pL
Mobile Phases:	A - Water + 10 mMol / ammonium formate + 0.08% (v/v) formic acid at pH ca 3.5. B - 95% Acetonitrile + 5% A + 0.08% (v/v) formic acid

⁵ Method A (3.75 min; either positive (pos) or positive and négative (pos / neg) ionisation)

Column: Gemini 5pm, C18, 30 mm x 4.6mm (Phenomenex).

Température: 35°C.

Gradient:

Time (min)	Solvent A (%)	Solvent B (%)	Flow (mL/min)
0	95	5	2
0.25	95	5	2
2.50	95	5	2
2.55	5	95	3
3.60	5	95	3
3.65	5	95	2
3.70	95	5	2
3.75	95	5	2

Method B (1.9 min;either positive (pos) or positive and négative (pos / neg) ionisation)

Column: Gemini 5μιη, Cl8, 30 mm x 4.6mm (Phenomenex).

-25 Température: 35°C.

Gradient:

Time (min)	Solvent A (%)	Solvent B (%)	Flow
(mL/min)
0	95	5	1.1
0.12	95	5	1.1
1.30	5	95	1.1
1.35	5	95	1.7
1.85	5	95	1.7
1.90	5	95	1.1
1.95	95	5	1.1

Préparative HPLC

Some compounds of the invention were purified by préparative HPLC. These were 5 performed on a Waters FractionLynx MS autopurification System, with a Gemini® 5 pm

C18(2), 100 mm x 20 mm i.d. column from Phenomenex, running at a flow rate of 20 cm³min·¹ with UV diode array détection (2HW00 nm) and mass-directed collection. Gradients used for each compound are shown in Table 1.

At pH 4: solvent A = 10 mM ammonium acetate in HPLC grade water + 0.08% v/v formic 10 acid. Solvent B = 95% v/v HPLC grade acetonitrile + 5% v/v solvent A + 0.08% v/v formic acid.

At pH 9: solvent A = 10 mM ammonium acetate in HPLC grade water + 0.08% v/v ammonia solution. Solvent B = 95% v/v HPLC grade acetonitrile + 5% v/v solvent A + 0.08% v/v ammonia solution.

-26The mass spectrometer was a Waters Micromass ZQ2000 spectrometer, operating in positive or négative ion electrospray ionisation modes, with a molecular weight scan range of 150 to 1000.

Préparation la: 2-tert-Butyl 7-methyl 6-[(nonafluorobutanesulfonyl)oxy]-l,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate

Step A: tert-Butyl 7-formyl-6-hydroxy-J,2,3,4-tetrahydroisoquinoline-2-carboxylate /m-Butyl 6-hydroxy-3,4-dihydro-l//-isoquinoline-2-carboxylate (15.0 g, 0.06 mol) is dissolved in 96 mL of 7% dimethoxymagnesium in methanol (0.06 mol) solution and stirred for 30 minutes at room température. The reaction mixture is then concentrated and co-evaporated with toluene to afford a powder, which is then suspended in toluene (300 ml). Paraformaldéhyde (6.32 g, 0.21 mol) is added and the suspension heated to reflux. A further 6.32 g of paraformaldéhyde (0.21 mol) is added and allowed to stir for 48 h. The reaction mixture is cooled to room température, diluted with ethyl acetate and washed with 1 N HCl. The organic phase is separated and the aqueous washed with ethyl acetate. The organics are combined, filtered through a celite pad and the filtrate washed with brine, dried over magnésium sulphate, filtered and concentrated in vacuo. The crude material is taken up in dichloromethane, loaded onto isolute and purified on CombiFlash (220 g silica, dichloromethane to 3% methanol/dichloromethane) to afford the undesired regioisomer cleanly as an oil. The remaining fractions are combined, concentrated to a solid, and repurified on CombiFlash (220 g silica, iso-hexane to 30% ethyl acetate/ iso-hexane). The product is obtained as a 2:1 ratio in favour of desired regioisomer.

LC/MS (C15H19NO4) 177 [M-Boc+H]⁺; RT 1.29 (Method B)

Step B: 2-tert-Butyl 7-methyl 6-hydroxy-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate

To a stirred solution of 6.4 g of a mixture of regioisomers of the aldéhyde obtained in Step A (approx. 4.22 g, 15.23 mmol) in methanol (250 mL) is added sodium cyanide (0.75 g, 0.02 mol). After 1 minute, activated manganèse dioxide (10.03 g, 115.4 mmol) is added and the reaction is stirred at ambient température ovemight. The reaction mixture is filtered through a celite pad and concentrated. The crude material is purified on

-27CombiFlash (220 g silica, iso-hexane to 20% ethyl acetate/ iso-hexane) and dried in vacuo to afford a solid.

LC/MS (Ci₆H₂]NO₅) 208 [M-Boc+H]⁺; RT 1.40 (Method B)

Step C: 2-tert-Butyl 7-methyl 6-[(nonafluorobutanesulfonyl)oxy]-l,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate

To a solution of the phénol obtained in Step B (5.97 g, 19.41 mmol) in dichloromethane (10 mL) cooled to 0 °C is added triethylamine (8.1 mL, 58.23 mmol), followed by nonafluorobutane sulphonyl fluoride (10.46 mL, 58.23 mmol). After complété addition, the mixture is left to warm to room température and stirred for 1 day, after which time a further 10.46 mL of the sulphonylating reagent is added and stirring is maintained for a further day. 20.92 ml is subsequently added and the reaction stirred for a further 4-5 days. The reaction mixture is cooled to 0 °C and water (100 mL) is added. The mixture is extracted with dichloromethane and the organic layers dried over magnésium sulphate, filtered and concentrated in vacuo. The crude material is taken up in dichloromethane, loaded onto isolute and purified on CombiFlash (120 g silica, iso-hexane to 10% ethyl acetate/ iso-hexane), and dried in vacuo to afford an oil which slowly crystallises to a solid.

LC/MS (C₂oH₂₀N07F₉S) no ionisation; RT 1.62 (Method B)

Préparation lb: 2-tert-Butyl 7-methyl 6-(trifluoromethanesuIfonyloxy)-l,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate

To a solution of the phénol from Step B of Préparation la (2.06 g, 6.70 mmol) and pyridine (1.27 mL, 20.1 mmol) in dichloromethane (75 mL) is added triflic anhydride (1.69 mL, 10.05 mmol) at -10 - 0 °C over 30 min. The mixture is stirred at 0 °C for 2 h, then icewater (50 mL) is added and the mixture is acidified with dilute aqueous hydrochloric acid to give pH 2-3. The mixture is extracted with ethyl acetate and the organic extracts are washed sequentially with with brine and saturated aqueous copper sulfate, dried over magnésium sulphate, and concentrated in vacuo to afford the product.

-28Préparation le: terf-Butyl 7-formyl-6-(trifluoromethanesulfonyloxy)-l,2,3,4tetrahydroisoquinoline-2-carboxylate

To a solution of the product from Step A of Préparation la (3.1 g, 11.2 mmol) in anhydrous dichloromethane (50 mL), cooled in an ice-bath, is added pyridine (4.52 mL, 56 mmol) followed by slow addition of triflic anhydride (2.75 mL, 16.8 mmol). The mixture is allowed to warm to ambient température and left stirring for ca 16 h.

The reaction is diluted with ice-cold water, acidified with dilute HCl to ~ pH 3, and then extracted into ethyl acetate, and washed with saturated aqueous copper sulphate solution. The organic phase is dried over magnésium sulphate, filtered and evaporated. The crude material is purified by column chromatography on silica, eluting with a gradient of isohexane to 25% ethyl acetate/iso-hexane to afford the desired product as a mixture with the corresponding regioisomer (ierAbutyl 5-formyl-6-(trifluoromethanesulfonyloxy)-l,2,3,4tetrahydroisoquinoline-2-carboxylate).

Préparation ld: 2-tert-ButyI 5-methyl 6-bromo-2,3-dihydro-LH-isoindoIe-2,5dicarboxylate

Step A: 5-Bromobenzene-l,2,4-tricarboxylic acid

Bromotrimethyl benzene (40.7 g, 205 mmol) was added to a mixture of water (3.25 L), potassium permanganate (232 g, 1.468 mol) and sodium carbonate (28.5 g, 206 mmol). The mixture was stirred at reflux for 60 h. Ethanol (820 mL) was added dropwise, and the résultant mixture was filtered hot through celite, then allowed to cool to ambient température. The filtrate was acidified with concentrated aqueous HCl, and the organic solvent was removed in vacuo. The solid product was isolated by filtration.

Step B: 6-Bromo-l,3-dioxo-2,3-dihydro-lH-isoindole-5-carboxylic acid

The product from Step A (42.8 g, 148 mmol) and ammonium bromide (43.5 g, 444 mmol) were finely powdered, and homogenised. The resulting solid mixture was heated at 230 240 °C for 2 h while carefully mixing every 15 min. The mixture was allowed to cool to ambient température, then added to water (230 mL), acidified to pH 1-2 with concentrated

I

-29aqueous HCl, and extracted with multiple portions of ethyl acetate. The combined organic extracts were evaporated, and the résultant solid was triturated with a minimal amount of ethyl acetate, and then subsequently with éthanol to afford the desired product as a solid.

Step C: (4-Methoxyphenyl)methyl 6-bromo-2-[(4-methoxyphenyl)methyl]-l,3-dioxo-2,3dihydro-lH-isoindole-5-carboxylate

The product from Step B (40 g, 148 mmol), l-(chloromethyl)-4-methoxybenzene (48.7 g, 311 mmol), and potassium carbonate (61.3 g, 444 mmol) were added to DMF (760 mL) and the mixture was heated at 45 °C for ca 16 h. Water (1140 mL) was added, and the résultant precipitate was isolated by filtration, dissolved in chloroform (1100 mL), and dried (sodium sulphate). Evaporation afforded the desired product as a solid.

Step D: {6-Bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-5-yl}methanol

The product from Step C (55.4 g, 108.5 mmol) was suspended in dry THF (165 mL) and borane-THF (IM in THF; 542 mL, 542 mmol) was added dropwise under argon. After 30 min the mixture was heated to 60 °C for 6 h. Methanol (244.5 mL) was added dropwise (liberating gas) and the résultant solution was evaporated under reduced pressure to a volume of 300 mL. Methanol (170 mL) and 10% aqueous HCl (220 mL) were added and the résultant mixture was heated at 70 °C for 3.5 h. The solution was evaporated under reduced pressure, and the residue was partitioned between saturated aqueous potassium carbonate and dichloromethane. The aqueous phase was extracted with dichloromethane, and the combined organic extracts were concentrated in vacuo and purified by flash column chromatography, eluting with a gradient of 5 - 60% ethyl acetate / hexane to afford the desired product.

Step E: tert-Butyl5-bromo-6-(hydroxymethyl)-2,3-dihydro-lH-isoindole-2-carboxylate

A solution of the compound from Step D (11.3 g, 32.5 mmol) in trifluoroacetic acid (145 mL) was heated as rapidly as possible at 200 °C under microwave irradiation for 7 min. The trifluoroacetic acid was removed under vacuum, 10% aqueous sodium hydroxide (185 mT.) was added, and the résultant mixture was carefully triturated / homogenised, then extracted with several portions of dichloromethane. The combined organic extracts were evaporated, then dissolved in a 1:1 mixture of methanol/dichloromethane (210 mL) and diI

I

-30tert-butyl dicarbonate (1.2 eq) was added. After 40 min, the solvent was removed in vacuo and the crude material was purified by flash column chromatography on silica, eluting with 1:1 hexane/ethyl acetate to afford the product.

Step F: tert-Butyl 5-bromo-6-formyl-2,3-dihydro-l fI-isoindole-2-carboxylate

The product from Step E (5 g, 15.2 mmol) was dissolved in dichloromethane (63.5), and Dess-Martin periodinane (8.4 g, 19.8 mmol) was added portion-wise. After 1 h, the mixture was concentrated in vacuo and the crude material was purified by flash column chromatography on silica, eluting with a gradient of 2%-15% ethyl acetate/hexane to afford the desired product.

Step G: 2-tert-Butyl 5-methyl 6-bromo-2,3-dihydro-lH-isoindole-2,5-dicarboxylate

The compound from Step F (1.63 g, 5.0 mmol), manganèse dioxide (8.69 g, 100 mmol), sodium cyanide (1.47 g, 30 mmol) and acetic acid (601 mg, 10.0 mmol) were suspended in methanol (50 mL) and the mixture was stirred for ca 16 h. The reaction was filtered through celite, concentrated in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was concentrated in vacuo and purified by flash column chromatography on silica, eluting with a gradient of 0% - 10% ethyl acetate/hexane to afford the desired product.

Préparation le: /c/7-Butyl 5-bromo-6-[( 35)-3-( morpholin-4-yIniethy 1)-1,2,3,4tetrahydroisoquinoline-2-carbonyl ]-2,3-dihydro-lH-isoindole-2-carboxylate

Step A: 6-Bromo-2-[(tert-butoxy)carbonyl]-2,3-dihydro-lH-isoindole-5-carboxylic acid

To a solution of the product of Préparation ld (1 g, 2.81 mmol) in dioxane (5 mL) is added a solution of lithium hydroxide monohydrate (236 mg, 5.62 mmol) in water (5 mL), and the reaction is heated to 90 °C. After 40 min, the reaction is allowed to cool, and is diluted with water and acidified to ~ pH 2 with 2N aqueous HCl. The mixture is extracted with ethyl acetate, and the organic extracts are dried and evaporated under reduced to pressure to afford the product as a solid.

LC/MS (Ci₄H₁₆BrNO₄) 342 [M+H]⁺; RT 2.30 (Method A)

- 31 Step B: tert-Bntyl 5-bromo-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2-carboxylate

To a solution of the product from Step A (933 mg, 2.73 mmol) in DMF (10 mL) is added triethylamine (1.33 mL, 9.55 mmol), HBTU (1.04 g, 2.73 mmol) followed by the product of Préparation 2a (832 mg, 2.73 mmol) and the mixture is stirred at ambient température for ca 16 h. The reaction is diluted with water and the resulting precipitate is filtered and washed with water. The solid is taken-up in ethyl acetate, dried over magnésium sulphate, filtered and evaporated. The crude material is purified by column chromatography over silica gel, eluting with a gradient of iso-hexane to 1:1 ethyl acetate/iso-hexane to afford the product as a foam.

LC/MS (C₂₈H₃4BrN₃O4) 556 [M+H]⁺; RT 2.35 (Method A)

Préparation lf: tert-Butyl 5-bromo-6-[(3J?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2-carboxylate

The procedure is as in Préparation le, replacing the product of Préparation 2a used in Step C with (3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride obtained from Préparation 2b.

LC/MS (C₂₄H₂₇BrN₂O₃) 471 [M+H]⁺; RT 2.76 (Method A)

Préparation lg: 6-Bromo-2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7carboxylic acid

Step A: 2-(3-Bromo-4-methoxyphenyl)ethanamine

To a solution of 2-(4-methoxyphenyl)ethanamine (25.0 g, 0.165 mol) in glacial acetic acid (300 mL) was added a solution of bromine (31.7 g, 0.198 mol) in glacial acetic acid (200 mL) dropwise. A white precipitate formed immediately, and the reaction was stirred at rt for 48 h. The white solid was filtered off and washed with hexane to obtain the hydrobromide sait. The mother liquor was evaporated and it was washed with a small amount of acetic acid and hexane. These salts were dissolved in water and the pH was

- 32 adjusted to 8. The suspension was extracted with DCM and dried, and concentrated under reduced pressure. The crude product was used in the next step without further purification.

Step B: N-[2-(3-Bromo-4-methoxyphenyl)ethyl]-2,2,2-trifluoroacetamÎde

2-(3-bromo-4-methoxyphenyl)ethanamine (600 mg) was dissolved in 6 mL TF AA and 6 mL DCM and the mixture was stirred for lh. It was cooled in ice bath and 24 mL water was added to the mixture. The organic phase was washed with water several times, dried and concentrated under reduced pressure. The crude product was used in the next step without further purification.

Step C: l-(6-Bromo-7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2,2,2trifluoroethanone

To a solution of 40 % sulphuric acid in acetic acid (150 mL) was added A-[2-(3-bromo-4methoxyphenyl)ethyl]-2,2,2-trifluoroacetamide (15.5 g, 52.4 mmol) and paraformaldéhyde (2.4 g, 80 mmol). The reaction mixture was stirred at room température for 18 h, poured into cold water and extracted with ethyl acetate. The combined organic layer was washed with sodium hydrogen carbonate solution, dried and concentrated under reduced pressure. The crude product was purified with flash chromatography (eluent: n-hexane:EtOAc gradient).

Step D: l-(6-Bromo-7-hydroxy-3,4-dihydroisoquinolin-2(lH)-yl)-2,2,2-trifluoroethanone

Under argon atmosphère a solution of l-(6-bromo-7-methoxy-3,4-dihydroisoquinolin2(177)-yl)-2,2,2-trifluoroethanone (1 mmol) in 20 mL DCM was slowly added to a precooled solution of boron tribromide (1 mmol) in 30 mL DCM at -30 °C. The resulting solution was slowly warmed to -12 °C and stirred for 16 h. The reaction was quenched by adding ice and the product was extracted with EtOAc. The organic phase was washed with water and saturated aqueous NaCl and dried, The crude product was purified with flash chromatography (eluent: n-hexane:DCM gradient).

Step E: 6-Bromo-2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate

TC A VA

Vv A jîÜA WÈA n

-33l-(6-bromo-7-hyoroxy-3,4-dihydroisoquinolin-2(l//)-yl)-2,2,2-trifluoroethanone (5.72 g, 17.7 mmol) and 2.2 mL pyridine (2.12 g, 26.5 mmol) was dissolved in DCM (130 mL). At 0°C 21.2 mL (21.2 mmol) trifluoromethanesulfonic anhydride (IM in DCM) was added dropwise and the température was left to be warmed to rt. When the reaction reached an appropriate conversion it was diluted with brine. The layers were separated and the organics were dried with Na₂SÛ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 6-bromo-2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate.

Step F: 6-Bromo-2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid 6-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (912 mg, 2.0 mmol) and 146 mg (dppf)PdCl₂ (0.2 mmol) were dissolved in 15 mL DMF and 5 mL H₂O. 560 pL TE A (404 mg, 4.0 mmol) was added and the mixture was stirred at 75°C under CO atmosphère (1 bar). When the reaction reached an appropriate conversion it was diluted with DCM, extracted with 0.2 M HCl_aq. The layers were separated, the organics were dried with Na₂SO4 filtered and concentrated under reduced pressure. The crude product was purified with flash chromatography using DCM and methanol as eluents to obtain 6-bromo-2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid.

Préparation lha: l-{6-Bromo-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-2-yl}-2,2,2trifluoroethan- 1-one

To a solution of the acid from Préparation lg (2 g, 0.01 mol) in Α,Α-dimethylformamide (15 mL)was added A,A-diisopropylethylamine (1.98 mL, 11.36 mmol), the amine from Préparation 2a (1.39 g, 5.96 mmol) and HBTU (2.15 g, 5.68 mmol), and the mixture was stirred at ambient température for ca 16 h. The reaction was concentrated in vacuo then redissolved in ethylacetate, and washed with water and brine. The organic extract was dried over magnésium sulphate, concentrated in vacuo, and purified by flash column chromatography (40 g silica, dichloromethane to 3% methanol in dichloromethane).

I

-34LC/MS (C₂₆H₂7BrF₃N₃O₃) 566 [M+H]⁺; RT 1.26 (Method B)

Préparation lhb:

l-{6-Bromo-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-

carbonyl]-l,2,3,4-tetrahydroisoquinolin-2-yl}-2,2,2-trifluoroethan-l-one

The procedure is as in Préparation lha, replacing the amine from Préparation 2a with the | 5 amine from Préparation 2b.

LC/MS (C22H₂oBrF₃N₂0₇) 481 [M+H]⁺; RT 1.46 (Method B)

I

Préparation 2a:

(35)-3-(Morpholin-4-ylmethyI)-l,2,3,4-tetrahydroisoquinoline

dihydrochloride

Step A: Benzyl (3S)-3-(4-morpholinylcarbonyl)-3,4-dihydro-2(lH)-isoquinoline carboxylate

To a solution of 5 g of (35)-2-[(benzyloxy)carbonyl]-l,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (16 mmol) in 160 mL of dichloromethane there are added 1.5 mL of morpholine (17.6 mmol) and then 9 mL of N,N,Mtriethylamine (64 mmol), 3.3 g of 1ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDC) (19.2 mmol) and 2.6 g of 15 hydroxybenzotriazole (HOBT) (19.2 mmol). The reaction mixture is stirred at ambient température ovemight and is then poured onto a solution of ammonium chloride and extracted with ethyl acetate. The organic phase is subsequently dried over magnésium sulphate and then filtered and evaporated to dryness. The crude product so obtained is then purifîed by chromatography over silica gel (dichloromethane/methanol gradient). The product is obtained in the form of a foam.

I

I ¹H-NMR: δ (400 MHz; dmso-d6; 353°K): 7.30 (m, 5H benzyl); 7.15 (m, 4H aromatic);

5.2-5.0 (m, 3H, 2H benzyl, 1H dihydroisoquinoline); 4.75-4.5 (2d, 2H dihydroisoquinoline); 3.55-3.3 (m, 8H morpholine); 3.15-2.9 (2dd, 2H dihydroisoquinoline)

IR: v: >C=O: 1694; 1650 cm¹

- 35 Step B: Benzyl (3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(lH)-isoquinoline carboxylate

To a solution of 5.3 g of the product obtained in Step A (13.9 mmol) in 278 mL of tetrahydrofuran there are added 14 mL of BH₃Me2S (27.8 mmol) at ambient température. The whole is heated for 4 hours at 80°C. It is allowed to return to ambient température, and then there are added 7 mL (14 mmol) of BH₃Me2S. The reaction mixture is again heated at 80°C for 2 hours. The tetrahydrofuran is subsequently evaporated off, and there are then added slowly methanol and then 5.6 mL of 5N hydrochloric acid (27.8 mmol). The mixture is stirred at ambient température ovemight and then at 80°C for one hour. There is subsequently added a saturated NaHCCh solution to the reaction mixture at 0°C until a pH of 8 is reached, and then extraction with ethyl acetate is carried out. The organic phase is subsequently dried over magnésium sulphate and then filtered and evaporated to dryness. The title product is obtained in the form of an oil.

’H-NMR: δ (400 MHz; dmso-d6; 353°K): 7.43-7.30 (unresolved peak, 5H benzyl); 7.19 (m, 4H aromatic); 5.16 (m, 2H, 2H benzyl); 4.79-4.29 (d, 2H dihydroisoquinoline); 4.58 (m, 1H dihydroisoquinoline); 3.50 (m, 4H morpholine); 3.02-2.80 (dd, 2H dihydroisoquinoline); 2.42-2.28 (unresolved peak, 5H, 4H morpholine, 1H morpholine); 2.15 (dd, 1H morpholine)

IR: v: >CH: 2810 cm¹; v: >C=O: 1694 cm'¹; v: >C-O-C<: 1114 cm¹; v: >CH-Ar: 751; 697 cm'¹

Step C: (3S)-3-(4-Morpholinylmethyl)-l,2,3,4-tetrahydroisoquinoline

To a solution of 4.9 g of the compound of Step B (13.4 mmol) in 67 mL of éthanol there is added 0.980 g of palladium dihydroxide (20% by mass) at ambient température. The reaction mixture is placed under 1.2 bar of hydrogen at ambient température for 4 hours. It is subsequently passed over a Whatman filter, and then the palladium is rinsed several times with éthanol. The filtrate is evaporated to dryness. The title product is obtained in the form of an oil.

’lI-NMR: δ (400 MHz; dmso-d6; 300°K): 7.12-7.0 (unresolved peak, 4H aromatic); 3.92 (s, 2H tetrahydroisoquinoline); 3.60 (t, 4H morpholine); 2.98 (m, 1H

-36tetrahydroisoquinoline); 2.68 (dd, ÎH tetrahydroisoquinoline); 2.5-2.3 (unresolved peak, 8H, 1H tetrahydroisoquinoline, 6H morpholine, 1H NH)

IR: v: >NH: 3322 ciri^l; v: >C-O-C<: 1115 cm ^1; v: >CH-Ar: 742 cm¹

Step D: (3S)-3-(4-Morpholinylmethyl)-l,2,3,4-tetrahydroisoquinoline dihydrochloride

The free base obtained in Step C is dissolved in a minimum volume of dichloromethane. To the stirred solution at room température is added IM HCl solution in diethyl ether (3 equiv). The reaction is stirred for 15 minutes, after which time diethyl ether is added. The resulting precipitate is filtered, washed with diethyl ether, then dried under vacuum to afford the product.

Préparation 2b: (3R)-3-Methyl-l,2,3,4-tetrahydroisoquinoline

Step A: 3-Methyl-l,2,3,4-tetrahydroisoquinoline

To a solution of 3-methylisoquinoline and NiC12*6H2O (1.2 eq) in methanol (3 mL /mmol), cooled to 0°C, is added sodium borohydride (12 eq) portion-wise over 1 h. The reaction mixture is stirred at ambient température for 1 h, then quenched by addition of water. The solvent is removed under reduced pressure, and the residue is partitioned between ethyl acetate and water. The organic phase is dried over sodium sulphate and evaporated to afford the crude product.

Step B: (3R)-3-Methyl-l,2,3,4-tetrahydroisoquinoline

The product from Step A (4.5 g) is dissolved in a 1:9 isopropanol/heptane mixture (55 mL), and the résultant solution is repeat-injected onto an IC Column (50x500mm, 20 um particle size), eluting with 5:95 mixture of 2-propanol/heptane containing 0.05% diethylamine, with a flow rate of 50 ml/min at ambient température. Under these conditions the (7?)-isomer eluted as the second fraction.

Préparation 2c: tert-Butyl [(3.8)-1,2,3.4-t et rahydroisoqiiinoIin-3-ylinethyl] carbamate

Step A: Benzyl (3S)-3-(hydroxymethyl)-3,4-dihydro-lH-isoquinoline-2-carboxylate

- 37 This compound is obtained using a protocol from the literature (R. B. Kawthekar et al South Africa Journal of Chemistry 63, 195, 2009) starting from 15 g of (35)-1,2,3,4tetrahydroisoquinolin-3-ylmethanol (91.9 mmol) in the presence of benzyl chloroformate and triethylamine dissolved in dichloromethane. After purification on silica gel (gradient petroleum ether/ AcOEt), the title product is obtained in the form of an oil.

*H NMR: Ô (300 MHz; DMSO-d6; 300K): 7.33 (m, 5H, aromatic Hs, O-benzyl); 7.15 (s, 4H, aromatic Hs, H tetrahydroisoquinoline); 5.13 (s, 2H, CH2-PI1); 4.73 (d, 1H, H tetrahydroisoquinoline); 4.47 (m, H, CH2OH); 4.36 (m, 1H, H tetrahydroisoquinoline); 4.28 (d, 1H, H tetrahydroisoquinoline); 3.39 (dd, 1H, CH2OH); 3.23 (dd, 1H, CH2OH); 2.93 (dd, 1H, H tetrahydroisoquinoline); 2.86 (dd, 1H, H tetrahydroisoquinoline).

IR: v OH: 3416 cm'¹; v <C=O 1694 cm'¹; v aromatic >C-H: 754 cm'¹

Step B: Benzyl (3S)-3-(azidomethyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate

This compound is obtained using a protocol from the literature (D. Pagé et al J. Med. Chem, 44, 2387, 2001) starting from 23 g of the compound obtained in Step A (77.3 mmol) in the presence of diphenylphosphoryl azide and triphenylphosphine dissolved in THF. After purification on silica gel (gradient petroleum ether / AcOEt), the title product is obtained in the form of an oil.

^!H NMR: δ (400 MHz; DMSO-d6; 300K): 7.36 (m, 5H, aromatic Hs, O-benzyl); 7.19 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 5.16 (s, 2H, CH2-Ph); 4.76 (d, 1H, H tetrahydroisoquinoline); 4.53 (m, 1H, H tetrahydroisoquinoline); 4.30 (m, 1H, H tetrahydroisoquinoline); 3.28 (m, 2H, CH₂N₃); 3.06 (dd, 1H, H tetrahydroisoquinoline); 2.78 (dd, 1H, H tetrahydroisoquinoline)

IR: v N₃: 2095 cm'¹; v <0=0:1694 cm'¹; v aromatic >C-H: 754 cm'¹

Step C: Benzyl (3S)-3-(aminomethyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate

To a solution of 20.9 g (64.5 mmol) of the azido compound obtained in Step B in 650 mL of THF there are successively added 25.5 g (97.2 mmol) of triphenylphosphine and 157 mL of water. The complété batch is heated at reflux for 2 hours 30 minutes. The reaction mixture is then concentrated to dryness and the residual oil is then taken up in isopropyl

- 38 ether. A white precipitate appears, which is filtered off and washed with isopropyl ether. The filtrate is then concentrated to dryness and is then purified by chromatography on silica gel (gradient CH₂Cl₂/MeOH). The title product is obtained in the form of an oil.

¹H NMR: Ô (400 MHz; DMSO-d6; 300K): 7.40 (m, 5H, aromatic Hs, O-benzyl); 7.20 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 5.15 (s, 2H, CH2-Ph); 4.75-4.3 (m, 2H, H tetrahydroisoquinoline); 4.30 (d, 1H, H tetrahydroisoquinoline); 2.90 (m, 2H, CH₂NH₂); 2.45 (m, 2H, H tetrahydroisoquinoline); 1.40 (m, 2H, NH₂)

IR: v NH₂; 3400-3300 cm’¹; v <00: 1688 cm’¹

Step D: Benzyl (3S)-3-{[(tert-butoxycarbonyl)amino]methyl}-3,4-dihydroisoquinoline2(lH)-carboxylate

To a solution of 18.4 g (62.1 mmol) of the compound obtained in Step C in 630 mL of dichloromethane there are successively added 17.5 mL (124 mmol) of triethylamine and, in portions, 14.9 g (68.3 mmol) of di-te/7-butyl dicarbonate. The complété batch is stirred at ambient température for 2 hours. The reaction mixture is then concentrated, and then ethyl acetate is added. The organic phase is successively washed with IM HCl solution, saturated NaCl solution, saturated NaHCCL solution and then saturated NaCl solution. After drying, concentrating to dryness and purification by chromatography on silica gel (gradient petroleum ether / AcOEt), the title product is obtained in the form of an oil.

¹H NMR: δ (400 MHz; DMSO-d6; 300K): 7.35 (m, 5H, aromatic Hs, O-benzyl); 7.15 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 6.51 (m, 1H, NHBoc); 5.12 (s, 2H, CH₂-Ph); 4.76 (d, 1H, H tetrahydroisoquinoline); 4.51 (m, 1H, H tetrahydroisoquinoline); 4.36 (d, 1H, H tetrahydroisoquinoline); 2.95 (m, 3H, H tetrahydroisoquinoline + CH₂NHBoc); 2.71 (d, 1H, H tetrahydroisoquinoline); 1.34 (s, 9H, NHBoc)

IR: v NH: 3351 cm'; v <C=O: 1686 cm'¹

Step E: tert-Butyl [(3S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]carbamate

To a solution of 21 g (53 mmol) of the compound obtained in Step D in 600 mL of ethyl acetate there are added 2.1 g of palladium-on-carbon 10 %. The complété batch is stirred at ambient température under 1.3 bar of dihydrogen pressure for 5 hours. The reaction

-39-

mixture is then filtered, and then concentrated to dryness. The title product is obtained in the form of a solid.

NMR: δ (400 MHz; DMSO-d6; 300K): 7.15 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 6.85 (t, 1H, NHBoc); 3.90 (m, 2H, H tetrahydroisoquinoline); 3.00 (m, 2H, CH2NHB0C); 2.80 (m, 1H, H tetrahydroisoquinoline); 2.65 (dd, 1H, H tetrahydroisoquinoline); 2.40 (dd, 1H, H tetrahydroisoquinoline); 1.40 (s, 9H, NHBoc) IR: v NH: 3386-3205 cm'¹ (NH amide); v <00: 1688 cm’¹; v NH: 1526 cm'¹ (NH amine)

Préparation 2d:

(35)-3-[2-(Morpholin-4-yl)ethyl]-l,2,3,4-tetrahydroisoquinoline

hydrochloride

Step A: tert-Butyl (3S)-3-(2-morpholino-2-oxo-ethyl)-3,4-dihydro-lH-isoquinoline-2carboxylate

To a solution of 3 g (10.30 mmol) of [(35')-2-(ierAbutoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]acetic acid in 100 mL of dichloromethane there are added, dropwise, 1.10 mL (11.32 mmol) of morpholine and, dropwise throughout, 4.3 mL (30.9 mmol) of triethylamine, 2.20 g (12.40 mmol) of 1,2-dichloromethane and 1.70 g (1.68 mmol) of hydroxybenzotriazole. The complété batch is stirred at ambient température for 15 hours. The reaction mixture is then diluted with dichloromethane and washed successively with IM HCl solution, saturated NaHCCL solution and then saturated NaCl solution until neutral. The organic phase is then dried over MgSCL, filtered and concentrated to dryness. After purification by column chromatography on silica gel (dichloromethane /MeOH), the title product is obtained in the form of an oil.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.20-7.10 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.70 (m, 1H, aliphatic Hs, CH tetrahydroisoquinoline); 4.75-4.20 (2m, 2H, aliphatic Hs, CH₂ alpha to tetrahydroisoquinoline N); 3.60 (m, 8H, aliphatic Hs, morpholine); 3.00 and 2.70 (2 dd, 2H, aliphatic H, tetrahydroisoquinoline); 2.50-2.20 (2d, 2H, aliphatic Hs, CH₂CO); 1.40 (s, 9H, ^lBu)

IR: v C=O: 1687; 1625 cm¹ ~ ». ;

. · .... —; ,A\

-40Step B: l-(Morpholin-4-yl)-2-[(3S)-l,2,3,4-tetrahydroisoquinolin-3-yl]ethanone hydrochloride

To a solution of 2.88 g (7.18 mmol) of the compound obtained in Step A in 16 mL of dichloromethane there are added, dropwise, 80 mL (80 mmol) of IM ethereal HCl solution. The complété batch is stirred at ambient température for 15 hours, the suspension is then filtered and the precipitate is washed with ether. After drying, the title product is obtained in the form of a solid.

'H NMR: δ (400 MHz; dmso-d6; 300K): 9.80-9.50 (m, 2H, NH₂ ⁺); 7.30-7.10 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.30 (m, 2H, aliphatic Hs, CH₂ alpha to tetrahydroisoquinoline N); 3.80 (m, 1H, aliphatic Hs, CH tetrahydroisoquinoline); 3.703.40 (2m, 8H, aliphatic Hs, morpholine); 3.15 and 2.8 (m, 4H, aliphatic H, CH₂tetrahydroisoquinoline and CH₂CO)

IR: v -NH₂ ⁺: 2800-1900 cm¹; v C=O: 1620 cm¹

Step C: (3S)-3-[2-(Morpholin-4-yl)ethyl]-l,2,3,4-tetrahydroisoquinoline hydrochloride

A solution of 2.2 g (7.44 mmol) of the compound obtained in Step B in 22 mL of MTBE and 5 mL of dichloromethane is prepared. After cooling in an ice bath at 0°C, there are then added, dropwise, 15 mL (15 mmol) of a IM solution of LÎA1H4 in tetrahydrofuran. The complété batch is then stirred at ambient température for 6 hours. It is placed at 0°C, and there is then added, dropwise, 1 mL of 5M NaOH solution. The complété batch is stirred at ambient température for 45 minutes. The solid is then filtered off and washed with MTBE and then with dichloromethane, and the filtrate is concentrated to dryness. The oil thereby obtained is diluted with dichloromethane and there are added, dropwise, 6.3 mL of IM ethereal HCl solution. The complété batch is stirred at ambient température for 1 hour and then filtered. The crystals thereby obtained are washed with ethyl ether. After drying, the title product is obtained in the form of a solid.

’H NMR: δ (400 MHz; dmso-d6; 300K): 11.35 + 9.80 (2m, 2H, NH₂ ⁺); 10.00 (m, H, NH⁺); 7.20 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.30 (s, 2H, aliphatic Hs, CH₂alpha to tetrahydroisoquinoline N); 4.00 + 3.85 (2m, 4H, aliphatic Hs, CH₂ alpha to morpholine N); 3.70 (m, 1H, aliphatic Hs, CH tetrahydroisoquinoline); 3.55-3.30 (m, 4H,

-41 aliphatic Hs, CH alpha to morpholine O and CH₂-Morpholine ); 3.15 (dd, 1H, aliphatic H, CH2 tetrahydroisoquinoline); 3.10 (m, 2H, aliphatic H, CH alpha to morpholine O); 2.90 (dd, 1H, aliphatic H, CH₂ tetrahydroisoquinoline); 2.30 + 2.15 (2m, 2H, aliphatic H, CH₂tetrahydroisoquinoline)

IR: v NH⁺ / -NH₂ ⁺: between 3500 and 2250 cm¹; v C=C: weak 1593 cm'¹; v aromatic C-H: 765 cm¹

Préparation 2e: tert-Butyl {2-[(3S)-l,2,3,4-tetrahydroisoquinolin-3-ylJethyl} carbamate

Step A: Benzyl (3S)-3-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate

The title compound is obtained starting from (35)-2-[(benzyloxy)carbonyl]-l,2,3,4tetrahydroisoquinoline-3-carboxylic acid, based on a protocol from the literature (Jinlong Jiang et al Bioorganic & Médicinal Chemistry Letters, 14, 1795, 2004).

Step B: Benzyl (3S)-3-{2-[(inethylsulphonyl)oxy]ethyl}-3,4-dihydroisoquinoline-2(lH)carboxylate

To a solution of 10.6 g of the compound of Step A (35.6 mmol) in 350 mL of anhydrous CH2CI2, placed at 0°C, there are successively added triethylamine 10.1 mL (71.2 mmol) and then, dropwise, methanesulphonyl chloride 3.1 mL (39 mmol). The reaction mixture is then stirred at ambient température for 2 hours. Hydrolysis is then canied out by slowly adding water. The product is extracted several times with CH2CI2. The organic phases are then combined and successively washed with IN HCl solution, saturated NaCl solution, saturated NaHCO₃ solution and saturated NaCl solution until neutral. They are then dried over MgSO₄ and concentrated to dryness. After purification by chromatography on silica gel (gradient petroleum ether/ AcOEt), the expected product is obtained in the form of a foam.

LC/MS: m/z = (M + H)⁺ = 375

Step C: Benzyl (3S)-3-(cyanomethyl)-3,4-dihydroisoquinoline-2( 1 H)-carboxylate

To a solution of 15.4 g of the compound obtained in Step B (41.02 mmol) in 250 mL of

-42anhydrous DMSO there are added 22 g (449 mmol) of sodium cyanide. The complété batch is then heated at 60°C for 12 hours. It is allowed to cool and then the reaction mixture is diluted by adding ethyl acetate. Hydrolysis is then carried out using saturated NaHCCh solution. After again extracting twice with ethyl acetate, the organic phases are combined, washed with H₂O, dried over MgSCU and concentrated to dryness. After purification by chromatography on silica gel (hexane/ AcOEt 7/3), the expected product is obtained in the form of an oil.

LC/MS: m/z - [M+H]⁺ = 307.1

Step D: Benzyl (3S)-3-(2-aminoethyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate

To a solution of 15.4 g of the compound obtained in Step C (50.3 mmol) in 300 mL of anhydrous THF, placed at 0°C, there is added, dropwise, a IN solution of BH₃-THF. The reaction mixture is allowed to gradually corne back to ambient température and then the complété batch is stirred for 14 hours. The reaction mixture is then hydrolysed by slowly adding saturated NH4CI solution. After extracting twice with ethyl acetate, the organic phases are combined and dried over MgSCL. After concentrating to dryness, the expected product is obtained in the form of a foam which is used directly, without purification, in the next, protection step.

Step E: Benzyl (3S)-3-{2-[(tert-butoxycarbonyl)amino]ethyl}-3,4-dihydroisoquinoline2(lH)-carboxylate

To a solution of 15.6 g of the compound obtained in Step D (50.3 mmol) in 670 mL of CH₂C1₂, there are successively added 13.2 g (60.36 mmol) of Boc₂O in portions, 14 mL (100.6 mmol) of triethylamine, and DM AP in a catalytic amount. The complété batch is stirred at ambient température for 5 hours. The reaction mixture is then hydrolysed with water and extracted twice with CH₂C1₂. The organic phases are combined, washed with water and dried over MgSO.4. After concentrating to dryness and purification by chromatography on silica gel (gradient heptane/AcOEt), the expected product is obtained in the form of an oil.

LC/MS: m/z = (M + H)⁺ = 411

-43Step F: tert-Butyl {2-[(3S)-l,2,3,4-tetrahydroisoquinolin-3-yl]ethyl]carbamate

To a solution of 10.4 g of the compound obtained in Step E (25.5 mmol) in 210 mL of anhydrous MeOH there are added 2.71 g (2.55 mmol) of Pd/C 10%. The complété batch is degassed for 30 minutes and then stirred under a hydrogen atmosphère for 16 hours. The reaction mixture is then filtered and concentrated to dryness. The expected product is obtained in the form of a solid which is taken up in a mixture of pentane/Et₂O (90/10), triturated and filtered. After drying, the product is obtained in the form of a solid.

’ll NMR: δ (400	MHz;	dmso-d6;	300K): 7.1-6.98	(m,	4H,	aromatic	Hs,
tetrahydroisoquinoline) ;	6.83	(m,	1H,	CH₂NHBoc); 3.85	(s,	2H,	aliphatic	Hs,
tetrahydroisoquinoline) ;	3.09	(q,	2H,	CH₂NHBoc); 2.73	(m,	1H,	aliphatic	Hs,

tetrahydroisoquinoline); 2.70 and 2.39 (2m, 2H, aliphatic Hs, tetrahydroisoquinoline); 1.63 (m, 2H, aliphatic Hs); 1.38 (s, 9H, NHCOOtBu)

IR: v: >NH: 3378, -3201 cm'¹ (amine, amide); v: >C=O: 1683 cm'¹ (amide); v: >NH: 1524 cm¹ (amide); v: >C=O: 1168 cm¹

LC/MS: m/z = [M+H]⁺ = 277

Préparation 2f : (3R)-3-[3-(Morpholin-4-yl)propyl]-l,2,3,4-tetrahydroisoquinoline dihydrochloride

Step A: {(3S)-2-[(4-Methylphenyl)sulphonyl]-l,2,3,4-tetrahydroisoquinolin-3-yl}methyl

4-methylbenzenesulphonate

The procedure is the same as that of Step A of Préparation Γ.

Step B: tert-Butyl 2-({(3R)-2-f(4-methylphenyl)sulphonyl]-l,2,3,4-tetrahydroisoquinolin-

3-yl}methyl)-3-(morpholin-4-yl)-3-oxopropanoate

To a suspension of 1 g of NaH (60 %) (25.08 mmol) in 30 mL of MTBE there are added, dropwise, a solution of 5 g of /eri-butyl 3-morpholino-3-oxopropanoate (21.81 mmol) in 20 mL of anhydrous MTBE. This suspension stirred at ambient température for 1 hour and

-44then the compound obtained in Step A is added in the form of a powder. The batch is stirred at 60°C for 30 hours. 100 mL of saturated ammonium chloride solution are added. The resulting solution is extracted with dichloromethane. The organic phase is then dried over MgSCL, filtered and concentrated to dryness. After purification by column chromatography over silica gel (dichloromethane/MeOH), the expected product is obtained in the form of an oil.

NMR 'il (500 MHz, dmso-d6) δ ppm : 7.63/7.59 (2d, 2 H), 7.3/7.26 (2d, 2 H), 7.13 (m, 2 H), 7.09/6.97 (2t, 2 H), 4.64/4.55/4.36/4.28 (2AB, 2 H), 4.25/4.11 (2m, 1 H), 3.81 (m, 1 H), 3.73-3.48 (m, 4 H), 3.57-3.32 (m, 4 H), 2.51 (m, 2 H), 2.32/2.31 (2s, 3 H), 1.88/1.79 (2m, 2 H), 1.39/1.38 (2s, 9 H)

IR (ATR) cm’¹: v : >C=O : 1731 (ester); v : >C=O : 1644 (amide) ; v : -SO2 : 13341156 ; v : >C-O-C< : 1115; γ : >CH-Ar : 815-746-709

Step C: 2-({(3R)-2-[(4-Methylphenyl)sidphonyl]-l,2,3,4-tetrahydroisoquinolin-3yl}methyl)-3-(morpholin-4-yl)-3-oxopropanoic acid

To a solution of 9.5 g (17.97 mmol) of the compound obtained in Step B in 40 mL of dioxane there are added, dropwise, 20 mL of a 4M solution of HCl in dioxane. The batch is stirred at ambient température for 48 hours and then the solution is concentrated to dryness. After drying, the expected product is obtained in the form of an oil.

NMR 'H (400 MHz, dmso-d6) δ ppm : 12.75 (m, 1 H), 7.6 (2*d, 2 H), 7.3 (2*d, 2 H), 7.1/6.95 (2*m, 4 H), 4.7-4.2 (d, 2 H), 4.25/4.12 (2*m, 1 H), 3.9-3.3 (m, 9 H), 2.55 (d, 2 H), 2.3 (2*s, 3 H), 1.8 (t, 2 H)

IR (ATR) cm¹ : v : -OH : 3500 à 2000; v : >C=O : 1727 (acide) ; v : >C=O : 1634 (amide) ; v :-SO2 : 1330-1155

Step D: 3-{(3R)-2-[(4-Methylphenyl)sulphonyl]-l,2,3,4-tetrahydroisoquinolin-3-yl}-l(morpholin-4-yl)propan-l-one

To a solution of 7.80 g (16.51 mmol) of the compound obtained in Step C in 100 mL of DMSO there are added 1.16 g (19.83 mmol) of solid sodium chloride and then, dropwise, 5 mL of water. The batch is stirred at 130°C for 1 hour and then the solution is concentrated to %. The reaction mixture is then diluted with dichloromethane and washed successively with saturated lithium chloride solution and then with saturated NaCl solution. The organic phase is then dried over MgSO₄, filtered and concentrated to dryness. After purification by column chromatography over silica gel (cyclohexane/ethyl acetate), the expected product is obtained in the form of an oil.

NMR ’H (400 MHz, dmso-d6) δ ppm : 7.65 (d, 2 H), 7.3 (d, 2 H), 7.15/7 (2 m, 4 H), 4.6 (d, 1 H), 4.25 (d, 1 H), 4.2 (m, 1 H), 3.5 (m, 4 H), 3.4 (2 m, 4 H), 2.6 (2 dd, 2 H), 2.35 (s, 3 H), 2.3 (m, 2 H), 1.5 (quad., 2 H)

IR (ATR) cm' : v : >C=O : 1639 ; v : -SO2 : 1331-1156 ; γ : >CH-Ar : 815-675

Step E: (3R)-2-[(4-Methylphenyl)sulphonyl]-3-[3-(morpholin-4-yl)propyl]-l,2,3,4tetrahydroisoquinoline

To a solution of 6.0 g (14.0 mmol) of the compound obtained in Step D in 60 mL of MTBE and 14 mL of dichloromethane there are added 1.06 g (28 mmol) of LAH in portions over 5 minutes. The batch is stirred at ambient température for 15 hours. There are added, dropwise, 1.5 mL of water and stirring is carried out for 15 minutes. There are then added, dropwise, 1.5 mL of 5M sodium hydroxide solution and stirring is carried out for 15 minutes. The reaction mixture is then diluted with MTBE and dichloromethane. The suspension is then filtered and the precipitate is washed with MTBE and dichloromethane. The organic phase is then dried over MgSO₄, filtered and concentrated to dryness. After purification by column chromatography over silica gel (dichloromethane/EtOH/NH₄OH), the expected product is obtained in the form of an oil.

NMR *H (400 MHz, dmso-d6) δ ppm : 7.68 (d, 2 H), 7.32 (d, 2 H), 7.1 (massif, 4 H), 4.65/4.23 (AB, 2 H), 4.2 (m, 1 H), 3.55 (t, 4 H), 2.7/2.6 (ABx, 2 H), 2.35 (s, 3 H), 2.25 (t, 4 H), 2.2 (t, 2 H), 1.4/1.3 (2m, 4 H) IR (ATR) cm'¹ : v : -SO2 : 1333-1158

Step F: (3R)-3-[3-(Morpholin-4-yl)propyl]-l,2,3,4-tetrahydroisoquinoline

To a solution of 1.50 g (3.62 mmol) of the compound obtained in Step E in 20 mL of anhydrous methanol there are added 2.0 g (82.3 mmol), in portions, of magnésium

- 46 turnings. The batch is stirred in the presence of ultrasound for 96 hours. The reaction mixture is then filtered, the solid is washed several times with methanol, and the filtrate is concentrated to dryness. After purification by column chromatography over silica gel (dichloromethane/EtOH/NITiOH), the expected product is obtained in the form of an oil.

NMR Ή (400 MHz, dmso-d6) δ ppm : 7.3 (d, 2 H), 7.1 (t, 2 H), 7.1 (d+t, 3 H), 7 (d, 2 H), 3.9 (s, 2 H), 3.55 (t, 4 H), 2.75 (m, 1 H), 2.72/2.45 (dd, 2 H), 2.35 (t, 4 H), 2.25 (t, 2 H), 1.6 (m,2H), 1.45 (m, 2 H)

IR (ATR) cm'¹ : v : >NH2+/NH+ : 3500-2300 ; v : >C-O-C< :1115

High-resolution mass spectroscopy (ESI+-IÎIMHR) :

Formule brute : C_]6 H₂₄ N₂ O [M+H]⁺calculated: 261.1961 [M+H]⁺measured: 261.1959

Step________G: (3R)-3-[3-(Morpholin-4-yl)propyl]-l,2,3,4-tetrahydroisoquinoline dihydrochloride

The free base obtained in Step F is dissolved in a minimum volume of dichloromethane. To the stirred solution at room température is added IM HCl solution in diethyl ether (3 equiv). The reaction is stirred for 15 minutes, after which time diethyl ether is added. The resulting precipitate is filtered, washed with diethyl ether, then dried under vacuum to afford the product.

Préparation 2g: A,A-Dimethyl[(35)-l,2,3,4-tetrahydroisoquinolin-3ylmethyl] amine dihydrochloride

The procedure is as in the process of Préparation 2a, replacing the morpholine used in Step A by N,/V-dimethylamine.

	-47 -
Préparation 2h:	(3S)-3-[(4-Methylpiperazin-l-yl)methyl]-l,2,3,4-

tetrahydroisoquinoline trihydrochloride

The procedure is as in the process of Préparation 2a, replacing the morpholine used in Step A by 1-methyl-piperazine and using 4.5 équivalents of IM HCl solution in diethyl ether in Step D (salification step).

Préparation 3a:

4-[(teri-Butyldimethylsilyl)oxy|-.V-inethylaniline

To a solution of 3.69 g 4-methylamino-phenol (30 mmol) and 3.20 g imidazole (47 mmol) in 65 mL of dichloromethane containing 1% éthanol, 5.88 g Zerl-butyl-dimethylsilyl chloride (39 mmol) is added with rapid stirring at ambient température. After 30 minutes the mixture is poured onto 160 mL water. The organic phase is separated and the aqueous phase is extracted with 50 mL dichloromethane. The combined organic phases are subsequently dried over magnésium sulphate and then filtered and evaporated to dryness. The crude product so obtained is then purified by chromatography over silica gel (hexane/ethyl acetate 100:1) to give the product (6.2 g, 87%) as an oil.

Préparation 3b: 4-(Benzyloxy)-A-phenylaniline

Benzyl bromide (1.79 mL, 15.08 mmol) was added to a mixture of 4hydroxydiphenylamine (2.54 g, 13.71 mmol), césium carbonate (5.58g, 1.25 equiv) and potassium iodide (283 mg, 0.1 equiv) in acetone (20 mL).

The mixture was stirred and heated at 50°C for 1.25 h. After this time, a further portion of benzyl bromide (0.2 eq) and césium carbonate (0.2 eq) were added and the mixture was heated for 45 min. The reaction mixture was allowed to cool to ambient température, then diluted with ethyl acetate, filtered, and the solvent removed in vacuo. The residue was purified by flash chromatography (Combiflash; 120g SilaSep Silica column) eluting with 0-20% ethyl acetate in hexane gradient to afford the desired product as a solid.

LC/MS (Ci₉H₁₇NO) 276 [M+H]⁺; RT 1.48 (Method B)

-V- ~ y

-48Préparation 3c: 4-(Benzyloxy)-A-ethylaniline

Step A: tert-Butyl-N-[4-(benzyloxy)phenyl]carbamate

To a mixture of n?ri-butyl-/V-(4-hydroxyphenyl)carbamate (25 g, 0.12 mol) and potassium carbonate (24.77 g, 0.18 mol) in DMF (400 mL) was added benzyl bromide (22.48 g, 0.13 mmol) and the reaction was heated at 50 °C for 16 h. The reaction was allowed to cool to ambient température, and water (100 mL) was added, causing the précipitation of a white solid. Further water (500 mL) was added and the résultant suspension was stirred for 30 min. The solid material was isolated by filtration, washed with water and dried under vacuum. This solid material was then dissolved in dichloromethane (250 mL), dried over magnésium sulfate and concentrated in vacuo to afford the desired material (32.05 g, 0.11 mmol) as a white crystalline solid.

LC/MS (Ci₈H₂iNO₃) 200 [M-Boc+H]⁺; RT 1.45 (Method B)

Step B: tert-Butyl-N-[4-(benzyloxy)phenyl]-N-ethylcarbamate

To a cooled solution of the compound obtained in Step A (5 g, 16.7 mmol) in THF (50 mL) was added sodium hydride (1.34 g, 33.4 mmol) portion-wise, and the résultant mixture was allowed to stir for 40 min. Iodoethane (2.69 mL, 33.4 mmol) was added and the reaction was allowed to stir at ambient température for 1 h and then at 40 °C for ca 16 h. The reaction was cooled, quenched with water and then extracted with ethyl acetate. The organic phase was washed successively with aqueous sodium thiosulfate solution, aqueous sodium bicarbonate solution, and brine. The organic extract was dried over magnésium sulphate, fïltered and concentrated in vacuo, and then adsorbed onto isolute and purified by chromatography (CombiFlash Rf, 80 g RediSep™ silica cartridge) eluting in a gradient of iso-hexane to 15 % ethyl acetate in iso-hexane to afford the desired product (5.37 g, 16.4 mmol).

LC/MS (C20H25NO3) 228 [M-Boc+H]⁺; RT 1.52 (Method B)

Step C: 4-(Benzyloxy)-N-ethylaniline

To a solution of compound obtained in Step B (5.37 g, 16.4 mmol, 1 eq) in dichloromethane (50 mL) was added trifluroacetic acid (5 mL) and the mixture was stirred

-49 at ambient température for 2 hours. The reaction mixture was diluted with water and basified with aqueous IM sodium hydroxide. The organic extract was dried over magnésium sulphate, filtered, concentrated in vacuo and then adsorbed onto isolute and purified by chromatography (CombiFlash Rf, 40 g RediSep™ silica cartridge) eluting in a gradient of iso-hexane to 25 % ethyl acetate in iso-hexane to afford the product as a yellow oil (3.24 g, 14.25 mmol).

LC/MS (C₎₅H₁₇NO) 228 [M+H]⁺; RT 1.03 (Method B)

Préparation 3d: 4-(Benzyloxy)-/V-propylaniline

The procedure is as in Préparation 3c, replacing iodoethane used in Step B with 1iodopropane.

LC/MS (Ci₆Hi₉NO) 242 [M+H]⁺; RT 1.21 (Method B)

Préparation 3e:

4-(Benzyloxy)-/V-butylaniline

The procedure is as in Préparation 3c, replacing iodoethane used in Step B with 1iodobutane.

LC/MS (Ci₇H₂₁NO) 256 [M+H]⁺; RT 1.56 (Method B)

Préparation 3f: 4-({4-[(ter/-Butyldimethylsilyl)oxy]phenyl}amino)-l,5-dimethyllH-pyrrole-2-carbonitrile

Step A: 4-Bromo-l,5-dimethyl-lH-pyrrole-2-carbonitrile

A solution of bromine (6.58 mL, 0.13 mol) in acetic acid (60 mL) is added dropwise with the aid of a dropping funnel to a solution of l,5-dimethyl-17/-pyrrole-2-carbonitrile (15.0 g, 0.12 mol) in acetic acid (300 mL). The whole is stirred at ambient température for 24 hours. The reaction mixutre is then poured into a beaker containing 300 mL of water. The solid formed is fdtered off and rinsed with water. It is then dissolved in

-50dichloromethane (300 mL) and the organic phase is washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo to give the expected product in the form of a solid.

*H NMR (CDC1₃) δ ppm: 2.25 (s, 3 H), 3.67 (s, 3 H), 6.74 (s, 1 H)

Step B: 4-({4-[(tert-Butyldimethylsilyl)oxy ]phenyl}amino )-l,5-dimethyl-lH-pyrrole-2carbonitrile

A solution of the compound of the preceding step (1.5 g, 7.53 mmol), 4-[(fërtbutyldimethylsilyl)oxy]aniline (2.02 g, 9.04 mmol), sodium ierAbutoxide (1.45 g, 15.06 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.13 g, 0.30 mmol) in toluene (20 mL) is purged with nitrogen. Tris(dibenzylideneacetone)dipalladîum(0) (0.28 g, 0.30 mmol) is added, and then the reaction mixture is heated at 90°C until the reaction is complété (monitored by TLC). Heating is stopped and the mixture is allowed to return to ambient température. Water (75 mL) is added and the mixture is extracted with ethyl acetate (3 x 75 mL). The combined organic phases are washed with brine and then concentrated. The crude product is absorbed on silica gel and purified by flash chromatography over silica gel with a mixture of ethyl acetate and heptane (0 to 30%). The product so obtained is dissolved while hot in heptane and is allowed to precipitate with stirring at ambient température and then at 0°C. The solid is filtered off and the operation is repeated on the filtrate to give the expected compound in the form of a solid.

*H NMR (400 MHz, CDC1₃) δ ppm: 0.15 (s, 6 H), 0.97 (s, 9 H), 2.13 (s, 3 H), 3.66 (s, 3 H), 4.68 (br. s, 1 H), 6.49 (d, J= 8.5 Hz, 2 H), 6.64 (s, 1 H), 6.66 (d, J= 8.7 Hz, 2 H) ¹³C NMR (100 MHz, CDC1₃) δ ppm: 4.34, 9.72, 18.30, 25.88, 32.94, 101.27, 114.37, 114.70, 116.41, 120.73, 124.52, 131.23, 141.54, 148.27

MS (ESI+): [M+H]⁺ measured: 342.3

Préparation 4a:

N- [4- (Benzyloxy)phenylJ -N-me thy 1 -3-( tetramethy 1 -1,3,2-

dioxaboro!an-2-yl)-5,6,7,8-tetrahydroindolizine-l-carboxamide

I

-51 Step A: l-Formylpiperidine-2-carboxylic acid

To a mixture of DL-pipecolinic acid (33.45 g, 259 mmol) in formic acid (250 mL) cooled to 0 °C, is added acetic anhydride (171 mL, 1.81 mol) drop-wise over ca 60 minutes. The reaction mixture is allowed to warm to room température, stirred for ca 16 hours and then cooled in an ice-water bath. Water (250 mL) is added, the mixture is stirred for 10 minutes and then concentrated in vacuo. Toluene is added and evaporated in vacuo (3 x 50 mL) to azeotropically remove water and acetic acid, and then the residue is dissolved in dichloromethane (60 mL), filtered through a hydrophobie frit and the filtrate evaporated in vacuo to afford the product as an oil.

Step B: Methyl 5,6,7,8-tetrahydroindolizine-l-carboxylate

I

To a stirring solution of formylated pipecolinic acid obtained in Step A (13.26g 84.48 mmol) in dichloroethane (100 mL) is added tosyl chloride (17.69 g, 92.8 mmol) followed by methyl-alpha-chloroacrylate (15.4 mL, 151.86 mmol). Triethylamine (23.52 mL, 168.74 mmol) is then added dropwise. The reaction mixture is stirred for 10 minutes, before heating to reflux. After 3 hours the reaction is cooled to room température and a further portion of methyl-alpha-chloroacrylate (6.0 mL, 59.1 mmol) is added followed by dropwise addition of triethylamine (11 mL, 78.9 mmol) and the reaction is heated at reflux for ca. 16 h. The reaction mixture is allowed to cool to room température, partitioned between dichloromethane and IM HCl, filtered through a pad of celite and the phases separated. The organic phase is washed sequentially with IN HCl, saturated NaHCO₃solution and then brine. The organic extract is dried over magnésium sulphate, fdtered and concentrated in vacuo and then adsorbed onto silica gel and purified by chromatography (CombiFlash Rf, 220g RediSep™ silica cartridge) eluting in a gradient of iso-hexane to 30% ethyl acetate in iso-hexane to obtain an oil.

LC/MS (C10H13NO2) 180 [M+H]⁺; RT 1.13 (Method B)

Step C: 5,6,7,8-Tetrahydroindolizine-l-carboxylic acid

To a solution of the ester obtained in Step B (2 g, 11.2 mnol) in dioxane (15 mL) is added a solution of LiOH (936 mg, 22.3 mmol) in water (15 mL) and the reaction stirred at 100 °C for 5 hours. The reaction is cooled, diluted with water, acidified to ~ pH 2 with 2M HCl

I

-52and the resulting precipitate is filtered and washed with water and then dried under vacuum to afford the product as a powder.

LC/MS (Ο₉Ηΐ]ΝΟ₂) 166 [M+H]⁺; RT 1.72 (Method A)

Step D: N-[4-(Benzyloxy)phenyl]-N-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The acid obtained in Step C (1 g, 6.05 mmol) is azeotroped with a minimal volume of toluene and then dissolved in anhydrous dichloromethane (50 mL). This is cooled to -10 °C under nitrogen and oxalyl chloride (2M in dichloromethane, 3 mL, 6.05 mmol) is added dropwise and then stirred for an hour maintaining the température at -10 °C. A solution of pyridine (0.73 mL, 9.08 mmol) and 4-(benzyloxy)-7V-methylaniline (1.42 g, 6.7 mmol) in dichloromethane (3 mL) is added drop-wise to the reaction mixture at -10 °C and then allowed to warm to ambient température. Further pyridine (0.24 mL, 3 mmol) is added after 4 hours and stirring is maintained at ambient température for ca. 16 h. The reaction mixture is loaded onto a pre-packed silica column and purified in a gradient of Ao-hexane to 40% ethyl acetate/Ao-hexane to afford the desired product as a powder.

LC/MS (C23H24N2O2) 361 [M+H]⁺; RT 2.68 (Method A)

Step E: N-[4-(Benzyloxy)phenyl]-3-bromo-N-methyl-5,6,7,8-tetrahydroindolizine-lcarboxamide

To a solution of the compound obtained in Step D (3.49 g, 9.68 mmol) in tetrahydrofuran (35 mL), cooled to -78 °C under nitrogen, is added 2V-bromosuccinimide (1 eq) portionwise and then the résultant mixture is stirred for 1 hour. The reaction is allowed to warm to ambient température, then diluted with ethyl acetate and washed with 10% sodium thiosulphate solution, saturated sodium bicarbonate solution and brine. The organic phase is subsequently dried over magnésium sulphate, filtered and concentrated in vacuo. The crude product is purified by chromatography over silica gel in a gradient of iso-hexane to 1:1 ethyl acetate/iso-hexane, then triturated with ether and filtered to afford a powder.

LC/MS (C₂3H23N₂O2Br) 439 [M+H]⁺; RT 2.74 (Method A)

Step F: N-[4-(Benzyloxy)phenyl]-N-methyl-3-(tetramethyl-l,3,2-dioxaborolan-2-yl)-

5,6,7,8-tetrahydroindolizine-l-carboxamide ' ' Γ,··· Λ

- 53 To a solution of the bromide obtained in Step E (6.47g, 14.73 mmol) in anhydrous tetrahydrofuran (83 mL), cooled to -78°C, is added n-butyl lithium solution in hexanes (2.17 M, 7.47 mL, 16.20 mmol) drop-wise over ca 20 mins. After a further 15 minutes, 2isoproyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.61 mL, 17.67 mmol) is added dropwise and stirring is continued for 15 min. The reaction mixture is quenched at -78°C by the addition of 20 mL saturated ammonium chloride solution, and then allowed to warm to ambient température. The reaction mixture is partitioned between water and ethyl acetate and the phases separated. The organic phase is washed with water, saturated NaCl solution, then rnied over magnésium sulphate, filtered and the filtrate concentrated in vacuo to a solid. The solid is then triturated with diethyl ether, filtered, washed with cold ether and dried in vacuo to afford the product as a powder.

LC/MS (C₂₉H35BN₂O₄) 487 [M+H]⁺; RT 1.59 (Method B)

Préparation 4b: A-[4-(Benzyloxy)phenyl]-/V_>l,2-trimethyl-5-(tetramethyl-l,3,2dioxaborolan-2-yl)-LH-pyrrole-3-carboxamide

Step A: Ethyl l,2-dimethyl-lH-pyrrole-3-carboxylate

To a cooled solution of 2-methyl-///-pyrrole-3-carboxylate (5 g, 32.64 mmol) in THF (50 ml) is added 60% NaH in minerai oil (2.61 g, 65.28 mmol) and the résultant mixture is stirred at 0 °C for 40 minutes. Methyl iodide (4.07 ml, 65.28 mmol) is then added and allowed to stir for 1 hour. The reaction is quenched by the dropwise addition of water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The organic extracts are washed sequentially with 10% aqueous thiosulphate solution and brine, then dried over magnésium sulphate, filtered and concentrated. The crude product is taken-up in dichloromethane and loaded onto isolute for purification on CombiFlash (120 g silica, Hex to 20% EtOAc/Hex) to yield the desired product as an oil.

LC/MS (C₉Hi₃NO₂) 168 [M+H]⁺; RT 1.11 (Method B)

Step B: l,2-Dimethyl-lH-pyrrole-3-carboxylic acid

- 54 To a solution of the product from Step A (5.3 g, 31.7 mmol) in l,4-dioxane (60 mL) is added IM LiOH (2.66 g, 63.4 mmol) in water (60 ml) and the reaction stirred at 100 °C for ca 16 h. The reaction is allowed to cool to ambient température, diluted with water and acidified with 2M HCl. The resulting precipitate is collected by vacuum filtration to afford the desired product. The filtrate is extracted with ethyl acetate and the organic extracts dried over magnésium sulphate, filtered and concentrated to obtain an additional crop of desired product.

LC/MS (C7H9NO2) no ionisation; RT 0.71 (Method B)

Step C: N-[4-(Benzyloxy)phenyl]-N,l,2-trimethyl-lH-pyrrole-3-carboxatnide

The acid obtained from Step B (1 g, 7.19 mmol) is dissolved in dichloromethane (20 ml) and to this is added l-chloro-A,A,2-trimethyl-l-propenylamine (1.15 g, 8.62 mmol) and stirred at ambient température for 2 hours. The mixture is concentrated to an oil which is re-dissolved in toluene (50 mL). A solution of 4-(benzyloxy)-/V-methylaniline (1.84 g, 8.62 mmol) in toluene (10 ml) is added and the résultant mixture is stirred at reflux for 2 hours. The reaction is allowed to cool to ambient température and left to stand for ca 16 h. The reaction is partitioned between ethyl acetate and water, separated, and the organics are washed with water, dried over magnésium sulphate, filtered and concentrated. The crude product is purified on CombiFlash (80 g silica, Hex to 60% EtOAc) to obtain the desired product as a solid.

LC/MS (C₂iH2₂N₂O2) 335 [M+H]⁺; RT 1.33 (Method B)

Step D: N-[4-(Benzyloxy)phenyl]-5-bromo-N,l,2-trimethyl-lH-pyrrole-3-carboxamide

The product from Step C (1.74 g, 5.19 mmol) is dissolved in THF (20 ml) and cooled to 78 °C. A-Bromosuccinimide (924 mg, 5.19 mmol) is then added portion-wise until complété addition and then stirred for 15 minutes. The reaction mixture is allowed to warm to ambient température, diluted with ethyl acetate and washed sequentially with 10% sodium thiosulfate solution, saturated sodium bicarbonate solution and brine. The organics are then dried over magnésium sulphate, filtered and concentrated. The crude material is taken-up in dichloromethane, loaded onto isolute and purified on CombiFlash (80 g silica, Hex to 70 % EtOAc/Hex) to afford the product as a solid.

I

LC/MS (C₂]H_2lN₂O₂Br) 413 [M+H]⁺; RT 1.42 (Method B)

Step E: N-[4-(Benzyloxy)phenyl]-N, l,2-triinethyl-5-(tetramethyl-l,3,2-dioxaborolan-2yl)-lH-pyrrole-3-carboxamide

The bromide from Step D (1.74 g, 4.21 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2dioxaborolane (0.94 g, 5.05 mmol) are combined and dissolved in anhydrous THF (20 ml). The reaction mixture is cooled to - 78 °C under nitrogen, followed by the dropwise addition of 2M n-BuLi (2.13 ml, 4.25 mmol) over 50 minutes. The reaction is then quenched by the addition of saturated aqueous ammonium chloride solution, and allowed to warm to ambient température, diluted in ethyl acetate and then washed with water followed by brine. The organics are dried over magnésium sulphate, filtered and concentrated to an oil, which solidifies on addition of ether. Re-evaporation and drying in vacuo affords the desired product.

LC/MS (C27H33BN2O4) 461 [M+H]⁺; RT 1.51 (Method B)

Préparation 4c:

N, 1,2-Trimethyl-A-phenyl-5-(tetramethyl-l,3,2-dioxaborolan-2-

yl)-LH-pyrrole-3-carboxamide

The procedure is as in Préparation 4b, replacing 4-(benzyloxy)-7V-methylaniline used in Step C with /V-methylaniline.

LC/MS (C₂₀H₂₇BN₂O3) 355 [M+H]⁺; RT 1.39 (Method B)

I

Préparation 4d: jV>/V-Dibutyl-l,2-dimethyl-5-(tetramethyl-l,3,2-dioxaboroIan-2| 20 yl)-lH-pyrroIe-3-carboxamide * The procedure is as in Préparation 4b, replacing 4-(benzyloxy)-7V-methylaniline used in ® Step C with dibutylamine

LC/MS (C2iH₃7BN₂O₃) 377 [M+H]⁺; RT 1.55 (Method B)

-56Préparation 4e: N-{4-[(tert-ButyIdimethylsilyl)oxy]phenyl}-;V-methyl-3(tetramethyl-l,3,2-dioxaboroIan-2-yl)-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Préparation 4a, replacing 4-(benzyloxy)-N-methylaniline in Step D with 4-[(ieri-butyldimethylsilyl)oxy]-jV-methylaniline from Préparation 3a.

Préparation 4f: .V-[4-(BenzyIoxy)phenylj-.V-phenyl-3-(tetraniethyl-l.3.2dioxaborolan-2-yl)-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Préparation 4a, replacing 4-(benzyloxy)-7V-methylaniline in Step D with 4-(benzyloxy)-7V-phenylaniline from Préparation 3b.

Préparation 4g: Æ-[4-(BenzyIoxy)phenyI]-7V-ethyl-l,2-dimethyl-5-(tetramethyI- l,3,2-dioxaborolan-2-yl)-lH-pyrrole-3-carboxamide

The procedure is as in Préparation 4b, replacing 4-(benzyloxy)-A-methylaniline used in Step C with 4-(benzyloxy)-/V-ethylaniline from Préparation 3c.

LC/MS (C₂₈H₃₅BN₂O₄) 475 [M+H]⁺; RT 1.49 (Method B)

Préparation 4h: V-|4-(Benzyloxy)phenyl]-1.2-diniethyl- V-propyi-5-(tetraniethyl-

1.3.2- dioxaborolan-2-yl)-lH-pyrrole-3-carboxamide

The procedure is as in Préparation 4b, replacing 4-(benzyloxy)-7V-methylaniline used in Step C with 4-(benzyloxy)-7V-propylaniline from Préparation 3d.

LC/MS (C₂9H₃7BN₂O₄) 489 [M+H]⁺; RT 1.57 (Method B)

Préparation 4i: 7V-[4-(Benzyloxy)phenyl]-iV-butyl-l,2-dimethyl-5-(tetramethyI-

13.2- dioxaboroIan-2-yl)-lH-pyrroIe-3-carboxamide _____. - ' f p ; - A \ ' \ ' ! ....

Λ U

- 57 The procedure is as in Préparation 4b, replacing 4-(benzyloxy)-jV-methylaniline used in Step C with 4-(benzyloxy)-/V-butylaniline from Préparation 3e.

LC/MS (C30H39BN2O4) 503 [M+H]⁺; RT 1.55 (Method B)

Préparation 5a: 6-(l-{[4-(Benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-2-[(terAbutoxy)carbonyl]-l,2,3,4-tetrahydroisoquinoline-7carboxylic acid

Step A: 2-tert-Butyl 7-methyl 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate

The boronic ester obtained in Préparation 4a (1.22 g, 2.50 mmol) and the triflate obtained in Préparation lb (1.1 g, 2.50 mmol) are suspended in 15 mL of anhydrous N,Ndimethylformamide and the mixture is degassed (bubbling with N₂) for 45 minutes. Cs₂CO3 (1.63 g, 5 mmol) and bis(di-terAbutyl(4-dimethylaminophenyl)-phosphine) dichloroplladium(II) (88.5 mg, 0.13 mmol) are added and the résultant mixture is sealed and immediately heated in the microwave at 130°C for 30 minutes. The reaction mixture is concentrated and re-dissolved in ethyl acetate, washed with brine, dried over magnésium sulphate, filtered and concentrated. The crude product is purifïed by flash chromatography on CombiFlash (120 g silica, dichloromethane to 20% methanol/dichloromethane) to afford the desired product.

LC/MS (C39H43N3O6) 650 [M+H]⁺; RT 1.54 (Method B)

Step B: 6-(l-{[4-(Benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8-tetrahydroindolizin-3yl)-2-[(tert-butoxy)carbonyl]-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid

To a solution of the ester obtained in Step A (730 mg, 1.12 mmol) in dioxane (10 mL) is added a solution of LiOH (94 mg, 2.24 mmol) in water (5 mL). The reaction is then heated at 90 °C for ca 16 h. A further 94 mg of LiOH (2.24 mmol) in water (5 mL) is added and stirred for 1 hour to complété the reaction. The mixture is cooled, diluted with water and acidified to ~ pH 4 with dilute aqueous HCl. The precipitate which forms is stirred for 30

I

-58minutes and then filtered off, washed with cold water and dried under vacuum to afford the desired product.

LC/MS (C38H41N3O6) 636 [M+H]⁺; RT 1.46 (Method B)

Préparation 5b: 2-tert-Butyl 7-lithio 6-(4-{[4(benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyl-LH-pyrrol-2-yl)-l, 2,3,4tetrahydroisoquinoline-2,7-dicarboxylate

Step A: 2-tert-Butyl 7-methyl 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5dimethyl-lH-pyrrol-2-yl)-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate

The boronic ester from Préparation 4b (1 g, 1.7 mmol) and the nonaflate from Préparation la (0.94 g, 2.04 mmol) are dissolved in DMF (20 mL) and degassed (bubbling nitrogen) for 20 minutes. Césium carbonate (1.3 g, 4.04 mmol) and bis(di-teri-butyl(4dimethylaminophenyl)phosphine)dichloropalladium(II) (60 mg, 0.085 mmol) are added and the résultant mixture is immediately heated in the microwave at 130 °C for 30 minutes. The DMF is evaporated, and the residue dissolved in ethyl acetate, washed with brine, then dried over magnésium sulphate, filtered and concentrated. The crude material is taken up in dichloromethane, loaded onto isolute and purified on CombiFlash (120 g silica, Hex to 70 % EtOAc/Hex to obtain the product as a foam.

LC/MS (C37H41N3O6) 624 [M+H]⁺; RT 1.55 (Method B)

Step B: 2-tert-Butyl 7-lithio 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5dimethyl-lH-pyrrol-2-yl)-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate

To a solution of the ester obtained in Step A (2.17 g, 3.48 mmol) in dioxane (20 ml) is added an aqueous solution of LiOH (2 M; 3.48 mL, 6.96 mmol), and the résultant mixture is heated at reflux for ca 16 h. The reaction mixture is allowed to cool to ambient température and the solids removed by filtration. The solution is concentrated to obtain the desired product as a solid.

LC/MS (C₃₆H₃₉N3O6) 610 [M+H]⁺; RT 1.47 (Method B)

I

-59Préparation 5c: 2-[(terriButoxy)carbonyl]-6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-l,2,3,4-tetrahydroisoquinoline-7carboxylic acid

Step A: 2-tert-Butyl 7-methyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2yl}-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate

The procedure is as in Step A of Procedure 5b, replacing 7V-[4-(benzyloxy)phenyl]-jV,l,2trimethyl-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-17/-pyrrole-3-carboxamide with the product from Procedure 4c.

Step B: 2-[(tert-Butoxy)carbonyl]-6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lHpyrrol-2-yl}-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid

The procedure is as in Step B from Procedure 5a, replacing 2-tert-butyI 7-methyl 6-(l-{ [4(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8-tetrahydroindolizin-3-yl)-l, 2,3,4tetrahydroisoquinoline-2,7-dicarboxylate with the product from Step A.

Préparation 5d: 2-tert-Butyl 7-lithio 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-lfiTpyrrol-2-yl] -1,2,3,4-tetrahy droisoquinoline-2,7-dicarboxylate

The procedure is as in Préparation 5b, replacing /V-[4-(benzyloxy)phenyl]-/V,l,2-trimethyl-

5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l/7-pyrrole-3-carboxamide with the product from Procedure 4d.

Préparation 5e: 2-[(teri-Butoxy)carbonyl]-6-{l-[(4hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-l, 2,3,4tetrahydroisoquinoIine-7-carboxylic acid

Step A: tert-Butyl 6-[l-({4-[(tert-butyldimethylsilyl)oxy]phenyl}(methyl)carbamoyl)-

5,6,7,8-tetrahydroindolizin-3-yl]-7-formyl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate ' ' ; ? HT .

-60The triflate from eparation le (610 mg, 1.49 mmol), the boronic ester from Préparation 4e (910 mg, 1.79 mmol) and potassium carbonate (412 mg, 2.98 mmol) are dissolved in THF/Water and degassed (nitrogen bubbling) for 15 mins. To this is added tetrakis(triphenylpiiosphine)palladium(0) (5mol%) and the résultant mixture is stirred at room température for 45 min. The reaction is diluted with ethyl acetate, washed with water followed by brine, and the organics dried over magnésium sulphate and evaporated under reduced pressure. The crude product thus obtained is purified on CombiFlash (40 g silica; isohexane to ethyl acetate), affording the desired product.

LCZMS (C₃7H49N3O₅Si) 644 [M+H]⁺; RT 1.71 (Method B)

Step B: 2-tert-Butyl 7-methyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate

The procedure is as in Step B of Préparation la, replacing the 2:1 isomer mixture of tertbutyl 7-formyl-6-hydroxy-l,2,3,4-tetrahydroisoquinoline-2-carboxylate and iert-butyl 5formyl-6-hydroxy-l,2,3,4-tetrahydroisoquinoline-2-carboxylate with tert-butyl 6-[l-({4[(teri-butyldimethylsilyl)oxy]phenyl}(methyl)carbamoyl)-5,6,7,8-tetrahydroindolizin-3yl]-7-formyl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate. The reaction was heated at 45 °C extemal température for 24 h to facilitate completion of the observed partial desilylation.

Step C: 2-[(tert-Butoxy)carbonyl]-6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid

The procedure is as in Step B of Préparation 5a, replacing 2-teri-butyl 7-methyl 6-(l-{[4(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8-tetrahydroindolizin-3-yl)-l,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate with 2-tert-butyl 7-methyl 6-{l-[(4hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl} -1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate.

Préparation 5f: 2-tert-butyl 7-lithio 6-(4-{[4(benzyloxy)phenyl](ethyl)carbamoyl}-l,5-dimethyl-lH-pyrrol-2-yl)-l,2,3,4tetrahydroisoquinoline-2,7-dicarboxyIate

.... — * qr⁷ '

-6l The procedure is as in Préparation 5b, replacing N-[4-(benzyloxy)phenyl]-2V,l,2-trimethyl5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-17/-pyrrole-3-carboxamide with the product from Procedure 4g.

LC/MS (C₃₇H_4lN₃O₆) 624 [M+H]⁺; RT 1.50 (Method B)

Préparation 5g:

2-tert-butyl 7-lithio 6-(4-{[4-

(benzyloxy)phenyl](propyl)carbamoyl}-l,5-dimethyl-lH-pyrrol-2-yl)-l,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate

The procedure is as in Préparation 5b, replacing A-[4-(benzyloxy)phenyl]-A,l,2-trimethyl5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l//-pyrrole-3-carboxamide with the product from Procedure 4h.

LC/MS (C₃₈H₄₃N₃O₆) 638 [M+H]⁺; RT 1.54 (Method B)

Préparation 6aa: A'-[4-(Benzyloxy)phenyl]-A-inethyl-3-{7-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoIine-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide, bis-trifluoroacetic acid sait

Step A: tert-Butyl 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of the acid obtained in Préparation 5a (150 mg, 0.24 mmol) in N,Ndimethylformamide (2 mL) is added triethylamine (0.13 mL, 0.96 mmol), HBTU (91 mg, 0.24 mmol) and the (35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline dihydrochloride obtained in Préparation 2a (72 mg, 0.24 mmol). The reaction is stirred at room température for 15 minutes and then diluted with water, and the resulting suspension stirred. The product is then extracted with ethyl acetate and the organic extract dried over magnésium sulphate, filtered and concentrated. The Crude material is purified on CombiFlash (12 g silica, dichloromethane to 4% methanol/dichloromethane) and then dried in vacuo to obtain the product as a glassy solid.

-62LC/MS (C52H59N5O6) 850 [M+H]⁺; RT 1.49 (Method B)

Step B: N-[4-(Benzyloxy)phenyl]-N-methyl-3-{7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide, bis-trifluoroacetic acid sait

The Boc-protected material obtained in Step A (173 mg, 0.2 mmol) is dissolved in dichloromethane (10 mL) and to this is added trifluoroacetic acid (1 mL). The reaction is allowed to stir for 1 hour at ambient température and then concentrated in vacuo. The residue is triturated in diethyl ether to afford a precipitate which is filtered off and dried under vacuum.

LC/MS (C47H51N5O4) 750 [M+H]⁺; RT 1.10 (Method B)

Préparation 6ab: A-[4-(Benzyloxy)phenyl]-A-methyl-3-{7-[(3Æ)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoIin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide; trifluoroacetic acid sait

Step A: tert-Butyl 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

1.2.3.4- tetrahydroisoquinoline-2-carboxylate

To a stirring solution of the acid obtained from Préparation 5a (0.87 g, 1.36 mmol) in DMF (10 mL) was added diisopropylethylamine (0.47 mL, 2.72 mmol) and (3R)-3-methyl-

1.2.3.4- tetrahydroisoquinoline from Préparation 2b (210 mg, 1.43 mmol) followed by HBTU (516 mg, 1.36 mmol). The reaction was stirred for 1 h, then diluted with water and extracted with ethyl acetate. The organic extracts were sequentially washed with aqueous sodium bicarbonate and brine, then dried over magnésium sulphate and evaporated in vacuo. The crude procuct was taken-up in dichloromethane, loaded onto isolute and purified on CombiFlash (40 g silica, isohexane to ethyl acetate gradient) to afford the desired product as a foam.

LC/MS (C48H₅2N₄O₅) 765 [M+H]⁺; RT 1.62 (Method B) < J -Ldi A CA

-63Step B: N-[4-(Benzyloxy)phenyl]-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide; trifluoroacetic acid sait

The Boc-protected product from Step A (0.90 g, 1.18 mmol) was dissolved in dichloromethane (10 mL) and to this was added TFA (1 mL). The reaction was stirred for 1 h, then solvent was removed under reduced pressure, and residual solvent was removed under high vacuum. Addition of ether to the résultant oil induced the oil to solidify. The mixture was stirred for 45 min, then cooled, filtered, and washed with cold ether to afford the desired product. Concentration of the filtrate afforded further solid product. The combined solids were dried under vacuum to afford the product.

LC/MS (C43H44N4O3) 665 [M+H]⁺; RT 1.24 (Method B)

Préparation 6ba: A'-[4-(Benzyloxy)phenyl|- V.L2-triinethvl-5-{7-|(5.S)-3(morpholin-4-ylmethyl)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinoIin-6-yl}-7H-pyrrole-3-carboxamide; bis trifluoroacetic acid sait

Step A: tert-Butyl 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyl-lHpyrrol-2-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The lithium sait from Préparation 5b (1.07 g, 1.74 mmol) is taken-up in DMF (10 mL) and to this is added triethylamine (0.97 ml, 6.96 mmol), HBTU (660 mg, 1.74 mmol), and the (3S)-3-(morpholin-4-ylmethy 1)-1,2,3,4-tetrahydroisoquinoline dihydrochloride obtained in Préparation 2a (0.58 g, 1.91 mmol) and the résultant mixture is then stirred for 15 minutes at ambient température. The reaction is diluted with water and extracted with ethyl acetate. The organic extract is dried over magnésium sulphate, filtered and concentrated. The crude material is taken up in dichloromethane, loaded onto isolute and purified on CombiFlash (40 g silica, dichloromethane to 5% MeOH/dichloromethane) to afford the desired product.

LC/MS (C50H57N5O6) 824 [M+H]⁺; RT 1.44 (Method B)

- 64 Step B: N-[4-(Benzyloxy)phenyl]-N,l,2-trimethyl-5-{7-[(3S)-3-(morpholin-4-ylmethyl)-

1.2.3.4- tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-lHpyrrole-3-carboxamide; bis trifluoroacetic acid sait

The Boc-protected product from Step A (705 mg, 0.86 mmol) is dissolved in dichloromethane and to this is added trifluoroacetic acid (1.33 ml). The résultant mixture is then allowed to stir at ambient température for ca 16 h. The reaction is concentrated in vacuo and the residue triturated with ether to afford a precipitate which is filtered and dried under vacuum to yield the desired product.

LC/MS (C45H49N5O4) 724 [M+H]⁺; RT 1.07 (Method B)

Préparation 6bb: V-[4-(Benzyloxy)phenyl]-A^r, l,2-triinethyl-5-(7-[(3/?)-3-methyl-

1.2.3.4- tetrahydroisoquinoline-2-carbonyl] -1,2,3,4-tetrahydroisoquinoIin-6-y 1} - 1Hpyrrole-3-carboxamide; trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-1,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with (3R)-3-methyl-l,2,3,4tetrahydroisoquinoline from Préparation 2b.

LC/MS (C41H42N4O3) 639 [M+H]⁺; RT 1.18 (Method B)

Préparation 6bc: V-[4-(Benzyloxy)phenyl|-A^?,L2-trimethyl-5-{7-[(3S)-3-|2(morpholin-4-yI)ethyl] -1,2,3,4-tetrahydroisoquinoline-2-carbonyl] -1,2,3,4tetrahydroisoquinolin-6-yl}-l//-pyrrole-3-carboxainide; bis-trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-1,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with (3S)-3-[2-(morpholin-4-yl)ethylJ-

1.2.3.4- tetrahydroisoquinoline dihydrochloride obtained from Préparation 2d.

LC/MS (C46H51N5O4) 738 [M+H]⁺; RT 1.07 (Method B)

Préparation 6bd:

- 65 - A-[4-(Benzyloxy )phenyl ]-A, 1,2-trimethyl-5-{7-[(37?)-3-[3-

(morpholin-4-yl)propyl]-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxamide

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with (3R)-3-[3-(morpholin-4-yl)propylJ-

1,2,3,4-tetrahydroisoquinoline dihydrochloride from Préparation 2f. The intermediate was isolated as the free base.

LC/MS (C47H53N5O4) 752 [M+H]⁺; RT 1.03 (Method B)

Préparation 6be:

.V-[4-(Benzyloxy)phenyl]-5-{7-[(3.S')-3-[(diinethylamino)methyl]-

l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-Ai,l,2trimethyl-lH-pyrroIe-3-carboxamide; bis-trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing (3Sj-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with dimethyl[(35)-l,2,3,4tetrahydroisoquinolin-3-ylmethyl]amine dihydrochloride from Préparation 2g.

LC/MS (C43H47N5O3) 682 [M+H]⁺; RT 1.02 (Method B)

Préparation 6bf:

A-[4-(Benzyloxy)phenyl]-/V,l,2-trimethyl-5-{7-[(3S)-3-[(4-

methylpiperazin-1 -yl)methyl] -1,2,3,4-tetrahy dr oisoquinoline-2-carbonyl] -1,2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxamide; tris-trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with (3S)-3-[(4-methylpiperazin-lyl)methyl]-l,2,3,4-tetrahydroisoquinoline trihydrochloride from Préparation 2h.

LC/MS (C₄6H₅₂N₆O3) 737 [M+H]⁺; RT 1.04 (Method B)

-66Préparation 6ca: A,l,2-Trimethyl-5-{7-[(3S')-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-A-phenyl-lHpyrrole-3-carboxamide; bis-trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing 2-tert-butyl 7-lithio 6-(4-( [4(benzyloxy)phenyl](methyl)carbamoyl}-1,5-dimethyl- 17/-pyrrol-2-yl)-1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate in Step A with 2-[(tert-butoxy)carbonyl]-6-{l,5dimethyl-4-[methyl(phenyl)carbamoyl]-17Z-pyrrol-2-yl}-l,2,3,4-tetrahydroisoquinoline-7carboxylic acid from Préparation 5c.

LC/MS (C38H43N5O3) 618 [M+H]⁺; RT 0.93 (Method B)

Préparation 6cb: A,l,2-Trimethyl-5-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyI]-1.2,3.4-tetrahydroisoquinolin-6-yl}-V-phenyl- 1Hpyrrole-3-carboxamide; trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with (37?)-3-methyl-l,2,3,4tetrahydroisoquinoline from Préparation 2b; and replacing 2-tert-butyl 7-lithio 6-(4-((4(benzyloxy)phenyl] (methy l)carbamoy 1} -1,5-dimethy 1-17/-pyrrol-2-y 1)-1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate in Step A with 2-[(tert-butoxy)carbonyl]-6-(l,5dimethyl-4-[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl} -1,2,3,4-tetrahydroisoquinoline-7carboxylic acid from Préparation 5c.

Préparation 6cd: A,l,2-Trimethyl-5-{7-[(3/?)-3-[3-(inorpholin-4-yl)propyl|-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-A^r-phenyl-lZ7pyrrole-3-carboxamide

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with (37?)-3-[3-(morpholin-4-yl)propylJ-

1,2,3,4-tetrahydroisoquinoline dihydrochloride from Préparation 2f; and replacing 2-tertbutyl 7-lithio 6-(4-([4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyl-lH-pyrrol-217896

-67yl)-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate in Step A with 2-[(tertButoxy)carbonyl]-6-{ l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-17/-pyrrol-2-yl)-l ,2,3,4tetrahydroisoquinoline-7-carboxylic acid from Préparation 5c. The intermediate was isolated as the free base.

LC/MS (C₄oH47N₅0₃) 646 [M+H]⁺; RT 0.91 (Method B)

Préparation 6ce: A,l,2-trimethyl-5-{7-[(3S)-3-[(4-methylpiperazin-l-yl)methyl]-

1.2.3.4- tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-Aphenyl- l//-pyrrole-3-carboxainide; tris-trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with (3Sj-3-[(4-methylpiperazin-lyl)methyl]-l,2,3,4-tetrahydroisoquinoline trihydrochloride from Préparation 2h, and replacing 2-ieri-butyl 7-lithio 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-I,5dimethyl-17/-pyrrol-2-yl)-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate in Step A with 2-[(ie/‘i-butoxy)carbonyl]-6-{ 1,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl }-

1.2.3.4- tetrahydroisoquinoline-7-carboxylic acid from Préparation 5c.

LC/MS (C₃₉H46N₆O₂) 631 [M+H]⁺; RT 0.91 (Method B)

Préparation 6da: A⁷AM)ibutyl-l,2-dimethyI-5-{7-[(3.S)-3-(morpholin-4-ylmethyl)-

1.2.3.4- tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4-tetrahydroisoquinolin-6-yl}- 1Hpyrrole-3-carboxamide; bis-trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing 2-ierZ-butyl 7-lithio 6-(4-{[4(benzyloxy)phenyl](methyl)carbamoyl} -1,5-dimethyl- l/7-pyrrol-2-yl)-1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate in Step A with 2-zeri-butyl 7-lithio 6-[4(dibutylcarbamoyl)-l,5-dimethyl-l/-/-pyrrol-2-yl]-l,2,3,4-tetrahydroisoquinoline-2,7dicarboxylate from Préparation 5d.

LC/MS (C₃₉H₅₃N₅O₃) 640 [M+H]⁺; RT 1.10 (Method B)

-68Préparation 6db: .\.V-I)ibutvl-l.2-diniethvI-5-{7-|(3/?)-3-methvl-l.2.3.4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-lH-pyrroIe-3carboxamide; trifluoroacetic acid sait

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with (3R)-3-methyl-l,2,3,4tetrahydroisoquinoline from Préparation 2b; and replacing 2-tert-butyl 7-lithio 6-(4-{[4(benzyloxy)phenylj (methyl)carbamoyl} -1,5-dimethyl-1 H-pyrrol-2-yl)-1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate in Step A with 2-tert-butyl 7-lithio 6-[4(dibutylcarbamoyl)-1,5-dimethyl-lH-pyrrol-2-yl]-1,2,3,4-tetrahydroisoquinoline-2, Ίdicarboxylate from Préparation 5d.

Préparation 6dc: A,2V-DibutyI-l,2-dimethyl-5-[7-(l,2,3,4-tetrahydroisoquinoline-2carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yI J-lH-pyrrole-3-carboxamide

The procedure is as in Préparation 6ba, replacing (3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline dihydrochloride in Step A with tetrahydroisoquinoline; and neutralising the product solution in Step B with dilute aqueous sodium hydroxide solution.

LC/MS (C34H44N4O2) 541 [M+H]⁺; RT 1.14 (Method B)

Préparation 6e: ;V-(4-Hydroxyphenyl)-A'-methyl-3-{7-[(3.S’)-3-(inorpholin-4ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonylJ-1,2,3,4-tetrahydroisoquinolin-6yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide dihydrochloride

Step A: tert-Butyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin~4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step A of Préparation 6aa, replacing 6-(l-{[4(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8-tetrahydroindolizin-3-yl)-2-[(tert-

-69butoxy)carbonyl]-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid in Step A with 2-{(tertbutoxy)carbonyl]-6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl} -1,2,3,4-tetrahydroisoquinoIine-7-carboxylic acid from Préparation 5e.

LC/MS (C45H53N5O6) 760 [M+H]⁺; RT 1.25 (Method B)

Step B: N-(4-Hydroxyphenyl)-N-methyl-3-{7-[(3S)~3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-1 -carboxamide dihydrochloride

The compound obtained in Step A (135 mg, 0.18 mmol) is dissolved in ethyl acetate (6.75 mL) and to this concentrated HCl (148 uL, 1.78 mmol) is added and allowed to stir for 30 minutes. Minimal IPA is then added dropwise to encourage précipitation. The solid is then filtered off, washed with ethyl acetate and dried under vacuum ovemight to afford a solid.

LC/MS (C₄₀H4₅N₅O4) 660 [M+H]⁺; RT 0.89 (Method B)

Préparation 6f: A^T-[4-(Benzyloxy)phenyl]-A-ethyl-l,2-dimethyl-5-{7-[(3S)-3(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-l//-pyrrole-3-carboxaniide

The procedure is as in Préparation 6ba, replacing 2-zeri-butyl 7-lithio 6-(4-((4(benzyloxy)phenyl] (methyl)carbamoyl} -1,5-dimethyl-1 H-pyrrol-2-yl)-1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate in Step A with 2-tert-butyl 7-lithio 6-(4-((4(benzyloxy)phenyl](ethyl)carbamoyl} -1,5-dimethyl- lH-pyrrol-2-yl)-1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate from Préparation 5f; and neutralising the product solution in Step B with dilute aqueous sodium hydroxide solution.

LC/MS (C46H₅iN₅O₄) 738 [M+H]⁺; RT 1.08 (Method B)

-70Préparation 6g: A-[4-(Benzyloxy)phenyl]-l,2-dimethyl-5-{7-[(3S')-3-(morpholin-

4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-

6-yl}-/V-propyl-lH-pyrroIe-3-carboxamide

The procedure is as in Préparation 6ba, replacing 2-fôrLbutyl 7-lithio 6-(4-{[4(benzyloxy)phenyl] (methyl)carbamoyl} -1,5-dimethyl- l/7-pyrrol-2-yl)-1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate in Step A with 2-tert-butyl 7-lithio 6-(4-{[4(benzyloxy)phenyl] (propyl)carbamoyl} -1,5-dimethyl-1 H-pyrrol-2-yl)-1,2,3,4tetrahydroisoquinoline-2,7-dicarboxylate from Préparation 5g; and neutralising the product solution in Step B with dilute aqueous sodium hydroxide solution.

LC/MS (C₄7H₅₃N₅O4) 752 [M+H]⁺; RT 1.17 (Method B)

Préparation 6h: A-[4-(Benzyloxy)phenyl]-A^r-butyl-l,2-dimethyl-5-{7-[(3S)-3(morpholin-4-ylmethyI)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-W-pyrrole-3-carboxamide

Step A: N-[4-(benzyloxy)phenyl]-N-butyl-l,2-dimethyl-5-{7-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,·4-tetrahydroisoquinoline-2-carbonyl]-2-(trifluoroacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxamide

A solution of tetrahydrofuran/ water (5:1, 7 mL) was degassed for 20 min. To a mixture of the boronate ester from Préparation 4i (246 mg, 0.49 mmol) and the bromide from Préparation lha (332.78 mg, 0.59 mmol) followed by 7mL of the stock solution. This was degassed for a further 5 min and to this solution was added césium carbonate (319.05 mg, 0.98 mmol, 2 eq) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(ii) (17.33 mg, 0.02 mmol, 0.05 eq) and then heated to 95 °C in the microwave for 40 min. The reaction was diluted in ethyl acetate and washed with brine. The organic extract was dried over magnésium sulfate and concentrated in vacuo, and adsorbed onto isolute and purified on CombiFlash (12 g silica, dichloromethane to 4% methanol in dichloromethane).

LC/MS (C₅oH₅4F₃N₅05) 862 [M+H]⁺; RT 1.53 (Method B) . ” ~ f ’5j ' '

Ü .. j.l j. 4/.

- 7l Step B: N-[4-(benzyloxy)phenyl]-N-butyl-l,2-dimethyl-5-{7-[(3S)-3-(morpholin-4ylmethy 1)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6yl}-lH-pyrrole-3-carboxamide

To a solution of the product from Step A (138 mg, 0.16 mmol) in éthanol (6 mL) was added a solution of potassium carbonate (132.75 mg, 0.96 mmol) in water (1.2 mL) and the mixture was allowed to stir at reflux for 1 h. The reaction was allowed to cool to ambient température and the organic solvent was concentrated in vacuo. The solution left behind was washed with Ethyl Acetate. The organic phase was washed with water and saturated sodium chloride. The organic extract was dried over magnésium sulfate and concentrated in vacuo. The product was used directly in the next step assuming quantitative transformation.

LC/MS (C48H55N5O4) 766 [M+H]⁺; RT 1.23 (Method B)

Préparation 7aa: A^r-[4-(Benzyloxy)phenyl]-N-methyl-3-{6-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lfi^r-isoindol-5-yl}-

5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: tert-Butyl 5-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2-carboxylate

A mixture of bromide from Préparation le (845 mg, 1.45 mmol) , the boronic ester from Préparation 4a (886 mg, 1.82 mmol) and césium carbonate (991 mg, 3.04 mmol) in THF (9.0 mL) and water (3.6 mL) is degassed by purging with nitrogen, followed by bubbling nitrogen through for 5 min. The mixture is heated to 60 C, at which point the PdCl₂(AtaPhos)₂ catalyst (54 mg, 0.08 mmol) is added and the reaction is allowed to stir for 3 h.

The mixture is allowed to cool to ambient température, then diluted with ethyl acetate, and washed sequentially with water and brine. The organic phase is dried over magnésium sulphate, and concentrated in vacuo.

-72The crude material was purified on by flash column chromatography (40 g silica; dichloromethane to 5 % MeOH/dichloromethane) to afford the product as a glassy solid.

LC/MS (C5iH₅7N₅O₆) 836 [M+H]⁺; RT 1.53 (Method B)

Step B: N-[4-(Benzyloxy)phenyl]-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

To a stirred solution of the product from Step A (850 mg, 1.02 mmol) in dichloromethane (20 mL) is added trifluoroacetic acid (5 mL) and the mixture is stirred for for 1 h. Water is added, followed by 2N aqueous sodium hydroxide solution until the aqueous phase was basic. The organic phase is then separated, dried over magnésium sulphate, and concentrated in vacuo to afford the product as a solid.

LC/MS (C46H49N5O4) 736 [M+H]⁺; RT 1.12 (Method B)

Préparation 7ab: A^r-[4-(BenzyIoxy)phenyl]-A'-methyl-3-{6-[(3A)-3-inethyI-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-LS^r-isoindol-5-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide; trifluoroacetic acid sait

Step A: tert-Butyl5-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

2,3-dihydro-lH-isoindole-2-carboxylate

A mixture of THF (20 mL) and water (8 mL) is degassed by multiple évacuation / nitrogen purge cycles and bubbling nitrogen through the mix. 20 mL of this mixture is subsequently added via syringe to a mixture of the bromide from Préparation lf (0.88g, 1.87 mmol), the boronic ester from Préparation 4a (1.09 g, 2.25 mmol) and césium carbonate (1.22 g, 3.74 mmol) under nitrogen. PdC12(Ata-Phos)2 (66 mg, 0.09 mmol) is then added and the reaction is immediately heated under microwave irradiation at 95°C for 20 min.

The reaction mixture is diluted with ethyl acetate (100 mL) and sequentially washed with water (2 x 50 mL), then saturated NaCl (aq) (2 x 50 mL), dried over magnésium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash

- ; t

I

chromatography vCombiflash, 80g, eluting with gradient 0 to 80% ethyl acetate in hexane) to afford the p: et as a foam.

LC/MS (C47H Os) 751 [M+H]⁺; RT 1.61 (Method B)

Step B: N-[4-(. zyloxy)phenyl]-N-methyl-3-{6-[(3R)-3-methyl-l,2,3,45 tetrahydroisoqv. .oline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide; trifluoroacetic acid sait

To a solution o^c product from Step A (152 mg, 0.20 mmol) in dichloromethane (3 mL) is added trifluo cetic acid (0.7 mL) and the reaction is stirred at ambient température for ca 16 h. Solv t was removed in vacuo and the resulting solid is triturated with ether collected by fiL ion.

LC/MS (C₄₂H42N₄O3) 651 [M+H]⁺; RT 2.39 (Method A)

I

Préparation 7ba: A-(4-BenzyIoxyphenyl)-N,l,2-trimethyl-5-[6-[(3S)-3- (morpholinomt iyl)-3,4-dihydro-177-isoquinoline-2-carbonyl]isoindolin-5-yl]pyrrole- j 3-carboxamide hydrochloride

Step A: tert-Butyl 5-bromo-6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-lH-isoquinoline-

2-carbonyl]isoindoline-2-carboxylate

6-Bromo-2-teri-butoxycarbonyl-isoindoline-5-carboxylic acid (0.70 g), TBTU (0.823 g) and DMAP (25 mg) was dissolved dichloromethane (35 ml) and diisopropylethylamine (1.75 ml) was added. After 3 minutes stirring at room température 4-[[(3S)-l,2,3,420 tetrahydroisoquinolin-3-yl]methyl]morpholine hydrochloride (0.656 g) was added and stirred for lh. After the completition of the reaction it was diluted with dichloromethane (100 ml) and washed with water (50 ml), dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography over silicagel (dichloromethane / methanol, gradient 1-10%) to give the title compound.

High-resolution mass (ESI+):

Empirical formula: C₂8H3₄BrN3O₄

-74[M+H]⁺ calculated: 556.1813 [M+H]⁺ measured: 556.1790

IR v: C-H: 2930 cm>00: 1697, 1635 cm¹; C-O-C: 1113 cm¹

Step B: tert-Butyl 5-[4-[(4-benzyloxyphenyl)-methyl-carbamoyl]-l,5-dimethyl-pyrrol-2yl]-6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-lH-isoquinoline-2-carbonyl]isoindoline-

2- carboxylate

The product from Step A (284 mg, 0.51 mmol) and A-(4-benzyloxyphenyl)-A,l,2trimethyl-pyrrole-3-carboxamide (205 mg, 0.61 mmol) from Step C of Préparation 4b were dissolved in dimethylacetamide (5 mL) then nitrogen was bubbled through the solution for 5 min. Potassium acetate (0.11 g, 1.12 mmol) and bis(triphenylphosphine)palladium(II) dichloride (20 mg) were added to the mixture then it was heated up to 140 °C then after 20 min stirring water (20 pL) was added. Stirring at 140 °C under nitrogen atmosphère was continued for additional 16 hours. The reaction mixture was allowed to cool to room température then evaporated. The residue was partitioned between dichloromethane (50 mL) and water (10 mL). The organic phase was washed with water (10 mL), dried over Na₂SO4 and evaporated. The crude product was purified by flash chromatography over silicagel (dichloromethane / methanol, gradient 1-10%) to give the title compound.

Step C: N-(4-benzyloxyphenyl)-N,l,2-trimethyl-5-[6-[(3S)-3-(morpholinomethyl)-3,4dihydro-lH-isoquinoline-2-carbonyl]isoindolin-5-yl]pyrrole-3-carboxamide hydrochloride

The product from Step B (140 mg) was stirred in a 4M HCl in dioxane (15 ml) solution for 30 min at room température. After the completition of the reaction ail the solvents were removed to yield 170 mg of the title product.

Préparation 7bb: A'-|4-(Benzyloxy)phenyl|-.V,l,2-triinethyl-5-{6-[(3/?)-3-inethyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyI]-2,3-dihydro- l//-isoindol-5-yI}-l//-pyrroIe-

3- carboxamide

-75Step A: tert-Butyl 5-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyl-lHpyrrol-2-yl)-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydrolH-isoindole-2-carboxylate

A mixture of A-[4-(Benzyloxy)phenyl]-A,l,2-trimethyl-lH-pyrrole-3-carboxamide from Step C of Préparation 4b (150 mg, 0.45 mmol), the bromide from Préparation lf (317 mg, 0.67 mmol), potassium acetate (88 mg, 0.9 mmol) in dimethylacetamide (2 mL) is degassed by bubbling with nitrogen gas for 20 min. Bis(triphenylphosphine)palladium dichloride (31.5 mg, 0.04 mmol) is added, and the reaction is heated at 144 °C. Over the next 8 h, 2 further 0.1 eq portions of bis(triphenylphosphinepalladium dichloride are added. The reaction is then left stirring for ca 16 h. The reaction is allowed to cool to ambient température, and is concentrated in vacuo. The residue is partitioned between ethyl acetate and water, separated, and the organic phase is washed with water, dried (magnésium sulphate), and concentrated in vacuo. The crude material is purified by flash column chromatography (24 g silica, isohexane to ethyl acetate gradient) to afford the desired product.

LC/MS (C45H48N4O5) 725 [M+H]⁺; RT 1.57 (Method B)

Step B: N-[4-(Benzyloxy)phenyl]-N,l,2-trimethyl-5-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-lH-pyrrole-3carboxamide

To a solution of the product from Step A (260 mg, 0.36 mmol) in dichloromethane (5 mL) is added trifluoroacetic acid (1 mL) and the mixture is stirred at ambient température for ca 16 h. The mixture is partitioned between water and dichloromethane, and basified with IM aqueous sodium hydroxide. The organic phase is dried (magnésium sulphate), evaporated, and purified on CombiFlash (12 g silica, dichloromethane to 5% methanol/dichloromethane) to afford the product as a glassy solid.

LC/MS (C40H40N4O3) 625 [M+H]⁺; RT 1.20 (Method B)

-7610

Préparation 7fc (morpholinomei yl]indolizine-l-c

Step A: N-(4-Bet:

Indolizine-1 -carbo : ¹ mixture (40/40 ir? 2 and the mixture ' the acyl chloriC. / dichloromethane (_ and triethylamine ambient temperatuï fc zy!oxyphenyI)-A-methyl-3-[6-[(3S)-3,uro-l//-isoquinoline-2-carbonyl |isoindolin-5ydrochloride ¹ - ^yl)-N-methyl-indolizine~l-carboxamide (0.4 g, 5.6 mmol) was dissolved in dichloromethane/THF ‘ ;hloro-N,M2-trimethyl-1-propenylamine (0.8 mL) was added nom température for 10 minutes. After the completion of the mixture was evaporated and redissolved in dry azyloxy-A-methylaniline hydrochloride (1.67 g, 6.7 mmol) 6.75 mmol) were added and the reaction was stirred at

h. The solution was washed with saturated aqueous

NaHCO3 solution, anu bnut, then dried over Na₂SO4 and evaporated. The crude product was purified by fias raphy over silicagel (dichloromethane / methanol, gradient

1-10%) to give the ciesirt rarerial.

Step B: tert-Butyl 5 Hzyloxyphenyl)-methyl-carbamoyl]indolizin-3-yl]-6-[(3S)-3(morpholinomethy . <'>-lH-isoquinoline-2-carbonyl]isoindoline-2-carboxylate

The compound of Préparation le (278 mg, 0.5 mmol) and the product from Step A (240 mg, 0.70 mmol) we ,d in dimethylacetamide (5 mL) then nitrogen was bubbled through the solution for 5 min. Potassium acetate (0.11 g, 1.12 mmol) and bis(triphenylphosphinc)pal.;.jium(II) dichloride (20 mg) were added to the mixture, it was heated to 110 °C then aftc: .20 min stirring water (20 pL) was added. Stirring at 110 °C under a nitrogen atmosphère was continued for additional 5 hours. The reaction mixture was allowed to cool to ambient température then evaporated. The residue was dissolved in THF, filtered through a pad of Celite and after removal of solvent by évaporation the crude product was purified by préparative HPLC (H₂O-TFA/acetonitrile; gradient elution). The pH of the appropriate combined fractions was adjusted to 10 by Na₂CO3 then the acetonitrile was removed under reduced pressure. The precipitated solid was filtered then dried to yield the title compound.

Step C: N-(4-Benzyloxyphenyl)-N-methyl-3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro lH-isoquinoline-2-carbonyl]i3oindolin-5-yl]indolizine‘l-carboxamide hydrochloride

-77The product from Step B (167 mg) was stirred in a 4M HCl in dioxane (15 ml) solution for 30 min at room température. After the completition of the reaction ail the solvents were removed to afford the desired product.

Préparation 7fb: A-(4-Benzyloxyphenyl)-V-niethyl-3-[6-[(3Æ)-3-methyl-3,4dihydro-lÆ-isoquinoline-2-carbonyl]isoindolin-5-yl]indolizine-l-carboxamide hydrochloride

Step A: tert-Butyl 5-[l-[(4-benzyloxyphenyl)-methyl-carbamoyl]indolizin-3-yl]-6-[(3R)-3methyl-3,4-dihydro-lH-isoquinoline-2-carbonyl]isoindoline-2-carboxylate

The procedure is as in Step B of Préparation 7fa, replacing /m-Butyl 5-bromo-6-[(35)-3(morpholinomethyl)-3,4-dihydro-lH-isoquinoline-2-carbonyl]isoindoline-2-carboxylate with the compound of Préparation lf. The product is purifïed by préparative HPLC (H₂OTFA/acetonitrile; gradient elution).

Step B: N-(4-benzyloxyphenyl)-N-methyl-3-[6-[(3R)-3-methyl-3,4-dihydro-lHisoquinoline-2-carbonyl]isoindolin-5-yl]indolizine-l-carboxamide hydrochloride

The procedure is as in Step C of Préparation 7fa, replacing fôrr-butyl 5-(1-((4benzyloxyphenyl)-methyl-carbamoyl]indolizin-3-yl]-6-[(3S')-3-(morpholinomethyl)-3,4dihydro-177-isoquinoline-2-carbonyl]isoindoline-2-carboxylate with the product from Step A.

The following Examples are obtained using the compounds of the appropriate Préparations described above. When no spécifie procedure is detailed, the corresponding Example can be obtained by repeating the procedure described for analogues Examples (i.e. whose structure is close) detailed elsewhere in the spécification, choosing the appropriate starting materials and using the basic knowledge of the man skilled in the art.

- 78 Example 1: iert-Butyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholm-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl] -1,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is described in Step A of Préparation 6e.

LC/MS (C₄5H53N₅O₆) 760 [M+H]⁺; RT 1.25 (Method B)

Example 2: A^r-(4-Hydroxyphenyl)-A-methyl-3-{7-[(3S)-3-(morpholin-4ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] -1,2,3,4-tetrahydroisoquinolin-6yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide dihydrochloride

The procedure is described in Step B of Préparation 6e.

LC/MS (C₄oH4₅N₅0₄) 660 [M+H]⁺; RT 0.89 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄oH₄5N50₄ [M+H]⁺ calculated: 660.3544 [M+H]⁺ measured: 660.3522

Example 3: 3-[2-(Benzenesulfonyl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyI]-l,2,3,4-tetrahydroisoquinolin-6-yl]-/V-(4hydroxyphenyl)-A^r-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: 4-{N-methyl 3-[2-(benzenesulfonyl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl]-5,6,7,8tetrahydroindolizine-1 -amido}phenyl benzenesulfonate

To a solution of the product of Préparation 6e (35 mg, 0.05 mmol) in dichloromethane (1 mL) is added triethylamine (52 pL, 0.375 mmol) and the mixture is cooled to 0 °C. Benzenesulfonyl chloride (17 pL, 0.13 mmol) is added dropwise, and the résultant mixture

----* —

-79is stirred at 0 °C for 1 h. The reaction is diluted with dichloromethane, washed with IM aqueous sodium hydroxide solution, followed by brine, and dried over magnésium sulphate. The solvent is removed in vacuo, and the crude product is purified on CombiFlash (4 g silica; dichloromethane to 5% MeOH/dichloromethane).

LC/MS (C₅2H₅3N₅O₈S2) 798 [M-C₆H₅SO₂]·; RT 1.41 (Method B)

Step B: 3-[2-(Benzenesulfonyl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4hydroxyphenyl)-N-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The product from Step A is dissolved in methanol (2 mL), potassium hydroxide (10 eq) is added, and the résultant mixture is allowed to stir at ambient température for 7 h. Concentration in vacuo, and purification on CombiFlash (4 g silica; dichloromethane to 5% methanol/dichloromethane) affords the desired product as a solid.

LC/MS (C46H49N5O6S) 800 [M+H]⁺; RT 1.21 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O6S [M+H]⁺ calculated: 800.3476 [M+H]⁺ measured: 800.3485

Example 4:

A^T-(4-Hydroxyphenyl)-A-methyl-3-{7-[(3S)-3-(morpholin-4-

ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-phenylmethanesulfonyl- l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in the process of Example 3, replacing benzenesulfonyl chloride in Step A with phenylmethanesulfonyl chloride.

LC/MS (C47H₅iN₅O₆S) 814 [M+H]⁺; RT 1.23 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H51N5O6S

- 80[M+H]⁺ calculated: 814.3633 [M+H]⁺ measured: 814.3602

Example 5:

A^r-(4-Iiydroxyphenvl)-A-me4hyl-3-{7-[(3S')-3-(niorpholin-4-

ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(naphthaIene-2-sulfonyl)5 l,2,3,4-tetrahydroisoqumolin-6-yl}-5,6,7,8-tetrahydromdolizine-l-carboxamide

The procedure is as in the process of Example 3, replacing benzenesulfonyl chloride in Step A with naphthalene-2-sulfonyl chloride.

LC/MS (QoHsiNsOôS) 850 [M+H]⁺; RT 1.31 (Method B)

High-resolution mass (ESI+):

Empirical formula: C5oH₅iN₅0₆S [M+H]⁺ calculated: 850.3633 [M+H]⁺ measured: 850.3624

Example 6: /ert-Butvl 5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,415 tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lZi^r-isoindole-2-carboxylate

A solution of the product from Step A of Préparation 7aa (16 mg, 0.02 mmol) in éthanol (10 mL) is added to 10% Pd/C (catalytic amount) and the mixture is shaken under an atmosphère of hydrogen for ca 16 h. The mixture is filtered through celite, subsequently eluting with methanol, and removing the solvents under reduced pressure.

LC/MS (C44H51N5O6) 746 [M+H]⁺; RT 1.25 (Method B)

High-resolution mass (ESI+):

Empirical formula: C44H51N5O6 [M+H]⁺ calculated: 746.3912

aï ni

-8I [M+H]⁺ measureu. ,-ru.j909

Example 7: (4-Hydroxyphenyl)-A-methyl-3-{6-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,4-teliuhydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isomdol-5-yI}-

5,6,7,8-tetrahydroiniJizine-l-carboxamide; dihydrochloride sait

Example 6 (45 mg, 0.05 mmol) was dissolved in a minimal amount of methanol and to this was added 4M solntio of HCl in 1,4-dioxane (1 mL), and the mixture was allowed to stir at ambient temperam /or ca 1 hr. The reaction was then diluted with dry diethyl ether (ca 5 mL) and the precipbate was collected by filtration and washed with a minimum of cold diethyl ether to afford e product.

LC/MS (C39H43N5O4) 646 [M+H]⁺; RT 0.89 (Method B)

High-resolution mass (ESI+):

Empirical formula: C39H43N5O4 [M+H]⁺ calculated: 64o.3388 [M+H]⁺ measured: 646.3385

Example 8:

jV-(4-Hydroxyphenyl)-/V-methyl-3-{6-[(3S)-3-(morpholin-4-

ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-2,3-dihydroLff-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide; hydrochloride sait

Step A: N-(4-Hydroxyphenyl)-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-2,3-dihydro-lH-isoindol-5-yl}-

5,6,7,8-tetrahydroindolizine-l-carboxamide

To a solution of product obtained from Préparation 7aa (50 mg, 0.07 mmol) in dichloromethane (2 mL) was added V,Mdiisopropylethylamine (0.1 mmol) and the mixture was cooled to 0 °C. To the résultant solution was added dropwise 2-phenylacetyl chloride (0.102 mmol) and after 5 min the reaction was diluted with dichloromethane, and

-82washed sequentially with aqueous IM sodium hydroxide, and brine. The organic extract was dried over magnésium sulfate, filtered and concentrated in vacuo, adsorbed onto isolute, and purified by chromatography (CombiFlash Rf, 40 g RediSep™ silica cartridge) eluting in a gradient of iso-hexane to 25 % ethyl acetate. The residue was then dissolved in éthanol (5 mL) and to this was added 10% Pd/C (catalytic amount) and the mixture stirred under a hydrogen atmosphère for ca 16 h. The mixture was filtered through celite, subsequently eluting with methanol, and solvent was removed under reduced pressure. The residue was adsorbed onto isolute and purified by chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge) eluting in a gradient of dichloromethane to 5 % methanol in dichloromethane to afford the desired product.

LC/MS (C47H49N5O5) 764 [M+H]⁺; RT 1.18 (Method B)

Step B: N-(4-Hydroxyphenyl)-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-2,3-dihydro-lH-isoindol-5-yl}-

5,6,7,8-tetrahydroindolizine-l-carboxamide; hydrochloride sait

The product from Step A was dissolved in isopropyl alcohol (0.5 mL) and ethereal HCl (IM; 0.13 mL) was added. The mixture was stirred for 30 min, then concentrated in vacuo. Trituration of the residue with ether afforded the desired product as a solid.

LC/MS (C₄7H4₉N₅O5) 764 [M+H]⁺; RT 1.16 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H49N5O5 [M+H]⁺ calculated: 764.3806 [M+H]⁺measured: 764.3807

Example 9: ;V-(4-Ilydroxyphenvl)-A'-methyl-3-{6-[(3.S)-3-(inorphoIin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(3-phenylpropanoyl)-2,3dihydro-lZZ-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide hydrochloride

-83The procedure is as in Example 8, replacing 2-phenylacetyl chloride in Step A with 3phenylpropanoyl chloride.

LC/MS (C₄8H5iN₅O₅) 778 [M+H]⁺; RT 1.19 (Method B)

High-resolution mass (ESI+):

Empirical formula: Ο^Η₅ιΝ₅θ5 [M+H]⁺ calculated: 778.3963 [M+H]⁺ measured: 778.3973

Example 10: /V-(4-Hydroxyphenyl)-iV-methyl-3-{6-[(31?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-5,6,7,8- tetrahydroindolizine-l-carboxamide

The procedure is as described in Example 7, replacing Example 6 with product from Préparation 7ab.

LC/MS (C₃₅H36N₄O₃) 561 [M+H]⁺; RT 1.04

Example 11:

7V-(4-Hydroxyphenyl)-/V-methyl-3-{6-[(3S)-3-(morpholin-4-

ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-propanoyl-2,3-dihydro-117° isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide hydrochloride

Step A: N-[4-(Benzyloxy)phenyl]-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-propanoyl-2,3-dihydro-lH-isoindol-5-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

To a solution of the compound from Préparation 7aa (50 mg, 0.068 mmol) in dichloromethane (2 mL) is added DIPEA (17 uL, 0.10 mmol) and the mixture is cooled to 0 °C. Propionyl chloride (9 uL, 0.10 mmol) is added dropwise, and after 30 min the mixture is diluted with dichloromethane, washed sequentially with IM aqueous NaOH and brine, dried over magnésium sulphate, and concentrated in vacuo. Purification by flash

-84column chromatography (4 g silica; dichloromethane to 5% MeOH/dichloromethane) afforded the product as a glassy solid.

LC/MS (C₄9H₅₃N₅O₅) 792 [M+H]⁺; RT 1.30 (Method B)

Step B: N-(4-Hydroxyphenyl)-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-propanoyl-2,3-dihydro-lH-isoindol-5-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

A solution of the product from Step A (18.7 mg, 0.024 mmol) in éthanol (5 mL) is added to 10% Pd/C (catalytic amount) and the mixture is shaken under an atmosphère of hydrogen for ca 16 h. The mixture is filtered through celite, subsequently eluting with methanol, and removing the solvents under reduced pressure. The crude product is purified by flash column chromatography (4 g silica; dichloromethane to 5% MeOH/dichloromethane) to afford the desired product as a glassy solid.

LC/MS (C42H47N5O5) 702 [M+H]⁺; RT 1.08 (Method B)

Step C: N-(4-Hydroxyphenyl)-N-inethyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-propanoyl-2,3-dihydro-lH-isoindol-5-yl}-5,6,7,8tetrahydroindolizine-1 -carboxamide hydrochloride

The product from Step B is dissolved in isopropyl alcohol (0.5 mL) and ethereal HCl (IM; 0.13 mL) is added. The mixture is stirred for 30 min, then concentrated in vacuo. Trituration of the residue with ether afforded the desired product as a solid.

LC/MS (C42H47N5O5) 702 [M+H]⁺; RT 1.10 (Method B)

High-resolution mass (ESI+):

Empirical formula: C^PLnNsOs [M+H]⁺ calculated: 702.3650 [M+H]⁺ measured: 702.3684

	- 85 -
Example 12:	3-{2-Benzoyl-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro- l//-isoindol-5-vl}-.\-(4hydroxyphenyl )-A -methyl-5,6,7,8-t.etrahydroindolizine-1 -carboxamide hydrochloride

The procedure is as in Example 8, replacing 2-phenylacetyl chloride in Step A with benzoyl chloride.

LC/MS (C46H47N5O5) 750 [M+H]⁺; RT 1.17 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H47N5O5 [M+H]⁺ calculated: 750.3650 [M+H]⁺ measured: 750.3648

Example 13:

teri-Butyl 5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-

tetrahydroindolizin-3-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl ]-2,3-dihydro-lH-isoindole-2-carboxylate

The procedure is described in Example 6, replacing the product obtained in Step A of Préparation 7aa with the product obtained in Step A of Préparation 7ab.

LC/MS (C40H44N4O5) 661 [M+H]⁺; RT 1.42 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄oH44N₄05 [M+H]⁺ calculated: 661.3384 [M+H]⁺measured: 661.3352

Example 14:

A-(4-Hydroxyphenyl)-jV-methyl-3-{6-[(3R)-3-methyl-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-2,3-dihydro-lH-isoindol-5-yl}

5,6,7,8-tetrahydroindolizine-l-carboxamide

- 86-

The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 7ab.

LC/MS (C43H42N4O4) 679 [M+H]⁺; RT L31 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H4₂N₄O₄ [M+H]⁺ calculated: 679.3279 [M+H]⁺ measured: 679.3298

Example 15:

A^r-(4-Hydroxyphenyl)-2V-methyl-3-{6-[(3R)-3-methyl-l,2,3,4-

tetrahydroisoqumoline-2-carbonyl]-2-(3-phenylpropanoyl)-2,3-dihydro-l/7-isoindol-

5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 7ab, and replacing 2phenylacetyl chloride in Step A with 3-phenylpropanoyl chloride.

LC/MS (C44H44N4O4) 693 [M+H]⁺; RT 2.57 (Method A)

High-resolution mass (ES1+):

Empirical formula: C44H44N4O₄ [M+H]⁺ calculated: 693.3435 [M+H]⁺ measured: 693.3441

Example 16:

Phenyl 5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-

tetrahydroindolizin-3-yl}-6-[(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-ljT-isoindole-2-carboxylate hydrochloride

- 87 The procedure is as in Example 8, replacing 2-phenylacetyl chloride in Step A with phenyl chloroformate.

LC/MS (C₄₆H47N₅O₆) 766 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C4₆H₄7N5C>6 [M+H]⁺ calculated: 766.3599 [M+H]⁺ measured: 766.3602

Example 17: 2V-/eri-Butyl-5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2-carboxamide hydrochloride

Step A: 5-(l-{[4-(Benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8-tetrahydroindolizin-3yl)-N-tert-butyl-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindole-2-carboxamide

To a solution of the compound of Préparation 7aa (30 mg, 0.04 mmol) in dichloromethane (2 mL) is added DIPEA (10 uL, 0.06 mmol) and the mixture is cooled to 0 °C. tert-Butyl isocyanate (7 uL, 0.06 mmol) is added and the reaction is stirred for 10 min, then diluted with dichloromethane and washed sequentially with IM aqueous NaOH and brine. The organic phase is dried over magnésium sulphate, fïltered and concentrated in vacuo. The crude material is taken-up in dichloromethane, loaded onto isolute and purified on CombiFlash (4 g silica, dichloromethane to 5% methanol/ dichloromethane) to afford the desired product as a glassy solid that was used directly in the next step.

Step B: N-tert-Butyl-5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2-carboxamide

-88The product from Step A (25 mg) is dissolved in EtOH and to this is added 10% Pd/C (catalytic amount) and the mixture is allowed to stir under an atmosphère of hydrogen for ca 16 h. The reaction is filtered through celite, eluting with methanol and concentrated in vacuo to afford the desired product.

LC/MS (C44H₅2N₆O₅) 745 [M+H]⁺; RT 2.20 (Method A)

Step C: N-tert-Butyl-5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindclizin-3-yl}-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2-carboxamide hydrochloride

To a solution of the product from Step B in isopropyl alcohol (0.5 mL) is added ethereal HCl (IM; 0.17 mL, 0.17 mmol) and the mixture is stirred for 30 min. The solvent is removed in vacuo and trituration with ether affords the desired product as a solid.

LC/MS (C44H₅₂N₆O5) 745 [M+H]⁺; RT 1.10 (Method B)

High-resolution mass (ESI+):

Empirical formula: C^Hs^ôOs [M+H]⁺ calculated: 745.4072 [M+H]⁺ measured: 745.4081

Example 18:

3-[2-(EthanesulfonyI)-6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-l//-isoindol-5-yl]-ïV-(4hydroxyphenyl)-.V-methyl-5,6,7,8-tetrahydroindolizine-l-carboxainide hydrochloride

The procedure is as in Example 8, replacing 2-phenylacetyl chloride in Step A with ethanesulfonyl chloride.

LC/MS (C₄iH4₇N₅O₆S) 738 [M+H]⁺; RT 1.07 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H47N5O6S

-89[M+H]⁺ calculated: 738.3320 [M+H]⁺ measured: 738.3316

Example 19: 3-[2-(Benzenesulfonyl)-6-[(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4tetrahvdroisoquiiwline-2-carb(myl|-2.3-(lilivdro-l//-isoindol-5-yl|-A'-(4hydroxyphenyl)-2V-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide hydrochloride

The procedure is as in Example 8, replacing 2-phenylacetyl chloride in Step A with benzenesulfonyl chloride.

LC/MS (C₄5H47N₅O₆S) 786 [M+H]⁺; RT 1.16 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H47N5O6S [M+H]⁺ calculated: 786.3320 [M+H]⁺ measured: 786.3339

Example 20: 3-{2-Cyclopropanecarbonyl-6-[(3/?)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-LH-isoindol-5-yl}-iV-(4hydroxyphenyl)-Ai-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Step A and Step B of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 7ab, and replacing 2phenylacetyl chloride in Step A with cyclopropanecarbonyl chloride.

LC/MS (C39H40N4O4) 629.7 [M+H]⁺; RT 2.41 (Method A)

High-resolution mass (ESI+):

Empirical formula: C39H40N4O4 [M+H]⁺ calculated: 629.3122

-90[M+H]⁺ measured: 629.3129

Example 21: A-(4-Hydroxyphenyl)-A-methyl-3-{6-[(3S')-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylethanesulfonyl)-2,3dihydro-17?-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide hydrochloride

The procedure is as in Example 8, replacing 2-phenylacetyl chloride in Step A with 2phenylethane-l-sulfonyl chloride.

LC/MS (C₄7H₅iN₅O6S) 814 [M+H]⁺; RT 1.21 (Method B)

Example 22: iV-(4-HydroxyphenyI)-.V-niethvl-3-{6-[(3.S)-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(pyridine-3-sulfonyl)-2,3dihydro-lH-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide hydrochloride

The procedure is as in Example 8, replacing 2-phenylacetyl chloride in Step A with pyridine-3-sulfonyl chloride.

LC/MS (C₄₄H4₆N₆O₆S) 787 [M+H]⁺; RT 1.09 (Method B)

High-resolution mass (ESI+):

Empirical formula: C^HUôNôOôS [M+H]⁺ calculated: 787.3272 [M+H]⁺ measured: 787.3243

Example 23: 3- [2-(2-BenzyIpropanoy 1) -6- [(37?)-3-methyl-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lZ7-isoindol-5-yl]-7V-(4hydroxyphenyl)-V-metliyl-5,6,7.8-tetrahydroindolizine-l-carboxamide

- 9l Step A: N-[4-7^ . _Jxy_i/phenyl]-3-[2-(2-benzylpropanoyl)-6-[(3R)-3-methyl-l,2,3,4tetrahydroisoqi.......:)line-2 carbonyl]-2,3-dihydro-lH-isoindol-5-yl]-N-methyl-5,6,7,8tetrahydroindolizine-l-carboxamide

To a solution of 'be product from Préparation 7ab (52 mg, 0.07 mmol) in tetrahydrofuran (3 mL) was added AQV-diisopropylethylamine (37 pL, 0.21 mmol) and HBTU (27 mg, 0.07 mmol), followed by 2-methyl-3-phenylpropanoic acid (17 mg, 0.10 mmol). The reaction was stirred at ambient température for ca 16 h, then partitioned between ethyl acetate and w;> ^ried magnésium sulphate, and concentrated in vacuo. Purification by flash columr romamjraphy (silica; iso-hexane to ethyl acetate gradient) afforded the desired product.

LC/MS (C₅2H₅2N,O₄) 797 [M+H]⁺; RT 2.91 (Method A)

Step B: 3-[2-(2-Benzylpropanoyl)-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindol-5-yl]-N-(4-hydroxyphenyl)-N-methyl-5,6,7,8tetrahydroindolizine-l-carboxamide

The product from Step A was dissolved in éthanol (10 mL) and to this was added 10% Pd/C (catalytic amount) and the mixture was allowed to stir under an atmosphère of hydrogen for ca 16 h. The reaction was filtered through celite, eluting with methanol and concentrated in vacuo. Purification by flash column chromatography (silica; iso-hexane to ethyl actetate gradient) afforded the desired product.

LC/MS (C₄₅H₄₆N₄O₄) 707 [M+H]⁺; RT 2.64 (Method A)

High-resolution mass (ESI+):

Empirical formula: C^H^bLCL [M+H]⁺ calculated: 707.3592 [M+H]⁺ measured: 707.3600

-92Example 24: 3-(2-{2-[(4-Chlorophenyl)methyl]propanoyl}-6-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-177-isoindol-5-yl)-lV-(4hydroxyphenyl)-/V-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

To a solution of the product from Example 10 (20 mg, 0.03 mmol) in dichloromethane (3 ml) was added TEA (13 ul, 0.09 mmol), HATU (12 mg, 0.03 mmol) and the 3-(4chlorophenyl)-2-methylpropanoic acid (6 mg, 0.03 mmol), and stirred at ambient température for ca 16 h. The reaction was diluted with dichloromethane and washed with water, dried over magnésium sulphate, filtered and concentrated in vacuo. The crude material was purifïed by column chromatography in a gradient of dichloromethane to 10% methanol/dichloromethane.

LC/MS (C45H45N4O4CI) 741 [M+H]⁺; RT 2.71 (Method A)

High-resolution mass (ESI+):

Empirical formula: C45H45N4O4CI [M+H]⁺ calculated: 741.3202 [M+H]⁺ measured: 741.3246

Example 25: A-(4-Hydroxyphenyl)-A-methyl-3-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[(4-methylphenyl)methyl]propanoyl}-2,3dihydro-lH-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Example 23, replacing 2-methyl-3-phenylpropanoic acid in Step A with 2-methyl-3-(4-methylphenyl)propanoic acid.

LC/MS (C4₆H4₈N₄O4) 721 [M+H]⁺; RT 2.70 (Method A)

High-resolution mass (ESI+):

Empirical formula: C46H48N4O4 [M+H]⁺ calculated: 721.3748 [M+H]⁺measured: 721.3740 >1 Vf AT

Àλ .

-93Example 26: A-(4-Hydroxyphenyl)-A-methyl-3-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[4-(trifluoromethoxy)phenyl]acetyl}-2,3dihydro-lH-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Example 23, replacing 2-methyl-3-phenylpropanoic acid in Step A with 2-[4-(trifluoromethoxy)phenyl]acetic acid.

LC/MS (C44H41N4O5F3) 763 [M+H]⁺; RT 2.70 (Method A)

High-resolution mass (ESI+):

Empirical formula: C44H41N4O5F3 [M+H]⁺calculated: 763.3102 [M+H]⁺ measured: 763.3102

Example 27: V-(4-llydroxyphenyl)- V-methyl-3-{7-|(3//)-3-inethyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide; trifluoroacetic acid sait

Step A: tert-Butyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoylJ-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The product from Préparation 6ab (95 mg, 0.12 mmol) is dissolved in éthanol (5 mL) and to this is added 10% Pd/C (catalytic amount) and the mixture is allowed to stir under an atmosphère of hydrogen for ca 6 h. The reaction is filtered through celite, eluting with methanol and concentrated in vacuo to afford the desired product.

LC/MS (C41H46N4O5) 675 [M+H]⁺; RT 1.43 (Method B)

Step B: N-(4-Hydroxyphenyl)-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide; trifluoroacetic acid sait

-94The product from Step A is dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.1 mL) is added. After stirring at for ca. 16 h at ambient température the reaction is concentrated in vacuo and azeotroped with toluene (x3) to afford the desired product as the trifluoroacetic acid sait.

LC/MS (C36H38N4O3) 575 [M+H]⁺; RT 1.00 (Method B)

High-resolution mass (ESI+):

Empirical formula: C36H38N4O3 [M+H]⁺ calculated: 575.3017 [M+H]⁺ measured: 575.2998

Example 28: ïV-(4-Hydroxyphenyl)-A-methyl-3-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(pyridin-2-ylmethyl)-2,3-dihydro-lH-isoindol-

5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Step B of Example 29, replacing the compound from Step A with Example 10, and replacing cyclohexylacetaldehyde with pyridine-2-carbaldehyde.

LC/MS (C41H41N5O3) 652 [M+H]⁺; RT 1.06 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H41N5O3 [M+H]⁺ calculated: 652.3282 [M+H]⁺ measured: 652.3269

Example 29: 3-[2-(2-Cyclohexylethyl)-6-[(3R)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl] -2,3-dihydro- lH-isoindol-5-yl] -N- (4hydroxyphenyl)-A-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

-95Step A: N-[4-(Benzyloxy)phenyl]-N-methyl-3-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

To a solution of the compound of Step A of Préparation 7ab (150 mg, 0.20 mmol) in dichloromethane (5 mL) is added trifluoroacetic acid (0.5 mL) and the reaction is stirred for ca 16 h. The mixture is diluted with dichloromethane, washed with IN aqueous sodium hydroxide, dried (magnésium sulphate) and condensed under reduced pressure. Purification on CombiFlash (4 g silica, dichloromethane to 10% methanol/dichloromethane) afforded the desired product as a gum.

LC/MS (C42H42N4O3) 651 [M+H]⁺; RT 1.2 (Method B)

Step B: N-[4-(Benzyloxy)phenyl]-3-[2-(2-cyclohexylethyl)-6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl]-N-methyl-5,6,7,8tetrahydroindolizine-l-carboxamide

To a stirring solution of the product from Step A (57.5 mg, 0.088 mmol) in THF (2 mL) is added cyclohexylacetaldehyde (13.4 mg, 0.11 mmol) followed by sodium triacetoxyborohydride (22.5 mg, 0.106 mmol) and the reaction was stirred for ca 16 h. The mixture is concentrated under reduced pressure, and purified on CombiFlash (4 g silica, dichloromethane to 3% methanol/dichloromethane) to afford the desired product as a gum.

LC/MS (C₅oH₅6N₄0₃) 761 [M+H]⁺; RT 1.37 (Method B)

Step C: 3-[2-(2-Cyclohexylethyl)-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindol-5-yl]-N-(4-hydroxyphenyl)-N-methyl-5,6,7,8tetrahydroindolizine-l-carboxamide

To a solution of the product from Step B (13 mg, 0.019 mmol) in dichloromethane (2 mL), cooled to 0 °C, is added boron trichloride (2M solution in dichloromethane; 0.1 mL, 0.2 mmol). After 5 h the reaction is quenched by addition of methanol, and concentrated in vacuo. Purification by préparative HPLC afforded the desired product.

LC/MS (C₄3H₅oN₄03) 671 [M+H]⁺; RT 1.16 (Method B)

High-resolution mass (ESI+):

-96Empirical formula: C43H50N4O3 [M+H]⁺ calculated: 671.3956 [M+H]⁺measured: 671.3955

Example 30: A-(4-Hydroxyphenyl)-A-methyl-3-{6-[(37?)-3-methyl-l,2,3,4tetrahydroisoquh ’me-2-carbonyl]-2-(3-phenylpropyI)-2,3-dihydro-lH-isoindo!-5yl}-5,6,7,8-tetrahy(lroindolizine-l-carboxamide

The procedure is as described in Step B of Example 29, replacing the compound from Step A with Example 10, and replacing cyclohexylacetaldehyde with 3-phenylpropanal.

LC/MS (C44H46N4O3) 679 [M+H]⁺; RT 1.16 (Method B)

High-resolution mass (ESI+):

Empirical formula: C +4H46N4O3 [M+H]⁺ calculated: 679.3643 [M+H]⁺ measured: 679.3612

Example 31: A-(4-Hydroxyphenyl)-A-methyl-3-{6-[(3R)-3-methyl-l,2,3,415 tetrahydroisoquinoline-2-carbonyl]-2-{2-[2-(pyrazin-2-yi)-l,3-thiazol-4-yl]acetyl}-2,3dihydro-lH-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: N-[4-(benzyloxy)phenyl]-N-methyl-3-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[2-(pyrazin-2-yl)-l,3-thiazol-4-yl]acetyl}-2,3dihydro-lH-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

To a solution of the product from Préparation 7ab (50 mg, 0.07 mmol) in dichloromethane (3 ml) was added triethylamine (29.2 pL, 0.21 mmol) and HATU (27 mg, 0.07 mmol), followed by 2-[2-(pyrazin-2-yl)-l,3-thiazol-4-yl]acetic acid (14.46 mg, 0.07 mmol), and the mixture was stirred at ambient température for ca 16 h. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried over magnésium

F Ο λ fm 4

--4 lüK v A .*

-97sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica; dichloromethane to 5% methanol in dichloromethane gradient) afforded the desired product.

LC/MS (C₅iH47N₇O₄S) 854 [M+H]⁺; RT 2.77 (Method A)

Step B: N-(4-Hydroxyphenyl)-N-methyl-3-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[2-(pyrazin-2-yl)-l,3-thiazol-4-yl]acetyl}-2,3dihydro-lH-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

A solution of the product from Step A ( 1 eq, 46 mg) in dichloromethane (5 ml) was cooled to 0 °C and to this was added was added boron trichloride (IM in dichloromethane, 100 pL). The reaction was allowed to warm to ambient température for ca 16 h, and was then quenched with methanol and partitioned between dichloromethane and water. The organic extract was dried over magnésium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica; dichloromethane to 10% methanol in dichloromethane gradient) afforded the desired product.

LC/MS (C44H41N7O4S) 764 [M+H]⁺; RT 2.44 (Method A)

High-resolution mass (ESI+):

Empirical formula: C44H41N7O4S [M+H]⁺ calculated: 764.3014 [M+H]⁺ measured: 764.2994

Example 32: 3-[2-(3-Cyclohexylpropanoyl)-6-[(3R)-3-methyl-l,2,3,4tetrahydroiso(juinoline-2-carbonyl]-2,3-dihydro-I/Z-isoindol-5-yl]<V-(4hydroxyphenyI)-ïV-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: N-f4-(Benzyloxy)phenyl]-3-[2-(3-cyclohexylpropanoyl)-6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl]-N-methyl-5,6,7,8tetrahydroindolizine-l-carboxamide

- 98 To a solution of the compound from Préparation 7ab (52 mg, 0.066 mmol) in THF (3 mL) are added DIPEA (37 pL, 0.21 mmol) and HBTU (27 mg, 0.07 mmol) followed by 3cyclohexylpropionic acid (18 pL, 0.10 mmol) and the mixture is stirred at ambient température for ca 16 h.

The reaction is partitioned between water and ethyl acetate, separated, and the organic phase is dried (magnésium sulphate) and concentrated in vacuo. Purification by flash column chromatography on silica gel, eluting with a gradient of iso-hexane to ethyl acetate afforded the product as a gum.

LC/MS (C₅iH₅6N₄O4) 789 [M+H]⁺; RT 3.00 (Method A)

Step B: 3-[2-(3-Cyclohexylpropanoyl)-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-

2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl]-N-(4-hydroxyphenyl)-N-methyl-5,6,7,8tetrahydroindolizine-l-carboxamide

A solution of the product from Step A (50 mg, 0.06 mmol) in éthanol (10 mL) is added to Pd/C (catalytic), and the mixture is shaken under an atmosphère of hydrogen for ca 16 h. The mixture is filtered through celite, eluting with methanol, and then concentrated in vacuo. The crude material is purified by flash column chromatography on silica, eluting with a gradient of dichloromethane to 5% methanol/dichloromethane to afford the product as a solid.

LC/MS (C^HsoîLCfi) 699 [M+H]⁺; RT 2.76 (Method A)

High-resolution mass (ESI+):

Empirical formula: C44H50N4O4 [M+H]⁺ calculated: 699.3905 [M+H]⁺ measured: 699.3926

Example 33: 3-{2-Benzyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl j-2,3-dihydro-l//-isoindol-5-yl}-₁V-(4-hydroxyphenyl)-iV-inethyl-5,6,7,8tetrahydroindolizine-l-carboxamide

-99The procedure is as described in Step B of Example 29, replacing the compound from Step A with the compound from Example 10, and replacing cyclohexylacetaldehyde with benzaldehyde.

LC/MS (C42H42N4O3) 651 [M+H]⁺; RT 1.11 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H42N4O3 [M+H]⁺calculated: 651.3330 [M+H]⁺measured: 651.3300

Example 34: A-(4-Hydroxyphenyl)-A-methyl-3-{7-[(31?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-propanoyl-l,2,3,4-tetrahydroisoquinolin-6-yl}-

5,6,7,8-tetrahydroindoIizine-l-carboxamide

The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6ab, and replacing 2phenylacetyl chloride in Step A with propanoyl chloride.

LC/MS (C39H4.2N4.O4) 631 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C39H42N4O4 [M+H]⁺ calculated: 631.3279 [M+H]⁺ measured: 631.3252

Example 35: 3-{2-Benzoyl-7-|(3/?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-A-(4-hydroxyphenyl)-A-methyl-5,6,7,8tetrahy droindolizine-1 -carboxamide

- ιοο The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6ab, and replacing 2phenylacetyl chloride in Step A with benzoyl chloride.

LC/MS (C43H42N4O4) 679 [M+H]⁺; RT 1.31 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H42N4O4 [M+H]⁺ calculated: 679.3279 [M+H]⁺ measured: 679.3331

Example 36: A-(4-Hydroxyphenvl)-A^;-inethvl-3-{7-[(3/?)-3-inethyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4-tetrahydroisoquinolin-

6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6ab.

LC/MS (C₄₄H44N₄O4) 693 [M+H]⁺; RT 1.32 (Method B)

High-resolution mass (ESI+):

Empirical formula: C44H44N₄O₄ [M+H]⁺ calculated: 693.3435 [M+H]⁺ measured: 693.3447

Example 37: A-(4-Hydroxyphenyl)-A^?-inethyl-3-{7-[(3/?)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(3-phenylpropanoyl)-l,2,3,4O tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizme-l-carboxamide ► T ' Λ -W <* > /7 — -i wZlx U 4. ..

- 101 The procedure is as described in Step A of Exainple 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6ab, and replacing 2phenylacetyl chloride in Step A with 3-phenylpropanoyl chloride.

LC/MS (C45H46N4O4) 707 [M+H]⁺; RT 1.36 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H46N4O4 [M+H]⁺ calculated: 707.3592 [M+H]⁺ measured: 707.3557

Example 38: A-(4-lIydroxyphenyl)-V-methyl-3-{6-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-phenylmethanesulfonyl-2,3dihydro-LH-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine- 1-carboxamide

The procedure is as described in Step A of Example 8, replacing 2-phenylacetyl chloride in Step A with phenylmethanesulfonyl chloride.

LC/MS (C₄6H49N₅O₆S) 800 [M+H]⁺; RT 1.15 (Method B)

High-resolution mass (ES1+):

Empirical formula: C46H49N5O6S [M+H]⁺ calculated: 800.3476 [M+H]⁺ measured: 800.3487

Example 39: 3-[2-(Benzenesulfonyl)-7-[(37?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl]-/V-(4hydroxyphenyl)-/V-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

- 102The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa with the product from Préparation 6ab, and replacing 2-phenylacetyl chloride in Step A with benzenesulfonyl chloride.

LC/MS (C42H42N4O5S) 715 [M+H]⁺; RT 1.37 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H42N4O5S [M+H]⁺ calculated: 715.2949 [M+H]⁺ measured: 715.2937

Example 40:

iV-(4-HydroxyphenyI)-iV-methyl-3-{7-[(3R)-3-methyl-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2-phenylmethanesulfonyl-l,2,3,4tetrahydroisoquinolm-6-yl}-5,6,7,8-tetrahydroindolizine-l-earboxamide

The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa with the product from Préparation 6ab, and replacing 2-phenylacetyl chloride in Step A with phenylmethanesulfonyl chloride.

LC/MS (C43H44N4O5S) 729 [M+H]⁺; RT 1.37 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H44N4O5S [M+H]⁺ calculated: 729.3105 [M+H]⁺ measured: 729.3135

Example 41: A'-(4-lIvdroxyphenyl)-A-methyl-3-{7-[(3/?)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(naphthalene-2-sulfonyl)-l, 2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

- 103 The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa with the product from Préparation 6ab, and replacing 2-phenylacetyl chloride in Step A with naphthalene-2-sulfonyl chloride.

LC/MS (C46H44N4O5S) 765 [M+H]⁺; RT 1.44 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H44N4O5S [M+H]⁺ calculated: 765.3105 [M+H]⁺ measured: 765.3140

Example 42: Æ-(4-Hydroxyphenyl)-/V-methyl-3-{6-[(3S')-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-[2-(pyridin-3-yl)acetyl]-2,3dihydro-lH-isoindol-5-yl }-5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: N-[4-(benzyloxy)phenyl]-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(pyridin-3-yl)acetyl]-2,3-dihydro-lH-isoindol-5yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

To a solution of the product from Préparation 7aa (40 mg, 0.05 mmol) in DMF (2 mL) was added triethylamine (28 pL, 0.2 mmol), and HBTU (19 mg, 0.05 mmol) followed by 2(pyridin-3-yl)acetic acid hydrochloride (9.4 mg, 0.05 mmol), and the mixture was stirred at ambient température for 1 h. The reaction was concentrated in vacuo and directly used in the next step.

LC/MS (C53H54N6O5) no ionisation; RT 1.20 (Method B)

Step B: V-(4-IIydroxyphenyl)-;Vmiethy 1-3-{6-|(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(pyridin-3-yl)acetyl]-2,3-dihydro-LHisoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The product from Step A (25 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. To this was added boron trichloride (IM; 0.15 mL, 0.15 mmol) and the

- 104mixture was stirred at ambient température for 2 h. The reaction was poured onto ice/water and extracted with dichloromethane. The organic extract was washed with brine, dried over magnésium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (4 g silica; dichloromethane to 5% methanol/ dichloromethane) afforded the desired product.

LC/MS (C₄6H48N₆O₅) 765 [M+H]⁺; RT 0.95 (Method B)

High-resolution mass (ESl-v):

Empirical formula: C46H48N6O5 [M+2H]²⁺ calculated: 383.1916 [M+2H]²⁺ measured: 383.1952

Example 43: teri-Butyl 5-{l-[(4-hydroxyphenyl)(phenyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yI}-6-[(37?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-l//-isoindole-2-carboxylate

The procedure is described in Steps A and B of Example 44.

LC/MS (C45H46N4O5) 723 [M+H]⁺; RT 1.47 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H46N4O5 [M+H]⁺ calculated: 723.3541 [M+H]⁺ measured: 723.3546

Example 44: A-(4-Hydroxyphenyl)-3-{6-[(31?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-A-phenyl-5,6,7,8tetrahydroindolizine-1 -carboxamide

- 105 Step A: tert-Butyl 5-(l-{[4-(benzyloxy)phenyl](phenyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

2,3-dihydro-lH-isoindole-2-carboxylate

A mix of THF (20 mL) and water (8 mL) is degassed by multiple évacuation / nitrogen purge cycles and bubbling nitrogen through. 4 mL of this mixture is added via syringe to a mixture of the boronic ester from Préparation 4f (117 mg, 0.28 mmol), the bromide from Préparation lf (169 mg, 0.36 mmol) and césium carbonate (182 mg, 0.56 mmol). Nitrogen is bubbled through the mix for another 3 mins. Bis(di-tert-butyl(4dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mg, 5 mole%) is added and the reaction is immediately heated at 95 °C under microwave irradiation for 30 mins.

The reaction mixture is diluted with ethyl acetate (30 mL) and washed sequentially with water (2 x 30 mL) and saturated NaCl (aq) (1 x 50 mL), dried over magnésium sulphate, filtered and evaporated. The crude material is purified by flash chromatography (Combiflash, 12g silica, eluting with gradient 0 to 100% ethyl acetate in hexane) to afford the product as an oil.

LC/MS (C52H52N4O5) 813 [M+H]⁺; RT 1.66 (Method B)

Step B: tert-Butyl 5-{l-[(4-hydroxyphenyl)(phenyl)carbamoylJ-5,6,7,8tetrahydroindolizin-3-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

2,3-dihydro-lH-isoindole-2-carboxylate

A solution of the product from Step A (94 mg, 0.12 mmol) in éthanol (5 mL) is hydrogenated over 10% Pd/C catalyst under an atmosphère of hydrogen for ca 16 h. The mixture was filtered through celite, eluting with éthanol, and concentrated in vacuo. Purification by flash chromatography on silica gel (CombiFlash Rf, 4g SiO2 silica column) eluting with 0 to 100% ethyl acetate in hexane afforded the product as a solid.

LC/MS (C₄₅H₄6N₄O5) 723 [M+H]⁺; RT 1.47 (Method B)

Step C: N-(4-Hydroxyphenyl)-3-{6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-N-phenyl-5,6,7,8-tetrahydroindolizine-lcarboxamide : : . ' ' . Ύ I .1

- 106To a solution et . product from Step B (40 mg, 0.055 mmol) in anhydrous dichloromethane (4 mL·) under nitrogen is added trifluoroacetic acid (180 uL, 2.33 mmol) and the reaction ; . ed for ca 16 h. The mixture is diluted with dichloromethane (25 mL) and washed s. ntially with IM NaOH (aq) solution (20 mL) and saturated NaCl (aq) solution (20 ml... The organic phase is dried over sodium sulphate, filtered and evaporated. The crude material is purified by flash chromatography on silica gel (CombiFlash Rf, 4g, SilaSep column) eluting with 0 to 15% Methanol in dichloromethane to afford a glassy j 1 Trituration with diethyl ether and évaporation afforded the desired product as a solid.

LC/MS (C40H38N4O3) 523 [M+H]⁺; RT 1.08 (Method B)

High-resolution mass (ESI+):

Empirical formula: C40H38N4O3 [M+H]⁺calculated: 6z3.3017 [M+H]⁺ measured: 623.3028

Example 45: Phenyl 5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoIine-2carbonyl]-2,3-dihydro-l//-isoindole-2-carboxylate

The procedure is as in Step A of Example 8, replacing the product from Préparation 7aa with the product from Préparation 7ab, and replacing 2-phenylacetyl chloride with phenyl chloroformate.

LC/MS (C₄2H4oN₄0₅) 681 [M+H]⁺; RT 1.36 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H40N4O5 [M+H]⁺calculated: 681.3071 [M+H]⁺measured: 681.3057

... -- - — , ¹ Γρ . î \

- 107 -

Example 46:

Phenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-

tetrahydroindolizin-3-yI}-7-[(3Æ)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step A of Example 8, replacing the product from Préparation 7aa with the product from Préparation 6ab, and replacing 2-phenylacetyl chloride with phenyl chloroformate.

LC/MS (C43H42N4O5) 695 [M+H]⁺; RT 1.41 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H42N4O5 [M+H]⁺ calculated: 695.3228 [M+H]⁺ measured: 695.3193

Example 47: /c/Z-Butyl 6-{l-[(4-hydroxyphenyI)(methyi)carbamoyl]-5,6,7,8tetrahydroindolï zin-3-yl }-7 - [(31î)-3-methyl-1,2,3,4-tetrahy droisoquinoline-2carbonyI]-l,2,3,4-tetrahydroisoquinoline-2-carboxy!ate

Step A: tert-Butyl 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is described in Step A of Préparation 6ab.

LC/MS (C₄₈H₅2N₄O₅) 765 [M+H]⁺; RT 1.62 (Method B)

Step B: tert-Butyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate

A solution of the product from Step A (50 mg, 0.07 mmol) in éthanol (5 mL) is added to

Pd/C (catalytic), and the mixture is shaken under an atmosphère of hydrogen for ca 16 h.

- 108 The mixture is filtered through celite, eluting with methanol, and then concentrated in vacuo. The crude material is purified by flash column chromatography on silica, eluting with a gradient of dichloromethane to 5% methanol/dichloromethane to afford the product as a solid.

LC/MS (C41H46N4O5) 675 [M+H]⁺; RT 1.42 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H46N4O5 [M+H]⁺ calculated: 675.3541 [M+H]⁺measured: 675.3571

Example 48: A^r-ter/-Butyl-6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindoIizin-3-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl] -1,2,3,4-tetrahydroisoquinoline-2-carboxamide

The procedure is as in Step A of Example 8, replacing the product from Préparation 7aa with the product from Préparation 6ab, and replacing 2-phenylacetyl chloride with 2isocyanato-2-methylpropane.

LC/MS (C41H47N5O4) 674 [M+H]⁺; RT 1.33 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H47N5O4 [M+H]⁺ calculated: 674.3701 [M+H]⁺ measured: 674.3706

Example 49: 3-{2-[2-(4-Chlorophenoxy)acetyl]-6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-lV-(4hydroxyphenyl)-A-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide ^J , .. i _Lj A V- à .«t À ΕΈ

- 109Step A: N-[4-(Benzyloxy)phenyl]-3-{2-[2-(4-chlorophenoxy)acetyl]-6-[(3R)-3-metliyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-N-methyl-

5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Step A of Example 8, replacing the product from Préparation 7aa with the product from Préparation 7ab, and replacing 2-phenylacetyl chloride with 2-(4chlorophenoxy)acetyl chloride.

LC/MS (C50H47N4O5CI) 819 [M+Hf; RT 1.56 (Method B)

Step B: 3-{2-[2-(4-Chlorophenoxy)acetyl]-6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-N-(4-hydroxyphenyl)N-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Step B of Example 42, replacing with the product from Step A of Example 42 with the product from Step A of Example 49.

LC/MS (C43H41N4O5CI) 729 [M+H]⁺; RT 1.37 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H41N4O5CI [M+H]⁺ calculated: 729.2838 [M+H]⁺ measured: 729.2809

Example 50: 3-{2-[2-(3-Chlorophenoxy)acetyl]-6-[(3J?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyI]-2,3-dihydro-l£f-isoindol-5-yl}-A-(4hydroxyphenyl)-/V-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Example 49, replacing 2-(4-chlorophenoxy)acetyl chloride in Step A with 2-(3-chlorophenoxy)acetyl chloride.

LC/MS (C43H41N4O5CI) 729 [M+H]⁺; RT 1.37 (Method B)

High-resolution mass (ESI+):

- I ΙΟ Empirical formula: C43H41N4O5CI [M+H]⁺ calculated: 729.2838 [M+H]⁺ measured: 729.2871

Example 51:

A-(4-Hydroxyphenyl)-3-{2-[2-(4-methoxyphenyl)acetyl ]-6-[(3R)-

3-methvl-l.2,3.4-tetrahydroisoquinoliiie-2-carl)onyl|-2.3-dihvdro-l//-isoindol-5-yl }-Amethyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

High-resolution mass (ESI+):

Empirical formula: C44H44N4O5 [M+H]⁺ calculated: 709.3392 [M+H]⁺ measured: 709.3382

Example 52:

iV-(4-Hydroxyphenyl)-zV-methyl-3-{6-[(3R)-3-methyl-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2-(2-phenoxyacetyl)-2,3-dihydro-177-isoindol-5yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 7ab, and replacing 2phenylacetyl chloride in Step A with 2-phenoxyacetyl chloride.

LC/MS (C43H42N4O5) 695 [M+H]⁺; RT 1.31 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H₄₂N4O5 [M+H]⁺ calculated: 695.3228 [M+H]⁺ measured: 695.3252

- 111 Example 53: 3-{2-[2-(4-Cyanophenyl)acetyl]-7-[(31?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2 carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-A-(4hydroxyphenyl)-A-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Example 24, replacing the product from Example 10 with the product from Example 27, and replacing 3-(4-chlorophenyl)-2-methylpropanoic acid with 2-(4-cyanophenyl)acetic acid.

LC/MS (C₄5H4₃N₅O₄) 718 [M+H]⁺; RT 1.29

Example 54: 7V-(4-Hydroxyphenyl)4V-methyl-3-{7-[(31?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(4-methylphenyl)acetyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

LC/MS (C45H46N4O4) 707 [M+H]⁺; RT 2.65 (Method A)

High-resolution mass (ESI+):

Empirical formula: C45H46N4O4 [M+H]⁺ calculated: 707.3592 [M+H]⁺ measured: 707.3556

Example 55: 5-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-?7-methyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-

2-carbonyl]-2,3-dihydro-l//-isoindole-2-carboxamide

Step A: tert-Butyl 5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

2,3-dihydro-lH-isoindole-2-carboxylate

To a solution of the compound of Step A of Préparation 7ab (400 mg, 0.53 mmol) in éthanol (10 mL) is added 10% Pd/C (catalytic), and the mixture is stirred under an atmosphère of hydrogen for ca 16 h. The mixture is filtered through celite, concentrated

- 112 under reduced pressure, and purified by flash column chromatography on silica to afford the product as a glassy solid.

LC/MS (C₄oH44N₄0₅) 661 [M+H]⁺; RT 1.41 (Method B)

Step B: N-(4-Hydroxyphenyl)-N-methyl-3-{6-[(3R)-3-methyl-I,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide; trifluoroacetic acid sait

To a solution of the product from Step A (300 mg) in dichloromethane (5 mL) is added trifluoroacetic acid (excess) and the mixture is allowed to stir at ambient température for ca 16 h. The reaction is concentrated in vacuo and triturated with ether to afford the product as a solid.

LC/MS (C₃5H₃₆N₄O₃) 561 [M+H]⁺; RT 1.01 (Method B)

Step C: 5-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-6[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2carbonyl chloride

To a solution of the product from Step B (100 mg, 0.15 mmol) in dichloromethane (2 mL), cooled to 0 °C, is added DIPEA (61 uL, 0.37 mmol) followed by portion-wise addition of triphosgene (44 mg, 0.15 mmol). The reaction is allowed to warm to ambient température and stirred for 1 h, then partitioned between dichloromethane and IM aqueous HCl. The organic phase is dried over magnésium sulphate and concentrated in vacuo to afford the product as a mixture of trichloromethyl 5-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl} -6-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindole-2-carboxylate and 5-{l-[(4- hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-6-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2-carbonyl chloride that was used directly in the next step without further purification.

LC/MS (C₃₇H₃₅C1₃N₄O₅) 721 [M+H]⁺; RT 1.44, (C₃₆H3₅C1N₄O4) 623 [M+H]⁺; RT 1.32 (Method B)

- 113 Step D: 5-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-Nmethyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lHisoindole-2-carboxamide

To a solution of the product from Step C (50 mg, 0.07 mmol) in acetonitrile (2 mL) is added methylamine (2M in THF; 346 uL, 0.69 mmol) and DIPEA (61 uL, 0.31 mmol) and the mixture is stirred for ca 16 h. Solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water, the organic phase is dried over magnésium sulphate, and the solvent is removed in vacuo. The residue is dissolved in 1,4-dioxane (2 mL) and a IM aqueous solution of NaOH (5 mL) was added dropwise. After 1 h the mixture is diluted with water, acidified with IM aqueous HCl, and extracted with ethyl acetate. The organic extracts are dried over magnésium sulphate and concentrated under reduced pressure. Purification on CombiFlash (4 g silica, dichloromethane to 5% MeOH/dichloromethane) afforded the desired product as a solid.

LC/MS (C₃7H₃₉N₅O4) 618 [M+H]⁺; RT 2.27 (Method A)

High-resolution mass (ESI+):

Empirical formula: Ο₃7Η₃₉Ν₃Ο4 [M+H]⁺calculated: 618.3075 [M+H]⁺measured: 618.3069

Example 56: 3-[2-(Ethanesulfonyl)-7-[(31?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl]-/V-(4hydroxyphenyl)-A-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Step A and Step B of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6ab, and replacing 2phenylacetyl chloride in Step A with ethanesulfonyl chloride.

LC/MS (C₃₈H4₂N₄O₅S) 667 [M+H]⁺; RT 1.27 (Method B)

High-resolution mass (ESI+):

- H4Empirical formula: C38H42N4O5S [M+H]⁺ calculated: 667.2949 [M+H]⁺ measured: 667.2935

Example 57: 3-{2-Ethyl-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoqumoline-25 carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-7V-(4-hydroxyphenyl)-A-methyl-5,6,7,8tetrahydromdolizine-l-carboxamide

LC/MS (C38H42N4O3) 603 [M+H]⁺; RT 1.05 (Method B)

High-resolution mass (ESI+):

Empirical formula: C38H42N4O3 [M+H]⁺ calculated: 603.3330 [M+H]⁺ measured: 603.3270

Example 58: 4-Aminophenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

Step A: 4-nitrophenyl 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-7-[(3 R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonylJ- l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of the product from Préparation 7ab (43 mg, 0.07 mmol) in dichloromethane (5 mL) was added 4-nitrophenyl chloroformate (18 mg, 0.09 mmol) and allowed to stir at ambient température ca 16 h. The reaction was diluted with dichloromethane and washed with IN HCl, NaHCCfi and brine. The organic phase was dried over magnésium sulphate, filtered and concentrated in vacuo, and taken forward assuming quantitative transformation.

LC/MS (C₅oH47N₅0₇) 830 [M+H]⁺; RT 1.58 (Method B)

- Il5Step B: 4-Aminophenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of the compound of Step A (54 mg, 0.07 mmol) in éthanol (10 mL) is added 10% Pd/C (catalytic), and the mixture is stirred under an atmosphère of hydrogen for ca 16 h. The reaction mixture was filtered through celite and concentrated under reduced pressure.

LC/MS (C43H43N5O5) 708 [M-H]'; RT 1.26 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H43N5O5 [M+H]⁺ calculated: 710.3337 [M+H]⁺ measured: 710.3302

Example 59: 4-Acetamidophenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]

-5,6,7,8-tetrahydroindolizin-3-yl]-7-[(32?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

4-Aminophenyl 6- {l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin3-yl}-7-[(37?)-3-methyl-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinoline-2-carboxylate [Example 58] (23 mg, 0.03 mmol) is dissolved in dichloromethane (5 mL) followed by the addition of DIPEA (0.17 mL, 1 mmol) and cooled to 0°C. Acetyl chloride (3 pL, 0.04 mmol) is added and the reaction mixture is stirred for ca 16 h at ambient température. Ammonia in methanol (7 N; 1 mL) is added, and the résultant mixture is washed with saturated NaHCO₃ solution and brine, dried over magnésium sulphate, filtered and concentrated. The product is purified by FlashChrom (24 g silica, dichloromethane to 5% methanol/ dichloromethane).

LC/MS (C₄5H4₅N₅O₆) 752 [M+H]⁺; RT 1.25 (Method B)

High-resolution mass (ESI+):

- Il6Empirical formula: C45H45N5O6 [M+H]⁺ calculaied: 752.3443 [M+H]⁺ measumd: 752.3461

Example 60:

5-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-

tetrahydroindc an-3-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-A’-phcmyl-2,3-dihydro-LH-isoindole-2-carboxamide

The procedure is as described in Step A and Step B of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 7ab, and replacing 2phenylacetyl chloride in Step A with phenyl isocyanate.

LC/MS (C₄₂H4iN₅O₄) 680 [M+H]⁺; RT 1.29 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H41N5O4 [M+H]⁺ calculated: 680.3231 [M+H]⁺ measured: 680.3225

Example 61:

A-Benzyl-5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-

tetrahydroindolizin-3-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-l//-isoindole-2-carboxamide

The procedure is as described in Step A and Step B of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 7ab, and replacing 2phenylacetyl chloride in Step A with benzyl isocyanate.

LC/MS (C₄3H₄₃N₅O₄) 694 [M+H]⁺; RT 1.28 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H43N5O4

- 117 [M+H]⁺ calculated: 694.3388 [M+H]⁺ measured: 694.3392

Example 62: Benzyl 5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl|-2,3-dihydro-l//-isoindole-2-carboxylate

A solution of the product obtained from Example 10 (53 mg, 0.08 mmol) in dichloromethane (5 mL) was cooled to 0 °C and to this was added N,Ndiisopropylethylamine (0.18 mmol) and benzyl chloroformate (14.7 mg, 0.09 mmol). The reaction was stirred at ambient température for 15 min, then diluted with dichloromethane and washed successively with IM aqueous sodium hydroxide, and brine. The organic extract was dried over magnésium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; gradient of dichloromethane to 5 % methanol in dichloromethane) afforded the desired product.

LC/MS (C43H42N4O5) 695 [M+H]⁺; RT 1.40 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄3H42N₄O5 [M+H]⁺ calculated: 695.3228 [M+H]⁺measured: 695.3241

Example 63: Phenyl 5-{4-[(4-hydroxyphenyI)(methyl)carbamoyI]-l,5dimethyl-LH-pyrrol-2-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindole-2-carboxylate

- Il8The procedure is as in Example 8, replacing the product from Préparation 7aa with the product from Préparation 7bb, and replacing 2-phenylacetyl chloride in Step A with phenyl chloroformate.

LC/MS (C40H38N4O5) 655 [M+H]⁺; RT 1.33 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄oH₃₈N₄05 [M+H]⁺ calculated: 655.2915 [M+H]⁺ measured: 655.2897

Example 64:

l//-pyrrolo[2,3-/?]pyridin-5-ylmethyl 5-{l-[(4-

hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-6-[(3J?)-3methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2carboxylate

Step A: 4-Nitrophenyl lH-pyrrolo[2,3-b]pyridin-5-ybnethyl carbonate

To a solution of l/7-pyrrolo[2,3-Z?]pyridin-5-ylmethanol (148 mg, 1 mmol) and N,Ndiisopropylethylamine (261 pL, 1.5 mmol) in DCM (10 mL) was added 4-nitrophenyl chloroformate (202 mg, 1 mmol) and the mixture was stirred at ambient température. After concentrating in vacuo, purification by flash column chromatography (silica; ethyl acetate) afforded the desired material.

LC/MS (C₁₅HnN₃O5) 314 [M+H]⁺; RT 1.19 (Method B)

Step B: lH-pyrrolo[2,3-b]pyridin-5-ylmethyl 5-{l-[(4hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindotizin-3-yl}-6-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindole-2-carboxylate

To a solution of the product from Example 10 (10 mg, 0.02 mmol) in tetrahydrofuran (1 ml) was added ALV-diisopropyiethylamine (11 pL, 0.06 mmol) followed by the product from Step A (6 mg, 0.02 mmol), and the mixture was stirred at ambient température for ca

m· Λ ; JÀ . ,· , ... a-

- Il916 h. After this time, further Α,Α-diisopropylethylamine (Il pL, 0.06 mmol) and product from Step A (6 mg, 0.02 mmol) were added to affect full conversion. Purification by flash column chromatography (silica; gradient of iso-hexane to ethyl acetate) followed by évaporation and trituration with diethyl ether afforded the desired product.

LC/MS (C44H₄2N₆O₅) 735 [M+H]⁺; RT 2.48 (Method A)

Example 65:

5-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-

tetrahydroindolizin-3-yl}-6-[(3Æ)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-A-[4-(4-methylpiperazin-l-yl)phenyl]-2,3-dihydro-lH-isoindole-2carboxamide

The procedure is as in Example 8, replacing the product from Préparation 7aa with the product from Préparation 7ab, and replacing 2-phenylacetyl chloride in Step A with l-(4isocyanatophenyl)-4-methylpiperazine.

LC/MS (C₄₇H₅iN₇O₄) 776 [M-H]'; RT 2.18 (Method A)

High-resolution mass (ESI+):

Empirical formula: C4₇H5iN₇O₄ [M+2H]²⁺ calculated: 389.7074 [M+2H]²⁺measured: 389.7107

Example 66: A-(4-Hydroxyphenyl)-A-methyl-3-{6-[(3Æ)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(3-phenylpyrrolidine-l-carbonyl)-2,3-dihydro l//-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-caiboxamide

Step A: 3-Phenylpyrrolidine-l-carbonyl chloride

A solution of the 3-phenylpyrrolidine hydrochloride (50 mg, 0.27 mmol) and N,Ndiisopropylethylamine (0.14 mL, 0.81 mmol) in dichloromethane (2 ml) was cooled to 0°C. To this was added triphosgene (81 mg, 0.27 mmol) and the mixture was stirred at ambient température. The reaction was subsequently diluted with water and the product extracted into dichloromethane, dried over magnésium sulphate and purified by flash column chromatography (silica; gradient of iso-hexane to 10% ethyl acetate in iso-hexane) to afford the desired product.

LC/MS (ChHi₂NOC1) 210 [M+H]⁺; RT 2.56 (Method A)

Step B: N-(4-Hydroxyphenyl)-N-methyl-3-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(3-phenylpyrrolidine-l-carbonyl)-2,3-dihydro-lHisoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as for Example 8, replacing the product from Préparation 7aa with the product from Préparation 7ab, and replacing 2-phenylacetyl chloride with the acid chloride obtained in Step A of Example 66.

LC/MS (C46H47N5O4) 734 [M+H]⁺; RT 2.68 (Method A)

High-resolution mass (ESI+):

Empirical formula: C46H47N5O4 [M+H]⁺ calculated: 734.3701 [M+H]⁺ measured: 734.3673

Example 67: A-(4-Hydroxyphenyl)-A-methyl-3-{7-[(31î)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl] -2-(3-phenylpy rrolidine- 1-carbonyl) -1,2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamîde

The procedure is as for Step A from Example 11, replacing the product from Préparation 7aa with the product from Example 27, and replacing propionyl chloride with the acid chloride obtained in Step A of Example 66.

LC/MS (C₄7H49N₅O₄) 748 [M+H]⁺; RT 2.71 (Method A)

High-resolution mass (ESI+):

Empirical formula: C47H49N5O4

- 121 [M+H]⁺ calculâtes. 748.3857 [M+H]⁺measurec 748.3815

Example 68: Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lfi^r-pyrrol-2-yl}-7-[(31?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is i.r Example 8, replacing the product from Préparation 7aa with the product from Préparation 6bb, and replacing 2-phenylacetyl chloride in Step A with phenyl chloroformate.

LC/MS (C41H40N4O5) 669 [M+H]⁺; RT 1.35 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H40N4O5 [M+H]⁺ calculated: 669.3071 [M-rH]⁺ measured: 659.3045

Example 69: Phenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl] -1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride

Step A: N-[4-(Benzyloxy)phenyl]-N-methyl-3-{7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide dihydrochloride

The product from Step A of Préparation 6aa (549 mg, 0.65 mmol) is dissolved in methanol (5 mL), then a solution of HCl in dioxane (4M; 10 mL) is added and the mixture is allowed to stir for ca 16 h. Ether is added, resulting in the précipitation of a solid which is collected by filtration and washed with ether to afford the desired product.

ΤΓ.“ Π ~ ·· J. s. ‘ „ J

- 122 LC/MS (C47H51N5O4) 750[M+H]⁺; RT l .09 (Method B)

Step______B; Phenyl 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The product from Step A (100 mg, 0.12 mmol) is dissolved in dichloromethane (5 mL) and to this is added DIPEA (174 uL, 1 mmol) and the solution cooled to 0°C. Phenyl chloroformate (18 uL, 0.14 mmol) is added and the mixture is stirred for 30 minutes before diluting with dichloromethane, washing sequentially with IM NaOH and brine, and then drying over magnésium sulphate. The solvent is removed in vacuo, and the residue is taken up in dichloromethane and purified on CombiFlash (12 g silica; dichloromethane to 5% methanol/dichloromethane) to afford the product as a solid.

LC/MS (C54H55N5O6) 870[M+H]⁺; RT 1.45 (Method B)

Step C: Phenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-

3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride

A solution of the product from Step B (96.6 mg, 0.11 mmol) in éthanol (5 mL) is added to a catalytic amount of 10% Pd/C, and the mixture is shaken under an atmosphère of hydrogen gas for ca 16 h. The mixture is filtered through celite and evaporated, whereby the residue is dissolved in a minimum amount of isopropyl alcohol. To the résultant solution is added ethereal HCl (IM, 0.5 mL), followed by ether, and the solid product is collected by vacuum filtration.

LC/MS (C47H4₉N₅O₆) 780[M+H]⁺; RT 1.21 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H₄9N₅O6 [M+H]⁺ calculated: 780.3756 [M+H]⁺measured: 780.3791

- 123 Example 70: A-(4-Hydroxyphenyl)-A-methyl-3-{7-[(3S)-3-(morpholin-4ylmethyl)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l, 2,3,4tetrahydroisoquinolm-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa.

LC/MS (C₄8H₅iN₅O₅) 778 [M+H]⁺; RT 1.14 (Method B)

Example 71: 6-{ l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-A-phenyl-l,2,3,4-tetrahydroisoquinoline-2-carboxamide

The procedure is as in Step A of Example 8, replacing the product from Préparation 7aa in

Step A with the product from Préparation 6aa, and replacing 2-phenylacetyl chloride with phenyl isocyanate.

LC/MS (C43H43N5O4) 694 [M+H]⁺; RT 1.31 (Method B)

High-resolution mass (ESI+):

Empirical formula: C^H^NsCU [M+H]⁺ calculated: 694.3388 [M+H]⁺ measured: 694.3356

Example 72: A-(4-Ilydroxy pheny l)-ïV-methy I-3-{6-[(3R)-3-methy 1-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylethyl)-2,3-dihydro-lH-isoindol-5-yl}-

5,6,7,8-tetrahydroindolizine-l-carboxamide

LC/MS (C₄3H44N4O3) 665 [M+H]+; RT 1.10 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H44N4O3 [M+HJ* calculated: 665.3486 [M+H]⁺ measured: 665.3477

Example 73:

Æ-Benzyl-6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8 tetrahydroindolizin-3-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoqmnoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxamide

The procedure is as in Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa, and replacing 2-phenylacetyl chloride with benzyl isocyanate.

LC/MS (C44H45N5O4) 708 [M+H]⁺; RT 1.3 (Method B)

High-resolution mass (ESI+):

Empirical formula: C44H45N5O4 [M+H]⁺ calculated: 708.3544 [M+H]⁺ measured: 708.3556

Example 74: 6-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7V-methyl-7-[(3Æ)-3-methyl-l,2,3,4-tetrahydroisoquinoline-

2-carbonyl ]-Æ-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxamide

Step A: 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8-tetrahydroindolizin-3-yl)-

7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carbonyl chloride

A solution of the product from Préparation 6ab (50 mg, 0.08 mmol) in dichloromethane (5 mL) was cooled to 0 °C and to this was added A,A-diisopropylethylamine (0.3 mmol) followed by triphosgene (22.3 mg, 0.08 mmol), and the mixture was allowed to stir at ambient température for 1 h. The reaction was partitioned between dichloromethane and IM aqueous HCl, and the organic extract was dried over magnésium sulphate. After

- 125 concentration in vacuo, the material was used directly in the next step assuming quantitative transformation.

LC/MS (C44H43N4O4CI) 727 [M+H]⁺; RT 1.54 (Method B)

Step B: 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8-tetrahydroindolizin-3-yl)N-methyl-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-N-phenyl-l,2,3,4tetrahydroisoquinoline-2-carboxamide

To a solution of product obtained from Step A (62 mg, 0.08 mmol) in Acetonitrile (5 mL) was added N,N-diisopropylethylamine (0.40 mmol) and TZ-methylaniline (80.4 mg, 0.75 mmol), and the mixture was stirred at ambient température for ca 16 h. The reaction mixture was diluted with ethyl acetate and successively washed with aqueous sodium bicarbonate, and brine. The organic extract was dried over magnésium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (4 g silica, dichloromethane to 5% methanol in dichloromethane) afforded the desired product.

LC/MS (C₅iH₅iN₅O₄) 798 [M+H]⁺; RT 1.56 (Method B)

Step C: 6-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-Nmethyl-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-N-phenyl-l,2,3,4tetrahydroisoquinoline-2-carboxamide

To a solution of product obtained in Step B (60 mg, 0.08 mmol) in éthanol (5 mL) was added 10% Pd/C (catalytic amount) and the mixture was shaken under an atmosphère of hydrogen for ca 16 h. The mixture was filtered through celite, subsequently eluting with methanol, and the solvent was removed in vacuo. Purification by flash column chromatography (4 g silica; dichloromethane to 5% methanol in dichloromethane) afforded the desired product as a solid.

LC/MS (C44H45N₅O₄) 708 [M+H]⁺; RT 1.35 (Method B)

High-resolution mass (ESI+):

Empirical formula: C44H45N5O4 [M+H]⁺ calculated: 708.3544

I

- 126 [M+H]⁺measv.ed: 708.3543

Example 75:

A-(4-Hydroxyphenyl)-/V,l,2-trimethyl-5-{7-[(37î)-3-methyl-

l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4- tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxamide

The procedure is as in Example 8, replacing the product from Préparation 7aa in Step A with the produ·-. oin Préparation 6bb.

LC/MS (C42H42N4O4) 667 [M+H]⁺; RT 1.27 (Method B)

I

Example 76: iV-ter/-Butyl-5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8f tetrahydroindolizin-3-yl}-6-[(37?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-210 carbonyl] -2,3-dihydro-lH-isoindole-2-carboxamide

I

The procedure is as in Example 8, replacing the product from Préparation 7aa with the | product from Préparation 7ab, and replacing 2-phenylacetyl chloride with fôrt-butyl isocyanate.

| LC/MS (C40H45N5O4) 660 [M+H]⁺; RT 1.29 (Method B)

High-resolution mass (ES1+):

Empirical formula: C40H45N5O4 [M+H]⁺ calculated: 660.3544 [M+H]⁺ measured: 660.3529

I

I Example 77: 6-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8- tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4m tetrahydroisoquinoline-2-carbonyl]-/V-phenyl-l,2,3,4-tetrahydroisoquinoline-2 carboxamide

I

- 127 The procedure is as in Example 8, replacing the product from Préparation 7aa with the product from Préparation 6aa, and replacing 2-phenylacetyl chloride with phenyl isocyanate.

LC/MS (C₄₇H₅₀N₆O₅) 779 [M+H]⁺; RT l.l2

Example 78:

7V-Benzyl-6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-

tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxamide

The procedure is as in Example 8, replacing the product from Préparation 7aa with the product from Préparation 6aa, and replacing 2-phenylacetyl chloride with benzyl isocyanate.

LC/MS (C₄₈H₅₂N₆O₅) 793 [M+H]⁺; RT 1.12

High-resolution mass (ESI+):

Empirical formula: QgHsaNôOs [M+H]⁺ calculated: 793.4072 [M+H]⁺ measured: 793.4067

Example 79: 6-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-vl}-V-inethyl-7-[(3/?)-3-methyl-1,2,3,4-tetrahydroisoquinoline-

2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxamide

The procedure is as in Example 74, replacing /V-methylaniline in Step B with Nbenzylmethylamine.

LC/MS (CsslLjNsCU) 632 [M+H]⁺; RT 1.16 (Method B)

High-resolution mass (ESI+):

Empirical formula: C3₈H₄]N5O₄

a

I

- 128 [M+H]⁺ calculated: 632.3231 [M+H]⁺ measured: 632.3232

Example 80: A-(4-Hydroxyphenyl)-A,l,2-trimethyl-5-{6-[(31?)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-2,3-dihydro-LH^r- isoindol-5-yl}-lH-pyrrole-3-carboxamide

Step A: N-[4-(Benzyloxy)phenyl]-N,l,2-trimethyl-5-{6-[(3R)-3-methyl-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-2,3-dihydro-lH-isoindol-5-yl}1 H-pyrrole-3-carboxamide

To a solution of the compound from Préparation 7bb (50 mg, 0.08 mmol) in dichloromethane (2 mL), cooled to 0 °C, are added DIPEA (28 uL, 0.16 mmol) and phenylacetyl chloride (13 uL, 0.10 mmol). After stirring for 10 min, the reaction is diluted with dichloromethane, sequentially washed with IM aqueous NaOH and brine, dried (magnésium sulphate), and concentrated in vacuo. The crude material is purified on CombiFlash (4 g silica, dichloromethane to 3% methanol/dichloromethane) to afford the 15 product.

LC/MS (C48H46N4O4) 743 [M+H]⁺; RT 1.47 (Method B)

Step B: N-(4-Hydroxyphenyl)-N,l,2-trimethyl-5-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-2,3-dihydro-lH-isoindol-5-yl}lH-pyrrole-3-carboxamide

A solution of the product from Step A (59 mg, 0.08 mmol) in éthanol was added to 10% Pd/C (catalytic) and the mixture was shaken at ambient température under an atmosphère of hydrogen for ca 16 h. Filtration through celite, évaporation of solvents under vacuum, and purification on CombiFlash (4 g silica, dichloromethane to 5% methanol/dichloromethane) afforded the desired product.

LC/MS (C41H40N4O4) 653 [M+H]⁺; RT 1.25 (Method B)

High-resolution mass (ESI+):

-Là

- 129Empirical formula: C^HwlSLO.;

[M+H]⁺calculated: 653.3122 [M+H]⁺ measured: 653.3137

Example 81: A-/er/-Butyl-5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-A^r-methyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-

2-carbonyl]-2,3-dihydro-lH-isoindole-2-carboxamide

The procedure is as in Example 74, replacing the product from Préparation 6ab in Step A with the product from Préparation 7ab, and replacing /V-methyl aniline in Step B with Nterr-butylmethylamine.

LC/MS (C41H47N5O4) 674 [M+H]⁺; RT 1.38 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H47N5O4 [M+H]⁺ calculated: 674.3701 [M+H]⁺ measured: 674.3720

Example 82: 5-{l-[(4-Hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-A-methyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-

2-carbonyl]-ïV-phenyl-2,3-dihydro-l//-isoindole-2-carboxamide

The procedure is as in Example 74, replacing the product from Préparation 6ab with the product from Préparation 7ab.

LC/MS (C43H43N5O4) 694 [M+H]⁺; RT 1.33 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H43N5O4

- 130[M+H]⁺ calculated: 694.3388 [M+H]⁺ measured: 694.3395

Example 83: A-(4-Hydroxyphenyl)-A-methyl-3-{6-[(3jR)-3-methyl-l,2,3,4tetrahydroisoqumoline-2-carbonyl]-2-(3-phenylazetidine-l-carbonyl)-2,3-dihydrolH-isoindol-5-yl}-5,6,7,8-tetrahydromdolizine-l-carboxamide

The procedure is as in Example 74, replacing the product from Préparation 7aa with the product from Préparation 7ab, and replacing TV-methylaniline with 3-phenylazetidine hydrochloride.

LC/MS (C45H45N5O4) 720 [M+H]⁺; RT 2.62 (Method A)

High-resolution mass (ESI+):

Empirical formula: C45H45N5O4 [M+H]⁺ calculated: 720.3544 [M+H]⁺ measured: 720.3536

Example 84: A-(4-Hydroxyphenyl)-A-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(3-phenylazetidine-l-carbonyl)-l,2,3,4tetrahydroisoqumolm-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Example 74, replacing the product from Préparation 7aa with the product from Préparation 6ab, and replacing A-methylaniline with 3-phenylazetidine hydrochloride.

LC/MS (C46H47N5O4) 734 [M+H]⁺; RT 2.66 (Method A)

High-resolution mass (ESI+):

Empirical formula: C46H47N5O4 [M+H]⁺ calculated: 734.3701

- I3l [M+H]⁺ measured: 73s .->668

Example 85: i Benzyl-5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3 yl}-A-methyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-

2-carbonyl]-2,3-dihydro-lZZ-isoindole-2-carboxamide

Step A: N-Benzyl-5-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-'^x-N-methyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro - i-lsoindole-2-carboxamide

The procedure is as in Step A and Step B of Example 74, replacing the product from Préparation 6ab in Step A with the product from Préparation 7ab, and replacing Nmethylaniline in Step B with V-benzylmethylamine.

LC/MS (C51H51N5O4) 798 [M+H]⁺; RT 1.55 (Method B)

Step B: N-Benzyl-5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-N-methyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindole-2-carboxamide

The product from Step A (46 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0 °C. To this was added boron trichloride (IM in dichloromethane; 0.18 mmol) dropwise. The reaction was stirred at ambient température for 1 h, then quenched by the addition of methanol (5 mL) and concentrated in vacuo. The crude material was partitioned between ethyl acetate and water, and the organic extract was washed with brine, dried (magnésium sulphate) and concentrated in vacuo. Purification by flash column chromatography (4 g silica, dichloromethane to 5% methanol in dichloromethane) afforded the desired product.

LC/MS (CmILsNsCM 708 [M+H]⁺; RT 1.36 (Method B)

High-resolution mass (ESI+):

Empirical formula: C44H45N5O4 [M+H]⁺ calculated: 708.3544

·. i ' -> -y \ fp-. «

G' ^îk · > i 7 :

' - «· V-;' f 1 *.

- 132 [M+H]⁺ measured: 708.3542

Example 86: 3-{2-[2-(2-Chlorophenoxy)acetyl]-6-[(37î)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-A-(4hydroxyphenyl)-A-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: N-[4-(Benzyloxy)phenyl]-3-{2-[2-(2-chlorophenoxy)acetyl]-6-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-N-methyl-

5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Step A of Example 11, replacing the product from Préparation 7aa with the product from Préparation 7ab, and replacing propionyl chloride with 2-(2chlorophenoxy)acetyl chloride.

LC/MS (C₅oH47N₄0₅C1) 819 [M+H]⁺; RT 1.53 (Method B)

Step B: 3-{2-[2-(2-Chlorophenoxy)acetyl]-6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-N-(4-hydroxyphenyl)N-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Step B of Example 85, replacing the product in Step A of Example 85 with the product of Step A in Example 86.

LC/MS (C43H41N4O5CI) 729 [M+H]⁺; RT 1.35 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H41N4O5CI [M+H]⁺ calculated: 729.2838 [M+H]⁺ measured: 729.2820

Example 87: \'-(4-Hydroxyphenyl)-A-methy 1-3-(6-|(3/?)-3-methy 1-1,2,3,4tetrahydroisoqumoline-2-carbonyl]-2-[2-(phenylamino)acetyl]-2,3-dihydro-l/Zisoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

- 133 The procedure is as described in Example 23, replacing 2-methyl-3-phenylpropanoic acid in Step A with 2-(phenylamino)acetic acid.

LC/MS (C43H43N5O4) 694 [M+H]⁺; RT 2.58 (Method A)

High-resolution mass (ESI+):

Empirical formula: C43H43N5O4 [M+H]⁺ calculated: 694.3388 [M+H]⁺ measured: 694.3357

Example 88:

Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-

dimethyl-l//-pyrrol-2-yl}-7-[(3.S)-3-(morpholin-4-ylniethyl)-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride

The procedure was as described for Example 69, replacing the compound from Préparation 6aa with the compound from Préparation 6ba.

LC/MS (C45H47N5O6) 754 [M+H]⁺; RT 1.17 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H47N5O6 [M+H]⁺ calculated: 754.3599 [M+H]⁺ measured: 754.3598

Example 89:

.V-(4-lIydroxyphenyl)-.V. l,2-trimethyl-5-{7-[(3S)-3-(morpholin-4-

ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrroIe-3-carboxamide

The procedure is as in Example 8, replacing the product from Préparation 7aa with the product from Préparation 6aa.

- 134LC/MS (C46H49N5O5) 752 [M+H]⁺; RT 1.10 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O5 [M+H]⁺ calculated: 752.3806 [M+H]⁺ measured: 752.3797

Example 90: /V-(4-Hydroxyphenyl)-iV-methyl-3-{7-[(31?)-3-methyI-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[(25)-2-phenylpropanoyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Example 23, replacing the product of 7ab with the product of Préparation 6ab, and replacing 2-methyl-3-phenylpropanoic acid in Step A with (25)-2phenylpropanoic acid.

LC/MS (C45H46N4O4) 707 [M+H]⁺; RT 2.65 (Method A)

High-resolution mass (ESI+):

Empirical formula: C₄₅H₄6N₄O₄ [M+H]⁺ calculated: 707.3592 [M+H]⁺ measured: 707.3589

Example 91: A-(4-Hydroxyphenyl)-A-methyl-3-{7-[(3R)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[(21?)-2-phenylpropanoyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Example 23, replacing the product of 7ab with the product of Préparation 6ab, and replacing 2-methyl-3-phenylpropanoic acid in Step A with (2R)-2phenylpropanoic acid.

LC/MS (C₄₅H4₆N₄O₄) 707 [M+H]⁺; RT 2.66 (Method A)

- 135 High-resolution mass (ESI+):

Empirical formula: C45H46N4O4 [M+H]⁺ calculated: 707.3592 [M+H]⁺ measured: 707.3589

Example 92: iV-(4-Hydroxyphenyl)-/V-methyl-3-{6-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[(phenylcarbamoyl)methyl]-2,3-dihydro-liy^risoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 7ab, and replacing 2-phenylacetyl chloride in Step A with 2-chloro-Æ-phenylacetamide

LC/MS (C43H43N5O4) 694 [M+H]⁺; RT 1.18 (Method B)

Example 93: Benzyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3Æ)-3-methyl-l, 2,3,4- tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 62, replacing the product from Example 10 with the product from Example 27.

LC/MS (C44H44N4O5) 709 [M+H]⁺; RT 1.41 (Method B)

High-resolution mass (ESI+):

Empirical formula: C44H44N₄O5 [M+H]⁺ calculated: 709.3384 [M+H]⁺ measured: 709.3387

Example * tetrahydroL tetrahydro- 136 Benzyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8izin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4ioline-2-carbonyI]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate ^roxyphenyl)-N-methyl-3-{7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,45 tetrahydroisoq:. noline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindo jne-l-carboxamide, trifluoroacetic acid sait

Step A: N-(4-1

To a solut’ .. i : a product from Step A of Préparation 6aa (43 mg, 0.065 mmol) in dichioromcL mL) is added trifluoroacetic acid (0.4 mL), and the mixture is stirred at ambient tempe re for ca 16 h. The solvent is removed in vacuo to afford the desired product which r sed directly in the next step without further purification.

LC/MS (C40H45N5O4) 660 [M+H]⁺; RT 0.87 (Method B)

Step B: Benzyl l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-

3-yl}-7-[(3S)-3 -(iaorpholÎn-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

1,2,3,4-tetrahyi . isoquinoline-2-carboxylate

I

I I I

I

The product fro: · Step A (43 mg, 0.06 mmol) is dissolved in dichloromethane (2 mL) and cooled to 0°C. To this is added triethylamine (42 uL, 0.3 mmol) followed by benzyl chloroformate (9 uL) and the mixture is stirred for 15 minutes. The reaction mixture is diluted with dichloromethane and washed sequentially with IM aqueous NaOH, and brine. The organics are dried over magnésium sulphate, filtered and concentrated and the residue taken-up in methanol. To the methanolic solution is added IM aqueous NaOH and the mixture is heated for 2 hours at 50°C. The reaction mixture is concentrated in vacuo, partitioned between ethyl acetate and brine, and the organics dried over magnésium sulphate. After évaporation, the crude product is purified by flash column chromatography over silica (4 g), eluting with a gradient of dichloromethane to 5% methanol/dichloromethane.

LC/MS (C48H₅iN₅O₆) 794 [M+H]⁺; RT 1.21 (Method B)

High-resolution mass (ESI+):

Empirical formula: C48H51N5O6

- 137 [M+H] ' calculated: 794.3912 [M+H]⁺ measured: 794.3908

Example 95: A-(4-Hydroxyphenyl)-/V-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylbutanoyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as described in Example 23, replacing the product of 7ab with the product of Préparation 6ab, and replacing 2-methyl-3-phenylpropanoic acid in Step A with 1phenylcyclopropane-1 -carboxylic acid.

LC/MS (C₄6H48N₄O₄) 721 [M+H]⁺; RT 2.72 (Method A)

High-resolution mass (ESI+):

Empirical formula: C₄6H₄8N₄O₄ [M+H]⁺ calculated: 721.3748 [M+H]⁺ measured: 721.3740

Example 96: /V-(4-Hydroxyphenyl)-A-methyl-3-{7-[(3jl?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(4-{[2-(morpholin-4yl)ethyl]amino}phenyl)acetyl]-l, 2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

Step A: Ethyl 2-(4-{[2-(morpholin-4-yl)ethyl]amino}phenyl)acetate

To a boiling tube was added ethyl 2-(4-bromophenyl)acetate (317 mg, 1.3 mmol), the 2(morpholin-4-yl)ethan-l-amine (257 pL, 1.96 mmol), potassium phosphate tribasic (386 mg, 1.82 mmol) and (2-biphenyl)di-iert-butylphosphine (0.1 mol%) followed by toluene (6 mL). The reaction was degassed with nitrogen followed by the addition of bis(dibenzylideneacetone)palladium(0) (0.05 mol%). The reaction was then heated at 100 °C under nitrogen for ca 6 h. The reaction was diluted with dichloromethane and washed

- 138with water. The organic extract was dried over magnésium sulphate, filtered and loaded onto a column for purification on silica in a gradient of iso-hexane to ethyl acetate.

LC/MS (C_]6H₂₄N₂O₃) 293 [M+H]⁺; RT 1.74 (Method A)

Step B: Sodium 2-(4-{[2-(morpholin-4-yl)ethyl]amino}phenyl)acetate

To a solution of the product obtained in Step A (61 mg, 0.21 mmol) in methanol (5 ml) was added 2M NaOH (21 pL, 0.42 mmol). The reaction was stirred at ambient température for ca 16 h. The reaction was then filtered through a cotton wool plug and concentrated in vacuo, then triturated with ether, filtered and solvents removed in vacuo.

LC/MS (Ci₄H₂₀N₂O₃) 265 [M+H]⁺; RT 0.50 (Method A)

Step C: N-[4-(Benzyloxy)phenyl]-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(4-{[2-(morpholin-4yl)ethyl]amino}phenyl)acetyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

To a solution of the product from Préparation 6ab (40 mg, 0.05 mmol) in dichloromethane (3 ml) was added A,A-diisopropylethylamine (20 uL, 0.15 mmol) and HBTU (20 mg, 0.5 mmol) followed by the sodium sait from Step B (23 mg, 0.8 mmol). The reaction was stirred at ambient température for ca 16 h. The reaction was diluted with dichloromethane and washed with water. The organic extract was dried over magnésium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica; dichloromethane to 5% methanol in dichloromethane) followed by trituration with ether afforded the desired product as a cream powder.

LC/MS (C₅₇H₆₂N₆O₅) 911 [M+H]⁺; RT 2.51 (Method A)

Step D: N-(4-Hydroxyphenyl)-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(4-{[2-(morpholin-4yl)ethyl]amino}phenyl)acetyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

A solution of the product from Step C (68 mg, 0.07 mmol) in éthanol (5 mL) was added to 10% Pd/C (catalytic) and the mixture was shaken at ambient température under an

- 139atmosphère of hydrogen for ca 16 h. Filtration through celite, évaporation of solvents under vacuum, and purification on CombiFlash (4 g silica, dichloromethane to 5% methanol in dichloromethane) afforded the desired product.

LC/MS (CsoHsôNôOj) 819 [M-H]‘; RT 2.21 (Method A)

Example 97:

.V-(4-Hydroxyphenyl)-A^;-methyl-3-{7-[(3/?)-3-methyl-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2-{2-[4-(4-methylpiperazin-l-yl)phenyl]acetyI}- l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Example 96, replacing 2-(morpholin-4-yl)ethan-1 -amine in Step A with 1-methylpiperazine.

LC/MS (C49H54N6O4) 791 [M+H]⁺; RT 2.20 (Method A)

High-resolution mass (ESI+):

Empirical formula: C49H54N6O4 [M+H]⁺ calculated: 791.4279 [M+H]⁺ measured: 791.4268

Example 98:

4-Methylphenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxyIate hydrochloride

The procedure was as described for Example 99, replacing 3-methylphenol in Step B with

4-methylphenol.

LC/MS (C₄₈H5iN₅O₆) 794 [M+H]⁺; RT 1.25 (Method B)

- 140 Example 99: 3-Methylphenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S')-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

Step A: 6-(l-{[4-(Benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8-tetrahydroindolizin-3yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carbonyl chloride

To a solution of the compound from Préparation 6aa (150 mg, 0.17 mmol) in dichloromethane (5 mL), cooled to 0 °C, is added DIPEA (89 uL, 0.51 mmol) followed by the portion-wise addition of triphosgene (52 mg, 0.17 mmol). After stirring for 1 h, the reaction mixture is partitioned between dichloromethane and IM aqueous HCl, and the phase is dried over magnésium sulphate, filtered and concentrated to afford a mixture of trichloromethyl 6-( 1 - {[4-(benzyloxy)phenyl](methyl)carbamoyl} -5,6,7,8tetr ahydroindolizin-3-yl)-7-[(35)-3-(morpholin-4-ylmethyl)-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate and 6-( 1 {[4-(benzyloxy)phenyl](methyl)carbamoyl )-5,6,7,8-tetrahydroindolizin-3-yl)-7-[(3S)-3(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4tetrahydroisoquinoline-2-carbonyl chloride that is used directly in the next step without further purification, and assuming quantitative transformation.

Step B: 3-Methylphenyl 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of the product from Step A (30 mg) in acetonitrile (5 ml) is added potassium carbonate (17 mg, 0.123 mmol) and 3-methylphenol (13 uL, 0.123 mmol) and the mixture is heated at 65°C for 2 hours. The reaction is cooled to room température, diluted in ethyl acetate and washed with brine. The organics are dried over magnésium sulphate, filtered and concentrated. The crude material is taken-up in dichloromethane, loaded onto isolute and purified on CombiFlash (4 g silica, dichloromethane to 5% methanol/dichloromethane).

- I4l Step C: 3-Methylphenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

A solution of the product from Step B (30 mg, 0.03 mmol) in éthanol is added to 10% Pd/C (catalytic) and the mixture is shaken under an atmosphère of hydrogen for ca 16 h. Filtration through celite, évaporation, and purification on CombiFlash (4 g silica, dichloromethane to 5% MeOH/dichloromethane) afforded the desired product . The appropriate fractions were combined and concentrated to obtain the desired product.

LC/MS (C₄8H₅iN₅O₆) 794 [M+H]⁺; RT 1.25 (Method B)

High-resolution mass (ESI+):

Empirical formula: C^Hsi NsOg [M+H]⁺ calculated: 794.3912 [M+H]⁺ measured: 794.3925

Example 100: 2-Methylphenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyI]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure was as described for Example 99, replacing 3-methylphenol in Step B with 2-methylphenol.

LC/MS (C₄8H₅₁N₅O₆) 794 [M+H]⁺; RT 1.25 (Method B)

High-resolution mass (ESI+):

Empirical formula: CjsEFiNsOô [M+H]⁺ calculated: 794.3912 [M+H]⁺ measured: 794.3877

	- 142 -
Example 101:	iV-(4-Hydroxyphenyl)-5-{2-[2-(4-methoxyphenyl)acetyl]-6-[(37î)-

3-methyl-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl ]-2,3-dihydro-lH-isoindol-5-yl}iV,l,2-trimethyl-l/7-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C42H42N4O5 [M+H]⁺ calculated: 683.3235 [M+H]⁺ measured: 683.3213

Example 102:

5-{2-[2-(4-Fluorophenyl)acetyl]-6-[(31?)-3-methyl-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-N-(4hydroxyphenyl)-ïV,l,2-trimethyl-lH^r-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C41H39FN4O4 [M+H]⁺ calculated: 671,3035 [M+H]⁺ measured: 671.3039

Example 103: lV-(4-Hydroxyphenyl)-A,l,2-trimethyl-5-{6-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenoxyacetyl)-2,3-dihydro-ljHisoindol-5-yl}-l//-pyrrole-3-carboxamidc

High-resolution mass (ESI+):

Empirical formula: C41H40N4O5 [M+H]⁺ calculated: 669.3079 [M+H]⁺ measured: 669.3084

- 143 Example 104: A-(4-hydroxyphenyl)-?/,l,2-trimethyl-5-{6-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenoxypropanoyl)-2,3-dihydro-H7isoindol-5-yl}-l#-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C42H42N4O5 [M+H]⁺ calculated: 683.3235 [M+H]⁺ measured: 683.3210

Example 105: 4-Chlorophenyl 5-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5· dimethyI-LH-pyrrol-2-yl}-6-[(3Æ)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindole-2-carboxylate

High-resolution mass (ESI+):

Empirical formula: C40H37CIN4O5 [M+H]⁺ calculated: 689.2532 [M+H]⁺ measured: 689.2539

Example 106: 4-Fluorophenyl 5-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-6-[(3Æ)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-l//-isoindole-2-carboxylate

High-resolution mass (ESI+):

Empirical formula: C4oH₃7pN₄05 [M+H]⁺ calculated: 673.2828 [M+H]⁺ measured: 673.2832

- 144 Example 107. 4-Methylphenyl 5-{4-[(4-hydroxyphenyl)(methyl)carbamoyI]l,5-dimethyl-LH-pyrrol-2-yl}-6-[(37?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl] -2,3-dihydro- LH-isoindole-2-carboxylate

High-resolution mass (ESI+):

Empirical formula: C41H40N4O5 [M+H]⁺ calculated: 669.3079 [M+H]⁺ measured: 669.3065

Example 108:

3-{2-[2-(4-{[2-(Dimethylamino)ethyl]amino}phenyl)acetyl]-7-

[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-/V-(4-hydroxyphenyl)-/V-methyl-5,6,7,8tetrahydroindolizine-l-carboxamide hydrochloride

The procedure is as in Example 96, replacing 2-(morpholin-4-yl)ethan-l-amine in Step A with (2-aminoethyl)dimethylamine.

LC/MS (C48H54N6O4) 777 [M-H]’; RT 2.20 (Method A)

Example 109:

Æ-(4-Hydroxyphenyl)-7V-methyl-3-{7-[(31?)-3-methyl-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2-(l-phenylcyclopropanecarbonyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: N-[4-(benzyloxy)phenyl]-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(l-phenylcyclopropanecarbonyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

To a solution of the product from Préparation 6ab (43 mg, 0.06 mmol) in dichloromethane (5 ml) was added Hunig’s Base (32 pL, 0.18 mmol) and HBTU (23 mg, 0.06 mmol) followed by 1-phenylcyclopropane-l-carboxylic acid (9 mg, 0.06 mmol), and stirred at ambient température for ca 16 h. The reaction was diluted with dichloromethane and

- 145 washed with water, followed by aqueous IM HCl and then brine. The organic extract was dried over magnésium sulfate, filtered and loaded onto a column and purified in ethyl acetate to obtain the desired product.

LC/MS (C53H52N4O4) 809 [M+H]⁺; RT 2.92 (Method A)

Step B: N-(4-HydroxyphenyÎ)-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(l-phenylcyclopropanecarbonyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

A solution of the product from Step A (47.6 mg, 0.06 mmol) in anhydrous dichloromethane (5 ml) was cooled to 0 °C and to this was added boron trichloride (IM in DCM, 120 pL, 0.12 mmol). The reaction was stirred at ambient température for ca 16 h. The reaction was quenched with methanol (5 mL), and the reaction was diluted with dichloromethane. The organic phase was washed with water, dried over magnésium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography in a gradient of dichloromethane to 5% methanol in dichloromethane followed by trituration with ether and dried in vacuo.

LC/MS (C46H46N4O4) 719 [M+H]⁺; RT 2.65 (Method A)

High-resolution mass (ESI+):

Empirical formula: C46H46N4O4 [M+H]⁺ calculated: 719.3592 [M+H]⁺ measured: 719.3556

Example 110: lV-Ethyl-5-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-6-[(3Æ)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl] -2,3-dihydro-1//-isoindole-2-carboxamide

High-resolution mass (ESI+):

Empirical formula: C36H39N5O4

- 146 ΙΜ ΜΙΓ c;. kdm Γ 082 [M+H]⁺me^r κό: ôv 078

Example 111 : V-Benzyl-5-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-1//· r yl}-6-[(3/?)-3-methvl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-?..' ¹ H-isoindole-2-carboxamide

High-resoluL τ iw 20 i+):

Empirical forr .Î41N5O4 [M+H]⁺ calculated: oo8.3239 [M+H]⁺ measured: 668.3203

Example 112: -{2-Acetyl-6-[(37?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2· carbonyl]-2,3 dih ^? lJ/-isoindol-5-yl}-A-(4-hydroxyphenyl)-A,l,2-trimethyl-lHpyrrole-3-car boxaam de

High-resolution mass (ESI+):

Empirical formula: C₃₅H36N₄O₄ [M+H]⁺calculated: 577.2817 [M+H]⁺ measured: 577.2782

Example 113:

A-(4-Hydroxyphenyl)-A-methyl-3-{7-[(32?)-3-methyl-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[(4-methylpiperazin-lyl)methyl]phenyl}acetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,820 tetrahydroindolizine-l-carboxamide

Step A: 2-{4-[(4-methylpiperazin-l-yl)methyl]phenyl}acetic acid

-Jt.

- 147 To a suspension of 4(bromomethyl)phenyl acetic acid (100 mg, 0.44 mmol) in acetonitrile (2 ml) was added potassium carbonate (126 mg, 0.88 mmol) and A-methylpiperazine (100 pL, 0.88 mmol), and the reaction stirred at ambient température for ca 16 h. The reaction was filtered and washed with ethyl acetate. The filtrate was basified with methanolic sodium hydroxide and then concentrated in vacuo. The crude material was dissolved in methanol and loaded onto a PE-ΑΧ column which had been pre-wetted with dichloromethane. The column was then washed with dichloromethane and methanol, and the product eluted with 10% formic acid/dichloromethane.

LC/MS (C14H20N2O2) 249 [M+H]⁺; RT 0.42 (Method A)

S/cp B: N-[4-(benzyloxy)phenyl]-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-(4-[(4-methylpiperazin-lyl)methyl]phenyl}acetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

To a solution of the product from Préparation 6ab (50 mg, 0.08 mmol) in dichloromethane (3 mL) was added triethylamine (56 pL, 0.4 mmol) and HBTU (30 mg, 0.08 mmol) followed by the acid obtained in Step A (30 mg, 0.1 mmol) in dichloromethane (2 mL). The reaction was stirred at ambient température for ca 2 h. The reaction was diluted with dichloromethane and washed with water, dried over magnésium sulphate, filtered and concentrated in vacuo. The reaction was purified by column chromatography on 10 g silica column in a gradient of dichloromethane to 5% methanol in dichloromethane.

LC/MS (C₅7H62N₆O4) 448 [M+2H]²⁺; RT 2.51 (Method A)

Step C: N-(4-Hydroxyphenyl)-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-{4-[(4-methylpiperazin-lyl)methyl]phenyl}acetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8tetrahydroindolizine-l-carboxamide

A solution of the product from Step B (44 mg, 0.05 mmol) in éthanol (10 mL) is added to 10% Pd/C (catalytic) and the mixture is shaken under an atmosphère of hydrogen for ca 16 h. Filtration through celite, évaporation, and purification on column chromatography (4 g

- 148 silica, dichloromethane to 5% methanol in dichloromethane) afforded the desired product.

Trituration with diethyl ether afforded the desired product.

LC/MS (C₅oH56N₆0₄) 803 [M-H]’; RT 2.20 (Method A)

High-resolution mass (ESI+):

Empirical formula: C50H56N6O4 [M+2H]²⁺ calculated: 403.2254 [M+2H]²⁺ measured: 403.2252

Example 114: Phenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-

2-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4- tetrahydroisoquinoline-2-carboxylate

A solution of the product obtained from Préparation 6cb (50 mg, 0.08 mmol) and N,Ndiisopropylethylamine (70 pL, 0.4 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0 °C. To this was added phenylchloroformate (11 pL, 0.09 mmol), and the mixture was stirred at ambient température for 15 min. The reaction was diluted with 15 dichloromethane, then washed with aqueous IM sodium hydroxide, and brine. The organic extract was dried over magnésium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (4 g silica, dichloromethane to 4% methanol in dichloromethane) afforded the desired product.

LC/MS (C41H40N4O4) 653 [M+H]⁺; RT 1.48 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H40N4O4 [M+H]⁺ calculated: 653.3122 [M+H]⁺ measured: 653.3159

- 149Example 115: Phenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-LH-pyrrol-

2-yl}-7-[(3S')-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]- l,2,3,4-tetrahydroisoquinoline-2-carboxyIate

The procedure is as in Ex ample 114, replacing the product from Préparation 6cb with the product from Préparation 6ca.

LC/MS (C45H47N5O5) 738 [M+H]⁺; RT 1.28 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H47N5O5 [M+H]⁺ calculated: 738.3650 [M+H]⁺ measured: 738.3655

Example 116: 7V-(4-Hydroxyphenyl)-5-{2-[3-(4-methoxyphenyl)propyl]-6-[(31î)-

3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-LH-isoindol-5-yl}-

N, 1,2-trimethyl-lH-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C43H46N4O4 [M+H]⁺ calculated: 683.3599 [M+H]⁺ measured: 683.3608

Example 117:

iV,l,2-trinmthyI-5-{7-[(3S')-3-(morpholin-4-ylmethyl)-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4-tetrahydroisoquinolin-

6-yl}-V-phenyl-l//-pyrrole-3-carboxamide

The procedure is as in Example 114, replacing the product from Préparation 6cb with the product from préparation 6ca, and replacing phenyl chloroformate with phenylacetyl chloride.

- 150LC/MS (C46H49N5O4) 736 [M+H]⁺; RT 1.23 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O4 [M+H]⁺ calculated: 736.3857 [M+H]⁺ measured: 736.3828

Example 118: 2V,l,2-Trimethyl-5-{7-[(32?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l, 2,3,4- tetrahydroisoquinolin6-yl}-.V-phenyl-l//-pyrrole-3-carboxaniide

The procedure is as in Example 114, replacing phenyl chloroformate with phenylacetyl chloride.

LC/MS (C42H42N4O3) 651 [M+H]⁺; RT 1.40 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H42N4O3 [M+H]⁺ calculated: 651.3330 [M+H]⁺ measured: 651.3344

Example 119: A^r,l,2-Trimethyl-5-{7-[(3R)-3-methyI-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-/V-phenyl-lHpyrrole-3-carboxamide hydrochloride

The product from Préparation 6cb (22 mg, 0.03 mmol) was dissolved in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate (10 mL). The organic phase was separated, dried over magnésium sulfate and concentrated in vacuo. The solid was then dissolved in methanol (2 mL) and to this was added IM HCl in diethyl ether (0.15 mL, 5 eq.), stirred for 30 min, and then concentrated in vacuo. The solid was then triturated in a

- 15Ï small amount of diethyl ether and the solids were isolated by filtration. They were washed with cold ether before being dried under vacuum for 1 h.

LC/MS (C34H36N4O2) 533 [M+H]⁺; RT 1.08 (Method B)

Example 120:

4-Fluorophenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl} -7 - [(3S)-3- (morpholin-4-yImethyl) -1,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa, and replacing 2phenylacetyl chloride in Step A with 4-fluorophenyl chloroformate.

LC/MS (C47H48N5O6F) 798 [M+H]⁺; RT 1.22 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H₄gN₅O₆F [M+H]⁺calculated: 798.3661 [M+H]⁺ measured: 798.3663

Example 121:

4-Methoxyphenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl] -7 - [(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as described in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa, and replacing 2phenylacetyl chloride in Step A with 4-methoxyphenyl chloroformate.

LC/MS (C₄₈H₅iN₅O₇) 810 [M+H]⁺; RT 1.21 (Method B)

High-resolution mass (ESI+):

Empirical formula: C48H51N5O7

- 152 [M+H]⁺calculated: 810.3861 [M+H]⁺measured: 810.3826

Example 122: 4-Chlorophenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-yImethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

Step A: 4-Chlorophenyl 6-(l-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-5,6,7,8tetrahydroindolizin-3-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step A of Example 11, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa, and replacing propionyl chloride with 4chlorophenyl chloroformate.

LC/MS (C₅4H5₄C1N₅O₆) 904 [M+H]⁺; RT 1.51 (Method B)

Step B: 4-Chlorophenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step B of Example 85, replacing the product of Step A in Example 85 with the product of Step A in Example 122.

LC/MS (C47H48CIN5O6) 814 [M+H]⁺; RT 1.27 (Method B)

Example 123: 3-{2-[2-(3-{[2-(DimethyIamino)ethyl]amino}phenyl)acetyl]-7[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoqumolm-6-yl}-/V-(4-hydroxyphenyl)-A-methyl-5,6,7,8tetrahydroindolizine-1 -carboxamide

- 153 The procedure is as in Example 96, replacing 2-(morpholin-4-yl)ethan-l-amine in Step A with (2-aminoethyl)dimethylamine, and replacing ethyl 2-(4-bromophenyl)acetate in Step A with methyl 2-(3-bromophenyl)acetate.

LC/MS (C₄₈H₅₄N₆O₄) 777 [M-H]’; RT 2.23 (Method A)

Example 124: 4-(Trifluoromethyl)phenyl 6-{l-[(4hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3(morpholin-4-ylmethyl)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 74, replacing the product from Préparation 6ab in Step A with the product from Préparation 6aa, and replacing A-methylaniline in Step B with 4(trifluoromethy l)phenol.

LC/MS (C₄₈H₄₈N₅O6F3) 848 [M+H]⁺; RT 1.31 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄₈H₄₈N5C>6F3 [M+H]⁺ calculated: 848.3629 [M+H]⁺ measured: 848.3615

Example 125: 4-(Trifluoromethoxy)phenyl 6-{l-[(4hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydromdolizin-3-yl}-7-[(35)-3(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 74, replacing the product from Préparation 6ab in Step A with the product from Préparation 6aa, and replacing A-methylaniline in Step B with 4(trifluoromethoxy)phenol.

LC/MS (C₄₈H_4SN₅O₇F3) 864 [M+H]⁺; RT 1.31 (Method B)

- 154 High-resolution mass (ESI+):

Empirical formula: C48H48N5O7F3 [M+H]⁺ calculated: 864.3579 [M+H]⁺ measured: 864.3576

Example 126: 4-Ethylphenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5.6.7.8- tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholm-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 74, replacing the product from Préparation 6ab in Step A with the product from Préparation 6aa, and replacing A-methylaniline in Step B with 4ethylphenol.

LC/MS (C₄9H₅3N₅O₆) 808 [M+H]⁺; RT 1.32 (Method B)

High-resolution mass (ES1+):

Empirical formula: C19H53N5O6 [M+H]⁺ calculated: 808.4069 [M+H]⁺ measured: 808.4026

Example 127: 4-Cyanophenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5.6.7.8- tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 74, replacing the product from Préparation 6ab in Step A with the product from Préparation 6aa, and replacing A-methylaniline in Step B with 4hydroxybenzonitrile.

LC/MS (C₄8H48N₆O₆) 805 [M+H]⁺; RT 1.18 (Method B)

- 155 Example 128: 2-Methoxyphenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoqumoline-2-carbonyl] -1,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step A of Example 8, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa, and replacing 2-phenylacetyl chloride with 2-methoxyphenyl chloroformate.

LC/MS (C₄₈H5iN₅O7) 810 [M+H]⁺; RT 1.20 (Method B)

Example 129: ,V-(4-I lyd roxypheny l)-ïV-methy l-3-{7-[ (3R)-3-methy 1-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[4-(morpholin-4-ylmethyl)phenyl]acetyI}-

1.2.3.4- tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydromdolizme-l-carboxamide

Step A: N-[4-(Benzyloxy)phenyl]-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[4-(morpholin-4-ylmethyl)phenyl]acetyl}-

1.2.3.4- tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure is as in Step A and B of Example 113, replacing /V-methylpiperazine in Step A with morpholine.

LC/MS (C₅6H5₉N₅O₅) 882 [M+H]⁺; RT 2.51 (Method A)

Step B: N-(4-Hydroxyphenyl)-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[4-(morpholin-4-ylmethyl)phenyl]acetyl}- l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

A solution of the product from Step A (49 mg, 0.06 mmol) in anhydrous dichloromethane (5 ml) was cooled to 0 °C and to this was added boron trichloride (IM in DCM, 170 pL,

0.17 mmol). The reaction was stirred at ambient température for ca 16 h. The reaction was quenched with methanol (5 mL), and the reaction was diluted with dichloromethane. The organic phase was washed with water, dried over magnésium sulfate, filtered and concentrated in vacuo. The crude product was purified by colurnn chromatography in a gradient of dichloromethane to 7% methanol in dichloromethane followed by trituration with ether and dried in vacuo.

- 156 LC/MS (C49H53N5O5) 792 [M+H]⁺; RT 2.20 (Method A)

High-resolution mass (ESI+):

Empirical formula: C49H53N5O5 [M+2H]²⁺ calculated: 396.7096 [M+2H]²⁺ measured: 396.7104

Example 130: A^r-(4-lIvdroxyphenyl)-A^r,l,2-trimethyl-5-{7-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(3-phenylpropanoyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-l//-pyrrole-3-carboxamide

The procedure was as in Example 23, replacing the product from Préparation 7ab in Step A with the product from Préparation 6ba, and replacing 2-methyl-3-phenylpropanoic acid in Step A with 3-phenylpropanoic acid.

LC/MS (C47H₅iN₅O₅) 766 [M+H]⁺; RT 1.14 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H51N5O5 [M+H]⁺ calculated: 766.3963 [M+H]⁺ measured: 766.3955

Example 131: (V-(4-HydroxyphenyI)-/V,l,2-trimethyl-5-{7-[(3S)-3-(morpholin-4yhnethyl)-1,2,3,4-tetrahvdroisoquinoline-2-carbonvl]-2-[(2/i)-3-phenylprop-2-enoyI]- l,2,3,4-tetrahydroisoquinolin-6-yl}-lff-pyrrole-3-carboxamide

The procedure was as in Example 109, replacing the product from Préparation 6ab with the product from Préparation 6ba, and replacing 2-methyl-3-phenylpropanoic acid with (2£)-3phenylprop-2-enoic acid.

LC/MS (C47H₄₉N₅O₅) 764 [M+H]⁺; RT 1.15 (Method B)

- 157 High-resolution mass (ESI+):

Empirical formula: C47H49N5O5 [M+H]⁺ calculated: 764.3806 [M+H]⁺ measured: 764.3779

Example 132:

5-[2-(3-Cyclohexylpropanoyl)-7-[(3S)-3-(morpholin-4-ylmethyI)-

l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoqiiinolin-6-yI]-A-(4· hydroxyphenyl)-V,l,2-trimethyl-l//-pyrrole-3-carboxamide

The procedure was as in Example 23, replacing the product from Préparation 7ab in Step A with the product from Préparation 6ba, and replacing 2-methyl-3-phenylpropanoic acid in Step A with 3-cyclohexylpropanoic acid.

LC/MS (C47H57N5O5) 772 [M+H]⁺; RT 1.25 (Method B)

Example 133: Phenyl 5-{l-[(4-hydroxyphenyl)(phenyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-6-[(31?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carb()nyl]-2,3-dihydro-l//-isoindole-2-carboxylate

High-resolution mass (ESI+):

Empirical formula: C₄₇H₄3N₄O5 [M+H]⁺ calculated: 743.3228 [M+H]⁺ measured: 743.3234

Example 134: A-(4-hydroxyphenyl)-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l, 2,3,4-tetrahydroisoquinolin6-yl}-V-phenyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

High-resolution mass (ESI+):

- 158Empirical formula: C49H47N4O4 [M+H]⁺ calculated: 755.3592 [M+H]⁺ measured: 755.3595

Example 135: A-(4-Hydroxyphenyl)-5-{2-[3-(3-methoxyphenyl)propanoyl]-75 [(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyI]-l, 2,3,4tetrahydroisoquinolin-6-yl}-jV,l,2-trimethyl-lH-pyrrole-3-carboxamide

The procedure was as in Example 23, replacing the product from Préparation 7ab in Step A with the product from Préparation 6ba, and replacing 2-methyl-3-phenylpropanoic acid in Step A with 3-(2-methoxyphenyl)propanoic acid.

LC/MS (C₄8H53N₅O₆) 796 [M+H]⁺; RT 1.14 (Method B)

High-resolution mass (ESI+):

Empirical formula: C48H53N5O6 [M+H]⁺ calculated: 796.4069 [M+H]⁺ measured: 796.4068

Example 136: W-(4-Hydroxyphenyl)-5-{2-[(2E')-3-(3-methoxyphenyl)prop-2enoyl]-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoIine-2-carbonyl]- l,2,3,4-tetrahydroisoquinolin-6-yl}-A',l,2-triinethyl-l//-pyrrole-3-carboxamide

The procedure was as in Example 109, replacing the product from Préparation 6ab with the product from Préparation 6ba, and replacing 2-methyl-3-phenylpropanoic acid with (227)-320 (2-methoxyphenyl)prop-2-enoic acid.

LC/MS (C₄8H₅iN₅O6) 794 [M+H]⁺; RT 1.16 (Method B)

High-resolution mass (ESI+):

Empirical formula: C4₈H₅iN₅O6

-SV-—..,____ r , .. . A - A d

-'·'Ά . , A R

- 159[M+H]⁺calculated: 794.3912 [M+H]⁺ measured: 794.3908

Example 137: 5-{2-[(2E)-3-(3,4-dichlorophenyl)prop-2-enoyl]-7-[(3S)-3(morpholin-4-ylmethyl)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinolin-6-yl}-V-(4-hvdroxyphenyl)-A, l,2-trimethyl-l//-pyrrole-3carboxamide

The procedure was as in Example 109, replacing the product from Préparation 6ab with the product from Préparation 6ba, and replacing 2-methyl-3-phenylpropanoic acid with (2E)-3(3,4-dichlorophenyl)prop-2-enoic acid.

LC/MS (C47H47N5O5CI2) 832 [M+H]⁺; RT 1.27 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄7H₄7N5O₅C1₂ [M+H]⁺ calculated: 832.3027 [M+H]⁺ measured: 832.3000

Example 138: 3-{2-[3-(4-{[2-(Dimethylamino)ethyl]amino}phenyl)propanoylJ-

7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoIine-2-carbonyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-A-(4-hydroxyphenyl)-A-methyl-5,6,7,8tetrahydroindolizine-l-carboxamide

The procedure is as described in Example 96, replacing 2-(morpholin-4-yl)ethan-l-amine in Step A with (2-aminoethyl)dimethylamine, and replacing ethyl 2-(4bromophenyl)acetate in Step A with methyl 3-(4-bromophenyl)propanoate.

LC/MS (C₄9H₅6N₆O₄) 791 [M-H]’; RT 2.22 (Method A)

High-resolution mass (ESI+):

- 160Empirical formula: C49H₅6N₆O₄ [M+H]⁺ calculated: 793.4436 [M+H]⁺ measured: 793.4411

Example 139: 4-Methylphenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoylJl,5-dimethyl-l//-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 11, replacing the product from Préparation 7aa with the

Product from Préparation 6ba, and replacing propionyl chloride with 4-methylphenyl chloroformate.

LC/MS (C46H49N5O6) 768 [M+H]⁺; RT 1.22 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O6 [M+H]⁺ calculated: 768.3756 [M+H]⁺ measured: 768.3723

Example 140: 4-Chlorophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

Step A: 4-Chlorophenyl 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyllH-pyrrol-2-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step A of Example 11, replacing the product from Préparation 7aa in Step A with the product from Préparation 6ba, and replacing propionyl chloride with 4chlorophenyl chloroformate.

- 161 LC/MS (C₅2H52N₅O₆Cl) 878[M+H]⁺; RT 1.48 (Method B)

Step B: 4-Chlorophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lHpyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step B of Example 85, replacing product in Step A of Example 85 with product of Step A in Example 140.

LC/MS (C₄5H46N₅O₆C1) 788 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H46N5O6CI [M+H]⁺ calculated: 788.3209 [M+H]⁺ measured: 788.3191

Example 141:

4-Carbamoylphenyl 6-{l-[(4-

hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3(morpholin-4-ylmethyI)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoIine-2-carboxylate

The procedure is as in Example 74, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa, and replacing A-methylaniline with 4hydroxy benzamide.

LC/MS (C48H50N6O7) 823 [M+H]⁺; RT 1.06 (Method B)

High-resolution mass (ESI+):

Empirical formula: C48H50N6O7 [M+H]⁺calculated: 823.3814 [M+H]⁺ measured: 823.3788

- 162 Example 142:

4-(Dimethylcarbamoyl)phenyl 6-{l-[(4- hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3(morpholin-4-ylmethyl)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 74, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa, and replacing /V-methylaniline with 4-hydroxy-A,/Vdimethylbenzamide.

LC/MS (C₅oH₅₄N₆07) 851 [M+H]⁺; RT 1.11 (Method B)

High-resolution mass (ESI+):

Empirical formula: C50H54N6O7 [M+H]⁺calculated: 851.4127 [M+H]⁺ measured: 851.4094

Example 143: 4-(i//-imidazol-l-yl)phenyi 6-{l-[(4hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoIine-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 74, replacing the product from Préparation 7aa in Step A with the product from Préparation 6aa, and replacing N-methylaniline with 4-(17/imidazol-1 -yl)phenol.

LC/MS (C₅oH5iN₇0₆) 846 [M+H]⁺; RT 1.03 (Method B)

High-resolution mass (ESI+):

Empirical formula: C50H51N7O6 [M+2H]²⁺ calculated: 423.7023 [M+2H]²⁺ measured: 423.7023

7Î /’ ·’ T

- 163 Example 144: 3-[2-(2-{4-[(Dimethylamino)methyl]phenyl}acetyl)-7-[(31?)-3methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6yl]-A-(4-hydroxyphenyl)-A-methyl-5,6,7,8-tetrahydroindoIizine-l-carboxamide

The procedure is as in Example 113, replacing replacing iV-methylpiperazine in Step A with dimethylamine.

LC/MS (C₄₇H5iN₅O4) 748 [M-H]'; RT 2.18 (Method A)

High-resolution mass (ESI+):

Empirical formula: C47H51N5O4 [M+H]⁺ calculated: 750.4014 [M+H]⁺ measured: 750.3984

Example 145:

5-{2-[2-(4-Cyanophenyl)acetyl]-7-[(37?)-3-methyl-l,2,3,4-

tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-A-(4hydroxy phenyl)-ïV,l,2-trimethyl-l//-pyrrole-3-carboxainide

The procedure is as in Example 109, replacing the product from Préparation 6ab in Step A with the product from Préparation 6bb, and replacing 1-phenylcyclopropane-l-carboxylic acid in Step A with 2-(4-cyanophenyl)acetic acid.

LC/MS (C43H41N5O4) 692 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H41N5O4 [M+H]⁺ calculated: 692.3231 [M+H]⁺ measured: 692.3199

- 164 Example 146: 4-CyanophenyI 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyI]-l,5dimethyl-lH-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 573, replacing 3,4-dichlorophenol in Step B with 4hy droxy benzonitrile.

LC/MS (C46H₄₆N₆O6) 779 [M+H]⁺; RT 1.14 (Method B)

Example 147: 4-Cyanophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-LH-pyrrol-2-yl}-7-[(3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyI]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 573, replacing the product from Préparation 6ba with the product from Préparation 6bb, and replacing 3,4-dichlorophenol in Step B with 4hydroxybenzonitrile.

LC/MS (C47H39N5O5) 694 [M+H]⁺; RT 1.29 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H39N5O5 [M+H]⁺ calculated: 694.3024 [M+H]⁺ measured: 694.3044

Example 148: 4-Cyano-2-methoxyphenyl 6-{l-[(4hydroxyphenyI)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3S)-3(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 573, replacing the product from Préparation 6ba with the product from Préparation 7aa, and replacing 3,4-dichlorophenol in Step B with 4hydroxybenzonitrile.

AJ ‘TT

- 165 LC/MS (C49H₅₀N₆O₇) 835 [M+H]⁺; RT 1.19 (Method B)

High-resolution mass (ESI+):

Empirical formula: C49H50N6O7 [M+H]⁺ calculated: 835.3814 [M+H]⁺ measured: 835.3833

Example 149: 5-{2-[2-(4-{[2-(Dimethylamino)ethyl]amino}phenyl)acetyl]-7[(3/?)-3-methyl-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinolin-6-vl}-;V,l,2-trimethyl-;V-phenvl-l//-pyrrole-3-carboxamide

The procedure is as in Example 96, replacing 2-(morpholin-4-yl)ethan-l-amine in Step A with (2-aminoethyl)dimethylamine, and replacing the product from Préparation 6ba in Step C with the product obtained from Préparation 6cb.

LC/MS (C46H52N6O3) 737 [M+H]⁺; RT 1.13 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H52N6O3 [M+H]⁺ calculated: 737.4174 [M+HJ⁺ measured: 737.4173

Example 150: 5-{2-[2-(4-Cyanophenyl)acetyl]-7-[(3J?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}-A',l,2tri methyl-'V-phenyl-l//-pyrrole-3-car boxa mide

The procedure is as in Example 109, replacing the product from Préparation 6ab in Step A with the product from Préparation 6cb, and replacing 1-phenylcyclopropane-l-carboxylic acid in Step A with 2-(4-cyanophenyl)acetic acid.

LC/MS (C43H41N5O3) 676 [M+H]⁺; RT 1.36 (Method B)

- I66High-resolution mass (ESI+):

Empirical formula: C43H41N5O3 [M+H]⁺ calculated: 676.3282 [M+H]⁺ measured: 676.3249

Example 151:

5-{2-[2-(4-Cyanophenyl)acetyl]-7-[(3S)-3-(morpholin-4-

ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6yl}-V,l,2-trimethyl-A^r-phenyI-l//-pyrrole-3-carboxamide

The procedure is as in Example 109, replacing the product from Préparation 6ab in Step A with the product from Préparation 6ca, and replacing 1-phenylcyclopropane-l-carboxylic acid in Step A with 2-(4-cyanophenyl)acetic acid.

LC/MS (C₄7H48N₆O₄) 761 [M+H]⁺; RT 1.19 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H48N6O4 [M+H]⁺ calculated: 761.3810 [M+H]⁺ measured: 761.3811

Example 152:

4-Cyanophenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-

LH-pyrrol-2-yI}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyI]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step A and B Example 573, replacing 3,4-dichlorophenol in Step B with 4-hydroxybenzonitrile.

LC/MS (C₄6H4₆N₆O₅) 763 [M+H]⁺; RT 1.26 (Method B)

High-resolution mass (ES1+):

- 167 Empirical formula: C46H46N6O5 [M+H]⁺ calculated: 763.3602 [M+H]⁺ measured: 763.3572

Example 153: 4-{[2-(DimethyIamino)ethyl]ammo}phenyl 6-{l-[(4hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3R)-3methyl-l,2,3,4-tetrahydroisoquinolme-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2carboxylate

The procedure is as in Example 489, replacing the product from Préparation 6cb with the product from Préparation 6ab.

LC/MS (C₄7H₅₂N₆O₅) 779 [M-H]’; RT 2.27 (Method A)

High-resolution mass (ESI+):

Empirical formula: C₄7H5₂N6O5 [M+2H]²⁺calculated: 391.2072 [M+2H]²⁺measured: 391.2081

Example 154: 3-[2-(2-{4-[2-(Dimethylamino)ethoxy]phenyl}acetyl)-7-[(3R)-3methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6yl]-A-(4-hydroxyphenyl)-A'-inethyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: methyl 2-{4-[2-(dimethylamino)ethoxy]phenyl}acetate

To a solution of methyl 4-hydroxyphenylacetate (50 mg, 0.3 mmol) in acetone (5 mL) was added césium carbonate (196 mg, 0.6 mmol) followed by 2-dimethylaminoethyl chloride hydrochloride (45 mg, 0.31 mmol) and the reaction stirred at ambient température for ca 16 h. To this was added sodium iodide (45 mg, 0.3 mmol) and the mixture was heated at 60 °C for ca 48 h. The reaction was cooled to ambient température, diluted with dichloromethane and washed with water, dried over magnésium sulphate, filtered and

- 168 concentrated in vacuo and loaded onto a pre-packed 10 g silica column and purified by column chromatography in a gradient of dichloromethane to 10% methanol in dichloromethane to afford the desired product.

LC/MS (C13H19NO3) 238 [M+H]⁺; RT 1.49 (Method A)

Step B: sodium 2-{4-[2-(dimethylamino)ethoxy]phenyl}acetate

To a solution of methyl 2-{4-[2-(dimethylamino)ethoxy]phenyl}acetate (19 mg, 0.08 mmol) in methanol (3 mL) was added sodium hydroxide (2M, 80 pL, 0.16 mmol) and the reaction stirred at ambient température for ca 48 h. The reaction was concentrated in vacuo to afford the desired product and taken on assuming quantitative transformation.

LC/MS (C12H17NO3) 224 [M+H]⁺; RT 0.53 (Method A)

Step C: N-[4-(benzyloxy)phenyl]-3-[2-(2-{4-[2-(dimethylamino)ethoxy]phenyl}acetyl)-7[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinolin-6-yl]-N-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

To a suspension of the product from Step B (16 mg, 0.06 mmol) in dichloromethane (5 mL) was added the product from Préparation 6ab (50 mg, 0.06 mmol) followed by triethylamine (27 pL, 0.19 mmol) and HBTU (24 mg, 0.06 mmol) and the reaction stirred at ambient température for ca 16 h. The reaction was diluted with dichloromethane and washed with water, dried over magnésium sulphate, filtered and concentrated in vacuo and loaded onto a pre-packed 10 g silica column in dichloromethane and purified by column chromatography in a gradient of dichloromethane to 10% methanol in dichloromethane

LC/MS (C55H59N5O5) 435.5 [M+2H]²⁺; RT 2.54 (Method A)

Step D: 3-[2-(2-{4-[2-(Dimethylamino)ethoxy]phenyl}acetyl)-7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl]-N-(4hydroxyphenyl)-N-methyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

To a solution of the product obtained from Step C (51.8 mg, 0.04 mmol, 1 eq) in éthanol (5 mL) was added 10% Pd/C (catalytic). The reaction was stirred under a hydrogen atmosphère for ca 48. The reaction was filtered through a celite cartridge and washed with

- 169 methanol and concentrated in vacuo and purified by reverse phase préparative HPLC (ILO-TFA/acetonitrile; gradient elution).

LC/MS (C₄8H53N₅O₅) 778 [M-H]’; RT 2.20 (Method A)

Example 155: 4-[2-(Dimethylcarbamoyl)ethyl]phenyl 6-{l-[(4hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-[(3R)-3methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2carboxylate

The procedure is as in Example 786, replacing the product from Préparation 6cb in Step A with the product from Préparation 6ab, and 4-hydroxybenzonitrile in Step B with 3-(4hydroxyphenyl)-/V,yV-dimethylpropanamide..

LC/MS (C₄8H₅₁N₅O6) 794 [M+H]⁺; RT 2.57 (Method A)

High-resolution mass (ESI+):

Empirical formula: C48H51N5O6 [M+H]⁺ calculated: 794.3912 [M+H]⁺ measured: 794.3950

Example 156: N-(4-Hydroxyphenyl)-N-methyl-3-{6-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenoxyacetyl)-2,3dihydro-lH-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

High-resolution mass (ESI+):

Empirical formula: C47H49N5O6 [M+H]⁺ calculated: 780.3763 [M+H]⁺ measured: 780.3759

	- 170-
Example 157:	l,l-Dioxo-lk⁶-thiolan-3-yl 5-{4-[(4-

hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-6-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoIine-2-carbonyl]-2,3-dihydro-lZ/-isoindole-2-carboxylate

High-resolution mass (ESI+):

Empirical formula: C38H40N4O7S [M+H]⁺ calculated: 697.2698 [M+H]⁺ measured: 697.2696

Example 158:

2V-(4-Hydroxyphenyl)-3-{6-[(3R)-3-methyl-l,2,3,4-

tetrahydroisoquinoIine-2-carbonyl]-2-(2-phenoxyacetyl)-2,3-dihydro-lZ/-isoindol-5yl}-N-{ l-methyl-lif-pyrrolo[2,3-Z>]pyridin-5-yI}-5,6,7,8-tetrahydroindolizine-1carboxamide

Example 159: A^r-(4-Hydroxyphenyl)-2V,l,2-trimethyl-5-{6-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenoxyacetyl)-2,3dihydro-lH-isoindol-5-yl}-lH-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C45H47N5O6 [M+H]⁺ calculated: 754.3606 [M+H]⁺ measured: 754.3574

Example 160: 5-{2-[2-(Benzyloxy)acetyl]-6-[(3R)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-A-(4hydroxyphenyl)-ïV,l,2-trimethyl-lH-pyrrole-3-carboxamide

High-resolution mass (ESI+):

-171Empirical formula: C42H42N4O5 [M+H]⁺ calculated: 683.3235 [M+H]⁺ measured: 683.3238

Example 161: Phenyl 6-[4-(dibutvkarbamovl)-l,5-dimethyl-l//-pvrrol-2-vl]-7(l,2,3,4-tetrahydroisoquinoIine-2-carbonyl)-l,2,3,4-tetrahydroisoquinoline-2carboxylate

The product from Préparation 6dc (81 mg, 0.15 mmol, 1 eq) in dichloromethane (5 mL) was cooled to 0°C. To this was added ΛζΑ-diisopropylethylamine (52 qL, 0.3 mmol) followed by phenyl chloroformate (21 uL, 0.16 mmol) and the mixture was allowed to stir for 15 min. The reaction was diluted with dichloromethane and washed sequentially with IM aqueous NaOH, and brine. The organic extracts were dried over magnésium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography (CombiFlash R_f, 12 g RediSep™ silica cartridge; gradient of dichloromethane to 5 % methanol in dichloromethane) afforded the desired product.

LC/MS (C₄iH4₈N₄O4) 661 [M+H]⁺; RT 1.57 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄iH₄₈N4O₄ [M+H]⁺ calculated: 661.3748 [M+H]⁺ measured: 661.3769

Example 162: A',V-Dibutyl-l,2-diniethvl-5-[2-(2-phenvlacetyl)-7-(l,2,3,4tetrahydroisoquinoline-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl|-l//-pyrrole-3carboxamide

λ k. · ;

- 172 The procedure is as in Example 161, replacing phenyl chloroformate with phenylacetyl chloride.

LC/MS (C42H50N4O3) 659 [M+H]⁺; RT 1.52 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H50N4O3 [M+H]⁺ calculated: 659.3956 [M+H]⁺ measured: 659.3969

Example 163: Phenyl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-l//-pyrroI-2-yl]-7[(3//)-3-met hv 1-1,2,3,4-tetr ahy droisoquinoline-2-carbonyl] -1,2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 161, replacing the product from Préparation 6dc with product from Préparation 6db.

LC/MS (C42H50N4O4) 675 [M+H]⁺; RT 1.52 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄2H₅oN404 [M+H]⁺ calculated: 675.3905 [M+H]⁺ measured: 675.3900

Example 164: V,.V-I)ibutyl-l,2-dimethyl-5-{7-[(3/?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyI)-l,2,3,4-tetrahydroisoquinolin6-ylj-l//-pvrrole-3-carboxamide

The procedure is as in Example 161, replacing the product from Préparation 6dc with product from Préparation 6db, and replacing phenyl chloroformate with phenylacetyl chloride.

- 173 LC/MS (C43H₅₂N₄O₃) 673 [M+H]⁺; RT 1.51 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄₃H52N₄O₃ [M+H]⁺ calculated: 673.4112 [M+H]⁺ measured: 673.4087

Example 165: ApV-Dibutyl-l,2-dimethyl-5-{7-[(3S)-3-(morpholin-4-ylmethyl)- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-l//-pyrroIe-3-carboxamide

To a solution of the product of Préparation 6da (112 mg, 0.13 mmol) in dichloromethane (5 mL) was added ?/,4/-diisopropylethylamine (112 pL, 0.64 mmol) followed by phenylacetyl chloride (17 uL, 0.14 mmol) and the mixture was allowed to stir for 15 min. The reaction was diluted with dichloromethane and washed sequentially with IM aqueous sodium hydroxide, and brine. The organic extracts were dried over magnésium sulphate, filtered and concentrated. Purification by flash column chromatography (CombiFlash Rf, 12 g RediSep™ silica cartridge) eluting with a gradient of dichloromethane to 5 % methanol in dichloromethane afforded the desired product.

LC/MS (C₄7H₅9N₅O₄) 758 [M+H]⁺; RT 1.40 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄7H₅9N₅O₄ [M+H]⁺ calculated: 758.4640 [M+H]⁺ measured: 758.4648

- 174Example 166: /V-(4-Hydroxyphenyl)-yV-methyl-3-{6-[(3S)-3-(morpholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenoxyacetyl)-2,3dihydro-lH-isoindol-5-yl}indolizine-l-carboxamide

High-resolution mass (ESI+):

Empirical formula: C47H45N5O6 [M+H]⁺ calculated: 776.3450 [M+HJ⁺ measured: 776.3430

Example 167: 2V-(4-Hydroxyphenyl)-/V-methyl-3-{6-[(3/f)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenoxyacetyl)-2,3-dihydro-LH-isoindol-5yl}indolizine-l-carboxamide

High-resolution mass (ESI+):

Empirical formula: C43H38N4O5 [M+H]⁺calculated: 691.2922 [M+H]⁺measured: 691.2913

Example 168: 4-Methylphenyl 5-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-

5,6,7,8-tetrahydroindolizin-3-yl}-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2,3-dihydro-lH-isoindole-2-carboxylate

High-resolution mass (ESI+):

Empirical formula: C43H42N4O5 [M+H]⁺ calculated: 695.3235 [M+H]⁺ measured: 695.3230

- 175 Example 169: A-(4-Hydroxyphenyl)-A-methyl-3-{7-[(3R)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[3-(4-methylpiperazin-l-yi)phenyl]acetyl}- l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

Step A: methyl 2-[3-(4-methylpiperazin-l-yl)phenyl]acetate

To a boiling tube was added methyl 2-(3-bromophenyl)acetate (250 mg, 1.09 mmol), 1methylpiperazine (0.18 mL, 1.64 mmol), di-tert-butyl(2-phenylphenyl)phosphane, (32.57 mg, 0.11 mmol) and potassium phosphate tribasic (463.32 mg, 2.18 mmol) which were then suspended in toluene (5 mL) and degassed by sparging with nitrogen for 5 min. Tris(Dibenzylideneacetone)Dîpalladium(0) (49.97 mg, 0.05 mmol) was then added to the reaction and stirred at 90 °C under nitrogen for ca 16 h. The reaction was filtered and solids washed with dichloromethane and concentrated in vacuo, and then loaded onto a pre-packed 10 g silica column in dichloromethane and purified by column chromatography in a gradient of dichloromethane to 5% methanol in dichloromethane.

LC/MS (Ci₄H₂oN₂0₂) 249 [M+H]⁺; RT 1.56 (Method B)

Step B: sodium 2-[3-(4-methylpiperazin-l-yl)phenyl]acetate

To a solution of the product from Step A (39.3 mg, 0.16 mmol) in methanol (5 mL) was added sodium hydroxide (2M, 0.16 mL, 0.32 mmol) and the reaction stirred at ambient température for ca 16 h. The reaction was concentrated in vacuo and triturated with diethyl ether to afford the desired product.

LC/MS (C₁₃H₁₈N₂O₂) 235 [M+H]⁺; RT 0.69 (Method B)

Step C : N-[4-(benzyloxy)phenyl]-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[3-(4-methylpiperazin-l-yl)phenyl]acetyl}- l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

To a solution of the product from Préparation 6ab (50 mg, 0.06 mmol) in dichloromethane (3 mL)was added HBTU (24.35 mg, 0.06 mmol) and triethylamine (26.79 pL, 0.19 mmol) followed by the product from Step B (24.68 mg, 0.1 mmol) and the reaction stirred at ambient température for ca 16 h. The reaction was diluted with dichloromethane and washed with water and brine. The organic extract was dried over magnésium sulphate, filtered and concentrated in vacuo, and loaded onto a pre-packed 5 g silica column in ‘ ~ - 3 TT λ

A· . . A UMV

- 176dichloromethane and purified by column chromatography in a gradient of dichloromethane in 5% methanol in dichloromethane.

LC/MS (QeHôoNôCU) 881 [M+H]⁺; RT 2.52 (Method B)

Step D : N-(4-Hydroxyphenyl)-N-methyl-3-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-{2-[3-(4-methylpiperazin-l-yl)phenyl]acetyl}- l,2,3,4-tetrahydroisoquinolin-6-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

To a solution the product from Step C (45 mg, 0.05 mmol) in éthanol (10 mL) was added 10% Pd/C (catalytic), and stirred under a hydrogen atmosphère at ambient température for ca 16 h. The reaction was filtered through a celite cartridge, which was washed with methanol and the fïltrate was concentrated in vacuo, and loaded onto a pre-packed 5 g silica column in dichloromethane and purified by column chromatography in a gradient of dichloromethane to 5% methanol in dichloromethane.

LC/MS (C₄9H₅₄N₆O4) 791 [M+H]⁺; RT 2.21 (Method B)

High-resolution mass (ESI+):

Empirical formula: C49H54N6O4 [M+2H]²⁺ calculated: 396.2176 [M+2H]²⁺ measured: 396.2176

Example 170: 5-{4-[(4-IIydroxyphenyl)(methyl)carbainoyl]-L5-dimethyl-l//pyrrol-2-yl}-/V-methyl-6-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

2,3-dihydro-l//-isoindoIe-2-carboxamide

High-resolution mass (ESI+):

Empirical formula: C35H37N5O4 [M+H]⁺ calculated: 592.2926 [M+H]⁺ measured: 592.2925 < ,

- 177 Example 171: A-(4-Hydroxyphenyl)-A-methyl-3-{6-[(31?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(phenylsulfanyl)acetyl]-2,3-dihydro-lHisoindol-5-yl}-5,6,7,8-tetrahydroindolizine-l-carboxamide

High-resolution mass (ESI+):

Empirical formula: C43H42N4O4S [M+H]⁺ calculated: 711.3007 [M+H]⁺ measured: 711.3001

Example 172: 5-{2-[2-(2H-l,3-Benzodioxol-5-yl)acetyl]-6-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-l//-isoindol-5-yl}-;V-(4- hydroxyphenyl)-7V,l,2-trimethyl-lH-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C42H40N4O6 [M+H]⁺ calculated: 697.3028 [M+H]⁺ measured: 697.2994

Example 173: 5-(2-[(2S)-2-Amino-2-phenylacetyl]-6-{[(3R)-3-methyI-3,4dihydroisoquinolin-2(lH)-yl]carbonyl}-2,3-dihydro-lJT-isoindol-5-yI)-A-(4hydroxyphenvl)-.V,l,2-triinelhvl-l//-pvrrole-3-carl)oxamide

High-resolution mass (ESI+):

Empirical formula: C₄iH4iN5O₄ [M+H]⁺ calculated: 668.3239 [M+H]⁺ measured: 668.3238

- I78 Example 174:5-(2-lï2.R)-2-Amino-2-phenvlacetvll-6-{|ï3.Æ)-3-methvl-3.4dihydroisoquinolin-2(lJ7)-yl]carbonyl}-2,3-dihydro-lH-isoindol-5-yl)-A-(4hydroxyphenyl)-A,l,2-trimethyl-lH-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C41H41N5O4 [M+H]⁺ calculated: 668.3239 [M+H]⁺ measured: 668.3247

Example 175:2V-(4-Hvdroxvphenvl)-5-(2-[(27?)-2-hvdroxv-2-phenvlacetvll-6-ir(37?)-3metliyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-2.3-dihydro-l//-isoindol-5-yl)-

A,l,2-trimethyl-llⁱl^r-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C₄iH₄oN₄05 [M+H]⁺ calculated: 669.3079 [M+H]⁺ measured: 669.3063

Example 176:5-i2-r2-(l-Piperidvhacetvl]-6-r(3/?)-3-methvl-1.2.3.4-tetrahydro isoquinoline-2-carbonyl]-2,3-dihydro-lH-isoindol-5-yl}-A-(4-hydroxyphenyl)-A,l,2trimethyl-l/Z-pyrrole-3-carboxamide

High-resolution mass (ESI+):

Empirical formula: C4oH45N₅04 [M+H]⁺ calculated: 660.3552 [M+H]⁺ measured: 660.3512

- 179Example l77:5-r2-[2-(l,3-BenzodioxoI-5-vl)acetvl]-6-[(3l?)-3-methyl-3.4-dihydro-1/7isoquinoline-2-carbonyl]isoindolin-5-yl]-/V,l,2-trimethyl-A-(l-methylpyrrolo[2,3-

b]pyridin-5-yl)pyrrole-3-carboxamide

Example 178:5-[2-i2-(l,3-Benzodioxol-5-vl)acetvl]-6-i(3i?)-3-methvl-3.4-dihvdro-l^isoqumoline-2-carbonyl]isomdolm-5-yl]-/V-(4-hydroxyphenyl)-l,2-dimethyl-jV-(lmethyl-lZZ-pyrazol-4-yl)pyrrole-3-carboxamide

Example 179:iV-(4-Hvdroxyphenyl)-/V,12-trimethvl-5-r6-[(37?)-3-methvl-3.4-dihvdrol//-isoquinoline-2-carbonyl|-2-[(2Æ)-2-phenyIpropanoyl]isoindolin-5-yl]pyrrole-3carboxamide

Example 180:N-(4-Hvdroxyphenvl)-2V,lJI-trnnethvl-5-[6-r(31^l?)-3-methvl-3.4-dihvdrol//-isoquinoline-2-carbonyl]-2-[2-(3-thienyl)acetyI]isoindolin-5-yl]pyrrole-3carboxamide

Example 181:N-(4-Hvdroxvphenyl)-iV,l,2-trimethvl-5-[6-i(31^l?)-3-methvl-3,4-dihydroLff-isoquinoline-2-carbonyl]-2-[(2S)-2-phenylpropanoyl]isoindolin-5-yl]pyrroIe-3carboxamide

Example 182:5-r2-r3-(4-Chlorophenoxy)propanoyl1-6-r(31?)-3-methyI-3,4-dihydro-lH^r- isoquinoline-2-carbonyl]isoindolin-5-yr]-A'-(4-hydroxyphenyl)-iV,l,2-triinethylpyrrole-3-carboxamide

Example 183:AM4-Hvdroxvphenvl)-A'^r,l,2-trimethvl-5-[6-[(3.R)-3-methyI-3,4-dihvdrolH^r-isoquinoline-2-carbonyl]-2-(2-pyrrol-l-ylacetyl)isoindolin-5-yl]pyrrole-3carboxamide

Example 184:Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lHpyrroI-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

I

- 180I

I

I ,0

I

I 20

I

I ,0

I

I 20

I

Example 185:Phenyl 6-{4-[ethyl(4-hydroxyphenyl)carbamoyl]-l,5-dimethyl-17/pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyI)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with product from Préparation 6f, and replacing phenylacetyl chloride in Step A with phenyl chloroformate.

LC/MS (C₄6H49N₅O₆) 768 [M+H]⁺; RT 1.21 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O6 [M+H]⁺ calculated: 768.3756 [M+H]⁺ measured: 768.3741

Example 186:Phenyl 6-{4-[(4-hydroxyphenyl)(propyl)carbamoyl]-l,5-dimethyl-l//pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-yImethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l>2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 777, replacing the product from Préparation 6be in Step A with the product from Préparation 6g, and replacing phenylacetyl chloride in Step A with phenyl chloroformate.

LC/MS (C₄7H₅iN₅O₆) 782 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H51N5O6 [M+H]⁺ calculated: 782.3912 [M+H]⁺ measured: 782.3927

I

- 181 Example 187:Phenyl 6-{4-[butyl(4-hydroxyphenyl)carbamoyl]-l,5-dimethyl-177pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl] -1,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 777, replacing the product from Préparation 6be in Step A 5 with the product from Préparation 6h, and replacing phenylacetyl chloride in Step A with phenyl chloroformate.

LC/MS (C48H53N5O6) 796 [M+H]⁺; RT 1.29 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄₈H5₃N5O6 [M+2H]²⁺calculated: 398.7071 [M+2H]²⁺ measured: 398.7075

Example 188:Phenyl 6-{4-[(4-hydroxyphenyl)(phenyl)carbanioyl]-l,5-dimethyI-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoline-2(LH)-carboxylate

Example 189:PhenvI 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-LfiT-pyrrol-2-yl}-

7-{[(3S)-3-(morphoIin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZ/)-yl]carbonyl}-3,4dihydroisoquinoline-2(177)-carboxylate

Example 190:PhenvI 6-{4-[ethyl(phenyl)carbamoyl]-l,5-dimethyl-l/7-pyrrol-2-yl}-7{[(3S)-3-(morpholin-4-ylmethy])-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,420 dihydroisoquinoline-2(17/)-carboxylate

- 182 Example 191:Phenvl 6-{l,5-dimethyl-4-[phenyl(propyl)carbamoyl]-177-pyrrol-2-yl}7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(12i)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 192:Phenvl 6-{4-[butyl(phenyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-75 {[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinoline-2(ljH^r)-carboxylate

Example 193:Phenvl 6- [4-(diphenyIcarbamoyl)> 1,5-dimethy 1-l//-py rrol-2-yl]-7{[(3S)-3-(morpholin-4-ylmethyI)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 194:Phenvl 6-{4-[butyl(methyl)carbamoyl]-l,5-dimetbyl-l//-pyrrol-2-yl}-7{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxylate

Example 195:Phenvl 6-{4-[butyl(ethyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZ/)-yl]carbonyl}-3,415 dihy droisoquinoline-2( 1 //)-carboxy lat e

Example 196:Phenvl 6-{4-[butyl(propyl)carbamoyl]-l,5-dimethyl-LH^r-pyrrol-2-yl}-7{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZr>-yl]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxylate

- 183 Example 197:Phenyl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-lZZ-pyrrol-2-yl]-7-[(3S)-3(morpholin-4-ylmethyl)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 165, replacing phenylacetyl chloride with phenyl chloroformate.

LC/MS (C46H57N5O5) 760 [M+H]⁺; RT 1.40 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H57N5O5 [M+H]⁺ calculated: 760.4432 [M+H]⁺ measured: 760.4449

Example 198:Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbam«yl]-l,5-dimethyl-l//pyrrol-2-yl}-7-{[(3jR)-3-methyl-3,4-dihydroisoquinolin-2(LH)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 199:Phenvl 6-{l^-dimethyI-4-[methyl(phenyl)carbamoyl]-lfiT-pyrrol-2-yl}7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinoline-2(17/)-carboxylate

Example 200:Phenyl 6-{4-[(4-hydroxyphenyl)(phenyl)carbanioyl]-l,5-dimethyl-l//pyrrol-2-yl}-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carboiiyl}-3,4dihydroîsoquinoline-2(liï)-carboxylate

Example 201:Phenyl 6-[4-(diphenylcarbamoyl)-l,5-dimethyl-l//-pyrrol-2-yl]-7{[(3/?)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yI]carbonyl}-3,4-dihydroisoquinoline2(l//)-carboxylate

Γ U · ·· ·-” 4

- 184 Example 202:Phenyl 6-{4-[butyl(methyl)carbamoyl]-l,5-dimethyl-lÆ-pyrrol-2-yl}-7{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline2(lfiF)-carboxylate

Example 203:Phenyl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-lH-pyrrol-2-yl]-7-{[(3R)5 3-niethyl-3,4-dihydroiso(juinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)carboxylate

Example 204:PhenvI 7-(3,4-dihydroisoquinolin-2(l/7j-ylcarbonyl)-6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lZf-pyrrol-2-yl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 205:Phenvl 7-(3,4-dihydroisoquinoiin-2(l/7)-ykarbonyi)-6-{l,5-diinethyl-4[methyl(phenyl)carbanwyl]-lH-pyrrol-2-yI}-3,4-dihydroisoquinoline-2(lH)carboxylate

Example 206:Phenvl 7-(3,4-dihydroisoquinolin-2(lH^r)-ylcarbonyl)-6-{4-[(4hydroxyphenyl)(phenyl)carbamoyl]-l^-dimethyl-lH-pyrrol-2-yl}-3,415 dihydroisoquinoline-2(lf/)-carboxylate

Example 207:Phenvl 7-(3,4-dihydroisoquinolin-2( 1 //)-y IcarbonyI)-6-[4(diphenylcarbamoyl)-l,5-dimethyl-lH-pyrrol-2-yl]-3,4-dihydroisoquinoline-2(lH)carboxylate

- 185 Example 208:Phenyl 6-{4-[butyl(methyl)carbamoyl]-l,5-dimethyl-lZ/-pyrrol-2-yl}-7(3,4-dihydroisoquinolin-2(lZ7)-ylcarbonyl)-3,4-dihydroisoquinoline-2(lH)carboxylate

Example 209:Phenyl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-l//-pyrrol-2-yl]-7-(3,4dihydroisoquinolin-2(lH)-ylcarbonyl)-3,4-dihydroisoquinoline-2(l_JH)-carboxylate

Example 210;Phenyl 7-{[(3S)-3-(aminomethyl)-3,4-dihydroisoquinolin-2(lff)yI]carbonyl}-6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l//-pyrrol-2yl}-3,4-dihydroisoquinoline-2(Lfir)-carboxylate

Example 211;Phenyl 7-[(3S)-3-[(dimethylamino)methyl]-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

Step A: Phenyl 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyl-lH-pyrrol-

2-yl)-7-[(3S)-3-[(dimethylamino)methyl]-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step A of Example 777, replacing phenylacetyl chloride with phenyl chloroformate.

LC/MS (C50H51N5O5) 802 [M+H]⁺; RT 1.34 (Method B)

Step B: Phenyl 7-[(3S)-3-[(dimethylamino)methyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}- l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step B of Example 777, but purification was via préparative HPLC (H₂O-TFA/acetonitrile; gradient elution).

LC/MS (C43H45N5O5) 712 [M+H]⁺; RT 1.13 (Method B)

- )86High-resolution mass (ESI+):

Empirical formula: C43H45N5O5 [M+H]⁺ calculated: 712.3493 [M+H]⁺ measured: 712.3496

Example 212;Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l//pyrrol-2-yI}-7-{[(3S)-3-(pyrrolidin-l-ylmethyl)-3,4-dihydroisoquinolin-2(lH^r)yl]carbonyl}-3,4-dihydroisoqumolme-2(llï)-carboxylate

Example 213:Phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l//pyrrol-2-yl}-7-{[(3S)-3-(piperidin-l-ylmethyl)-3,4-dihydroisoquinolin-2(LiOyl]carbonyl}-3,4-dihydroisoquinoline-2(ll^cr)-carboxylate

Example 214;Phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l//pyrrol-2-yl}-7-[(3.S’)-3-[(4-methyipiperazin-l-yl)methyl]-L2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2_?3,4-tetrahydroisoquinoline-2-carboxylate

2-yl)-7-[(3S)-3-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step A of Example 777, replacing the compound from Préparation 6be with the compound from Préparation 6bf, and replacing phenylacetyl chloride with phenyl chloroformate.

LC/MS (C53H56N6O5) 857 [M+H]⁺; RT 1.34 (Method B)

- 187 Step B: Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2yl}-7-[(3S)-3-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step B of Example 777, but purification was via préparative HPLC (fLO-TFA/acetonitrile; gradient elution).

LC/MS (C₄6H5oN₆0₅) 767 [M+H]⁺; RT 1.14 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H50N6O5 [M+2H]²⁺ calculated: 384.1994 [M+2H]²⁺ measured: 384.1995

Example 215:Phenyl 7-{[(3S)-3-[2-(dimethylamino)ethyl]-3,4-dihydroîsoquinolin2( lH)-yl]carbonyI}-6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l/7pyrrol-2-yl}-3,4-dihydroisoquinoline-2(17/)-carboxylate

Example 216;PhenvI 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lHpyrroI-2-yl}-7-[(3S)-3-[2-(morpholin-4-yl)ethyl]-1^23?4-tetrahydroisoquinoline-2carbonyl] -1,2,3,4-t etrahydroisoquinoline-2-carboxylate

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with product from Préparation 6bc, and replacing phenylacetyl chloride in Step A with phenyl chloroformate.

LC/MS (C₄₆H49N₅O6) 768 [M+H]⁺; RT 1.14 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O6 [M+H]⁺ calculated: 768.3756 «

- 188 [M+H]⁺ measured: 768.3756

Example 217:Phenyl 7-{[(3S)-3-(aminomethyl)-3,4-dihydroisoquinolin-2(l/Z)yl]carbonyl}-6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-llï-pyrrol-2-yl}-3,4dihydroisoquirmline-2(l//)-carboxylate ⁵ Example 218:Phenvl 7-{[(3S)-3-[(dimethylamino)methyl]-3,4-dihydroisoquinolm2(l//)-yl]carbonyl}-6-{l,5-dimethyl-4-[me4hvl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-

3.4- dihydroisoquinoline-2(l/Z)-carboxylate

Example 219:Phenvl 6-{ 1,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-y 1}7-{[(3S)-3-(pyrrolidin-l-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,410 dihydroisoquinoline-2(LH^r)-carboxylate

Example 220;Phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lfiT-pyrrol-2-yl}7-{[(3S)-3-(piperÎdin-l-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yI]carbonyl}-3,4dihydroisoquinolme-2(lH)-carboxylate

Example 221:Phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}15 7-{[(3S)-3-[(4-metliylpiperazin-l-yl)methyl]-3,4-dihydroisoquinolin-2(lfi^r)yl]carbonyl}-3,4-dihydroisoquinoline-2(l/7)-(.arboxylate

Example 222;Phenvl 7-{[(35)-3-[2-(dimethylamino)ethyl]-3,4-dihydroisoquinolin2(n/)-yl]carbonyl}-6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lfi^r-pyrrol-2-yl}-

3.4- dihydroisoquinoIine-2(lH)-carboxylate

- 189Example 223:Phenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}7-{[(3S)-3-[2-(morpholin-4-yI)ethyl]-3,4-dihydroisoquinolin-2(liy^r)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 224:Phenvl 7-{|(3S)-3-(aminomethyl)-3,4-dihydroisoquinolin-2(l//)5 yl]carbonyl}-6-[4-(dibutylcarbamoyl)-l,5-dimethyl-lH-pyrrol-2-yl]-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 225:Phenvl 6-[4-(dibutyIcarbamoyl)-l,5-dimethyl«lH^r-pyrrol-2-yl]-7-{[(3S)-

3-[(dimethylamino)methyl]-3,4-dihydroisoquinolin-2(l£0-yl]carbonyl}-3,4dihydroîsoquinoline-2(lH)-carboxylate

Example 226:Phenyl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-lfiT-pyrrol-2-yl]-7-{[(35)-

3-(pyrrolidin-l-ylmethyl)-3,4-dihydroisoquinolin-2(llï)-yl]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxylate

Example 227:phenvl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-l//-pyrrol-2-yl]-7-{[(3S)-

3-(piperidÎn-l-ylmethyl)-3,4-dihydroisoquinolin-2(l£0-yl]carbonyl}-3,4- dihydroisoquinoline-2(llï)-carboxylate

Example 228:PhenyI 6-[4-(dibutylcarbamoyl)-l,5-dimetbyl-l/7-pyrrol-2-yl]-7-{[(3S)-

3-[(4-methylpiperazin-l-yl)methyl]-3,4-dihydroisoquinolin-2(lZ/)-yl]carbonyl}-3,4dihydroisoquinoline-2(lfi^r)-carboxylate

- 190Example 229:Phenyl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-lH-pyrrol-2-yl]-7-{[(3S)-

3-[2-(dimethylamino)ethyl]-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinoline-2(lfl^r)-carboxylate

Example 230:Phenvl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-l//-pyrrol-2-yl]-7-{[(3S)-

3-[2-(morpholin-4-yl)ethyl]-3,4-dihydroisoquinolin-2(lfl^r)-yl]carbonyl}-3,4dihydroisoquinoline-2(lfiT)-carboxyl£te

Example 231:A^f-(4-Hvdroxvphenvl)-;V.L2-trimethvl-5-l7-{[(3S')-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolm-2(l£0-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-lH-pyrrole-3-carboxamide

Example 232:2V-Butvl-jV-(4-hvdroxvphenvl)-l,2-dimethvl-5-i7-i(3S)-3-(morpholin-4ylmethyl)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l, 2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxamide

The procedure is as in Example 777, replacing the product from Préparation 6be in Step A with the product from Préparation 6h.

LC/MS (C₄9H₅5N₅O₅) 794 [M+H]⁺; RT 1.23 (Method B)

High-resolution mass (ESI+):

Empirical formula: C49H55N5O5 [M+2H]²⁺ calculated: 397.7174 [M+2H]²⁺measured: 397.7178

Example 233:iV-(4-Hvdroxvphenvl)-1.2-dimethvl-5-l7-|[(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(ljF/)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-X-phenyl-l//-pyrrole-3-carboxamide

- I9l Example 234:ML2-Trimethvl-5-F7-IF(3S)-3-(morpholm-4-ylmethyl)-3,4dihydroisoquinolin-2(l#)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]4V-phenyl-lH-pyrrole-3-carboxamide

Example 235:A-Butvl-l,2-dimethvl-5-F7-{F(3S)-3-Fmorpholin-4-ylmethyD-3.45 dihydroisoquinolin-2(ljE0-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquiiwlin-6-yI]-iV-phenyl-l//-pyrroIe-3-carboxamide

Example 236:l,2-Dimethvl-5-F7-ÎF(3S)-3-(morpholin-4-vlmethvD-3.4dihydroisoquim)lin-2(I//)-yI]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]4V,/V-diphenyl-lH-pyrrole-3-carboxamide

Example 237:/V-Butvl-Ml,2-trimethyl-5-F7-{F(3S)-3-(morpholin-4-vlmethvl)-3.4dihydroisoquim)lin-2(l//)-yl]carb(>nyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolm-6-yl]-ljff-pyrrole-3-carboxamide

Example 238:A^r.iV-Dibutvl-l^-dimethvl-5-F7-{F(3S)-3-(morpholm-4-vlmethvl)-3,4dihydroisoquinolin-2(lH^r)-yl]carbonyl}-2-(phenylacetyl)-l_;723>415 tetrahydroisoquinolm-6-yl]-l//-pyrroIe-3-carboxamide

Example 239:A-(4-Hvdroxyphenyl)-2V,l_<2-trimethvl-5-F7-{ Γ (37?)-3-methyl-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-l//-pvrrole-3-carboxamide

- 192Example 240:A,l,2-Trimethvl-5-[7-{i(37?)-3-methvl-3.4-dihvdroisoquinolin-2(17/)yl]carbonyl}-2-(phenylacetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl]-A-phenyl-LHpyrrole-3-carboxamide

Example 241:A^f-(4-Hvdroxyphenvl)-lJ!-dimethvl-5-i7-([(3R)-3-methvl-3.4dihydroisoquinolin-2(l//)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-iV-phenyl-lir-pyrrole-3-carboxamide

Example 242:lj!-Dimethvl-5-[7-(r(3R)-3-methvl-3.4-dihvdroisoauinolin-2(lLnyl]carbonyl}-2-(phenylacetyl)-l,2,3,4-te4rahydrois()quinolin-6-yl]-;V,iV-diphenyl-l//pyrrole-3-carboxamide

Example 243:/V-lhitvl-A\L2-trimethvl-5-[7-{[(3/?)-3-methvl-3.4-dihvdroisoquinolin2(l//)-yl]carbonyl}-2-(phenyIacetyI)-l,2,3,4-tetrahydroisoquinolin-6-yl]-l//-pyrrole-3carboxamide

Example 244:iV,/V-Dibutvl-1.2-dîmethvl-5-r7-{r(32?)-3-methvl-3.4-dihydroisoquinolîn2(lfiF)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4-tetrahydroisoquinolm-6-yl]-lH-pyrrole-3carboxamide

Example 245:6-{4-[ï4-IIvdroxvphenvl)(methvlkarbamovll-1.5-dimethvl-l//-pvrrol-2yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-Aⁱphenyl-l,2,3,4-tetrahydroisoquinolme-2-carboxamide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step

A with the compound from Préparation 6ba, and replacing phenylacetyl chloride with benzyl iscocyanate.

LC/MS (C₄5H48N₆O₅) 753 [M+H]⁺; RT 1.14 (Method B)

- 193 High-resolution mass (ESI+):

Empirical formula: C45H48N6O5 [M+H]⁺ calculated: 753.3740 [M+H]⁺ measured: 753.3759 ⁵ Example 246:6-{4-ÎButvK4-hvdroxvphenvl)carbamovll-1.5-dimethvl-lH-pyrrol-2-yl}7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-lVphenyl-3,4-dihydroisoquinoline-2(lfi^r)-carboxamide

Example 247: 6-{4-r(4-Hydrox¥phenvl)(phenvl)carbamovll-13-dimethvl-lH-pyrrol-2yl}-7-{[(3S)-3-(morpholin-4-ylmethyi)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-A10 phenyl-3,4-dihydroisoquinoline-2(lfl^r)-carboxamide

Example 248:6-1 L5-DimethyI-4-[methvl(phen¥l)carbamovll-li7-pvrrol-2-vl}-7-{r(3S)-

3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZ/)-yl]carbonyl}-A-phenyl-3,4dihydroisoquino!ine-2(l//)-carboxamide

Example 249:6-l4-[Butvl(phenvl)carbamovl1-l,5-dimethvl-lfir-pvrrol-2-vl)-7-ir(3S)-315 (morpholin-4-yhnethyl)-3,4-dihydroisoquinolin-2(l//)-yl]earbonyl}-A-phenyl-3,4dihydroisoquinoline-2(lH)-carboxamide

Example250:6-[4-(Diphenylcarbamoyl)-l,5-dimethyl-lH^r-pyrrol-2-yl]-7-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-A^r-phenyl-3,4dihydroisoquinoline-2(l//)-carboxamide

u.·· 1' ^.7- i n ; a iz Ajl «_ld Xk Vs/ «f il «if à

I

J -194Example 251:6-{4-[ButvI(methvl)carbamovll-l,5-dimethvl-lH-pvrrol-2-vl}-7-{[(35)-3| (morpholin-4-vhnethyl)-3,4-dihvdroisoquinolin-2(l//)-yl]carbonyI}-A^:-phenyl-3,4dihydroisoquinoline-2(177)-carboxamide

I | Example 252:6- l 4-( Dibut vlcar bamovl)-L5-dimeth vi-1 //-p vrrol-2-vl ]-7-{[(35)-35 (morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(n/)-yl]carbonyl}-2V-phenyl-3,4H dihydi'oisoquinoline-2(l//)-carboxainide

I

Example 253:6-[4-[(4-Hvdroxvphenvl)(methvl)carbaniovlI-1.5-diniethvl-l//-pvrrol-2| yl}-7-[(3/?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-jV-phenyl-l,2,3,4tetrahydroisoquinoIine-2-carboxamide i 10 The procedure is as in Example 777, replacing the compound from Préparation 6be in Step

IA with the compound from Préparation 6bb, and replacing phenylacetyl chloride with benzyl iscocyanate.

I LC/MS (C41H41N5O4) 668 [M+H]⁺; RT 1.31 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H41N5O4 [M+H]⁺ calculated: 668.3231 [M+H]⁺measured: 668.3211

I m Example 254:6-il3-Dimethvl-4-[methvl(phenvl)carbamovll-ljg-pvrrol-2-vll-7-{[(3J?l-

3-methyl-3,4-dihydroisoquinolin-2(lL0-yl]carbonyl}-iV-phenyl-3,4- dihydroisoquinoline-2(l//)-carboxamide

I

- 195 Example255:6-{4-[(4-Hydroxyphenyl)(phenyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2yl}-7-{[(37?)-3-methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-A-phenyI-3,4dihydroisoquinoline-2(l£D-carboxamide

Example 256:6-i4-([)iphenvlcarbaniovl)-1.5-diinethvl-l//-pyrrol-2-yll-7-{[(3A^,)-35 methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-7V-phenyl-3,4-dihydroÎsoquinoline2(l/7j-carboxamide

Example 257:6-f4-[Butvl(methvl)carbamovll-1.5-dimethvl-ljEr-pyrrol-2-yl}-7-{r(3/?)3-methyl-3,4-dihydroisoqumolin-2(lH)-yl]carbonyl}-A-phenyl-3,4dihydroisoquinoline-2(l/7)-carboxamide

Example 258:6-[4-(Dibutvlcarbamovl)-l,5-dîmethvl-17Z-pvrroI-2-vll-7-f[(3R)-3methyl-3,4-dihydroisoquinolin-2(l//)-yl|caibonyl}-iV-phenyl-3,4-dihydroisoquinoline2(l//)-carboxaniide

Example 259: ^-(4-11 vdroxvphenvl)-N,L2-tiimethvl-5-i7-{|(3Æ)-3-methvl-3.4dihydroisoquinolin-2(li0-yl]carbonyl}-2-(2-phenylethyl)-l,2,3,415 te4rahydroisoquinolin-6-yl]-l //-py rrole-3-carboxaniide

Example 260:Benzvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinolme-2(lH)-carboxylate

I

- 196Example 261:A-(4-Hvdroxvphenvl)-A^f,l,2-trimethvl-5-[7-{R3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(lfir)-yl]carbonyl}-2-(phenoxyacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-lH-pyrrole-3-carboxamide

Example 262:AA4-Hvdroxvphemvl)-7V,L2-trimethvl-5-(7-{[(3.R)-3-methvl-3,45 dihydroisoquinolin-2(l//)-yl]carbonyl}-2-[2-oxo-2-(phenyIamino)ethyl]-l,2.3,4tetrahydroisoqumolin-6-yl)-lH-pyrrole-3-carboxamide

Example 263:5-(2-BenzoYl-7-ir(3S)-3-(mt>rpholin-4-vlmethvl)-3,4-dihvdroisoquinolin2(lH)-yl]carbonyl}-1^23₅4-tetrahydroisoquinoliii-6-yl)-ÏV-(4-hydroxyphenyl)-7V,l>2trimethyl-lH-pyrrole-3-carboxamide

Example 264:Æ-(4-Hvdroxyphenvl)-A,l,2-trimethvl-5-(7-{[(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(l/T)-yl]carbonyl}-2-[(2E)-3-phenylprop-2-enoyl]- l,2,3,4-tetrahydroisoquinolin-6-yi)-l//-pyrrole-3-carboxamide

Example 265:AA4-Hvdroxvphenvl)-A\l,2-trimethvl-5-r7-{[(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-2-(3-phenylpropanoyl)-l,2,3,415 tetrahydroisoquin()lm-6-yI]-l//-pyrr()le-3-carboxamide

Example 266:6-M-r(4-Hvdroxvphenvl)(methvl)carbamovl]-l,5-dimethvl-l//-pyrrol-2yl}-A^r-methyl-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yljcar bony 1}-A-pheny l-3,4-dihydroisoquinoline-2( 1 //)-carboxamide

I

- 197 Example 267:6-{4-ÎButvl(4-hvdroxyphenvl)carbamoyll-1.5-dimethvl-lH-pvrrol-2-ynïV-methyl-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-/V-phenyl-3,4-dihydroisoquinolme-2(lH)-carboxamide

Example 268:6-14-r(4-HvdroxYphenyl)(phenvl)carbamovll-1.5-dimethvl-ljH-pvrrol-2yl}-/V-methyl-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-/V-phenyI-3,4-dihydroisoqumoline-2(l_JEr)-carboxaniide

Example 269:6-1 L5-Dimethyl-4-rmethyl(phenyl)carbamovll-lZ/-pyrrol-2-vll<Vmethyl-7-{[(3S)-3-(morpholin-4-yhnethyl)-3,4-dihydroisoquinoIin-2(l//)-yl]carbonyl}/V-phenyl-3,4-dihydroisoquinoHne-2(l//)-carboxainide

Example 270:6-{4-rButvl(phenvl)rarbamoyll-1.5-dimethyl-117-pvrrol-2-vll-2V-metliyl7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoqumolÎn-2(lH)-yl]carbonyl}-7Vphenyl-3,4-dihydroisoquinoline-2(l//)-carboxamide

Example 271:6-r4-(Diphenvlcarbamovl)-l,5-dimethvl-lfir-pyrrol-2-yl1-/V-methyl-7{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquÎnolin-2(l//)-yl]carbonyl}-zVphenyl-3,4-dihydroisoquinoline-2( l//)-carboxamide

Example 272;6-14-rButyl(methvl)carbamovll-1.5-dimethyl-lg-pyrrol-2-yll-iV-methyl7-{[(3S)-3-(morpholin-4-ylmethyI)-3,4-dihydroisoquinolin-2(l/i)-yl]carbonyl}-./Vphenyl-3,4-dihydroisoquinoline-2(LEl^r)-carboxamide

I

- 198 Example 273:6-[4-(Dibutvlcarbamovl)-1.5-dimethvl-l//-pyrrol-2-vl1-jV-methvl-7{[(35)-3-(niorpholin-4-ylmethvl)-3,4-dihydroisoquinolin-2( l//)-yl]carbonyl}-Aphenyl-3,4-dihydroisoqumolme-2(lH)-carboxamide

Example 274:6’{4-r(4-Hvdroxyphenvl)(methvl)carbamovll-13-dimethvl-lfi^r-pyrrol-25 yl}-/V-methyl-7-{[(31¹î)-3-methyl-3,4-dihydroisoquinolin-2(lfi^r)-yl]carbonyl}-N-phenyl-

3.4- dihydroisoquinoline-2(LlT)-carboxamide

Examgle_275:6-{l,5-Dimethyl-4-[metliyl(phenyl)carbamoyl]»liï-pyrrol-2-yl}-A^rmethyl-7-{[(37?)-3-methyl-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl}-A'-phenyl-3,4dihydroisoquinoline-2(lH^r)-carboxamide

Example 276:6-14-r(4-Hvdroxyphenvl)(phenvl)carbamovll-1.5-dimethvl-lÆ-pvrrol-2yl}-A^r-methyl-7-{[(3_JR)-3-methyl-3,4-dihydroisoquinolin-2(lZ/)-yl]carbonyl}-7V-phenyl-

3.4- dihydroisoqumoline-2(liiF)-carboxamide

Example 277:6-r4-(Diphenvlcarbamovl)-L5-dimethvl- l/Z-pvrrol-2-vll-ïV-methvl-7 {[(3R)-3-methyI-3,4-dihydr()isoquinolin-2(lH)-yl]carbonyl}-/V-phenyl-3,415 dihydroisoquinoline-2(l//)-carboxamide

Example 278:6-(4-rButvl(methvl)carbamovll-1.5-dimethv!-l//-pvrrol-2-vl)-;V-methvl7-{[(3R)-3-methyl-3,4-dihydroisoqumolin-2(lfi^r)-yl]carbonyl}-7V-phenyl-3,4dôiydroisoquinoline-2(lFZ)-carboxamide

- 199Example 279:6-r4-(DibutvlcarbamovI)-l,5-dimethvl-l.H^r-pvrrol-2-vri-./V-methyl-7{[(31?)-3-methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-A-phenyl-3,4dihydroisoquinoline-2(lH)-carboxamide

Example 280:5-f2-(Benzvlsulfonvl)-7-{|ï3.S)-3-(morpholin-4-vlmethvl)-3.4dihydroisoquinolin-2(lH^r)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-A^r-(4hydroxyphenyl)-AM,2-trimethyl-l//-pyrrole-3-carboxamide

Example 281:5-[2-(Benzvlsulfonvl)-7-{ [ (3S)-3-(morpholin-4-vlmeth vl)-3.4dihydroîsoquinolm-2(lH^r)-yl]carbonyl}-133,4-tetrahydroisoquinolin-6-yl]>/V,l_y2trimethyI-7V-phenyl-l//-pyrrole-3-carboxamide

Example 282:5-[2-(BenzvlsuIfonvl)-7-{f(3S)-3-(morpholin-4-vlmethvl)-3,4dihydroisoquinolin-2(lH)-yl]carbonyl}-l_>2_y3,4-tetrahydroisoquinolin-6-yl]-/V-(4hydroxyphenyl)-1^2-dimethyl-Æ-phenyl-llï-pyrrole-3-carboxamide

Example 283:5-l2-(Benzvlsulfonvl)-7-{[(3S')-3-(morpholin-4-vImethvl)-3,4dihydroisoquinolm-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-/V,zVdibutyl-l,2-dimethyl-l//-pyrroIe-3-carboxamide

Example 284:5-[2-(Benzvlsulfonvl)-7-{r(3Æ)-3-methvl-3,4-dihYdroisoquinolin-2(17/) yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-/V-(4-hydroxyphenyl)-/V,l,2trimethyl-l/f-pyrrole-3-carboxamide

I

I >0 !

I

I >0 !

I

Example285:5-[2-(Benzylsulfonyl)-7-{[(31?)-3-methyl-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-1^2,3,4-tetrahydroisoquinolin-6-yl]-Æ,l,2-trimethylW-phenyl-17/pyrrole-3-carboxamide

Example 286:5-|2-(Benzvlsulfonvl)-7-{|(3R)-3-methvl-3.4-dihvdroisoquinolin-2(l/f)yl]carbonylj-l,2,3,4-tetrahydr(>isoquinoIin-6-yl]-A’-(4-hydroxyphenyl)-1.2-dimethylA7-phenyl-l/f-pyrrole-3-carboxamide

Example 287:5-[2-(BenzYlsulfonyI)-7-{lï3Æ)-3-methvl-3.4-dihvdroisoquinolin-2(l//)yI]carbonyl}-lA3>4-tetrahydroisoqmnolin-6-yl]-A^-dibutyll,2-dimethyl-lH^rpyrroIe-3-carboxamide

Example 288:ÏV-(4-Hvdroxvphenvl)-A.lJ!-trîmethvl-5-r7-{[(3/?)-3-methyl-3,4dihydroisoquinolin-2(l£0-yl]carbonyl}-2-(phenylsulfamoyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-LH-pyrrole-3-carboxamide

Example 289: AU ,2-Trimethvl-5-i7-{ r(3/?)-3-methvl-3.4-dihvdroisoquinolin-2( 1 yl]carbonyl}-2-(phenylsulfamoyl)-l,2,3,44e4rahydroisoquinolin-6-yT]-A⁷-phenvl-l//pyrrole-3-carboxamide

Example 290:V-(4-Hvdroxvphenvl)-12-dimethvI-5-F7-( Γ (37?)-3-methvl-3.4dihydroisoquinolin-2(l/7)-yl]carbonyI}-2-(phenylsulfarnoyI)-l, 2,3,4tetrahydroisoquinolin-6-yl]-V-phenyl-l//-pyrroIe-3-carboxamide

-201 Example 291:iV,/V-Dibutvl-l,2-dimethyl-5-[7-{[(31?)-3-methvl-3.4-dihYdroisoauinolin2(l//)-yl]carbonyl}-2-(phenylsulfamoyl)-l,2,3,4-tetrahydroisoquinolm-6-yl]-lZ7pyrrole-3-carboxamide

Example 292:ïV-(4-Hvdroxyphenyl)-ïV, l,2-trimethyl-5-(2-|methvl(phenyl)sulfamovll5 7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yI]carbonyl}-l,2,3,4tetrahydroisoquinolin-6-yl)-l//-pyrrole-3-carboxamide

Example 293>V,L2-Trimethyl-5-(2-[methvl(phenyl)sulfamoyl|-7-{r(35)-3-(morpholin-

4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-1^3»4-tetrahydroisoquinolin6-yl)-N-phenyI-l//-pyrrole-3-carboxamide

Example 294:/V-(4-Hydroxyphenyl)-l,2-dimethyl-5-(2-[methyl(phenyl)sulfamoyl]-7{[□S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yljcarbonyl}-î,2,3,4tetrahydroisoquinolin-6-yl)-iV-phenyl-lZf-pyrrole-3-carboxamide

Example 295:iV.AM)ibutyl-L2-dimethyl-5-(2-[methyl(phenyl)sulfamoyl]-7-{ [(35)-3(morpholin-4-yImethyl)-3,4-dihydroisoquinoIm-2(l//)-yl]carbonyl[-l,2,3,415 tetrahydroisoqumoIin-6-yl)-lH-pyrrole-3-carboxamide

Example 296:N-(4-Hydroxyphenyl)-/V,1^2-trimethyl-5-(7-{[(3R)-3-methyl-3,4dihydroisoquînolin-2(lW)-yl]carbonyl}-2-[methyl(phenyl)sulfamoyl]-l^,3,4tetrahydroisoquinolin-6-yl)-lH-pyrrole-3-carboxamide

; *7 U, ; i ’	• ? s-· 1 Y.	* nr-
	. y?

-202Example 297:M l,2-Trimethvl-5-(7-{r(37?)-3-methvl-3.4-dihyaroisoquinolin-2( 177)yl]carbonyl}-2-[methyl(phenyl)sulfamoyl]-1^3»4-tetrahydroisoquinolin-6-yl)-Aphenyl-177-pyrrole-3-carboxamide

Example 298:A^r-(4-Hvdroxvphenvl)-l,2-dimethvl-5-(7-{r(37?)-3-methvl-3.4dihydroisoqumolin-2(177)-yl]carbonyl}-2-[methyl(phenyl)sulfamoyl]-l, 2,3,4tetr ' 'iydroisoquinolin-6-y!)-iV-phenyl-lH-pyrrole-3-carboxamide

Example 299:7V,/V-Dibutvl-lJ!-dimethvl-5-(7-fr(37?)-3-methvl-3,4-dihvdroisoquinolm 2(l/7)-yl]carbonyI}-2-[methyl(phenyl)sulfamoyl]-l,2,3,4-tetrahydroisoquinolm-6-yl)177-pyrrole-3-carboxamide

Example 300:A^r-(4-Hvdroxyphenvl)-7V,U-trimethvl-5-[7-{ [ (3S)-3-(morphoIin-4ylmethyl)-3,4-dihydroisoqmnolm-2(177)-yl]carbonyl}-2-(phenylsulfonyl)-l, 2,3,4tetrahydroisoquinolin-6-yl]-lfiF-pyrrole-3-carboxamide

Example 301:A^r,l^-Trimethvl-5-r7-{r(35)-3-(morpholin-4-vlmethyl)-3,4dihydroisoquinolm-2(177)-yl]carbonyl}-2-(phenylsulfonyl)-l, 2,3,4tetrahydiOÎsoquinolin-6-yl]-;V-phenyl-l/7-pyrroIe-3-carboxamide

Example 302:N-(4-Hvdroxyphenvl)-lJ!-dimethvl-5-r7-ir(35)-3-(morpholm-4ylmethyl)-3,4-dihydroisoqumolin-2(177)-yl]carbonyl}-2-(phenylsulfonyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-A⁷-phenyl-177-pyrrole-3-carboxamide

- 203Example 303:)V,A-Dibutyl-l,2-dimethvl-5-[7-{[(3S)-3-(morpholin-4-vlmethvl)-3.4dihydroisoquinolm-2(l//)-yl]carbonyl }-2-(phenylsulfonyl)-1,2,3,4tetrahydroisoquinolin-6-yl]-lH-pyrroIe-3-carboxamide

Example 3()4:2V-(4-Hvdroxvphenvl)-;VJ,2-trimethvl-5-l7-{[(3R)-3-methvl-3.45 dihydroisoquinolin-2(UÏ)-yl]carbonyl}-2-(phenylsulfonyl)-1^2,3,4tetrahydroisoquinolin-6-yl]-l.H^r-pyrrole-3-carboxamide

Example 305:iV,l,2-Trimethvl-5-[7-{r(37?)-3-methYl-3,4-dihydroisoquinolin-2(T7/)y 1 ]carbonyl}-2-(phenylsulfony 1)-1,2,3,4-tetrahydroisoquinoIin-ô-ylJ-A⁷-phenyl-177pyrroIe-3-carboxamide

Example 306:/V-(4-HvdroxvphenYl)-l,2-dimethyl-5-[7-{[(3Æ)-3-methvl-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-2-(phenylsulfonyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-7V-phenyl-177-pyrrole-3-carboxamide

Example 307:A.2V-DibutYl-l,2-dimethyl-5-i7-{[(3Æ)-3-methyl-3,4-dihydroisoquinolin2(l/7)-yl]carbonyI}-2-(phenylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-6-ylJ-l/f15 pyrrole-3-carboxamide

Example 308: Ph envi 6-1 l-K4-hvdroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindolizin-3-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(l/7)-yl]carbonyl}-3,4-dihydroisoquinoline-2(177)-carboxyIate

I

- 204Example 309:Phenyl 6-{l-[methyl(phenyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3yU-7-{[(3S)-3-(morpholin-4-ylmethyl)>3,4-dihydroisoquinolin-2(LE/)-yl]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxylate

Example 310:Phenvl 6-{l-[(4-hydroxyphenyl)(phenyl)carbamoyl]-5,6,7,8tetrahydromdolizin-3-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolm2(lH)'yl]carbonyl}-3,4-dihydroisoqmnolme-2(lf/)-carboxylate

Example 311:Phenvl 641-(diphenvIcarbamovD-5.6.7.8-tetrahydroindolizin-3-yll-7{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoquinolm-2(lfl^r)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 312:Phenvl 6-{l-[butyl(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoqumolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinoline-2(l/f)-carboxylate

Example 313;Phenvl 6-[ l-(dibuty lcarbamoy 1)-5,6,7,8-tetrahy droindolizin-3-y l]-7{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZZ)-yl]carbonyl}-3,4dihydroisoqumoline-2(lfi^r)-carboxylate

Example 314;Phenvl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8tetrahydroindoIizin-3-yl}-7-{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(l/7)yl]carbonyI)-3,4-dihydroisoquinoline-2(lfir)-carboxylate .s

I

- 205 Example 315;Phenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]indolizin-3-yl}-7{H3.S)-3-(inorpholin-4-ylnH'thyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 316:Phenyl 6-{l-[methyl(phenyl)carbamoyl]indolizin-3-yl}-7-{[(3S)-35 (morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinoline-2(ljET)-carboxylate

Example 317:Phenvl 6-{l-[(4-hydroxyphenyl)(phenyl)carbamoyl]indolîzin-3-yl}-7{[(3S)-3-(morpholin-4-ylmethyI)-3,4-dihydroisoquinolin-2(llï)-yl]carbonyl}-3,4dihydroîsoquinolme-2(lfir)-carboxylate

Example 318:Phenyl 6-[l-(diphenylcarbamoyl)indolizin-3-yl]-7-{[(3S)-3-(morpholin-

4-ylmethyl)-3,4-dihydroîsoquinolin-2(lfi0-yl]carbonyl}-3,4-dihydroisoqumolme2(l//)-carboxylate

Example 319;Phenvl 6-{l-[butyl(methyl)carbamoyl]indolizin-3-yl}-7-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyI}-3,415 dihydroisoqiiinoline-2(l//)-carboxylate

Example 320:Phenvl 641-(dibutvlcarbamoyl)indolizin-3-yi]-7-{[(3S)-3-(morpholin-4yImethyI)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyI}-3,4-dihydroisoquinoline-2(l//)carboxylate

- 206 Example 321:Phenyl 6-{l-[(4-hydroxyphenyl)(methyl)carbamoyl]indolizin-3-yl}-7{[(3/?)-3-methyl-3,4-dihydroisoquinolin-2(llï)-yl]carbonyl}-3,4-dihydroisoquinoline2(lH)-carboxylate

Example 322:Phenvl 6-{3-[(4-hydroxyphenyl)(methyl)carbamoyl]-lH-indol-l-yl}-75 {[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoqumolin-2(lZ/)-yl]carbonyl}-3,4dihydroisoquiiwline-2(l//)-carboxyIate

Example 323:PhenvI6-i3-rmethvl(phenvl)carbamoyll-lÆ^r-indol-l-yl}-7-(r(35)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(ljf/)-carboxylate

Example 324:Phenyl 6-{3-[(4-hydroxyphenyl)(phenyl)carbamoyI]-l//-indol-l-yl}-7{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lfi^r)-yl]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxylate

Example 325:Phenvl 6-r3-(diphenYlcarbamoyl)-l//-indol-l-vll-7-(r(3S)-3-(morpholin-

4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-

2(LH)-carboxylate

Example 326:Phenvl6-43-rbtttvlimethvl)carbamovll-lg-indoM-yl)-7-fr(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l_Jff)-yl]carbonyl}-3,4dihydroisoquinolme-2(l£D-carboxylate

I , · - ·„·-··,1

I ( ' i ‘.£·.

• » i · . z j*- .

*·- . ». k. x' -i

- 207 Example 327:Phenyl 6-|3-(aibutylcarbamoyl)-lH-indol-l-yl]-7-{[(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(i/T)-yl]carbonyl}-3,4-dihydroisoquÎnoline-2(ljF/)carboxylate

Example 328:Phenyl 6-{3-[(4-hydroxyphenyl)(methyl)carbamoyl]-l_JH^r-indol-l-yl}-75 {[(3R)-3-methyl-3,4-dihydroisoquinolin-2(ljH)-yl]carbonyl}-3,4-dihydroisoquinolme2(l/7)-carboxylate

Example 329: Phenyl 6-{3-[(4-hydroxyphenyl)(methyl)carbamoyl]-l//-indazoI-l-yl}-7{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(Uï)-yl]carbonyl}-3,4dihydroisoqumolme-2(liD-carboxylate

Example 330:Phenyl 6-{3-[methyl(phenyl)carbamoyl]-lH-indazol-l-yl}-7-{ [(35)-3(morpholin-4-yhnethyl)-3,4-dihydrois()quinolin-2(177)-yl]carbonyl}-3,4dihydroisoquin(>Iine-2(l//)-carboxyIate

Example 331 : Phenyl 64 34 (4-hydroxyphenyl)(phenyl)carbamoyl ]-lg-indazol- 1-yl }-7{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoIin-2(l//)-yl]carbonyl}-3,415 dihydroisoquinoline-2( 1//)-carboxvlate

Example 332:Phenyl 6-[3-(diphenylcarbamoyl)-lH-indazol-l-yl]-7-{[(35)-3(morphoIin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(l/7)-carboxylate

- 208 Example 333:Phenyl 6-{3-[butyl(methyl)carbamoyl]-lH-indazol-l-yl}-7-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(UT)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 334:Phenvl 6-[3-(dibutylcarbamoyl)-l//-indazol-l-yl]-7-{[(35)-35 (morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoqumolme-2(lH)-carboxylate

Example 335:Phenvl 6-{3-[(4-hydroxyphenyl)(methyl)carbamoyl]-lH-mdazol-l-yl}-7· {[(3R)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline2(lH)-carboxylate

Example 336:Phenvl 6-{4-chloro-3-[(4-hydroxyphenyl)(methyl)carbamoyl]-5-methyll//-pyrazol-l-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoliiie-2(l//)-carboxylate

Example 337;Phenvl 6-{4-chloro-5Tmethyl-3.-[methyl(phenyl)carbamoyl]-lH-pyrazol- l-yl}-7'{[(3S)-3-(morpholin-4-yImethyl)-3,4-dihydroisoquinolm-2(lJ/)-yl]carbonyl}-

3,4-dihydroisoqmnoline-2(Lff)-carboxylate

Example 338;Phenvl 6>{4-chloro-3-[(4-hydroxyphenyI)(phenyl)carbamoyI]-5-methyllH^r-pyrazol-l-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolm-2(lH)·· yl]carbonyl}-3,4-dihydroisoquinolme-2(lH^r)-carboxylate

-209Example 339:Phenyl 6-[4-chloro-3-(diphenylcarbamoyl)-5-methyl-lH-pyrazol-l-yl]7-{[(3S)-3-(morpholin-4-ylmethyI)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinoline-2(lZ/)-carboxylate

Example 340:Phenyl 6-{3-[butyl(methyl)carbamoyl]-4-chloro-5-methyl-llï-pyrazol-l5 yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl}-3,4dihydroisoquinoline-2(llï)-carboxylate

Example 341: Phenyl 6-[4-chloro-3-(dibutylcarbamoyl)-5-methyl-lHT-pyrazol-l-yl]-7{[(3S)-3-(morpholin-4-ylmethyI)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(l/f)-carboxylate o Example 342: Phenyl 6- {4-chloro-3- [(4-hydroxyphenyl)(methyl)carbamoyl] -5-methyll/7-pyrazol-l-yl}-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 343: Phenyl 6-{4-[(4>hydroxyphenyl)(methyl)carbamoyl]-2₎3’dimethyl-LH^r_______ pyrrol-l-yl}-7-{[(3S)-3-(inorpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)15 yljcarbonyl} -3.4-dihydroisoquinoline-2( llï)-carboxylate

Example 344; Phenyl 6-{2,3-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-l-yl}7-{[(3S)-3-(morpholin-4-yhnethyl)-3,4-dihydroisoquinolin-2(l//)-yI]carbonyl}-3,4dihydroisoqumoline-2(lH)-carboxylate

I

-210Example 345;Phenyl 6-{4-[(4-hydroxyphenyl)(phenyl)carbamoyl]-2,3-dimethyl-177| pyrroI-l-yl}-7-{[(3S)-3-(morpholin-4-yhnethyl)-3,4-dihydroisoqiiinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(17T)-carboxylate

I | Example 346:Phenvl 6-[4-(diphenylcarbamoyl)-23-dîmethyl-lff-pyrrol-l-yl]-75 {[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoquinolm-2(lH)-yl]carbonyl}-3,4 dihydroisoquinoline-2(170-carboxylate

I

Example 347:Phenvl 6-{4-[butyl(methyl)carbanioyl]-2,3-dimethyl-l//-pyrrol-l-yI}-7| {[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(LH^r)-carboxylate

I | ¹⁰ Example 348: Phenyl 6-[4-(dibutylcarbamoyl)-2,3-dimethyl-177-pyrrol-l-yl]-7-{[(35)3-(morphoIin-4-yhnethyl)-3,4-dihydroisoquinolm-2(l//)-yl]carbonyl}-3,4| dihydroisoquinoline-2(l/f)-carboxylate

Example 349: Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-2,3-dimethyl-17/pyrrol-l-yl}-7-{[(3jR)-3-methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4dihydroisoqumoline-2(lH)-carboxylate

Example 350:Phenvl 6-{2-[(4-hydroxyphenyl)(methyl)carbamoyl]-5-methyl-l,3thiazol-4-yl}-7-{[(3S)-3-(morphoIin-4-ylmethyl)-3,4-dihydroisoquinoIin-2(l/7)yl]carbonyl}-3,4-dihydroisoquinoline-2(17Z)-carboxylate

I

-211 Example 351:Phenyl 6-{5-methyl-2-[methyl(phenyl)carbamoyl]-l,3-thiazol-4-yl}-7{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lfi^r)-yl]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxylate

Example 352;Phenvl 6-{2-[(4-hydroxyphenyl)(phenyl)carbamoyl]-5-methyl-l,3thiazol-4-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(l£T)-carboxylate

Example 353:Phenvl6-[2-(diphenvlcarbamovl)-5-methvl-13-thiazol-4-vll-7-ir(3S)-3(morpholin-4-yIniethyl)-3,4-dihydroîsoquinolin-2(l//)-yl]carbonyi}-3,4dihydroisoqumoline-2(liO-carboxylate

Example 354:Phenvl 6-{2-[butyl(methyl)carbamoyl]-5-methyl-l,3-thiazol-4-yl}-7{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyI}-3,4dihydroisoquinoline-2(l/7)-carboxyIate

Example 355;Phenvl 6-[2-(dibutylcarbamoyl)-5-methyl-l,3-thiazol-4-yl]-7-{[(3S)-3(morphoIin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH^r)-carboxylate

Example 356:Phenvl 6-124 (4-hvdroxvphenyl)(methvl)carbamovll-5-methyl-l,3thiazol-4-yl}-7-{[(37?)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoqumolme-2(lHT)-carboxylate

I

-212Example 357:Phenyl 5-{4-[(4-hydroxyphenyl)(methyl)carbamoyI]-l,5-dimethyl-lHpyrrol-2-yl}-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lÆ)yljcarbonyl} -1,3-dihy dro-2H-isoindole-2-carboxylate

Example 358:Phenvl 7-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l>5-dimethyl-l#5 pyrrol-2-yl}-8{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lff)yl]carbonyl}l_J3,4,5-tetrahydro-2fI-2-benzazepme-2-carboxylate

Example 359: Phenvl7-i4-r(4-hvdroxyphenvI)(methvl)carbamovll-1.5-dimethyMHpyrrol-2-yl}-8{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoqumolm-2(1^0yl]carbonyl}-l^,4^-tetrahydro-3H-3-benzazepine-3-carboxylate

Example 360:V-(4-HYdroxvphenyD-;V.1.2-trimethvl-5-[7-{[(3.S0-3-(morpholin-4yhnethyl)-3,4-dihydroisoquinolin-2( l//)-yl]carbonyl}-l-oxo-2-(2-phenylethyl)-l,2,3,4 tetrahydroisoqumolin-6-yl]-lff-pyrrole-3-carboxamide

Example 361 :/V-(4-Hvdroxyphenvl)-2V.l J2-trimethvl-5-r 6-{ r(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(lfiT)-yl]carbonyl}-l-oxo-2-(2-phenylethyl)-2,315 dihydro-lH-isoindol-5-yl]-lfir-pyrrole-3-carboxamide

Example 362:Phenvl l,l-difluoro-6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-5-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoqiiinolin2(lH)-yl]carbonyl}-13-dihydro-2iT-isoindole-2-carboxylate jf ‘7'4'A - - -b )

VA Xi A

-215Example 363:PhenyI l,l,33-tetrafluoro-5-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-

1.5- dimethyl-l//-pyrrol-2-yl}-6-{[(3S)-3-(morpholm-4-ylmethyl)-3,4dihydroisoquinolin-2( l//)-yl]carbonyl}-l,3-dihydro-2//-isoindole-2-carboxvlate

Example 364:5-r33-Difluoro-6-{|ï3.S)-3-(inorpholin-4-vlmethvl)-3.45 dihydroisoquinolin-2(l/f)-yl]carbonyl}-l-oxo-2-(2-phenylethyl)-2,3-dihydro-lHisoindol-5-yl]-/V-(4-hydroxyphenyl)-A,1^2-trimethyl-LH-pyrrole-3-carboxamide

Example 365: Phenyl 6-(4-{[2-(dimethylamino)ethyl](4-hydroxyphenyl)carbamoyl}-

1.5- dime4hyl-l//-pyrrol-2-yl)-7-{[(3//)-3-niethyI-3,4-dihydroisoquinoIin-2(l//)yl]carbonyl}-3,4-dihydroisoquinolîne-2(llî)-carboxylate

Example 366:Phenyl 6-(4-{(4-hydroxyphenyl)[2-(morpholin-4-yl)ethyl]carbamoyl}l^-dimethyl-l/Z-pyrrol-2-yl)-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(l£?)yl]cx»rbonyl}-3,4-dihydroisoquinoline-2(l/ï)-carboxylate

Example 367:ïV-l2-(Dimethvlamino)ethvl1-/V-(4-hvdroxyphenyl)-l,2-dimethyl-5-[7{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yI]carbonyl}-2-(phenylacetyl)-l,2,3,415 tetrahydroisoquinolin-b-ylJ-ljfir-pyrrole-S-carboxamide

Example 368:/V-(4-Hvdroxvphenyl)-l,2-dimethyl-5-|7-{[(37/)-3-methyl-3,4dihydroisoquinolin-2(lZ/)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-/V-[2-(inorphoIin-4-yl)ethyI]-l/7-pyrroIe-3-carboxainide

I

-214Example 369;Phenyl 6-(4-{[2-(dimethylamino)ethyl](phenyI)carbamoyl}-l,5dimethyl-lH-pyrrol-2-yl)-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoIine-2( l//)-carboxylate

Example 370:Phenvl 6-(l,5-dimethyl-4-{[2-(morpholm-4yl)ethyl](phenyl)carbamoyl}-lH-pyrrol-2-yl)-7-{[(31?)-3-methyl-3,4dihydroisoquinolin-2(177)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l£0-carboxylate

Example 371:/V-[2-(DimethvIamino)ethvll-l_<2-dimethvl-5-r7-{r(3/?)-3-methyl-3.4dihydroisoquinolin-2(l//)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-;V-phenyl-l//-pyrroIe-3-carboxamide

Example 372:1.2-Dimethvl-5-r7-{fï31?)-3--methvl-3.4-dihvdroisoQuinolm-2(lZr)yl]carbonyl}-2-(phenylacetyl)-1^3j4-tetrahydroisoquinolin-6-yl]-/V-[2-(morpholin-4yl)ethyl]-/V-phenyl-lH-pyrrole-3-carboxamide

Example 373:Phenyl 6-(4-{butvir2-(dimethylamino)ethvlkarbamovl}-1.5-dimethYllH^yrrol-2'yl)-74E(3/0-3-methyl-3,4-dihydroisoqumolm-2(li7)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 374:Phenvl 6-(4-{butvH2-(morpholin-4-vI)ethvllcarbamovl)-l,5-dimethvll//-pyrrol-2-yl)-7-{[(3R)-3-methyl-3,4-dihydroisoquinoIm-2(l//)-yl]carbonyl}-3,4dihydroisoqumolme-2(lfiF)-carboxyIate

HJ

I

-215 Example 375:A-Butvl-A-[2-(dimethvlamino)ethvll-1.2-dimethvl-5-r7-{[(3/?)-3-methyl-

3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4- tetrahydroisoquinolin-6-yl]-lH-pyrrole-3-carboxapiide

Example 376:/V-Butyl-1,2-dimethyl-5- [7-{[(3R)-3-methyl-3,4-dihydroisoquinolin5 2(lff)-yl]carbonyI}-2-(phenylacetyl)-l^,3,4-tetrahydroisoquinolin-6-yl]-A^r-[2(morpholm-4-yl)ethyl]-lfiT-pyrrole-3-carboxamide

Example 377:Phenvl 6-{ l-[2-(dimethylamino)ethyl]-4-[(4hydroxyphenyl)(methyl)carbamoyl]-5-methyl-lH-pyrroE2-yl}-7-{[(3jR)-3-methyl-3,4dihydroisoquinoIin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 378:Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-5-methyl-l-[2(morpholin-4-yl)ethyl]-l£r-pyrrol-2-yl}-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 379:l-r2-(DimethYlamino)ethyl]-A-(4-hvdroxyphenyl)-A,2-dimethyl-5-[7{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl}-2-(phenylacetyl)-1,2,3,415 tetrahydroisoqumolîn-6-yI]-ljff-pyrrole-3-carboxamide

Example 380:/V-(4-Hvdroxvphenyl)-A,2-dimethyl-5-[7-{[(3R)-3-methyl-3,4dihydroisoquinolin-2(lH)-yIlcarbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinoIin-6-yl]-l-[2-(morpholin-4-yl)ethyl]-l//-pyrrole-3-carboxamide i-i. -44 2-i jL .J, À LL

- 216 Example 381:Phenyl 6-{l-[2-(dimethylamino)ethyl]-5-methyl-4[methyl(phenyl)carbamoyl]-lZf-pyrrol-2-yl}-7-{[(3Æ)-3-methyl-3,4dihydroisoquinolin-2(lZ7)-yl]carbonyl}-3,4-dihydroisoquinoIine-2(lH)-carboxylate

Example 382;Phenvl 7-{[(31?)-3-methyl-3,4-dihydroisoquinolin-2(lfiF)-yl]carbonyl}-65 {5-methyl-4-[methyl(phenyl)carbamoyl]-l-[2-(morpholin-4-yl)ethyl]-l/7-pyrrol-2-yl}-

3,4-dihydroisoquinoIine-2(l//)-carboxylate

Example 383:l-r2-(Dimethvlamino)ethvll-7V.2-dimethvl-5-[7-{r(3Æ)-3-methvl-3.4dihydroisoquinolin-2(lfiF)-yl]carbonyl}-2-(phenylacetyl)-l^,3,4tetrahydroisoquinolm-6-yl]-/V-phenyl-ljEir-pyrrole-3-carboxamide

Example 384:./V,2-DimethvI-5-l 7-{ Γ (3/?)-3-methvl-3.4-dihvdroiso(iuinolin-2( 1H)yl]carbonyl}-2-(phenylacetyl)-l,2,3,4-tetrahydroisoquinolm-6-yl]-l-[2-(morphoIm-4yl)ethyl]-/V-phenyl-l//-pyrrole-3-carboxamide

Example 385:Phenvl 6-{4-(dibutylcarbamoyl)-l-[2-(dimethylamino)ethyl]-5-methyl17/-pyrrol-2-yl}-7-{[(3/i)-3-methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,415 dihydroisoquinoline-2(l//)-carboxylate

Example 386:Phenvl6-I4-(dibutvlcarbamovl)-5-methvl-l-r2-(morpholin-4-vDethvlllZT-pyrrol-2-yl}-7-{[(3K)-3-methyl-3,4-dihydroisoqumolin-2(lii^r)-yl]carbonyl}-3,4dihydroisoquinolme-2(liO-carboxylate

I

- 217 .

Example387:A,ïv-Dibutyl-l-[2-(dimethylamino)ethyl]-2-methyl-5-[7-{[(3/î)-3-methyl-

3.4- dihydroisoc ai _l)lin-2(lZZ)-yl]carbonyl}-2-(phenylacetyl)-l_y2,3,4tetrahydroisoquinoIin-6-yl]-lZZ-pyrrole-3-carboxamide

Example 388:Α,Λ )ibutyl-2-methyl-5-[7-{[(3jR)-3-methyl-3,4-dihydroisoquinolin2(lH)-yl]carbonylL2-(phemylacetyl)-l,2,3,4-tetrahydroisoquinoIin-6-yl]-l-[2(morpho!in-4-yl)ethyl]-l//-pyrroIe-3-carboxamide

Example 389:2-(4-Methvlpiperazin-l-vl)phenvl 6-{4-[(4hydroxyphenyl)(msthyl)carbamoyl]-l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3R)-3-methyl-

3.4- dihydroisoquinolin«2(ljH)-yl]carbonyl}-3,4-dihydroisoquinolme-2(lH)carboxylate

Example 390:2-{ [2 (Dimethylamino)ethyl](methyl)amino}phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lZZ-pyrrol-2-yl}-7-{[(3_JR)-3-methyl-

3.4- dihydroîsoquir iin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)carboxylate

Example 391:2-{Γ 2-(Dimethvlammo)ethvllamino}phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l^-dimethyl-ljï-pyrrol-2-yl}-7-{[(31?)-3-methyl-

3.4- dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoqumoIme-2(lH)carboxylate

Example 392:2-r2-(Dimethylammo)ethoxy]phenyl 6-{4-[(4-hydroxyphenyl) (methyl)carbamoyl]-13-dimethyl-ljfiT-pyrrol-2-yl}-7-[(31î)-3-methyl-1^3?4tetrahydroisoquinoline-2-carbonyl]-l,23,4-tetrahydroisoquinoline-2-carboxylate

I

-218The procedure is as in Example 709, replacing the product from Préparation 6ba in Step A with the product from Préparation 6bb, and replacing benzyl 3-hydroxybenzoate from Step B with 3-[2-(dimethylamino)ethoxy]phenol.

LC/MS (C45H49N5O6) 754 [M-H]'; RT 2.27 (Method A)

High-resolution mass (ESI+):

Empirical formula: C4sH49N₅O6 [M+2H]²⁺calculated: 378.6914 [M+2H]²⁺ measured: 378.6926

Example 393:2-r2-(Dimethvlamino)ethvl]phenvI 6-(4-((410 hydroxyphenyl)(inethyl)carbamoyl]-l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3/?)-3-inethyl-

3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)carboxylate

Example 394; 2-( (Dimethvlamino)methvllphenvl 6-{4-[(4-hydroxyphenyl) (methyI)carbainoyl]-l,5-diinethyI-l//-pyrrol-2-yl}-7-{[(3R)-3-methyl-3,415 dihydroisoquinolm-2(lH)-yl]carbonyI}-3,4-dihydroisoquinoline-2(lH^r)-carboxylate

Example 395:2-(3-(Dimethvlamino)prop-l-vn-l-vl]phenvl 6-(4-((4hydroxyphenyl)(methyl)carbamoyl]-l,5-diinethyl-lH-pyrrol-2-yl}-7-{[(3R)-3-methyl-

3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)carboxylate

Example 396: A-(4-Hvdroxvphenvl)-(V.l,2-trimethvl-5-(7-( f (3R)-3-methvl-3,4dihydroisoquinolin-2(lH)-yl]carbonyl}-2-([2-(4-methylpiperazin-l-yl)phenyl]acetyl}- l,2,3,4-tetrahydroisoquinolin-6-yl)-l//-pyrrole-3-carboxamide

I

-219Example 397:5-(2-lï2-{r2-(DimethvIammo)ethvIl(methvDamino)phenyDacetyll-7{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-l>2,3.4tetrahydroisoquinolin-6-vl)-V-(4-hydroxyphenyl)-VJ,2-trimethyl-l//-pynole-3carboxamide

Example 398:5-(2-[(2-{ r2-(Dimethvlammo)ethyllamino}phenvl)acetvll-7-i Γ (3R1-3methyl-3,4-dihydroisoquinolin-2(lH^r)-yl]carbonyl}-l_y23_?4-tetrahydroisoquinolin-6yl)-;V-(4-hydroxyphenyl)-A^?,l,2-trimethyl-l//-pyrro!e-3-carboxamide

Example 399:5-Γ2-Η 2-Γ 2-(Dimethvlamino)ethoxv]phenvl }acetvl)-7-l Γ (3R)-3-methvl-

3,4-dihydroisoquiiu>lin-2(l/f)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinoIin-6-yl]>V-(4- hydroxyphenyD-Ml^-trimethyl-lJÏ-pyrrole-S-carboxamide

Example 400:5-[2-({2-f2-(Dimethvlamino)ethvl]phenyl)acetvl)-7-[r(3R)-3-methyl-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-X-(4hydroxyphenyl)-/V,1^2-trimethyl-lff-pyrrole-3-carboxamide

Example 401:5-r2-({2-r(Dimethvlamîno)methyllphenyl}acetyl)-7-{r(3R)-3-methyl-3,415 dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-iV-(4hydroxyphenyl)-yV,l,2-trimethyl-l/7-pyrrole-3-carboxamide

Example 402:5-r2-(|2-[3-(Dimethylamino)prop-l-yn-l-ynphenyl}acetyl)-7-{[(3R^,)-3methyl-3,4-dihydroisoquinolin-2(lfi^r)-yl]carbonyl}-1^23?4’tetrahydroisoqmnolin-6ylJ-AM4Jiydroxyphenyl)-AJl,24rimethyl-l//-pyrrole-3-carboxamide

Mu*

- 220 Example 403:2-(4-Methvlpiperazin-l-vl)phenvl 6-{ l,5-dimethyl-4[methyl(phenyl)carbamoyl]-llï-pyrrol-2-yl}-7-{[(3Z?)-3-methyl-3,4dihydroisoquinolin-2(lZO-yl]carbonyl}-3,4-dihydroisoquinoline-2(17Z)-carboxylate

Example 404:2-{F2-(Dimethvlamino)ethvl](methvDamino)phenyl 6-{l,5-dimethyl-45 [methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-{[(3R)-3-methyl-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoqiiinoline-2(l//)-carboxyIate

Example 405:2-{F2-(Dimethvlamino)ethvllaminoÎphenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyI]-l/7-pyrrol-2-yl}-7-{[(3R)-3-methyI-3,4dihydroisoquinolin-2(lfl^r)-yl]carbonyl}-3,4-dihydroisoquinoline-2(ljH^r)-carboxylate

Example 406:2-F2-(Dimethvlamino)ethoxv]phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3A^,)-3-methyl-3,4dihydroisoquinolm-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l/7)-carboxylate

Example 407:2-F2-(Dimethvlammo)ethvl]phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3Æ)-3-methyl-3,415 dihydroisoquinolin-2(l/7)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l/7)-carboxylate

Example 408:2-F(Dimeth vlamino)methvl]phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lfir-pyrrol-2-yl}-7-{[(3R)-3-methyl-3,4dihydroisoquinolin-2(LE0-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

I

-221 Example 4Q9:2-[3-(Dimethvlamino)prop-l-vn-l-yllphenyl 6-{l,5-dimethyl-4[methyl(phenyI)carbamoyl]-17/-pyrrol-2-yl}-7-{[(3J?)-3-methyl-3,4dihydroisoqmnolm-2(lJï)-yl]carbonyl}-3,4-dihydroisoquinoline-2(ltf)-carboxylate

Example 410:Mlv2-Trimethvl-5-(7-{|ï31?)-3-methvl-3.4-dihvdroisoqiimolin-2(177)5 yl]carb(myl)-2-{[2-(4-methylpiperazin-l-yl)phenyl]acetyl}-l,2,3,4tetrahydroisoquinolm-6-yl)-Æ-phenyI-lF-pyrrole-3-carboxamide

Example 411:5-(2-Γ(2-{ r2-(Dimethvlammo)ethvll(methvl)amino}phenvI)acetvll-7{[(3_JR)-3-methyl-3,4-dihydroisoquinolin-2(lfi^r)-yl]carbonyl}-l^_y3>4tetrahydroisoqumolin-6-yl)-/V,1^2-trimethyl-/V-phenyl-lfiF-pyrrole-3-carboxamide

Example_412:5-(2-[(2-{[2-(Dimethylammo)ethyl]amino}phenyl)acetyl]-7-{[(3J?)-3methyl-3,4-dihydroisoquinolin-2(lfi^r)-yl]carbonyl}-l^_?3,4-tetrahydroisoquinolin-6yl)-_!V,l,2-trimethyl-_iV-phenyl-l//-pyrrole-3-carboxamide

Example 413:5-[2-({2-[2-(Diniethvlamino)ethoxv]phenvl}acetyl)-7-{r(3Æ)-3-methvl-

3,4-dihydroisoquinolin-2(LE0-yl]carbonyl}-l_;33»4-tetrahydroisoqumoIin-6-yl]-iV,l^- trimethyl-lV-phenyl-lH-pyrrole-3-carboxamîde

Example 414:5-r2-((2-f2-(Dimethylamino)ethylIphenyllacetyl)-7-{r(3J?)-3-methyl-3,4dihydroisoquiiu)lin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolm-6-yl]-A^,,l,2trimethyl-;V-phenyl-l//-pyrrole-3-carboxamide

I

-222 Example 415:5-[2-({2-[(Dimethvlamino)methvllphenvl)acetvl)-7-ilï37?)-3-methvl-3.4(lihydroisoquinolin-2(l/7)-vl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yI]-N,l,2trimethyl-7V-phenyl-lH-pyrrole-3-carboxamide

Example 416:5-r2-({2-[3-(Dimethvlamino)prop-l-vn-l-vl]phenvllacetvl)-7-fR37?)-35 methyl-S^-dihydroisoquinolin^CliD-yllcarbonylî-l^^^-tetrahydroisoquinolin-ôyl]-A,l,2-trimethyl-?7-phenyl-lff-pyrrole-3-carboxamide

Example 417:2-(4-Methvlpiperazin-1-vl)phenvl 6-[4-(dibutylcarbamoyl)-l,5dimethyl-lW-pyrrol-2-yl]-7-{[(3K)-3-methyl-3,4-dihydroisoqumolin-2(l//)yl]carbonyl}-3,4-dihydroisoqmnolme-2(l//)-carboxylate

Example 418:2-{[2-(Dimethvlammo)ethvll(methyl)ammo)phenvl 6-[4(dibutylcarbamoyl)-l,5-dimethyl-l//-pyiTol-2-yl]-7-{[(3Æ)-3-methyl-3,4dihydroisoquinolm-2(lfi^r)-yI]carbonyl}-3,4-dihydroisoquinoIine-2(lH)-carboxylate

Example 419:2-{r2-(Dimethvlamino)ethvllammQ)phenvl 6-[4-(dibutylcarbamoyl)-l,5dimethyl- LHT-pyrrol-2-yl]-7-{ [(3R)-3-methyl-3,4-dihy droisoquinolin-2( 1H)15 yl]caiT)onyl}-3,4-dihydroisoqumolÎne-2(l//)-carboxylate

Example 420:2-i2-(Dimethvlamino)ethoxy]phenvl 6-[4-(dibutylcarbamoyl)-l,5dimethyl-l//-pyrn)l-2-yl]-7-{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-earboxylate

- 223 Example 421:2-[2-(Dimethvlamino)ethyl]phenyl 6-[4-(dibutylcarbamoyl)-l,5dimethyl-177-pyrrol-2-yl]-7-{[(37?)-3-methyl-3,4-dihydroisoquinolin-2(177)yl]carbonvl}-3,4-dihydroisoquinoline-2(177)-carboxylate

Example 422:2-r(Dimethylamino)methvllphenvl 6-[4-(dibutylcarbamoyl)-l,55 dimethyl-177-pyrrol-2-yl]-7-{[(37?)-3-methyl-3,4-dihydroisoqumoliii-2(lH)yl]carbonvI}-3,4-dihvdroisoquinoline-2(177)-carboxyIate

Example 423:2-r3-(Dimethvlammo)prop-l-vn-l-vllphenvl6-r4-(dibutvlcarbamovD- l,5-dimethyl-177-pyrroI-2-yl]-7-{[(377)-3-methyl-3,4-dihydroisoquinoIin-2(JL77)yI]carbonyI}-3,4-dihydroisoquinoIme-2(l//)-carboxylate

Example 424:ALV-Dibutyl-l,2-diinethYl-5-(7-{|(377)-3-methYl-3,4-dihydroisoquinolin2(177)-yl]carbonyl}-2-{[2-(4-methylpiperazin-l-yl)phenyl]acetyl}-l,2,3,4tetrahydroisoquinolin-6-yl)-177-pyrrole-3-carboxamide

Example 425:ALV-DibutYl-5-(2-[(2-{[2-(dimethyIamino)ethyl](methvl)amino} phenyI)acetyl]-7-{[(370-3-methyl-3,4-dihydroisoqumolm-2(177)-yl]carbonyl}-l,2,3,415 tetrahydroisoquinolin-6-yl)-l,2-dîmethyl-lH-pyrrole-3-carboxamide

Example 426:/VjV-Dibutvl-5-(2-R2-U2-(dimethvlamino)ethyl]amino}phenyI)acetyl]-7{[(3/?)-3-methyl-3,4-dihydroisoquinolm-2(l/7)-yl]carbonyl}-l,2,3,4tetrahydroisoquinolin-6-yl)-1^2-dimethyl-lff-pyrrole-3-carboxamide

- 224Example 427: iV,./V-Dibutvl-5-r2-({2-[2-(dimethvlammo)ethoxvlDhenyllacetvD-7n(3/?)-3-methyl-3,4-dihydroisoquinolin-2( l//)-yl]carbonyl}-l. 2,3,4tetrahydroisoquinolin-6-yl)-l,2-dimethyl-177-pyrrole-3-carboxamide

Example 428; jV,A^r-Dibutyl-5-[2-({2-[2-(dimethylamino)ethyl]phenyl}acetyl)-7-{[(3Æ)3-inethyl-3,4-dihydroisoquÎnolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6yl]-l,2-dimethyl-lH-pyrrole-3-carboxamide

Example 429: N,N-Dibutyl-5-[2-((2-[(dimethylamino)metliyl]phenyl}acetyl)-7-{[(3Zf)3-methyl-3,4-dihydroisoquinolin-2(li0-yl]carbonyl}-1^2,3,4-tetrahydroisoquinolin-6yI|-l,2-dimethyl-lH-pyrrole-3-carboxamide

Example 430:/V,/V-Dibutyl-5-[2-((2-[3-(dimethylamino)prop-l-yn-l-yl]phenyl}acetyl)7-{[(3R)-3-medhyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4tetrahydroisoquinolin-6-yl]-l,2-dimethyl-l//-pyrroIe-3-carboxamide

Example 431: 3-(4-Methylpiperazin-l-yl)phenyl 6-(44(4- hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3K)-3-methyI-

3.4- dihydroisoquiiK)lin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)carboxylate

Example 432: 3-{[2-(Dimethylamino)ethyl](methyl)amino}phenyl 6-(4-((4hydroxyphenyl)(methyl)carbamoyl]-13-dimethyl-lfiT-pyrrol-2-yl}-7-{[(31î)-3-methyl-

3.4- dihydroisoquînolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)carboxylate

- 225 Example 433: 3-{[2-(Dimethylamino)ethyl]amino}phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7-{[(3R)-3-methyl-

3.4- dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)carboxylate

Example 434: 3-[2-(Dimethylammo)ethoxy]phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7-[(3R)-3-methyl-

1.2.3.4- tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2carboxylate

The procedure is as in Example 709, replacing the product from Préparation 6ba in Step A with product from Préparation 6bb, and replacing benzyl 3-hydroxybenzoate from Step B with 3-[2-(dimethylamino)ethoxy]phenol.

LC/MS (C₄5H49N₅O₆) 754 [M-H]'; RT 2.24 (Method A)

High-resolution mass (ESI+):

Empirical formula: C45H49N5O6 [M+2H]²⁺ calculated: 378.6914 [M+2H]²⁺measured: 378.6918

Example 435: 3-r2-(Dimethylamino)ethynphenyl 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin2(l/7)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 436: 3-[(Dimethylamino)methyl]phenyl 6-{4-[(4-hydroxyphenyl) (methyl)carbamoyl]-l,5-dimethyl-lfiT-pyrrol-2-yI}-7-{[(3jR’)-3-methyl-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

- 226Example 437:3-[3-(Dimethvlamino)prop-l-vn-l-vl]phenvl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyi-l#-pyrrol-2-yl}-7-{[(31?)-3-methyl-

3.4- dihydroisoquinolin-2(l/Z)-yIJcarbonyl}-3,4-dihydroisoquinoline-2(lH)carboxylate

Example 438:iV-(4-Hvdroxvphenvl)4V,1.2-trimethvl-5474r(3R)-3-methyl-3.4dihydroisoquinolin-2(lH^r)-yl]carbonyl}-2-{[3-(4-methylpiperazin-l-yl)phenyl]acetyl}-

1.2.3.4- tetrahydroisoquinolin-6-yl)-l//-pyrrole-3-carboxamide

Example 439;5-(2-r(3-n2-(Dimethvlamino)ethvll(methvl)amino)phenvDacetyll-7{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(ljFf)-yl]carbonyl}-l,2,3,4tetrahydroisoquinolin-6-yl)-M(4-hydroxyphemyl)-/V,l,2-trimethyl-l//-pvrrole-3carboxamide

Example 440:5-(2-r(3-(r2-(DimethvIamino)ethvllamino)phenvl)acetvll-7-H (3R1-3methyl-3,4-dihydroisoquinoIin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolm-6yl)4V-(4-hy droxy phenyl)4V, 1,2-trimethyl-lfiF-py rrole-3-carboxamide

Example 441:542-(13424 Dimethvlaminokthoxv lphenvi lacet vl)-74 1 (3R)-3-methvl-

3.4- dihydroisoquinolm-2(l/7)-yl]carbonyl}-l,2,3,4-tetrahydroisoquniolin-6-yl]-zV-(4hydroxyphenyl)-/V,l,2-trimethyl-l//-pyrrole-3-carboxamide

Example 442:542-({342-(Dimethvlammo)ethvllphenvl)acetvD-74r(3R)-3-methvl-3.4dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-yV44hydroxyphemyl)-A\l,2-trimethyl-l//-pyrrole-3-carboxamide

- 227 Example 443:5-F2-({3-[(Dimethvlamino)methyl]phenyl}acetvl)-7-{[(3R)-3-methyl-3.4dihydroisoquinolin-2(lH)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-A-(4hydroxyphenyl)-.V,l,2-trimethyl-l//-pyrrole-3-carboxamide

Example_444:5-[2-({3-[3-(Dimethylamino)prop-l-yn-l-yl]phenyl}acetyl)-7-{[(3jR’)-35 methyl^^-dihydroisoquinolin^CliO-yllcarbonyn-l^^^-tetrahydroisoquinolin-ôyl|-iV-(4-hydiOxyphenyl)-zV,l,2-trimethyI-l//-pyrrole-3-carboxamide

Example 445;3-(4-Methvlpiperazm-l-vI)phenvl 6-{l,5-dimethyI-4-[methyl(phenyl) carbamoyl]-l//-pyrrol-2-yI}-7-{[(3Æ)-3-methyl-3,4-dihydroisoquînolm-2(l/f)yl]carbonyl}-3,4-dihydroisoqumoline-2(LfiF)-carboxylate

Example 446:3-1 [2-(Dimethylamino)ethyl](methyl)amino}phenyl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3jR)-3-methyl-l^,3,4tetrahydroisoquinoline-2-carbonyl]-l_>2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 786, replacing 4-hydroxybenzonitrile in Step B with 3-{[2(dimethylamino)ethyl](methyl)amino}phenol.

LC/MS (C46H52N6O4) no ionisation; RT 2.44 (Method A)

High-resolution mass (ESI+):

Empirical formula: C46H52N6O4 [M+2H]²⁺ calculated: 377.2098 [M+2H]²⁺ measured: 377.2100

I

- 228 Example 447:3-{F2-(Dimethvlamino)ethvllamino)phenvl 6-{l,5-dimethyl-4| [methvKphenyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3/?)-3-inethyl-3,4dihydroisoquinolin-2(liO-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

I | Example 448:3-r2-(Dimethvlamino)ethoxv]phenvl 6-{l,5-dimethyl-45 [methyl(phenyl)carbamoyl]-LfiT-pyrroI-2-yl}-7-[(37î)-3-methyl-1^2,3,4| tetrahydroisoquinoline-2-carbonyI]-l>2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 786, replacing 4-hydroxybenzonitrile in Step B with 3-[2| (dimethylamino)ethoxy]phenol.

LC/MS (C45H49N5O5) 740 [M+H]⁺; RT 1.20 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H49N5O5 [M+2H]²⁺ calculated: 370.6940 [M+2H]²⁺ measured: 370.6954

I

Example 449:3-r2-(Dimethvlamino)ethvllphenvl 6-{l,5-dimethyl-4| 15 [methyI(phenyl)carbamoyI]-l//-pyrrol-2-yl}-7-{[(3R)-3-inethyl-3,4dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinolme-2(LF/)-carboxylate

Example 450:3-r(Dimethvlamino)methvllphenvl 6-{l,5-dimethyl-4- — [methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3Æ)-3-methyl-3,4- dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

I

-229Example 451:3-i3-(Dimethvlamino)prop-l-vn-l-vl]phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lfiT-pyrrol-2-yl}-7-{[(3R)-3-methyl-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 452:NJ.2-Trimethvl-5-(74 [ (37?)-3-methvl-3.4-dihvdroisoauinolin-2( IfiD5 yl]carbonyl}-2-{[3-(4-methylpiperazin-l-yl)phenyI]acetyl}-l,2,3,4te4rahydroisoquinolin-6-yl)-Aⁱ-phenyl-l//-pyrrole-3-carboxamide

Example 453:5-12-Γ (3-il2-(Dimethvlamino)ethvll(methvl)amino)phenvl)acetvn-7{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(l//j-yl]carboiiyI}-l,2,3,4tetrahydroisoquin()lin-6-yl)-/V,l,2-triniethyl-iV-phenyl-l//-pyrrole-3-carboxamide

Example 454:5-(2-)(3-) r2-(Dimethvlamino)ethyl]amino)phenvl)acetvll-7-{ Γ (377)-3methyI-3,4-dihydroisoqiiinolin-2(l/7)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinoIin-6yl)-N,1^2-trimethyl-7V-phenyl-lH-pyrrole-3-carboxamide

Example 455:5-)2-( {3-l2-(Dimethvlamino)ethoxy]phenvl)acetvl)-7-| [ (377)-3-methyl-

3,4-dihydroisoquinolin-2(TZf)-yl]carbonyl}-l,2,3,4-tetrahydroisoqiiinolin-6-yl]-iV,l,2- trimethyl-/V-phenyl-17/-pyrrole-3-carboxamide

Example 456:5-i2-({3-i2-(Dimethylamino)ethvl]phenvl}acetyl)-7-{)(3R)-3-methyl-3,4dihydroisoquînolin-2(lH)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-7V,l,2trimethyl-iV-phenyl-177-pyrrole-3-carboxarnide

- 230Example 457:5-i2-({3-[(Dimethvlamino)methvl]phenvl)acetvl)-7-ii(37?)-3-methvl-3.4dihydroisoquinolin-2( l//)-yl]carbonyl}-l,2,3,4-te4rahvdroisoquinolin-6-yl]-ïV,l,2trimethyl-/V-phenyl-17/-pyrrole-3-carboxamide

Example 458:5-i2-({3-r3-(DimethvIamino)prop-l-vn-l-vllphenvBacetyD-7-{r(37?)-35 methyl-3,4-dihydiOisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6yl]-/V,l,2-trimethyl-2V-phenyl-lH-pyrrole-3-carboxamide

Example 459:3-(4-Methvlpiperazin-l-vl)phenvl 6-[4-(dibutylcarbamoyl)-l,5dimethyl-l//-pyrrol-2-yl]-7-{[(3Æ)-3-me4hyl-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoqumolme-2(LH)-carboxylate

Example 460:3-iÎ2-(Dimethvlamino)ethvll(methvl)amino Îphenvl 6-[4filibutylcarbamoyl)-l,5-dimethyl-l//-pyrrol-2-yl]-7-{[(37?)-3-methyl-3,4dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l/r)-carboxylate

Example 461:3-{r2-(Dimethvlammo)ethvllamino Iphenvl 6-[4-(dibutylcarbamoy 1)-1,5 dimethyl-l/7-pyrroI-2-yl]-7-{[(3/?)-3-methyl-3,4-dihydroisoquinolin-2(l//)15 yl]carbonyl}-3,4-dihydroisoqmnoline-2(lZZ)-carboxylate

Example 462:3-f2-(Dimethvlamino)ethoxv]phenvl 6-[4-(dibutylcarbamoyl)-l,5dimethyl-lfiT-pyrrol-2-yl]-7-{[(3Æ)-3-methyl-3,4-dihydroisoquinoIin-2(lH)yl]carbonyl}-3,4-dihydroisoqumolme-2(lH)-carboxylate

-231 Example 463:3-[2-(Dimethvlamino)ethyl]phenvl 6-[4-(dibutyIcarbamoyl)-l,5dimethyl-lH-pyrrol-2-yl]-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoqumoline-2(177)-carboxylate

Example 464:3- Γ (Dimethvlamino)methvllphenvl 6-[4-(dibutylcarbamoyl)-l,55 dimethyl-l//-pyrrol-2-yI]-7-{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(lJ7)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 465:3-F3-(Dimethvlammo)prop-l-vn-l-vllphenvl 6-r4-(dibutvlcarbamoyD- l,5-dimethyl-lH-pyrrol-2-yl]-7-{[(31?)-3-methyl-3,4-dihydroisoqmnolm-2(lfiDyl]carbonyI}-3,4-dihydroisoqumoline-2(l//)-carboxyIate

Example 466:;VuV-Dibutvl- 1.2-diinethyl-5-(7-{ [ (37?)-3-methyl-3,4-dihvdroisoqumolin2(l//)-yl]carbonyl}-2-{[3-(4-methylpiperazin-l-yl)phenyl]acetyl}-l,2,3,4tetrahydroisoquinolin-6-yl)-l//-pyrrole-3-carboxamide

Example 467:/V.zV-Dibutvl-5-(2-r(3-{[2-(dimethvlamino)ethvl|(methYl)aminol phenyl)acetyl]-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,415 tetrahydroisoquiiwlin-6-yl)-1,2-dimethyl-l//-pyrrole-3-carboxamide

Example 468:iV./V-Dibutvl-5-(2-i(3-|[2-(diinethYlamino)ethyl]amino}phenyl)acetyl]-7{[(3/?)-3-methyl-3,4-dihydroisoquinolm-2(lH)-yl]carbonyl}-l_>23,4tetrahydroisoquinolm-6-yl)-1^2-dimethyl-lH-pyrrole-3-carboxamide

- 232 Example 469: /V,(V-Dibutyl-5- [2-((3-(2-(dimethvIamino)ethoxy]phenvl lacetvl)-7{[(3/?)-3-methyl-3,4-dihydroisoquinolin-2(lI0-yl]carbonyl}-1^2,3,4tetrahydroisoquinolin-6-yl]-l,2-dimethyl-lH-pyrrole-3-carboxamide

Example 470:N,/V-Dibutvl-5-r2-(f3-i2-(dimethvlamino)ethvl]phenvllacetyl)-7-(r(31?)3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3<4-tetrahydroisoquinolin-6yl]-l,2-dimethyl-l/Z-pyrrole-3-carboxamide

Example 471:A//V-DibutvI-5-r2-({3-Î(dimethvlamino)methvl]phenvllacetyD-7-(r(31?)3-methyl-3,4-dihydroisoquinolin-2(l//)-yT]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6yl]-l,2-dimethyl-17/-pyrrole-3-carboxamide

Example 472:MA^f-Dibutvl-5-r2-(f3-r3-(dimethvlamino)prop-l-vn-l-vllphenyllacetyD7-{[(31?)-3-methyl-3,4-dihydroisoquinolin-2(lfiO-yl]carbonyl}-l,2,3,4tetrahydroisoquinolin-6-yl]-l,2-dimethyl-l//-pyrrole-3-carboxamide

Example 473:4-(4-Methvlpiperazm-l-vl)phenvl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyI-l//-pvrr()l-2-yl}-7-{[(3/?)-3-methyl-

3,4-dihydroisoqmnolin-2(llï)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lfi^r)- carboxylate

Example 474:4’ir2-(Dimethvlammo)ethvll(methvl)amino)phenyl 6-{4-[(4hydroxyphenyl)(methyI)carbamoyl]-l,5-dimethyl-l//-pyrrol-2-yl}-7-[(37i)-3-inethyl l,2,3,4-tetrahydroisoqumoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolme-2carboxylate

- 233 The procedure is as in Example 709, replacing the product from Préparation 6ba in Step A with the product from Préparation 6bb, and replacing benzyl 3-hydroxybenzoate from Step B with 4-{[2-(dimethylamino)ethyl](methyl)amino}phenol.

LC/MS (C46H₅₂N₆O₅) 767 [M-H]'; RT 2.26 (Method A)

Example 475:4-1f2-(Dimethvlamino)ethvllamino)phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7-{[(3/?)-3-methyI-

3.4- dihydroisoquinolin-2(lfi^r)-yl]carbonyl}-3,4-dihydroisoquinoline-2(Uî)carboxylate

Example 476:4- Γ2 - ( Dimeth vlami nolethox y lphen vl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyI-l//-pyrrol-2-yl}-7-[(3Æ)-3-methyl-

1.2.3.4- tetrahydroisoquinoIine-2-carbonyl]-l,2.3,4-tetrahydroisoquinoline-2carboxylate

The procedure is as in Example 709, replacing the product from Préparation 6ba in Step A with the product from Préparation 6bb, and replacing benzyl 3-hydroxybenzoate from Step B with 4-[2-(dimethylamino)ethoxy]phenol.

LC/MS (C45H49N5O6) 754 [M-H]'; RT 2.21 (Method A)

High-resolution mass (ESI+):

Empirical formula: C45H49N5O6 [M+2H]²⁺ calculated: 378.6914 [M+2H]²⁺ measured: 378.6926

Example 477;4-r2-(Dimethvlamino)ethyl]phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l//-pyrrol-2-yl]-7-{[(3Æ)-3-methyl-

- 234 Example 478:4-[(Dimethvlamino)methvl1phenvl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7-{[(37î)-3-methyI-

3.4- dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lÆ)carboxylate

Example 479:4-r3-(Dimethvlamino)prop-l-vn-l-vl]phenvl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7-{[(3R)-3-methyl-

3.4- dihydroisoquinolin-2(li0-yl]carbonyl}-3,4-dihydroisoquinoline-2(170carboxylate

Example 480:A'-(4-Hvdioxvphenvl)-jV.1.2-trimethvl-5-(7-H(37?)-3-inethvl-3.410 dihydroisoqumolm-2(ljfiD-yl]carbonyl}-2-{[4-(4-methylpiperazin-l-yl)phenyl]acetyl}-

1.2.3.4- tetrahydroisoquinolin-6-yl)-l/7-pyrrole-3-carboxamide

Example 481:5-(24(4-{f2-(Dimethvlammo)ethvll(methvl)amino)phenyl)acetyll-7{[(3/?)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyI}-l,2,3,4tetrahydroisoquinolin-6-yl)-A^z-(4-hydroxyphenyl)-A⁷,l,2-trimethyl-l//-pyrrole-315 carboxamide

Example 482:5-(2-[(4-{i2-(Dimethvlamino)ethvllamino)phenyl)acetyll-7-fi(3R)-3methyl-3,4-dihydroisoquinolin-2(l/f)-yl]carbonyI}-l,2,3,4-tetrahydroisoquinolin-6yl)-A^r-(4-hydroxyphenyl)-2V,l,2-trimethyl-l//-pyrrole-3-carboxamide

I

- 235 Example 483:5-r2-({4-[2-(Dimethylamino)ethoxylphenyl}acetyl)-7-{[(3/?)-3-metbyl3,4-dihydroisoquinolin-2(117)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl]-/V-(4hydroxyphenyl)-2V,l,2-trimethyl-U7-pyrrole-3-carboxamide

Example 484:5-r2-({4-f2-(Dimethvlammo)ethvl]phenvl)acetyD-7-{[(3Æ)-3-methyl-3_T4dihydroisoquinolin-2(lW)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinoIin-6-ylJ-AL(4hydroxyphenyO-^l^-trimethyl-lW-pyrrole-S-carboxamide

Example 485:5-F2-({4-r(Dimethvlamino)methvllphenvnacetvl)-7-ir(31?)-3-metliyl-3,4dihydroisoqmnolin-2(LH)-yl]carbonyl}-l_r23,4-tetrahydroisoquinolm-6-yl]-/V-(4hydroxyphenyl)-/V,l,2-trimethyl-lH-pyrrole-3-carboxamide

Example 486:5-i2-((4-r3-(Dimethvlamino)prop-l-vn-l-vllphenvl)acetvl)-7-fr(3R)-3methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6yl]-A^,-(4-hydroxyphenyl)-zV,l,2-triinethyl-l//-pyrroIe-3-carboxaniide

Example 487;4-(4-Methvlpiperazin-l--vl)phenvl 6-{ l,5-dimethyl-4[methyl(phenyI)carbamoyl]-l//-pyrrol-2-yl}-7-{[(37?)-3-methyI-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 488:4-{T2-(Dimethvlammo)ethvll(methvl)aminoÎphenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyI]-17/-pyrrol-2-yl}-7-[(31?)-3-methyl-l,2,3,4tetrahydroisoquinolme-2-carbonyl]-1^3,4-tetrahydroisoquinoline-2-carboxyIate

Step A: 6-{l,5-Dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3R)-3-methyll,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carbonyl chloride

I

- 236 The procedure is as in Step A of Example 573, replacing the product from Préparation 6ba with the product from Préparation 6cb.

LC/MS (C₃₅H35ClN₄O3) 595 [M+H]⁺; RT 2.73 (Method A)

Step B: 4-{[2-(Dimethylamino)ethyl](methyl)amino}phenyl 6-{l,5~dimethyl-45 [methyl(phenyl)carbamoyl]-l H-pyrrol-2-yl}-7-[(3 R)-3-methyl-l,2,3,4I

I

I tetrahydr<)isoquiii()liiie-2-carbonylj-1,2,3,4-ietraliydroisoquinoline-2-carb()xylate

To a solution of the carbamoyl chloride obtained from Step A (55 mg, 0.09 mmol) in acetonitrile (5 mL) was added potassium carbonate (128 mg, 0.92 mmol) and 4(dimethylamino)ethyl](methyl)amino}phenol (22 mg, 0.11 mmol), and the reaction was 10 stirred at 60 °C for ca 16 h. The reaction was allowed to cool to ambient température, diluted with dichloromethane and washed with water. The organic extract was dried over magnésium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica; dichloromethane to 10% methanol/dichloromethane) afforded the desired product as a cream solid.

LC/MS (C₄₆H₅₂N₆O₄) 753 [M+H]⁺; RT 2.42 (Method A)

High-resolution mass (ESI+):

Empirical formula: C^tfeNôCfi [M+2H]²⁺ calculated: 377.2098 [M+2H]²⁺ measured: 377.2102

Example 489:4-{ r2-(DimethvIamino)ethvllamino}phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-[(3A)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-1^23j4-tetrahydroisoquinoline-2-carboxylate

Step A: 6-{I,5-Dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3R)-3-methyl· l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carbonyl chloride

I

- 237 The procedure is as in Step A of Example 573, replacing the product from Préparation 6ba with the product from Préparation 6cb.

LC/MS (C₃5H₃5ClN₄O3) 595 [M+H]⁺; RT 2.73 (Method A)

Step B: 4-{[(tert-Butoxy)carbonyl][2-(dimethylamino)ethyl]amino}phenyl 6-{l,5dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Step B of Example 573, replacing the product of Step A in Example 573 with the product of Step A in Example 489, and replacing 3,4-dichlorophenol with féri-butyl /V-[2-(dimethylamino)ethyl]-/V-(4-hydroxyphenyl)carbamate.

LC/MS (CsoHsgNôOô) no ionisation; RT 2.54 (Method A)

Step C: 4-{[2-(Dimethylamino)ethyl]amino}phenyl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of product obtained in Step B (31 mg, 0.04 mmol, 1 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL) and the mixture was stirred at ambient température for ca 4 h. The reaction was diluted with water and basified with aqueous 2M sodium hydroxide. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnésium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography (10 g silica; dichloromethane to 10% methanol in dichloromethane) afforded the desired product as a white powder.

LC/MS (C45H50N6O4) no ionisation; RT 2.38 (Method A)

High-resolution mass (ESI+):

Empirical formula: C45H50N6O4 [M+2H]²⁺ calculated: 370.2020 ; ... · · ' rj,·

Ti 1 < >

- 238 [M+2H]ⁱ⁺ measured: 370.2038

Example 490:4-r2-(DimethvIamino)ethoxy]phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lfi^r-pyrrol-2-yl}-7-{[(3R)-3-methyl-3,4dihydroisoquinolm-2(llî)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate ⁵ Example 491:4-r2-(Dimethvlamino)ethvllphenvl 6-{l,5-dimethyl-4[methyKphenyI)carbamoyi]-17/-pyrrol-2-yl}-7-{[(3/?)-3-methyl-3,4dihydroisoquino!in-2(lH)-yI]carbonyl}-3,4-dihydroisoquinoline-2(lI/)-carboxylate

Example 492:4-r(Dimethvlamino)methvl|phenvl 6-{l,5-dimethyl-4[methyl(phemyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3Æ)-3-methyl-3,410 dihydroisoqmnolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lZ0-carboxylate

Example 493:4-[3-(Dimethvlamino)prop-l-vn-l-vllphenv! 6-{l,5-dimethyI-4[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3Æ)-3-inethyl-3,4dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinolme-2(lH)-carboxylate

Example 494:ML2-Trimethvl-5-(7-{r(3R)-3-methvl-3.4-dihvdroisoauinolin-2(17/l15 yl]carbonyl}-2-{[4-(4-methylpiperazin-l-yI)phenyl]acetyl}-l,2,3,4tetrahydroisoquinolin-6-yl)-2V-phenyl-lH-pyrrole-3-carboxamide

Example 495:5-(2-r(4-ir2-(Dimethvlamino)ethvll(methvDamino)phenvDacetyll-7{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]€arbonyl}-l,2,3,4tetrahydroisoqiiinolin-6-yi)-AU,2-trime4hyl-A'-phenyl-l//-pyrrole-3-carboxamide

-239Example 496:5-(2-[(4-{[2-(Dimethvlamino)ethyl]ammo)phenvl)acetvll-7-{r(3R)-3methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinoIin-6yl)-iV,l,2-trimethyl-N-phenyl-17/-pyrroIe-3-carboxamide

Example497:5-[2-({4-[2-(Dimethylamino)ethoxy]phenyl}acetyl)-7-{[(3R)-3-methyl-

3,4-dihydroîsoqumolin-2(l£0-yl]carbonyl}-1^23?4-tetrahydroisoquinolin-6-yl]-/V,l»2trimethyl-;V-phenyl-l/Z-pyrrole-3-carboxaniide

Example 498:5-[2-({4-[2-(Dimethvlamino)ethvl]phenvllacetvl)-7-([ï3R)-3-methyl-3.4dihydroisoquinoIin-2(l//)-yl]carbonyI}-l,2,3,4-tetrahydroisoquinoIin-6-yl]-A\l,2trimethyl’/V-phenyl-lH-pyrrole-3-carboxamide

Example 499:5-r2-(i4-r(Dimethvlamino)methyl]phenyllacetvl)-7-{r(3R)-3-methvl-3.4dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-ylEV,l,2trimethyI-iV-phenyl-lff-pyrrole-3-carboxamîde

Example 500:5-f2-({4-l3-(DimethyIamino)Drop-l-vn-l-yl]phenyllacetvl)-7-i[(3R)-3methyl-3,4-dihydroi.soquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6yl]-/V,l,2-trimethyl-/V-phenyl-lH-pyrrole-3-carboxanude

Example 501:4-(4-Methvlpiperazin-l-vDphenvl 6-[4-(dibuty lcarbamoy 1)-1,5dimethyl-l//-pyrrol-2-yl]-7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoIine-2(l_JH^r)-carboxylate

I

I I

I

- 240Example 502:4-( [2-(Dimethvlamino)ethyl1(methvl)amino}phenvl 6-[4(dibutylcarbamoyl)-l^-dimethyl-l//-pyrroI-2-yl]-7-{[(31?)-3-methyl-3,4dihydroisoquinolin-2(l£T)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate g Example 503:4-H2-(DimethYlammo)ethvl]ammo)phenvl 6-[4-(dibutylcarbamoyl)-l,55 dimethyl-lff-pyrrol-2-yl]-7-{[(31?)-3-methyl-3,4-dihydroisoquinolm-2(lH)| yl]carbonyl}-3,4-dihydroisoquinoline-2(lZZ)-carboxylate

I

Example 504:4-r2-(Dimethvlamino)ethoxy]phenvl 6-[4-(dibutylcarbamoyl)-l,5| (1^6^1<1&φγΐΊΓθΙ-2-γ1]-74[(3Α>>ηβΑγ1>3_>4-άίΚγάτοΐ$ος[ΐώιο1ίιι<2(1Η)yl]carbonyl}-3,4-dihydroisoquinoline-2(l/f)-carboxyIate | 10 Example 505;4-r2-(Dimethvlammo)ethvllphenyl 6-[4-(dibutylcarbamoyl)-l,5dimethyl-lff-pyrrol-2-yl]-7-{[(31î)-3-methyl-3,4-dihydroisoquinolin-2(lH) yl]carbonyl}-3,4-dihydroisoquinoIine-2(l//)-carboxylate

I . Example 506:4-Γ (Dimethvlammo)methvllphenvl 6-[4-(dibutylcarbamoyl)-l,5

B dimethyl-lH-pyrrol-2-yl]-7-{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(l//)* 15 yl]carbonyl}-3,4-dihydroisoqumoline-2(lH)-carboxylate

Example 507:4-[3-(Dimethvlamino)prop-l-vn-l-vl]phenvl 6-r4-(dibutvlcarbamovl)-

1,5-dimethyl- 17/-pyrrol-2-yl]-7-{ [(3J{)>3-methyl-3,4-dibydroisoqi]mo]in<2(l£f)·* * yl]carbonyl}-3,4-dihydroisoquinoline-2(l/7)-carboxyIate

I

I i ..·_ζι

I

I -241I Example 508:.\A-l)ibutyl-l,2-diinethvI-5-(7-n(3/?)-3-niethvl-3.4-dihvdrois()quin(>lin2(ll^tZ)-yl]carbonyl}-2-{[4-(4-methyIpiperazin-l-yl)phenyl]acetyl}-1^3,4| tetrahydroisoquinolin-6-yl)-lH-pyrrole-3-carboxamide

I

Example 509;AGV-Dibutvl-5-(2-lï4-{r2-(dimethvlamîno)ethvl](methvDammol | 5 phenyl)acetyl]-7-{[(3Zi)-3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4tetrahydroisoquinolin-6-yl)-l>2-dimethyl-lH-pyiTole-3-carboxaimde

I | Example 510:NJV-Dibutvl-5-(2-r(4-{[2-(dimethvlamino)ethvllammo)phenvl)acetvIl-7{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(177)-yl]carbonyl}-l,2,3,4| tetrahydroisoquinolm-6-yl)-l^-dimethyl-lH-pyrrole-3-carboxamide

I _ 10 Example 511:ïVJV-Dibutvl-5-r2-({4-r2-(dimethylamino)ethoxvlphenvl)acetvl)-7I {[(3Æ)-3-methyI-3,4-dihydroisoquinolin-2(l//)-yl]carboiiyl}-l,2,3,4| tetrahydroisoquinolin-6-yll-l,2-dimethyI-l//-pyrrole-3-carboxamide i Example 512:jVuV-Dibutvl-5-[2-({4-[2-(dimethvlamino)ethvl|phenyl}acetvl)-7-{[(3R)m 3-methyl-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoqumolin-6- • 15 yl]-l,2-dimethyl-l//-pyrroIe-3-carboxamide

I

Example 513:/VJV-Dibutvl-5-[2-(|4-[(dimethylammo)methyllphenyl}acetvl)-7-|[(3R)- * 3-methyl-3,4-dihydroisoqumolin-2(lH)-yIJcarbonyl}-l,2,3,4-tetrahydroisoqumolin-6- | y!]-l,2-dimethyl-l//-pyTrole-3-carboxamide

I

- 242Example 514:VJV-Dibutvl-5-[2-(i4-i3-(dimethvlamino)prop-l-vn-l-yllphenyl)acetyI)7-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(lfil)-yl]carbonyl}-l, 2,3,4tetrahydroi quinolin-6-yl]-l,2-dimethyl-lH-pyrrole-3-carboxamide

Example 515:Disodium 4-lïf L2-Dimethvl-5-l7-(l(3S')-3-(morpholin-4-vlmethyl)-3.4dihydroisoquinolin-2(lH)-yl]carbonyl}-2-(phenoxycarbonyl)-l, 2,3,4tetrahydroisc _iuinolin-6-yl]-l//-pyrroI-3-yl}carbonyl)(niethyl)ainino]pheny!

phosphate

Example 516:Disodium 4-i({1.2-dimethvl-5-i7-|[(3S)-3-(rnorpholin-4-vlmethvl)-3.4dihydroisoqumolin-2(lfi0-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-17f-pyrrol-3-yl}carbonyl)(methyl)amino]phenyl phosphate

ExampIe517:Disodium4-[methyl({3-[7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoqumolm-2(lH)-yl]carbonyl}-2-(phenoxycarbonyl)-1^2,3,4tetrahydroisoquinolin-6-yl]-5,6,7,8-tetrahydroindolizin-l-yl}carbonyl)amino]phenyl phosphate

Example 518;Disodium 4-rmethvl({ 3-17-11(35)-3-( morpholm-4-vImethyl)-3.4dihydroisoquinolin-2(l//)-yl]carbonyl}-2-(pheny!acetyl)-l,2,3,4tetrahydroisoquinolin-6-yl]-5,6,7,8-tetrahydroindolizin-l-yl}carbonyl)ammo]phenyl phosphate

Example 519:Disodium 4-[({l,2-dimethyl-5-[7-{[(3R)-3-methyl-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-2-(phenoxy carbonyl)-l, 2,3,4^; ~ r~' - , * ,

-243 tetrahydroisoquinolîn-6-yl]-177-pyrrol-3-yl}carbonyl)(methyl)amino]phenyl phosphate

Example 520:Disodium 4-[({l,2-dimethyl-5-[7-{[(31?)-3-methyl-3,4dihydroisoquinolin-2(LiZ)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,45 tetrahydroisoquinolin-6-yl]-lH-pyrrol-3-yl}carbonyl)(methyl)amino]phenyl phosphate

Example 521:Disodium 4-[methyl({3-[7-{[(3Æ)-3-methyl-3,4-dihydroisoquinolin2(lH)-yl]carbonyl}-2-(phenoxycarbonyl)-l^_!3,4-tetrahydroisoquinolin-6-yl]-5,6,7,8tetrahydroindolizin-l-yl}carbonyl)amino]phenyl phosphate

Example 522:Disodium 4-[niethyl({3-[7-{[(3/?)-3-methyl-3,4-dihydroisoquinolin2(llï)-yl]carbonyl}-2-(phenylacetyl)-l, 2,3,4-tetrahydroisoquinolîn-6-yl]-5,6,7,8tetrahydroindolizin-l-yl}carbonyl)amino]phenyl phosphate

Example 523; Phenyl 6-{ 1 -ethyl-4-[(4-hydroxyphenyl)(methyl)carbamoyl]-5-methyllH-pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroîsoquinolin-2(lH)15 yl]carbonyl}-3,4-dihydroisoqumolme-2(lEf)-carboxylate

Example 524:Phenvl6-il-(2-hvdroxyethyl)-4-r(4-hydroxyphenyI)(methyl)carbamoyl1-

5-methyl-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-

2(lW)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

I

- 244 Example 525:Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l-(2methoxyethyl)-5-methyl-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(li0-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 526:Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-5-methyl-l-(2,2,2trifluoroethyl)-LfiF-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yl]cai4)onyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 527: Phenyl 6-i l-ethvl-5-methYl-4-[methvl(Dhenvl)carbamoyll-l//-pvrrol-2yl}-7-{[(3S)“3-(morpholin-4-ylmethyl)-3_>4-dihydroisoquinolin-2(li0-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 528: Phenyl 6-{l-(2-hydroxyethyl)-5-methyl-4-[methyl(phenyl)carbamoyl]lH^r-pyrrol-2-yl}-7-{[(3S)3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 529:Phenvl 6-{l'(2-methoxyethyl)-5-methyl-4-[methyl(phenyl)carbamoyl]lH-pyrrol-2-yl}-7-{[(3S’)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yI]carbonyl}-3,4-dihydroisoquinoline-2(17/)-carboxylate

Example 530;Phenvl 6-{5-methyl-4-[inethyl(phenyl)carbamoyl]-l-(2,2,2trifiuoroethyl)-l//-pyrrol-2-yI}-7-{[(3S)-3-(morphoIni-4-ylmethyI)-3,4dihydroisoquinolin«2(LE/)-yl]carbonyl}>3,4>dihydroisoquinoline-2(lfl)-carboxylate

I

- 245 Example 531:Phenyl 6-[4-(dibutylcarbamoyl)-l-ethyl-5-methyl-177-pyrrol-2-yl]-7{[(3S)-3-(morpholin-4-ylmethyI)-3,4-dihydroisoqumolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH)-carboxylate

Example 532:Phenvl 6-[4-(dibutylcarbamoyl)-l-(2-hydroxyethyl)-5-methyl-lHpyrrol-2-yl]-7-{[(35)-3-(morpholm-4*ylmethyl)>3,4-dihydroisoquinolin-2(l/0yI]carbonyl}-3,4-dihydroisoquinoline-2(l/7)-carboxyIate

Example 533:Phenyl 6-r4-(dibutylcarbamoyl)-l-(2-methoxyethyl)-5-methyl-lHrpyrrol-2-yl]-7-{[(3S)-3-(m()rpholin-4-yImethyl)-3,4-dihydroisoquînolm-2(l/f)ylJcarbonylî^^-dihydroisoquinolme^ClEO-carboxylate

Example 534:Phenyl 6-[4-(dibutvlcarbamoyl)-5-methyl-l-(2,2,2-trifluoroethyl)-l//pyrrol-2-yl]-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lfiT)yl]carbonyl}-3,4-dihydroisoquinoline-2(Lff)-carboxylate

Example 535:2-Methylphenyl6-{4-F(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl- 17/-pyrrol-2-yl}-7-{ [(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(lff)-yl]carbonyl}-3,4-dihydroisoquinolme-2(lfiT)-carboxylate

Example 536:3-Methvlphenvl 6-{4-F(4-hy droxyphenyl)(methyl)carbamoylj-l,5dîmethyl-l//-pyrrol-2-yl}-7-{[(3S)-3-(morphoIin-4-ylmethyl)-3,4-dihydroisoquinolin2(l//)-vl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

I

- 246Example 537:4-Methylphenvl 6-{4-[(4-hydroxyphenyl)(methyI)carbamoyl]-l,5dimethyl-lÆ-pyrrol-2-yl}-7-{[(3S)-3-(morpholiii-4-ylmethyl)-3,4-dihydroisoquinolin2(l_Jff)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l£D-carboxylate

Example 538:2-ChlorophenvI 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dime4hyl-l//-pviTol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoqiiinoIin2(l//)-yl]carbonyI}-3,4-dihydroisoquino!ine-2(l/f)-carboxyIate

Example 539:3-ChIorophenyl6-{4-[(4-hvdroxyphenvl)(methvlkarbamovll-1.5dimethyl-l/7-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyI)-3,4-dihydroisoquinolin2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l_JH)-carboxylate

Example 540:4-Chlorophenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l>5dimethyl-lH-pyrrol-2-yl}-7-{[(3S)-3-(morphoIin-4-ylmethyl)-3,4-dihydroisoqumolin2(l/f)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lZ7)-carboxylate

Example 541:2-HvdroxyphenvI 6-{4-[(4-hydroxyphenyI)(methyl)carbamoyl]-l,5dimethyl-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(lff)-yl]carbonyl}-3,4-dîhydroisoquÎnoline-2(lH)-carboxylate

Example 542:3-Hydroxyphenvl 6-(4-i(4-hvdroxvphenvlkmethvlkarbamovll-1.5dimethyl-Lfir-pyrrol-2-yl}-7-{[(3S)-3-(morphoIin-4-yImethyl)-3,4-dihydroisoquinolin2(lH)-yl]carbonyl}-3,4-dihydroisoqumoline-2(LH)-carboxylate

Example 543;4-Hvdroxyphenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lff-pyrrol>2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

I

- 247 Example 544:2-Methoxyphenvl 6-{4-[(4-hydroxyphenyI)(methyl)carbamoyl]-l,5dimethyl-lÆ-pyrrol-2-yl}-7-{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(llï)-yl]carbonyl}-3,4-dihydroisoqmnoline-2(LH)-carboxylate

Example 545:3-Methoxyphenvl 6- {4- [(4-hydroxy phenyl) (methyl)carbamoyl] -1,5 « dimethyl-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(lfiF)-yl]carbonyl}-3,4-dihydroisoquinolme-2(ll^lï)-carboxylate

Example 546:4-Methoxyphenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-liï-pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoqmnolin2(l£0-yl]carbonyl}-3,4-dihydroisoquinoIme-2(lH)-carboxyIate

Example 547:2-(MethvIamino)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]- l,5-dimethyl-lET-pyrrol-2-yl}-7-{[(35)-3-(morpholin-4-ylmethyI)-3,4- dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l/f)-carboxylate

Example 548:3-(Methvlamino)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoylJ- l,5-dimethyl-lH-pyrrol-2-yl}-7-{[(35)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolm-2(lH^F)-yI]carbonyl}-3,4-dihydroisoquinoline-2(lH)“Cai‘boxylate

Example 549:4-(Methvlamino)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]- l,5-dimethyl-lfi^F-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(177)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

I

- 248 Example 550:2-(Dimethvlamino)phenvI 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]- l,5-dimethyl-lZl^r-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoqumolm-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 551:3-(Dimethvlamino)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]- l,5-diniethyl-17Z-pyrrol-2-yl}-7-{[(3.S)-3-(morpholin-4-ylniethyl)-3,4- dihydroisoquinolm-2(l£0-yl]carbonyl}-3,4-dihydroisoquinoline-2(llï)-carboxylate

Example 552:4-(Dimethvlammo)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoylJ- l,5-dime4hyl-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4dihydroisoquinoIin-2(177)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l/f)-carboxylate

Example 553:2-(Acetylamino)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoylJ- l,5-dimethyl-17/-pyrrol-2-yl}-7-{[(3S)-3-(inorpholin-4-yImethyl)-3,4- dihydroisoquinolin-2(lZf)-yl]carbonyl}-3,4-dihydroisoquinoline-2(llï)-carboxyIate

Example 554:3-( Acetvlamino)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]« l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3>S)-3-(morpholin-4-yImethyl)-3,4dihydroisoqumolin-2(ljE0yl]carbonyl}-3,4-dihydroisoquinoline-2(lfl^r)-carboxylate

Example 555:4-(Acetvlammo)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]- l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoIine-2(l/I)-carboxyIate

I

- 249 J Example 556:2-(Trifluoromethyl)phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]

-l,5-dimethyl-LH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4| dihydroisoquinolin-2(lfiF)-yl]carbonyl}-3,4-dihydroisoquinoline-2(LH)-carboxylate

I

Example 557;3-(Trifluoromethyl)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl] | 5 -l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinoIin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 558:4-(Trifluoromethvl)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl] -l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(l/f)-yl]carbonyl}-3,4-dihydroisoquinolme-2(l£0-carboxyIate

I _ 10 Example 559:2-Cyanophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5I dimethyl-lH^r-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolm_B 2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxyIate

Example 560:3-Cvanophenvl 6-{4-[(4-hydroxyphenvl)(methyl)carbamovl]-l,5-

dimethyl-l/7-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is an in Example 573, replacing 3,4-dichlorophenol in Step B with 3hydroxybenzonitrile.

LC/MS (C₄6H46N₆O6) 779 [M+H]⁺; RT 1.14 (Method B)

High-resolution mass (ESI+):

| 20 Empirical formula: C46H46N6O6 [M+H]⁺ calculated: 779.3552 [M+Hf measured: 779.3515

I

Example 561:4-Cvanophenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-LF7-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate | Example 562;2-Ethynylphenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,55 dimethyl-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin| 2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

I

Example 563:3-Ethvnvlphenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5| dimethyl-l//-pyrrol-2-yI}-7-{[(3S)-3-(morphoIin-4-yImethyl)-3,4-dihydroisoquinolin2(l//)-yl]carbonyI}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 564:4-Ethynvlphenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4tetrahydroisoquinoline-2-carbonyl] -1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of the product obtained from Example 784 (53 mg, 0.06 mmol, 1 eq) and triethylamine (10 pL, 0.1 mmol) in THF (1 mL) were added bis(triphenylphosphine)palladium(II) dichloride (5 mg, 0.01 mmol, 0.12 eq), copper(I) iodide (0.7 mg, 3.84 pmol), and trimethylsilylacetylene (36 pL, 0.26 mmol, 4 eq) and the mixture was heated at 60°C for ca 16 h. The reaction was allowed to cool to ambient température, then evaporated and purified préparative HPLC (H2O-TFA/acetonitrile; gradient elution) to afford the desired product.

LC/MS (C47H47N5O6) 778 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H47N5O6

I

-251 [M+H]⁺ calculated: 778.3599 [M+H]⁺ measured: 778.3635

Example 565:2,3-Dichlorophenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lfir-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(l//)-yi]carbonyI}-3,4-dihydroisoqumoIine-2(l//)-carboxylate

Example 566:Naphthalen-l-vl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dime4hyl-l//-pyTrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(17/)-carboxylate

Example 567: l//-Indol-7-yl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-ljH^r-pyrrol-2-yl}-7-{[(3S)'3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(177)-carboxylate

Example 568; l-MethvI-l//-indol-7-vI 64 4-r(4-hvdroxvphenvl)(methvl)carbamovlll^-dimethyl-ljHr-pyrrol-2-yl}-7>{[(3S)-3-(morpholîii-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 569: lfiT-Indol-4-vl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyI-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(lH)-yl]carbonyl}-3_>4-dihydroisoquinoline-2(lH)-carboxylate

Example 570:1-Methyl- l//-indol-4-vl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]- l,5-dimethyl-177-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-diliydroisoqiiinoline-2(lfiD-carboxylate

- 252 Example 571; 117-Pvrrolof2,3-/>]pyridin-4-vl 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-l,5-dimethyl-llï-pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4dihydroisoquinolm-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(liî)-carboxylate

Example 572: l-Methyl-lI.7-H>yrroM2.3-£]pyridîn-4-vl hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lfir-pyrrol-2-yl}-7-{[(35)-3(morpholîn-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(LE/)-carboxyIate

Example 573:3.4-Dichlorophenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

Step A: 6-(4-{[4-(Benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyl-lH-pyrrol-2-yl)-7[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinolîne-2-carbonyl chloride

To a solution of the compound from Préparation 6ba (450 mg, 0.47 mmol) and N,Ndiisopropylethylamine (0.41 mL, 2.36 mmol) in dichloromethane (45 mL), cooled to 0 °C, was added triphosgene (139 mg, 0.47 mmol) and the mixture was stirred for 1 h at ambient température. The reaction was diluted with dichloromethane and was washed with IM aqueous HCl. The organic extract was dried over magnésium sulfate, filtered and concentrated in vacuo to afford a yellow solid that was used directly in the next step without further purification, and assuming quantitative transformation.

LC/MS (C46H4₈C1N₅O5) 786 [M+H]⁺; RT 1.33 (Method B)

Step B: 3,4-Dichlorophenyl 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5dimethyl-lH-pyrrol-2-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

I

To a solution of the compound from Step A (41 mg, 0.05 mmol) in acetonitrile (5 mL) was added potassium carbonate (72 mg, 0.52 mmol), DMAP (0.052 mmol) and 3,4dichlorophenol (0.52 mmol) and the mixture heated at 60 °C for ca 16 h. The reaction mixture was diluted with ethyl acetate and was washed with saturated aqueous sodium bicarbonate, and brine. The organic extract was dried over magnésium sulfate and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to 5 % methanol in dichloromethane) afforded the desired product.

LC/MS (C52H51CI2N5O6) 912 [M+H]⁺; RT 1.48 (Method B)

Step C: 3,4-Dichlorophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl· lH-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of the compound from Step A in dichloromethane (5 mL), cooled to 0 °C, was added drop-wise boron trichloride (1 M in dichloromethane; 5 eq.). The reaction was then allowed to warm to ambient température and continue stirring for ca 16 h. The reaction was quenched by the addition of water (10 mL) and the phases were separated. The organic phase was washed successively with aqueous sodium bicarbonate, and brine. The organic extract was dried over magnésium sulphate, fîltered and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to 5 % methanol in dichloromethane) afforded the desired product.

LC/MS (C₄₅H45C1₂N₅O₆) 822 [M+H]⁺; RT 1.28 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H45N5O6CI2 [M+H]⁺ calculated: 822.2820 [M+H]⁺ measured: 822.2832

- 254 Example 574:Naphthalen-2-yl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyi]-l,2,3,4-tetrahydroisoquinoIine-2-carboxylate

The procedure is an in Example 573, replacing 3,4-dichlorophenol in Step B with naphthalen-2-ol.

LC/MS (C49H49N5O6) 804 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C49H49N5O6 [M+H]⁺ calculated: 804.3756 [M+H]⁺ measured: 804.3767

Example 575: lH-Indol-6-yl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-1 //-py r rol-2-y 1} -7 - [(3S)-3-(morpholi n-4-yIme thy 1)-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is an in Example 573, replacing 3,4-dichlorophenol in Step B with 3Hindol-6-ol.

LC/MS (C₄7H4₈N₆O₆) 793 [M+H]⁺; RT 1.15 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H48N6O6 [M+H]⁺ calculated: 793.3708 [M+H]⁺measured: 793.3690

Example 576:1-Methvl-LH-indol-6-vl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]l^-dimethyl-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l/7)-carboxylate

I

- 255 Example 577:1/7-1ndol-5-vl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-l7/-pyiTol-2-yl}-7-|(3.S)-3-(morpholin-4-ylniethyl )-1, 2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is an in Example 573, replacing 3,4-dichlorophenol in Step B with 1Hindol-5-ol.

LC/MS (C₄7H₄₈N₆O₆) 793 [M+H]⁺; RT 1.13 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H48N6O6 [M+2H]²⁺ calculated: 397.1890 [M+2H]²⁺ measured: 397.1879

Example 578: l-Methvl-lfiF-indol-5-vl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]l,5-dimethyl-Lff-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 579: l/7-lArroloF2,3-Z>]pyridin-5-vl 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-l,5-dimethyl-lfi^r-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,23,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoqumoline-2-carboxylate

The procedure is an in Example 573, replacing 3,4-dichlorophenol in Step B with 1Hpyrrolo[2,3-&]pyridin-5-ol.

LC/MS (C₄6H4₇N₇O₆) 794 [M+H]⁺; RT 1.07 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H4₇N₇O6 [M+2H]²⁺ calculated: 397.6867

- 256 [Μ+2Η]“⁺ measured: 397.6880

Example 580: l-Methyl-lH-DyrroloriJ-^lpyridin-S-vI 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l/7-pyrrol-2-yl}-7-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoqumoliii-2(lH)-yl]carbonyl}-3,4dihydroisoqumoline-2(lH)-carboxylate

Example 581: 1 /7-PvrroIoF23-Z>1pvridin-4-vl6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3/?)-3-methyl-3,4-dihydroisoquinolin2(17/)-yI]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 582: l/Z-Pvrrolor23-Z>1pyridm-5-vl 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-l,5-dimethyl-l//-pyrrol-2-yl}-7-{[(3/?)-3-methyl-3,4-dihydroisoquinolin2(lJ/)-yl]carbonyI}-3,4-dihydr()isoquinoline-2(l//)-carboxylate

Example 583:2-(MethvlsulfanvI)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-

1.5- dimetliyl-IJ/-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolm-2(llï)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 584:3-(Methvlsulfanvl)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-

1.5- dimethyl-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyI)-3,4- dahydroisoqumolm-2(LH^r)-yl]carbonyl}-3,4-dîhydroisoqmnoline-2(LH^r)-carboxylate

Example 585:4-(Methvlsulfanvl)phenvl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]l^-dimethyl-lH-pyrrol-2>yl}-7-{[(35)-3-(morpholîn-4-ylmethyl)-3,4dihydroisoquinolm-2(lff)-yl]carbonyl}-3,4-dihydroisoqumoline-2(lfi0-carboxylate

- 257 Example 586:2-(Dimethylcarbamovl)phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l/Z-pyrrol-2-yl}-7-{[(3/?)-3-methyl-

3,4-dihydroisoquinolin-2(LfiD-yI]carbonyl}-3,4-dihydroisoqumoIine-2(lfiD· carboxylate

Example 587;3-(Dimethylcarbamovl)phenvl 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-l,5-dimethyl-liy^r-pyrrol-2-yl}-7-{[(37f)-3-methyl-3,4-dihydroisoquinolin2(lH)-yl]carbonyl}-3,4-dihydroisoquinolme-2(lH)-carboxylate

Example 588:4-(Dimethvlcarbamovl)phenvI 6-{4-[(4-hydroxyphenyl)(methyl) carbamoyl]-l,5-dimethyl-lZ7-pyrrol-2-yl}-7-{[(3/?)-3-methyl-3,4-dihydroisoqumolm10 2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 589:2-Methvlphenvl 6-{l,5-dimethyl-4-[methyI(phenyl)carbamoyl]-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 590:3-MethvlphenvI 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-L6T15 pyrrol-2-yl}-7-{ [(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoqumolin-2(lfir)yl]carbonyl}-3,4-dihydroisoquinoline-2(l/7)-carboxylate

Example 591:4-Methvlphenvl ô-tl^-dimethyM-tmethyliphenyPcarbamoylJ-lirpyrrol-2-yl}-7-[(35)-3-(morpholin-4-ylmethyl)-1^2,3,4-tetrahydroisoquinoline-2carbonyl] -1,2,3,4-tetrahydroisoquinoIine-2-carboxyIate

-258 The procedure is as in Example 785, replacing the product from Préparation 6cb with the product from Préparation 6ca.

LC/MS (C46H49N5O5) 752 [M+H]⁺; RT 1.34 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O5 [M+H]⁺ calculated: 752.3806 [M+H]⁺ measured: 752.3836

Example 592:2-Chlorophenvl 6-{l,5-dimethyI-4-[methyl(phenyI)carbamoyl]-lHpyrrol-2-yI}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)10 yI]carbonyl}-3,4-dihydroisoquinoline-2(LH)-carboxylate

Example 593:3-Chlorophenvl 6-{l,5-dimethyl-4-[methyl(phenyi)carbainoylJ-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 594:4-Chlorophenvl 6-{L5-dimethyl-4-[methyl(phenyl)carbamoyl]-l/715 pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 595:2-Hvdroxyphenvl 6-{l,5-dimethyl-4-[methyI(phenyl)carbamoyl]-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

- 259 Example 596:3-Hydroxyphenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l£7pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yl] carbony l} -3,4-dihydroisoquinoline-2( 1 //)-carboxylate

Example 597;4-Hvdroxyphenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l£f5 pyrrol-2-yl}-7-{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolm-2(lH^r)yl]carbonyl}-3,4-dihydroisoquinolîne-2(LH^r)-carboxylate

Example 598:2-Methoxvphenvl 6-f 1.5-dimethvl-4-rmethvl(phenvl)carbamoyll-1//pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolm-2(lfi0yl]carbonyl}-3,4-dihydroisoqumoIme-2(lfl)-carboxyIate

Example 599:3-Methoxyphenyl 6-{ 1,5-dimethyl-4-[methyl(phenyl)carbanioylj-17/pyrrol-2-yl}-7-{[(35)-3-(niorpholin-4-ylmethyl)-3,4-dihydroisoquinoIin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 600:4-Methoxvphenvl 6-{l,5-dimetliyl-4-[methyl(phenyl)carbamoyl]-l//pyrrol-2-yl}-7-{[(3S)-3-(morphoIin-4-ylinethyl)-3,4-dihydroisoquinolin-2(l//)15 yl]carbonyl}-3,4-dihydroisoquinoline-2(lE0-carboxylate

Example 601 ; 2-(Methvlammo)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

- 260Example 602:3-(Methvlamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(ll/)-carboxylate

Example 603:4-(Methvlamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoylJ5 lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoqumolm-2(lH)yl]carbonyl}-3,4-dihydroisoquinolme-2(lH)-carboxylate

Example 604:2-(Dimethvlamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl) carbamoyl]-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4dihydroisoquinoIin-2(lH)-yI]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 605:3-(Dimethvlamino)phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 606:4-(Dimethvlamino)phenvl 6-{l,5-dnnethyl-4-[methyI(phenyl) carbamoyl]-LfiT-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,415 dihydroisoqumolîn-2(Lfir)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lZO-carboxylate

Example 607:2-( Acetvlamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyI)carbamoyl]l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyI)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4dihydroisoquinoline-2(l_Jff)-carboxylate

-261Example 608:3-(Acetylamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(177)yl]carbonyl}-3,4-dihydroisoquinolme-2(lZ/)-carboxylate

Example 609;4-(Acetvlamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoylJ5 17/-pyrrol-2-yI}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZf)yl]carbonyl}-3,4-dihydroisoquinoline-2( l//)-carboxylate

Example 610:2-(Triflporomethvl)phenvl 6-{ 1,5-dîmethyl-4[methyl(phenyl)carbamoyl]-l//-pyiTol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4dihydroisoquinolin-2(17/)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 611:3- (T rifluoromethyl)phenyl 6-{ l,5-dimethyl-4-[methyl(phenyl) carbamoyl]-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yr]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 612:4-(Trifluoromethyl)phenvl 6-{l,5-dimethyl-4-[methyl(phenyI) carbamoyl]-l//-py rrol-2-yl }-7-{ [(3S)-3-(morphoIin-4-ylmethyl)-3,415 dihydroisoquinolin-2(l//)-yl]carbonyI}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 613:2-Cvanophenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l/7pyrrol2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoqumolm-2(lfi0yl]carbonyl}-3,4-dihydroisoquinoline-2(lH^r)-carboxylate

I

- 262 Example 614:3-Cyanophenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lJ7pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(LfiF)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 615:4-Cvanophenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l/75 pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-yImethyl)-3,4-dihydroisoquinolm-2(lH)yl]carbonyl}-3,4-dihydroisoquinolme-2(127)-carboxylate

I

Example 616:2-Ethynvlphenvl 6-{ l_<5-dimethvl-4-rmethvl(phenvl)carbamoyll-IfiTf pyrrol-2-yl}-7-{[(3S)-3-(inorpholin-4-yImethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoqumoline-2(lH^r)-carboxylate | 10 Example 617:3-Ethvnvlphenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-117pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquînolin-2(lfir)| yl]carbonyl}-3,4-dihydroisoquinoline-2(ljEiO-carboxylate

I — Example 618:4-Ethvnvlphenvl 6-fl.5-dimethvl-4-rmethyl(phenvltearbamoyll-lH pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)_K 15 yl]carbonyl}-3,4-dihydroisoquinoline-2(177)-carboxylate

I

Example 619:2,3-Dichlorophenvl 6-{l,5-dimethyI-4-[methyl(phenyl)carbamoyl]-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoquinolin-2(ljfiDyl]carbonyl}«3,4-dihydroisoquinoline-2(lfiD-carboxylate

I

-263 Example 620:Naphthalen-l-yl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l/Zpyrrol-2-yl}-7-{[(3S)-3-(morphoIin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 621: l//-Indol-7-yl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-

2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yI]carbonyl}-

3.4-dihydroisoquinoline-2(l//)-carboxylate

Example 622: l-Methyl-l/Z-indol-7-vl 6-{l,5-dimethyl-4-[methyI(phenyl)carbamoylJl//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4-dihydroisoquinoliii-2(l//)yl]carbonyl}-3,4-dihydroisoquinoInie-2(lfiF)-carboxylate

Example 623:1//-lndol-4-yl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lfiT-pyrrol-

2-yI}-7-{[(3S)-3-(morplwlin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-

3,4-dihydroisoquinolme-2(l//)-carboxylate

Example 624;l-Methyl-l//-indol-4-yl 6-{l,5-dimethyI-4-[methyl(phenyl)carbamoylJl//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolîn-2(l//)yl]carbonyl}-3,4-dihydroisoquinoIine-2(lH)-carboxylate

Example 625: l//-Pvrrolo[2.3-Z>lpyridin-4-vl 6-{ l,5-dimethyl-4[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3S)-3-(morphoIîn-4-ylmethyl)-3,4dihydroisoqumolm-2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lJï)-carboxylate

I

- 264Example 626: l-Methyl-l//-pyrroloF2.3-/>1pyridin-4-vl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4diliydroisoquinolin-2(l//)-vl]carbonyl}-3,4-dihydroisoquinoline-2( l//)-carboxylate

Example 627:3,4-Dichlorophenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l/7pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4-dihydroisoquinolin-2(lZ/)yl]carbonyI}-3,4-dihydroisoquinoline-2(lfiT)-carboxylate

Example 628;Naphthalen-2-yl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l/Zpyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(llï)-carboxylate

Example 629:lH-Indol-6-vl 6-{1,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-

2- yl}-7-[(35)-3-(morphoIin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonylJ- l,2,3,4-tetrahydroisoquinoline-2-carboxylate

Step A: 6-{l,5-Dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3S)-3(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l;2,3,4tetrahydroisoquinoline-2-carbonyl chloride and

Trichloromethyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3S)-

3- (morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate

To a solution of product from Préparation 6ca (200 mg, 0.32 mmol) and N,Ndiisopropylethylamine (0.17 mL, 0.97 mmol) in dichloromethane (10 mL), cooled to 0 °C, was added triphosgene (96 mg, 0.32 mmol) and the mixture was stirred at ambient température 1 h. The reaction was diluted with dichloromethane and washed with IM aqueous HCl. The organic extract was dried with magnésium sulfate, filtered and concentrated in vacuo to afford the desired products as a mixture.

- 265 LC/MS (C39H42CIN5O4) 680 [M+H]⁺; RT l .27, and ^o^ChNsOj) 778 [M+H]⁺; RT

1.36 (Method B)

Step B: lH-Indol-6-yl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,45 tetrahydroisoquinoline-2-carboxylate

To a solution of the material from Step A (50 mg, 0.06 mmol ) in acetonitrile (5 mL) was added potassium carbonate (44 mg, 0.32 mmol) followed by l/f-indol-6-ol (1.5 eq) and the mixture was heated at 60 °C for ca 16 h. The reaction was allowed to cool to ambient température, and was diluted with ethyl acetate (20 mL) and washed successively with IM 10 aqueous sodium hydroxide, and brine. The organic extract was dried over magnésium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to 10 % methanol in dichloromethane) afforded the desired product.

LC/MS (C₄7H4₈N₆O₅) 777 [M+H]⁺; RT 1.26 (Method B)

High-resolution mass (ESI+):

Empirical formula: C^HjgNôOs [M+H]⁺ calculated: 777.3759 [M+H]⁺ measured: 777.3795

Example 630:l-Methvl-lH-indol-6-vl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoylJ20 l//-pyrroI-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lÆ)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 631:LfiF-Indol-5-vl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-LH-pyrrol··

2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1^2,3,4-tetrahydroisoquinoline-2-carbonyl]L2,3,4-tetrahydroisoquinoline-2-carboxylate . ' v ·' . L

- 266The procedure is as in Example 629, replacing l//-indol-6-ol in Step B with l//-indol-5-ol, and purifying via préparative HPLC (HbO-TFA/acetonitrile; gradient elution).

LC/MS (C₄7H48N₆O₅) 777 [M+H]⁺; RT 1.28 (Method B)

High-resolution mass (ESI+):

Empirical formula: CpEUgNôOs [M+H]⁺ calculated: 777.3759 [M+H]⁺ measured: 777.3742

Example 632;l-Methvl-lH^r-indol-5-vl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoylJl//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 633: lH-Pvrrolor2.3-6]pvridin-5-vl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoqumoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolîne-2-carboxyIate

The procedure is as in Example 629, replacing 1//-indol-6-ol in Step B with IHpyrrolo[2,3-è]pyridin-5-ol.

LC/MS (C46H47N7Ü5) 778 [M+H]⁺; RT 1.18 (Method B)

High-resolution mass (ESI+):

Empirical formula: C^Hn^Os [M+2H]²⁺ calculated: 389.6892 [M+2H]²⁺ measured: 389.6874

I

- 267 Example_634:l-Methyl-177-pyrrolo[2,3-b]pyridin-5-yl 6-{l,5-dimethyl-4[methyl(phenyl)i rbamoyl]-lH-pyrroI-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 629, replacing lH-indol-6-ol in Step B with l-methyl-1775 pyrrolo[2,3-h]pyridin-5-ol, and purifying via préparative HPLC (H₂O-TFA/acetonitrile; gradient elution).

LC/MS (C47H49N7O5) 792 [M+H]⁺; RT 1.25 (Method B)

High-resolution c ass (ESI+):

Empirical formula: C47H49N7O5 [M+2H]²⁺ calculated: 396.6970 [M+2H]²⁺ measured: 396.6978

Example 635:Lg-PvrroIor2.3-Z>lpvridin-4-vl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lfiF-pyrrol-2-yl}-7-{[(3R)-3-methyl-3,4dihydroisoquinolin-2(llî)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 636:l//-Pvrrolo[2,3-àlpyridin-5-vl 6-11.5-dimethyl-4[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-[(3R)-3-methyl-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoqmnoline-2-carboxylate

The procedure is as in Example 786, replacing 4-hydroxybenzonitrile in Step B with 1Hpyrrolo[2,3-è]pyridin-5-ol.

LC/MS (C₄₂H4oN₆04) 693 [M+H]⁺; RT 1.34 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H40N6O4 [M+2H]²⁺ calculated: 347.1628

I

I _B - 268 [M+2H]²⁺ measured: 347.1639

I | Example 637:2-(MethvIsulfanvl)phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-{[(35)-3-(morpholin-4-ylmethyl)-3,4| dihydroisoquinoIin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoIine-2(l//)-carboxylate

I _ 5 Example 638:3-(Methvlsulfanvl)phenvl 6-{l,5-dimethyl-4I [methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4_ dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxyIate

Example 639:4-(Methvlsulfanvl)phenvl 6-{ l,5-dimethyl-4[methyl(phenyl)carbamoyl]-llï-pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,410 dihydroisoqumolin-2(lH)-yl]carbonyl}-3,4-dihydroisoqumoline-2(ljH)-carboxylate

Example 640:2-(Dimethvlcarbamovl)phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-177-pyrrol-2-yl}-7-{[(37î)-3-methyl-3,4dÎhydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxyIate

Example 641:3-(Dimethvlcarbamovl)phenvl 6-{l,5-dimethyl-415 [methyI(phenyl)carbamoyl]-lJ^t7-pyrrol-2-yl}-7-{[(3Æ)-3-methyl-3,4dihydroisoqinnoIm-2(l//)-yl]carbonyl}-3,4-dihydroisoqumoline-2(l//)-carboxylate

Example 642:4-(Dimethylcarbamoyl)phenyl 6-{ 1,5-dimethyl-4[methyl(phenyl)carbamoyl]-17/-pyrrol-2-yl}-7-{f(3/<^,)-3-methyl-3,4dihydroisoqumoliii-2(l/7)-yl]carbonyl}-3,4-dihvdroisoquinoline-2(l//)-carboxyIate

- 269Example 643:2-Methylphenyl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-l//-pyrrol-2-ylJ7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihvdroisoquinolipe-2(l//)-carboxyIate

Example 644:3-Methvlphenvl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-lE/-pyrrol-2-yl]5 7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(lH^r)-carboxylate

Example 645:4-Methvlphenvl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-l//-pyrroI-2-yl·]7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(liï)-yl]carbonyl}-3,4dihydroisoquinoline-2(l/7)-carboxylate

Example 646:2-Chlorophenvl 6-[4-(dibutylcarbamoyl)-l,5-dimethyl-l//-pyrrol-2-ylJ7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxylate

Example 647:3-ChIorophenvl 6-{ 1,5-dimethy l-4-[methyl(phenyl)carbamoy1]- 1HpyrroI-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoIin-2(l W)15 yljcarbonyl }-3,4-dihydroisoquinoline-2( l//)-carboxylate

Example 648:4-Chlorophenvl 6-{l,5-dirnethyl-4-[methyl(phenyl)carbamoyl]-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate ' ; ! . Â

- 270Example 649:2-Hydroxyphenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyI]-l/7pyrrol-2-yl}-7-{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZf)yl]carbonyl}-3,4-dihydroisoquinoline-2(llï)-carboxylate

Example 650:3-Hvdroxvphenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l//5 pyrrol-2-yl}-7-{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxyIate

Example 651:4-Hvdroxyphenvl ô-iljS-dimethyl-d-CmethylCphenyDcarbamoylJ-lWpyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(Lfir) yl]carbonyl}-3,4-dihydroisoquinoIine-2(lH)-earboxyIate

Example 652:2-methoxyphenvl 6-{l^>-dimethyl-4-[methyl(phenyl)carbamoyl]-U7pyrrol-2-yl}-7-{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lfi^r)' yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxyIate

Example 653:3-Methoxyphenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l//pvrroI-2-yl}-7-{ [(35)-3-( morpholm-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)15 yl]carbonyl}-3,4-dîhydroisoqmnoIine-2(l£D-carboxylate

Example 654:4-Methoxvphenvl 6-{l,5-dimethyl-4-[methylfchenyl)carbamoyl]-lfirpyrroI-2-yl}-7-{[(35)-3-(morphoIin-4-ylmethyI)-3,4-dihydroisoquinolin-2(lif)yl]carbonyl}-3,4-dihydroisoqumolme-2(EET)-carboxylate

- 2/l Example 655;2-(Methyiamino)phenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolm-2(177)yI]carbonyl}-3,4-dihydroisoquinoline-2( l//)-carboxylate

Example 656:3-(Methvlamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyI)carbamoyl]'· l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyI}-3,4-dihydroisoqiiinoline-2(l/7)-carboxylate

Example 657:4-(Methylamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]lfir-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4-dihydroisoquinolin-2(lfi?)yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 658:2-(Dimethvlamino)phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lZ7-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxy!aie

Example 659; 3-(Dimethylamino)phenyl 6-{ l,5-dimethyl-4-[methyl(phenyl) carbamoyl]-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,415 dihydroisoquinolin-2(liO-yl]carbonyl}-3,4-dihydroisoqumoline-2(lfO-carboxyIate

Example 660:44Dimethvlammo)phenvl 6-{l,5-dimethyI-4-[methyl(phenyl) carbamoyl]-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolm-2(LE0-yl]carbonyl}-3,4-dihydroîsoquinoline>2(Lff)-carboxylate

- 272 Example 661:2-(AcetvIamino)phenvl 6-{l,5-dimethyI-4-[methyI(phenyl)carbamoyl]U/-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoqmnolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 662:3-(Acetvlamino)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]5 1/7-py rrol-2-y 1} -7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2( 1H)yl]carbonyl]-3,4-dihydroisoqmnoline-2(liï)-carboxylate

Example 663:4-(Acetvlammo)phenvl 6-{l,5-dimethyl-4-[methyI(phenyl)carbamoyl]l/7-pyrroi-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(117)yI]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 664:2-(Trifluoromethvl)phenvl 6-11.5-dimethyl-4-rmethyl(phenyl) carbamoyl]-lH^r-pyrroI-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinoIin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(U7)-carboxylate

Example 665:3-(Trifluoromethvl)phenvI 6-i 1.5-dimethvl-4-[methvl(phenyD carbamoyl]- l//-pyrroI-2-yl}-7-{f(3S)-3-(morphoIin-4-yImethyl)-3,415 dihydroisoqumolm-2(lfir)-yl]carbonyl}-3,4-dihydroisoqumoline-2(lH)-carboxylate

Example 666:4-(Trifluoromethvl)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl) carbamoyl]-17/-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4dihydroisoquinolm-2(LH)-yl]carbonyl}-3_J4-dihydroisoquinolme-2(liO-carboxyIate

-273 Example 667:2-Cyanophenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lHpyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-3,4-dihydroisoquinoline-2(LE/)-carboxylate

Example 668:3-Cvanophenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l/Z5 pyrroI-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoIin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxyIate

Example 669:4-Cvanophenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbainoyl]-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoqmnolm-2(liOyl]carbonyl}-3,4-dihydroisoqumolme-2(LfiT)-carboxylate

Example 670:2-Ethynylphenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lHpyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4-dihydroisoquinolin-2(l//JyI]carbonyl}-3,4-dihydroisoqumoline-2(l!ï)-carboxylate

Example 671:3-EthvnvlphenvI 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lHpyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4-dihydroisoquinolin-2(l//)15 yl]carbonyl}-3,4-dihydroisoquinolme-2(lH)-carboxylate

Example 672:4-Ethvnvlphenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lZ7pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoqumolme-2(lH)-carboxylate

- 274Example 673:23-Dichlorophenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-177pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lL0yl]carbonyl}-3,4-dihydroisoquinolme-2(17ï)-carboxylate

Example 674:Naphthalen-l-vl 6-{l^-dimethyl-4-[methyl(phenyl)carbamoyl]-lH5 pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoquinolm-2(lH)yI]carbonyl}-3,4-dihydroisoquinolme-2(lfiT)-carboxylate

Example 675: l//-Indol-7-vl 6-{l,5-dimethyI-4-[methyl(phenyl)carbamoyl]-l//-pyrrol-

2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyD-3,4-dihydroisoquinolin-2(l//)-yI]carbonyl}-

3,4-dihydroisoquinolme-2(lH)-carboxylate

Example 676; l-MethvI-l//-indol-7-vl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]17/-pyrrol-2-yl}-7-{[(3S)-3-(morphoHn-4-ylme4hyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinoline-2(lJ7)-carboxyIate

Example 677:177-IndoI-4-vI 6-{ l,5-dimethyl-4-[methyl(phenyI)carbamoyl]-l//-pyrrol-

2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolm-2(lH)-yl]carbonyl}-

3,4-dihydroisoquinoline-2(ljH^r)-carboxylate

Example 678:l-Methvl-177-indol-4-vl 6-{l,5-dimethyl-4-[methyl(phenyI)carbamoyl]lZ7-pyrrol-2-yl}7>{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZr)yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

I

I Example 679:l//-Pvrrolor2,3-6lpyridin-4-vl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-17/-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4| dihydroisoquinolin-2(l//)-yI]carbonyl}-3,4-dihydroisoquinolme-2(ljff)-carboxylate

I

Example 680: l-Methyl-lg-pyrrolor2 J-blpvridm-4-vl 6-{l,5-dimethyl-4| 5 [methyl(phenyl)carbamoyl]-l/7-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethy!)-3,4dihydroisoquinolin-2(ljff)-yl]carbonyl}-3,4-dihydroisoquinolme-2(llï)-carboxylate

H Example 681:3,4-Dichlorophenyl 6-{l,5-dimethyl-4-[methyI(phenyl)carbamoyl]-l//· pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquînolin-2(l//)- yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

I _ 10 Example 682:Naphthalen-2-vl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH- pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4-dihydroisoquinolin-2(l/7)- m yl]carbonyl}-3,4-dihydroisoquinoline-2(LH)-carboxylate

Example 683:l//-Indol-6-vl 6-{l,5-diinetliyl-4-[methyl(phenyl)carbamoyl]-17/-pyrrol-

2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}- * 15 3,4-dihydroisoquinoline-2(l//)-carboxylate

I

Example 684:1-Methyl- l//-indol-6-yl 6-{ l,5-dimethyl-4-[methyl(phenyl)carbamoyl]l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoqmnolin-2(l//)-

B yl]carbonyl}-3,4-dihydroisoquinoline-2(l/7)-carboxylate

I I

I

- 276Example 685:1//-lndol-5-vI 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-

2-yl}-7-{[(3S’)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-vl]carbonyl}-

3,4-dihydroisoquinoline-2(l#)-carboxylate

Example 686:1-Methyl- l//-indol-5-vl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]5 lfi^r-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(ll^cT)yl]carbonyl}-3,4-dihydroisoquinoline-2(17Z)-carboxylate

Example 687; l/Z-Pvrroloi2,3-/> ]pvridin-5-vl 6-{ l,5-dimethyl-4[methyl(phenyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 688: l-Methvl-l//-pvrrolor2.3-6|pvridiii-5-vl 6-{l,5-dimethyl-4[metbyl(phemyl)carbamoyl]-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 689; l/7-Pvrrolo[23-61pvridin-4-vl 6-{l,5-dimethyl-4-—........

[methyl(phenyI)carbamoyl]-lff-pyrrol-2-yl}-7-{[(37?)-3-methyl-3,415 dihydroisoqmnolin-2(liiDyl]carbonyl}-3,4-dihydroîsoquinolme“2(Lfir)-carboxylate

Example 690:l/7-PvrroloF2.3-l>lpvridin-5-vl 6-fL5-dimethvl-4[methyl(phenyl)carbamoyl]-lZ/-pyrrol-2-yl}-7-{[(3Æ)-3-methyI-3,4dihydroisoquinolm-2(Lff)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

- 277 Example 69i:2-(Methylsulfanyl)phenyl 6-{l,5-dimethyl-4-[methyl(phenyl) carbamoyl]-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2( l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

Example 692;3-(Methvlsulfanvl)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl) carbamoyl]-LH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(lfi^r)-yl]carbonyl}-3,4-dihydroîsoquinoline-2(l£r)-carboxylate

Example 693:4-(Methvlsulfanvl)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl) carbanioyl]-l//-pyrrol-2-yl}-7-{[(3S’)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(llî)-yl]carbonyl}-3,4-dihydroisoquinoline-2(lfl)-carboxylate

Example 694:2-(Dimethylcarbamoyl)phenvl 6-{l,5-dimethyl-4-[methyl(phenyl) carbamoyl]-lH-pyrrol-2-yl}-7-{[(31î)-3-methyl-3,4-dihydroisoquinolin-2(lH^r)yl]carbonyI}-3,4-dihydroisoquinoIine-2(l//)-carboxyiate

Example 695:3-(DimethyIcarbamovl)phenvl 6-{ 1,5-dimethy 1-4-[methyl (phenyl) carbamoyl]-lH-pyrroI-2-yl}-7-{[(3/?)-3-methyl-3,4-dihydroisoquinolin-2(l//)15 yl]carbonyl}-3,4-dihydroisoquinolme-2(lff)-carboxylate

Example 696:4-(DimethvlcarbamovI)phenvl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yI}-7-{[(3/?)-3-methyl-3,4dihydroisoquinoIin-2(l/jT)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)-carboxylate

-278Example 697:Phenvl 7-{[(3S)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(lfi^r)yl]carbonyl}-6-{4-[(4-hydroxyphenyl)(methyl)carbainoyl]-L5-dimethyl-l//-pyrrol-2yl}-3,4-dihvdroisoquinoline-2( l//)-carboxylate

Example 698:5-r7-{r(35)-3-(HvdroxvmethvD-3.4-dihydroisoquinolin-2(l£D5 yl]carbonyl}-2-(phemylacetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl]-7V-(4hydroxyphenyl)-2V,L2-trimethyl-l//-pyrrole-3-carboxamide

Example 699;Phenvl 6-{l,5-dimethyl-4-[methyI(phenyl)carbamoyl]-l//-pyrrol-2-yl}7-{[(35)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxylate

Example 700:547-f Γ (35)-3-(Hvdroxvniethvll-3.4-dihvdroiso<juiiiolin-211//1yl]carbonyl}-2-(phenylacetyl)>l_y2,3,4-tetrahydroisoquinolin-6-yl]-A/,1^2-trimethyl-/Vphenyl-l//-pyrrole-3-carboxamide

Example 701:Phenvl 6-[4-(dibutvlcarbamoyll-1.5-dimethvl-l/Z-pvrrol-2-yll-7-H(3S)-

3-(hydroxymethyl)-3,4-dihydroisoqumolin-2(lH)-yl]carbonyl}-3,4- dihydroisoquinolme-2(110-carboxylate

Example 702:.N,N-Dibutvl-5474F(3S')-34hvdroxvmethvl)-3.4-dihydroisoquinoIin2(UÏ)-yl]carbonyl}-2-(phenylacetyl)-1^3>4-tetrahydroisoqumolin-6-yl]“l^-dimethyll//-pyrrole-3-carboxamide

- 279 Example 703:Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lZZpyrrol-2-yl}-7-{[(3S)-3-(methoxymethyl)-3,4-dihydroisoquinolin-2(lZ/)-yl]carbonyl}-

3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 704:Λ-( 4 Jlvdroxyphenvl)-5-| 7-{ [ (3S )-3-( methoxvmethy 1)-3.45 dihydroÎsoquinolin-2(17/)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4tetrahydroisoquinolin-ô-yll-A^jl^-trimethyl-llï-pyrrole^-carboxamide

Example 705:Phenvl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-l/7-pyrrol-2-yl}7-{[(3S)-3-(methoxymethyl)-3,4-dihydroisoquinolin-2(l//)-yi]carbonyl}-3,4dihydroisoquinoline-2(l//)-carboxyIate o Example 706:5-[7-{ [(3S)-3-(Methoxymethyl)-3,4-dihydroisoquinolin-2(lH)yl]carbonyl}-2-(phenylacetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl]-/V,l,2-trimethyl-/Vphenyl-lH-pyrrole-3-carboxamide

Example 707;Phenvl 6-[4-(dibutyk\irbamoyl)-l,5-dimethyl-lf7-pyrrol-2-yl]-7-{[(3S)-

3-(methoxymethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-_________ dihydroisoquinoline-2(l/f)-carboxylate

Example 708:NJV-Dibutvl-5-r7-{ Γ (3S)-3-(methoxvmethvl)-3,4-dihydroisoquinolin2(l//)-yl]carbonyl}-2-(phenylacetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl]-l,2-dimethyllH-pyrrole-3-carboxamide

I

- 280 Example 709:3-(6-f4-lï4-Hvdroxvphenvl)(methvl)carbamovl1-1.5-dimethvl-l#pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2>3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carbonyloxy)benzoic acid

Step A: 6-(4-{[4-(Benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyl-lH-pyrrol-2-yl)-75 [(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carbonyl chloride

To a solution of the product from Préparation 6ba (450 mg, 0.47 mmol, 1 eq) in dichloromethane (45 mL), cooled to 0 °C, was added 77,77-diisopropylethylamine (0.41 mL, 2.36 mmol, 5 eq) and triphosgene (139 mg, 0.47 mmol, 0.99 eq), and the mixture was

stirred for 1 h at ambient température. The reaction was diluted with dichloromethane and washed with IM aqueous HCl. The organic phase was dried over magnésium sulfate and concentrated in vacuo to afford a yellow solid that was used directly in the next step without further purification, and assuming quantitative transformation.

LC/MS (C₄6H4₈C1N₅O₅) 786 [M+H]⁺; RT 1.33 (Method B)

Step B: 3-[(Benzyloxy)carbonyl]phenyl 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}- l,5-dimethyl-lH-pyrrol-2-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4- tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of product obtained from Step A (41 mg, 0.05 mmol) in Acetonitrile (5 mL) was added potassium carbonate (71.87 mg, 0.52 mmol), DMAP (0.052 mmol) and benzyl 3-hydroxybenzoate (0.52 mmol) and the mixture was heated at 60 °C for 16 h.

The reaction mixture was diluted with ethyl acetate, and washed successively with aqueous sodium bicarbonate, and brine. The organic extracts were dried (MgSO₄) and concentrated in vacuo. Purification by flash column chromatography (4 g silica; dichloromethane to 5% MeOH/dichloromethane) afforded the desired product.

LC/MS (C60H59N5O8) no ionisation; RT 1.46 (Method B)

Step C: 3-(6-{4-[(4-Hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinoline-2-carbonyloxy)benzoic acid

Λ.

I

-281 To a solution of the product obtained in Step B (42 mg, 0.04 mmol, 1 eq) in éthanol (8 mL) was added 10% Pd/C (50 mg) and the mixture was shaken under an atmosphère of hydrogen for ca 4 h. The reaction was filtered through celite, subsequently eluting with methanol, and concentrated in vacuo. Purification by flash column chromatography (4 g silica; dichloromethane to 5% methanol/ dichloromethane) afforded the desired product as a solid.

LC/MS (C46H47N5O8) 798 [M+H]⁺; RT 1.07 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H47N5O8 [M+H]⁺ calculated: 798.3497 [M+H]⁺ measured: 798.3438

Example 7I0:3-{2-[6-{44(4-Hvdroxvphenvl)(methvl)carbamovll-L5-dimethvl-l//pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4-dihydroisoqumolin-2(l/7)yl]carbonyl}-3,4-dihydroisoquinolin-2(l//)-yl]-2-oxoethyl}benzoic acid

Example 711:3-(ir6-fl^-Dimethvl-4-rmethvl(phenvl)carbamovll-lH-pvrrol-2-vH-7{[(35)-3-(morpholin-4-yl methyl )-3,4-dihydroisoqui nolin-2(17/)-yl ]carbonyl[-3,4dihydroisoquinolin-2(lH^r)-yl]carbonyl}oxy)benzoic acid

Example 712:3-l2-[6-[L5-DimethYl-4-[methvl(phenvDcarbamovll-177-PYrrol-2-vl}-7{[(35)-3-(morphoMn-4-ylmethyl)-3,4-dihydroisoqumolin-2(LH)-yl]carbonyl}-3,4dihydroisoquinolin-2(17/)-yl]-2-oxoethyl}benzoic acid

Example 713:3-[([6-[4-(Dibutvlcarbamovl)-l,5-dimethyl-l//-pyrrol-2-yll-7-{[(35)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinolin-2(lH)-yl}carbonyl)oxy]benzoic acid

- 282 Example714:3-(2-{6-[4-(Dibutylcarbamoyl)-l,5-dimethyl-lH-pyrroI-2-yl]-7-{[(3S)-3(morphoIin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yI]carbonyl}-3,4dihydroisoquinolin-2(LfiD-yl}-2-oxoethyl)benzoic acid

Example 715:3-(6-{4-r(4-Hvdroxyphenvl)(methvl)carbamovll-13-dimethvl-lZf5 pyrroI-2-yI}-7-[(3/?)-3-methyi-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l, 2,3,4tetrahydroisoquinoline-2-carbonyloxy)benzoic acid

The procedure is as in Example 709, replacing the product from Préparation 6bb with the product from Préparation 6bf, in Step A.

LC/MS (C42H40N4O7) 711 [M-H]'; RT 1.27 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H40N4O7 [M+2H]²⁺ calculated: 713.2970 [M+2H]²⁺ measured: 713.2962

Example 716:342-r6-{4-r(4-Hvdroxyphenvl)(methvDcarbamovll-1.5-dimethyl-lH15 pyrrol-2-yl}-7-{[(31?)-3-methyl-3,4-dihydroisoquinolin-2(LH^r)-yl]carbonyl}-3,4dihydroisoquinolin-2(LH)-yl]-2-oxoethyl}benzoic acid

Example717:3-({[6-{l,5-Dimethyl-4-[methyl(phenyl)carbamoyl]-Lfir-pyrrol-2-yl}-7{[(3R)-3-methyl-3,4-dihydroisoqumolin-2(LH)-yl]carbonyl}-3,4-dihydroisoquinolin2(l//)-yI]carbonyl}oxy)benzoic acid

I

- 283 I Example_718:3-{2-[6-{l,5-Dimethyl-4-[methyl(phenyl)carbamoyl]-l/7-pyrrol-2-yl}-7{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoquinolin| 2(liO-yl]-2-oxoethyl}benzoic acid

I

Example 719:3-r({6-r4-(Dibutvlcarbamoyl)-L5-dimethyl-lH-pyrrol-2-yll-7-F [(370-3| 5 methyl-3,4-dihydroisoquinolin-2(lH)-yI]carbonyl}-3,4-dihydroisoquinolin-2(lfi0yl}carbonyl)oxy]benzoic acid

Example 720:3-(2-f6-[4-(Dibutvlcarbamovl)-L5-dimethvI-17Z-pvrrol-2-vll-7-f[(37O-3methyl-3,4-dihydroisoquinolin-2(17ï)-yl]carbonyl}-3,4-dihydroisoquinolin-2(li7)-yl}-

2-oxoethyl)benzoic acid

I

Example 721:4-(6-(4-[(4-Hvdroxyphenyl)(methvl)carbamoyl1-l,5-dimethvl-177^rpyrrol-2-yl}-7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyI]-l,2,3,4-tetrahydroisoquinoline-2-carbonyloxy)benzoic acid

The procedure is as in Example 709, replacing benzyl 3-hydroxybenzoate from Step B with benzyl 4-hydroxybenzoate.

LC/MS (C₄6H47N₅O₈) 798 [M+H]⁺; RT 1.07 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H4₇N5O₈ [M+H]⁺ calculated: 798.3497 [M+H]⁺ measured: 798.3475

I

- 284Example 722:4-{2-i6-{44(4-HvdroxYphenyl)(methvl)carbamovll-L5-dimethyl-lHpyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)yl]carbonyl}-3,4-dihydroisoquinolin-2(17/)-yl]-2-oxoethyl}benzoic acid

Example 723:4-(|f6-{L5-Dimethvl-4-rniethvI(phenvl)carbainovll-l//-Dvrrol-2-yI}-75 )[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(17/)-yl]carbonyl}-3,4dihydroisoquinolin-2(l//)-yl]carbonvl}oxy)benzoic acid

Example 724:4-(246-{l,5-Dimethvl-4-rmethvl(phenvDcarbamoyll-lg-pyrrol-2-yl}-7{[(3S)-3-(morphoIin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/f)-yl]carbonyl}-3,4dihydroisoquinolin-2(177)-yl]-2-oxoethyl}benzoicacid

Example 725:44()644-(Dibutvlcarbamovl)-1.5-dimethvl-177-pyrrol-2-yll-7-(r(3.S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquin()lin-2(l//)-yl]carbonyl}-3,4dihydroisoquinolin-2(l//)-yl}carbonyl)oxy]benzoic acid

Example 726:4-(2-) 6-r4-(DibutvlcarbamovD-l .5-dimethvl-l/7-Dvrrol-2-vIl-7-! lï3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH^r)-yl]carbonyl}-3,415 dihydroisoquinolin-2(l//)-yl}-2-oxoethyI)benzoic acid

Example 727; 4-0 F 6-{ 44 (4-Hvdroxyphenvl)(methvlkarbamovll-1.5-dimethvl-l 77pyrrol-2-yl}-7-{[(37î)-3-metliyl-3,4-dihydroisoquinolin-2(lH^F)-yl]carbonyl}-3,4dihydroisoquinolin-2(17/)-yl]carbonyl}oxy)benzoic acid

- 285 Example 728:4-{2-Î6-{4-i(4-Hvdroxvphenvl)(methvl)carbamoyll-1.5-dimethyl-17/pyrrol-2-yl}-7-{[(37?)-3-methyl-3,4-dihydroisoquinolin-2(117)-yl]carbonyl)-3,4dihydroisoquinolin-2(l//)-yl]-2-oxoethyl}benzoic acid

Example 729:4-({r6-{l,5-Dimethvl-4-rmethvl(phenvDcarbamoyll-lH-pyrrol-2-yl}-7{[(3/?)-3-methyl-3,4-dihydroisoquinolin-2(lfir)-yl]carbonyl}-3,4-dihydroisoquinoIin2(LH)-yl]carbonyl}oxy)benzoic acid

Example 730:4-i2-r6-{1.5-Dimethvl-4-rmethvl(phenvlkarbamovll-lZ/-pvrrol-2-vll-7{[(3Æ)-3-methyl-3,4-dihydroisoquinolin-2(l/f)-yl]carbonyl}-3,4-dihydroisoquinolin2(l//)-yI]-2-oxoethyl}benzoic acid

Example_731:4-[({6-[4-(Dibutylcarbamoyl)-l,5-dimethyl-lZir-pyrrol-2-yl]-7-{[(3jR)-3methyl-3,4-dihydroisoquinolin-2(l//)-yI]carbonyI}-3,4-dihydroisoquinolin-2(l//)yl}carbonyl)oxy]benzoic acid

Example 732:4-(2-{6-r4-(Dibutvlcarbamovl)-l,5-dimethvl-l//-pvrrol-2-vl1-7-{i(3Æ)-3methyl-3_s4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4-dihydroisoqumolin-2(l/ï)-yl}-

2-oxoethyl)benzoic acid

Example 733:3-(6-(4-Γ (4-HvdroxvphenYl)(methvl)carbamovl]-L5-dimethvl-l//pyrrol-2-yl}-7-[(3S)-3-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyloxy)benzoic acid

The procedure is as in Example 709, replacing the product from Préparation 6ba with the product from Préparation 6bf, in Step A.

LC/MS (C₄₇H5oN₆0₇) 811 [M+H]⁺; RT 2.16 (Method A)

-286High-resolution mass (ESI+):

Empirical formula: C47H50N6O7 [M+2H]²⁺ calculated: 406.1943 [M+2H]²⁺ measured: 406.1944

Example 734:3-f2-r6-{4-r(4-Hvdroxvphenvl)(methvl)carbamovll-1.5-dimethvl-l#pyrrol-2-yl}-7-{[(3S)-3-[(4-methylpÎperazin-l-yl)methyl]-3,4-dihydroisoquinolin2(lH)-yl]carbonyl}-3,4-dihydroisoquinolin-2(lfir)-yl]-2-oxoethyl}benzoic acid

Example 735:3-(6-ll,5-Dimethvl-4-rmethvl(phenvl)carbamovll-lH-pvrrol-2-vl)-7[(3S)-3-[(4-methylpiperazin-l-yl)methyl]-1^3»4-tetrahydroisoquinoline-2-carbonylJl^:3>4-tetrahydroisoquinoline-2-carbonyloxy)benzoic acid

The procedure is as in Example 709, replacing the product from Préparation 6ba with the product from Préparation 6ce, in Step A.

LC/MS (C47H50N6O6) 795 [M+H]⁺; RT 1.4 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H50N6O6 [M+2H]²⁺ calculated: 398.1969 [M+2H]²⁺measured: 398.1985

Example 736:3-{2-r6-{L5-Dimethvl-4-rmethvl(DhenvDcarbamoyll-l//-pyrrol-2-vlI-7{[(3S)-3-[(4-methylpiperazin-l-yl)me4hyl]-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl·}-

3,4-dihydroisoquinolin-2(l/7)-yl]-2-oxoethyl}benzoic acid /

-287 Example_737:3-[({6-[4-(Dibutylcarbamoyl)-l,5-dimethyl-l//-pyrrol-2-yl]-7-{[(35)-3[(4-methylpiperazin-l-yl)methyl]-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinolin-2(l//)-yI)carbonyl)oxy ibenzoic acid

Example 738:3-(2-{6-[4-(Dibutvlcarbamovl)-1.5-dimethvl-l//-PYrrol-2-vH-7-( [(35)-35 [(4-methylpiperazin-l-yl)methyl]-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinoIin-2(lH)-yl}-2-oxoethyl)benzoic acid

Example 739:4-({r6-{4-r(4-Hvdroxyphenvl)(methvl)carbamoyll-13-dimethvl-lg·» pyrrol-2-yl}-7-{[(3S)-3-[(4-methylpiperazm-l-yl)methyl]-3,4-dihydroisoquinolm2(lfiF)-yl]carbonyl}-3,4-dihydroisoquinolin-2(liï)-yl]carbonyl}oxy)benzoic acid

Example 740:4-12-r6-{4-[(4-llYdroxvphenvl)(niethvl)carbainovl 1- 1.5-diinethvl-17/pyrrol-2-yl}-7-{[(35)-3-[(4-methylpiperazin-l-yl)methyl]-3,4-dihydroisoquinolin2(l/7)-yl]carbonyl}-3,4-dihydroisoquinolin-2(l//)-yl]-2-oxoethyl}benzoic acid

Example 741:4-({ Γ 6-11.5-Dimethvl-4-[ methvl(phenvl)carbamovll- l//-pyrrol-2-vl 1-7{[(3S)-3-[(4-methyIpiperazin-l-yl)methyl]-3,4-dihydroisoqumolm-2(ljff)-yl]carbonyl}15 3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}oxy)benzoic acid

Example 742;4-i2-[6-il^-Dimethyl-4-rmethvI(phenvl)carbamoyll-lg-pyrrol-2-yB-7{[(3S)-3-[(4-methylpiperazin-l-yl)methyl]-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-

3,4-dihydroisoquinolin-2(lH)-yl]-2-oxoethyl}benzoic acid

- 288 Example 743:4-[({6-i4-(Dibutvlcarbamovl)-1.5-dimethyl-lH-pvrrol-2-vi]-7-K(3S)-3|(4-methylpiperazin-l-yl)methyl]-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4dihydroisoquinolin-2(17/)-yl}carbonyl)oxy]benzoic acid

Example 744:4-(2-{6-[4-(Dibutvlcarbainovl)-1.5-dirnethvl-lH-pvrrol-2-yll-7-(l(3S4-35 [(4-methylpiperazin-l-yl)methyl]-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-3,4dihydroisoquinolin-2(lH)-yl}-2-oxoethyl)benzoic acid

Example 745:5-(2-Acetyl-7-if(3>S)-3-(morpholm-4-vlmethvl)-3.4-dihydroisoqiiinolin2(lfiO-yl]carbonyl}-1^3,4-tetrahydroisoqumolin-6-yl)-/V-(4-hydroxyphenyl)-l^dimethyl-A-phenyl-l//-pyrrole-3-carboxamide

Example 746; 5-(2-Acetvl-7-{ r(37?)-3-methvl-3.4-dihvdroisoqumolin-2( 1H)yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)-zV-(4-hydroxyphenyl)-l,2-dimethylzV-phenyl-lH-pyrrole-3-carboxamide

Example 747:/V-(4-Hvdroxyphenvl)-lJ2-dimethvl-5-(2-methyl-7-ir(3jR)-3-methyl-3.4dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yr)-/V-phenyl15 l//-pyrrole-3-carboxamide

Example 748:5-(2-Acetvl-7-{ r(3S)-3-(morpholin-4-vlmethvl)-3.4-dihvdroisoquinolin2(lfiD-yl]carbonyl}-l^^,4-tetrahydroisoquinolin-6-yl)-/V-(4-hydroxyphenyl)-l^dimethyl-A-(l-methyl-lH-pyrroIo[2,3-à]pyridin-5-yl)-lH-pyrrole-3-carboxamide

I

-289Example 749:5-(2-Acetyl-7-{[(31?)-3-methvl-3,4-dihvdroisoquinolin-2(177)yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)-A-(4-hydroxyphenyl)-l,2-dimethylA-(l-methyl-l//-pyrrolo[2,3-Z>]pyridin-5-yl)-lH-pyrrole-3-carboxamide

Example 750:A-(4-Hvdroxvphenyl)-l,2-dimethyl-5-(2-niiethvl-7-n(3/Q-3-methvl-3.4dihydroisoquinolin-2(l/7)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)-/V-(lmethyl-llï-pyrrolo[23-ô]pyridin-5-yl)-lH^r-pyrrole-3-carboxamide

Example 751:5-(2-Acetvl-7-{|(3S)-3-(morphoIin-4-vImethvl)-3,4-dihvdroisoquinolin2(lf/)-yl]carbonyI}-l,23,4-tetrahydroisoquinolin-6-yl)-zV-(4-hydroxyphenyl)-l,2dimethyl-A-(pyridm-4-yl)-lH-pyrrole-3-carboxamide

Example 752: 5-(2-AcetvI-7-{ [(3Æ)-3-meth vl-3,4-dihvdroisoquinolin-2(lZ/)yl]carbonyl}-l,2,3,4-tetrahydroisoquinolm-6-yI)-/V-(4-hydroxyphenyl)-l,2-dimethyljV-(pyridin-4-yl)-liT-pyrroIe-3-carboxamide

Example 753:ïV-(4-Hvdroxvphenvl)- l,2-dimethyl-5-(2-methvl-7-! H3R)-3-methvl-3.4dihydroisoquinolin-2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinoIin-6-yl)-iV(pyridin-4-yl)-lÆ-pyrrole-3-carboxamide

Example 754:5-(2-Acetvl-7-|[(3S)-3-(morpholin-4-vlmethyl)-3,4-dihvdroisoquinolin2(l_JfiF)-yl]carbonyl}-l,2,3,4-tetrahydroisoqumolin-6-yl)-l,2-dimethyl-AQV-diphenyll//-pyrrole-3-carboxamide

I

- 290Example 755:5-(2-Acetvl-7-{r(31?)-3-methvl-3,4-dihvdroisoquinolin-2(l/f)yIlcarbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)-l,2-dimethyl-AÇV-diphenyl-l//pyrrole-3-carboxamide

Example 756:1^2-Dimethyl-5-(2-methvl-7-{ Γ (3Æ)-3-methvl-3.4-dihvdroisoquinolin5 2(lH^r)-yl]carbonyl}-l^,3,4-tetrahydroisoquinolm-6-yl)-ïVA^r-diphenyl-lfif-pyrrole-3carboxamide

Example 757:5-(2-AcetYl-7-{[(3S)-3-(morpholîn-4-vlmethvl)-3.4-dihvdroisoquinolin2(17/)-yl]carbonyI}-l,2,3,4-tetrahydroisoquinolin-6-yI)-l,2-dimethyl-/V-(l-methyl-lHpyrrolo[23-6]pyridm-5-yl)-AT-phenyl-lL?-pyrrole-3-carboxamide

Example 758:5-(2-Acetvl-7-{r(3Æ)-3-methvl-3.4-dihvdroiso<iuinolin-2(l//lyl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)-l,2-dimethyl-ïV-(l-rnethyl-l/7pyrrolo[2,3-6jpyridin-5-yl)-;V-phenyl-l//-pyrrole-3-carboxamide

Example 759:lJ!-Dimethvl-5-(2-methvl-7-[[(37?)-3-methvl-3.4-dihvdroisoquin()lin2(lH)-yl]carbonyl}-l_>23,4>tetrahydroisoquinolin-6-yl)-A^r-(l-methyl-lIf-pyrrolo[2315 ô]pyridin-5-y l)-iV-phenyl- LET-py rrole-3-carboxamide

Example 760:5-(2-Acetvl-7-{[(3S)-3-(morpholin-4-vlmethvl)-3.4-dihvdroisoquinolîn2(l//)-yl]€arbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)-l,2-dimethyl-/V-phenyl-_J'V(pyridm-4-yl)-17/-pyrrole-3-carboxamide

- 291 Example 761:5-(2-Acetyl-7-{[(37?)-3-methvl-3,4-dihvdroisoquinolin-2( 1H}yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)-1^2-dimethyl-A-phenyl-A-(pyridin-4yl)-l//-pyrrole-3-carboxamide

Example 762;l^-Dimethvl-5-(2-methvl-7-if(31?)-3-methvl-3.4-dihvdroisoqumolin2(l//)-yl]carbonyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)-/V-pheiiyI-N-(pyridin-4-yI)-lHpyrroIe-3-carboxamide

Example 763:4-Methvlphenvl 6-{4-[(4-hydroxyphenyl)(l-methyl-lH^r-pyrazol-4yl)carbamoyl]>l,5-dimethyl-liî-pyrrol-2-yl}-7-{[(3S)-3-(morpholm-4-ylmethyl)-3,4dihydroisoqumolm-2(lfiO-yl]carbonyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate

Example 764:4-MethvlphenvI 6-{l-[(4-hydroxyphenyl)(l-methyl-lfi^r-pyrazol-4yl)carbamoyl]-5,6,7,8-tetrahydromdolizin-3-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-

3,4-dihydroisoquinolm-2(lH)-yl]carbonyl}>3,4-dihydroisoqumoline-2(liZ)carboxylate

Example 765:4-Methvlphenyl 6-{4-[(4-hydroxyphenyl)(pyridm-4-yl)carbamoyl]-l,5dimethyl-l//-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(lH)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l/f)-carboxylate____________ .

Example 766:4-Methylphenvl 6-{l-[(4-hydroxyphenyl)(pyridin-4-yl)carbamoyl]-

5,6,7,8-tetrahydromdolizin-3-yl}-7-{[(3S)-3-(morpholm-4-yImethyl)-3,4dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(liy^r)-carboxylate

Example 767:4-Methylphenyl 6-{4-[(4-hydroxyphenyl)(l-methyl-l//-pyrrolo[2,3h]pyridin-5-yl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7-{[(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(llï)-yl]carbonyl}-3,4-dihydroisoqmnolme-2(ljH^r)carboxylate

-292 Example 768:4-Methvlphenyl 6-{l-[(4-hydroxyphenyl)(l-methyl-lZ/-pyrroIo[2,3&]pyridin-5-yl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl}-7-{[(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(l/f)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l/f)carboxylate

Example 769;4-Methvlphenvl 6-(l,5-dimethyl-4-{(l-methyl-l//-pyrazol-4-yl)[4(phosphonooxy)phenyl]carbamoyl}-lH-pyrrol-2-yl)-7-{[(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl}-3,4-dihydroisoquinoline-2(l//)carboxylate

Example770:4-MethyIphenyl 6-(l-{(l-methYl-l//-pvrazol-4-vl)r4-(phosphonooxy) phenyI]carbamoyl}-5,6,7,8-tetrahydroindolizin-3-yl)-7-{[(3S)-3-(morpholin-4ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyI}-3,4-dihydroisoquinoline-2(l//)carboxylate

Example 771:4-Methvlphenvl 6-(l,5-dimethyl-4-{[4-(phosphonooxy)phenyl](pyridm-

4- yl)carbamoyl}-l//-pyrrol-2-yl)-7-{[(3S)-3-(morpholin-4-yImethyl)-3,4dihydroisoquinolin-2(110-yI]carbonyl}-3,4-dihydroisoqmnoline-2(lH^r)-carboxylate

Example 772:4-Methvlphenvl 7-{ [(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(lH)-yl]carbonyl}-6-(l-{[4-(phosphonooxy)phenyl](pyridin-4yl)carbamoyl}-5,6,7,8-tetrahydroindoIizm-3-yl)-3,4-dihydroisoquinoline-2(lH)carboxylate

Example 773:4-Methvlphenvl 6-(L5-dimethvl-4-((l-methvl-lH-pvrroloF2.3-à]pyridin-

5- yl)[4-(phosphonooxy)phenyl]carbamoyl}-17/-pyrrol-2-yl)-7-{[(3S)-3-(morpholin-4ylinethyl)-3,4-dihydroÎsoquinolin-2(l//)-yi]carbonyI}-3,4-dihydroisoquinolme-2(l//)carboxylate

Example 774:4-Methylphenvl 6-(l-{(l-methyl-l//-pyrrolo[2,3-/>]pyridin-5-yl)[4(phosphonooxy)phenyl]carbamoyl}-5,6,7,8-tetrahydroindolizin-3-yl)-7-{[(3S)-3I

- 293 (morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lZ/)-yl]carbonyl}-3,4dihydroisoquinoline-2(177)-carboxylate

Example 775: 2-[2-(Dimethylcarbamoyl)ethyl]phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl- l//-pyrrol-2-vl}-7-[(3/?)-3-methyll,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2carboxylate

The procedure is as in Example 709, replacing the product from Préparation 6ba in Step A with the product from Préparation 6bb, and replacing benzyl 3-hydroxybenzoate from Step B with 3-(2-hydroxyphenyl)-/V,A-dimethylpropanamide.

LC/MS (C46H49N5O6) 768 [M+H]⁺; RT 2.51 (Method A)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O6 [M+2H]²⁺ calculated: 384.6914 [M+2H]²⁺ measured: 384.6929

Example 776: 3-[2-(Dimethylcarbamoyl)ethyl]phenyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimetIiyl-l//-pyrrol-2-yl}-7-[(37i)-3-methyll,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2carboxylate

The procedure is as in Example 709, replacing the product from Préparation 6ba in Step A with the product from Préparation 6bb, and replacing benzyl 3-hydroxybenzoate from Step B with 3-(3-hydroxyphenyl)-7V,/V-dimethyIpropanamide.

LC/MS (C46H49N₅O6) 768 [M+H]⁺; RT 2.50 (Method A)

High-resolution mass (ESI+):

Empirical formula: C46H49N5O6 [M+2H]²⁺ calculated: 384.6914

I

- 294 [M+2H]²⁺ measured: 384.6913

Example 777: 5-{7-[(3S)-3-[(Dimethylamino)methyl]-l, 2,3,4tetrahydroisoquinolme-2-carbonyl]-2-(2-phenyIacetyI)-l,2,3,4-tetrahydroisoquinolin-

6-yl}-A-(4-hydroxypht^,nyl)-/V,l,2-trimethyl-l//-pyTrole-3-carboxaniide

Step A: N-[4-(Benzyloxy)phenyl]-5-{7-[(3S)-3-[(dimethylamino)methyl]-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4-tetrahydroisoquinolin-6yl}-N,l,2-trimethyl-lH-pyrrole-3-carboxamide

A solution of the compound from Préparation 6be (50 mg, 0.05 mmol) and N,Ndiisopropylethylamine (48 pL, 0.27 mmol) in dichloromethane (5 mL) was cooled to 0°C. To this was added phenylacetyl chloride (8 pL, 0.06 mmol) and the reaction was then stirred at ambient température for 1 h. The reaction mixture was diluted with dichloromethane, washed with IM aqueous sodium hydroxide, and then brine. The organic extract was dried over magnésium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to 10 % methanol in dichloromethane) afforded the desired product.

LC/MS (C₅iH53N₅O₄) 800 [M+H]⁺; RT 1.26 (Method B)

Step B: 5-{7-[(3S)-3-[(dimethylamino)methyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-2-(2-phenylacetyl)-l,2,3,4-tetrahydroisoquinolin-6-yl}-N-(4-hydroxyphenyl)N,l,2-trimethyl-lH-pyrrole-3-carboxamide

To a solution of the material from Step A (30 mg, 0.04 mmol) in éthanol (5 mL) was added 10% Pd/C (catalytic amount) and the mixture was shaken under an atmosphère of hydrogen for ca 16 h. The mixture is filtered through celite, subsequently eluting with methanol, and concentrated under reduced pressure. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to 7 % methanol in dichloromethane) afforded the desired product.

LC/MS (C44H47N5O4) 710 [M+H]⁺; RT 1.07 (Method B) il

Zi

I

- 295 High-resolution mass (ESI+):

Empirical formula: C44H47N5O4 [M+H]⁺calculated: 710.3701 [M+H]⁺ measured: 710.3702

Example 778:M-(4-Hvdroxvphenvl)-V.L2-trimethvl-5-f7-R3S)-3-[(4-methvlpiDerazin- l-yl)methyl]-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-l//-pyrrole-3-carboxamide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6bf.

LC/MS (C47H52N6O4) 765 [M+H]⁺; RT 1.08 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H5₂N6O₄ [M+H]⁺ calculated: 765.4123 [M+H]⁺measured: 765.4141

Example 779:AM4-Hvdroxvphenvl)-A\L2-triinethvl-5-{7-[(3S)-3-[2-(morpholin-4yl)ethyl]-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxainide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with product from Préparation 6bc.

LC/MS (C47H51N5O5) 766 [M+H]⁺; RT 1.08 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H51N5O5 [M+H]⁺ calculated: 766.3963

-296 [M+H]⁺ measured: 766.3982

Example 780:A-Ethvl-/V-(4-hvdroxvphenvl)-12-dimethvl-5-l7-r(3S)-3-(morDholin-4ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l,2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxamide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with product from Préparation 6f.

LC/MS (C47H51N5O5) 766 [M+H]⁺; RT 1.15 (Method B)

High-resolution mass (ESI+):

Empirical formula: C47H51N5O5 [M+H]⁺ calculated: 766.3963 [M+H]⁺ measured: 766.3967

Example 781:(V-(4-Hvdroxvphenvl)-l^-dimethvl-5-i7-r(3S)-3-(morpholin-4ylmethyl)-1^3»4-tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-l^î^,4' tetrahydroisoquinoIin-6-yl}vV-propyl-l//-pyrrole-3-carboxamide

The procedure is as in Example 777, replacing the product from Préparation 6be in Step A with the product from Préparation 6g.

LC/MS (C₄₈H₅₃N₅O₅) 780 [M+H]⁺; RT 1.19 (Method B)

High-resolution mass (ESI+):

Empirical formula: C48H53N5O5 [M+H]⁺ calculated: 780.4119 [M+H]⁺ measured: 780.4101

I

- 297 Example 782: 5-{7-[(3.S)-3-[(Dimethylamino)methyl]-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinolin-

6-yl}-AA(4-hydroxyphenyl)-Æ,l,2-trimethyl-lH-pyrrole-3-carboxamide

LC/MS (C38H40F3N5O4) 688 [M+H]⁺; RT 1.07 (Method B)

High-resolution mass (ESI+):

Empirical formula: C38H40N5O4F3 [M+H]⁺ calculated: 688.3105 [M+H] ^r measured: 688.3094

Example 783:A-(4-Hvdroxyphenvl)-7V,lJÎ-trimethvl-5-(7-[(3S)-3-r(4-methvlpiperazin10 l-yl)methyl]-l^,3,4-tetrahydroisoquinoline-2-carbonyl]-2-(trifluoroacetyl)-l_r23»4tetrahydroisoquinolin-6-yl}-l//-pyrrole-3-carboxamide

LC/MS (C41H45N6O4F3) 743 [M+H]⁺; RT 1.09 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H45N6O4F3 [M+2H]²⁺ calculated: 372.1800 [M+2H]²⁺measured: 372.1801

Example 784: 4-Bromophenyl 6-{4-[(4-hydroxyphenyI)(methyl)carbamoylJ-l,5dimethyl-l//-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,23,4-tetrahydroisoquinoline-2-carboxylate

Step A: 4-Bromophenyl 6-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyllH-pyrrol-2-yl)-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of the compound from Préparation 6ba (108 mg, 0.11 mmol) and N,Ndiisopropylethylamine (0.1 mL, 0.57 mmol) in dichloromethane (15 mL), cooled to 0 °C,

I

-298 was added triphosgene (34 mg, 0.11 mmol) and the mixture was stirred for 1 h at ambient température. The reaction was diluted with dichloromethane and washed with IM aqueous HCl. The organic extract was dried over magnésium sulfate, filtered and concentrated in vacuo to afford a yellow solid. To a solution of this solid in acetonitrile (10 mL) was added potassium carbonate (152 mg, 1.1 mmol), DMAP (13 mg, 0.11 mmol) and 4-bromophenol (98 mg, 0.57 mmol) and the mixture was heated at 60 °C for ca 16 h. The reaction was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate, and brine. The organic extract was dried over magnésium sulfate and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to5 % methanol in dichloromethane) afforded the desired product (79 mg, 0.09 mmol).

LC/MS (C₅2H52BrN₅O₆) 922 [M+H]⁺; RT 1.50 (Method B)

Step B: 4-Bromophenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lHpyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The product from Step A was dissolved in dichloromethane (10 mL) and cooled to 0 °C. To this was added boron trichloride (5 eq.) drop-wise. The reaction was then allowed to warm to ambient température for 1 h. The reaction mixture was adsorbed onto isolute and purified by chromatography (CombiFlash Rf, 12 g RediSep™ silica cartridge) eluting in a gradient of dichloromethane to 5 % methanol in dichloromethane to afford the desired product.

LC/MS (C₄5H46BrN₅O6) 832 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H46N6OôBr [M+2H]²⁺ calculated: 416.6388 [M+2H]²⁺ measured: 416.6374

- 299 Example 785: 4-Methylphenyl 6-{ 1,5-dimethyl-4-[methyl(phenyl)carbamoyl]lH-pyrrol-2-yl}-7-[(3Z?)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3>4tetrahydroisoquinoline-2-carboxylate

To a solution of product from Préparation 6cb (50 mg, 0.09 mmol) and N,Ndiisopropylethylamine (38 pL, 0.19 mmol) in dichloromethane (5 mL), cooled to 0 °C, was added 4-methylphenyl chloroformate (15 pL, 0.1 mmol) and the mixture was stirred at ambient température for 1 h. The reaction was diluted with dichloromethane, then washed successively with IM aqueous sodium hydroxide, and brine. The organic extract was dried over magnésium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 12 g RediSep™ silica cartridge; dichloromethane to 5 % methanol in dichloromethane) afforded the desired product.

LC/MS (C42H42N4O4) 667 [M+H]⁺; RT 1.50 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H42N4O4 [M+H]⁺ calculated: 667.3279 [M+H]⁺ measured: 667.3287

Example 786: 4-Cyanophenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoylJl//-pyrrol-2-yl}-7-[(3R)-3-methyl-L2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate

Step A: 6-{l,5-Dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinotine-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carbonyl chloride

To a solution of the product from Préparation 6cb (300 mg, 0.56 mmol) and N,Ndiisopropylethylamine (0.29 mL, 1.69 mmol) in dichloromethane (10 mL), cooled to 0 °C, was added triphosgene (167 mg, 0.56 mmol) and the mixture was allowed to warm to ambient température over 1 h. The reaction was diluted with dichloromethane, washed with IM aqueous HCl, and dried over magnésium sulphate. Concentration in vacuo

- 300afforded a yellow solid that was used directly in the next step without further purification, and assuming quantitative transformation.

LC/MS (C₃₅H3₅ClN₄O3) 595 [M+H]⁺; RT 1.41 (Method B)

Step B: 4-Cyanophenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate

To a solution of the carbamoyl chloride from Step A (50 mg, 0.072 mmol) in acetonitrile (5 mL) was added potassium carbonate (50 mg, 0.36 mmol) and 4-hydroxybenzonitrile (10 mg, 0.086 mmol). After heating at 60 °C for ca. 16 h the reaction was allowed to cool to ambient température, then diluted with ethyl acetate and washed successively with IM aqueous sodium hydroxide, and brine. The organics extract was dried over magnésium sulphate, concentrated in vacuo, and purified by préparative HPLC to afford the desired product.

LC/MS (C₄₂H39N₅O₄) 678 [M+H]⁺; RT 1.41 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄₂H₃9N₅O4 [M+H]⁺ calculated: 678.3075 [M+H]⁺ measured: 678.3086

Example 787: 3-[2-(Dimethylcarbamoyl)ethyl]phenyl 6-{l,5-dimethyl-4[methyl(phenyl)carbamoyl]-lH-pyrrol-2-yl}-7-[(3/?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 786, replacing 4-hydroxybenzonitrile in Step B with 3-(3hydroxyphenyl)-A,A-dimethylpropanamide.

LC/MS (C₄₆H49N₅O₅) 752 [M+H]⁺; RT 1.39 (Method B)

High-resolution mass (ESI+):

-301 Empirical formula: C46H49N5O5 [M+2H]²⁺ calculated: 376.6940 [M+2H]²⁺ measured: 376.6930

Example 788: 4-[2-(Dimethylcarbamoyl)ethyl]phenyl 6-{l,5-dimethyl-4[methyl(phenyl)€arbamoyl]-l/7-pyrrol-2-yl}-7-[(37?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 786, replacing 4-hydroxybenzonitrile in Step B with 3-(4hydroxyphenyl)-?Z,?/-dimethylpropanamide.

LC/MS (C46H49N5O5) 752 [M+H]⁺; RT 1.38 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H49N₅O₅ [M+2H]²⁺ calculated: 376.6940 [M+2H]²⁺ measured: 376.6926

Example 789: 177-Indol-5-yl 6-{L5-dimethyl-4-[methyl(phenyl)carbainoyl]-177pyrrol-2-yl}-7-[(37?)-3-methyl-L2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 786, replacing 4-hydroxybenzonitrile in Step B with 177indol-5-ol.

LC/MS (C43H41N5O4) 692 [M+H]⁺; RT 1.41 (Method B)

High-resolution mass (ESI+):

Empirical formula: C43H41N5O4 [M+H]⁺calculated: 692.3231 [M+H]⁺measured: 692.3210

I

- 302 Example 790: Cyclohexyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3.4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6bb, and replacing phenylacetyl chloride with cyclohexyl chloroformate.

LC/MS (C₄₁H46N4O₅) 675 [M+H]⁺; RT 1.45 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H46N4O5 [M+H]⁺ calculated: 675.3541 [M+H]⁺ measured: 675.3548

Example 791: Cyclohexyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-Lff-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l_r2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6ba, and replacing phenylacetyl chloride with cyclohexyl chloroformate.

LC/MS (C₄₅H₅₃N₅O₆) no ionisation; RT 1.28 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H5₃NsO6 [M+H]⁺ calculated: 760.4069 [M+H]⁺ measured: 760.4078

I

- 303 Example 792:

A-Cyclohexyl-6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5 dimethyl-l//-pyrrol-2-yl)-7-[(3R)-3-methyl-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxamide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6bb, and replacing phenylacetyl chloride with cyclohexyl isocyanate.

LC/MS (C41H47N5O4) 674 [M+H]⁺; RT 1.34 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄iH47N5O₄ [M+H]⁺ calculated: 674.3701 [M+H]⁺ measured: 674.3696

Example 793: A-Cyclohexyl-6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dirnethyl-l/7-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4tetrahydroisoquinoline-2-carbonyll-1^2,3,4-tetrahydroisoquinoline-2-carboxamide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6ba, and replacing phenylacetyl chloride with cyclohexyl isocyanate.

LC/MS (C45H54N6O5) no ionisation; RT 1.18 (Method B)

High-resolution mass (ESI+):

Empirical formula: C45H54N6O5 [M+H]⁺ calculated: 759.4228 [M+H]⁺measured: 759.4192

- 304 Example 794: 5-[2-(2-CyclohexylacetyI)-7-[(3S)-3-(morpholin-4-ylmethyl)- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl|-V-(4hydroxyphenyl)-A⁷,l,2-trimethyl-l//-pyrroIe-3-carboxaniide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6ba, and replacing phenylacetyl chloride with 2cyclohexylacetyl chloride.

LC/MS (C46H55N5O5) no ionisation; RT l .24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C46H55N5O5 [M+H]⁺ calculated: 758.4276 [M+H]⁺ measured: 758.4247

Example 795: 5-[2-(2-Cyclohexylacetyl)-7-[(3R)-3-methyl-l,2.3,4tetrahydroisoquinoline-2-carbonyi]-l,2,3,4-tetrahydroisoquinolin-6-yl]-AM4hy d r oxy pheny 1) - A, 1,2-trimethyl-l/7-pyrrole-3-carboxamide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6bb, and replacing phenylacetyl chloride with 2cyclohexylacetyl chloride.

LC/MS (C42H48N4O4) 673 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C42H48N4O4 [M+H]⁺ calculated: 673.3748 [M+H]⁺ measured: 673.3741

-305 Example 796: Cyclopentyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-LH-pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l, 2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6ba, and replacing phenylacetyl chloride with cyclopentyl chloroformate.

LC/MS (C^f^NsOô) 746 [M+H]⁺; RT 1.24 (Method B)

High-resolution mass (ESI+):

Empirical formula: C44H51N5O6 [M+H]⁺ calculated: 746.3912 [M+H]⁺ measured: 746.3891

Example 797: (lR,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l/7-pyrrol-2-yl}-7-[(3S)-3(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6ba, and replacing phenylacetyl chloride with (lR,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl chloroformate.

LC/MS (C49H₆iN₅O₆) 816 [M+H]⁺; RT 1.47 (Method B)

High-resolution mass (ESI+):

Empirical formula: C49H61N5O6 [M+H]⁺ calculated: 816.4695 [M+H]⁺measured: 816.4717

- 306Example 798: 5-{2-[2-(Adamantan-l-yl)acetyl]-7-[(3S)-3-(morpholin-4ylmethyl)-1^2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,23»4-tetrahydroisoquinolin-6yl}-jV-(4-hydroxyphenyl)-/V,l,2-trimethyl-lH-pyrrole-3-carboxamide

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6ba, and replacing phenylacetyl chloride with 2(adamantan-l-yl)acetyl chloride.

LC/MS (C₅oH₅9N₅0₅) 810 [M+H]⁺; RT 1.32 (Method B)

High-resolution mass (ESI+):

Empirical formula: C50H59N5O5 [M+H]⁺ calculated: 810.4589 [M+H]⁺ measured: 810.4586

Example 799: iV-(4-Hydroxyphenyl)-;V,l,2-trimethyl-5-{7-[(3R)-3-inethyl-l,2,3,4tetrahydroisoqumoline-2-carbonyl]-2-[2-(piperidin-l-yI)acetyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-177-pyrrole-3-carboxamide

Step A: N-[4-(Benzyloxy)phenyl]-N,l,2-trimethyl-5-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(piperidin-l-yl)acetyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxamide

To a solution of the compound from Préparation 6bb (50 mg, 0.08 mmol) in DMF (2 mL) was added 2-(l//-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (30 mg, 0.08 mmol), AL/V-diisopropylethylamine (41 pL, 0.23 mmol, 3 eq), and 2-(piperidin-l-yl)acetic acid (13 mg, 0.09 mmol), and the mixture was stirred at ambient température for ca. 16 h. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnésium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to 10 % methanol in dichloromethane) afforded the desired product.

LC/MS (C48H53N5O4) no ionisation; RT 1.29 (Method B)

- 307Step B: N-(4-Hydroxyphenyl)-N,l,2-trimethyl-5-{7-[(3R)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-2-[2-(piperidin-l-yl)acetyl]-l,2,3,4tetrahydroisoquinolin-6-yl}-lH-pyrrole-3-carboxamide

To a solution of the product from Step A (30 mg, 0.04 mmol) in éthanol (5 mL) was added

10% Pd/C (catalytic amount) and the mixture was shaken under an atmosphère of hydrogen for ca 16 h. The mixture was filtered through celite, eluted with methanol, and the filtrate concentrated in vacuo. Purification by préparative HPLC (H₂OTFA/acetonitrile; gradient elution) afforded the desired product.

LC/MS (C₄iH4₇N₅O4) 674 [M+H]⁺; RT 1.09 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H47N5O4 [M+2H]²⁺ calculated: 337.6887 [M+2H]²⁺ measured: 337.6887

Example 800: (lr,4r)-4-{[(ierLButoxy)carbonyl]amino}cydohexyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-l//-pyrroI-2-yl}-7-[(3/(!)-3-methyll^,3,4-tetrahydrôisoquinoline-2-carbonyl]-l^_r3j4-t^et^ralⁱydroisoquinoline-2carboxylate

Step A: (lr,4r)-4-{[(tert-Butoxy)carbonyl]amino}cyclohexyl chloroformate

Triphosgene (69 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0 °C. To this was added a solution of tert-butyl 77-(4-hydroxycyclohexyl)carbamate (100 mg,

0.46 mmol) and triethylamine (0.06 mL, 0.46 mmol, 2 eq) in dichloromethane (1 mL) drop-wise. After stirring for 2 h at ambient température, the reaction was concentrated in vacuo then re-dissolved / suspended in dichloromethane and filtered. The filtrate (2 mL) was used directly in the next step, assuming a quantitative transformation.

-308 Step B: (lr,4r)-4-{[(tert-Butoxy)carbonyl]amino}cyclohexyl 6-(4-{[4(benzyloxy)phenyl](methyl)carbamoyl}-l,5-dimethyl-lH-pyrrol-2-yl)-7-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

A solution of product from Préparation 6bb (50 mg, 0.08 mmol) in dichloromethane (3 mL) was cooled to 0 °C. To this was added triethylamine (54 pL, 0.39 mmol) and the solution of the product from Step A (0.49 mmol) and the mixture was stirred for 30 min at ambient température. The reaction was diluted with dichloromethane then washed sequentially with IM aqueous sodium hydroxide, and brine. The organic phase was dried over magnésium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to 3 % methanol in dichloromethane) afforded the desired product.

LC/MS (C53H61N5O7) 780 [M-Boc+H]⁺; RT 1.60 (Method B)

Step C: (lr,4r)-4-{[(tert-Butoxy)carbonyl]amino}cyclohexyl 6-{4-[(4hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl}-7-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a solution of the product from Step B (96 mg, 0.11 mmol) in éthanol (5 mL) was added 10% Pd/C (catalytic amount) and the mixture was shaken under an atmosphère of hydrogen for ca. 16 h. The mixture was filtered through celite, eluted with methanol, and the filtrate concentrated in vacuo. Purification by flash column chromatography (CombiFlash Rf, 4 g RediSep™ silica cartridge; dichloromethane to 5 % methanol in dichloromethane) afforded the desired product.

LC/MS (C₄6H₅₅N₅O₇) 790 [M+H]⁺; RT 1.43 (Method B)

High-resolution mass (ESI+):

Empirical formula: C₄₆H₅5N₅O7 [M+H]⁺ calculated: 790.4174 [M+H]⁺ measured: 790.4166

-309Example 801: (lr,4r)-4-Aminocyclohexyl 6-{4-[(4hydroxyphenyI)(inethyl)carbamoyI]-l,5-dimethyl-l//-pyrrol-2-yl}-7-[(3/?)-3-inethyl1^2,3,4-tetrahydroisoquinoline-2-carbonyl]-1^2,3,4-tetrahydroisoquinoline-2carboxylate hydrochloride

The product from Example 800 (48 mg, 0.06 mmol) was dissolved in 4M HCl in 1,4dioxane (5 mL) and stirred at ambient température for ca 15 min. The reaction was concentrated in vacuo to obtain a solid which was suspended in ether and stirred for 1 h at 0 °C. The solid was filtered, washed with ether, and dried under vacuum to afford the desired product.

LC/MS (C₄iH47N₅O₅) 690 [M+H]⁺; RT 1.10 (Method B)

High-resolution mass (ESI+):

Empirical formula: C41H47N5O5 [M+2H]²⁺ calculated: 345.6861 [M+2H]²⁺ measured: 345.6864

Example 802: (lr,4r)-4-(Dimethylamino)cyclohexyl 6-{4-[(4hydroxyphenyI)(methyI)carbamoyl]-l,5-dimethyI-LH-pyrrol-2-yl}-7-[(3R)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-L2,3,4-tetrahydroisoquinoline-2carboxylate

To a solution of the product from Example 801 (20 mg, 0.03 mmol, 1 eq) in methanol (2 mL) was added paraformaldéhyde (4 mg, 0.14 mmol), acetic acid (8 pL, 0.14 mmol, 5 eq) and sodium cyanoborohydride (9 mg, 0.14 mmol), and the mixture was stirred at ambient température for ca 16 h. The reaction was quenched by the addition of water (1 mL) and extracted with dichloromethane. The organic extract was washed sequentially with water, and brine, and then dried over magnésium sulfate, filtered and concentrated in vacuo. Purifiction by préparative HPLC (H2O-TFA/acetonitrile; gradient elution) afforded the desired product

LC/MS (C₄₃H5iN5O₅) 718 [M+H]⁺; RT 1.10 (Method B)

... .Jnk wy

-310High-resolution mass (ESI+):

Empirical formula: C43H51N5O5 [M+2H]²⁺ calculated: 359.7018 [M+2H]²⁺ measured: 359.7017

Example 803:

4-(zV-Methylacetamido)phenyl 6-{4-[(4-

hydroxyphenyl)(methyl)carbamoyl]-13-dimethyl-lH-pyrrol-2-yl}-7-[(3S)-3(morpholin^-ylmethyll-l^yJ^-tetrahydroisoquinoline-l-carbonyB-l^^^tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 709, replacing benzyl 3-hydroxybenzoate from Step B with 7V-(4-hydroxyphenyl)-?/-rnethylacetarnide.

LC/MS (C48H52N6O7) 825 [M+H]⁺; RT 1.07 (Method B)

High-resolution mass (ESI+):

Empirical formula: C48H52N6O7 [M+2H]²⁺ calculated: 413.2022 [M+2H]²⁺ measured: 413.2031

Example 804:

4-[2-(Dimethylcarbamoyl)ethyl]phenyl 6-{4-[(4-

hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl)-7-[(31?)-3-methyl- l,2,3,4-tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2- carboxylate

The procedure is as in Example 709, replacing the product from Préparation 6ba in Step A with the product from Préparation 6bb, and replacing benzyl 3-hydroxybenzoate from Step B with 3-(4-hydroxyphenyl)-/VjV-dimethylpropanamide.

LC/MS (C46H49N5O6) 384 [M+2H]²⁺; RT 2.49 (Method A)

High-resolution mass (ESI+):

I

- 311 I I

I

I >0

I

Empirical formula: C46H49N5O6 [M+2H]²⁺calculated: 384.6914 [M+2H]²⁺ measured: 384.6933

Example 805: Tolyl 6-[4-[(5-cyano-l,2-dimethyI-lH-pyrrol-3-yI)-(4hydroxyphenyl)carbamoyl]-l,5-dimethyl-lZ7-pyrrol-2-yl]-7-[(3S)-3(morpholinomethyl)-3,4-dihydro-lH-isoquinoline-2-carbonyl]-3,4-dihydro- 1Hisoquinoline-2-carboxylate hydrochloride

Step A: Benzyl 7-formyl-6-(4-ethoxycarbonyl-l,5-dimethyl-lH-pyrrol-2-yl)-3,4-dihydrolH-isoquinoline-2-carboxylate

To a solution of 1.3 g of ethyl l,2-dimethyl-l//-pyrrole-3-carboxylate (7.97 mmol) in 15 mL of A/TV-dimethylacetamide there are successively added 2.5 g of benzyl 6-bromo-7formyl-3,4-dihydro-l//-isoquinoline-2-carboxylate (6.64 mmol), 1.3 g of potassium acetate (13.3 mmol), and then the batch is stirred under argon for 20 minutes. 0.2 g of palladium catalyst PdCl₂(PPh₃)₂ (0.33 mmol) is then added. The reaction mixture is then heated at 85°C for 4.5 hours. The mixture is allowed to retum to ambient température and is then diluted with ethyl acetate. After filtration, the organic phase is washed with saturated aqueous sodium chloride solution, dried over magnésium sulphate, filtered and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel (petroleum ether / ethyl acetate gradient). The title product is obtained in the 20 form of a yellow foam.

’H NMR (400 MHz, dmso-d6) δ ppm: 9.78 (s, 1 H), 7.78 (s, 1 H), 7.45-7.3 (m, 5 H), 7.32 (s, 1 H), 6.39 (s, 1 H), 5.14 (s, 2 H), 4.72 (m, 2 H), 4.18 (q, 2 H), 3.68 (m, 2 H), 3.31 (s, 3 H), 2.93 (t, 2 H), 2.55 (s, 3 H), 1.25 (t, 3 H)

I

Step B: 2-Benzyloxycarbonyl-6-(4-ethoxycarbonyl-l,5-dimethyl-lH-pyrrol-2-yl)-3,4 25 dihydro-lH-isoquinoline-7-carboxylic acid

-312A solution containing 1.3 g of the compound obtained in Step A (2.82 mmol) and 2.4 mL (22.6 mmol) of 2-methyl-2-butene in a mixture composed of 2.5 mL of acetone and 2.5 mL of tetrahydrofuran is prepared. There are added, dropwise at 0°C, 20 mL of an aqueous solution containing a mixture of 0.64 g of NaClCL (7.05 mmol) and 1.4 g of NaHPCfi (9.88 mmol). The batch is then stirred vigorously at ambient température for 16 hours. The reaction mixture is then concentrated to remove the acetone and the tetrahydrofuran. Ethyl acetate is added and the organic phase is washed with water and then with saturated aqueous sodium chloride solution, dried over magnésium sulphate, filtered and concentrated to dryness. The yellow foam then obtained is subsequently used without being otherwise purified.

*H NMR (400 MHz, dmso-d6) δ ppm: 12.75 (m, 1 H), 7.69 (s, 1 H), 7.44-7.3 (m, 5 H), 7.14 (s, 1 H), 6.2 (s, 1 H), 5.14 (s, 2 H), 4.67 (m, 2 H), 4.15 (q, 2 H), 3.67 (m, 2 H), 3.21 (s, 3 H), 2.86 (m, 2 H), 2.49 (s, 3 H), 1.24 (t, 3 H)

Step C: Benzyl 6-(4-ethoxycarbonyl-l,5-dimethyl-lH-pyrrol-2-yl)-7-[(3S)-3(morpholinomethyl)-3,4-dihydro-lH-isoquinoline-2-carbonyl]-3,4-dihydro-lHisoquinoline-2-carboxylate

To a solution of 1.5 g of the compound obtained in Step B (2.49 mmol) in 13 mL of dichloromethane there are added 0.636 g of 4-[[(3S)-1,2,3,4-tetrahydroisoquinolin-3-ylJmethyljmorpholine (2.74 mmol), 1.1 mL of A/A/TV-triethylamine (7.47 mmol), 0.51 g of 1ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDC) (2.99 mmol) and then 0.4 g of hydroxybenzotriazole (HOBT) (2.99 mmol). The reaction mixture is stirred at ambient température for 16 hours and is then diluted with a mixture of dichloromethane and saturated sodium hydrogen carbonate solution. After séparation of the phases, the organic phase is dried over magnésium sulphate, filtered and evaporated to dryness. The crude product thereby obtained is then purified by chromatography over silica gel (dichloromethane / ethyl acetate gradient). The product is obtained in the form of a white foam.

’H NMR (500 MHz, dmso-d6) δ ppm: 7.4-7.3 (m, 5 H), 7.25-7.15 (4*s, 2 H), 7.2-6.9 (m,

H), 6.32/6.28/6.1 (3*bs, 1 H), 5.15 (3*s, 2 H), 5.15/4.85/3.7 (3*m, 1 H), 5-4 (m, 2 H),

-3134.7 (m, 2 H), 4.1 (m, 2 H), 3.78/3.6 (2*m, 2 H), 3.6-3.4 (m, 4 H), 3.45/3.39/3.2 (3*s, 3 H),

3-2.45 (m, 2 H), 2.9 (m, 2 H), 2.5-1.9 (4*m, 4 H), 2.5/2.41/2.05 (4*bs, 3 H), 2.35-1.7 (m, 2 H), 1.2/1.1 (3*t, 3 H) ¹³C NMR (500 MHz, dmso-d6) Ô ppm: 130/125, 129-126, 128, 110, 66.5, 66.5, 59, 57.5, 53.5, 49.5/44.5/43, 45.5, 44.5/41, 41.5, 31.5, 30/29, 28, 15, 11.5

Step D: l,2-Dimethyl-5-[7-[(3S)-3-(morpholinomethyl)-3,4-dihydro-lH-isoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl]-lH-pyrrole-3-carboxylic acid

To a solution of 1.1 g of the compound obtained in Step C (1.59 mmol) in 8 ml of éthanol there is added 0.9 ml of aqueous 5N sodium hydroxide solution (4.77 mmol). The reaction mixture is stirred at ambient température for 24 hours at 80°C and a second addition of 0.9 ml of aqueous 5N sodium hydroxide solution is made. After being in contact for a period of 24 hours at the same température, this operation is carried out a second time. The éthanol is then concentrated and the reaction mixture is diluted with water before adding aqueous IN hydrochloric acid solution until the pH is 7. After extracting the aqueous phase with dichloromethane, the organic phases are combined and concentrated to dryness to obtain the title product in the form of a yellow foam.

’H NMR (500 MHz, dmso-d6) δ ppm: 7.2-6.9 (m, 4 H), 7.05/7 (2*s, 2 H), 6.31/6.25/6.1 (3*s, 1 H), 5.1/4.85/3.7 (3*m, 1 H), 4.15/4.1 (m, 2 H), 3.91/3.81 (bs+dd, 2 H), 3.6-3.4 (m, 4 H), 3.4/3.35/3.15 (3*s, 3 H), 3-2.9 (m, 2 H), 2.9-1.9 (m, 2 H), 2.75 (m, 2 H), 2.5/2.4/1.98 (3*s, 3 H), 2.5-1.9 (m, 6 H) ¹³C NMR (500 MHz, dmso-d6) δ ppm: 130/125, 129-126, 110.5, 66.5, 57/54, 49.5/44.5/43,47.5, 44, 43.5, 32, 30, 29, 11.5

Step E: l,2-Dimethyl-5-[2-(4-methylphenoxy)carbonyl-7-[(3S)-3-(morpholinomethyl)-

3,4-dihydro-lH-isoquinoline-2-carbonyl]-3,4-dihydro-lH-isoquinolin-6-yl]-lH-pyrrole-

3-carboxylic acid

- 314 To a solution of 0.35 g of the compound obtained in Step D (0.66 mmol) in 1 ml of dioxane there is added, at 0°C, 0.33 ml of aqueous 2N sodium hydroxide solution (0.66 mmol) and, each in several portions, 0.106 ml of p-tolyl chloroformate (0.73 mmol) and 0.36 ml of aqueous 2N sodium hydroxide solution (0.73 mmol). The reaction mixture is stirred for 2 hours at ambient température and is then diluted with water and extracted with dichloromethane. The aqueous phase is acidified and then extracted with dichloromethane. The organic phases are combined, dried over magnésium sulphate, filtered and concentrated.

The residue obtained is taken up in 12 ml of methanol and 3.2 ml of aqueous IN potassium hydroxide solution (3.26 mmol) and then the reaction mixture is stirred at ambient température for 20 minutes. After adding aqueous 0.1N hydrochloric acid solution until the pH is 4, the mixture is extracted with dichloromethane. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnésium sulphate, filtered and concentrated. The residue is then taken up in a mixture of dichloromethane and i.s’o-propyl ether. The solid then obtained is filtered off and washed with ether. The title product is obtained in the form of a solid, which is subsequently used without being otherwise purified.

’H NMR (500 MHz, dmso-d6) δ ppm: 11.5 (bs, 1 H), 7.28 (bs, 1 H), 7.2-6.9 (m, 4 H), 7.2 (bd, 2 H), 7.02 (bd, 2 H), 6.88 (bs, 1 H), 6.35/6.28/6.12 (3*s, 1 H), 5.11/4.85/3.7 (3*m, 1 H), 4.85-4.65 (m, 2 H), 4.8-4.1 (m, 2 H), 4.2-3.6 (m, 2 H), 3.6-3.4 (m, 4 H), 3.45/3.4/3.18 (3*s, 3 H), 3-1.8 (m, 2 H), 2.97 (ml, 2 H), 2.5/2.41/1.99 (4*s, 3 H), 2.5-1.9 (4*m, 4 H), 2.35/2.18 (2*m, 2 H), 2.25 (bs, 3 H) ¹³C NMR (500 MHz, dmso-d6) δ ppm: 130, 129, 129-126, 125, 122, 110.5, 66.5, 58, 54, 49.5/44/43,45.5, 44.5/41.5, 41.5, 32, 30-29, 28, 20.5, 11

Step_________F: Tolyl 6-[4-[(5-cyano-l,2-dimethyl-lH-pyrrol-3-yl)-(4hydroxyphenyl)carbamoyl]-l,5-dimethyl-lH-pyrrol-2-yl]-7-[(3S)-3-(morpholinomethyl)-

3,4-dihydro-lH-isoquinoline-2-carbonyl]-3,4-dihydro-lH-isoquinoline-2-carboxylate hydrochloride

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I To a solution of 0.232 g of the compound obtained in Step E (0.35 mmol) in 9 mL of dichloroethane there is added 0.05 mL of l-chloro-A,A2-trimethyl-prop-l-en-1-amine | (0.385 mmol). The reaction mixture is stirred at ambient température for 2 hours and there is then added 0.131 g of 4-[4-[iert-butyl(dimethyl)silyl]oxyanilino]-l,5-dimethyl-lH| 5 pyrrole-2-carbonitrile (0.385 mmol, product of Préparation 3f). The batch is stirred at 80°C ovemight. The reaction mixture is diluted with a mixture of dichloromethane and saturated | aqueous sodium hydrogen carbonate solution. After séparation of the phases, the organic phase is dried over magnésium sulphate, filtered and concentrated to dryness. The crude product thereby obtained is subsequently used without being otherwise purified.

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To a solution of the compound thereby obtained in 1.8 ml of tetrahydrofuran there is added

0.53 ml of a IN solution of tetrabutylammonium fluoride in tetrahydrofuran (13.5 mmol).

The reaction mixture is stirred at ambient température for 1 hour and is then diluted with a mixture of dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane and then the organic phases are combined, dried over magnésium sulphate, filtered and concentrated. The crude product is then purified by chromatography over silica gel (dichloromethane / methanol gradient). The solid thereby obtained is converted to the hydrochloride form, dissolved in a mixture of acetonitrile and water, filtered and then lyophilised to isolate the title product.

High-resolution mass (ESI/FI A/HR and MS/MS):

Empirical formula: C52H53N7O6 [M+H]⁺ calculated: 872.4130 [M+H]⁺ measured: 872.4130

Elemental microanalysis: (%, theoretical:measured) %C=68.75:68.07; %H=5.99:5.90; %N=10.79:10.68; %Cf=3.90:3.84

Examnle 806: A'-(4-HydroxyphenyI)-5-(2-[(2S’)-2-hydroxy-2-phenylacetyl|-6{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(LH^r)-yl]carbonyl}-2,3-dihydro-LH-isoindol-

5-yl)-A,l,2-trimethyl-l//-pyrrole-3-carboxamide

- 316 Example 807: Cyclohexyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-lH-pyrrol-2-yl}-7-[(3S)-3-[2-(morpholin-4-yl)ethyl]-l, 2,3,4tetrahydroisoqumoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

A with the compound from Préparation 6bc, and replacing phenylacetyl chloride with cyclohexyl chloroformate.

LC/MS (C46H55N5O6) 774 [M+H]⁺; RT 1.22 (Method B)

Example 808: Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-l//-pyrrol-2-yI}-7-[(3R)-3-[3-(inorpholin-4-yl)propyl]-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoqumoline-2-carboxylate

A with product from Préparation 6bd; and replacing phenylacetyl chloride in Step A with phenyl chloroformate.

LC/MS (C47H51N5O6) 782 [M+H]⁺; RT 1.15 (Method B)

Example 809: Cyclohexyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5dimethyl-UT-pyrrol-2-yl}-7-[(3jR)-3-[3-(morpholm-4-yl)propyl]-l,2,3,4tetrahydroisoqumoIme-2-carbonyl]-l,2,3,4-tetrahydroisoquinolme-2-carboxylate

The procedure is as in Example 777, replacing the compound from Préparation 6be in Step A with the compound from Préparation 6bd, and replacing phenylacetyl chloride with cyclohexyl chloroformate.

LC/MS (C47H57N5O6) 788 [M+H]⁺; RT 1.21 (Method B)

Example 810: Phenyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-LH-pyrrol-

2-yl}-7-[(3R)-3-[3-(morpholin-4-yl)propyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

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	-317-
Example 811:	Cyclohexyl 6-{l,5-dimethyl-4-[methyl(phenyl)carbamoyl]-1 H-

pyrrol-2-yl}-7-[(3Æ)-3-[3-(morpholin-4-yl)propyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate

The procedure is as in Example 114, replacing the product from Préparation 6cb with the 5 product from Préparation 6cd, and replacing phenyl chloroformate with cyclohexyl chloroformate.

LC/MS (C₄₇H57N₅O₅) 772 [M+H]⁺; RT 1.33 (Method B)

- 318 PHARMACOLOGICAL STUDY

EXAMPLE A: Inhibition of Bcl-2 by the fluorescence polarisation technique

The fluorescence polarisation tests were carried out on microplates (384 wells). The Bcl-2 protein, labelled (histag-Bcl-2 such that Bcl-2 corresponds to the UniProtKB® primary accession number: P10415), at a final concentration of 2.50xl0‘⁸ M, is mixed with a fluorescent peptide (Fluorescein-REIGAQLRRMADDLNAQY), at a final concentration of l.OOxlO’⁸ M in a buffer solution (Hepes 10 mM, NaCl 150 mM, Tween20 0.05%, pH 7.4), in the presence or in the absence of increasing concentrations of test compounds. After incubation for 2 hours, the fluorescence polarisation is measured.

The results are expressed in IC50 (the concentration of compound that inhibits fluorescence polarisation by 50%) and are presented in Table 1 below.

The results show that the compounds of the invention inhibit interaction between the Bcl-2 protein and the fluorescent peptide described hereinbefore.

EXAMPLE B: In vitro cytotoxicity

The cytotoxicity studies were carried out on the RS4;11 leukaemia cell line and on H146 small Cell Lung Carcinoma cell line. The cells are distributed onto microplates and exposed to the test compounds for 48 hours. The cell viability is then quantified by a colorimétrie assay, the Microculture Tétrazolium Assay (Cancer Res., 1987, 47, 939-942).

The results are expressed in IC50 (the concentration of compound that inhibits cell viability by 50%) and are presented in Table 1 below.

The results show that the compounds of the invention are cytotoxic.

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Table 1: ICgo of Bcl-2 inhibition (fluorescence polarisation test) and of cytotoxicity for RS4;11 cells

	ICso (nM) Bcl-2 FP	IC₅₀ (nM) MTT RS4;11
Example 1	13	140
Example 2	397	> 1880
Example 3	18	236
Example 4	9.2	71
Example 5	43	70
Example 6	95	> 1880
Example 7	72% @3.3μΜ	1080
Example 8	7.3	98
Example 9	9.0	125
Example 10	127	ND
Example 11	22	763
Example 12	43	759
Example 13	108	729
Example 14	7.9	27
Example 15	19	93
Example 16	6.0	27
Example 17	91	1760
Example 18	38	1290
Example 19	47	774
Example 20	20	> 150
Example 21	14	112
Example 22	70	> 150
Example 23	13	61
Example 24	19	> 150
Example 25	29	144
Example 26	30	86
Example 27	83	ND
Example 28	23	> 150

- 320-

	IC_5O (nM) Bcl-2 FP	JC₅₀(nM)MTTRS4:ll
Example 29	28	> 150
Example 30	16	119
Example 31	7.4	113
Example 32	47	141
Example 33	33	460
Example 34	4.9	19
Example 35	4.7	8.5
Example 36	4.8	6.2
Example 37	4.9	18
Example 38	23	532
Example 39	14	106
Example 40	3.6	34
Example 41	26	78
Example 42	38	> 150
Example 43	77	502
Example 44	13	443
Example 45	15	20
Example 46	3.7	2.8
Example 47	12	45
Example 48	8.7	40
Example 49	23	58
Example 50	18	26
Example 51	5.5	23
Example 52	3.8	56
Example 53	2.4	5.0
Example 54	4.0	2.4
Example 55	16	372
Example 56	3.8	59
Example 57	65	1250
Example 58	4.2	3.3
Example 59	3.2	6.8

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-321 -

	lCso (nM) Bcl-2 FP	IC₅₀ (nM)MTTRS4:Il
Example 60	5.9	46
Example 61	4.4	85
Example 62	20	113
Example 63	4.4	12
Example 64	27	204
Example 65	6.5	51
Example 66	16	80
Example 67	9.4	51
Example 68	2.9	1.8
Example 69	3.1	3.46
Example 70	5.1	9.8
Example 71	3.7	9.9
Example 72	21	229
Example 73	4.3	36
Example 74	6.1	94
Example 75	4.0	6.2
Example 76	24	> 150
Example 77	4.0	84
Example 78	4.4	142
Example 79	5.6	> 150
Example 80	5.5	71
Example 81	21	> 150
Example 82	17	> 150
Example 83	15	122
Example 84	4.9	33
Example 85	6.1	58
Example 86	5.5	60
Example 87	5.1	43
Example 88	3.5	3.9
Example 89	3.5	24
Example 90	6.2	39

	1C_5O (nM) Bcl-2 FP	IC₅₀ (nM) MTTRS4.il
Example 91	7.0	73
Example 92	20	105
Example 93	5.1	11
Example 94	5.6	19
Example 95	14	115
Example 96	3.9	9.1
Example 97	4.9	15
Example 98	3.8	1.8
Example 99	5.5	13
Example 100	3.9	6.5
Example 101	2.6	31
Example 102	5.0	75
Example 103	3.6	46
Example 104	6.7	65
Example 105	7.3	31
Example 106	5.3	38
Example 107	3.5	6.9
Example 108	2.7	15
Example 109	8.6	89
Example 110	19	329
Example 111	8.4	64
Example 112	42	394
Example 113	3.6	25
Example 114	3.8	28
Example 115	3.4	24
Example 116	21	181
Example 117	2.5	39
Example 118	3.4	43
Example 119	622	> 150
Example 120	2.5	8.2
Example 121	2.9	2.8

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	IC_5Û (nM) Bcl-2 FP	IC₅₀ (nM) MTT RS4;11
Example 122	2.6	5.4
Example 123	5.3	8.3
Example 124	12	50
Example 125	8.7	49
Example 126	5.9	5.2
Example 127	3.3	6.4
Example 128	3.5	8.2
Example 129	3.3	39
Example 130	3.1	36
Example 131	4.0	11
Example 132	4.6	32
Example 133	7.0	8.2
Example 134	4.3	2.0
Example 135	8.4	99
Example 136	6.7	24
Example 137	9.4	47
Example 138	12	114
Example 139	5.1	0.84
Example 140	6.6	4.0
Example 141	5.9	82
Example 142	5.5	53
Example 143	5.5	9.3
Example 144	4.8	82
Example 145	4.2	5.5
Example 146	2.8	6.0
Example 147	3.2	2.3
Example 148	3.0	10
Example 149	11	124
Example 150	4.3	16
Example 151	5.3	19
Example 152	6.5	29

- 324 I

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	IC₅₀ (nM) Bcl-2 FP	IC₅₀ (nM)MTT RS4;11
Example 153	4.2	3.6
Example 154	3.9	5.9
Example 155	3.2	2.9
Example 156	6.8	121
Example 157	21	>600
Example 158	4.6	3.5
Example 159	8.5	163
Example 160	6.9	86
Example 161	68	> 150
Example 162	33	> 150
Example 163	27	> 150
Example 164	14	> 150
Example 165	18	> 150
Example 166	6.4	58
Example 167	6.5	20
Example 168	5.7	6.6
Example 169	3.3	3.0
Example 170	12	491
Example 171	5.1	63
Example 172	3.4	28
Example 173	55	>600
Example 174	5.9	407
Example 175	4.2	90
Example 176	78	ND
Example 185	3.7	4.5
Example 186	2.5	4.5
Example 187	3.0	4.6
Example 197	26	> 150
Example 211	3.4	6.9
Example 214	2.7	4.1

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	IC>o (nM) Bcl-2 FP	ICso (nM)MTT RS4;11
Example 216	2.4	2.9
Example 232	2.9	11
Example 245	4.2	92
Example 253	5.2	22
Example 392	2.0	14
Example 434	2.9	1.6
Example 446	4.3	14
Example 448	4.0	8.2
Example 474	4.5	2.6
Example 476	1.8	ND
Example 488	5.3	13
Example 489	3.2	68
Example 560	8.8	70
Example 564	4.5	3.3
Example 573	18	43
Example 574	8.8	11
Example 575	6.3	12
Example 577	5.9	4.7
Example 579	4.4	17
Example 591	2.5	7.0
Example 629	7.2	9.0
Example 631	5.2	8.2
Example 633	6.1	22
Example 634	6.9	21
Example 636	11	34
Example 709	4.8	> 150
Example 715	2.2	> 150
Example 721	4.9	>150
Example 733	1.5	> 150
Example 735	12	> 150

- 326 -

	IC₅o (nM) Bcl-2 FP	IC₅o(nM)MTTRS4;ll
Example 775	2.4	6.3
Example 776	2.2	1.1
Example 777	4.1	30
Example 778	3.1	52
Example 779	2.9	24
Example 780	3.5	17
Example 781	2.6	9.7
Example 782	51	112
Example 783	23	> 150
Example 784	5.1	2.9
Example 785	3.3	7.8
Example 786	8.4	24
Example 787	5.0	6.2
Example 788	4.4	14
Example 789	8.9	14
Example 790	3.4	20
Example 791	2.8	54
Example 792	4.6	21
Example 793	4.4	92
Example 794	4.6	70
Example 795	5.3	32
Example 796	6.2	48
Example 797	21	125
Example 798	9.1	76
Example 799	15	> 150
Example 800	2.0	3.2
Example 801	2.7	> 150
Example 802	4.0	99
Example 803	4.6	37
Example 804	3.6	2.2

- 327 -

	IC₅₀ (nM) Bcl-2 FP	IC_}u(nM)MTTRS4;ll
Example 805	3.1	0.12
Example 806	33	> 150
Example 807	3.9	26
Example 808	2.7	1.6
Example 809	3.1	9.8
Example 811	3.8	94

ND: not de ? ?mined

For partial mhibitors, the percentage fluorescence polarisation inhibition for a given concentration of the test compound is indicated. Accordingly, 72% @3.3 μΜ means that 72 % fluorescence polarisation inhibition is observed for a concentration of test compound 5 equal to 3.3 μΜ.

EXAMPLE C; Induction of caspase activity in vivo

The ability of the compounds of the invention to activate caspase 3 is evaluated in a xenograft model of RS4; 11 leukaemia cells.

lxlO⁷ RS4;11 cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after the graft, the animais are treated orally with the various 10 compounds. Sixteen hours after treatment, the tumour masses are recovered and lysed, and the caspase 3 activity is measured in the tumour lysâtes.

This enzymatic measurement is carried out by assaying the appearance of a fluorigenic cleavage product (DEVDase activity, Promega). It is expressed in the form of an activation factor corresponding to the ratio between the two caspase activities: the activity for the 15 treated mice divided by the activity for the control mice.

The results show that the compounds of the invention are capable of inducing apoptosis in RS4;11 tumour cells in vivo.

4*

- 328 EXAMPLE D: Quantification of the cleaved form of caspase 3 in vivo

The ability of the compounds of the invention to activate caspase 3 is evaluated in a xenograft model of RS4;11 leukaemia cells.

T

1x10 RS4;11 cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after the graft, the animais are treated orally with the various compounds. After treatment, the tumour masses are recovered and lysed, and the cleaved (activated) form of caspase 3 is quantifîed in the tumour lysâtes.

The quantification is carried out using the Meso Scale Discovery (MSD) ELISA platform test, which specifically assays the cleaved form of caspase 3. It is expressed in the form of an activation factor corresponding to the ratio between the quantity of cleaved caspase 3 in the treated mice divided by the quantity of cleaved caspase 3 in the control mice.

EXAMPLE E: Anti-tumour activity in vivo

The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of RS4;11 leukaemia cells.

lxlO⁷ RS4;11 cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after the graft, when the tumour mass has reached about 150 mm , the mice are treated orally with the various compounds in two different régimes (daily treatment for fïve days per week for two weeks, or two treatments weekly for two weeks). The tumour mass is measured twice weekly from the start of treatment.

The results obtained therefore show that the compounds of the invention are capable of inducing significant tumour régression during the treatment period.

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I -329 EXAMPLE F: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 811 5g

Wheat starch............................................................................................................ 20g

Maize starch............................................................................................................. 20g

Lactose..................................................................................................................... 30g

Magnésium stéarate................................................................................................. 2g

Silica........................................................................................................................ 1g

Hydroxypropylcellulose.......................................................................................... 2g

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- 330 -

Claims

1. Compound of formula (I) :

r₃ wherein:

5 ♦ Het represents a heteroaryl group, ♦ T represents a hydrogen atom, a linear or branched (Ci-Cô)alkyl group optionally substituted by one to three halogen atoms, an alkyl(Ci-C4)-NRiR2 group or an alkyl(Ci-C4)-OR6 group, ♦ Rf and R2 independently of one another represent a hydrogen atom or a linear or

10 branched (Ci-Côjalkyl group, or Ri and R2 form with the nitrogen atom carrying them a heterocycloalkyl group, ♦ R3 represents a linear or branched (Ci-Côjalkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl group, a (C3-Cio)cycloalkyl-(C]-C6)alkyl group wherein the alkyl group may be

15 linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated, ♦ R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (Ci-Céjalkyl group, it being understood that one or more carbon atoms of the groups defined

I

I hereinbefore, or carbon atoms of their possible substituents, may be deuterated, ♦ R5 represents a hydrogen atom or a halogen atom, a linear or branched (C]-C₆)alkyl group, or a linear or branched (Ci-Côjalkoxy group, ♦ P 5 represents a hydrogen atom or a linear or branched (Ci-Cô)alkyl group, ♦ R₇ represents a group selected from R’₇, R’₇-CO-, R’₇-O-CO-, NR’₇R”₇-CO-, R’₇-SO₂-, R’₇-NR”₇-SO2- wherein R’₇ et R”₇ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl, a heterocycloalkyl, an aryl group, or a heteroaryl, * Rs and R₉ represent, independently of one another, an oxo group or a halogen atom, ♦ p and p’ are, independently of one another, integers equal to 0, 1, 2, 3 or 4, ♦ q and q’ are, independently of one another, integers equal to 1, 2 or 3, it being understood that when compound of formula (I) contains a hydroxy group, this latter group may be optionally substituted by one of the following groups: 15 -P0(0M)(0M’), -PO(OM)(OMi⁺), -PO(O’Mi⁺)(OM2⁺), -PO(O’)(O)M3²⁺,

-PO(OM)(O[CH₂CH₂O]_nCH3), or -PO(OMi⁺)(O[CH₂CH₂O]_nCH₃), wherein M and M’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl or a heterocycloalkyl, both of them being composed of from 5 to 6 ring members, while M/ and M₂ ⁺ independently of one another represent a pharmaceutically acceptable monovalent cation, M₃ ²⁺ represents a pharmaceutically acceptable divalent cation and n is an integer comprised between 1 to 5, it also being understood that:

- aryl means a phenyl, naphthyl, biphenyl or indenyl group, heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quatemary nitrogens), cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, which may include fused, bridged or spiro ring Systems,

- 332 “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group, composed of from 3 to 10 ring members, and containing from one to 3 hetero atoms selected from oxygen, sulphur, SO, SO₂ and nitrogen, it being understood that bicyclic group may be fused or spiro type,

5 it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 3 groups selected from: optionally substituted linear or branched (Ci-Cô)alkyl ; optionally substituted linear or branched (C2-C6)alkenyl group; optionally substituted linear or branched (C₂-Cô)alkynyl group; (C3-C6)spiro; optionally substituted linear or branched (Ci-Ce) alkoxy;

10 (Ci-C6)alkyl-S-; hydroxyl; oxo (or N-oxide where appropriate); nitro; cyano; -COOR'; -OCOR'; -NR'R; R’CONR”-; NR’R”CO-; linear or branched (Ci-C₆)polyhaloalkyl; trifluoromethoxy; (Ci-Celalkylsulphonyl; halogen; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted aryloxy; optionally substituted arylthio; optionally substituted cycloalkyl or optionally substituted heterocycloalkyl, it being

15 understood that R’ and R independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Cô)alkyl group or an aryl group, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

2. Compound of formula (IA) according to claim 1 :

¹ 4T 3

-333 r₃ (ΙΑ) wherein:

♦ W represents a C-A3 group or a nitrogen atom, ♦ X, Y and Z represent a carbon atom or a nitrogen atom, it being understood that only one of them represent a nitrogen atom, while the two others represent carbon atoms, ♦ Aj, A2 and A3 independently of one another represent a hydrogen atom or a halogen atom, a linear or branched (Ci-Cejpolyhaloalkyl group, a linear or branched (Cj-Côjalkyl group or a cycloalkyl group, or A3 represents a hydrogen atom (when W represents a C-A₃ group) while Ai and A₂ form together with the atoms carrying them an optionally substituted aromatic or non-aromatic ring Cy, composed of 5, 6 or 7 ring members, which may contain from one to 4 hetero atoms selected independently from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-Côjalkyl group or a group -C(O)-O-Alk wherein Alk is a linear or branched (Ci-Cô)alkyl group, or W represents a nitrogen atom while Ai and A₂ form together with the atoms carrying them an optionally substituted aromatic or non-aromatic ring Cy, composed of 5, 6 or 7 ring members, which may contain from one to 4 hetero atoms selected independently from oxygen, sulphur and nitrogen, it being

-334understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-C6)alkyl group or a group -C(O)-O-Alk wherein Alk is a linear or branched (Ci-Cg)alkyl group, ♦ T represents a hydrogen atom, a linear or branched (Ci~C6)alkyl group optionally substituted by one to three halogen atoms, an alkyl(Ci-C₄)-NRiR₂, group or an alkyl(Ci-C4)-ORô group, ♦ Ri and R₂ independently of one another represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group, or Ri and R₂ form with the nitrogen atom carrying them a heterocycloalkyl, ♦ R3 represents a linear or branched (Ci-C₆)alkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl group, a (C3-Cio)cycloalkyl-(Ci-C6)alkyl group wherein the alkyl group may be linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated, ♦ R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (Ci-Cô)alkyl group, it being understood that one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated, ♦ R5 represents a hydrogen atom or a halogen atom, a linear or branched (Ci-C6)alkyl group, or a linear or branched (Ci-C6)alkoxy group, ♦ Rô represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, ♦ R7 represents a group selected from R’7, R’7-C0-, R’7-O-CO-, NR^R’^-CO-, R’7-SO₂-, R’₇-NR”₇-SO₂- wherein R’7 et R”7 independently of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C₂-Ce)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a cycloalkyl, a heterocycloalkyl, an aryl group, or a heteroaryl, ♦ Rg and R₉ represent, independently of one another, an oxo group or a halogen atom, ♦ p and p’ are, independently of one another, integers equal to 0, 1, 2, 3 or 4, ♦ q and q’ are, independently of one another, integers equal to 1, 2 or 3, it being understood that when compound of formula (I) contains a hydroxy group, this latter group may be optionally substituted by one of the following groups:

- 335 -ΡΟ(ΟΜ)(ΟΜ’), ~ΡΟ(ΟΜ)(Ο’Μ]⁺), -ΡΟ(Ο Μι⁺)(Ο“Μ2⁺), -ΡΟ(Ο )(Ο )Μ3²⁺,

-PO(OM)(O[CH₂CH₂O]_nCH₃), or -ΡΟ(Ο Mi⁺)(O[CH2CH2O]nCH3), wherein Μ and Μ’ independently of one another represent a hydrogen atom, a linear or branched (Cj-Côjalkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl or a heterocycloalkyl, both of them being composed of from 5 to 6 ring members, while M/ and M2⁺ independently of one another represent a pharmaceutically acceptable monovalent cation, M3²⁺ represents a pharmaceutically acceptable divalent cation and n is an integer comprised between 1 to 5, it also being understood that:

- aryl means a phenyl, naphthyl, biphenyl or indenyl group, heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quatemary nitrogens), cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, which may include fused, bridged or spiro ring Systems, “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group, composed of from 3 to 10 ring members, and containing from one to 3 hetero atoms selected from oxygen, sulphur, SO, SO₂ and nitrogen, it being understood that bicyclic group may be fused or spiro type, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 3 groups selected from: optionally substituted linear or branched (Ci-Cô)alkyl; optionally substituted linear or branched (C₂-Cô)alkenyl group; optionally substituted linear or branched (C₂-Cô)alkynyl group; (C₃-Cô)spiro; optionally substituted linear or branched (Cj-Côjalkoxy; (Ci-Cô)alkyl-S-; hydroxyl; oxo (or A-oxide where appropriate); nitro; cyano; -COOR'; -OCOR'; -NR'R; R’CONR”-; NR’R”CO-; linear or branched (Ci-Célpolyhaloalkyl; trifluoromethoxy; (Ci-Côjalkylsulphonyl; halogen; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted aryloxy; optionally substituted arylthio; optionally substituted cycloalkyl or optionally substituted heterocycloalkyl, it being : ')ΓΓ ; t _; .. .

- 336 understood that R' and R independently of one another represent a hydrogen atom, an optionally substituted linear or branched (CrCô)alkyl group or an aryl group, it being possible for the Cy moiety defined in formula (I) to be substituted by from 1 to 3 groups selected from linear or branched (Ci-Cô)alkyl, linear or branched

5 (Ci-Côjpolyhaloalkyl, hydroxy, linear or branched (Ci-C₆)alkoxy, COOH, NRi'Ri and halogen, it being understood that Rf and Rf' hâve the same définitions than the groups R' and R mentioned hereinbefore, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

10 3. Compound of formula (IA-1) according to claim 1 or 2:

o wherein X, Y, W, Ai, A₂, R3, R4, R5, R7, Rs, R9, T, p, p’, q and q’ are as defined in claim 2, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

15 4. Compound of formula (IA-2) according to claim 1 to 3:

-337- wherein Ai, Ai, R3, R4, R7 and T are as defined in claim 2, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

5. Compound of formula (I) according to any one of daims 1 to 4 wherein R4 represents a phenyl substituted at the para position by a group of formula -OPO(OM)(OM’), -ΟΡΟ(ΟΜ)(Ο'ΜΓ), -OPOCO’M/XOW), -OPO(O‘)(O')M₃ ²⁺, -OPO(OM)(O[CH2CH2O]nCH3), or -OPO(O‘Mi⁺)(O[CH2CH₂O]_nCH₃), wherein M and M’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C₂-Cô)alkenyl group, a linear or branched (C₂-Cg)alkynyl group, a cycloalkyl or a heterocycloalkyl, both of them being composed of from 5 to 6 ring members, while Mi⁺ and M2⁺ independently of one another represent a pharmaceutically acceptable monovalent cation, M3 represents a pharmaceutically acceptable divalent cation and n is an integer comprised between 1 to 5, it being understood that the phenyl group may be optionally substituted by one or more halogen atoms.

6. Compound of formula (I) according to any one of daims 1 to 5 wherein Het represents one of the following groups: 5,6,7,8-tetrahydroindolizine, indolizine or 1,2dimethyl- lH-pyrrole.

- 338 -

7, Compound of formula (I) according to any one of daims 1 to 6 wherein q=l and q-1·

8. Compound of formula (I) according to any one of daims 1 to 6 wherein q=2 and q’=l.

9. Compound of formula (I) according to any one of daims 1 to 8 wherein T represents a hydrogen atom, a methyl group, a (morpholin-4-yl)methyl group, a

3-(morpholin-

4-yl)propyl group, a dimethylaminomethyl group, or a (4-methylpiperazin-lyl)methyl group.

10, Compound of formula (I) according to any one of daims 1 to 9 wherein R3 represents a linear or branched (Ci-C6)alkyl group, an aryl group or a heteroaryl group.

11, Compound of formula (I) according to daim 1 to 10 wherein R3 represents a group selected from phenyl, methyl, ethyl, propyl, butyl, 1-methyl-l/7-pyrrolo[2,3-h]pyridine or

5-cyano-1,2-dimethyl-lH-pyrrole.

12. Compound of formula (I) according to any one of daims 1 to 11 wherein R4 represents a linear or branched (Ci-C

6)alkyl group or an aryl group.

13* Compound of formula (I) according to daim 1 to 12 wherein R4 represents a phenyl or 4-hydroxyphenyl group.

14. Compound of formula (I) according to any one of daims 1 to 13 wherein R7 represents a group R’₇-CO- or R’₇-O-CO-.

15. Compound of formula (I) according to any one of daims 1 to 14 wherein R’7 represents an aryl optionally substituted, a cycloalkyl optionally substituted or an alkyl optionally substituted.

Compound of formula (I) according to any one of daims 1 to 15 wherein p=p’=0.

- 339 17, Compound of formula (I) according to any one of daims 1 to 15 which is • V-(4-Hydroxyphenyl)-A-methyl-3-{7-[(37?)-3-methyl-l,2,3,4-tetrahydro isoquinoline-2-carbonyl]-2-(2-phenylacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl }-

5,6,7,8-tetrahydroindolizine-1 -carboxamide;

• Phenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydroindolizin-3yl} -7-[(37?)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonylJ-1,2,3,4-tetrahydro isoquinoline-2-carboxylate;

» Phenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl- 177-pyrrol-2-yl} -

7-[(3Æ)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonylJ-1,2,3,4-tetrahydro isoquinoline-2-carboxylate;

• Phenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,

8-tetrahydroindolizin-3yl} -7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonylJ-

1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;

• Phenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl- l//-pyrrol-2-yl} -

7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonylJ-

1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;

• 4-Methylphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl} -7- [(35)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate hydrochloride;

• 2-Methylphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl} -7-[(3S)-3-(morpholin-4-ylmethyJ)-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Methoxyphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Chlorophenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl]-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl] -1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Ethylphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl }-7-[(35)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

i ?. y. >

** * v _À a

- 340- • 4-Cyanophenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 2-Methoxyphenyl 6-{ l-[(4-hydroxyphenyl)(methyl)carbamoyl]-5,6,7,8-tetrahydro indolizin-3-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonylj-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Methylphenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl-177pyrrol-2-yl}-7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonylj-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Chlorophenyl 6- {4- [(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl-1H- pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Cyanophenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l ,5-dimethyl- IH- pyrrol-2-yl}-7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Cyanophenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl- 1H- pyrrol-2-yl)-7-[(37?)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonylJ-1,2,3,4tetrahydroisoquinoline-2-carboxylate;

• 4- {[2-(Dimethylamino)ethyl]amino} phenyl 6- {1 - [(4-hydroxyphenyl)(methyl) carbamoyl]-5,6,7,8-tetrahydroindolizin-3-yl} -7 - [(37?)-3 -methyl-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• Phenyl 6-{4-[(4-hydroxyphenyl)(propyl)carbamoyl]-1,5-dimethyl- 177-pyrrol-2-yl} 7-[(3S)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonylJ-

1.2.3.4- tetrahydroisoquinoline-2-carboxylate;

• Phenyl 6- {4- [butyl(4-hydroxyphenyl)carbamoyl] -1,5 -dimethyl-1 H-pyrrol-2-y 1} -7[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-1,2,3,4tetrahydroisoquinoline-2-carboxylate;

• Phenyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl-1 H-pyrrol-2-yl} 7-[(3S)-3-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• A-Butyl-A-(4-hydroxyphenyl)-1,2-dimethyl-5- {7-[(35)-3-(morpholin-4-ylmethyl)-

1.2.3.4- tetrahydroisoquinoline-2-carbonyl]-2-(2-phenylacetyl)-1,2,3,4-

- 341 tetrahydroisoquinolin-6-yl} -1 77-pyrrole-3-carboxamide;

1,5-dimethyl-1 7/-pyrrol-2-yl} -7-[(37?)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-{ [2-(Dimethylamino)ethyl](methyl)amino}phenyl 6-{4-[(4-hydroxyphenyl) (methyl)carbamoyl]-l,5-dimethÿl-177-pyrrol-2-yl]-7-[(37?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyJ]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Ethynylphenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoylJ-1,5-dimethyl-172pyrrol-2-yl} -7- [(35)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonylj-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• N aphthalen-2-yl 6- {4- [ (4-hy droxyphenyl)(methyl)carbamoyl] -1,5 -dimethyl-177- pyrrol-2-yl}-7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 177-Indol-5-yl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-177- pyrrol-2-yl}-7-[(35)-3-(morpholin-4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 3-[2-(Dimethylcarbamoyl)ethyl]phenyl 6- {4-[(4-hydroxyphenyl)(methyl) carbamoyl]-1,5-dimethyl- 177-pyrrol-2-yl} -7-[(37?)-3-methyl-1,2,3,4tetrahydroisoquinoline-2-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-Bromophenyl 6- {4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-177- pyrrol-2-yl} -7 - [(35)-3-(morpholin-4-y lmethyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• (lr,4r)-4-{ [(7eri-Butoxy)carbonyl]amino}cyclohexyl 6-{4-[(4-hydroxyphenyl) (methyl)carbamoyl]-l,5-dimethyl-177-pyrrol-2-yl}-7-[(37?)-3-methyl-l,2,3,4tetrahydroisoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate;

• 4-[2-(Dimethylcarbamoyl)ethyl]phenyl 6- {4- [(4-hydroxyphenyl)(methyl) carbamoyl]-1,5-dimethyl- 177-pyrrol-2-yl} -7-[(37?)-3-methyl-1,2,3,4-tetrahydro isoquinoline-2-carbonyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate; or • Cyclohexyl 6-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-l,5-dimethyl-177-pyrrol2-yl} -7-[(37?)-3- [3-(morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-2carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate.

- 342 Process for the préparation of a compound of formula (I) according to claim 1 characterised in that there is used as starting material the compound of formula (II):

r₃ wherein Het, R3, R4, R₈, R

9, p, p’, q and q’ are as defined for formula (I) and Alk

5 represents a linear or branched (Ci-Cé) alkyl group, the ester function of which compound of formula (II) is hydrolysed to yield the corresponding carboxylic acid which is then subjected to peptide coupling with a compound of formula (III) :

10 wherein R₅ and T are as defined for formula (I), to yield the compound of formula (IV) :

- 343 R₃ wherein Het, R3, R4, R5, Rg, R9, T, p, p’, q and q’ are as defined for formula (I), compound of formula (IV) which is deprotected and subjected to an acylation or a sulfonylation reaction, and which can optionally be subjected to the action of a 5 pyrophosphate or a phosphonate dérivative in basic conditions, to yield the compound of formula (I), which compound of formula (I) may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a 10 conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected and subsequently deprotected, as required by

- 344 the synthesis.

IfL Process according to claim 17 for the préparation of a compound of formula (IA-1) characterised in that there is used as starting material the compound of formula (V):

Alk \

5 wherein X, Y, W, Ai and A₂ are as defined for formula (IA) and Alk represents a linear or branched (Ci-Cô) alkyl group, the ester function of which compound of formula (V) is hydrolysed to yield the carboxylic acid or the corresponding carboxylate, which may be converted into an acid dérivative such as acyl chloride or the corresponding anhydride before being coupled with an amine 10 NHR3R4 wherein R3 and R4 hâve the same meanings as for formula (IA), to yield the compound of formula (VI):

wherein X, Y, W, Ai, A₂, R3 and R4 are as defined for formula (IA), compound of formula (VI) which is then halogenated and further converted into the

15 corresponding borohydride dérivative of formula (VII) :

- t.

c ^Λ · U ' λ * r₃ (Vil) wherein X, Y, Y, Ai, A₂, R3 and R4 are as defined for formula (IA), and

Rbi and Rb2 represent a hydrogen, a linear or branched (Ci-Cô) alkyl group, or Rbi and Rb₂form with the oxygen atoms carrying them an optionally methylated ring,

5 which compound of formula (VII) is further subjected to coupling with a compound of formula (VIII):

/\ wherein Rg, R9, p, p’, q and q’ are as defined for formula (IA), and

Alk’ represents a linear or branched (Cj-Cô) alkyl group, and

10 L represents a leaving group selected from halogen or sulfonate, to yield the compound of formula (ΠΑ-1) :

wherein X, Y, W, Ai, A₂, R3, R4, Rs, R9, P, p’> q, and q’ are as defined for formula (IA) and Alk’ is as defined previously, the ester function of which compound of formula (IIA-1) is hydrolysed to yield the

5 corresponding carboxylic acid which is then subjected to peptide coupling with a compound of formula (III) :

wherein R5 and T are as defined for formula (IA), to yield the compound of formula (IVA-1) :

f *

-Iz xi

- 347 r₃ (IVA-1) wherein X, Y, W, Ai, A₂, R₃, R4, R5, R₈, R9, T, p, p’, q, q’ are as defined for formula (IA), compound of formula (IVA-1) which is deproteeted and subjected to an acylation or a sulfonylation reaction, and which can optionally be subjected to the action of a 5 pyrophosphate or a phosphonate dérivative in basic conditions, to yield the compound of formula (IA-1):

r₃ (IA-1) wherein X, Y, W, Ai, A₂, R₃, R4, R5, R7, Rs, R9, T, p, p’, q and q’ are as defined for formula (IA), which compound of formula (IA-1 ) may be purified according to a conventional séparation

5 technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of 10 the synthesis intermediates can be protected and subsequently deprotected, as required by the synthesis.

2ÎL Process according to claim 18 or 19 for the préparation of a compound of formula (I) wherein one of the groups R₃ and R4 is substituted by a hydroxy function, characterised in that the amine NHR₃R4 is subjected beforehand to a protection reaction of 15 the hydroxy function prior to coupling with the carboxylic acid formed from the compound of formula (V), or with a corresponding acid dérivative thereof, the resulting protected function subsequently undergoes a deprotection reaction at the last stage of the process.

21. Pharmaceutical composition comprising a compound of formula (I) according to

- 349 any one of daims 1 to 17 or an addition sait thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

22. Pharmaceutical composition according to claim 21 for use as pro-apoptotic agents.

23. Pharmaceutical composition according to claim 21 for use in the treatment of cancers and of auto-immune and immune System diseases.

24, Pharmaceutical composition according to claim 21 for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, cesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.

25, Use of a pharmaceutical composition according to claim 21 in the manufacture of médicaments for use as pro-apoptotic agents.

Use of a pharmaceutical composition according to claim 21 in the manufacture of médicaments for use in the treatment of cancers and of auto-immune and immune system diseases.

27. Use of a pharmaceutical composition according to claim 21 in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, cesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.

28. Compound of formula (I) according to any one of claims 1 to 17, or an addition sait thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, cesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate * l i- . ·

WA À,;..y

-350cancer and small-cell lung cancer.

22, Use of a compound of formula (I) according to any one of daims 1 to 17, or an addition sait thereof with a pharmaceutically acceptable acid or base, in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus,

5 chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.

Association of a compound of formula (I) according to any one of daims 1 to 17 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti10 métabolites, protéasome inhibitors, kinase inhibitors and antibodies.

31. Pharmaceutical composition comprising an association according to claim 30 in combination with one or more pharmaceutically acceptable excipients.

32, Association according to claim 30 for use in the treatment of cancers.

33» Use of an association according to claim 30 in the manufacture of médicaments for 15 use in the treatment of cancers.

34, Compound of formula (I) according to any one of daims 1 to 17 for use in association with radiotherapy in the treatment of cancers.