NZ626623B - New pyrrole compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

New pyrrole compounds, a process for their preparation and pharmaceutical compositions containing them

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Publication number
NZ626623B
NZ626623B NZ626623A NZ62662314A NZ626623B NZ 626623 B NZ626623 B NZ 626623B NZ 626623 A NZ626623 A NZ 626623A NZ 62662314 A NZ62662314 A NZ 62662314A NZ 626623 B NZ626623 B NZ 626623B
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NZ
New Zealand
Prior art keywords
formula
compound
methyl
yll
dimethyl
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NZ626623A
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NZ626623A (en
Inventor
Ijen Chen
James Edward Paul Davidson
Nanteuil Guillaume De
Didier Durand
Imre Fejes
Olivier Geneste
Annefrancoise Guillouzic
Jeanmichel Henlin
Diguarher Thierry Le
Tiran Arnaud Le
I Jen Chen
Anne Francoise Guillouzic
Jean Michel Henlin
Original Assignee
Les Laboratoires Servier
Vernalis (R&D) Ltd
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Priority claimed from FR1357258A external-priority patent/FR3008975A1/en
Application filed by Les Laboratoires Servier, Vernalis (R&D) Ltd filed Critical Les Laboratoires Servier
Publication of NZ626623A publication Critical patent/NZ626623A/en
Publication of NZ626623B publication Critical patent/NZ626623B/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Abstract

Disclosed herein is a pyrrole compound of formula I, wherein the variables are defined in the specification, pharmaceutical compositions containing the compound and processes for the preparation thereof. Additionally disclosed is the use of the compounds or compositions in the treatment of cancers, auto-immune disease and disease of the immune system. In one embodiment the compound is 5-(5-chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamide. auto-immune disease and disease of the immune system. In one embodiment the compound is 5-(5-chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamide.

Description

N NE EW W P PY YR RR RO OL LE E C CO OM MP PO OU UN ND DS S,, A A P PR RO OC CE ES SS S F FO OR R T TH HE EI IR R P PR RE EP PA AR RA AT TI IO ON N AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to new pyrrole compounds, to a process for their preparation and to pharmaceutical compositions containing them.
The compounds of the present invention are new and have 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 nucleus, DNA fragmentation and also biochemical phenomena such as the activation of caspases which cause damage to key structural components of the cell, so inducing its disassembly and death. Regulation of the process of apoptosis is complex and involves the activation or repression of several intracellular signalling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).
Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and ischaemia. Conversely, deficits in the implementation of apoptosis play a significant role 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 colorectal 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 resistance to chemotherapy and in the clinical prognosis of patients affected by cancer. There is, therefore, a therapeutic need for compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.
In addition to being new, the compounds of the present invention have pro-apoptotic properties making it possible to use them in pathologies involving a defect in apoptosis, such as, for example, in the treatment of cancer, auto-immune diseases and diseases of the immune system.
The present invention relates more especially to compounds of formula (I): wherein: ♦ A and A , each independently of the other, represent a hydrogen or halogen atom, a linear or branched (C -C )polyhaloalkyl group, a linear or branched (C -C )alkyl 1 6 1 6 group or a cycloalkyl group, ♦ T represents a hydrogen atom, a linear or branched (C -C )alkyl group optionally substituted by from one to three halogen atoms, a group (C -C )alkyl-NR R , or a 1 4 1 2 group (C -C )alkyl-OR , 1 4 6 ♦ R and R , each independently of the other, represent a hydrogen atom or a linear or branched (C -C )alkyl group, or R and R form with the nitrogen atom carrying them a heterocycloalkyl, ♦ R represents a linear or branched (C -C )alkyl group, a linear or branched 3 1 6 (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a cycloalkyl 2 6 2 6 group, a (C -C )cycloalkyl-(C -C )alkyl group wherein the alkyl moiety is linear 3 10 1 6 or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated, ♦ R represents an aryl group, a heteroaryl group, a cycloalkyl group or a linear or branched (C -C )alkyl group, it being understood that one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated, ♦ R represents a hydrogen or halogen atom, a linear or branched (C -C )alkyl group, 1 6 or a linear or branched (C -C )alkoxy group, ♦ R represents a hydrogen atom or a linear or branched (C -C )alkyl group, 6 1 6 ♦ R , R , R and R , each independently of the others, represent R , a halogen atom, a a b c d 7 linear or branched (C -C )alkoxy group, a hydroxy group, a linear or branched (C -C )polyhaloalkyl group, a trifluoromethoxy group, -NR R ', nitro, R -CO- 1 6 7 7 7 (C -C )alkyl-, R -CO-NH-(C -C )alkyl-, NR R '-CO-(C -C )alkyl-, NR R '-CO- 0 6 7 0 6 7 7 0 6 7 7 (C -C )alkyl-O-, R -SO -NH-(C -C )alkyl-, R -NH-CO-NH-(C -C )alkyl-, R -O- 0 6 7 2 0 6 7 0 6 7 CO-NH-(C -C )alkyl-, a heterocycloalkyl group, or the substituents of one of the pairs (R ,R ), (R ,R ) or (R ,R ) form together with the carbon atoms carrying them a b b c c d a ring composed of from 5 to 7 ring members, which may contain from one to 2 hetero atoms selected from oxygen and sulphur, it also being understood that one or more carbon atoms of the ring defined hereinbefore may be deuterated or substituted by from one to 3 groups selected from halogen and linear or branched (C -C )alkyl, ♦ R and R ', each independently of the other, represent a hydrogen, a linear or branched (C -C )alkyl, a linear or branched (C -C )alkenyl, a linear or branched 1 6 2 6 (C -C )alkynyl, an aryl or a heteroaryl, or R and R ', together with the nitrogen 2 6 7 7 atom carrying them, form a heterocycle composed of from 5 to 7 ring members, it 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 quaternary nitrogens), - "cycloalkyl" means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to 10 ring members, - "heterocycloalkyl" means any mono- or bi-cyclic, non-aromatic, condensed or spiro group composed of from 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, SO and nitrogen, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the groups alkyl, alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3 groups selected from: linear or branched (C -C )alkyl optionally substituted by a group selected from methoxy, hydroxy or morpholine; (C -C )spiro; linear or branched (C -C )alkoxy 3 6 1 6 optionally substituted by a morpholine; (C -C )alkyl-S-; hydroxy; oxo (or N-oxide where appropriate); nitro; cyano; -COOR'; -OCOR'; NR'R''; linear or branched (C - C )polyhaloalkyl; trifluoromethoxy; (C -C )alkylsulphonyl; halogen; aryl optionally 6 1 6 substituted by one or more halogen atoms; heteroaryl; aryloxy; arylthio; cycloalkyl; heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups, it being understood that R' and R'', each independently of the other, represent a hydrogen atom or linear or branched (C -C )alkyl group optionally substituted by a methoxy, to their enantiomers and diastereoisomers, and to addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Advantageously, A represents a hydrogen atom or a methyl group.
Furthermore, A preferably represents a linear or branched (C -C )alkyl group optionally substituted by a 2 1 6 group selected from halogen, hydroxy, linear or branched (C -C )alkoxy, NR'R'' and morpholine.
In another embodiment of the invention, A represents a linear or branched (C -C )polyhaloalkyl group or a 2 1 6 cyclopropyl group.
Even more preferably, A and A both represent a methyl group.
In a preferred embodiment of the invention, T represents a linear or branched (C -C )alkyl. In another preferred embodiment, T represents a group alkyl(C -C )-NR R , and more particularly a group alkyl(C -C )- 1 4 1 2 1 4 NR R wherein R and R form with the nitrogen atom carrying them a heterocycloalkyl. 1 2 1 2 In preferred compounds of the invention, T represents a methyl, aminomethyl, (morpholinyl)methyl, (4- methylpipérazinyl)methyl, 2-(morpholinyl)ethyl, [2-(morpholinyl)ethoxy]methyl, hydroxymethyl, [2-(dimethylamino)ethoxy]methyl, hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl, 1-oxa azaspiro[3.3]heptylmethyl, 3-(morpholinyl)propyl or trifluoromethyl group. Even more preferably, T represents a (morpholinyl)methyl, methyl or 3-(morpholinyl)propyl group.
Preferably, R and R each represent a hydrogen atom and (R ,R ), together with the carbon atoms carrying a d b c them, form a 1,3-dioxolane group or a 1,4-dioxane group; or R , R and R each represent a hydrogen atom a c d and R represents a hydrogen or halogen atom or a methoxy group. Even more preferably, R and R each b a d represent a hydrogen atom and (R ,R ), together with the carbon atoms carrying them, form a 1,3-dioxolane group; or R , R and R each represent a hydrogen atom and R represents a halogen, preferably a chlorine or a c d b fluorine atom.
In another embodiment of the invention, R and R each represent a hydrogen atom, R represents a hydrogen a d b or halogen atom and R a hydroxy or methoxy group, or: R and R each represent a hydrogen atom, R c a d b represents a hydroxy or methoxy group and R a halogen atom.
Alternatively, R , R and R advantageously each represent a hydrogen atom and R represents a group a b d c selected from R -CO-NH-(C -C )alkyl-, R -SO -NH-(C -C )alkyl-, R -NH-CO-NH-(C -C )alkyl- and R -O- 7 0 6 7 2 0 6 7 0 6 7 CO-NH-(C -C )alkyl-. For those specific compounds, R preferably represents a linear or branched (C - 0 6 3 1 C )alkyl or a heteroaryl optionally substituted by a linear or branched (C -C )alkyl, and R represents a 4- 6 1 6 4 hydroxyphenyl group. Even more preferably, R represents a methyl.
Preferred R groups are as follows: phenyl; 4-hydroxyphenyl; 3-fluorohydroxyphenyl; 2- hydroxypyrimidine; 3-hydroxypyridine. Even more preferably, R represents a 4-hydroxyphenyl group.
In preferred compounds of the invention, R represents a linear or branched (C -C )alkyl group (preferably 3 1 6 methyl), aryl or heteroaryl, all being optionally substituted. The groups aryl and heteroaryl are more especially preferred. Finally, R preferably represents a group selected from phenyl, 1H-pyrazole, 1H-indole, 1H-indazole, pyridine, pyrimidine, 1H-pyrrolo[2,3-b]pyridine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 1H- benzimidazole, 1H-pyrrole, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-b]pyridine, 5H-pyrrolo[3,2- d]pyrimidine, thiophene, pyrazine, 1H-pyrazolo[3,4-b]pyridine, 1,2-oxazole, and 1H-pyrazolo[1,5- a]pyrimidine, those groups optionally having one or more substituents selected from halogen, linear or branched (C -C )alkyl, linear or branched (C -C )alkoxy, cyano, cyclopropyl, oxetane, tetrahydrofuran, -CO- 1 6 1 6 O-CH , trideuteriomethyl, 2-(morpholinyl)ethyl and 2-(morpholinyl)ethoxy. More preferably, R represents a group 1-methyl-1H-pyrazolyl, pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl, 5- cyanomethyl-1H-pyrrolyl, 5-cyano-1,2-dimethyl-1H-pyrrolyl, 1-methyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridinyl, 5-cyanomethyl(trideuteriomethyl)-1H-pyrrolyl.
Preferred compounds according to the invention are included in the following group: (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol- 4-yl)-1H-pyrrolecarboxamide, (5-chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N- (4-hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H-pyrrolecarboxamide, -N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(6-{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxolyl)-1H-pyrrolecarboxamide, -N-(4-hydroxyphenyl)-1,2-dimethyl(6-{[(3R)methyl-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(pyridinyl)-1H-pyrrole carboxamide, (5-fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol- 4-yl)-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H- pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(5-cyanomethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)- 1,2-dimethyl-1H-pyrrolecarboxamide, -N-(5-cyanomethyl-1H-pyrrolyl)(5-fluoro{[(3S)(morpholinylmethyl)- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2- dimethyl-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)- 1,2-dimethyl-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide, -N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)(5-fluoro{[(3S)(morpholinyl- methyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- 1,2-dimethyl-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-[5-cyanomethyl(trideuteriomethyl)-1H-pyrrolyl]- N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material the compound of formula (II): (II) wherein R , R , R and R are as defined for formula (I), a b c d which compound of formula (II) is subjected to a Heck reaction, in an aqueous or organic medium, in the presence of a palladium catalyst, of a base, of a phosphine and of the compound of formula (III): (III) wherein the groups A and A are as defined for formula (I) and Alk represents a linear or branched (C -C )alkyl, to obtain the compound of formula (IV): (IV) wherein A , A , R , R , R and R are as defined for formula (I) and Alk is as defined 1 2 a b c d hereinbefore, the aldehyde function of which compound of formula (IV) is oxidised to a carboxylic acid to form the compound of formula (V): wherein A , A , R , R , R and R are as defined for formula (I) and Alk is as defined 1 2 a b c d hereinbefore, which compound of formula (V) is then subjected to peptide coupling with a compound of formula (VI): (VI) wherein T and R are as defined for formula (I), to yield the compound of formula (VII): (VII) wherein A , A , R , R , R , R , T and R are as defined for formula (I) and Alk is as defined hereinbefore, 1 2 a b c d 5 the ester function of which compound of formula (VII) is hydrolysed to yield the corresponding carboxylic acid or carboxylate, which may be converted into an acid derivative such as the corresponding acyl chloride or anhydride before being coupled with an amine NHR R wherein R and R have the same meanings as for formula (I), to yield 3 4 3 4 the compound of formula (I), which compound of formula (I) may be purified according to a conventional separation 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 separation technique, it being understood that, at any time considered appropriate in the course of the above-described process, certain groups (hydroxy, amino…) of the reagents or intermediates of synthesis may be protected and then deprotected according to the requirements of synthesis.
More particularly, when one of the groups R or R of the amine NHR R is substituted by a hydroxy 3 4 3 4 function, the latter may be subjected beforehand to a protection reaction prior to any coupling with the carboxylic acid formed from the compound of formula (VII), or with a corresponding acid derivative thereof, the resulting protected compound of formula (I) subsequently undergoes a deprotection reaction and is then optionally converted into one of its addition salts with a pharmaceutically acceptable acid or base.
The present invention relates also to an alternative process for the preparation of compounds of formula (I'), which are particular cases of the compounds of formula (I) as defined hereinbefore: (I') wherein: - A , A , R , R , R , R , T and R are as defined for formula (I), 1 2 a d 3 4 5 - R and R are such that one represents a hydrogen and the other a group selected from R -CO-NH-(C -C )alkyl-, R -SO -NH-(C -C )alkyl-, R -NH-CO-NH- 7 0 6 7 2 0 6 7 (C -C )alkyl- and R -O-CO-NH-(C -C )alkyl-, 0 6 7 0 6 which preparation process uses as starting material a compound of formula (II'): (II') wherein: - R and R are as defined for formula (I), - Hal represents a halogen atom, - X and X are such that one represents a (C -C )alkyl-NH group while the other 1 2 0 6 2 represents a hydrogen atom, which compound of formula (II') is then subjected to peptide coupling with a compound of formula (VI): (VI) wherein T and R are as defined for formula (I), to yield the compound of formula (III'): (III') wherein: - R , R , T and R are as defined for formula (I), a d 5 - Hal represents a halogen atom, - X and X are such that one represents a (C -C )alkyl-NH group while the other 1 2 0 6 2 represents a hydrogen atom, which compound of formula (III') is subjected to a Heck reaction, in an aqueous or organic medium, in the presence of a palladium catalyst, of a base, of a phosphine and of a compound of formula (IV'): (IV') wherein A , A , R and R are as defined for formula (I), 1 2 3 4 to form the compound of formula (V'): (V') wherein: - A , A , R , R , R , R , T and R are as defined for formula (I), 1 2 a d 3 4 5 - X and X are such that one represents a (C -C )alkyl-NH group while the other 1 2 0 6 2 represents a hydrogen atom, which compound of formula (V') is then subjected to an acylation or sulphonylation reaction to yield the compound of formula (I'), which compound of formula (I') may be purified according to a conventional separation 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 separation technique, it being understood that, at any time considered appropriate in the course of the above-described process, certain groups (hydroxy, amino…) of the reagents or intermediates of synthesis may be protected and then deprotected according to the requirements of synthesis.
The compounds of formulae (II), (III), (II'), (IV'), (VI) and the amine NHR R 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 have pro- apoptotic properties. The ability to reactivate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancers, auto-immune diseases and diseases of the immune system.
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, cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the 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. Among non- Hodgkin lymphomas, there may be mentioned more preferably follicular lymphomas, mantle cell lymphomas, diffuse large B-cell lymphomas, small lymphocytic lymphomas and marginal zone B-cell lymphomas.
The present 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, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
The dosage varies according to the sex, age 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.
In one aspect the invention provides a pharmaceutical composition comprising a combination of formula (I) according to the invention and an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies, in combination with one or more pharmaceutically acceptable excipients.
Furthermore, the present invention relates also to the combination of a compound of formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, anti- metabolites, proteasome inhibitors, kinase inhibitors and antibodies.
The invention also provides a use of a compound of formula (I) of the invention and an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies, in the manufacture of a medicament for use in the treatment of cancers.
The invention also provides a use of a compound of formula (I) of the invention in the manufacture of a medicament for use in the treatment of cancers wherein the medicament is for sequential or simultaneous administration with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies.
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 have the same specificity of binding as the antibody from which they are descended. According to the present invention, antibody fragments of the invention can be obtained starting from antibodies by methods such as digestion by enzymes, such as pepsin or papain, and/or by cleavage of the disulfide bridges by chemical reduction. In another manner, the antibody fragments comprised in the present invention can be obtained by techniques of genetic recombination likewise well known to the person skilled in the art or else by peptide synthesis by means of, for example, automatic peptide synthesizers such as those supplied by the company Applied Biosystems, etc.
Scaffold proteins that can be related or not to monoclonal antibodies are understood to mean a protein that contains or not an immunoglobulin fold and that yields a binding capacity similar to a monoclonal antibody. The 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 three- dimensional molecular organization (such as, for example, crystallography or NMR), small size, no or only a low degree of post-translational modifications, easy to produce, express and purify. Such a protein scaffold can be, but without limitation, a structure selected from the group consisting in fibronectin and preferentially the tenth fibronectin type III domain (FNfn10), lipocalin, anticalin (Skerra A., J. Biotechnol., 2001, 74(4):257-75), the protein Z derivative from the domain B of staphylococcal protein A, thioredoxin A or any protein with a repeated domain such as an "ankyrin repeat" (Kohl et al., PNAS, 2003, vol.100, No.4, 1700-1705), "armadillo repeat", "leucine-rich repeat" or "tetratricopeptide repeat".
There could also be mentioned a scaffold derivative from toxins (such as, for example, scorpion, insect, plant or mollusc toxins) or protein inhibitors of neuronal nitric oxide synthase (PIN).
The term 'comprising' as used in this specification and claims means 'consisting at least in part of'. When interpreting statements in this specification and claims which include the term 'comprising', other features besides the features prefaced by this term in each statement can also be present. Related terms such as 'comprise' and 'comprised' are to be interpreted in similar manner.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
The following Preparations and Examples illustrate the invention without limiting it in any way.
P Pr re ep pa ar ra at tiio on n 1 1: :4 4- -C Ch hllo or ro o- -2 2- -[ [4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]b be en nz zo oiic c acid acid Step A: Ethyl 1,2-dimethyl-1H-pyrrolecarboxylate To a solution of 10 g of ethyl 2-methyl-1H-pyrrolecarboxylate (65.3 mmol) and 8.95 mL (130.6 mmol) of methyl iodide in 70 mL of dimethylformamide placed at 0°C there are added, in three portions, 2.61 g (65.3 mmol) of sodium hydride (NaH) 60 % . The batch is then stirred at 0°C for 1 hour. Then, the reaction mixture is hydrolysed by the addition of 420 mL of ice-cold water. The reaction mixture is then diluted with ethyl acetate, successively washed with 0.1M aqueous hydrochloric acid (HCl) solution, saturated aqueous LiCl solution and then brine. The organic phase is then dried over MgSO , filtered, concentrated to dryness and purified by chromatography over silica gel (petroleum ether/AcOEt gradient).
H NMR: δ (400 MHz; dmso-d6; 300K): 6.65 (d, 1H pyrrole); 6.3 (1d, 1H pyrrole); 4.1 (1q, 2H, OCH CH ); 3.5 (s, 3H N-pyrrole); 2.4 (s, 3H pyrrole); 1.5 (1t, 3H OCH CH ) 2 3 2 3 -1 -1 IR: ν: >C=O: 1688 cm ; ν: C-O-C: 1172 cm Step B: Ethyl 5-(5-chloroformylphenyl)-1,2-dimethyl-1H-pyrrolecarboxylate To a solution of 10.5 g of the compound obtained in Step A (62,8 mmol) in 65 mL of N,N- dimethylacetamide there are successively added 15.2 g of 2-bromochlorobenzaldehyde (69 mmol), 12.3 g of potassium acetate (125.6 mmol) and then the batch is stirred under argon for 20 minutes. There are then added 2.2 g of palladium catalyst PdCl (PPh ) 2 3 2 (3.14 mmol). The reaction mixture is then heated at 130°C overnight. The mixture is allowed to return to ambient temperature and it is then diluted with dichloromethane.
Animal charcoal is added (2 g per g of product) and the batch is stirred at ambient temperature for 1 hour and then filtered. The organic phase is then washed with water, dried over MgSO and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel (petroleum ether/AcOEt gradient). The title product is obtained in the form of a solid.
H NMR: δ (400 MHz; dmso-d6; 300K): 9.8 (s, 1H, formyl); 7.91-7.69-7.61 (d, 3H, aromatic Hs); 6.5 (s, 1H pyrrole); 4.2 (q, 2H, OCH CH ); 3.4 (s, 3H, CH -N-pyrrole); 2 3 3 2.55 (s, 3H pyrrole); 1.28 (t, 3H, OCH CH ) Step C: 4-Chloro[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]benzoic acid A solution is prepared containing 12.85 g of the compound obtained in Step B (42 mmol) and 35.7 mL (336 mmol) of 2-methylbutene in a mixture containing 20 mL of acetone and 20 mL of tetrahydrofuran. There are added, dropwise, 200 mL of an aqueous solution containing a mixture of 13.3 g of sodium chlorite (NaClO ) (147 mmol) and 14.5 g of sodium hydrogen phosphate (NaHPO ) (105 mmol). The batch is then vigorously stirred at ambient temperature for 7 hours. The reaction mixture is then concentrated to remove the acetone. Ethyl acetate is added, and the organic phase is washed with water, dried over MgSO and then concentrated to dryness. The residue is then taken up in a minimum of ethyl ether. The solid then obtained is filtered off, washed with ether and then dried in vacuo at 40°C overnight. The title product is obtained in the form of a solid, which is subsequently used without being otherwise purified.
H NMR: δ (400 MHz; dmso-d6; 300K): 13 (m, 1H COOH); 7.85-7.6-7.41(d,dd, wd, 3H, aromatic Hs); 6.3 (s, 1H, H pyrrole); 4.15 (q, 2H, OCH CH ); 3.25 (s, 3H, CH -N- 2 3 3 pyrrole); 2.5 (s, 3H, CH -pyrrole); 1.25 (t, 3H, OCH CH ) 3 2 3 -1 -1 IR: ν: -OH: 3100-2500 cm acid; ν: >C=O: 1681 cm ester + acid P Pr re ep pa ar ra at tiio on n 2 2: :2 2- -[ [4 4- -( (E Et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]b be en nz zo oiic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing, on the one hand, the ethyl 2-methyl-1H-pyrrolecarboxylate used in Step A by ethyl 1H-pyrrole carboxylate and, on the other hand, the 2-bromochlorobenzaldehyde used in Step B by 2-bromo-benzaldehyde.
P Pr re ep pa ar ra at tiio on n 3 3: :4 4- -C Ch hllo or ro o- -2 2- -[ [4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]b be en nz zo oiic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing the ethyl 2- methyl-1H-pyrrolecarboxylate used in Step A by ethyl 1H-pyrrolecarboxylate.
P Pr re ep pa ar ra at tiio on n 4 4: : 6 6- -[ [4 4- -( (E Et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- -1 1,,3 3- -b be en nz zo od diio ox xo olle e- -5 5- - carboxylic acid carboxylic acid The procedure is in accordance with the process of Preparation 1, replacing, on the one hand, the ethyl 2-methyl-1H-pyrrolecarboxylate used in Step A by ethyl 1H-pyrrole carboxylate and, on the other hand, the 2-bromochlorobenzaldehyde used in Step B by 6-bromo-1,3-benzodioxolecarbaldehyde. -1 -1 IR: ν: -OH: 3500-2300 cm acid; ν: >C=O: 1688-1670 cm ester + acid Preparation 5: 4-Chloro[4-(ethoxycarbonyl)ethyl-1H-pyrrolyl]benzoic acid Preparation 5: 4-Chloro[4-(ethoxycarbonyl)ethyl-1H-pyrrolyl]benzoic acid The procedure is in accordance with the process of Preparation 1, replacing in Step A, on the one hand, the ethyl 2-methyl-1H-pyrrolecarboxylate by ethyl 1H-pyrrole carboxylate and, on the other hand, the methyl iodide by ethyl iodide (see the protocol described in US 6,258,805 B1).
Preparation 6: 4-Chloro[1-cyclopropyl(ethoxycarbonyl)-1H-pyrrolyl]benzoic Preparation 6: 4-Chloro[1-cyclopropyl(ethoxycarbonyl)-1H-pyrrolyl]benzoic a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing in Step A, on the one hand, the ethyl 2-methyl-1H-pyrrolecarboxylate by ethyl 1H-pyrrole carboxylate and, on the other hand, the methyl iodide by cyclopropylboronic acid (see the protocol described in Bénard S. et al, Journal of Organic Chemistry 73(16), 6441-6444, 2008).
P Pr re ep pa ar ra at tiio on n 7 7: : 4 4- -C Ch hllo or ro o- -2 2- -[ [4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1- -( (p pr ro op pa an n- -2 2- -y yll) )- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- - benzoic acid benzoic acid The procedure is in accordance with the process of Preparation 1, replacing in Step A, on the one hand, the ethyl 2-methyl-1H-pyrrolecarboxylate by ethyl 1H-pyrrole carboxylate and, on the other hand, the methyl iodide by isopropyl iodide (see the protocol described in Okada E. et al, Heterocycles 34(7), 1435-1441, 1992).
P Pr re ep pa ar ra at tiio on n 8 8: : 4 4- -F Fllu uo or ro o- -2 2- -[ [4 4- -( (m me et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]b be en nz zo oiic c acid acid The procedure is in accordance with the process of Preparation 1, replacing, in Step A, the ethyl 2-methyl-1H-pyrrolecarboxylate by methyl 2-methyl-1H-pyrrolecarboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 2-bromo fluorobenzaldehyde. -1 -1 IR: ν: -OH: 2727-2379 cm acid; ν: >C=O: 1687 cm P Pr re ep pa ar ra at tiio on n 9 9: : 6 6- -{ {1 1- -[ [2 2- -( (B Be en nz zy yllo ox xy y) )e et th hy yll] ]- -4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -5 5- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- - y yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo olle e- -5 5- -c ca ar rb bo ox xy ylliic c a ac ciid d Step A: Ethyl 1-[2-(benzyloxy)ethyl]methyl-1H-pyrrolecarboxylate The procedure is in accordance with the process of Step A of Preparation 1, replacing the methyl iodide used as alkylating agent by benzyl 2-bromoethyl ether.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.32 (t, 2H, aromatic Hs, H meta benzyl ether); 7.3 (t, 1H, aromatic H, H para benzyl ether); 7.23 (d, 2H, aromatic Hs, H ortho benzyl ether); 6.72 (d, 1H, H- pyrrole); 6.35 (d, 1H, H- pyrrole); 4.48 (s, 2H, aliphatic Hs, O-CH - Ph); 4.15 (q, 2H, aliphatic Hs, O-CH -CH ); 4.1 (t, 2H, aliphatic Hs, CH -O-CH -Ph); 3.7 2 3 2 2 (t, 2H, aliphatic Hs, CH -CH -O-CH -Ph); 2.45 (s, 3H, CH - pyrrole); 1.25 (t, 3H, 2 2 2 3 aliphatic Hs, O-CH -CH ) IR: ν: >C=O: 1689 cm Step B: 6-{1-[2-(Benzyloxy)ethyl](ethoxycarbonyl)methyl-1H-pyrrolyl}-1,3- benzodioxolecarboxylic acid The procedure is in accordance with the processes of Steps B and C of Preparation 1, replacing the 2-bromochlorobenzaldehyde by 6-bromo-1,3-benzodioxole carbaldehyde.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.35 (s, 1H, aromatic H, H benzodioxole); 7.30 (m, 3H, aromatic Hs, H benzyl ether); 7.25 (s, 1H, aromatic H, H benzodioxole); 7.10 (d, 2H, aromatic Hs, H ortho benzyl ether); 12.55 (broad s, 1H, COOH); 6.75 (s, 1H, H- pyrrole); 6.15 (broad s, 2H, aliphatic Hs, O-CH -O); 4.30 (s, 2H, aliphatic Hs, O-CH -Ph); 4.15 (q, 2H, aliphatic Hs, O-CH -CH ); 3.9 (m, 2H, aliphatic Hs, CH -CH -O-CH -Ph); 2 3 2 2 2 3.40 (t, 2H, aliphatic Hs, CH -CH -O-CH -Ph); 2.50 (s, 3H, CH - pyrrole); 1.25 (t, 3H, 2 2 2 3 aliphatic Hs, O-CH -CH ) -1 -1 IR: ν: -OH: 3200-2300 cm acid; ν: >C=O: 1687 cm acid P Pr re ep pa ar ra at tiio on n 1 10 0: : 2 2- -{ {1 1- -[ [3 3- -( (B Be en nz zy yllo ox xy y) )p pr ro op py yll] ]- -4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -5 5- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- - 2 2- -y yll} }- -4 4- -f fllu uo or ro ob be en nz zo oiic c a ac ciid d The procedure is in accordance with the process of Preparation 9, replacing the benzyl 2- bromoethyl ether used in Step A by benzyl 3-bromopropyl ether and also the 6-bromo-1,3- benzodioxolecarbaldehyde used in Step B by 2-bromofluorobenzaldehyde. -1 -1 IR: ν: -OH: 3200-2305 cm acid; ν: >C=O: 1690 cm acid P Pr re ep pa ar ra at tiio on n 1 11 1: : 6 6- -[ [4 4- -( (E Et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- -1 1,,3 3- -b be en nz zo o- - d diio ox xo olle e- -5 5- -c ca ar rb bo ox xy ylliic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing the 2-bromo chlorobenzaldehyde used in Step B by 6-bromo-1,3-benzodioxolecarbaldehyde.
Preparation 12: 4-Methoxy[4-(methoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]- Preparation 12: 4-Methoxy[4-(methoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]- benzoic acid benzoic acid The procedure is in accordance with the process of Preparation 1, replacing the ethyl 2- methyl-1H-pyrrolecarboxylate used in Step A by methyl 2-methyl-1H-pyrrole carboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 2-bromo methoxybenzaldehyde. -1 -1 IR: ν: -OH: 3000-2500 cm acid; ν: >C=O: 1693 + 1670 cm acid + ester P Pr re ep pa ar ra at tiio on n 1 13 3: : 7 7- -[ [4 4- -( (M Me et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- -2 2,,3 3- -d diih hy yd dr ro o- - 1 1,,4 4- -b be en nz zo od diio ox xiin n- -6 6- -c ca ar rb bo ox xy ylliic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing in Step A the ethyl 2-methyl-1H-pyrrolecarboxylate by methyl 2-methyl-1H-pyrrolecarboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 7-bromo-2,3-dihydro-1,4- benzodioxincarbaldehyde. -1 -1 IR: ν: -OH: 3100-2500 cm acid; ν: >C=O: 1690 + 1674 cm acid + ester P Pr re ep pa ar ra at tiio on n 1 14 4: : 4 4- -F Fllu uo or ro o- -5 5- -m me et th ho ox xy y- -2 2- -[ [4 4- -( (m me et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- - p py yr rr ro oll- -2 2- -y yll] ]b be en nz zo oiic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing in Step A the ethyl 2-methyl-1H-pyrrolecarboxylate by methyl 2-methyl-1H-pyrrolecarboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 2-bromofluoro methoxybenzaldehyde.
P Pr re ep pa ar ra at tiio on n 1 15 5: : 4 4- -F Fllu uo or ro o- -5 5- -h hy yd dr ro ox xy y- -2 2- -[ [4 4- -( (m me et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- - 2 2- -y yll] ]b be en nz zo oiic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing in Step A the ethyl 2-methyl-1H-pyrrolecarboxylate by methyl 2-methyl-1H-pyrrolecarboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 2-bromofluoro hydroxy-benzaldehyde.
P Pr re ep pa ar ra at tiio on n 1 16 6: : 6 6- -[ [4 4- -( (E Et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1- -m me et th hy yll- -5 5- -t tr riif fllu uo or ro om me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- - 1,3-benzodioxolecarboxylic acid 1,3-benzodioxolecarboxylic acid The procedure is in accordance with the process of Preparation 1, replacing in Step A the ethyl 2-methyl-1H-pyrrolecarboxylate by ethyl 2-(trifluoromethyl)-1H-pyrrole carboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 6-bromo-1,3- benzodioxolecarbaldehyde.
P Pr re ep pa ar ra at tiio on n 1 17 7: : 6 6- -[ [4 4- -( (E Et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1- -e et th hy yll- -5 5- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- -1 1,,3 3- - benzodioxolecarboxylic acid benzodioxolecarboxylic acid The procedure is in accordance with the process of Preparation 11, replacing the methyl iodide by ethyl iodide (see the protocol described in US 6,258,805 B1).
Preparation 18: 6-[4-(Ethoxycarbonyl)methyl(trifluoromethyl)-1H-pyrrolyl]- Preparation 18: 6-[4-(Ethoxycarbonyl)methyl(trifluoromethyl)-1H-pyrrolyl]- 1 1,,3 3- -b be en nz zo od diio ox xo olle e- -5 5- -c ca ar rb bo ox xy ylliic c a ac ciid d Step A: Ethyl 1-methyl(trifluoromethyl)pyrrolecarboxylate Ethyl 4,4,4-trifluorooxo-butanoate (29 ml, 0.219 mmol) is added to methylamine (40 % solution in water) (50 ml, 0.580 mmol) cooled to 10°C; a white precipitate forms. 1,2-Dibromoethyl acetate (prepared according to Molecules, 16, 9368-9385; 2011) is added dropwise. The reactor is then sealed and heated at 70°C for 45 minutes. The reaction mixture is cooled, then extracted with ethyl acetate, dried over sodium sulphate (Na SO ) and evaporated to dryness. The crude reaction product obtained is purified by chromatography over silica gel using heptane and ethyl acetate as eluants. The expected compound is obtained in the form of crystals.
H NMR (400 MHz, dmso-d6) δ ppm: 7.11 (d, 1 H), 6.52 (d, 1 H), 4.21 (quad, 2 H), 3.8 (s, 3 H), 1.27 (t, 3 H) F NMR (400 MHz, dmso-d6) δ ppm:-53.9 IR (ATR) cm 3145 + 3128 ν -CH, 1711 ν >C=O, 1183 + 1117 + 1078 ν -CF3 Step B: 6-[4-(Ethoxycarbonyl)methyl(trifluoromethyl)-1H-pyrrolyl]-1,3-benzo- dioxolecarboxylic acid The procedure is in accordance with the protocol described in Steps B and C of Preparation 1, replacing the 2-bromochlorobenzaldehyde used in Step B by 6-bromo- 1,3-benzodioxolecarbaldehyde.
P Pr re ep pa ar ra at tiio on n 1 19 9: : 6 6- -[ [1 1- -( (2 2- -B Be en nz zy yllo ox xy ye et th hy yll) )- -4 4- -e et th ho ox xy yc ca ar rb bo on ny yll- -5 5- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- - 1 1,,3 3- -b be en nz zo od diio ox xo olle e- -5 5- -c ca ar rb bo ox xy ylliic c a ac ciid d Step A: Ethyl 1-(2-benzyloxyethyl)methyl-pyrrolecarboxylate Ethyl 2-methyl-1H-pyrrolecarboxylate (10 g, 65.3 mmol) is dissolved in 100 mL of dimethylformamide under argon cooled to 0°C, and then 2-bromoethoxymethylbenzene (28.1 g, 130.6 mmol) is added all at once. The reaction mixture is placed under stirring.
There is then added thereto, at 0°C, in three portions, NaH (1.72 g, 71.83 mmol) over a period of 15 minutes. The reaction mixture is stirred for 15 minutes at 0°C, and then for hours at ambient temperature. It is then poured into an ice bath and then extracted 3 times with ethyl acetate. The organic phase is washed 3 times with saturated aqueous lithium chloride solution, dried over MgSO , filtered and then evaporated to dryness. The residue thereby obtained is purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The expected compound is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 7.32 (t, 2 H), 7.3 (t, 1 H), 7.23 (d, 2 H), 6.72 (d, 1 H), 6.35 (d, 1 H), 4.48 (s, 2 H), 4.15 (quad., 2 H), 4.1 (t, 2 H), 3.7 (t, 2 H), 2.45 (s, 3 H), 1.25 (t, 3 H) IR (ATR) cm : 1689 ν -C=O Step B: Ethyl 1-(2-benzyloxyethyl)(6-formyl-1,3-benzodioxolyl)methyl-pyrrole- 3-carboxylate The procedure is in accordance with the process of Step B of Preparation 1, replacing the 2-bromochlorobenzaldehyde by 6-bromo-1,3-benzodioxolecarbaldehyde.
H NMR (400 MHz, dmso-d6) δ ppm: 9.5 (s, 1 H), 7.3 (s, 1 H), 7.25 (m, 3 H), 7.05 (m, 2 H), 7 (s, 1 H), 6.4 (s, 1 H), 6.2 (bs, 2 H), 4.25 (s, 2 H), 4.2 (quad., 2 H), 4.05 (m, 2 H), 3.4 (m, 2 H), 2.55 (s, 3 H), 1.25 (t, 3 H) Step C: 6-[1-(2-Benzyloxyethyl)ethoxycarbonylmethyl-1H-pyrrolyl]-1,3-benzo- dioxolecarboxylic acid The procedure is in accordance with the process of Step C of Preparation 1.
H NMR (400 MHz, dmso-d6) δ ppm: 12.55 (bs, 1 H), 7.35 (s, 1 H), 7.3 (m, 3 H), 7.2 (m, 3 H), 6.75 (s, 1 H), 6.15 (s, 2 H), 4.3 (s, 2 H), 4.15 (quad., 2 H), 3.9 (m, 2 H), 3.4 (t, 2 H), 2.5 (s, 3 H), 1.25 (t, 3 H) IR (ATR) cm :3200-2300 ν -OH, 1687 (+ shoulder) ν-C=O carboxylic acid + conjugated ester Preparation 20: 6-[4-(Ethoxycarbonyl)ethylmethyl-1H-pyrrolyl]-1,3-benzo- Preparation 20: 6-[4-(Ethoxycarbonyl)ethylmethyl-1H-pyrrolyl]-1,3-benzo- d diio ox xo olle e- -5 5- -c ca ar rb bo ox xy ylliic c a ac ciid d The procedure is in accordance with the protocol described in Preparation 11, replacing the methyl iodide by ethyl iodide.
H NMR (400 MHz, dmso-d6) δ ppm: 12.49 (bs, 1 H), 7.33 (s, 1 H), 6.89 (s, 1 H), 6.17 (s, 2 H), 6.13 (s, 1 H), 4.15 (quad, 2 H), 3.69 (quad, 2 H), 2.51 (s, 3 H), 1.24 (t, 3 H), 1.01 (t, 3 H) P Pr re ep pa ar ra at tiio on n 2 21 1: : 6 6- -[ [4 4- -( (E Et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1- -( (2 2- -f fllu uo or ro oe et th hy yll) )- -5 5- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- - 1,3-benzodioxolecarboxylic acid 1,3-benzodioxolecarboxylic acid The procedure is in accordance with the process of Preparation 11, replacing the methyl iodide by 1-bromofluoroethane.
H NMR (400 MHz, dmso-d6, 300K) δ ppm: 12.53 (bs, 1 H), 7.34 (s, 1 H), 6.9 (s, 1 H), 6.16 (s, 1 H), 6.16 (s, 2 H), 4.4 (dt, 2 H), 4.15 (quad, 2 H), 4.01 (m, 2 H), 2.51 (s, 3 H), 1.24 (t, 3 H) F NMR (400 MHz, dmso-d6, 300 K) δ ppm: -222 -1 -1 -1 IR: ν: -OH: 3700-2400 cm acid; ν: >C=O: 1689 cm acid; ν: >CF: 1213 cm P Pr re ep pa ar ra at tiio on n 2 22 2: : 6 6- -{ {4 4- -( (E Et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1- -m me et th hy yll- -5 5- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- - pyrrolyl}-1,3-benzodioxolecarboxylic acid pyrrolyl}-1,3-benzodioxolecarboxylic acid Step A: 3,3-Diethoxypropanoic acid To a solution of 25 g of ethyl 3,3-diethoxypropionate (131 mmol) in 79 mL of methanol there are added 13.1 mL of aqueous 35 % sodium hydroxide solution (452 mmol). The reaction mixture is stirred at ambient temperature for 3 hours. The reaction mixture is then concentrated to remove the methanol. After dissolving the undissolved material by adding water, aqueous 5N HCl solution is added to obtain a pH of 5. Dichloromethane is added and then the organic phase is washed with brine. After drying over MgSO and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.
H NMR (400 MHz, dmso-d6) δ ppm: 12.2 (s, 1 H), 4.8 (t, 1 H), 3.58/3.47 (2m, 4 H), 2.5 (d, 2 H), 1.09 (t, 6 H) Step B: Ethyl 5,5-diethoxyoxo-pentanoate To a solution of 16 mL of 3-ethoxyoxomalonic acid (135 mmol) in 40 mL of tetrahydrofuran there are added, under argon, 21.9 g of powdered magnesium (90.4 mmol).
The mixture obtained is then heated at 80°C for 7 hours. After returning to ambient temperature, this mixture is transferred by cannula to a solution of 10 g of the compound obtained in Step A (61.7 mmol) in 64 mL of tetrahydrofuran to which there has previously been added, in portions, 11 g of carbonyldiimidazole (66 mmol). The reaction mixture is stirred for 3 days at ambient temperature. After concentration, the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO ) solution. The mixture is stirred vigorously until no more gas is evolved. After separation of the phases, the organic phase is washed successively with water, saturated aqueous NaHCO solution and finally brine. After drying over MgSO and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.
H NMR (400 MHz, dmso-d6) δ ppm: 4.84 (t, 1 H), 4.08 (q, 2 H), 3.59 (s, 2 H), 3.56/3.46 (2m, 4 H), 2.8 (d, 2 H), 1.18 (t, 3 H), 1.09 (t, 6 H) Step C: Ethyl 2-(2,2-diethoxyethyl)methyl-pyrrolecarboxylate To a solution of 11.8 g of the compound obtained in Step B (50.8 mmol) in 76 mL of water there are added, dropwise at 0°C, 6.6 ml of aqueous 40 % methylamine solution (76.2 mmol). The reaction mixture is stirred and gently reheated to ambient temperature over 5 hours. After returning to 0°C, 8.8 mL of aqueous 40 % methylamine solution (102 mmol) and then 16.6 mL of aqueous 50 % chloroacetaldehyde solution (127 mmol) are each added dropwise at a temperature of less than 10°C. The reaction mixture is stirred at ambient temperature for 16 hours and then diluted with ethyl acetate. The organic phase is washed with brine, dried over MgSO and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The title product is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 6.7 (d, 1 H), 6.33 (d, 1 H), 4.55 (t, 1 H), 4.15 (q, 2 H), 3.6 (m, 2 H), 3.6 (s, 3 H), 3.3 (m, 2 H), 3.15 (d, 2 H), 1.25 (t, 3 H), 1.05 (t, 6 H) Step D: Ethyl 1-methyl(2-morpholinoethyl)pyrrolecarboxylate To a solution of 3.8 g of the compound obtained in Step C (14.05 mmol) in 28 mL of tetrahydrofuran there are added 58 mL of aqueous 10 % sulphuric acid solution. The reaction mixture is stirred at ambient temperature for 2 hours and then diluted with a mixture of ethyl acetate and water. After separation, the organic phase is washed with brine, dried over MgSO and concentrated to dryness. To a solution of the residue thereby obtained in 70 mL of dichloroethane there are added a solution of 13.5 mL of morpholine (14.5 mmol) in a mixture composed of 30 mL of dichloroethane and 3.6 mL of 4N aqueous HCL solution in dioxane (14.5 mmol), and then 7.4 g of sodium triacetoxyborohydride (NaBH(OAc) ) (35.13 mmol). The reaction mixture is stirred at ambient temperature for 3 hours and then diluted with a mixture of dichloromethane and saturated aqueous NaHCO solution. After separation of the phases and extraction of the aqueous phase with dichloromethane, the organic phases are dried over MgSO and concentrated to dryness.
The crude product thereby obtained is purified by chromatography over silica gel using dichloromethane and methanol as eluants. The title product is isolated in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 6.66 (d, 1 H), 6.31 (d, 1 H), 4.14 (q, 2 H), 3.58 (s, 3 H), 3.57 (m, 4 H), 3.05 (m, 2 H), 2.45-2.38 (m, 6 H), 1.24 (t, 3 H) Step E: 6-{4-(Ethoxycarbonyl)methyl[2-(morpholinyl)ethyl]-1H-pyrrolyl}-1,3- benzodioxolecarboxylic acid The procedure is in accordance with Steps B and C of Preparation, 1 replacing the 2- bromochlorobenzaldehyde used in Step B by 6-bromo-1,3-benzodioxole carbaldehyde.
Preparation 23: 6-[4-(Ethoxycarbonyl)methyl(morpholinylmethyl)-1H- pyrrolyl]-1,3-benzodioxolecarboxylic acid Step A: Ethyl 4,4-diethoxyoxo-butanoate To a solution of 40 g of ethyl diethoxyacetate (227 mmol) in 67 mL of ethyl acetate there are added under argon, in portions, 6 g of sodium (261 mmol). The reaction mixture is then stirred at ambient temperature for 48 hours. There are added 10 mL of methanol, and then the mixture is hydrolysed with 65 mL of water. The pH of the reaction mixture is adjusted to pH 6 by adding 1N aqueous HCl solution. The mixture is separated and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over MgSO , filtered and concentrated to dryness. The title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.
H NMR (400 MHz, CDCl ) δ ppm: 3.6 (s, 2 H), 1.28 (t, 9 H), 3.7-3.6 (2m, 4 H), 4.7 (s, 1 H), 4.2 (quad, 2 H) Step B: Ethyl 2-(2,2-diethoxymethyl)methyl-pyrrolecarboxylate The title compound is obtained in accordance with the process described in Step C of Preparation 22, starting from the ethyl 4,4-diethoxyoxo-butanoate obtained in the preceding Step.
H NMR (400 MHz, dmso-d6) δ ppm: 6.73 (d, 1 H), 6.32 (d, 1 H), 6.23 (s, 1 H), 4.17 (q, 2 H), 3.7 (s, 3 H), 3.68/3.43 (2m, 4 H), 1.26 (t, 3 H), 1.13 (t, 6 H) Step C: Ethyl 1-methyl(2-morpholinomethyl)pyrrolecarboxylate The title compound is obtained in accordance with the process described in Step D of Preparation 22, starting from the ethyl 2-(2,2-diethoxymethyl)methyl-pyrrole carboxylate obtained in the preceding Step.
H NMR (400 MHz, dmso-d6) δ ppm: 6.74 (d, 1 H), 6.32 (d, 1 H), 4.15 (q, 2 H), 3.8 (s, 2 H), 3.65 (s, 3 H), 3.5 (m, 4 H), 2.32 (m, 4 H), 1.22 (t, 3 H) Step D: 6-[4-(Ethoxycarbonyl)methyl(morpholinylmethyl)-1H-pyrrolyl]-1,3- benzodioxolecarboxylic acid The procedure is in accordance with the protocol described in Steps B and C of Preparation 1, replacing the 2-bromochlorobenzaldehyde used in Step B by 6-bromo- 1,3-benzodioxolecarbaldehyde.
Preparation 24: 6-[4-(Methoxycarbonyl)(2-methoxyethyl)methyl-1H-pyrrol yl]-1,3-benzodioxolecarboxylic acid Step A: Methyl 2-(2-methoxyethyl)methyl-pyrrolecarboxylate The title compound is obtained in accordance with the protocol of Step C of Preparation 22, using methyl 5-methoxyoxovalerate.
H NMR (400 MHz, dmso-d6) δ ppm: 6.69 (wd, 1 H), 6.31 (wd, 1 H), 3.69 (s, 3 H), 3.59 (s, 3 H), 3.49 (t, 2 H), 3.2 (s, 3 H), 3.11 (t, 2 H) Step B: 6-[4-(Methoxycarbonyl)(2-methoxyethyl)methyl-1H-pyrrolyl]-1,3-benzo- dioxolecarboxylic acid The procedure is in accordance with the protocol described in Steps B and C of Preparation 1, replacing the 2-bromochlorobenzaldehyde used in Step B by 6-bromo- 1,3-benzodioxolecarbaldehyde.
Preparation 25: 2-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]benzoic acid Preparation 25: 2-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]benzoic acid The procedure is in accordance with the process of Preparation 1, replacing the 2-bromo chlorobenzaldehyde used in Step B by 2-bromobenzaldehyde.
H NMR (400 MHz, dmso-d6) δ ppm: 12.81 (m, 1 H), 7.84 (m, 1 H), 7.59 (m, 1 H), 7.51 (m, 1 H), 7.35 (m, 1 H), 6.23 (s, 1 H), 4.16 (q, 2 H), 3.24 (s, 3 H), 2.5 (s, 3 H), 1.25 (t, 3 H) P Pr re ep pa ar ra at tiio on n 2 26 6: : 5 5- -F Fllu uo or ro o- -2 2- -[ [4 4- -( (m me et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- - b be en nz zo oiic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing in Step A the ethyl 2-methyl-1H-pyrrolecarboxylate by methyl 2-methyl-1H-pyrrolecarboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 2-bromofluoro- benzaldehyde.
H NMR (400 MHz, dmso-d6) δ ppm: 7.6 (dd, 1 H), 7.42 (m, 2 H), 6.22 (s, 1 H), 4.15 (q, 2 H), 3.21 (s, 3 H), 2.5 (s, 3 H), 1.23 (t, 3 H) F NMR (400 MHz, dmso-d6) δ ppm: -113 Preparation 27: 2-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]fluoro Preparation 27: 2-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]fluoro methoxybenzoic acid methoxybenzoic acid The procedure is in accordance with the process of Preparation 1, replacing in Step A the ethyl 2-methyl-1H-pyrrolecarboxylate by methyl 2-methyl-1H-pyrrolecarboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 2-bromomethoxy fluorobenzaldehyde.
H NMR (400 MHz, dmso-d6) δ ppm: 9.65 (d, 1 H), 7.67 (d, 1 H), 7.24 (d, 1 H), 6.48 (s, 1 H), 4.19 (q, 2 H), 3.97 (s, 3 H), 3.38 (s, 3 H), 2.56 (s, 3 H), 1.26 (t, 3 H).
Preparation 28: 2-(4-Ethoxycarbonyl-1,5-dimethyl-1H-pyrrolyl)fluoro Preparation 28: 2-(4-Ethoxycarbonyl-1,5-dimethyl-1H-pyrrolyl)fluoro m me et th ho ox xy yb be en nz zo oiic c a ac ciid d The procedure is in accordance with Preparation 1, replacing the 2-bromo chlorobenzaldehyde used in Step B by 4-fluoromethoxybenzaldehyde.
H NMR (400 MHz, dmso-d6) δ ppm: 12.9 (m, 1 H), 7.6 (d, 1 H), 7.22 (d, 1 H), 6.23 (s, 1 H), 4.2 (quad, 2 H), 3.95 (s, 3 H), 3.25 (s, 3 H), 2.5 (s, 3 H), 1.25 (t, 3 H) P Pr re ep pa ar ra at tiio on n 2 29 9: : 5 5- -C Ch hllo or ro o- -2 2- -[ [4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]b be en nz zo oiic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing the 2-bromo chlorobenzaldehyde used in Step B by 2-bromochlorobenzaldehyde.
Preparation 30: 2-{1-[2-(Benzyloxy)ethyl](ethoxycarbonyl)methyl-1H-pyrrol Preparation 30: 2-{1-[2-(Benzyloxy)ethyl](ethoxycarbonyl)methyl-1H-pyrrol yl}chlorobenzoic acid yl}chlorobenzoic acid The procedure is in accordance with the process of Preparation 19, replacing the 6-bromo- 1,3-benzodioxolecarbaldehyde by 2-bromochlorobenzaldehyde.
P Pr re ep pa ar ra at tiio on n 3 31 1: : 5 5- -M Me et th ho ox xy y- -2 2- -[ [4 4- -( (m me et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- - b be en nz zo oiic c a ac ciid d The procedure is in accordance with the process of Preparation 1, replacing in Step A the ethyl 2-methyl-1H-pyrrolecarboxylate by methyl 2-methyl-1H-pyrrolecarboxylate and also the 2-bromochlorobenzaldehyde used in Step B by 2-bromomethoxy- benzaldehyde.
H NMR (400 MHz, dmso-d6) δ ppm: 12.8 (bs, 1 H), 7.34 (wd, 1 H), 7.26 (d, 1 H), 7.15 (dd, 1 H), 6.19 (s, 1 H), 3.84 (s, 3 H), 3.69 (s, 3 H), 3.22 (s, 3 H), 2.5 (s, 3 H) P Pr re ep pa ar ra at tiio on n 3 32 2: : 6 6- -[ [1 1- -( (2 2,,2 2- -D Diif fllu uo or ro oe et th hy yll) )- -4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -5 5- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- - y yll] ]- -1 1,,3 3- -b be en nz zo od diio ox xo olle e- -5 5- -c ca ar rb bo ox xy ylliic c a ac ciid d The procedure is in accordance with the protocol of Preparation 19, replacing the 2- bromoethoxymethylbenzene used in Step A by 2-bromo-1,1-difluoro-ethane.
Preparation 1': (3R)Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride Preparation 1': (3R)Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride Step A: {(3S)[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolinyl}methyl 4-methylbenzenesulphonate To a solution of 30.2 g of [(3S)-1,2,3,4-tetrahydroisoquinolinyl]methanol (185 mmol) in 750 mL of dichloromethane there are successively added 91.71 g of tosyl chloride (481 mmol) and then, dropwise, 122.3 mL of N,N,N-triethylamine (740 mmol). The reaction mixture is then stirred at ambient temperature for 20 hours. It is then diluted with dichloromethane, washed successively with 1M HCl solution, saturated aqueous NaHCO solution and then brine until neutral. The organic phase is then dried over MgSO , filtered and concentrated to dryness. The solid obtained is then dissolved in a minimum volume of dichloromethane and then cyclohexane is added until a precipitate is formed. This precipitate is then filtered off and washed with cyclohexane. After drying, the title product is obtained in the form of crystals.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.75 (d, 2H, aromatic Hs, ortho O-tosyl); 7.6 (d, 2H, aromatic Hs, ortho N-tosyl); 7.5 (d, 2H, aromatic Hs, meta O-tosyl); 7.3 (d, 2H, aromatic Hs, meta N-tosyl); 7.15-6.9 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.4- 4.15 (dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 4.25 (m, 1H, aliphatic H, tetrahydroisoquinoline); 4.0-3.8 (2dd, 2H, aliphatic Hs, CH -O-tosyl); 2.7 (2dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.45 (s, 3H, O-SO -Ph- CH ); 2.35 (s, 3H, N-SO - 2 3 2 Ph- CH ) IR: ν: -SO : 1339-1165 cm Step B: (3R)Methyl[(4-methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinoline To a suspension of 8.15 g (214.8 mmol) of lithium aluminium hydride (LiAlH ) in 800 mL of methyl tert-butyl ether (MTBE) there are added 101.2 g of the ditosyl compound obtained in Step A (214.8 mmol) dissolved in 200 mL of MTBE. The batch is then heated at 50°C for 2 hours. It is allowed to cool and placed at 0°C, and there are then added, dropwise, 12 mL of 5N NaOH solution. The batch is stirred at ambient temperature for 45 minutes. The solid thereby obtained is then filtered off and washed with MTBE and then with dichloromethane. The filtrate is then concentrated to dryness. The title product is then obtained in the form of a solid.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.70 (d, 2H, aromatic Hs, ortho N-tosyl); 7.38 (d, 2H, aromatic Hs, meta N-tosyl); 7.2-7.0 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.4 (m, 2H, aliphatic Hs, tetrahydroisoquinoline); 4.3 (m, 1H, aliphatic H, tetrahydroisoquinoline); 2.85-2.51 (2dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.35 (s, 3H, N-SO -Ph- CH ); 0.90 (d, 3H, tetrahydroisoquinoline-CH ) 2 3 3 IR : ν: -SO : 1332-1154 cm Step C: (3R)Methyl-1,2,3,4-tetrahydroisoquinoline To a solution of 31.15 g (103.15 mmol) of the monotosyl compound obtained in Step B in 500 mL of anhydrous methanol there are added, in portions, 3.92 g (161 mmol) of magnesium turnings. The batch is stirred in the presence of ultrasound for 96 hours. The reaction mixture is then filtered and the solid is washed several times with methanol. The filtrate is then concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and ammonia-in-ethanol as eluants, the title product is obtained in the form of an oil.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.05 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 3.90 (m, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.85 (m, 1H, aliphatic H, tetrahydroisoquinoline); 2.68-2.4 (2dd, 2H, aliphatic Hs, tetrahydro- isoquinoline); 1.12 (d, 3H, tetrahydroisoquinoline-CH ); 2.9-2.3 (m, broad, 1H, HN (tetrahydroisoquinoline)) IR: ν: -NH: 3248 cm Step D: (3R)Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride To a solution of 14.3 g (97.20 mmol) of the compound obtained in Step C in 20 mL of anhydrous ethanol there are added, dropwise, 100 mL of a 1M solution of HCl in ether.
The batch is stirred at ambient temperature 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 crystals.
H NMR: δ (400 MHz; dmso-d6; 300K): 9.57 (m, broad, 2H, NH (tetrahydro- isoquinoline); 7.22 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.27 (s, 2H, aliphatic Hs, tetrahydroisoquinoline); 3.52 (m, 1H, aliphatic H, tetrahydroisoquinoline); 3.03--2.85 (2dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 1.39 (d, 3H, tetrahydroisoquinoline-CH ) + -1 -1 IR: ν: -NH : 3000-2300 cm ; ν: aromatic -CH: 766 cm P Pr re ep pa ar ra at tiio on n 2 2'': :tte er rtt- -B Bu ut ty yll [ [( (3 3S S) )- -1 1,,2 2,,3 3,,4 4- -t te et tr ra ah hy yd dr ro oiis so oq qu uiin no olliin n- -3 3- -y yllm me et th hy yll] ]c ca ar rb ba am ma at te e Step A: Benzyl (3S)(hydroxymethyl)-3,4-dihydro-1H-isoquinolinecarboxylate 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 (3S)-1,2,3,4- tetrahydroisoquinolinylmethanol (91,9 mmol) in the presence of benzyl chloroformate and triethylamine in solution in dichloromethane. After purification by chromatography over silica gel using petroleum ether and ethyl acetate as eluants, the title product is obtained in the form of an oil.
H NMR: δ (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, CH -Ph); 4.73 (d, 1H, H tetrahydroisoquinoline); 4.47 (m, H, CH OH); 4.36 (m, 1H, H tetrahydroisoquinoline); 4.28 (d, 1H, H tetrahydroisoquinoline); 3.39 (dd, 1H, CH OH); 3.23 (dd, 1H, , CH OH); 2.93 (dd, 1H, H tetrahydroisoquinoline); 2.86 (dd, 1H, H tetrahydroisoquinoline) -1 -1; -1 IR: ν: OH: 3416 cm ; ν: <C=O 1694 cm ν:aromatic >C-H: 754 cm Step B: Benzyl (3S)(azidomethyl)-3,4-dihydroisoquinoline-2(1H)-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 in solution in THF.
After purification by chromatography over silica gel using petroleum ether and ethyl acetate as eluants, 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, CH -Ph); 4.76 (d, 1H, H tetrahydroisoquinoline); 4.53 (m, 1H, H tetrahydroisoquinoline); 4.30 (m, 1H, H tetrahydroisoquinoline); 3.28 (m, 2H, , CH N ); 3.06 (dd, 1H, H tetrahydroisoquinoline); 2.78 (dd, 1H, H tetrahydroisoquinoline) -1 -1; -1 IR: ν: N : 2095 cm ; ν: <C=O:1694 cm ν: aromatic >C-H: 754 cm Step C: Benzyl (3S)(aminomethyl)-3,4-dihydroisoquinoline-2(1H)-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 batch is refluxed for 2 hours 30 minutes. The reaction mixture is then concentrated to dryness and the residue oil is then taken up in isopropyl ether. A white precipitate appears; it is filtered off and washed with isopropyl ether. The filtrate is then concentrated to dryness and then purified by chromatography over silica gel using dichloromethane and methanol as eluants. The title product is obtained in the form of an oil.
H NMR: δ (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, CH -Ph); 4.75-4.3 (m, 2H, H tetrahydroisoquinoline); 4.30 (d, 1H, H tetrahydroisoquinoline); 2.90 (m, 2H, , CH NH ); 2.45 (m, 2H, H tetrahydroisoquinoline); 1.40 (m, 2H, NH ) -1 -1 IR: ν: NH : 3400-3300 cm ; ν: <C=O: 1688 cm Step D: Benzyl (3S){[(tert-butoxycarbonyl)amino]methyl}-3,4-dihydroisoquinoline- 2(1H)-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-tert-butyl dicarbonate. The batch is stirred at ambient temperature for 2 h. The reaction mixture is then concentrated and ethyl acetate is then added. The organic phase is successively washed with 1M HCl solution, brine, saturated aqueous NaHCO solution and then brine. After drying, concentrating to dryness and purifying by chromatography over silica gel using petroleum ether and ethyl acetate as eluants, the title product is obtained in the form of an oil.
H 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, CH -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 + CH NHBoc); 2.71 (d, 1H, H tetrahydroisoquinoline); 1.34 (s, 9H, NHBoc) -1 -1 IR: ν: NH: 3351 cm ; ν: <C=O: 1686 cm Step E: tert-Butyl [(3S)-1,2,3,4-tetrahydroisoquinolinylmethyl]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 batch is stirred at ambient temperature under a pressure of 1.3 bars of dihydrogen for 5 hours. The reaction mixture is then filtered and then concentrated to dryness. The title product is obtained in the form of a solid.
H NMR: δ (400 MHz; DMSO-d6; 300K): 7.15 (m, 4H, aromatic Hs, H tetrahydro- isoquinoline); 6.85 (t, 1H, NHBoc); 3.90 (m, 2H, H tetrahydroisoquinoline); 3.00 (m, 2H, CH NHBoc); 2.80 (m, 1H, H tetrahydroisoquinoline); 2.65 (dd, 1H, H tetrahydro- isoquinoline); 2.40 (dd, 1H, H tetrahydroisoquinoline); 1.40 (s, 9H, NHBoc) -1 -1; -1 IR: ν: NH: 3386-3205 cm (NH amide); ν: <C=O: 1688 cm ν: NH: 1526 cm (NH amine) P Pr re ep pa ar ra at tiio on n 3 3'': : ( (3 3S S) )- -3 3- -( (4 4- -M Mo or rp ph ho olliin ny yllm me et th hy yll) )- -1 1,,2 2,,3 3,,4 4- -t te et tr ra ah hy yd dr ro oiis so oq qu uiin no olliin ne e Step A: Benzyl (3S)(4-morpholinylcarbonyl)-3,4-dihydro-2(1H)-isoquinoline- carboxylate To a solution of 5 g of (3S)[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro isoquinolinecarboxylic acid (16 mmol) in 160 mL of dichloromethane there are added 1.5 mL of morpholine (17.6 mmol), then 9 mL of N,N,N-triethylamine (64 mmol), 3.3 g of 1-ethyl(3'-dimethylaminopropyl)-carbodiimide (EDC) (19.2 mmol) and 2.6 g of hydroxybenzotriazole (HOBt) (19.2 mmol). The reaction mixture is stirred at ambient temperature overnight; it is then poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is then dried over MgSO , and then filtered and evaporated to dryness. The crude product thereby obtained is then purified by chromatography over silica gel using dichloromethane and methanol as eluants. The product is obtained in the form of a foam.
H NMR: δ (400 MHz; dmso-d6; 353K): 7.30 (m, 5H benzyl); 7.15 (m, 4H, aromatic Hs); .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: ν: >C=O: 1694;1650 cm Step B: Benzyl (3S)(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate 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 borane-dimethylsulphide complex (BH Me S) (27.8 mmol) at ambient temperature. The batch is heated for 4 hours at 80°C. It is allowed to return to ambient temperature and there are then added 7 mL (14 mmol) of BH Me S.
The reaction mixture is again heated at 80°C for 2 hours. The tetrahydrofuran is then evaporated off and then there is slowly added methanol and then 5.6 mL of 5N aqueous HCl solution (27.8 mmol). The mixture is stirred at ambient temperature overnight, and then at 80°C for 1 hour. Saturated aqueous NaHCO solution is then added to the reaction mixture placed at 0°C until a pH of 8 is obtained, and extraction with ethyl acetate is then carried out. The organic phase is then dried over MgSO , 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; 353K): 7.43-7.30 (unresolved peak, 5H benzyl); 7.19 (m, 4H, aromatic Hs); 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) -1 -1 -1 IR: ν: >CH: 2810 cm ; ν: >C=O: 1694 cm ; ν: >C-O-C<: 1114 cm ; ν: >CH-Ar: 751; 697 cm Step C: (3S)(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline To a solution of 4.9 g of the compound of Step B (13,4 mmol) in 67 mL of ethanol there is added 0.980 g of palladium dihydroxide (20 % by weight) at ambient temperature. The reaction mixture is placed under 1.2 bars of hydrogen at ambient temperature for 4 hours.
It is then passed through a Whatman filter and the palladium is then rinsed several times with ethanol. The filtrate is evaporated to dryness. The title product is obtained in the form of an oil.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.12-7.0 (unresolved peak, 4H, aromatic Hs); 3.92 (s, 2H tetrahydroisoquinoline); 3.60 (t, 4H morpholine); 2.98 (m, 1H tetrahydroisoquinoline); 2.68 (dd, 1H tetrahydroisoquinoline); 2.5-2.3 (unresolved peak, 8H, 1H tetrahydroisoquinoline, 6H morpholine, 1H NH) -1; -1; -1 IR: ν: >NH: 3322 cm ν: >C-O-C<: 1115 cm ν: >CH-Ar: 742 cm P Pr re ep pa ar ra at tiio on n 4 4'': :( (3 3S S) )- -3 3- -[ [( (4 4- -M Me et th hy yll- -1 1- -p piip pe er ra az ziin ny yll) )m me et th hy yll] ]- -1 1,,2 2,,3 3,,4 4- -t te et tr ra ah hy yd dr ro o- - iis so oq qu uiin no olliin ne e The procedure is in accordance with the process of Preparation 3', replacing the morpholine used in Step A by 1-methyl-piperazine.
Preparation 5':(3S)[2-(Morpholinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline Preparation 5':(3S)[2-(Morpholinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride hydrochloride Step A: tert-Butyl (3S)(2-morpholinooxo-ethyl)-3,4-dihydro-1H-isoquinoline carboxylate To a solution of 3 g (10.30 mmol) of [(3S)(tert-butoxycarbonyl)-1,2,3,4- tetrahydroisoquinolinyl]acetic acid in 100 mL of dichloromethane, there are added dropwise 1.10 mL (11.32 mmol) of morpholine, still dropwise 4.3 mL (30.9 mmol) of triethylamine, 2.20 g (12.40 mmol) of EDC and 1.70 g (1.68 mmol) of HOBt (hydroxybenzotriazole). The batch is stirred at ambient temperature for 15 hours. The reaction mixture is then diluted with dichloromethane, successively washed with 1M HCl solution, saturated aqueous NaHCO solution and then brine until neutral. The organic phase is then dried over MgSO , filtered and concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and methanol as eluants, the title product is obtained in the form of an oil.
H 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, CH alpha to N tetrahydroisoquinoline); 3.60 (m, 8H, aliphatic Hs, morpholine); 3.00 and 2.70 (2dd, 2H, aliphatic H, tetrahydroisoquinoline); 2.50-2.20 (2d, 2H, aliphatic Hs, CH CO); 1.40 (s, 9H, Bu) IR: ν: C=O: 1687; 1625 cm Step B: 1-(Morpholinyl)[(3S)-1,2,3,4-tetrahydroisoquinolinyl]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 1M solution of HCl in ether. The batch is stirred at ambient temperature for 15 hours, and then the suspension is filtered and the precipitate 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, NH ); 7.30-7.10 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.30 (m, 2H, aliphatic Hs, CH alpha to N tetrahydroisoquinoline); 3.80 (m, 1H, aliphatic Hs, CH tetrahydroisoquinoline); 3.70-3.40 (2m, 8H, aliphatic Hs, morpholine); 3.15 and 2.8 (m, 4H, aliphatic H, CH tetrahydroisoquinoline and CH CO) + -1; -1 IR: ν: -NH : 2800-1900 cm ν: C=O: 1620 cm Step C: (3S)[2-(Morpholinyl)ethyl]-1,2,3,4-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 added thereto, dropwise, 15 mL (15 mmol) of 1M LiAlH solution in tetrahydrofuran. The batch is then stirred at ambient temperature for 6 hours. It is placed at 0°C, and there is then added, dropwise, 1 mL of 5N NaOH solution. The batch is stirred at ambient temperature 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 a 1M solution of HCl in ether. The batch is stirred at ambient temperature 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, NH ); 10.00 (m, H, NH ); 7.20 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.30 (s, 2H, aliphatic Hs, CH alpha to N tetrahydroisoquinoline); 4.00 + 3.85 (2m, 4H, aliphatic Hs, CH alpha to N morpholine); 3.70 (m, 1H, aliphatic Hs, CH tetrahydroisoquinoline); 3.55-3.30 (m, 4H, aliphatic Hs, CH alpha to O morpholine and CH -morpholine ); 3.15 (dd, 1H, aliphatic H, CH tetrahydroisoquinoline); 3.10 (m, 2H, aliphatic H, CH alpha to O morpholine); 2.90 (dd, 1H, aliphatic H, CH tetrahydroisoquinoline); 2.30 + 2.15 (2m, 2H, aliphatic H, CH - tetrahydroisoquinoline) + + -1; -1; IR: ν: NH / -NH : between 3500 and 2250 cm ν: C=C: weak 1593 cm ν: aromatic C-H: 765 cm Preparation 6': (3R)[3-(Morpholinyl)propyl]-1,2,3,4-tetrahydroisoquinoline Preparation 6': (3R)[3-(Morpholinyl)propyl]-1,2,3,4-tetrahydroisoquinoline Step A: {(3S)[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolinyl}methyl 4-methylbenzenesulphonate The process is the same as that of Step A of Preparation 1'.
Step B: tert-Butyl 2-({(3R)[(4-methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolin- 3-yl}methyl)(morpholinyl)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 tert-butyl 3-morpholinooxopropanoate (21.81 mmol) in mL of anhydrous MTBE. This suspension stirred at ambient temperature for 1 hour and then 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 aqueous ammonium chloride solution are added. The resulting solution is extracted with dichloromethane. The organic phase is then dried over MgSO , filtered and concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and MeOH as eluants, the expected product is obtained in the form of an oil.
H NMR (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 : ν: >C=O: 1731 (ester); ν: >C=O: 1644 (amide); ν: -SO2: 1334-1156; ν: >C-O-C<: 1115; γ : >CH-Ar: 815709 Step C: 2-({(3R)[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolin yl}methyl)(morpholinyl)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 temperature for 48 hours and then the solution is concentrated to dryness. After drying, the expected product is obtained in the form of an oil.
H NMR (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) -1 ; IR (ATR) cm : ν: -OH: 3500 to 2000 ν: >C=O: 1727 (acid); ν: >C=O: 1634 (amide); ν: - SO2: 1330-1155 Step D: 3-{(3R)[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolinyl} (morpholinyl)propanone 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 (NaCl) and then, dropwise, 5 mL of water. The batch is stirred at 130°C for 1 hour and then the solution is concentrated to ¾. The reaction mixture is then diluted with dichloromethane and washed successively with saturated aqueous lithium chloride solution and then with brine. The organic phase is then dried over MgSO , filtered and concentrated to dryness. After purification by chromatography over silica gel using cyclohexane and ethyl acetate as eluants, the expected product is obtained in the form of an oil.
H NMR (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 : ν: >C=O: 1639; ν: -SO2: 1331-1156; γ : >CH-Ar: 815-675 Step E: (3R)[(4-Methylphenyl)sulphonyl][3-(morpholinyl)propyl]-1,2,3,4- tetrahydroisoquinoline 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 temperature 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 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 MgSO , filtered and concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and ammonia-in- ethanol as eluants, the expected product is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 7.68 (d, 2 H), 7.32 (d, 2 H), 7.1 (unresolved peak, 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 : ν: -SO2: 1333-1158 Step F: (3R)[3-(Morpholinyl)propyl]-1,2,3,4-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 magnesium 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 chromatography over silica gel using dichloromethane and ammonia-in-ethanol as eluants, the expected product is obtained in the form of an oil.
H NMR (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, 2 H), 1.45 (m, 2 H) IR (ATR) cm : ν: >NH2+/NH+: 3500-2300; ν: >C-O-C<: 1115 High-resolution mass spectrometry (ESI+-/FIA/HR): Empirical formula: C H N O 16 24 2 [M+H] calculated: 261.1961 [M+H] measured: 261.1959 Preparation 7': (3S)[(9aS)-Octahydropiperazino[2,1-c]morpholinylmethyl]- 1,2,3,4-tetrahydroisoquinoline trihydrochloride Step A: tert-Butyl (9aS)oxo-octahydropiperazino[2,1-c]morpholinecarboxylate The synthesis of this compound is known in the literature (J. Med. Chem. 2012, 55, 5887 for the opposite enantiomer).
Step B: (9aS)-Octahydropiperazino[2,1-c]morpholinone hydrochloride A 4M solution of HCl in dioxane (60 mL, 240 mmol) is added to the compound tert-butyl (9aS)oxo-octahydropiperazino[2,1-c]morpholinecarboxylate (11.8 g, 46.0 mmol) cooled using an ice bath. The solution is then stirred at ambient temperature for 2 hours, and then at 50-60°C for 1.5 hours. The solution is then evaporated to dryness. The residue is co-evaporated with dioxane (3 x 20 mL) and then dried in vacuo to obtain the expected compound in the form of a solid.
H NMR (400 MHz, dmso-d6) δ ppm: 2.80 - 2.94 (m, 2 H), 2.94 - 3.05 (m, 1 H), 3.23 - 3.37 (m, 2 H), 3.59 - 3.69 (m, 1 H), 3.83 - 3.93 (m, 1 H), 3.95 - 4.04 (m, 1 H), 4.02 - 4.13 (m, 2 H), 4.45 - 4.55 (m, 1 H), 9.58 (br s, 2 H) Step C: tert-Butyl (3S)[(9aS)oxo-octahydropiperazino[2,1-c]morpholine carbonyl]-1,2,3,4-tetrahydroisoquinolinecarboxylate EDC (3.90 g, 20.3 mmol) is added to a solution of the compound of Step B (3.02 g, .7 mmol), (3S)[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinolinecarboxylic acid (4.6 g, 16.6 mmol), triethylamine (8.0 mL, 57.4 mmol) and HOBt (2.72 g, 20.1 mmol) in dichloromethane (150 mL). The mixture is stirred at ambient temperature for 21 hours. 1N aqueous HCl solution (105 mL) is added and the precipitate formed is filtered off using a Buchner funnel. The phases of the filtrate are separated. The aqueous phase is extracted with dichloromethane (2 x 10 mL). The combined organic phases are washed with 3N aqueous HCl solution (35 mL), then with aqueous 5 % potassium bicarbonate solution (2 x mL) and finally with brine (35 mL). The organic phase is dried over Na SO , filtered and then concentrated under reduced pressure. The product is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 1.38 - 1.57 (m, 9 H), 2.39 - 2.89 (m, 2 H), 2.89 - 3.34 (m, 3 H), 3.34 - 3.70 (m, 2 H), 3.90 - 4.06 (m, 1 H), 4.09 - 4.27 (m, 2 H), 4.30 - 5.00 (m, H), 5.20 - 5.37 (m, 1 H), 7.03 - 7.24 (m, 4 H) Step D: (3S)[(9aS)-Octahydropiperazino[2,1-c]morpholinylmethyl]-1,2,3,4- tetrahydroisoquinoline trihydrochloride 4M HCl solution in dioxane (45 mL, 180 mmol) is added to the compound of Step C (6.6 g, 46.0 mmol) cooled in an ice bath. The suspension is then stirred at ambient temperature for 24 hours and then it is evaporated to dryness. The residue is co-evaporated with MTBE and then dried in vacuo. The solid thereby obtained is suspended in tetrahydrofuran (160 mL), and then LiAlH (3,0 g, 79.1 mmol) is added. The suspension is refluxed for 6.5 hours, and it is then cooled in an ice bath. Water (3 mL) is then added over a period of 7 minutes. After 0.5 hours, 2N aqueous sodium hydroxide solution (6 mL) is added. Water (6 mL) is again added 0.25 hours later. Finally, Celite (7 g) and Na SO (25 g) are added 0.5 hours later. The suspension is filtered over Celite and rinsed with tetrahydrofuran (2 x 100 mL). The filtrate is concentrated to dryness. The oil thereby obtained is dissolved in MTBE (50 mL). The resulting solution is filtered and the filtrate concentrated. The residue is dissolved in methanol (60 mL), and then 4M HCl solution in dioxane (20 mL) is added. The solution is heated to 40°C and treated with activated charcoal (0.66 g), with stirring, for 1 hour. The suspension is filtered over Celite and rinsed with warm methanol. The filtrate is concentrated until the product starts to crystallise out.
Crystallisation is allowed to continue for 16 hours at ambient temperature. The solid obtained is filtered off and rinsed with a mixture of 2-propanol / MTBE (4/6) (2 x 20 mL), and then with MTBE (2 x 20 mL). After drying, the expected compound is obtained.
H NMR (400 MHz, D O) δ ppm: 2.28 - 2.44 (m, 1 H), 2.74 - 3.00 (m, 4 H), 3.08 - 3.27 (m, 3 H), 3.27 - 3.42 (m, 2 H), 3.43 - 3.56 (m, 2 H), 3.56 - 3.69 (m, 2 H), 3.76 - 3.95 (m, 2 H), 4.00 - 4.22 (m, 2 H), 4.35 - 4.50 (m, 2 H), 7.20 - 7.41 (m, 4 H) C NMR (100 MHz, D O) δ ppm: 29.00, 44.58, 50.30, 51.08, 51.17, 52.75, 53.17, 58.08, 61.60, 64.61, 66.37, 127.14, 127.71, 128.00, 128.77, 129.55, 131.15 MS (ESI): [M+H] 288.16 Preparation 8': (3S)(1-Oxaazaspiro[3.3]heptylmethyl)-1,2,3,4-tetrahydro- isoquinoline Step A: (3S)(Iodomethyl)[(4-methylphenyl)sulphonyl]-1,2,3,4-tetrahydro- isoquinoline The compound of Step A of Preparation 6' (4.0 g; 8.48 mmol) in acetonitrile (10 mL) is placed in a 27-ml microwave tube and then sodium iodide (1.40 g; 9.33 mmol) is added.
The reaction mixture is heated for 5 hours at 100°C using microwaves (200 W). It is then filtered and the solid is washed with dichloromethane. The filtrate is evaporated to dryness and then the residue is purified by chromatography over silica gel using heptane and ethyl acetate as eluants. The title compound is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 7.64 (d, 2 H), 7.28 (d, 2 H), 7.15-7 (m, 4 H), 4.5/4.3 (2d, 2 H), 4.14 (m, 1 H), 3.22 (m, 2 H), 2.82 (m, 2 H), 2.31 (s, 3 H) IR (ATR) cm : 1897 ν -Ar, 1333 + 1156 ν -SO2 Step B: (3S)[(4-Methylphenyl)sulphonyl](1-oxaazaspiro[3.3]heptylmethyl)- 1,2,3,4-tetrahydroisoquinoline The iodinated compound (2.5 g; 5.85 mmol) obtained in the preceding Step is dissolved in acetonitrile (50 mL). 1-Oxaazaspiro[3.3]heptane oxalate (1.21 g; 6.36 mmol) is added, followed by potassium carbonate (1.61 g; 11.7 mmol). The reaction mixture is heated for hours at reflux. The reaction mixture is filtered and washed with acetonitrile, and then is evaporated to dryness.
The compound is purified by chromatography over silica gel using dichloromethane and ammonia-in-methanol as eluants. The title compound is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 7.68 (d, 2 H), 7.32 (d, 2 H), 7.14-7 (m, 4 H), 4.53/4.2 (dd, 2 H), 4.34 (t, 2 H), 3.95 (m, 1 H), 3.5/3.4/2.98 (3m, 4 H), 2.7 (t, 2 H), 2.68- 2.58 (m, 2 H), 2.34 (s, 3 H), 2.31-2.24 (m, 2 H) IR (ATR) cm : 1333 + 1156 ν -SO2 Step C: (3S)(1-Oxaazaspiro[3.3]heptylmethyl)-1,2,3,4-tetrahydroisoquinoline The tosylated compound of the above Step (1.3 g; 3.26 mmol) is dissolved in 10 mL of methanol. Powdered magnesium (633 mg; 26.08 mmol) is added in portions of 160 mg every 3 hours. The reaction mixture is stirred in an ultrasound bath 15 hours. It is then filtered over Celite, washed with copious amounts of methanol, and then evaporated to dryness. The compound is purified by chromatography over silica gel using dichloromethane and ammonia-in-methanol as eluants. The compound is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 7.01 (m, 4 H), 4.46 (t, 2 H), 3.85 (s, 2 H), 3.51/3.05 (dd, 2 H), 2.73 (t, 2 H), 2.61/2.4 (m, 4 H), 2.4 (m, 1 H), 2.4 (m, 1 H) IR (ATR) cm : 3325 ν >NH Preparation 9': (3S)[(9aR)-Octahydropiperazino[2,1-c]morpholinylmethyl]- 1,2,3,4-tetrahydroisoquinoline trihydrochloride Step A: tert-Butyl (9aR)oxo-octahydropiperazino[2,1-c]morpholinecarboxylate Synthesis of this compound is described in the literature (J. Med. Chem. 2012, 55, 5887).
Step B: (9aR)-Octahydropiperazino[2,1-c]morpholinone hydrochloride A 4M solution of HCl in dioxane (39 mL, 154 mmol) is added to the compound of Step A (11.3 g, 44.1 mmol). The solution is then stirred at ambient temperature for 5 hours, and then a 4M solution of HCl in dioxane (12 mL, 48 mmol) is added again. The mixture is stirred for 16 hours. The solution is then evaporated to dryness to yield the expected product in the form of a solid.
H NMR (400 MHz, dmso-d6) δ ppm: 2.79 - 2.93 (m, 2 H), 3.02 (td, J = 13.1, 2.7 Hz, 1 H), 3.22 - 3.34 (m, 2 H), 3.59 - 3.67 (m, 1 H), 3.86 - 3.96 (m, 1 H), 3.96 - 4.01 (m, 1 H), 4.05 (AB q, J = 13.3 Hz, 2 H), 4.48 (dd, J = 14.1, 2.5 Hz, 1 H), 9.71 (br. s, 1 H), 9.91 (br. s, 1 H) Step C: tert-Butyl (3S)[(9aR)oxo-octahydropiperazino[2,1-c]morpholine carbonyl]-1,2,3,4-tetrahydroisoquinolinecarboxylate EDC (5.17 g, 27.0 mmol) is added to a solution of the compound of the above Step (4.0 g, .7 mmol), (3S)[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinolinecarboxylic acid (6.04 g, 21.8 mmol), triethylamine (11.6 mL, 83.1 mmol) and HOBt (3.65 g, 27.0 mmol) in dichloromethane (100 mL). The mixture is stirred at ambient temperature for 16 hours. 1N aqueous HCl solution (70 mL) is added and the precipitate formed is filtered off using a Buchner funnel. The phases of the filtrate are separated. The organic phase is washed with saturated aqueous potassium carbonate solution and is then concentrated under reduced pressure. The residue is pre-absorbed onto silica gel and is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to yield the expected compound in the form of a solid.
H NMR (400 MHz, dmso-d6) δ ppm: 1.25 - 1.58 (m, 9 H), 2.50 - 2.76 (m, 2 H), 2.76 - 3.25 (m, 3 H), 3.37 - 3.76 (m, 2 H), 3.92 - 4.50 (m, 5 H), 4.06 (s, 2 H), 4.66 (d, J = 15.6 Hz, 1 H), 4.76 - 5.28 (m, 1 H), 7.05 - 7.31 (m, 4 H) Step D: (3S)[(9aR)-Octahydropiperazino[2,1-c]morpholinylmethyl]-1,2,3,4- tetrahydroisoquinoline trihydrochloride A 4M solution of HCl in dioxane (24.0 mL, 96.2 mmol) is added to a solution of the compound of Step C (8.00 g, 12.25 mmol) in dichloromethane (25 mL). The mixture is stirred at ambient temperature for 16 hours and is then concentrated to dryness. The crude product obtained is added to a suspension of LiAlH (1.97 g, 51.91 mmol) in tetrahydrofuran (140 mL). The mixture is refluxed until the reaction (monitored by LC- MS) is complete and it is then cooled to 0˚C. Water (2.5 mL) is added dropwise. After stirring for 10 minutes, aqueous 2M sodium hydroxide solution (5 mL) is added dropwise.
Water (5 mL) is again added after stirring for 10 minutes. There are finally added Celite (4 g) and Na SO (12 g) after stirring for an additional 10 minutes. The suspension is filtered over Celite and the filtrate is concentrated to dryness. The crude residue thereby obtained is dissolved in methanol (80 mL), and then a 4M solution of HCl in dioxane (16.75 mL, 67.0 mmol) is added. The mixture is stirred at ambient temperature for 3 hours, and then concentrated to dryness. The residue is dissolved in a minimum of warm methanol (70 mL), and then MTBE (3-5 mL) is added. The solution is cooled at 0˚C for 1 hour in an ice-cold water bath, and the product precipitates out. A little MTBE (2-3 mL) is again added and the mixture is allowed to stand for a further 1 hour at 0˚C. The solid obtained is filtered over a Buchner funnel and dried in vacuo to yield the expected compound in the form of a solid.
H NMR (400 MHz, CD OD) δ ppm: 2.65 (t, J = 11.1 Hz, 1 H), 2.74 - 2.97 (m, 4 H), 3.10 (d, J = 12.5 Hz, 1 H), 3.19 (dd, J = 17.6, 4.8 Hz, 1 H), 3.25 - 3.55 (m, 5 H), 3.59 - 3.74 (m, 2 H), 3.82 - 4.15 (m, 4 H), 4.45 (AB q, J = 15.9 Hz, 2 H), 7.21 - 7.35 (m, 4 H).
C NMR (100 MHz, CD OD) δ ppm: 30.21, 45.67, 50.22, 51.99, 52.90, 53.58, 53.71, 59.25, 62.58, 65.30, 67.07, 127.76, 128.40, 129.08, 129.36, 130.16, 131.95 MS (ESI): [M+H] 288.2 Preparation 1'':N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]methyl-pyrazolamine Preparation 1'':N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]methyl-pyrazolamine Step A: 4-{[tert-Butyl(dimethyl)silyl]oxy}aniline The title compound is obtained starting from 4-aminophenol in THF in the presence of imidazole and tert-butyl(dimethyl)silyl chloride in accordance with the protocol described in the literature (S. Knaggs et al, Organic & Biomolecular Chemistry, 3(21), 4002-4010; 2005).
H NMR: δ (400 MHz; dmso-d6; 300K): 6.45-6.55 (dd, 4H, aromatic Hs); 4.60 (m, 2H, NH -Ph); 0.90 (s, 9H, Si (CH ) CH(CH ) ); 0.10 (s, 6H, Si (CH ) CH(CH ) ) 2 2 2 3 2 2 2 3 2 + -1 IR: ν: -NH : 3300-3400 cm Step B: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]methyl-pyrazolamine To a solution of 30.8 g (0.137 mol) of the compound of Step A in 525 mL of anhydrous toluene there are successively added 29.8 g of sodium tert-butylate (0.310 mol), 4.55 g of Pd (dba) (also referred to as tris(dibenzylideneacetone)dipalladium(0)) (4.96 mmol), 4.81 g of 2-di-tert-butylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (9.91 mmol) and 12.8 mL of 4-bromomethyl-1H-pyrazole (0.124 mol). The batch is degassed under argon for 30 minutes and then refluxed for 3 hours. It is allowed to cool. The reaction mixture is concentrated to dryness and then taken up in dichloromethane, filtered over Celite and then concentrated to dryness again. The residue is then purified by chromatography over silica gel using dichloromethane and ethyl acetate as eluants to provide the expected product in the form of a solid.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.55 (s, 1H, pyrazole); 7.23 (s, 1H, pyrazole); 7.18 (broad s, 1H, NH -Ph);6.64 (m, 4H, aromatic Hs); 3.77 (s, 3H, CH -pyrazole); 0.90 (s, 9H, Si (CH ) CH(CH ) ); 0.12 (s, 6H, Si (CH ) CH(CH ) ) 2 2 3 2 2 2 3 2 + -1 -1 -1 IR: ν -NH : 3275 cm ; ν Ar and C=N: 1577 and 1502 cm ; ν -Si-C-: 1236 cm ; ν -Si-O- -1 -1 : 898 cm ; ν -Si-C-: 828, 774 cm P Pr re ep pa ar ra at tiio on n 2 2'''': :4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }- -N N- -p ph he en ny ylla an niilliin ne e To a solution of 12 g of 4-anilinophenol (64.7 mmol) in 200 mL of acetonitrile there are added, at ambient temperature, 6.7 g of imidazole (97.05 mmol) and 11.7 g of tert-butyl(dimethyl)silyl chloride (77.64 mmol).
The batch is stirred at 70°C for 4 hours. The reaction mixture is then poured into water and extracted with ether. The organic phase is then dried over MgSO , then filtered and evaporated to dryness. The crude product thereby obtained is then purified by chromatography over silica gel using petroleum ether and dichloromethane as eluants. The title product is obtained in the form of a powder.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.84 (s, 1H NH); 7.17 (t, 2H aniline); 6.98 (d, 2H phenoxy); 6.94 (d, 2H aniline); 6.76 (d, 2H phenoxy); 6.72(t, 1H aniline); 0.95 (s, 9H tert- butyl); 0.15 (s, 6H dimethyl) -1 -1 IR: ν: >NH: 3403 cm ; ν:>Ar: 1597 cm P Pr re ep pa ar ra at tiio on n 3 3'''': :tte er rtt- -B Bu utty yll 5 5- -[ [( (4 4- -{ {[ [tte er rtt- -b bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )a am miin no o] ]- -1 1H H- - indolecarboxylate indolecarboxylate The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by tert-butyl 5-bromo-1H-indolecarboxylate.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.85 (d, 1H); 7.78 (s, 1H); 7.55 (d, 1H); 7.15 (d, 1H); 6.95 (m, 3H); 6.75 (d, 2H); 6.58 (d, 1H); 1.65 (s, 9H); 1.00 (s, 9H); 0.2 (s, 6H) P Pr re ep pa ar ra at tiio on n 4 4'''': :N N- -( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )- -1 1- -m me et th hy yll- -1 1H H- -iin nd do oll- -5 5- - a am miin ne e The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 5-bromomethyl-1H-indole.
Preparation 5'':N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H-indazol Preparation 5'':N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H-indazol amine amine The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 5-bromomethyl-1H-indazole.
P Pr re ep pa ar ra at tiio on n 6 6'''': :N N- -( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )- -3 3- -f fllu uo or ro o- -4 4- -m me et th hy ylla an niilliin ne e The procedure is in accordance with the process of Preparation 1''', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 4-bromofluoromethylbenzene.
P Pr re ep pa ar ra at tiio on n 7 7'''': :N N- -( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )- -3 3- -f fllu uo or ro oa an niilliin ne e The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 1-bromofluorobenzene.
P Pr re ep pa ar ra at tiio on n 8 8'''': :4 4- -B Be en nz zy yllo ox xy y- -N N- -p ph he en ny yll- -a an niilliin ne e To a solution of 4-hydroxy-N-phenyl-aniline (30 g; 162 mmol) in acetonitrile (400 mL) there are added 58 g of Cs CO (178 mmol) and stirring is carried out for 15 minutes at ambient temperature. Benzyl bromide (22.5 mL; 178 mmol) is then added dropwise and then the reaction mixture is refluxed for 4 hours. After filtering and rinsing with acetonitrile, the filtrate is concentrated and purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The title product is then obtained in the form of a colourless solid.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.80 (m, 1H, NH); 7.45 (m, 2H, aryl); 7.40 (m, 2H, aryl); 7.30 (m, 1H, aryl); 7.15 (s, 2H, aryl); 7.05 (d, 2H, aryl); 6.9-7.0 (m, 4H, aryl); 6.70 (t, 1H, aryl); 5.05 (s, 2H, benzyl).
IR: ν: >NH: 3408 cm P Pr re ep pa ar ra at tiio on n 9 9'''': N N- -( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )p py yr riid diin n- -4 4- -a am miin ne e The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 4-bromopyridine. -1 -1 -1 IR: ν -NH-: 3200 and 2500 cm ; ν:-Si-O-: 902 cm ; ν:-Si-C-: 820 cm Preparation 10'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)fluoroaniline Preparation 10'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)fluoroaniline The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 1-bromofluorobenzene.
Preparation 11'':N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H- Preparation 11'':N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -a am miin ne e The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 5-bromomethyl-1H-pyrrolo[2,3-b]pyridine (obtained in accordance with a protocol from the literature: Heterocycles, 60(4), 865, 2003). -1 -1 IR: ν:-NH-: 3278 cm ; ν: aromatic -C=C- moieties: 1605 cm P Pr re ep pa ar ra at tiio on n 1 12 2'''': :N N- -( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )- -2 2- -m me et th ho ox xy yp py yr riim miid diin n- -5 5- - a am miin ne e The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 5-bromomethoxypyrimidine.
Preparation 13'':N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-2,3-dihydro- Preparation 13'':N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridinamine 1H-pyrrolo[2,3-b]pyridinamine The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 5-bromomethyl-2,3-dihydro-1H-pyrrolo- [2,3-b]pyridine.
P Pr re ep pa ar ra at tiio on n 1 14 4'''': :N N- -( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )- -1 1- -m me et th hy yll- -1 1H H- - b be en nz ziim miid da az zo oll- -5 5- -a am miin ne e The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 5-bromomethyl-1H-benzimidazole. 4 4 2 2 2 2 Preparation 15'':N -(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-N ,N -dimethyl- Preparation 15'':N -(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-N ,N -dimethyl- pyridine-2,4-diamine pyridine-2,4-diamine The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 4-bromo-N,N-dimethylpyridinamine.
P Pr re ep pa ar ra at tiio on n 1 16 6'''': :N N- -( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )p py yr ra az zo ollo o[ [1 1,,5 5- -a a] ]- - p py yr riim miid diin n- -6 6- -a am miin ne e The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 6-bromopyrazolo[1,5-a]pyrimidine. -1 -1 -1 IR: ν -NH-: 3272 cm ; ν -C=N-: 1634 cm ; ν -C=C-: 1616 cm Preparation 17'':N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]methyl-pyrazolo[3,4- Preparation 17'':N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]methyl-pyrazolo[3,4- b b] ]p py yr riid diin n- -5 5- -a am miin ne e The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 5-bromomethyl-pyrazolo[3,4-b]pyridine (obtained in accordance with a protocol from the literature: starting from 2-methyl-pyrazolamine and 2-bromopropanedial).
Preparation 18'':4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-1H- Preparation 18'':4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-1H- p py yr rr ro olle e- -2 2- -c ca ar rb bo on niit tr riille e Step A: 4-Bromo-1,5-dimethyl-1H-pyrrolecarbonitrile 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 1,5-dimethyl-1H-pyrrolecarbonitrile (15.0 g, 0.12 mol) in acetic acid (300 mL). The batch is stirred at ambient temperature for 24 hours. The reaction mixture is then poured into a beaker containing 300 mL of water. The solid formed is filtered off and rinsed with water. It is then dissolved in dichloromethane (300 mL) and the organic phase is washed with brine, dried over Na SO , filtered and concentrated in vacuo to yield the expected product in the form of a solid.
H NMR (CDCl ) 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)-1,5-dimethyl-1H-pyrrole carbonitrile A solution of the compound of the above Step (1.5 g, 7.53 mmol), 4-[(tert- butyldimethylsilyl)oxy]aniline (2.02 g, 9.04 mmol), sodium tert-butylate (1.45 g, .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)- dipalladium(0) (0.28 g, 0.30 mmol) is added, and then the reaction mixture is heated at 90˚C until the reaction is complete (monitored by TLC). Heating is stopped and the mixture is allowed to return to ambient temperature. 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 onto silica gel and purified by chromatography over silica gel using ethyl acetate and heptane as eluants. The product thereby obtained is dissolved in heptane in the warm state and is allowed to precipitate, with stirring, at ambient temperature, and then at 0˚C. The solid is filtered off and the operation is repeated on the filtrate to yield the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) 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) C NMR (100 MHz, CDCl ) 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 P Pr re ep pa ar ra at tiio on n 1 19 9'''': : 4 4- -[ [( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )a am miin no o] ]- -1 1- -m me et th hy yll- -1 1H H- - p py yr rr ro olle e- -2 2- -c ca ar rb bo on niit tr riille e Step A: 1-Methyl-1H-pyrrolecarbonitrile N,N-Dimethylformamide (3 mL) and 1,4-diazabicyclo[2.2.2]octane (0.49 g, 4.3 mmol) are added to a solution of pyrrolecarbonitrile (4 g, 43.4 mmol) in dimethyl carbonate (56 mL). The solution is stirred at 90°C for 15 hours, and is then heated at 110°C for 8 hours. The mixture is cooled to ambient temperature, and then ethyl acetate (80 mL) is added. The phases are separated and the organic phase is washed with water (2 x 80 mL) and 1N aqueous HCl solution (1 x 80 mL). The combined aqueous phases are extracted again with ethyl acetate (1 x 80 mL). The combined organic phases are washed with brine (1 x 80 mL), dried over MgSO , filtered and concentrated in vacuo to obtain the expected product in the form of a liquid.
H NMR (400 MHz, CDCl ) δ ppm: 3.78 (m, 2 H), 6.12 - 6.18 (m, 1 H), 6.74 - 6.82 (m, 1 H) Step B: 4-Bromomethyl-1H-pyrrolecarbonitrile N-Bromosuccinimide (6.2 g, 34.9 mmol) is added to a solution of 1-methyl-1H-pyrrole carbonitrile (3.7 g, 34.9 mmol) in N,N-dimethylformamide (150 mL). The solution is stirred for 15 hours at ambient temperature. Another amount of N-bromosuccinimide (2.0 g, 11 mmol) is added and the mixture is stirred for 3 hours. Silica (7 g) is then added and the suspension is then evaporated to dryness. The material pre-absorbed onto the silica is placed on a silica gel column and the product is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain the expected product in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 3.77 (s, 3 H), 6.75 (d, J = 1.7 Hz, 1 H), 6.80 (d, J = 1.7 Hz, 1 H) Step C: 4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)methyl-1H-pyrrole carbonitrile Nitrogen is bubbled through a solution of 4-bromomethyl-1H-pyrrolecarbonitrile (2.82 g, 15.2 mmol) and 4-[(tert-butyldimethylsilyl)oxy]aniline (4.08 g, 18.3 mmol) in toluene (55 mL) for 5 minutes. Sodium tert-butylate (2.92 g, 30.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (556 mg, 0.6 mmol) and 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl (255 mg, 0.6 mmol) are then added to the reaction mixture. The mixture is stirred for 1 hour at 80 C under nitrogen. The suspension is then cooled to ambient temperature and filtered over Celite. The Celite cake is then rinsed with ethyl acetate. The filtrate is washed with water and then with brine. The organic phase is dried over MgSO , filtered and concentrated in vacuo. The product is purified twice by chromatography over silica gel using ethyl acetate and heptane as eluants, and then by trituration in heptane to obtain the expected product in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 0.16 (s, 6 H), 0.97 (s, 9 H), 3.73 (s, 3 H), 6.57 (d, J = 1.9 Hz, 1 H), 6.64 - 6.66 (m, 1 H), 6.70 (s, 4 H); NMR C NMR (100 MHz, CDCl ) δ ppm: -4.48, 18.17, 25.72, 35.46, 103.01, 113.56, 113.69, 115.92, 119.55, 120.67, 129.04, 139.94, 148.85 MS (ESI+): [M+H] 328.25 Preparation 20'': N-[4-[tert-Butyl(dimethyl)silyl]oxyfluoro-phenyl]methyl-1H- pyrazolamine The procedure is in accordance with the protocol of Preparation 1'', replacing the 4- aminophenol used in Step A by 2-fluoroaminophenol.
H NMR (400 MHz, dmso-d6) δ ppm: 7.59 (bs, 1 H), 7.39 (m, 1 H), 7.24 (d, 1 H), 6.74 (dd, 1 H), 6.52 (dd, 1 H), 6.42 (ddd, 1 H), 3.76 (s, 3 H), 0.92 (s, 9 H), 0.1 (d, 6 H) Preparation 21'': 2-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyridine carbonitrile A solution composed of 2-bromopyridinecarbonitrile (5.00 g, 36.1 mmol), 4-[(tert- butyldimethylsilyl)oxy]aniline (8.06 g, 36.1 mmol), sodium tert-butylate (4.50 g, 46.9 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.458 g, 1.08 mmol) in toluene (50 mL) is purged with nitrogen. Tris(dibenzylideneacetone)- dipalladium(0) (0.99 g, 1.08 mmol) is then added to the reaction mixture, and then the batch is heated at 50˚C for 1.5 hours. The mixture is then allowed to cool to ambient temperature. Water is added and the reaction mixture is extracted with ethyl acetate (3 x 20 mL). The combined organic phases are washed with brine, and then concentrated under reduced pressure. The crude product is absorbed onto silica gel and purified by chromatography over silica gel using ethyl acetate and heptane as eluants. The product obtained is dissolved in the warm state in heptane and precipitates, with stirring, at ambient temperature, and then at 0˚C. After filtration, the expected compound is obtained in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 0.22 (s, 6 H), 1.00 (s, 9 H), 6.61 (br. s, 1 H), 6.81 - 6.84 (m, 2 H), 6.84 - 6.89 (m, 2 H), 7.12 - 7.17 (m, 2 H), 8.26 (dd, J = 5.1, 0.9 Hz, 1 H) C NMR (100 MHz, CDCl ) δ ppm: -4.29, 18.31, 25.78, 109.11, 114.73, 117.23, 121.17, 121.74, 124.93, 132.12, 149.79, 153.45, 158.00 MS (ESI+): [M+H] 326.19 Preparation 22'': N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]tetrahydrofuranyl- pyrazolamine 4-[tert-Butyl(dimethyl)silyl]oxyaniline (0.92 g, 3.48 mmol) and 4-iodotetrahydrofuran- 3-yl-pyrazole (0.78 g, 3.48 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) are stirred for one hour at ambient temperature in the presence of sodium tert-butylate (1.7 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl- 1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (84 mg, 0.122 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is crystallised from a mixture of heptane/ethyl acetate, filtered and washed with heptane and then purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the expected product.
H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.62 (d, 1H, pyrazole-H5), 7.29 (d, 1H, pyrazole-H3), 7.26 (s, 1H, NH), 6.68 (d, 2H, Ar-H), 6.64 (d, 2H, Ar-H), 4.93 (m, 1H, THF- 3'H), 3.95 (m, 1H, THF-5'H), 3.94 (m, 1H, THF-2'H), 3.87 (m, 1H, THF-2'H), 3.80 (m, 1H, THF-5'H), 2.33 (m, 1H, THF-4'H), 2.27 (m, 1H, THF-4'H), 0.93 (s, 9H, Bu), 0.12 (s, 6H, Me) -1 -1 -1 IR: ν C-H: 2857 cm ; ν aromatic: 1505 cm ; ν Si-C: 1249 cm Preparation 23'': 6-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyridine carbonitrile 4-Aminophenol (3.3 g, 30.2 mmol) is added to a solution of 6-chloropyridine carbonitrile (3.5 g, 25.3 mmol) in 1-methylpyrrolidinone (70 mL). The reaction mixture is heated at 140-150°C for 16 hours in a sealed flask. The batch is then cooled to ambient temperature. Imidazole (3.4 g, 49.9 mmol) and tert-butyl(dimethyl)silyl chloride (7.6 g, 50.4 mmol) are subsequently added and the mixture is stirred for 16 hours at ambient temperature. The mixture is diluted with water (140 mL) and the product is extracted with AcOEt (4 x 50 mL). The organic phases are combined and washed with water (3 x 50 mL), and then brine (1 x 50 mL). The organic phase is then dried over MgSO , filtered and concentrated in vacuo. The crude product is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain the title product.
H NMR (400 MHz, CDCl ) δ ppm: 0.20 (s, 6 H), 0.99 (s, 9 H), 6.74 (dd, J = 7.6, 4.9 Hz, 1 H), 6.81 - 6.88 (m, 3 H), 7.36 - 7.42 (m, 2 H), 7.74 (dd, J = 7.6, 1.9 Hz, 1 H), 8.34 (dd, J = 4.9, 1.9 Hz, 1 H) C NMR (100 MHz, CDCl ) δ ppm: -4.38, 18.21, 25.73, 92.58, 113.50, 116.53, 120.30, 123.20, 131.97, 141.67, 152.42, 152.45, 156.51 MS (ESI): [M+H] 326.24 Preparation 24'': 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyrimidine carbonitrile Step A: N-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}chloropyrimidinamine 4-Aminophenol (8.8 g, 80.6 mmol) and triethylamine (18.6 mL, 133.4 mmol) are added to a solution of 2,4-dichloropyrimidine (10.0 g, 67.1 mmol) in ethanol (150 mL).The reaction mixture is heated at 150°C for 14 hours in a sealed flask. The batch is then cooled to ambient temperature and the solvent is evaporated off in vacuo. Dichloromethane (200 mL) is added to the residue, and then imidazole (9.1 g, 133.7 mmol) and tert- butyl(dimethyl)silyl chloride (12.1 g, 80.3 mmol) are added. The mixture is stirred for 15 hours at ambient temperature. The reaction mixture is diluted with water (200 mL). The phases are separated and the organic phase is washed with brine (1 x 100 mL). It is then dried over MgSO , filtered and concentrated in vacuo. The residue is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain a solid.
The latter is triturated in heptane, filtered off and rinsed with heptane to yield the expected compound in the form of a solid.
H NMR (400 MHz, dmso-d6) δ ppm: 0.22 (s, 6 H), 0.99 (s, 9 H), 6.42 (d, J = 5.9 Hz, 1 H), 6.81 (br. s, 1 H), 6.85 - 6.90 (m, 1 H), 7.13 (d, J = 8.7 Hz, 2 H), 8.07 (d, J = 5.9 Hz, 2 H) Step B: 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyrimidinecarbonitrile Anhydrous N,N-dimethylformamide (10 mL) is placed under nitrogen in a flask and then the compound of Step A (670 mg, 2.0 mmol) is added. Zinc cyanide (468 mg, 4.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (404 mg, 0.3 mmol) are subsequently added.
Nitrogen is bubbled through the solution for 5 minutes and then the reaction mixture is stirred at 120 C for 2 hours under a nitrogen atmosphere. The reaction, monitored by LC- MS, is complete. The mixture is cooled to ambient temperature, and then water (15 mL) is added thereto. The product is extracted with AcOEt (3 x 25 mL). The organic phases are combined and washed with water (4 x 25 mL), and then with brine (1 x 25 mL). The organic phase is dried over MgSO , filtered and concentrated in vacuo. The residue is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 0.22 (s, 6 H), 0.99 (s, 9 H), 6.63 (d, J = 6.1 Hz, 1 H), 6.86 - 6.92 (m, 2 H), 7.03 (br. s, 1 H), 7.17 (d, J = 8.5 Hz, 2 H), 8.22 (d, J = 6.1 Hz, 1 H) C NMR (100 MHz, CDCl ) δ ppm: -4.51, 18.10, 25.55, 106.32, 115.92, 121.00, 125.22, 129.73, 144.55, 154.16, 156.07, 161.56 Preparation 25'': N-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}trideuteriomethyl-1H- pyrazolamine Step A: 4-Bromotrideuteriomethyl-1H-pyrazole 4-Bromo-1H-pyrazole (9.05 g, 61.6 mmol) is added in portions to a suspension of NaH (60 % in oil) (2.83 g, 70.8 mmol) in tetrahydrofuran (90 mL) cooled in an ice bath. After having taken away the ice bath, the solution is stirred at ambient temperature for 0.5 hours.
It is again cooled in an ice bath and iodomethane-d (5.0 mL, 80.3 mmol) is added. The solution is stirred at ambient temperature for 19 hours. The suspension is then concentrated. The evaporation residue is triturated with MTBE (90 mL) and filtered. The filtrate is concentrated in vacuo to obtain the expected compound in the form of an oil.
H NMR (400 MHz, CDCl ) δ ppm: 7.37 (s, 1 H), 7.43 (s, 1 H) Step B: N-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}trideuteriomethyl-1H-pyrazol amine 4-Bromotrideuteriomethyl-1H-pyrazole (9.6 g, 58.5 mmol), 4-[(tert-butyldimethyl- silyl)oxy]aniline (14.4 g, 64.6 mmol) and toluene (150 mL) are added to a 500-ml three- necked flask. The solution is degassed with nitrogen for 15 minutes, and then sodium tert- butylate (11.4 g, 0.12 mol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.77 g, 1.81 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.64 g, 1.79 mmol) are successively added. The suspension is heated at 85°C for 1.5 hours. The reaction mixture is then cooled to ambient temperature and water (270 mL) is added. The mixture is stirred for minutes. Celite (30 g) is then added and the suspension is filtered on a bed of Celite.
The phases of the filtrate are separated and the aqueous phase is extracted with ethyl acetate (3 x 200 mL). The combined organic phases are dried over Na SO and filtered.
Silica (36 g) is added to the filtrate and the batch is evaporated to dryness. The product is purified by chromatography over silica gel using ethyl acetate and heptane as eluants. The product obtained is recrystallised from heptane (80 mL) to obtain the expected compound.
H NMR (400 MHz, CDCl ) δ ppm: 0.16 (s, 6 H), 0.97 (s, 9 H), 4.92 (s, 1 H), 6.61 – 6.73 (m, 4 H), 7.25 (s, 1 H), 7.36 (s, 1 H) 13 1 C NMR (100 MHz, CDCl ) δ ppm: -4.37, 18.28, 25.86, 38.67 (sept., J = 21.0 Hz), 3 C-D 115.12, 120.73, 123.76, 126.52, 134.74, 141.07, 148.43 MS (ESI): [M+H] 307.08 Preparation 26'': N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl](oxetanyl)-1H- pyrazolamine Step A: 4-Bromo(oxetanyl)-1H-pyrazole 4-Bromo-1H-pyrazole (1.53 g, 10.7 mmol) is dissolved in anhydrous dimethylformamide (15 mL). 3-Bromooxetane (2.0 g, 14.6 mmol) and caesium carbonate (4.7 g, 14 mmol) are successively added thereto. The reaction mixture is heated for 8 hours at 130°C in a sealed flask. At the end of the reaction, the solvent is evaporated off in vacuo and the residue is purified by chromatography over silica gel using dichloromethane containing diethylamine and methanol as eluants to yield the expected compound.
Step B: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl](oxetanyl)-1H-pyrazolamine 4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.5 g, 7.2 mmol) and 4-bromo(oxetanyl)- pyrazole (1.6 g, 7.2 mmol) dissolved in anhydrous tetrahydrofuran (25 mL) are stirred for 3 hours at ambient temperature in the presence of sodium tert-butylate (3.7 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1'-biphenyl)[2- (2-aminoethyl)phenyl]palladium(II) (101 mg, 0.145 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is purified by chromatography over silica gel using dichloromethane containing diethylamine and ethyl acetate as eluants to yield the expected product.
H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.76 (s, 1H, pyrazole-5'H), 7.40 (s, 1H, pyrazole-3'H), 7.34 (br s, 1H, NH), 6.70 (d, 2H, Ar-H), 6.65 (d, 2H, Ar-H), 5.49 (m, 1H, oxetane), 4.89 (d, 4H, oxetane), 0.93 (s, 9H, Bu), 0.13 (s, 6H, Me) -1 -1 -1 IR: ν: C-H: 2955 cm ; aromatic: 1505 cm ; Si-C: 1237 cm Preparation 27'': Mixture of N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,5- Preparation 27'': Mixture of N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,5- d diim me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -a am miin ne e a an nd d N N- -( (4 4- -{ {[ [tte er rtt- -b bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )- -1 1,,3 3- - d diim me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -a am miin ne e Step A: Mixture of 4-bromo-1,5-dimethyl-1H-pyrazole and 4-bromo-1,3-dimethyl-1H- pyrazole To a suspension of NaH 60 % in oil (0.3 g; 7.45 mmol) in tetrahydrofuran (150 mL) there is added, at 10°C, 4-bromomethyl-1H-pyrazole dissolved in 15 mL of tetrahydrofuran dropwise, over 15 minutes. After stirring for 40 minutes at ambient temperature, iodomethane (0.45 mL; 7.45 mmol) is added dropwise, and then the reaction mixture is stirred overnight. After adding water, the reaction mixture is evaporated and taken up in dichloromethane. The organic phase is separated off and dried over MgSO , filtered and concentrated to dryness. The residue is purified by chromatography over silica gel to yield a mixture of the title compounds (4-bromo-1,3-dimethyl-pyrazole and 4-bromo-1,5- dimethyl-pyrazole respectively in a ratio of 4:6). 4-bromo-1,5-dimethyl-1H-pyrazole: H NMR (500 MHz, dmso-d6) δ ppm: 7.41 (s, 1 H), 3.76 (s, 3 H), 2.22 (s, 3 H) 4-bromo-1,3-dimethyl-1H-pyrazole: H NMR (500 MHz, dmso-d6) δ ppm: 7.81 (s, 1 H), 3.74 (s, 3 H), 2.09 (s, 3 H) Step B: Mixture of N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,5-dimethyl-1H-pyrazol- 4-amine and N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,3-dimethyl-1H-pyrazol amine The procedure is in accordance with Step B of Preparation 1'', replacing the 4-bromo methyl-1H-pyrazole by the mixture of isomers from Step A. A mixture of isomers in a ratio of 4:6 is obtained (respectively N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,5- dimethyl-1H-pyrazolamine and N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,3- dimethyl-1H-pyrazolamine).
Preparation 28'': N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]cyclopropyl-1H- pyrazolamine Step A: 4-Bromocyclopropyl-1H-pyrazole 4-Bromo-1H-pyrazole (1.76 g, 12 mmol) is dissolved in anhydrous dimethylformamide (15 mL). Cyclopropyl bromide (2.9 mL, 36 mmol) and caesium carbonate (7.8 g, 24 mmol) are successively added thereto. The reaction mixture is heated for 15 hours at 160°C in a sealed flask. At the end of the reaction, the solvent is evaporated off in vacuo and the residue is purified by chromatography over silica gel using heptane and dichloromethane as eluants to yield the expected compound.
Step B: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]cyclopropyl-1H-pyrazolamine 4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.64 g, 7.3 mmol) and 4-bromocyclopropyl-1H- pyrazole (1.4 g, 7.3 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) are stirred for 3 hours at ambient temperature in the presence of sodium tert-butylate (3.7 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1'-biphenyl)[2- (2-aminoethyl)phenyl]palladium(II) (101 mg, 0.146 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is purified by chromatography over silica gel using heptane and ethyl acetate as eluants to yield the expected product.
H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.61 (s, 1H, pyrazole-5'H), 7.23 (s, 1H, pyrazole-3'H), 7.22 (br s, 1H, NH), 6.65 (d, 2H, Ar-H), 6.63 (d, 2H, Ar-H), 3.64 (m, 1H, cyclopropyl-H), 1.00 – 0.91 (m, 4H, cyclopropyl), 0.93 (s, 9H, Bu), 0.12 (s, 6H, Me) -1 -1 -1 IR: ν: C-H: 2930 cm ; aromatic: 1504 cm ; Si-C: 1237 cm High-resolution mass spectrometry (ESI+): Empirical formula: C H N OSi 18 27 3 [M+H] calculated: 330.2003 [M+H] measured: 330.1989 Preparation 29'': 1,5-Dimethyl(phenylamino)-1H-pyrrolecarbonitrile The procedure is in accordance with the protocol of Preparation 1'', replacing the 4-{[tert- butyl(dimethyl)silyl]oxy}aniline used in Step B by aniline.
H NMR (400 MHz, dmso-d6) δ ppm: 7.19 (s, 1 H), 7.05 (t, 2 H), 6.79 (s, 1 H), 6.6 (m, 3 H), 3.61 (s, 3 H), 2.1 (s, 3 H) Preparation 30'': 1-Methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridinamine The procedure is in accordance with the protocol of Step B of Preparation 1'' using aniline and 5-bromomethyl-1H-pyrrolo[2,3-b]pyridine (obtained in accordance with a protocol from the literature: Heterocycles, 60(4), 865, 2003).
H NMR (400 MHz, dmso-d6) δ ppm: 8.1 (d, 1 H), 7.9 (s, 1 H), 7.7 (d, 1 H), 7.45 (d, 1 H), 7.17 (t, 2 H), 6.9 (d, 2 H), 6.7 (t, 1 H), 6.38 (d, 1 H), 3.8 (s, 3 H) Preparation 31'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)trideuteriomethyl- 1H-pyrrolo[2,3-b]pyridinamine The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 5-bromo(trideuteriomethyl)-1H-pyrrolo[2,3- b]pyridine (obtained in accordance with a protocol from the literature Heterocycles, 60(4), 865, 2003, replacing the methyl iodide by trideuterated methyl iodide).
H NMR (400 MHz, dmso-d6) δ ppm: 8.05 (d, 1 H), 7.6 (m+d, 2 H), 7.4 (d, 1 H), 6.85/6.7 (2d, 4 H), 6.3 (d, 1 H), 0.95 (s, 9 H), 0.15 (s, 6 H) Preparation 32'': 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)trideuterio- methyl-1H-pyrrolecarbonitrile Step A: 1-Trideuteriomethyl-1H-pyrrolecarbonitrile NaH (60 % in oil) (2.61 g, 65.2 mmol) is suspended in tetrahydrofuran (110 mL) at 0°C. 1H-Pyrrolecarbonitrile (5 g, 54.3 mmol) is added dropwise over 10 minutes. The reaction mixture is then warmed up to ambient temperature over 30 minutes. It is again cooled to 0°C, and then iodomethane-d (10.23 g, 70.6 mmol) is added. The reaction mixture is stirred for 16 hours under nitrogen at ambient temperature. The reaction mixture is then evaporated under reduced pressure, and then ethyl acetate (200 mL) and water (200 mL) are added. The phases are separated, and the aqueous phase is extracted with ethyl acetate (2 x 200 mL). The combined organic phases are washed with brine (1 x 80 mL), dried over MgSO , filtered and concentrated in vacuo. The residue is purified by chromatography over silica gel using ethyl acetate and heptane as eluants. The fractions are combined and evaporated in vacuo to obtain the expected compound.
H NMR (400 MHz, CDCl ) δ ppm: 6.13 (dd, J = 2.7, 3.9 Hz, 1 H), 6.75 (dd, J = 1.5, 4.1 Hz, 1 H), 6.79 (dd, J = 1.7, 2.6 Hz, 1 H) Step B: 4-Bromotrideuteriomethyl-1H-pyrrolecarbonitrile N-Bromosuccinimide (6.68 g, 37.5 mmol) is added to a solution of the compound of the above Step (4.09 g, 37.5 mmol) in N,N-dimethylformamide (188 mL). The solution is stirred for 16 hours at ambient temperature. The residue is purified by chromatography using ethyl acetate and heptane as eluants to obtain the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 6.75 (d, J = 1.7 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1 H) Step C: 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)trideuteriomethyl-1H- pyrrolecarbonitrile Nitrogen is bubbled through a solution composed of the compound obtained in the above Step (5.85 g, 31.1 mmol), 4-[(tert-butyldimethylsilyl)oxy]aniline (8 g, 35.8 mmol), sodium tert-butylate (3.88 g, 40.4 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (662 mg, 1.56 mmol) in toluene (260 mL) for 5 minutes. Tris(dibenzylideneacetone)- dipalladium(0) (1.43 g, 1.56 mmol) is then added. The mixture is stirred for 1 hour at 70°C under nitrogen. The suspension is then cooled to ambient temperature, diluted with ethyl acetate and filtered over Celite. The Celite cake is then rinsed with ethyl acetate. The filtrate is washed with water (3 times), and then brine (once). The organic phase is dried over Na SO , filtered and concentrated in vacuo. The product is purified twice by chromatography over silica gel using ethyl acetate and heptane as eluants, and then by reverse-phase chromatography using methanol and water as eluants to obtain the expected compound in the form of a powder.
H NMR (400 MHz, CDCl ) δ ppm: 0.17 (s, 6 H), 0.98 (s, 9 H), 4.96 (br. s, 1 H), 6.57 (d, J = 1.9 Hz, 1 H), 6.64 (d, J = 1.8 Hz, 1 H), 6.70 (br. s, 4 H) C NMR (100 MHz, CDCl ) δ ppm: -4.38, 18.26, 25.83, 34.83, 102.96, 113.69, 113.71, 115.95, 119.58, 120.75, 129.14, 140.10, 148.84 MS (ESI): [M+H] 331.09 Preparation 33'': 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)trideuterio- methylmethyl-1H-pyrrolecarbonitrile Step A: 5-Methyl-1H-pyrrolecarbonitrile The compound is prepared in accordance with the protocol described in Heterocycles 2011, 82, 1503.
Step B: 1-Trideuteriomethylmethyl-1H-pyrrolecarbonitrile A solution of 5-methyl-1H-pyrrolecarbonitrile (0.30 g, 2.82 mmol) in N,N-dimethyl- formamide (5 mL) is cooled to 0˚C. NaH (60 % in oil) (0.118 g, 2.96 mmol) is added in portions, and the reaction mixture is stirred at 0°C for 30 minutes. Iodomethane-d (4.15 mL, 67.2 mmol) is added in a single portion, and the reaction mixture is stirred at ambient temperature until the reaction is complete. It is then diluted with water (30 mL) and ethyl acetate (15 mL). The phases are separated and the aqueous phase is extracted a second time with ethyl acetate (15 mL). The combined organic phases are washed with water (1 x 50 mL), and then brine, and dried over Na SO . After filtration and concentration under reduced pressure, the residue is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to yield the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 2.25 (s, 3 H), 5.91 (dd, J = 3.9, 0.6 Hz, 1 H), 6.69 (d, J = 3.9 Hz, 1 H) Step C: 4-Bromotrideuteriomethylmethyl-1H-pyrrolecarbonitrile A solution of bromine (0.133 mL, 2.60 mmol) in acetic acid (1.5 mL) is added dropwise to a solution of the compound obtained in the above Step (0.305 g, 2.48 mmol) in acetic acid (5.5 mL) previously cooled to 0°C. The reaction mixture is stirred and gradually warmed up to ambient temperature over a period of 20 hours. The reaction mixture is poured into water (50 mL) and the mixture is extracted with dichloromethane (2 x 50 mL). The organic phase is dried over Na SO , filtered and concentrated under reduced pressure to yield the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 2.24 (s, 3 H), 6.73 (s, 1 H) Step D: 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)trideuteriomethylmethyl- 1H-pyrrolecarbonitrile A solution composed of the compound obtained in the above Step (7.00 g, 34.6 mmol), 4- [(tert-butyldimethylsilyl)oxy]aniline (8.90 g, 39.8 mmol), sodium tert-butylate (4.33 g, 45.0 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.441 g, 1.04 mmol) in toluene (70 mL) is purged with nitrogen. Tris(dibenzylideneacetone)- dipalladium(0) (0.951 g, 1.04 mmol) is added, and then the reaction mixture is heated at 65°C until the reaction, monitored by TLC, is complete. Heating is stopped and the mixture is cooled to ambient temperature. Water (200 mL) is added and the mixture is extracted with ethyl acetate (3 times). The combined organic phases are washed with brine, and then concentrated. The crude product is purified by chromatography over silica gel using ethyl acetate and heptane as eluants. The product obtained is dissolved in heptane in the warm state; it is allowed to precipitate out at ambient temperature and then at 0˚C to yield the expected product in the form of crystals.
H NMR (400 MHz, CDCl ) δ ppm: 0.15 (s, 6 H), 0.96 (s, 9 H), 2.12 (s, 3 H), 4.66 (br. s, 1 H), 6.46 - 6.51 (m, 2 H), 6.64 (s, 1 H), 6.64 - 6.69 (m, 2 H) C NMR (100 MHz, CDCl ) δ ppm: -4.37, 9.64, 18.26, 25.84, 31.62 - 32.87 (m), 101.14, 114.35, 114.66, 116.33, 120.68, 124.51, 131.17, 141.53, 148.18 MS (ESI): [M+H] 345.13 Preparation 34'': 5-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]methyl-1H- pyrazolecarbonitrile Step A: 5-Aminomethyl-1H-pyrazolecarbonitrile To a suspension of 1-methylnitro-1H-pyrazolecarbonitrile (2 g; 13.1 mmol) in a mixture of water (14 mL) and ethanol (120 mL) there are added HCl 37 % (170 µL) and iron filings (5.1 g; 91 mmol). The reaction mixture is heated for 5 hours at 50°C. After cooling to ambient temperature, the reaction mixture is filtered. The filtrate is concentrated to dryness and then purified by chromatography over silica gel using dichloromethane and ethyl acetate as eluants to yield the expected compound in the form of a solid.
H NMR (400 MHz, dmso-d6) δ ppm: 5.8 (s, 1 H), 5.7 (m, 2 H), 3.6 (s, 3 H) Step B: 5-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]methyl-1H-pyrazole carbonitrile The procedure is in accordance with the protocol of Step B of Preparation 1'', replacing the 4-bromomethyl-1H-pyrazole by (4-bromophenoxy)-(tert-butyl)dimethyl-silane and the 4-{[tert-butyl(dimethyl)silyl]oxy}aniline by the compound from Step A.
H NMR (400 MHz, dmso-d6) δ ppm: 8.15 (s, 1 H), 6.9 (d, 2 H), 6.75 (d, 2 H), 6.45 (s, 1 H), 3.75 (s, 3 H), 0.95 (s, 9 H), 0.15 (s, 6 H) Preparation 35'': 4-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]methyl[2- (morpholinyl)ethyl]-1H-pyrrolecarbonitrile The procedure is in accordance with the process of Preparation 33'', replacing the iodomethane-d in Step B by 2-(chloroethyl)morpholine hydrochloride.
H NMR (400 MHz, dmso-d6) δ ppm: 6.85 (s, 1 H), 6.75 (s, 1 H), 6.6 (d, 2 H), 6.5 (d, 2 H), 4.1 (t, 2 H), 3.55 (t, 4 H), 2.6 (t, 2 H), 2.4 (t, 4 H), 2.1 (s, 3 H), 0.9 (s, 9 H), 0.1 (s, 6 H) Preparation 36'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)[2-(morpholin yl)ethoxy]pyrimidinamine Step A: 4-[2-(5-Bromopyrimidinyl)oxyethyl]morpholine NaH (1.0 g, 25.0 mmol, 60 % in oil) suspended in anhydrous tetrahydrofuran is cooled at 0°C in an ice bath under argon, and then 2-morpholinoethanol (2.7 g, 20.7 mmol) is added dropwise. The ice bath is withdrawn and the suspension is stirred for 1 hour at ambient temperature. 5-Bromochloro-pyrimidine (4.0 g, 20.7 mmol) is then added at ambient temperature and the reaction mixture is stirred for 16 hours at ambient temperature.
Saturated aqueous ammonium chloride solution (10 mL) and water (10 mL) are added to the reaction mixture; the pH is adjusted to 9 by adding saturated aqueous NaHCO solution. The resulting solution is extracted 3 times with ethyl acetate, the organic phase is then washed with brine, dried over MgSO , and then evaporated to dryness. The expected compound precipitates out by means of the addition of petroleum ether.
H NMR (400 MHz, dmso-d6) δ ppm: 8.75 (s, 2 H), 4.4 (t, 2 H), 3.55 (t, 4 H), 2.7 (t, 2 H), 2.45 (t, 4 H) IR (ATR) cm 1562 ν >C=C< and C=N, 787 ν -C-H Ar Step B: N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)[2-(morpholinyl)ethoxy]- pyrimidinamine The procedure is in accordance with the protocol of Step B of Preparation 1'', replacing the 4-bromomethyl-1H-pyrazole by the compound from Step A.
H NMR (400 MHz, dmso-d6) δ ppm: 8.3 (s, 2 H), 7.8 (s, 1 H), 6.9/6.75 (2d, 4 H), 4.35 (t, 2 H), 3.55 (t, 4 H), 2.7 (t, 2 H), 2.45 (t, 4 H), 0.95 (s, 9 H), 0.15 (s, 6 H) IR (ATR) cm 3300 ν -NH, 1506 ν -NH, 837 ν -Si-Me, 837 and 778 ν -CH Ar Preparation 37'': 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,3-dimethyl-1H- pyrrolecarbonitrile Step A: 4-Methyl-N-(propenyl)benzenesulphonamide Allylamine (10.6 mL, 0.14 mol) is added over a period of 4 minutes to a solution of tosyl chloride (25.1 g, 0.13 mol) in dichloromethane (250 mL) cooled in an ice bath.
Triethylamine (24 mL, 0.18 mol) is added and then the solution is stirred at ambient temperature for 1.25 hours. Aqueous 3N HCl solution (60 mL) is added and the phases are then separated. The organic phase is washed with another amount of aqueous 3N HCl solution (60 mL) and then with 5 % aqueous sodium bicarbonate solution (60 mL). The organic phase is dried over Na SO , filtered and concentrated to obtain the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 2.43 (s, 3 H), 3.54 - 3.63 (m, 2 H), 4.50 (ls, 1 H), 5.05 - 5.22 (m, 2 H), 5.66 - 5.79 (m, 1H), 7.31 (d, J = 8.1 Hz, 2 H), 7.76 (d, J = 8.1 Hz, 2 H) Step B: 4-Methyl-N-(2-methylpropenyl)-N-(propenyl)benzene sulphonamide 3-Chloromethylpropene (20 mL, 0.20 mol) is added over a period of 5 minutes to a suspension of 4-methyl-N-(propenyl)benzenesulphonamide (27.9 g, 0.13 mol) and potassium carbonate (28.1 g, 0.20 mol) in N,N-dimethylformamide (200 mL) cooled in an ice bath. After 20 minutes, the suspension is stirred at ambient temperature for 18 hours.
The suspension is concentrated to dryness. The residue is taken up in ethyl acetate (250 mL) and water (110 mL). The aqueous phase is extracted with ethyl acetate (2 x 50 mL). The combined organic phases are washed successively with aqueous 3N HCl solution (50 mL), water (3 x 50 mL), aqueous 5 % potassium bicarbonate solution (50 mL), and finally brine (50 mL). The organic phase is dried over Na SO , filtered and concentrated to obtain the expected compound in the form of an oil.
H NMR (400 MHz, CDCl ) δ ppm: 1.69 (s, 3 H), 2.43 (s, 3 H), 3.70 (s, 2H), 3.75 - 3.79 (m, 2 H), 4.87 (d, J = 25.1 Hz, 1 H), 5.04 - 5.09 (m, 1 H), 5.09 - 5.12 (m, 1 H), 5.45 - 5.59 (m, 1H), 7.29 (d, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H) Step C: 3-Methyl(4-methylbenzenesulphonyl)-1H-pyrrole A solution of the compound obtained in Step B (15.2 g, 57.3 mmol) in toluene (550 mL) is heated at 80°C in the presence of (1,3-bis(2,4,6-trimethylphenyl)imidazolidinylidene)- dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (Grubbs' catalyst, 2nd generation) (150 mg, 0.18 mmol) for 1 hour. 2,3-Dichloro-5,6-dicyano-p-benzoquinone (16.1 g, 70.9 mmol) is then added in one portion, and the solution is heated at 80°C for 24 hours. The solution is filtered over Celite, and the filtrate is concentrated in vacuo. The product is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 2.02 (d, J = 1.0 Hz, 3 H), 2.39 (s, 3 H), 6.09 - 6.13 (m, 1H), 6.85 - 6.90 (m, 1 H), 7.03 - 7.07 (m, 1 H), 7.27 (d, J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H) Step D: 3-Methyl(4-methylbenzenesulphonyl)-1H-pyrrolecarbonitrile Aluminium chloride (19.4 g, 0.15 mol) is added all at once to a solution of 3-methyl(4- methylbenzenesulphonyl)-1H-pyrrole (13.0 g, 55.3 mmol) in 1,2-dichloroethane (230 mL) at ambient temperature. After stirring for 20 minutes, cyanogen bromide (11.11 g, 0.10 mol) is added in portions over a period of 20 minutes. After 4.5 hours, an additional amount of cyanogen bromide (1.94 g, 18.3 mmol) is added. After stirring for 17 hours at ambient temperature, the reaction mixture is poured slowly into a mixture of dichloromethane (300 mL) and water (600 mL) cooled to 0°C. The resulting mixture is stirred for 1 hour. Subsequently the phases are separated and the aqueous phase is extracted with dichloromethane (3 x 150 mL). The combined organic phases are washed with water (2 x 150 mL) and brine (150 mL). The organic phase is dried over Na SO , filtered and concentrated in vacuo to obtain the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 2.18 (s, 3 H), 2.43 (s, 3 H), 6.17 (d, J = 3.2 Hz, 1 H), 7.33 - 7.39 (m, 3 H), 7.90 (d, J = 8.5 Hz, 2 H) Step E: 4-Bromomethyl(4-methylbenzenesulphonyl)-1H-pyrrolecarbonitrile N-Bromosuccinimide (12.0 g, 67.4 mmol) is added all at once to a suspension of 3-methyl- 1-(4-methylbenzenesulphonyl)-1H-pyrrolecarbonitrile (14.45 g, 55.6 mmol) in N,N- dimethylformamide (60 mL) at ambient temperature. The mixture is stirred at ambient temperature for 29 hours and is then cooled in an ice bath. Saturated aqueous sodium bisulphite solution (90 mL), water (90 mL) and ethyl acetate (250 mL) are then added. The phases are separated, and then the aqueous phase is extracted with ethyl acetate (2 x 70 mL). The combined organic phases are washed with 5 % aqueous potassium bicarbonate solution (90 mL), water (3 x 90 mL), and then brine (3 x 90 mL). The organic phase is dried over Na SO , filtered and concentrated in vacuo. The crude product is purified by chromatography over silica gel using toluene and heptane as eluants to obtain the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 2.13 (s, 3 H), 2.45 (s, 3 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.43 (s, 1 H), 7.92 (d, J = 8.4 Hz, 2 H) Step F: 4-Bromo-1,3-dimethyl-1H-pyrrolecarbonitrile Potassium hydroxide (3.65 g, 65.1 mmol) is added all at once to a suspension of 4-bromo- 3-methyl(4-methylbenzenesulphonyl)-1H-pyrrolecarbonitrile (4.66 g, 13.7 mmol) in methanol (95 mL) cooled using an ice bath. After 15 minutes, the suspension is stirred at ambient temperature for 17 hours. The methanol is evaporated to dryness. The evaporation residue is taken up in MTBE (25 mL) and washed with water (25 mL). The aqueous phase is extracted with MTBE (2 x 25 mL). The combined organic phases are dried over Na SO , filtered and concentrated in vacuo. The residue obtained is dissolved in tetrahydrofuran (50 mL) and the solution is cooled using an ice bath. NaH (60 % in oil) (1.02 g, .5 mmol) is added. After 10 minutes, iodomethane (2.4 mL, 38.6 mmol) is also added.
The mixture is stirred at ambient temperature for 1.5 hours. The tetrahydrofuran is evaporated to dryness. The residue is taken up in dichloromethane and washed with water.
The aqueous phase is extracted with dichloromethane. The combined organic phases are dried over Na SO , filtered and concentrated in vacuo to obtain the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 2.16 (s, 3 H), 3.71 (s, 3 H), 6.74 (s, 1 H) Step G: 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,3-dimethyl-1H-pyrrole carbonitrile 4-Bromo-1,3-dimethyl-1H-pyrrolecarbonitrile (2.03 g, 10.2 mmol) and 4-[(tert- butyldimethylsilyl)oxy]aniline (3.41 g, 15.3 mmol) are dissolved in toluene (40 mL). The solution is degassed with nitrogen for 10 minutes. Sodium tert-butylate (1.18 g, 12.2 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.17 g, 0.41 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.187 g, 0.2 mmol) are then added. The mixture is heated at 100°C for 30 minutes and then cooled to ambient temperature. Water (50 mL) and Celite (6 g) are added. The suspension is filtered over Celite, and the filtrate is diluted with MTBE. The phases are separated and the aqueous phase is extracted with MTBE (2 x 50 mL). The combined organic phases are dried over Na SO and filtered. The residue is purified by chromatography over silica gel using ethyl acetate and heptane as eluants followed by reverse-phase chromatography using methanol and water as eluants. The product obtained is lyophilised to provide the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 0.15 (s, 6 H), 0.98 (s, 9 H), 2.05 (s, 3 H), 3.70 (s, 3 H), 4.69 (br. s, 1 H), 6.55 - 6.57 (m, 2 H), 6.64 - 6.69 (m, 3 H) C NMR (100 MHz, CDCl ) δ ppm: -4.37, 9.42, 18.27, 25.84, 35.50, 102.59, 113.77, 115.13, 120.72, 121.91, 126.77, 126.94, 140.98, 148.39 Preparation 38'': 4-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]ethyl methyl-1H-pyrrolecarbonitrile The procedure is in accordance with the process of Preparation 33'', replacing the iodomethane-d in Step B by iodoethane.
H NMR (400 MHz, dmso-d6) δ ppm: 6.85 (s, 1 H), 6.75 (s, 1 H), 6.6/6.5 (2d, 4 H), 4 (quad, 2 H), 2.1 (s, 3 H), 1.3 (s, 3 H), 0.9 (s, 9 H), 0.1 (s, 6 H) Preparation 39'': N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]ethoxy-pyrimidin amine Step A: 5-Bromoethoxy-pyrimidine -Bromochloro-pyrimidine (5.0 g, 25 mmol) is dissolved in ethanol (55 mL) and sodium ethylate (1.81 g, 26.6 mmol) is added in portions. The reaction mixture is stirred for 15 hours at ambient temperature. When the reaction is complete, the solvent is evaporated off, water (200 mL) is added, and then the reaction mixture is extracted with dichloromethane (2 x 100mL). The organic phase is dried over Na SO , and then evaporated to dryness to yield 5-bromoethoxy-pyrimidine.
Step B: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]ethoxy-pyrimidinamine 4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.8 g, 8 mmol) and 5-bromoethoxy-pyrimidine (1.6 g, 8 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) are stirred for 1 hour at ambient temperature in the presence of sodium tert-butylate (4 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)- phenyl]palladium(II) (111 mg, 0.16 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is triturated in heptane to obtain the expected compound after filtration.
H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 8.31 (s, 2H, pyrimidine-H), 7.80 (s, 1H, NH), 6.73 (d, 2H, Ar-H), 6.68 (d, 2H, Ar-H), 4.26 (q, 2H, CH CH ), 1.31 (t, 3H, CH CH ), 2 3 2 3 0.94 (s, 9H, Bu), 0.15 (s, 6H, Me) -1 -1 -1 IR: ν: aromatic: 1504 cm ; Si-C: 1247 cm ; C-O-C: 1057 cm Preparation 40'': tert-Butyl 6-[(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)amino]- pyridinyl carbonate Step A: 6-Bromopyridinyl tert-butyl carbonate To a solution of 5 g of 6-bromopyridinol (28.7 mmol) and 7.53 g of di-tert-butyl dicarbonate (34.5 mmol) in 50 mL of tetrahydrofuran there is added 0.18 g of 4- dimethylaminopyridine (1.4 mmol). The mixture is stirred at ambient temperature for 6 hours and then concentrated. The residue obtained is dissolved in a mixture of ethyl ether and water. After separation of the phases, the separated-off organic phase is dried over MgSO and concentrated to dryness. The title product is obtained in the form of a solid which is used in the next Step without being otherwise purified.
H NMR (400 MHz, dmso-d6) δ ppm: 8.4 (s, 1 H), 7.71 (s, 2 H), 1.5 (s, 9 H) Step B: tert-Butyl 6-[(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)amino]pyridinyl carbonate To a solution of 2.79 g of the compound obtained in Step A (10.2 mmol) in 15 mL of toluene and 15 mL of tetrahydrofuran there are added 1.18 g of sodium tert-butylate (12.2 mmol), and then the batch is stirred under argon for 15 minutes. There is then added 0.35 g of palladium catalyst (0.5 mmol). The reaction mixture is then stirred at ambient temperature for 16 hours and then filtered. The filtrate is concentrated and taken up in a mixture of dichloromethane and water. The organic phase is separated off and then washed with water, dried over MgSO , filtered and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel using dichloromethane and ethyl acetate as eluants. The residue is then taken up in a minimum of isopropyl ether. The solid then obtained is filtered off, washed with ether and then dried. The title product is obtained in the form of a solid, which is subsequently used without being otherwise purified.
H NMR (400 MHz, dmso-d6) δ ppm: 9 (s, 1 H), 8.35 (wd, 1 H), 8.3 (wd, 1 H), 8 (wd, 1 H), 7.45 (dd, 1 H), 7.45 (wd, 1 H), 6.8 (d, 1 H), 6.4 (wd, 1 H), 3.8 (s, 3 H), 1.5 (s, 9 H) Preparation 41'': 3-[4-[tert-Butyl(dimethyl)silyl]oxyanilino]benzonitrile The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 3-bromobenzonitrile.
H NMR (400 MHz, dmso-d6) δ ppm: 8.3 (s, 1 H), 7.3 (t, 1 H), 7.2/7.1 (2 dd, 2 H), 7.15 (t, 1 H), 7.05 (d, 2 H), 6.8 (d, 2 H), 0.95 (s, 9 H), 0.2 (s, 6 H) Preparation 42'': 4-[4-[tert-Butyl(dimethyl)silyl]oxyanilino]thiophenecarbonitrile The procedure is in accordance with the process of Preparation 1'', replacing the 4-bromo- 1-methyl-1H-pyrazole used in Step B by 4-bromothiophenecarbonitrile.
H NMR (400 MHz, dmso-d6) δ ppm: 8.35 (s, 1 H), 7.59 (wd, 1 H), 7.08 (wd, 1 H), 6.95 (d, 2 H), 6.75 (d, 2 H), 0.94 (s, 9 H), 0.16 (s, 6 H) The amines NHR R wherein R and R , each independently of the other, represent an aryl 3 4 3 4 or heteroaryl group are obtained in accordance with processes described in the literature (Surry D.S. et al., Chemical Science, 2011, 2, 27-50, Charles M.D. et al., Organic Letters, 2005, 7, 3965-3968). The reaction protecting the hydroxy function of the 4-anilinophenol described in Preparation 2" can be applied to various secondary amines NHR R (as defined hereinbefore) having one or more hydroxy functions, when they are available commercially. Alternatively, the secondary amines having at least one hydroxy substituent may be synthesised directly in a protected form, i.e. starting from reagents whose hydroxy function has been protected beforehand. Among the protecting groups, tert- butyl(dimethyl)silyloxy and benzyloxy are especially preferred.
Among the amines NHR R having a hydroxy substituent that are used for synthesising the compounds of the invention there may be mentioned: 4-(4-toluidino)phenol, 4-(4- chloroanilino)phenol, 4-(3-fluoromethylanilino)phenol, 4-[4-(trifluoromethoxy)anilino]- phenol, 4-[4-hydroxyanilino]phenol, {4-[(1-methyl-1H-indolyl)amino]phenyl}- methanol, 4-(2,3-dihydro-1H-indolylamino)phenol, 4-[(1-methyl-2,3-dihydro-1H-indol- 6-yl)amino]phenol, 4-[(1-methyl-1H-indolyl)amino]phenol, 4-[(1-methyl-1H-indol yl)amino]cyclohexanol, 4-[(1-methyl-1,2,3,4-tetrahydroquinolinyl)amino]phenol, 4-[(4- methyl-3,4-dihydro-2H-1,4-benzoxazinyl)amino]phenol, 4-[4-(diethylamino)anilino]- phenol, 4-(2,3-dihydro-1H-indenylamino)phenol, 4-[(1-methyl-1H-indazolyl)amino]- phenol, 4-[(1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-5'-yl)amino]phenol, 4- [(1,3,3-trimethyl-2,3-dihydro-1H-indolyl)amino]phenol, 4-[4-methoxy(trifluoro- methyl)anilino]phenol, 4-[4-(methylsulphanyl)(trifluoromethyl)anilino]phenol, 2- fluoro[(1-methyl-1H-indolyl)amino]phenol, 4-[(1-ethyl-1H-indolyl)amino]phenol, 4-[(1-ethyl-2,3-dihydro-1H-indolyl)amino]phenol, 4-[(1-isopropyl-2,3-dihydro-1H- indolyl)amino]phenol, 4-(butylamino)phenol, 3-[(1-methyl-1H-indolyl)amino] propanol, 4-[(1-methyl-1H-indolyl)amino]butanol, 4-[(3-fluoromethylphenyl)- amino]phenol, 4-[(3-chloromethylphenyl)amino]phenol, 4-[(4-fluorophenyl)amino]- phenol, 4-[(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)amino]phenol, 4-[(4-fluorophenyl)- amino]phenol, 4-[(2-fluorophenyl)amino]phenol, 4-[(3-fluorophenyl)amino]phenol, 4- [(2,4-difluorophenyl)amino]phenol, 4-[(3,4-difluorophenyl)amino]phenol, 3-[(4-hydroxy- phenyl)amino]benzonitrile, 4-[(3-methoxyphenyl)amino]phenol, 4-[(3,5-difluorophenyl)- amino]phenol, 4-[(3-methylphenyl)amino]phenol, 4-[(4-hydroxyphenyl)amino]benzo- nitrile, 4-[(3-chlorophenyl)amino]phenol, 4-(pyrimidinylamino)phenol, 4-[(cyclobutyl- methyl)amino]phenol, 2-[(4-hydroxyphenyl)amino]benzonitrile, 4-{[(1-methyl-1H- pyrazolyl)methyl]amino}phenol, 4-[(cyclopropylmethyl)amino]phenol, 4-{[(1-methyl- 1H-pyrazolyl)methyl]amino}phenol, 4-(butynylamino)phenol, 4-(pyrazinyl- amino)phenol, 4-(pyridinylamino)phenol, 4-(pyridazinylamino)phenol, 4-(pyrimidin- 5-ylamino)phenol, 4-(pyridinylamino)phenol, 4-[(3,5-difluoromethoxyphenyl)- amino]phenol, 4-(pyridinylamino)phenol, 4-[(3-fluoromethoxyphenyl)amino]phenol, 2-(phenylamino)pyrimidinol, 5-[(4-hydroxyphenyl)amino]methoxybenzonitrile, 4- {[3-(trifluoromethyl)phenyl]amino}phenol and 4-(methylamino)phenol.
The hydroxy function(s) of the secondary amines listed above is (are) protected beforehand by a suitable protecting group prior to any coupling to an acid derivative of the compound of formula (VII) as defined in the preceding general process.
P Pr re ep pa ar ra at tiio on n I I: : tte er rtt- -B Bu ut ty yll [ [2 2- -( (3 3- -iio od do o- -4 4- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )e et th hy yll] ]c ca ar rb ba am ma at te e Step A: 4-[2-(tert-Butoxycarbonylamino)ethyl]benzoic acid tert-Butyl dicarbonate (1.64 g; 7.5 mmol) is dissolved in 1,4-dioxane (5 mL) and the solution is added to a well-stirred solution of 4-(2-aminoethyl)benzoic acid (1.0 g; 5 mmol) in 1M aqueous sodium hydroxide solution (25 mL) and 1,4-dioxane (10 mL), and the mixture is then stirred at ambient temperature for 3 hours. The 1,4-dioxane is removed by evaporation in vacuo, and then ethyl acetate (200 mL) is added to the residue. The pH of the aqueous phase is adjusted to 1.5 with 2M aqueous HCl solution. The organic phase is separated off and the aqueous phase is then extracted with ethyl acetate (100 mL). The combined organic extracts are washed with water, dried over Na SO and evaporated to a volume of 10 mL. Heptane is added to the residue and then the solid precipitate is filtered off to yield the title compound.
H NMR (500 MHz, dmso-d6, 300K): 12.81 (br s, 1H, COOH), 7.85 (m, 2H, Ar-2' and 6'H), 7.31 (m, 2H, Ar-3' and 5'H), 6.91 and 6.51 (2x br s, 1H, NH), 3.16 (m, 2H, CH ), t 13 2.75 (t, 2H, CH ), 1.35 and 1.31 (2 x br s, 9H, Bu ); C NMR (125 MHz, dmso-d6, 300 K): 167.8 (q), 156.0 (CH), 145.3 (q), 129.8 (2 x CH), 129.3 (2 xCH), 129.1 (q), 78.0 (q), 41.5 (CH ), 35.9 (CH ), 28.7 (CH ) 2 2 3 Step B: 4-[2-(tert-Butoxycarbonylamino)ethyl]iodo-benzoic acid The compound of the above Step (0.88 g; 3.31 mmol), iodobenzene diacetate (1.07 g; 3.31 mmol), tetrabutylammonium iodide (1.22 g; 3.31 mmol), iodine (0.84 g; 3.31 mmol) and diacetoxypalladium (0.04 g; 0.165 mmol) are dissolved in 1,2-dichloroethane (8 mL), and the mixture is then heated in a microwave reactor at 80°C for 90 minutes. The cooled mixture is partitioned between saturated aqueous Na CO solution (30 mL) and the original solvent. The organic phase is separated off and the aqueous residue is extracted with diethyl ether (2 x 15 mL). The pH of the resulting aqueous solution is adjusted to 2 with 2M aqueous HCl solution and the product is then extracted with ethyl acetate (2 x 75 mL).
The organic phase is dried over Na SO and evaporated. The crude product is purified by chromatography over silica gel to yield the mixture of regioisomers, which are separated by preparative HPLC using water-TFA and acetonitrile as eluants. The pH of the appropriate combined fractions is adjusted to 5 with NaHCO , and then the acetonitrile is evaporated off under reduced pressure. The precipitate is recovered by filtration and then dried to yield the title compound.
H NMR (500 MHz, dmso-d6, 300K): 13.16 (broad s, 1H, COOH), 7.81 (s, 1H, Ar-3'H), 7.66 (d, 1H, Ar-6'H), 7.29 (d, 1H, Ar-5'H), 6.89 (t, 1H, NH), 3.14 (t, 1H, CH ), 2.69 (t, 1H, CH ), 1.35 (s, 9H, Boc) Step C: tert-Butyl [2-(3-iodo{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)ethyl]carbamate The compound of the above Step (0.714 g; 1.82 mmol), TBTU (0.73 g; 2.28 mmol), N- ethyl-N-isopropyl-propanamine (0.94 mL; 5.46 mmol) and N,N-dimethylpyridin amine (22 mg) are stirred in dichloromethane (20 mL) for 5 minutes, and then (3R) methyl-1,2,3,4-tetrahydroisoquinoline (0.282 g; 1.92 mmol) (cf. Preparation 1') is added.
The mixture is stirred for three more hours. The reaction mixture is diluted with dichloromethane (150 mL) and then washed with water (25 mL), dried over Na SO and evaporated. The crude product is purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the title compound.
High-resolution mass spectrometry (ESI+): Empirical formula: C H IN O 24 29 2 3 [M+H] calculated: 521.1303 [M+H] measured: 521.1282 -1 -1 -1 IR: ν: C-H: 2931 cm ; >C=O: 1706, 1627 cm ; amide: 1505 cm ; C-O-C: 1248, 1166 cm P Pr re ep pa ar ra at tiio on n I II I: : tte er rtt- -B Bu ut ty yll ( (4 4- -I Io od do o- -3 3- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }b be en nz zy yll) )c ca ar rb ba am ma at te e Step A: 2-Iodomethyl-benzoic acid 3-Methylbenzoic acid (6.12 g; 45 mmol), iodobenzene diacetate (14.49 g; 45 mmol), tetrabutylammonium iodide (16.62 g, 45 mmol), iodine (11.43 g; 45 mmol) and diacetoxypalladium (0.5 g; 2.2 mmol) are dissolved in 1,2-dichloroethane, and then the mixture is heated in a sealed tube at 85°C for 1 hour and 45 minutes. The cooled solution is purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the title compound.
Step B: Methyl 2-iodomethyl-benzoate The compound of the above Step (6.25 g, 23.9 mmol) is dissolved in anhydrous methanol (100 mL), and then SOCl (3.6 mL, 49 mmol) is added dropwise to the well-stirred solution. The solution is refluxed for 18 hours and then evaporated to a volume of 25 mL and then poured into crushed ice (100 g). The resulting mixture is extracted with diethyl ether (2 x 75 mL). The organic phase is washed with saturated aqueous NaHCO solution and then brine, dried over Na SO and evaporated to dryness to yield the title compound.
Step C: Methyl 5-(bromomethyl)iodo-benzoate The compound of the above Step (5.7 g; 20.7 mmol), N-bromo-succinimide (3.67 g; .7 mmol) and dibenzoyl peroxide (0.24 g; 1 mmol) are dissolved in carbon tetrachloride (40 mL) and then refluxed for 5 hours. New portions of N-bromosuccinimide (1.0 g; .6 mmol) and dibenzoyl peroxide (0.05 g; 0.2 mmol) are then added and heating is continued for 4 more hours. The reaction mixture is cooled to ambient temperature. The insoluble parts are removed by filtration, and the concentrated filtrate is then purified by chromatography over silica gel using heptane and ethyl acetate as eluants to yield the title compound.
Step D: Methyl 5-(aminomethyl)iodo-benzoate The compound of the above Step (0.53 g; 1.5 mmol) is dissolved in 7M methanolic ammonia (20 mL) and then stirred at ambient temperature for 1 hour. The solution is evaporated to dryness to yield the title compound, which was used in the next Step without purification.
Step E: 5-[(tert-Butoxycarbonylamino)methyl]iodo-benzoic acid Methyl 5-(aminomethyl)iodo-benzoate hydrobromide (0.56 g; 1.5 mmol) was dissolved in pyridine (10 mL), then di-tert-butyl dicarbonate (0.80 g; 3.6 mmol) is added and the mixture is stirred at ambient temperature for 30 minutes and then evaporated to dryness.
The residue is redissolved in methanol (10 mL), and then 2M aqueous NaOH solution (3 mL) and 2 mL of water are added. The resulting solution is stirred for 2 hours at 50°C, then diluted with water (20 mL), and the methanol is evaporated off under reduced pressure. The pH of the resulting aqueous solution is adjusted to 3 with 2M aqueous HCl solution; the product is then extracted with ethyl acetate. The organic phase is washed with brine, and then dried over Na SO and evaporated to dryness. The crude product is triturated with DCM. The solid formed is recovered by filtration to yield the title compound.
H NMR (500 MHz, dmso-d6, 300 K): 13.24 (broad s, 1H, COOH), 7.91 (d, 1H, Ar-3'H), 7.58 (d, 1H, Ar-6'H), 7.47 (t, 1H, NH), 7.09 (d, 1H, (Ar-5'H), 4.09 (d, 2H, CH ), 1.38 (s, 9H, Boc); C NMR (125 MHz, dmso-d6, 300K): 168.6 (q), 156.3 (q), 141.1 (q), 140.9 (CH), 137.1 (q), 131.6 (CH), 129.1 (CH), 92.2 (q), 78.5 (q), 28.7 (CH ) Step F: tert-Butyl (4-iodo{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}- benzyl)carbamate The compound of the above Step (1.62 g; 4.3 mmol), TBTU (2.76 g; 8.59 mmol), N-ethyl- N-isopropyl-propanamine (1.48 mL; 8.59 mmol) and N,N-dimethylpyridinamine (10 mg) are stirred in DCM (50 mL) for 5 minutes; (3R)methyl-1,2,3,4- tetrahydroisoquinoline (0.76 g; 5.15 mmol) (cf. Preparation 1') is then added and the mixture is stirred for 15 minutes more. The insoluble parts are removed by filtration, and then the concentrated filtrate is purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the title compound.
P Pr re ep pa ar ra at tiio on n I II II I: : tte er rtt- -B Bu ut ty yll ( (3 3- -b br ro om mo o- -4 4- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }b be en nz zy yll) )c ca ar rb ba am ma at te e Step A: Methyl 4-(aminomethyl)bromo-benzoate A solution of methyl 2-bromo(bromomethyl)benzoate (4.57 g; 14.84 mmol) in 50 mL of methanol is added dropwise to a well-stirred solution of ammonia in methanol (7M; 315 mL) at ambient temperature, and the solution is then stirred for 3 hours. All the solvents are evaporated off and the residue is purified by chromatography over silica gel using dichloromethane-methanol as eluants to yield the title compound.
Step B: 2-Bromo[(tert-butoxycarbonylamino)methyl]benzoic acid The compound of the above Step (4.04 g; 16.6 mmol) is dissolved in pyridine (55 mL) and then di-tert-butyl dicarbonate (5.43 g; 24.9 mmol) is added and the mixture is stirred at ambient temperature for 16 hours; it is then evaporated to dryness. The residue is redissolved in methanol (100 mL), and then 1M aqueous NaOH solution (54 mL) is added.
The resulting solution is stirred for 1.5 hours at 50°C and is then allowed to cool to ambient temperature. The pH of the solution is adjusted to 7 using 2M aqueous HCl solution; the methanol is then evaporated off under reduced pressure. The resulting aqueous solution is diluted with water (50 mL), and then the pH is adjusted to 3 using 2M aqueous HCl solution. The product is extracted with dichloromethane (2 x 100 mL). The organic phase is washed with brine, then dried over Na SO and evaporated to dryness to yield the title compound which is used in the next Step without purification. -1 -1 -1 -1 IR: ν: N-H: 3359 cm ; C-H: 2983 cm ; >C=O: 1685, 1603 cm ; amide: 1519 cm ; C-O- C: 1248, 1162, 1057 cm Step C: tert-Butyl (3-bromo{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}benzyl)carbamate The compound of the above Step (3.7 g; 11.2 mmol), TBTU (7.19 g; 22.4 mmol), N-ethyl- N-isopropyl-propanamine (3.86 mL; 22.4 mmol) and N,N-dimethylpyridinamine (48 mg) are stirred in dichloromethane (100 mL) for 5 minutes, and then (3R)methyl- 1,2,3,4-tetrahydroisoquinoline (1.98 g, 13.44 mmol) (cf. Preparation 1') is added, and the mixture is stirred for 1 hour more. The insoluble parts are removed by filtration, and then the concentrated filtrate is purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the title compound.
High-resolution mass spectrometry (ESI+): Empirical formula: C H BrN O 23 27 2 3 [M+H] calculated: 459.1285 [M+H] measured: 459.1282 H NMR (500 MHz, dmso-d6, 300K, presence of amide rotamers): 7.66-6.87 (m, 7H, aromatic), 5.34 and 4.12 (d, 2H, CH -isoquinoline), 5.02 and 4.97 and 3.87 and 3.83 (m, 1H, CH -isoquinoline), 4.17 (d, 2H, CH -benzyl), 3.18-2.48 (m, 1H, CH -isoquinoline), 2 2 2 1.16 and 1.14 and 1.10 and 0.98 (d, 3H, isoquinoline CH ), 1.31 and 1.41 (s, 9H, Boc).
E Ex xa am mp plle e 1 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide Step A: Ethyl 5-(5-chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl} phenyl)-1,2-dimethyl-1H-pyrrolecarboxylate To a solution of 1.4 g of the compound obtained in Preparation 1 (4.35 mmol) in 50 mL of dichloromethane there are successively added 0.7 g of the compound obtained in Preparation 1' (4.79 mmol), 0.7 g of HOBT (5.22 mmol), 0.81 g of EDC (5.22 mmol) and 1.6 mL of triethylamine (21.7 mmol). The batch is then stirred overnight at ambient temperature. The reaction mixture is then diluted with dichloromethane and washed 3 times with saturated aqueous NaHCO solution. The organic phase is then dried over MgSO , filtered, concentrated to dryness, and then purified by chromatography over silica gel using dichloromethane and methanol as eluants.
H NMR: δ (500 MHz; dmso-d6; 300K): 7.6-7.3 (m, 3H, aromatic Hs, 4-chlorophenyl); 7.2-6.85 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 6.45-6.3 (m, 1H, H pyrrole); 5.0- 4.8-3.8 (m, 1H, aliphatic H, tetrahydroisoquinoline); 5.3-3.75 (dd, 2H, aliphatic Hs tetrahydroisoquinoline); 4.2-4.0 (m, 2H, OCH CH ); 3.25 (s, 3H, CH -N-pyrrole); 3.0-2.2 2 3 3 (m, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.5 (s, 3H, CH -pyrrole); 1.25 (t, 3H, OCH CH ); 1.05 (d, 3H, tetrahydroisoquinoline-CH ) 2 3 3 -1 -1 IR: ν: >C=O: 1693 cm ester; ν: >C=O: 1625 cm amide Step B: 5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}- phenyl)-1,2-dimethyl-1H-pyrrolecarboxylic acid To a solution of 1.7 g of the compound obtained in Step A (3.77 mmol) in 5 mL of dioxane there is added 0.317 g of LiOH (7.5 mmol) dissolved in 5 mL of water. The batch is heated in a microwave apparatus for 4 hours at 100°C (power 140 W). The reaction mixture is then filtered and concentrated to dryness. The residue thereby obtained is taken up in dichloromethane (50 mL) and then saturated aqueous NH Cl solution is added thereto. The organic phase is washed with water and then with brine, dried over MgSO , filtered and concentrated to dryness. The title product is obtained in the form of a solid and is used directly in the next Step.
H NMR: δ (500 MHz; dmso-d6; 300K): 11.05 (broad s, 1H, COOH), 7.5-7.2 (m, 3H, aromatic Hs, 4-chlorophenyl); 7.2-6.9 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 6.45- 6.2 (m, 1H, aliphatic H, H pyrrole); 5.3-3.75 (dd, 2H, aliphatic Hs, tetrahydroisoquinoline); .0-4.8-3.8 (m, 1H, aliphatic H, tetrahydroisoquinoline); 3.5-3.2 (s, 3H, CH -N-pyrrole); 3.0-2.1 (aliphatic Hs, CH -tetraisoquinoline); 2.5-2.4-1.98 (m, 3H, CH -pyrrole); 1.05- 0.52 (m, 3H, aliphatic Hs, CH -tetraisoquinoline) -1 -1 IR : ν: -OH: 3500-2000 cm carboxylic acid; ν: >C=O: 1699 + 1658 cm carboxylic acid; ν: >C=N-: 1625 cm amide Step C: N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)(5-chloro{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide To a solution of 0.65 g of the compound obtained in Step B (1.54 mmol) in 15 mL of dichloroethane there is added, dropwise, 0.244 mL of 1-chloro-N,N,2-trimethyl-propenamine. The reaction mixture is stirred at ambient temperature for 1 hour, and there are then added 0.56 g of the compound of Preparation 1'' (1.84 mmol), 10 mL of dichloroethane and 0.376 g of 4-dimethylaminopyridine (DMAP) (3.07 mmol). The batch is stirred at 110°C overnight. The reaction mixture is concentrated, dissolved in dichloromethane and washed with saturated aqueous NaHCO solution. The title product is obtained in the form of an oil and is used directly in the next Step.
Step D: 5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}- phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrole carboxamide To a solution of 0.8 g of the compound obtained in Step C (1.03 mmol) in 2 mL of methanol, there are added 1.55 mL of a 1M solution of potassium hydroxide in methanol (1.55 mmol). The batch is stirred at ambient temperature for 30 minutes. The reaction mixture is then diluted with dichloromethane and successively washed with 1M aqueous HCl solution, saturated aqueous NaHCO solution and then brine until neutral. The organic phase is then dried over MgSO , filtered and evaporated. The crude product thereby obtained is purified by chromatography over silica gel using dichloromethane and methanol as eluants. The solid thereby obtained is dissolved in a mixture of water/acetonitrile until dissolution is complete, filtered and then lyophilised.
Elemental microanalysis: (%, theoretical:measured) %C=68.74:68.25; %H=5.43:5.69; %N=11.79:11.66; %Cl=5.97:5.95 High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 34 32 5 3 [M+H] calculated: 594.2266 [M+H] measured: 594.2289 Example 2.5-(2-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- Example 2.5-(2-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)methyl-N,N-diphenyl-1H-pyrrolecarboxamide yl]carbonyl}phenyl)methyl-N,N-diphenyl-1H-pyrrolecarboxamide Step A: tert-Butyl {[(3S){2-[4-(diphenylcarbamoyl)methyl-1H-pyrrolyl]benzoyl}- 1,2,3,4-tetrahydroisoquinolinyl]methyl}carbamate The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 2 and tert-butyl [(3S)-1,2,3,4-tetrahydroisoquinolinylmethyl]carbamate (see Preparation 2') in Step A, and N-phenylaniline in Step C.
Step B: 5-(2-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl} phenyl)methyl-N,N-diphenyl-1H-pyrrolecarboxamide A solution of the NH-Boc compound of Step A in dichloromethane is placed at 0°C. molar equivalents of trifluoroacetic acid are added thereto dropwise. The batch is stirred at ambient temperature for 4 hours until the starting material has disappeared completely.
The reaction mixture is then concentrated to dryness, taken up again and co-evaporated twice with toluene, then taken up in a mixture of acetonitrile/H O and finally lyophilised.
The title product is then obtained after a neutralisation step.
Elemental microanalysis: (%, theoretical:measured) %C=77.75:77.27; %H=5.97:5.73; %N=10.36:10.44 E Ex xa am mp plle e 3 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (4 4- -m me et th hy yllp piip pe er ra az ziin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro o- - iis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -( (1 1H H- -iin nd do oll- -5 5- -y yll) )- -1 1- - methyl-1H-pyrrolecarboxamide methyl-1H-pyrrolecarboxamide Step A: tert-Butyl 5-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl){[5-(5-chloro{[(3S) [(4-methylpiperazinyl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl) methyl-1H-pyrrolyl]carbonyl}amino]-1H-indolecarboxylate The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 3 and (3S)[(4-methylpiperazinyl)methyl]-1,2,3,4-tetrahydro- isoquinoline (see Preparation 4') in Step A, and the compound of Preparation 3'' in Step C.
Step B: 5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1H-indolyl)methyl-1H- pyrrolecarboxamide To a solution of 455 mg (0.49 mmol) of the product obtained in Step A in 5 mL of methanol there are added 135 mg (2.5 mmol) of KOH. After stirring for 3 hours at ambient temperature, the reaction mixture is concentrated, treated with saturated aqueous NaHCO solution and extracted with methylene chloride. The organic phase is then dried over MgSO , filtered and evaporated to dryness. The crude product thereby obtained is then purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the expected product in the form of a foam.
Elemental microanalysis: (%, theoretical:measured) %C=70.72:68.54; %H=5.79:5.37; %N=11.78:11.41; %Cl=4.97:4.79 High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 42 41 6 3 [M+H] calculated: 713.3007 [M+H] measured: 713.2973 E Ex xa am mp plle e 4 4..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -( (1 1H H- -iin nd do oll- -5 5- -y yll) )- -1 1- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -[ [( (4 4- - m me et th hy yllp piip pe er ra az ziin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - benzodioxolyl)-1H-pyrrolecarboxamide benzodioxolyl)-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 3 using the compound of Preparation 4 in Step A.
Elemental microanalysis: (%, theoretical:measured) %C=71.45:69.32; %H=5.86:5.22; %N=11.63:11.08 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 43 42 6 5 [M+H] calculated: 723.3295 [M+H] measured: 723.3262 Unless otherwise mentioned, the compounds of the following Examples are synthesised in accordance with the process of Example 1 using, in Step A: (i) the appropriate acid obtained according to one of Preparations 1 to 32 and (ii) the appropriate tetrahydroisoquinoline compound obtained according to one of Preparations 1' to 9' and, in Step C: (iii) the suitable NHR R amine (a non- exhaustive list is proposed in Preparations 1'' to 42''. The compounds thereby obtained are optionally subjected to a step of conversion into salt form in the presence of HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the hydrochloride of the expected compound is obtained.
E Ex xa am mp plle e 5 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (4 4- -m me et th hy yllp piip pe er ra az ziin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-indolyl)-1H-pyrrolecarboxamide hydrochloride methyl-1H-indolyl)-1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=64.54:64.9; %H=5.67:5.49; %N=10.5:10.4; %Cl=13.29:12.52; %Cl-=8.86:7.39 Example 6.5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4- Example 6.5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)ethyl-N-(4-hydroxyphenyl)-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)ethyl-N-(4-hydroxyphenyl)-N-(1- m me et th hy yll- -1 1H H- -iin nd do oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 44 45 6 3 [M+H] calculated: 741.3320 [M+H] measured: 741.3326 E Ex xa am mp plle e 7 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (4 4- -m me et th hy yllp piip pe er ra az ziin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)cyclopropyl-N-(4-hydroxyphenyl)- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)cyclopropyl-N-(4-hydroxyphenyl)- N-(1-methyl-1H-indolyl)-1H-pyrrolecarboxamide N-(1-methyl-1H-indolyl)-1H-pyrrolecarboxamide High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 45 45 6 3 [M+H] calculated: 753.3320 [M+H] measured: 753.3306 Example 8.5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4- Example 8.5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - indolyl)(propanyl)-1H-pyrrolecarboxamide indolyl)(propanyl)-1H-pyrrolecarboxamide High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 45 47 6 3 [M+H] calculated: 755.3476 [M+H] measured: 755.3466 E Ex xa am mp plle e 9 9..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -iin nd do oll- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- - [(4-methylpiperazinyl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- [(4-methylpiperazinyl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=65.26:65.8; %H=5.73:5.47; %N=10.38:10.48; %Cl=8.76:8.46; %Cl-=8.76:8.02 Example 10.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 10.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- - 3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=69.11:68.56; %H=5.8:5.31; %N=8.06:8.13; %Cl-=5.1:4.68 E Ex xa am mp plle e 1 11 1..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(3-hydroxypropyl)methyl-N- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(3-hydroxypropyl)methyl-N- phenyl-1H-pyrrolecarboxamide hydrochloride phenyl-1H-pyrrolecarboxamide hydrochloride Step A: 1-[3-(Benzyloxy)propyl](5-fluoro{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-phenyl- 1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 10 and the compound of Preparation 3' in Step A, and the compound of Preparation 2'' in Step C.
Step B: 5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(3-hydroxypropyl)methyl-N-phenyl-1H- pyrrolecarboxamide hydrochloride The compound of Step A is subjected to a deprotection reaction in accordance with a protocol analogous to that described in Step B of Example 23.
Elemental microanalysis: (%, theoretical:measured) %C=68.24:67.96; %H=6:5.79; %N=7.58:7.61; %Cl-=4.8:4.75 High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O 42 43 4 5 [M+H] calculated: 703.3296 [M+H] measured: 703.33294 Example 12.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 12.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - iin nd da az zo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=67.33:67.39; %H=5.65:5.18; %N=11.22:11.52; %Cl-=4.73:3.82 E Ex xa am mp plle e 1 13 3..N N- -( (3 3- -F Fllu uo or ro o- -4 4- -m me et th hy yllp ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- - {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=66.97:66.72; %H=5.62:5.21; %N=7.44:7.59; %Cl-=4.71:4.54 Example 14.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-indazolyl)(6- Example 14.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-indazolyl)(6- { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=66.62:66.59; %H=5.59:4.67; %N=10.84:10.85; %Cl-=4.57:4.24 E Ex xa am mp plle e 1 15 5..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- - 3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -p ph he en ny yll- -1 1H H- - pyrrolecarboxamide hydrochloride pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=68.28:67.07; %H=5.73:5.09; %N=7.77:7.75; %Cl-=4.92:5.71 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 41 40 4 6 [M+H] calculated: 685.3026 [M+H] measured: 685.3033 Example 16.N-(3-Fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl(6-{[(3S) Example 16.N-(3-Fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl(6-{[(3S) ( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- - 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=66.62:66.11; %H=5.45:5.2; %N=7.58:7.89; %Cl-=4.8:5.59 E Ex xa am mp plle e 1 17 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole- 3-carboxamide hydrochloride 3-carboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=67.51:66.91; %H=5.66:5.05; %N=7.87:7.88; %Cl-=4.98:5.75 Example 18.1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)methyl(6-{[(3S)[2- Example 18.1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)methyl(6-{[(3S)[2- ( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- - y yll) )- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Step A: 1-[2-(Benzyloxy)ethyl]-N-[4-(benzyloxy)phenyl]methyl(6-{[(3S)[2- (morpholinyl)ethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)- N-phenyl-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 9 and (3S)[2-(morpholinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline (see Preparation 5') in Step A, and 4-(benzyloxy)-N-phenylaniline (see Preparation 8'') in Step C.
Step B: 1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)methyl(6-{[(3S)[2-(morpholin- 4-yl)ethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-phenyl- 1H-pyrrolecarboxamide hydrochloride The compound of Step A is subjected to a deprotection reaction in accordance with a protocol analogous to that described in Step B of Example 23.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 38 40 6 5 [M+H] calculated: 729.3283 [M+H] measured: 729.3282 E Ex xa am mp plle e 1 19 9..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -5 5- -( (5 5- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- - 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-phenyl-1H- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-phenyl-1H- p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=69.63:69.45; %H=6.13:5.94; %N=7.92:7.79; %Cl-=5.01:4.58 Example 20.N-(4-Hydroxyphenyl)(5-methoxy{[(3R)methyl-3,4- Example 20.N-(4-Hydroxyphenyl)(5-methoxy{[(3R)methyl-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (p py yr riid diin n- -4 4- -y yll) )- -1 1H H- - p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=69.39:69.66; %H=5.66:5.46; %N=8.99:8.92; %Cl-=5.69:5.29 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 36 35 4 4 [M+H] calculated: 587.2653 [M+H] measured: 587.2649 Example 21.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(7- Example 21.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(7- { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -2 2,,3 3- - d diih hy yd dr ro o- -1 1,,4 4- -b be en nz zo od diio ox xiin n- -6 6- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=64.99:64.67; %H=5.86:5.67; %N=11.37:11.27; %Cl-=4.8:4.71 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 43 6 6 [M+H] calculated: 703.3236 [M+H] measured: 703.3239 E Ex xa am mp plle e 2 22 2..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (7 7- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- - 3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -2 2,,3 3- -d diih hy yd dr ro o- -1 1,,4 4- -b be en nz zo od diio ox xiin n- -6 6- -y yll) )- -N N- - phenyl-1H-pyrrolecarboxamide hydrochloride phenyl-1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=68.61:67.97; %H=5.89:5.59; %N=7.62:7.55; %Cl-=4.82:4.27 Example 23.1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)methyl(6-{[(3R)methyl- Example 23.1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)methyl(6-{[(3R)methyl- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Step A: 1-[2-(Benzyloxy)ethyl]-N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)methyl (6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N- (1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 9 and the compound of Preparation 1'' in Step C.
Step B: N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)(2-hydroxyethyl)methyl(6- {[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1- methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide To a solution of 6.86 g (8.19 mmol) of the compound of Step A in 70 mL of anhydrous methanol there are added 1.37 g of Pd/C 10%. The batch is degassed for 0.5 hours and then stirred at ambient temperature under dihydrogen pressure (1.5 bar) for 12 hours. The reaction mixture is then filtered and then concentrated to dryness. The expected product is obtained in the form of a solid.
H NMR: δ (500 MHz; dmso-d6; 300K): 7.7-7.4 (s, 1H, H pyrazole); 7.1-6.8 (s, 1H, H pyrazole); 7.3-6.9 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 7.0-6.7 (m, 2H, aromatic Hs); 6.9-6.4 (m, 2H, aromatic Hs); 6.8-6.4 (m, 2H, aromatic Hs); 6.1 (m, 2H, OCH O); 5.2 , 5.0, 4.7 (4s, H, H-pyrrole (presence of conformational isomers); 5.15 (d, 1H, aliphatic H, H tetrahydroisoquinoline); 4.9 (m, 1H, aliphatic H, H tetrahydroisoquinoline); 4.9-4.8 (m, 1H, CH OH); 4.7 (m, 1H, aliphatic H, H tetrahydroisoquinoline); 3.9 (d, 1H, aliphatic H, H tetrahydroisoquinoline); 3.85 (m, 1H, aliphatic H, H tetrahydroisoquinoline); 3.7 (m, 2H, aliphatic Hs, CH CH OH); 3.75 (2s, 3H, ); 3.5-3.2 (m, 2H, aliphatic Hs, CH CH OH); 3.0-2.4 (m, 2H, aliphatic H, H tetrahydroisoquinoline); 2.4-2.3 (4s, 3H, CH -pyrrole); 1.5, 0.95, 0.75 (4 d, 3H, CH - THIQ); 0.85 (broad s, 9H, Si(CH ) (CH(CH ) ); 0.15 (m, 6H, Si(CH ) (CH(CH ) ) 3 2 3 2 3 2 3 2 -1 -1 IR: ν: -OH: 3346 cm carboxylic acid; ν: >C=O: 1621 cm Step C: 1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)methyl(6-{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide The phenol function of the compound of Step B is deprotected following the process of Step D of Example 1.
Elemental microanalysis: (%, theoretical:measured) %C=68.23:68.12; %H=5.57:5.29; %N=11.05:10.79 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 36 36 5 6 [M+H] calculated: 634.2662 [M+H] measured: 634.2660 Example 24.N-(4-Hydroxyphenyl)(5-methoxy{[(3S)(morpholinylmethyl)- Example 24.N-(4-Hydroxyphenyl)(5-methoxy{[(3S)(morpholinylmethyl)- 3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=65.86:64.47; %H=6.09:5.88; %N=11.82:11.45; %Cl-=4.98:6.7 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 39 42 6 5 [M+H] calculated: 675.3289 [M+H] measured: 675.3287 E Ex xa am mp plle e 2 25 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrazolyl)-1H-pyrrolecarboxamide hydrochloride pyrazolyl)-1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=63.77:62.83; %H=5.63:5.83; %N=11.74:11.29; %Cl-=4.95:5.42 Example 26.N-(4-Hydroxyphenyl)methyl[2-(methylamino)ethyl](6-{[(3R) Example 26.N-(4-Hydroxyphenyl)methyl[2-(methylamino)ethyl](6-{[(3R) methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl- methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl- 1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The procedure is in accordance with Steps A, B and C of the process of Example 30 replacing the sodium azide used in Step B by methylamine. After purification over silica gel (CH Cl /MeOH/NH gradient), the compound obtained, 0.3 g (0.46 mmol), is dissolved 2 2 3 in 5 mL of anhydrous methanol and there is added, dropwise, 0.464 mL (0.47 mmol) of 1M HCl solution in ether. The batch is stirred for 0.5 hours at ambient temperature. The precipitate thereby obtained is filtered off and dried and then dissolved in a mixture of CH CN/H O before being lyophilised at low temperature. The expected product is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=65.05:64.64; %H=5.75:5.43; %N=12.3:12.3; %Cl-=5.19:5.39 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 37 38 6 5 [M+H] calculated: 647.2903 [M+H] measured: 647.2922 Example 27.1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)methyl(6-{[(3R) Example 27.1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)methyl(6-{[(3R) methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl- methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl- 1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The procedure is in accordance with the process of Example 26, replacing the methylamine in Step B by dimethylamine.
Elemental microanalysis: (%, theoretical:measured) %C=65.46:65.07; %H=5.93:5.87; %N=12.05:12.06; %Cl-=5.08:5.55 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 38 40 6 5 [M+H] calculated: 661.3060 [M+H] measured: 661.3045 E Ex xa am mp plle e 2 28 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (p py yr riid diin n- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- - 3-carboxamide hydrochloride 3-carboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=66.99:66.88; %H=5.14:5.28; %N=8.93:8.87; %Cl-=5.65:4.98 High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 32 4 3 [M+H] calculated: 591.2157 [M+H] measured: 591.2178 E Ex xa am mp plle e 2 29 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -{ {[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th ho ox xy y] ]m me et th hy yll} }- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - phenyl-1H-pyrrolecarboxamide hydrochloride phenyl-1H-pyrrolecarboxamide hydrochloride Step A: Methyl 5-(5-chloro{[(3S)(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolecarboxylate To a solution of 4.9 g of the compound of Preparation 1 in a mixture of 40 mL of dimethylformamide and 40 mL of tetrahydrofuran there are added 2.73 g (1.1 equivalents) of (3S)hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, 7.95 mL of diisopropylethyl- amine and 9.84 g (1.7 equivalents) of HATU. After stirring for 2 hours at ambient temperature, the reaction mixture is dried, taken up in ethyl acetate and then washed with % aqueous citric acid solution and water. The combined aqueous phases are extracted with ethyl acetate. The organic phases thereby obtained are combined, dried over Na SO , filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography over silica gel using dichloromethane and ethanol as eluants to yield the title compound.
H NMR: δ (500 MHz; dmso-d6; 300K): 7.6-7.4 (m, 3H, Cl-Ph); 7.2-6.9 (m, 4H, Ar(THIQ); 6.5-6.15 (broad 4s, 1H, pyrrole); 4.9-3.8 (6 d, 2H, NCH THIQ); 4.85-3.6 (m, 1H, NCH THIQ); 4.2-4.0 (m, 2H, OCH ester), 3.45-3.2 (3s, 3H, N-CH ); 3.35-3.0 (3m, 2H, HOCH ); 3.0-2.0 (m, 2H, THIQ); 2.5-2.1 (m, 3H, CH pyrrole); 1.25-1.1 (m, 3H, CH 2 3 3 ester) -1 -1 -1 IR: ν -OH: 3388 cm , ν >C=O: 1693 cm (conjugated ester), ν >C=O: 1620 cm (amide) Step B: Methyl 5-(5-chloro{[(3S){[2-(morpholinyl)ethoxy]methyl}-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolecarboxylate A solution of 1.7 g (3.2 mmol) of the compound obtained in the above Step in 20 mL of dimethylformamide is added, dropwise at 0°C, to a suspension of 0.280 g of NaH 60 % in oil (2.2 equivalents) in 10 mL of dimethylformamide. After stirring for 5 minutes at ambient temperature, a suspension of 0.68 g of 4-(2-bromoethyl)morpholine hydrobromide (1.1 equivalents) is added dropwise. The reaction mixture is stirred at ambient temperature for 45 minutes. There are then added, in two steps over 20 hours, 2.2 equivalents of 4-(2- bromoethyl)morpholine hydrobromide, and then 3 equivalents of NaH 60 % in oil. The reaction mixture is then poured into a mixture of 10 % aqueous ammonium chloride and ethyl acetate. The resulting organic phase is successively washed with water, and then with saturated aqueous LiCl solution and brine. It is then dried over Na SO , filtered and concentrated under reduced pressure. The oil obtained is purified by chromatography over silica gel using dichloromethane and ethanol as eluants to provide the expected product.
H NMR: δ (500 MHz; dmso-d6; 300K): 7.6-7.3 (m, 3H, Cl-Ph); 7.2-6.85 (m, 4H, Ar(THIQ); 6.5-6.15 (broad s, 1H, pyrrole); 5.25-3.8 (m, 2H, NCH THIQ); 5.05-3.75 (m, 1H, NCH THIQ); 4.2-4.0 (m, 2H, OCH ester), 3.5-3.25 (m, 3H, N-CH ); 3.6-2.75 (m, 8H, OCH morpholinoethoxymethyl); 2.95-2.05 (m, 2H, THIQ); 2.55-2.15 (m, 6H, NCH morpholinoethoxymethyl); 2.55-2.05 (m, 3H, CH pyrrole), 1.25-1.1 (m, 3H, CH ester) -1 -1 IR: ν >C=O: 1694 cm (conjugated ester), ν >C=O: 1629 cm (amide) Step C: 5-(5-Chloro{[(3S){[2-(morpholinyl)ethoxy]methyl}-3,4-dihydro- isoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolecarboxylic acid To a solution of 1.46 g of the compound of the above Step in 5 mL of dioxane there are added 5 mL of 1M aqueous LiOH solution. The batch is heated in a microwave apparatus (100 W) at 100°C for 2 hours. The reaction mixture is poured into water and then extracted with ethyl ether. The ethereal phase is extracted again with 10 mL of water. The aqueous phases are acidified to pH 5-6 by adding saturated aqueous ammonium chloride solution and then extracted twice with dichloromethane. The dichloromethane phase is dried over Na SO , filtered and concentrated to dryness. The title product is obtained in the form of a meringue.
H NMR: δ (500 MHz; dmso-d6; 300K): 11.4 (broad s, 1H, CO H), 7.6-7.3 (m, 3H, Cl- Ph); 7.2-6.8 (m, 4H, Ar(THIQ); 6.5-6.2 (broad 4s, 1H, pyrrole); 5.25-3.75 (m, 2H, NCH THIQ); 5.05-3.7 (3m, 1H, NCH THIQ); 3.5-3.2 (3s, 3H, N-CH ); 3.6-2.7 (m, 8H, OCH morpholinoethoxymethyl); 2.5-2.2 (m, 6H, NCH morpholinoethoxymethyl); 3.0-2.0 (m, 2H, THIQ), 2.5-2.0 (3s, 3H, CH pyrrole) -1 -1 IR: ν -OH: 3300-2200 cm , ν >C=O: 1697-1662 cm (double band, carboxylic acid), ν >C=O: 1628 cm (amide) Step D: N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)(5-chloro{[(3S){[2- (morpholinyl)ethoxy]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2- dimethyl-N-phenyl-1H-pyrrolecarboxamide The acid obtained in Step C (1.48 g) is suspended in 15 mL of 1,2-dichloroethane. 1.1 equivalents of 1-chloro-N,N,2-trimethylpropenylamine are added thereto. After stirring for 1 hour at ambient temperature, there are added 15 mL of toluene and 1.05 equivalents of the compound of Preparation 2''. The reaction mixture is heated for 14 hours at 110°C and then dried. The crude product thereby obtained is purified by chromatography over silica gel using dichloromethane and ethanol as eluants to yield the expected product.
H NMR: δ (500 MHz; dmso-d6; 300K): 7.55-7.25 (m, 3H, Cl-Ph); 7.25-6.6 (m, 9H, Ar(THIQ)+phenyl); 6.8-6.5 (m, 2H, phenoxy); 7.0-6.6 (m, 2H, phenoxy); 5.7-5.05 (broad 4s, 1H, pyrrole); 5.2-3.6 (8d, 2H, THIQ); 5.05-3.6 (4m, 1H, NCH THIQ), 3.6-2.9 (m, 8H, aliphatic morpholinoethoxymethyl); 3.4-3.2 (broad 3s, 3H, N-CH ); 3.0-2.1 (m, 2H, THIQ), 2.35 (m, 2H, NCH morpholinoethoxymethyl); 2.4-2.2 (m, 4H, NCH morpholine); 2.4-2.15 (broad 3s, 3H, CH pyrrole); 0.8 (broad 2s, 9H, SiC(CH ) ); 0.1 (4s, 6 H, SiCH ) 3 3 3 3 -1 -1 -1 IR: ν >C=O: 1635-1595 cm (double band), ν Si-O: 1117 cm , ν Si-C: 837 cm Step E: 5-(5-Chloro{[(3S){[2-(morpholinyl)ethoxy]methyl}-3,4-dihydroiso- quinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H- pyrrolecarboxamide hydrochloride To a solution of 0.7 g of the compound of Step D in 5 mL of methanol there is added 0.92 mL of a 1M solution of potassium hydroxide in methanol. After stirring for 1 hour minutes at ambient temperature, saturated aqueous sodium bicarbonate solution is added. The product which precipitates is extracted with ethyl acetate and then washed with water and brine. The resulting aqueous phases are extracted again with ethyl acetate. The organic phases thereby obtained are dried over Na SO , filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography over silica gel using dichloromethane and ammonia-in-ethanol as eluants to provide 0.536 g of the title product, in the form of the base. The latter is dissolved in acetonitrile and converted into salt form using 1M aqueous HCl solution. After a lyophilisation step, the expected product is obtained in the form of a solid.
Elemental microanalysis: (%, measured(theoretical)) %C=66.4(66.75);%H=5.98(5.87);%N=7.38(7.41);%Cl=9.42(9.38);%Cl =4.57(4.69) E Ex xa am mp plle e 3 30 0..1 1- -( (2 2- -A Am miin no oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- - 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- pyrazolyl)-1H-pyrrolecarboxamide hydrochloride pyrazolyl)-1H-pyrrolecarboxamide hydrochloride Step A: 2-{3-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)(1-methyl-1H-pyrazol yl)carbamoyl]methyl(6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolyl}ethyl methanesulphonate A solution of 4.65 g of the compound obtained in Step B of Example 23 (6.22 mmol) in 100 mL of anhydrous THF is placed at 0°C. There are successively added thereto 3.5 mL (12.44 mmol) of triethylamine and then, dropwise, 0.722 mL of methanesulphonic chloride (9.33 mmol) dissolved in 20 mL of THF. The batch is then stirred at ambient temperature for 2 hours. The reaction mixture is hydrolysed by addition of saturated aqueous NaHCO solution and then extracted twice with ethyl acetate. The organic phases are combined, dried over MgSO and concentrated to dryness. The expected compound is obtained in the form of a glassy solid.
H NMR: δ (500 MHz; dmso-d6; 300K): 7.7-7.45 (s, 1H, H pyrazole); 7.1-6.9 (s, 1H, H pyrazole); 7.2-6.4 (m, 8H, aromatic Hs); 6.95-6.65 (m, 2H, aromatic Hs); 6.1 (m, 2H, OCH O); 5.2, 4.6 (4s, H, H-pyrrole (presence of conformational isomers); 4.9, 4.6, 3.9, 3.8 (m, 1H), 5.05-3.75 (m, 1H, aliphatic H, H tetrahydroisoquinoline); 4.3-4.05 (m, 2H, aliphatic Hs, CH CH OSO CH ); 4.2-3.95 (m, 2H, aliphatic Hs, CH CH OSO CH ); 3.75- 2 2 2 3 2 2 2 3 2.7 (2s, 3H, CH -pyrazole); 3.0 (several s, 3H, CH OSO CH ); 3.05-2.5 (several m, 2H, 3 2 2 3 aliphatic Hs, H tetrahydroisoquinoline); 2.45-2.3 (several s, 3H, CH -pyrrole); 1.05, 0.75 (several d, 3H, CH -tetraisoquinoline); 0.9 (several s, 9H, Si(CH ) (CH(CH ) ); 0.1 (m, 3 3 2 3 2 6H, Si(CH ) (CH(CH ) ) 3 2 3 2 -1 -1 IR: ν: >C=O: 1626 cm , ν: -SO : 1349 and 1172 cm Step B: 1-(2-Azidoethyl)-N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)methyl(6- {[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1- methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide To a solution of 2 g (2.42 mmol) of compound of Step A in 20 mL of anhydrous DMF there is added 0.472 g (7.26 mmol) of sodium azide. The batch is stirred at 65°C for 4 hours 30 minutes. The reaction mixture is poured into saturated aqueous NaHCO solution and then extracted twice with ethyl acetate. The organic phases are combined and washed with saturated aqueous LiCl solution, dried over MgSO and concentrated to dryness. After purification over silica gel using dichloromethane and ammonia-in- methanol as eluants, the expected product is obtained in the form of a foam.
H NMR: δ (500 MHz; dmso-d6; 300K): 7.65-7.45 (several s, 1H, H pyrazole); 7.1-6.9 (several s, 1H, H pyrazole); 7.3-6.4 (several m, 6H, aromatic Hs); 7.1-6.9 (several s, 1H, aromatic Hs); 6.8, 6.5 (2m, 2H, aromatic Hs); 6.1 (several s, 2H, OCH O); 5.25- 4.65 (several s, 1H, H-pyrrole (presence of conformational isomers); 4.9, 4.6,3.8 (several m, 1H); 5.05-3.7 (several m, 4H, aliphatic Hs, H-THIQ + CH CH N ); 3.7 (several s, 3H, H 2 2 3 CH -pyrazole); 3.5-3.25 (m, 2H, CH CH N ); 3.1-2.4 (several m, 3H, CH -pyrrole); 2.45- 3 2 2 3 3 2.3 (several s, 3H, CH -pyrrole); 1.0-0.75 (several d, 3H, CH -THIQ); 0.9 (several s, 9H, Si(CH ) (CH(CH ) ); 0.1 (several s, 6H, Si(CH ) (CH(CH ) ) 3 2 3 2 3 2 3 2 -1 -1 -1 IR: ν:-N=N=N: 2100 cm , ν: >C=O: 1630 cm , ν: -Si-O-: 1035 cm Step C: 1-(2-Azidoethyl)-N-(4-hydroxyphenyl)methyl(6-{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide To a solution of 1.12 g of the compound obtained in Step B (14.49 mmol) in 5 mL of methanol there are added, dropwise, 7.24 mL of 1M methanolic potassium hydroxide solution (72.45 mmol). The batch is stirred at ambient temperature for 3 hours. The reaction mixture is then concentrated to dryness, taken up in dichloromethane, hydrolysed with saturated aqueous NaHCO solution and then extracted twice with dichloromethane.
The organic phases are then combined, washed with water, dried over MgSO and concentrated to dryness. The expected product is obtained in the form of a foam and used directly in the next Step.
H NMR: δ (500 MHz; dmso-d6; 300K): 9.60( (s, 1H, CH CH OH); 7.65-7.45 (several s, 1H, H pyrazole); 7.1-6.9 (several s, 1H, H pyrazole); 7.3-6.4 (several m, 6H, aromatic Hs); 7.1-6.9 (several s, 1H, aromatic Hs); 6.8, 6.5 (2m, 2H, aromatic Hs); 6.15 (several s, 2H, OCH O); 5.35- 4.8 (several s, 1H, H-pyrrole (presence of conformational isomers); 4.9, 4.6, 3.8 (several m, 1H, aliphatic H, H tetrahydroisoquinoline); 3.7 (several s, 3H, H CH - pyrazole); 3.5-3.25 (m, 2H, CH CH N ); 3.1-2.4 (several m, 3H, CH -pyrrole); 2.45-2.3 2 2 3 3 (several s, 3H, H THIQ); 2.45-2.3 (several s, 3H, CH -pyrrole); 1.0-0.75 (several d, 3H, CH -THIQ) -1 -1 -1 IR: ν:-OH: 3171 cm , ν:-N=N=N: 2100 cm , ν: >C=O: 1617 cm Step D: 1-(2-Aminoethyl)-N-(4-hydroxyphenyl)methyl(6-{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide hydrochloride To a solution of 1.27 g of the compound obtained in the above Step (1.93 mmol) in 15 mL of anhydrous ethanol there is added 0.154 g of Pd/C 10 %. The batch is degassed for 0.5 hours. It is then stirred for 12 hours at ambient temperature under hydrogen pressure (1.5 bar). The reaction mixture is then filtered and then concentrated to dryness. After purification by chromatography over silica gel (CH Cl /MeOH/NH gradient), an oily 2 2 3 residue is obtained. The residue is dissolved in 10 mL of anhydrous ethanol and then converted into salt form by adding two molar equivalents of a 1N solution of HCl in ethanol. The product is then dried before being dissolved in a minimum of a mixture of water and acetonitrile. After a lyophilisation step at low temperature, the expected product is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=64.62:63.84; %H=5.57:5.55; %N=12.56:12.36; %Cl-=5.3:5.56 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 36 36 6 5 [M+H] calculated: 633.2820 [M+H] measured: 633.2808 Example 31.N-(4-Hydroxyphenyl)(5-methoxy{[(3R)methyl-3,4- Example 31.N-(4-Hydroxyphenyl)(5-methoxy{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol- 4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Elemental microanalysis: (%, theoretical:measured) %C=71.29:70.17; %H=5.98:5.98; %N=11.88:11.49 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 36 5 4 [M+H] calculated: 590.2762 [M+H] measured: 590.2778 Example 32.Phenyl (4-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H- Example 32.Phenyl (4-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H- pyrrolyl}{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)- pyrrolyl}{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)- c ca ar rb ba am ma at te e Step A: N-(4-Benzyloxyphenyl)-N,1,2-trimethyl-pyrrolecarboxamide The process is analogous to that described in Step A of Example 45.
Step B: tert-Butyl [4-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-1,5-dimethyl-1H- pyrrolyl){[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl]- carbamate The compound of Preparation II (1.5 g; 2.96 mmol) and the compound of Step A (1.16 g; 3.44 mmol) are dissolved in dimethylacetamide (25 mL) and then nitrogen is bubbled through the solution for 5 minutes. Potassium acetate (0.586 g; 5.92 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.2 g; 0.295 mmol) are added to the mixture which is then heated to 100°C and, after stirring for 20 minutes, water (10 µL) is added. Stirring at 100°C under a nitrogen atmosphere is continued for 2 hours more. The reaction mixture is allowed to cool to ambient temperature and is then evaporated to a volume of 15 mL. The resulting mixture is filtered over a short Celite column and then purified by preparative HPLC using water-TFA and acetonitrile as eluants. The pH of the appropriate fractions is adjusted to 7 with NaHCO , and then the acetonitrile is evaporated off under reduced pressure. The aqueous residue is extracted with DCM. The organic phase is washed with brine, dried over Na SO and evaporated to dryness to yield the title compound.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 41 5 4 [M+H] calculated: 713.3705 [M+H] measured: 713.3709 Step C: 5-[4-(Aminomethyl){[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl]-N-[4-(benzyloxy)phenyl]-N,1,2-trimethyl-1H-pyrrolecarboxamide hydrochloride The compound of the above Step (1.18 g, 1.66 mmol) is dissolved/suspended in 4M HCl in dioxane (20 mL). The heterogeneous mixture is stirred for 30 minutes at ambient temperature and then evaporated to dryness to yield 1.19 g of the title compound which is used in the next Step without purification.
Step D: Phenyl (4-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol yl}{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)carbamate The title compound is obtained starting from the compound of the above Step in accordance with the protocol of Step D of Example 45.
Elemental microanalysis: (%, measured(theoretical)) %C=72.83(72.88);%H=6.01(5.96);%N=8.02(8.72) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 39 38 4 5 [M+H] calculated: 643.2922 [M+H] measured: 643.2916 E Ex xa am mp plle e 3 33 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -f fllu uo or ro op ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- - 1H-pyrrolecarboxamide hydrochloride 1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, measured(theoretical)) %C=65.75(65.84);%H=5.38(5.39);%N=7.62(7.68);%Cl=9.77(9.72);%Cl-=4.84(4.86) Example 34.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 34.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(3-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl- 2(1H)-yl]carbonyl}phenyl)-N-(3-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl- 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, measured(theoretical)) %C=65.61(65.84);%H=5.09(5.39);%N=7.76(7.68);%Cl-=4.83(4.86) E Ex xa am mp plle e 3 35 5..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -N N,,1 1,,2 2- -t tr riim me et th hy yll- -5 5- -( (2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -4 4- -{ {[ [( (p ph he en no ox xy ya ac ce et ty yll) )a am miin no o] ]m me et th hy yll} }p ph he en ny yll) )- - 1H-pyrrolecarboxamide 1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 32 using 2- phenoxyacetyl chloride as acylating agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %C=72.53(73.15);%H=5.76(6.14);%N=8.31(8.53) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 40 4 5 [M+H] calculated: 657.3079 [M+H] measured: 657.3061 Example 36.5-(4-{[(Ethylcarbamoyl)amino]methyl}{[(3R)methyl-3,4- Example 36.5-(4-{[(Ethylcarbamoyl)amino]methyl}{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl- 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 32 using ethyl isocyanate as acylating agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %C=70.88(70.8);%H=6.02(6.62);%N=11.17(11.8) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 39 5 4 [M+H] calculated: 594.3100 [M+H] measured: 594.3083 Example 37.5-(4-{[(Benzylcarbamoyl)amino]methyl}{[(3R)methyl-3,4- Example 37.5-(4-{[(Benzylcarbamoyl)amino]methyl}{[(3R)methyl-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -N N,,1 1,,2 2- -t tr riim me et th hy yll- - 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 32 using benzyl isocyanate as acylating agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %C=73.21(73.26);%H=5.98(6.3);%N=10.23(10.68) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 41 5 4 [M+H] calculated: 656.3239 [M+H] measured: 656.3256 E Ex xa am mp plle e 3 38 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (h hy yd dr ro ox xy ym me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole c ca ar rb bo ox xa am miid de e Elemental microanalysis: (%, measured(theoretical)) %C=70.97(71.34);%H=5.2(5.32);%N=6.96(6.93) Example 39.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3R)methyl-3,4- Example 39.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3R)methyl-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrazolyl)-1H-pyrrolecarboxamide pyrazolyl)-1H-pyrrolecarboxamide Elemental microanalysis: (%, measured(theoretical)) %C=69.81(69.64);%H=5.6(5.51);%N=11.55(11.6) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 34 5 5 [M+H] calculated: 604.2554 [M+H] measured: 604.2565 Example 40.Phenyl (3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H- Example 40.Phenyl (3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H- p py yr rr ro oll- -2 2- -y yll} }- -4 4- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }b be en nz zy yll) )- - c ca ar rb ba am ma at te e Step A: N-(4-Benzyloxyphenyl)-N,1,2-trimethyl-pyrrolecarboxamide The process is analogous to that described in Step A of Example 45.
Step B: 5-[5-(Aminomethyl){[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl]-N-[4-(benzyloxy)phenyl]-N,1,2-trimethyl-1H-pyrrolecarboxamide hydrochloride The compound of Preparation III (1.84 g; 3.99 mmol) and the compound of Step A (1.60 g; 4.48 mmol) are dissolved in dimethylacetamide (20 mL) and then nitrogen is bubbled through the solution for 5 minutes. Potassium acetate (0.78 g; 7.48 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.28 g; 0.4 mmol) are added to the mixture which is then heated to 105°C and, after stirring for 10 minutes, water (11 µL) is added. Stirring at 105°C under a nitrogen atmosphere is continued for 6 hours more. The reaction mixture is allowed to cool to ambient temperature, the resulting mixture is filtered over a short Celite column and is then purified by preparative HPLC using water-TFA and acetonitrile as eluants. The pH of the appropriate fractions is adjusted to 7 with NaHCO and then the acetonitrile is evaporated off under reduced pressure. The solid precipitate is removed by filtration and then dried (5 mbar, 45°C, 16 hours) to form tert-butyl [3-(4-{[4- (benzyloxy)phenyl](methyl)carbamoyl}-1,5-dimethyl-1H-pyrrolyl){[(3R)methyl- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl]carbamate which is dissolved/suspended in 4M HCl in dioxane (35 mL). The heterogeneous mixture is stirred for 30 minutes at ambient temperature and then evaporated to dryness to yield the title compound which is used in the next Step without purification.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 39 40 4 3 [M+H] calculated: 613.3180 [M+H] measured: 613.3194 -1 -1 -1 IR: ν: N-H+: 2854 cm ; >C=O: 1621 cm ; C-O-C: 1234, 1120, 1011 cm Step C: Phenyl (3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol yl}{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)carbamate The title compound is obtained starting from the compound of the above Step in accordance with the process of Step D of Example 45.
Elemental microanalysis: (%, measured(theoretical)) %C=73.2(72.88);%H=5.83(5.96);%N=8.13(8.72) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 39 38 4 5 [M+H] calculated: 643.2922 [M+H] measured: 643.2902 E Ex xa am mp plle e 4 41 1..N N- -( (3 3- -F Fllu uo or ro op ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- - m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- - 3-carboxamide 3-carboxamide Elemental microanalysis: (%, measured(theoretical)) %C=71.44(71.95);%H=4.95(5.22);%N=6.8(6.8) High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O 37 33 3 5 [M+H] calculated: 618.2399 [M+H] measured: 618.2392 Example 42.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3R)methyl-3,4- Example 42.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Elemental microanalysis: (%, measured(theoretical)) %C=71.32(71.65);%H=5.17(5.4);%N=10.67(10.71) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 39 36 5 5 [M+H] calculated: 654.2711 [M+H] measured: 654.2710 Example 43.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3R)methyl-3,4- Example 43.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-phenyl-1H-pyrrole dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-phenyl-1H-pyrrole c ca ar rb bo ox xa am miid de e Elemental microanalysis: (%, measured(theoretical)) %C=73.9(74.11);%H=5.16(5.55);%N=6.81(7.01) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 37 34 3 5 [M+H] calculated: 600.2493 [M+H] measured: 600.2495 E Ex xa am mp plle e 4 44 4..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]- - pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, measured(theoretical)) %C=66.41(66.62);%H=5.08(5.59);%N=10.85(10.84);%Cl-=4.68(4.57) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 43 42 6 6 [M+H] calculated: 739.3239 [M+H] measured: 739.3246 Example 45.Phenyl [2-(3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H- Example 45.Phenyl [2-(3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H- p py yr rr ro oll- -2 2- -y yll} }- -4 4- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- - p ph he en ny yll) )e et th hy yll] ]c ca ar rb ba am ma at te e Step A: N-(4-Benzyloxyphenyl)-N,1,2-trimethyl-pyrrolecarboxamide To a suspension of 1,2-dimethylpyrrolecarboxylic acid (2.085 g; 15 mmol) in 1,2- dichloroethane (40 mL) there is added 1-chloro-N,N,2-trimethyl-propenamine (2.37 mL; 17.9 mmol), and the solution formed is stirred for 1 hour. To the resulting solution there is added, dropwise, an ice-cold solution of 4-benzyloxy-N-methyl-aniline (3.73 g; 15 mmol) and N-ethyl-N-isopropyl-propanamine (7.75 mL; 45 mmol) in 1,2- dichloroethane (40 mL). The reaction mixture is stirred at ambient temperature for 1 hour; it is then diluted with dichloromethane (250 mL) and washed with water (2 x 30 mL), dried over Na SO and evaporated. The crude product is triturated with diethyl ether and the solid formed is filtered off to yield the title compound. -1 -1 -1 IR: ν: >C=O: 1616 cm ; amide: 1508 cm ; C-O-C: 1230, 1172, 1009 cm Step B: tert-Butyl {2-[3-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-1,5-dimethyl-1H- pyrrolyl){[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl]ethyl}- carbamate The compound of Preparation I (0.869 g; 1.67 mmol) and the compound of Step A (0.558 g; 1.67 mmol) are dissolved in dimethylacetamide (8 mL) and then nitrogen is bubbled through the solution for 5 minutes. Potassium acetate (0.33 g; 3.34 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.117 g; 0.167 mmol) are added to the mixture which is then heated to 140°C and, after stirring for 10 minutes, water (80 µL) is added. Stirring at 140°C under a nitrogen atmosphere is continued for 16 hours more. The reaction mixture is allowed to cool to ambient temperature and then evaporated. The residue is partitioned between dichloromethane (100 mL) and water (20 mL). The organic phase is washed with water (20 mL), dried over Na SO and evaporated. The residue was purified by preparative HPLC using water-TFA and acetonitrile as eluants. The pH of the appropriate fractions is adjusted to 12 using aqueous NaOH solution and then the acetonitrile is evaporated off under reduced pressure. The aqueous residue is extracted with dichloromethane (2 x 100 mL). The organic phase is dried over Na SO and evaporated to dryness to yield the title compound.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 45 50 4 5 [M+H] calculated: 727.3861 [M+H] measured: 727.3852 -1 -1 -1 IR: ν: >C=O: 1705, 1618 cm ; amide: 1509 cm ; C-O-C: 1242, 1166, 1012 cm Step C: 5-[5-(2-Aminoethyl){[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl]-N-[4-(benzyloxy)phenyl]-N,1,2-trimethyl-1H-pyrrolecarboxamide hydrochloride The compound of Step B (0.35 g; 0.48 mmol) was dissolved/suspended in 4M HCl in dioxane (3 mL). The heterogeneous mixture is stirred for 30 minutes at ambient temperature and then evaporated to dryness to yield the title compound which is used in next Step without being otherwise purified.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 42 4 3 [M+H] calculated: 627.3337 [M+H] measured: 627.3309 -1 -1 -1 -1 IR: ν: C-H: 2931 cm ; >C=O: 1608 cm ; amide: 1508 cm ; C-O-C: 1233, 1012 cm Step D: Phenyl 2-(3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol- 2-yl}{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)ethyl]- carbamate The compound of Step C (0.10 g; 0.15 mmol) is dissolved in dichloromethane. Phenyl chloroformate (0.027 g; 0.17 mmol) and diisopropylethylamine (0.097 g, 0.75 mmol) are added thereto. The reaction mixture is stirred at ambient temperature for 30 minutes. After dilution with dichloromethane (100 mL), the organic phase is washed with water (20 mL), evaporated and concentrated. The residue is then dissolved in ethanol and a Pd/C catalyst is added (10 mg). The reaction mixture is hydrogenated at atmospheric pressure at ambient temperature. When the reaction is complete, the catalyst is removed by filtration, the filtrate is concentrated and the crude product is purified by chromatography over silica gel using dichloromethane and methanol as eluants, to yield the title product.
Elemental microanalysis: (%, measured(theoretical)) %C=72.36(73.15);%H=6.15(6.14);%N=8.14(8.53) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 40 4 5 [M+H] calculated: 657.3077 [M+H] measured: 657.3062 Example 46.N-(4-Hydroxyphenyl)-N,1,2-trimethyl(2-{[(3R)methyl-3,4- Example 46.N-(4-Hydroxyphenyl)-N,1,2-trimethyl(2-{[(3R)methyl-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -5 5- -{ {2 2- -[ [( (p ph he en no ox xy ya ac ce et ty yll) )a am miin no o] ]e et th hy yll} }p ph he en ny yll) )- - 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 45 using 2- phenoxyacetyl chloride as acylating agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %C=72.74(73.41);%H=6.38(6.31);%N=7.65(8.35) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 41 42 4 5 [M+H] calculated: 671.3235 [M+H] measured: 671.3226 Example 47.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(6- Example 47.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(6- {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, measured(theoretical)) %C=64.25(64.59);%H=5.4(5.7);%N=11.41(11.59);%Cl-=4.93(4.89) E Ex xa am mp plle e 4 48 8..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -( (2 2- -m me et th ho ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- - { {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- - pyrrolecarboxamide pyrrolecarboxamide Elemental microanalysis: (%, measured(theoretical)) %C=68.07(68.45);%H=5(5.27);%N=10.74(11.09) E Ex xa am mp plle e 4 49 9..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e d diih hy yr ro oc ch hllo or riid de e Step A: N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 11 and (3S)(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (see Preparation 3') in Step A, and the compound of Preparation 11'' in Step C.
Step B: N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3- b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide dihydrochloride To a solution of 0.21 g (0.2 mmol) of the compound of Step A in 3 mL of acetic acid there are added 85 mg of sodium cyanoborohydride (5 equivalents). The reaction mixture is stirred for 3 hours at ambient temperature and then overnight at 50°C. There are then added 2.6 equivalents of sodium cyanoborohydride and the reaction mixture is heated at 50°C for 3 hours. The operation is repeated for a second time (addition of 2.6 equivalents of sodium cyanoborohydride and then heating at 50°C for 3 hours). After coevaporation of the acetic acid in the presence of toluene, the residue is taken up in 3 mL of methanol. The pH of the solution is adjusted to 12 using 1M methanolic potassium hydroxide solution. After stirring overnight at ambient temperature, the reaction mixture is poured into saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The resulting organic phase is washed with brine, dried over Na SO , filtered and concentrated under reduced pressure. The product obtained is purified by chromatography over silica gel (dichloromethane/ethanol/ammonia 94/6/0.6) and then over a Lichroprep RP18 column (water/acetonitrile/trifluoroacetic acid). After evaporation of the acetonitrile, the product is neutralised with sodium bicarbonate. It is then extracted with ethyl acetate. The organic phase is dried over Na SO , filtered and concentrated under reduced pressure. The residue obtained is dissolved in acetonitrile and converted into salt form with 1M aqueous HCl solution. After lyophilisation, the title product is obtained in the form of a solid.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 43 44 6 6 [M+H] calculated: 741.3395 [M+H] measured: 741.3400 E Ex xa am mp plle e 5 50 0..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -( (2 2- -m me et th ho ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- - { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 40 6 7 [M+H] calculated: 717.3031 [M+H] measured: 717.3031 Example 51.5-(5-{[(Benzylcarbamoyl)amino]methyl}{[(3R)methyl-3,4- Example 51.5-(5-{[(Benzylcarbamoyl)amino]methyl}{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl- 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 40 using benzyl isocyanate as acylating agent in Step C.
Elemental microanalysis: (%, measured(theoretical)) %C=73.39(73.26);%H=6.16(6.3);%N=10.08(10.68) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 41 5 4 [M+H] calculated: 656.3239 [M+H] measured: 656.3226 E Ex xa am mp plle e 5 52 2..5 5- -( (5 5- -{ {[ [( (E Et th hy yllc ca ar rb ba am mo oy yll) )a am miin no o] ]m me et th hy yll} }- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -N N,,1 1,,2 2- -t tr riim me et th hy yll- - 1H-pyrrolecarboxamide 1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 40 using ethyl isocyanate as acylating agent in Step C.
Elemental microanalysis: (%, measured(theoretical)) %C=71.4(70.8);%H=6.41(6.62);%N=11.24(11.8) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 39 5 4 [M+H] calculated: 594.3082 [M+H] measured: 594.3069 E Ex xa am mp plle e 5 53 3..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -N N,,1 1,,2 2- -t tr riim me et th hy yll- -5 5- -( (2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -5 5- -{ {[ [( (p ph he en no ox xy ya ac ce et ty yll) )a am miin no o] ]m me et th hy yll} }p ph he en ny yll) )- - 1H-pyrrolecarboxamide 1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 40 using 2- phenoxyacetyl chloride as acylating agent in Step C.
Elemental microanalysis: (%, measured(theoretical)) %C=72.32(73.15);%H=6.21(6.14);%N=7.84(8.53) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 40 4 5 [M+H] calculated: 657.3079 [M+H] measured: 657.3105 Example 54.N-(4-Hydroxyphenyl)-1,2-dimethyl(2-{[(3R)methyl-3,4- Example 54.N-(4-Hydroxyphenyl)-1,2-dimethyl(2-{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}{[(phenoxyacetyl)amino]methyl}phenyl)-N- dihydroisoquinolin-2(1H)-yl]carbonyl}{[(phenoxyacetyl)amino]methyl}phenyl)-N- ( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Elemental microanalysis: (%, measured(theoretical)) %C=73.87(73.04);%H=5.47(5.74);%N=10.26(10.87) E Ex xa am mp plle e 5 55 5..5 5- -( (5 5- -[ [2 2- -( ({ {[ [2 2- -( (4 4- -F Fllu uo or ro op ph he en ny yll) )e et th hy yll] ]s su ullp ph ho on ny yll} }a am miin no o) )e et th hy yll] ]- -2 2- -{ {[ [( (3 3R R) )- -3 3- - m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- - N,1,2-trimethyl-1H-pyrrolecarboxamide N,1,2-trimethyl-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 45 using 2-(4- fluorophenyl)ethanesulphonyl chloride as acylating agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %C=67.42(68.12);%H=5.76(6);%N=7.27(7.75);S=3.68(4.44) High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O S 41 43 4 5 [M+H] calculated: 723.3018 [M+H] measured: 723.3011 E Ex xa am mp plle e 5 56 6..5 5- -( (5 5- -{ {2 2- -[ [( (B Be en nz zy yllc ca ar rb ba am mo oy yll) )a am miin no o] ]e et th hy yll} }- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl- 1H-pyrrolecarboxamide 1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 45 using benzyl isocyanate as acylating agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %C=71.14(73.52);%H=6.47(6.47);%N=9.42(10.46) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 41 43 5 4 [M+H] calculated: 670.3395 [M+H] measured: 670.3390 Example 57.N-(4-Hydroxyphenyl)-N,1,2-trimethyl(2-{[(3R)methyl-3,4- Example 57.N-(4-Hydroxyphenyl)-N,1,2-trimethyl(2-{[(3R)methyl-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -5 5- -{ {2 2- -[ [( (p ph he en ny ylla ac ce et ty yll) )a am miin no o] ]e et th hy yll} }p ph he en ny yll) )- -1 1H H- - pyrrolecarboxamide pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 45 using phenylacetyl chloride as acylating agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %C=75.46(75.21);%H=6.11(6.46);%N=8.31(8.56) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 41 42 4 4 [M+H] calculated: 655.3286 [M+H] measured: 655.3285 E Ex xa am mp plle e 5 58 8..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -N N,,1 1,,2 2- -t tr riim me et th hy yll- -5 5- -( (2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -5 5- -{ {2 2- -[ [( (p ph he en ny yllc ca ar rb ba am mo oy yll) )a am miin no o] ]e et th hy yll} }p ph he en ny yll) )- - 1H-pyrrolecarboxamide 1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 45 using phenyl isocyanate as acylating agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %C=71.25(73.26);%H=6.12(6.3);%N=9.61(10.68) High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 41 5 4 [M+H] calculated: 656.3239 [M+H] measured: 656.3226 Example 59.5-(4-[({[2-(4-Fluorophenyl)ethyl]sulphonyl}amino)methyl]{[(3R) Example 59.5-(4-[({[2-(4-Fluorophenyl)ethyl]sulphonyl}amino)methyl]{[(3R) methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- N N,,1 1,,2 2- -t tr riim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 32 using 2-(4- fluorophenyl)ethanesulphonyl chloride as sulphonylation agent in Step D.
Elemental microanalysis: (%, measured(theoretical)) %H=5.19(5.83);%N=7.28(7.9);S=4.45(4.52);%C=66.17(67.78) High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O S 40 41 4 5 [M+H] calculated: 709.2866 [M+H] measured: 709.2866 E Ex xa am mp plle e 6 60 0..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -{ {[ [2 2- -( (d diim me et th hy ylla am miin no o) )e et th ho ox xy y] ]m me et th hy yll} }- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy y p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - phenyl-1H-pyrrolecarboxamide hydrochloride phenyl-1H-pyrrolecarboxamide hydrochloride The process of Example 29 is used, on the one hand replacing the 4-(2- bromoethyl)morpholine hydrobromide used in Step B by 2-chloroethyldimethylamine hydrochloride and on the other hand adding a catalytic amount of tetrabutylammonium iodide.
High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 40 41 4 4 [M+H] calculated: 677.2890 [M+H] measured: 677.2887 E Ex xa am mp plle e 6 61 1..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(pyridinyl)-1H- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(pyridinyl)-1H- p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 36 32 4 5 [M+H] calculated: 601.2445 [M+H] measured: 601.2424 E Ex xa am mp plle e 6 62 2..5 5- -( (5 5- -F Fllu uo or ro o- -4 4- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide Elemental microanalysis: (%, measured(theoretical)) %C=68.99(69.18);%H=5.89(5.64);%N=11.35(11.52) High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O 34 5 4 [M+H] calculated: 608.2668 [M+H] measured: 608.2640 E Ex xa am mp plle e 6 63 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]- carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]- pyridinyl)-1H-pyrrolecarboxamide pyridinyl)-1H-pyrrolecarboxamide Elemental microanalysis: (%, measured(theoretical)) %C=70.48(70.85);%H=5.67(5.32);%N=11.2(10.87) High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 38 34 5 3 [M+H] calculated: 666.2242 [M+H] measured: 666.2235 Example 64.N,1,2-Trimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)- Example 64.N,1,2-Trimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)- 3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 38 40 6 5 [M+H] calculated: 661.3133 [M+H] measured: 661.3125 Example 65.1,2-Dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S) Example 65.1,2-Dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol- (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol- 5- -y yll) )- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 43 42 6 5 [M+H] calculated: 723.3289 [M+H] measured: 723.3287 E Ex xa am mp plle e 6 66 6..4-Methylphenyl (4-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5- dimethyl-1H-pyrrolyl}{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}benzyl)carbamate The title compound is obtained in accordance with the process of Example 32 using 4- methylphenyl chloroformate as acylating agent in Step D.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 40 4 5 [M+H] calculated: 657.3079 [M+H] measured: 657.3076 Example 67.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 67.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, measured(theoretical)) %C=65.69(65.28);%H=5.38(5.77);%N=11.18(12.02);%Cl-=5.61(5.07) E Ex xa am mp plle e 6 68 8..5 5- -( (5 5- -F Fllu uo or ro o- -4 4- -h hy yd dr ro ox xy y- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide A 1N solution of tribromoborane (1.3 equivalents) in dichloromethane is poured rapidly, at ambient temperature, into a solution of the compound of Example 62 in dichloromethane.
This operation is repeated twice in order to complete the reaction in 5 hours. The reaction mixture is poured into anhydrous ethanol at 5°C. After stirring for 10 minutes, saturated aqueous NaHCO solution is added. The mixture is extracted with dichloromethane, dried over Na SO and concentrated to dryness. The crude product obtained is purified by preparative HPLC using water, TFA and acetonitrile as eluants. The pH of the appropriate fractions is adjusted to 12 with saturated aqueous NaHCO solution, and then the acetonitrile is evaporated off under reduced pressure. The aqueous residue is extracted with dichloromethane. The organic phase is dried over Na SO and evaporated to dryness to yield the title compound.
High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O 34 32 5 4 [M+H] calculated: 594.2511 [M+H] measured: 594.2517 E Ex xa am mp plle e 6 69 9..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -[ [( (4 4- -m me et th hy yllp piip pe er ra az ziin n- -1 1- - y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- - methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 44 45 7 5 [M+H] calculated: 752.3555 [M+H] measured: 752.3552 Example 70.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3S)[(4-methylpiperazin Example 70.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3S)[(4-methylpiperazin y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- - ( (p py yr riid diin n- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 41 42 6 5 [M+H] calculated: 699.3289 [M+H] measured: 699.3293 E Ex xa am mp plle e 7 71 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 42 41 6 4 [M+H] calculated: 723.3289 [M+H] measured: 723.3287 E Ex xa am mp plle e 7 72 2..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - benzimidazolyl)-1H-pyrrolecarboxamide benzimidazolyl)-1H-pyrrolecarboxamide Elemental microanalysis: (%, measured(theoretical)) %C=68.90(69.17);%H=5.32(5.67);%N=11.40(11.52) E Ex xa am mp plle e 7 73 3..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- - 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(pyridinyl)-1H- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(pyridinyl)-1H- pyrrolecarboxamide dihydrochloride pyrrolecarboxamide dihydrochloride High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 39 5 6 [M+H] calculated: 686.2973 [M+H] measured: 686.2971 E Ex xa am mp plle e 7 74 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (p py yr riid diin n- -4 4- -y yll) )- -1 1H H- - pyrrolecarboxamide hydrochloride pyrrolecarboxamide hydrochloride High-resolution mass spectrometry (ESI+): Empirical formula: C H ClN O 39 38 5 4 [M+H] calculated: 676.2685 [M+H] measured: 676.2684 Example 75.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl)(6- Example 75.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl)(6- { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -2 2- -( (t tr riif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=60.12:59.77; %H=4.92:4.76; %N=10.79:10.39 %Cl-=4.55:5.17 High-resolution mass spectrometry (ESI+): Empirical formula: C H F N O 39 37 3 6 6 [M+H] calculated: 743.2799 [M+H] measured: 742.2802 E Ex xa am mp plle e 7 76 6..2 2- -( (D Diif fllu uo or ro om me et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 7 77 7..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (m me et th ho ox xy ym me et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 7 78 8..2 2- -( (2 2,,2 2- -D Diif fllu uo or ro oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 79.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl)(6- Example 79.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl)(6- { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -2 2- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 80.N-(4-Hydroxyphenyl)(2-methoxyethyl)methyl-N-(1-methyl-1H- Example 80.N-(4-Hydroxyphenyl)(2-methoxyethyl)methyl-N-(1-methyl-1H- p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 8 81 1..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrazolyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide hydrochloride pyrazolyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide hydrochloride The procedure is in accordance with the general protocol of Example 1 using the compound of Preparation 22 in Step A. The product obtained is finally dissolved in acetonitrile and converted into salt form using 0.1M aqueous HCl solution. After a lyophilisation step, the expected compound is obtained in the form of a solid.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 42 6 6 [M+H] calculated: 703.3239 [M+H] measured: 703.3236 E Ex xa am mp plle e 8 82 2..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- pyrazolyl)(morpholinylmethyl)-1H-pyrrolecarboxamide pyrazolyl)(morpholinylmethyl)-1H-pyrrolecarboxamide The procedure is in accordance with the general protocol of Example 1 using the compound of Preparation 23 in Step A.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 39 40 6 6 [M+H] calculated: 689.3082 [M+H] measured: 689.3085 Example 83.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin Example 83.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- - 1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -2 2- -( (t tr riif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 84.2-(Difluoromethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- Example 84.2-(Difluoromethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - carboxamide carboxamide E Ex xa am mp plle e 8 85 5..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (m me et th ho ox xy ym me et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e Example 86.2-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- Example 86.2-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - carboxamide carboxamide E Ex xa am mp plle e 8 87 7..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- - y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- - 1,3-benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide 1,3-benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 8 88 8..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The procedure is in accordance with the general protocol of Example 1 using the appropriate Preparations. The product obtained is finally dissolved in acetonitrile and converted into salt form using 0.1M aqueous HCl solution. After a lyophilisation step, the expected compound is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=65.97:66.15; %H=5.78:5.46; %N=10.26:10.24; %Cl-=4.33:4.76 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H N O 45 46 6 7 [M+H] calculated: 783.3501 [M+H] measured: 783.3502 Example 89.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin Example 89.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin y yll) )- -2 2- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 90.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin Example 90.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin y yll) )- -2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 9 91 1..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (6 6- - {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxolyl)-1H-pyrrolecarboxamide benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 9 92 2..1 1- -E Et th hy yll- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -5 5- - ( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride The procedure is in accordance with the protocol described in Example 1, using the compounds from Preparations 20 and 3' in Step A and the compound from Preparation 1'' in Step C. The product obtained is finally dissolved in acetonitrile and converted into salt form using 0.1M aqueous HCl solution. After a lyophilisation step, the expected compound is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=64.99:65.61; %H=5.86:5.39; %N=11.37:11.43; %Cl=4.80:4.42 [M+H] measured: 703.3236 Example 93.N-(4-Hydroxyphenyl)(2-methoxyethyl)methyl-N-(1-methyl-1H- Example 93.N-(4-Hydroxyphenyl)(2-methoxyethyl)methyl-N-(1-methyl-1H- pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=64.01:64.10; %H=5.90:5.63; %N=10.92:10.88; %Cl-=4.61:4.70.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 41 44 6 7 [M+H] calculated: 733.3344 [M+H] measured: 733.3345 Example 94.1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- Example 94.1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The procedure is in accordance with the protocol described in Steps A-D of Example 1, using the compounds from Preparations 21 and 3' in Step A and the compound from Preparation 1'' in Step C. The product obtained is finally dissolved in acetonitrile and converted into salt form using 0.1M aqueous HCl solution. After a lyophilisation step, the expected compound is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=63.44:63.25; %H=5.59:5.09; %N=11.10:11.02; %Cl=4.68:4.74 High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O 40 41 6 6 [M+H] calculated: 721.3144 [M+H] measured: 721.3147 Example 95.1-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- Example 95.1-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 32 and the compound of Preparation 3' in Step A, and the compound of Preparation 1'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=61.97:61.89; %H=5.33:5.04; %N=10.84:10.85; %Cl =4.57:4.55 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H F N O 40 40 2 6 6 [M+H] calculated: 739.3050 [M+H] measured: 739.3052 E Ex xa am mp plle e 9 96 6..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrazolyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide hydrochloride pyrazolyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide hydrochloride S Stte ep p A A: : N N- -[ [4 4- -[ [tte er rtt- -B Bu utty yll( (d diim me etth hy yll) )s siilly yll] ]o ox xy yp ph he en ny yll] ]- -2 2- -m me etth hy yll- -5 5- -[ [6 6- -[ [( (3 3R R) )- -3 3- -m me etth hy yll- -3 3,,4 4- - dihydro-1H-isoquinolinecarbonyl]-1,3-benzodioxolyl]-N-(1-methyl-1H-pyrazol dihydro-1H-isoquinolinecarbonyl]-1,3-benzodioxolyl]-N-(1-methyl-1H-pyrazol yl)(2-morpholinoethyl)pyrrolecarboxamide yl)(2-morpholinoethyl)pyrrolecarboxamide The compound obtained in Step E of Example 99 is dissolved in 6 mL of tetrahydrofuran.
Sodium iodide (100 mg, 0.67 mmol) is added, followed by morpholine (0.21 mL, 2.53 mmol) dropwise. The reaction mixture is heated in a sealed flask at 90°C for 72 hours.
After cooling, the solution is evaporated to dryness and the residue is purified by chromatography over silica gel using dichloromethane and methanol as eluants. The expected product is obtained in the form of a foam.
H NMR (500 MHz, dmso-d6) δ ppm: 7.7-7.45 (4 bs, 1 H), 7.2-6.9 (m, 4 H), 7.1-6.4 (m, 2 H), 7.1-6.9 (4 bs, 1 H), 7-6.8 (4 m, 2 H), 6.75/6.48 (d+bs, 2 H), 6.1 (4 bs, 2 H), 5.25-4.7 (4 bs, 1 H), 5.2-3.8 (m, 2 H), 4.9/4.65/3.8 (3 m, 1 H), 3.75 (4 s, 3 H), 3.5 (bs, 4 H), 3-2 (m, H), 2.41/2.3 (2 bs, 3 H), 1.02/0.95/0.78 (3 bd, 3 H), 0.88 (m, 9 H), 0.1 (m, 6 H) IR (ATR) cm 1626 δ >C=O amides Step B: N-(4-Hydroxyphenyl)methyl(6-{[(3R)methyl-3,4-dihydroisoquinolin- Step B: N-(4-Hydroxyphenyl)methyl(6-{[(3R)methyl-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- -m me etth hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1- -[ [2 2- - ( (m mo or rp ph ho olliin n- -4 4- -y yll) )e etth hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The procedure is in accordance with the protocol described in Step D of Example 1. The product obtained is finally subjected to a step of conversion into salt form in the presence of HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 42 6 6 [M+H] calculated: 703.3239 [M+H] measured: 703.3238 E Ex xa am mp plle e 9 97 7..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- - yl)ethyl]-N-phenyl-1H-pyrrolecarboxamide hydrochloride yl)ethyl]-N-phenyl-1H-pyrrolecarboxamide hydrochloride The procedure is in accordance with the protocol described in Example 96 replacing the compound of Preparation 1'' by that of Preparation 2''.
Elemental microanalysis: (%, theoretical:measured) %C=68.61:68.12; %H=5.89:5.23; %N=7.62:7.54; %Cl-=4.82:4.66 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H N O 42 42 4 6 [M+H] calculated: 699.3177 [M+H] measured: 699.3173 Example 98.1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)methyl(6-{[(3R) Example 98.1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)methyl(6-{[(3R) methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-phenyl- methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-phenyl- 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The procedure is in accordance with the protocol described in Example 27 replacing the compound of Preparation 1'' by that of Preparation 2''. The product obtained is finally subjected to a step of conversion into salt form in the presence of 1M HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured) %C=69.30:69.20; %H=5.96:5.48; %N=8.08:8.08; %Cl-=5.11:5.03 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H N O 40 40 4 5 [M+H] calculated: 657.3071 [M+H] measured: 657.3066 E Ex xa am mp plle e 9 99 9..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -{ {2 2- -[ [( (2 2- -m me et th ho ox xy ye et th hy yll) )( (m me et th hy yll) )a am miin no o] ]e et th hy yll} }- -2 2- - m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - benzodioxolyl)-N-(1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide benzodioxolyl)-N-(1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide hydrochloride hydrochloride Step A: Ethyl 1-(2-benzyloxyethyl)methyl[6-[(3R)methyl-3,4-dihydro-1H- isoquinolinecarbonyl]-1,3-benzodioxolyl]pyrrolecarboxylate The procedure is in accordance with the protocol described in Step A of Example 1 replacing the compound of Preparation 1 by that of Preparation 19.
H NMR (500 MHz, dmso-d6) δ ppm: 7.35-6.95 (m, 9 H), 7-6.8 (several s, 2 H), 6.35-5.85 (several s, 1 H), 6.15 (several s, 2 H), 5.15-3.5 (several m, 4 H), 4.9/4.7/3.95 (several m, 1 H), 4.4 (m, 2 H), 4.2-3.95 (m, 2 H), 3.55 (m, 2 H), 3.1-2.35 (several m, 2 H), 2.5-2.2 (several s, 3 H), 1.25-1.1 (several m, 3 H), 1.05-0.7 (several d, 3 H) Step B: 1-(2-Benzyloxyethyl)methyl[6-[(3R)methyl-3,4-dihydro-1H- isoquinolinecarbonyl]-1,3-benzodioxolyl]pyrrolecarboxylic acid The procedure is in accordance with the protocol described in Step B of Example 1.
IR (ATR) cm : 3000-2500 ν -OH, 1675-1625 ν -C=O carboxylic acid + amide Step C: 1-(2-Benzyloxyethyl)-N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]methyl[6- [(3R)methyl-3,4-dihydro-1H-isoquinolinecarbonyl]-1,3-benzodioxolyl]-N-(1- methyl-1H-pyrazolyl)pyrrolecarboxamide -1H- The procedure is in accordance with the protocol described in Step C of Example 1.
H NMR (500 MHz, dmso-d6) δ ppm:7.7-7.5 (several s, 1 H), 7.35-6.5 (several m, 11 H), 7.1-6.9 (several s, 1 H), 6.95-6.5 (several s, 2 H), 6.8/6.5 (m, 2 H), 6.05 (several s, 2 H), .25-4.7 (several s, 1 H), 5.1-3.6 (several m, 4 H), 4.85/4.6/3.75 (several m, 1 H), 4.3 (m, 2 H), 3.7 (2xs, 3 H), 3.4 (m, 2 H), 3.05-2.4 (several m, 2 H), 2.4-2.25 (several s, 3 H), 1-0.75 (several d, 3 H), 0.9 (several s, 9 H), 0.1 (several s, 6 H) IR (ATR) cm : 1629 ν >C=O amides Step D: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl](2-hydroxyethyl)methyl[6- [(3R)methyl-3,4-dihydro-1H-isoquinolinecarbonyl]-1,3-benzodioxolyl]-N-(1- methyl-1H-pyrazolyl)pyrrolecarboxamide -1H- In a hydrogenating reactor, the compound of the above Step is dissolved in 30 mL of methanol. The solution is degassed by bubbling argon in, and palladium-on-carbon 10 % (550 mg) is added. The resulting suspension is stirred under a pressure of 1 bar of hydrogen for 15 hours, and then passed through a Whatman® filter. The catalyst is rinsed with methanol and the filtrate is evaporated in vacuo. The residue thereby obtained is purified by chromatography over silica gel using dichloromethane and methanol as eluants.
The expected product is obtained in the form of an oil.
H NMR (500 MHz, pyridine-d5) δ ppm: 7.7-7.4 (4 s, 1 H), 7.3-6.9 (m, 4 H), 7.1-6.8 (4 s, 1 H), 7-6.7 (m, 2 H), 6.9-6.4 (m, 2 H), 6.8-6.4 (4 m, 2 H), 6.1 (m, 2 H), 5.2/5/4.7 (4 s, 1 H), .15-3.9 (8 d, 2 H), 4.9-4.8 (m, 1 H), 4.9/4.7/3.85 (3 m, 1 H), 3.9-3.7 (m, 2 H), 3.75 (2 s, 3 H), 3.5-3.2 (m, 2 H), 3-2.4 (m, 2 H), 2.4-2.3 (4 s, 3 H), 1.05/0.95/0.75 (4 d, 3 H), 0.85 (bs, 9 H), 0.15-0 (m, 6 H) IR (ATR) cm :3346 ν -OH primary alcohol, 1621ν -C=O amides Step E: 2-[3-[[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-(1-methyl- -1 1H H- -pyrazolyl)- carbamoyl]methyl[6-[(3R)methyl-3,4-dihydro-1H-isoquinolinecarbonyl]-1,3- benzodioxolyl]pyrrolyl]ethyl methanesulphonate The compound of the above Step (2.37 g, 3.17 mmol) is dissolved in 30 mL of tetrahydrofuran. The reaction mixture is cooled to 0°C and there are successively added triethylamine (1.8 mL, 13.9 mmol) and, dropwise, methanesulphonyl chloride (0.40 mL, .17 mmol). The reaction mixture is stirred for 2 hours at 0°C. The reaction mixture is then poured into saturated aqueous sodium hydrogen carbonate solution and extracted 3 times with ethyl acetate. The organic phase is washed 3 times with brine, dried over MgSO , filtered and then evaporated to dryness. The evaporation residue is used without purification in the next Step.
H NMR (500 MHz, dmso-d6) δ ppm: 7.7-7.45 (several s, 1 H), 7.25-6.4 (m, 8 H), 7.1-6.9 (several s, 1 H), 6.95-6.65 (several s, 2 H), 6.1 (several s, 2 H), 5.2-4.6 (several s, 1 H), .05-3.75 (several d, 2 H), 4.9/4.6/3.9/3.8 (several m, 1 H), 4.3-4.05 (m, 2 H), 4.2-3.95 (m, 2 H), 3.75/3.7 (2 s, 3 H), 3.05-2.5 (several m, 2 H), 3 (several s, 3 H), 2.45-2.3 (several s, 3 H), 1.05-0.75 (several d, 3 H), 0.9 (several s, 9 H), 0.1 (several s, 6 H) IR (ATR) cm : 1626 ν -C=O, 1349 ν -SO , 1249 δ –CH3, 1172 ν -SO Step F: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl][2-[2-methoxyethyl(methyl)amino]- ethyl]methyl[6-[(3R)methyl-3,4-dihydro-1H-isoquinolinecarbonyl]-1,3- benzodioxolyl]-N-(1-methyl- -1 1H H- -pyrazolyl)pyrrolecarboxamide The compound of the above Step (1.33 mg, 1.61 mmol) is dissolved in 6 mL of tetrahydrofuran. Sodium iodide (100 mg, 0.67 mmol) is added, followed by dimethylamine (0.172 g, 1.932 mmol) dropwise. The reaction mixture is heated in a sealed flask at 60°C for 36 hours. After cooling, it is evaporated to dryness and purified by chromatography over silica gel using dichloromethane and ammonia-in-methanol as eluants. The expected product is obtained in the form of a foam.
H NMR (500 MHz, dmso-d6) δ ppm 7.7-7.45 (4 bs, 1 H), 7.2-6.9 (m, 4 H), 7.1-6.9 (4 bs, 1 H), 7-6.7 (4 m, 2 H), 7/6.45 (2 m, 2 H), 6.8/6.45 (2 m, 2 H), 6.1 (m, 2 H), .22/5.05/4.7 (4 bs, 1 H), 5.2-3.8 (m, 2 H), 4.91/4.65/3.9 (3 m, 1 H), 3.75 (2 bs, 3 H), 3.7 (m, 2 H), 3.2 (bs, 3 H), 3-2 (m, 2 H), 2.7-2 (ml, 6 H), 2.7-2 (m, 3 H), 2.45/2.35 (2 bs, 3 H), 1.05/0.95/0.8 (3 bd, 3 H), 0.9 (m, 9 H), 0.1 (m, 6 H) IR (ATR) cm 1628 (shoulder) δ –C=O amides Step G: N-(4-hydroxyphenyl)[2-[2-methoxyethyl(methyl)amino]ethyl]methyl[6- [(3R)methyl-3,4-dihydro-1H-isoquinolinecarbonyl]-1,3-benzodioxolyl]-N-(1- methyl- -1 1H H- -pyrazolyl)pyrrolecarboxamide hydrochloride The procedure is in accordance with the protocol described in Step D of Example 1. The product obtained is finally subjected to a step of conversion into salt form in the presence of 1M HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained. -1: + IR (ATR) cm 2000 to 3500 ν -NH /OH, 1615 ν >C=O amides, 1237-1161 δ >C-O-C<, 745 ν >CH-Ar High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 40 44 6 6 [M+H] calculated: 705.3395 [M+H] measured: 705.3391 E Ex xa am mp plle e 1 10 00 0..5 5- -( (5 5- -F Fllu uo or ro o- -4 4- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - (1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide hydrochloride (1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide hydrochloride The procedure is in accordance with the general protocol of Example 1 using the appropriate Preparations. The product obtained is finally dissolved in acetonitrile and converted into salt form using 0.1M aqueous HCl solution. After a lyophilisation step, the expected compound is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=64.23:64.31; %H=5.80:5.43; %N=11.52:11.46; %Cl-=4.86:4.95 High-resolution mass spectrometry (ESI+): Empirical formula: C H F N O 39 41 6 5 [M+H] calculated: 693.3195 [M+H] measured: 693.3194 Example 101. 5-(4-Fluoromethoxy{[(3S)(morpholinylmethyl)-3,4- Example 101. 5-(4-Fluoromethoxy{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- ( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 27 and the compound of Preparation 3' in Step A, and the compound of Preparation 1'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=64.23:63.12; %H=5.80:5.20; %N=11.52:11.38. %Cl =4.86:5.03 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H F N O 39 41 6 5 [M+H] calculated: 693.3195 [M+H] measured: 693.3195 Example 102. 5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4-dihydro- Example 102. 5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4-dihydro- iis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e t tr riih hy yd dr ro oc ch hllo or riid de e High-resolution mass spectrometry (ESI+): Empirical formula: C H Cl N O 43 44 7 3 [M+H] calculated: 742.3267 [M+H] measured: 742.3268 Example 103.5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4- Example 103.5-(5-Chloro{[(3S)[(4-methylpiperazinyl)methyl]-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 104.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolo[3,4-b]- Example 104.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolo[3,4-b]- p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 10 05 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- - dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 10 06 6..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- - N-phenyl-1H-pyrrolecarboxamide N-phenyl-1H-pyrrolecarboxamide The procedure is in accordance with the general protocol of Example 1 using the appropriate Preparations, it being understood that Step D is not carried out. The expected product is obtained in free base form.
Elemental microanalysis: (%, theoretical:measured) %C=70.72:69.77; %H=5.79:5.96; %N=11.78:11.43 High-resolution mass spectrometry (ESI+): Empirical formula: C H Cl N O 42 41 6 3 [M+H] calculated: 713.3001 [M+H] measured: 713.2998 Example 107.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 107.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 108. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 108. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (5 5- -c cy ya an no o- -1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -N N- -( (4 4- - h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and (3S)(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (see Preparation 3') in Step A, and the compound of Preparation 19'' in Step C. The product obtained is finally subjected to a step of conversion into salt form in the presence of HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured) %C=64.95:65.09; %H=5.45:5.20; %N=11.36:11.26; %Cl-=4.79:4.62 High-resolution mass spectrometry (ESI/+): Empirical formula: C H Cl N O 40 39 6 4 [M+H] calculated: 703.2794 [M+H] measured: 703.2789 Example 109. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 109. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(6-cyanopyridinyl)-N-(4-hydroxyphenyl)-1,2- 2(1H)-yl]carbonyl}phenyl)-N-(6-cyanopyridinyl)-N-(4-hydroxyphenyl)-1,2- d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 23'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI+-/FIA/ HR, ESI-/FIA): Empirical formula: C H Cl N O 40 37 6 4 [M+H] calculated: 701.2638 [M+H] measured: 701.2639 E Ex xa am mp plle e 1 11 10 0.. 5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-cyanopyridinyl)-N-(4-hydroxyphenyl)-1,2- 2(1H)-yl]carbonyl}phenyl)-N-(4-cyanopyridinyl)-N-(4-hydroxyphenyl)-1,2- d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=65.13:65.72; %H=5.19:4.76; %N=11.39:12.04; %Cl =4.81:4.45 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl N O 40 37 6 4 [M+H] calculated: 701.2638 [M+H] measured: 701.2643 E Ex xa am mp plle e 1 11 11 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -c cy ya an no op py yr riim miid diin n- -2 2- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- - dimethyl-1H-pyrrolecarboxamide dimethyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 11 12 2..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-[2-(dimethylamino)pyridinyl]-N-(4-hydroxyphenyl)- 2(1H)-yl]carbonyl}phenyl)-N-[2-(dimethylamino)pyridinyl]-N-(4-hydroxyphenyl)- 1,2-dimethyl-1H-pyrrolecarboxamide 1,2-dimethyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 11 13 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- b be en nz ziim miid da az zo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 114.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 114.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (p py yr ra az zo ollo o[ [1 1,,5 5- - a a] ]p py yr riim miid diin n- -6 6- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 115.5-(5-Chloro{[(3S)[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin- Example 115.5-(5-Chloro{[(3S)[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin- 8 8( (1 1H H) )- -y yllm me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- - h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - carboxamide dihydrochloride carboxamide dihydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 7' in Step A, and the compound of Preparation 1'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=61.01:60.17; %H=5.74:5.09; %N=12.15:12.02; %Cl =8.78:9.81 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl N O 41 44 7 4 [M+H] calculated: 734.3216 [M+H] measured: 734.3220 E Ex xa am mp plle e 1 11 16 6.. 5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aR R) )- -h he ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- - 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrole hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrole c ca ar rb bo ox xa am miid de e d diih hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 9' in Step A, and the compound of Preparation 1'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=61.01:61.90; %H=5.74:5.65; %N=12.15:12.14; %Cl=13.15:11.51 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H Cl N O 41 44 7 4 [M+H] calculated: 734.3216 [M+H] measured: 734.3218 Example 117.5-(5-Chloro{[(3S)(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 117.5-(5-Chloro{[(3S)(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 11 18 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (d diif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 11 19 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (t tr riif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 12 20 0..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (3 3- -c cy ya an no oa az ze et tiid diin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - (1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide (1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 12 21 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(1-ethyl-1H-pyrazolyl)-N-(4-hydroxyphenyl)-1,2- 2(1H)-yl]carbonyl}phenyl)-N-(1-ethyl-1H-pyrazolyl)-N-(4-hydroxyphenyl)-1,2- dimethyl-1H-pyrrolecarboxamide dimethyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 12 22 2..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(1-cyclopropyl-1H-pyrazolyl)-N-(4-hydroxyphenyl)- 2(1H)-yl]carbonyl}phenyl)-N-(1-cyclopropyl-1H-pyrazolyl)-N-(4-hydroxyphenyl)- 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 28'' in Step C.
Elemental microanalysis: (%, theoretical:measured) %C=68.12:67.94; %H=5.86:5.77; %N=11.92:11.65 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 40 41 6 4 [M+H] calculated: 705.2951 [M+H] measured: 705.2952 E Ex xa am mp plle e 1 12 23 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trifluoromethyl)- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trifluoromethyl)- 1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 124.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 124.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -[ [1 1- -( (d diif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -N N- -( (4 4- - h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 12 25 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -[ [1 1- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -1 1H H- -p py yr ra az zo oll- - 4-yl]-1,2-dimethyl-1H-pyrrolecarboxamide 4-yl]-1,2-dimethyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 12 26 6..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(oxetanyl)-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(oxetanyl)-1H- pyrazolyl]-1H-pyrrolecarboxamide pyrazolyl]-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 26'' in Step C.
High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 40 41 6 5 [M+H] calculated: 721.2900 [M+H] measured: 721.2902 Example 127. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 127. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -[ [1 1- -( (t te et tr ra ah hy yd dr ro of fu ur ra an n- - 3 3- -y yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 22'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=63.81:63.63; %H=5.75:5.74; %N=10.89:10.71; %Cl =4.59:4.52 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 41 43 6 5 [M+H] calculated: 735.3056 [M+H] measured: 735.3061 E Ex xa am mp plle e 1 12 28 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -[ [1 1- -( (2 2- -h hy yd dr ro ox xy y- -2 2- -m me et th hy yllp pr ro op py yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 12 29 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]- 2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]- pyridinyl)-N-phenyl-1H-pyrrolecarboxamide pyridinyl)-N-phenyl-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process described in Step B of Example 49 using Example 106 as starting material, it being understood that the product is not subjected to the step of conversion into salt form.
Elemental microanalysis: (%, theoretical:measured) %C=70.53:70.51; %H=6.06:5.81; %N=11.75:11.71 High-resolution mass spectrometry (ESI+-/FIA): Empirical formula: C H Cl N O 42 43 6 3 [M+H] calculated: 715.3158 [M+H] measured: 715.3159 E Ex xa am mp plle e 1 13 30 0.. 5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -f fllu uo or ro op ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- - 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 13 31 1.. 5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole carboxamide carboxamide Example 132. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 132. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-phenyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-phenyl-1H- p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 13 33 3.. 5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (2 2- -h hy yd dr ro ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 13 34 4.. 5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl- 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 13 35 5.. 5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl- 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl- 1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 136. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 136. 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 137.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 137.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 13 38 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- - 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 13 39 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazol 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 14 40 0..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 14 41 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- - 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 14 42 2..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)ethyl-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)ethyl-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- pyrazolyl)-1H-pyrrolecarboxamide pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 14 43 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)ethyl-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)ethyl-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 144.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 144.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1- -e et th hy yll- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- - d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 145.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 145.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 14 46 6..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 14 47 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(2-methoxyethyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(2-methoxyethyl)methyl-N-(1- methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 14 48 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)(2-fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)(2-fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 14 49 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1- -( (2 2- -f fllu uo or ro oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 15 50 0..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)(2-fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)(2-fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 15 51 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)(2,2-difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)(2,2-difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 152.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 152.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1- -( (2 2,,2 2- -d diif fllu uo or ro oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 153.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 153.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1- -( (2 2,,2 2- -d diif fllu uo or ro oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 15 54 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide yl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 15 55 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- pyrrolo[2,3-b]pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 15 56 6..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 15 57 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1- - [2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide [2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 15 58 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3- b]pyridinyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide b]pyridinyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 15 59 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro-1H- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 160.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 160.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -N N- - p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 161.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 161.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1- -[ [2 2- -( (d diim me et th hy ylla am miin no o) )e et th hy yll] ]- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 16 62 2..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1- -[ [2 2- -( (d diim me et th hy ylla am miin no o) )e et th hy yll] ]- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- - phenyl-1H-pyrrolecarboxamide phenyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 16 63 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)[2-(dimethylamino)ethyl]-N-(4-hydroxyphenyl)methyl-N-(1- yl]carbonyl}phenyl)[2-(dimethylamino)ethyl]-N-(4-hydroxyphenyl)methyl-N-(1- methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 16 64 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)[2-(dimethylamino)ethyl]-N-(4-hydroxyphenyl)methyl-N-(1- yl]carbonyl}phenyl)[2-(dimethylamino)ethyl]-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 16 65 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -{ {2 2- -[ [( (2 2- -m me et th ho ox xy ye et th hy yll) )( (m me et th hy yll) )a am miin no o] ]e et th hy yll} }- - 2-methyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide 2-methyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 16 66 6..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - carbonyl}phenyl)-N-(4-hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl}- carbonyl}phenyl)-N-(4-hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl}- 2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 16 67 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - carbonyl}phenyl)-N-(4-hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl}- carbonyl}phenyl)-N-(4-hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl}- 2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 16 68 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)(trifluoromethyl)-1H-pyrrolecarboxamide yl)(trifluoromethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 16 69 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(trifluoromethyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)(trifluoromethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 17 70 0..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (t tr riif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 171.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 171.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)(difluoromethyl)-N-(4-hydroxyphenyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)(difluoromethyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 172.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 172.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -2 2- -( (d diif fllu uo or ro om me et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 17 73 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)(difluoromethyl)-N-(4-hydroxyphenyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)(difluoromethyl)-N-(4-hydroxyphenyl)methyl-N-(1- methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide Example 174.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 174.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(methoxymethyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(methoxymethyl)methyl-N-(1- m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 175.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 175.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (m me et th ho ox xy ym me et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 17 76 6..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (m me et th ho ox xy ym me et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 17 77 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide yl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 17 78 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 179.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 179.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 180.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 180.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -2 2- -( (2 2,,2 2- -d diif fllu uo or ro oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 18 81 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)(2,2-difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)(2,2-difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide Example 182.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 182.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)(2,2-difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)(2,2-difluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 183.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 183.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 18 84 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 18 85 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 18 86 6..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) ( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 187.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 187.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3- b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 188.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 188.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 18 89 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) [2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide [2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide Example 190.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 190.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3- b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 191.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 191.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 19 92 2..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (t tr riif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - b]pyridinyl)-1H-pyrrolecarboxamide b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 19 93 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (t tr riif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 1 19 94 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (d diif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3- b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 195.5-(5-Chloro{[(3S)(difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 195.5-(5-Chloro{[(3S)(difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 196.5-(5-Chloro{[(3S)(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 196.5-(5-Chloro{[(3S)(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 19 97 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (f fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide Example 198.5-(5-Chloro{[(3S)[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin- Example 198.5-(5-Chloro{[(3S)[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- - p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 1 19 99 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aS S) )- -h he ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- - 8 8( (1 1H H) )- -y yllm me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 200.5-(5-Chloro{[(3S)[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin- Example 200.5-(5-Chloro{[(3S)[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- - p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 20 01 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aR R) )- -h he ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- - 8 8( (1 1H H) )- -y yllm me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 202.5-(2-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- Example 202.5-(2-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}chlorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- yl]carbonyl}chlorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 203.5-(2-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- Example 203.5-(2-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -5 5- -c ch hllo or ro op ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 20 04 4..5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -( (A Am miin no om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}chlorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- yl]carbonyl}chlorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide Example 205.5-(5-Chloro{[(3S)[(3-cyanoazetidinyl)methyl]-3,4- Example 205.5-(5-Chloro{[(3S)[(3-cyanoazetidinyl)methyl]-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- ( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 206.5-(5-Chloro{[(3S)[(3-cyanoazetidinyl)methyl]-3,4- Example 206.5-(5-Chloro{[(3S)[(3-cyanoazetidinyl)methyl]-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - ( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 20 07 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (1 1- -o ox xa a- -6 6- -a az za as sp piir ro o[ [3 3..3 3] ]h he ep pt t- -6 6- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - (1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide (1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 8' in Step A, and the compound of Preparation 1'' in Step C.
High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl N O 39 39 6 4 [M+H] calculated: 691.2794 [M+H] measured: 691.2796 E Ex xa am mp plle e 2 20 08 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (1 1- -o ox xa a- -6 6- -a az za as sp piir ro o[ [3 3..3 3] ]h he ep pt t- -6 6- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- (1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide (1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 20 09 9.. 5 5- -( (5 5- -F Fllu uo or ro o- -4 4- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - (1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride (1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride The procedure is in accordance with the general protocol of Example 1 using the appropriate Preparations. The product obtained is finally dissolved in acetonitrile and converted into salt form using 0.1M aqueous HCl solution. After a lyophilisation step, the expected compound is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=66.27:66.84; %H=5.69:5.15; %N=10.78:10.71; %Cl-=4.55:4.46 High-resolution mass spectrometry (ESI+-/FIA): Empirical formula: C H F N O 43 43 6 5 [M+H] calculated: 743.3352 [M+H] measured: 743.3353 E Ex xa am mp plle e 2 21 10 0.. 5 5- -( (5 5- -F Fllu uo or ro o- -4 4- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- (1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide (1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide h hy yd dr ro oc ch hllo or riid de e Step A: 5-(5-Fluoromethoxy{[(3S)(morpholinylmethyl)-3,4-dihydroiso- quinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the compound of Preparation 14 and (3S)(4-morpholinylmethyl)-1,2,3,4-tetrahydroiso- quinoline (see Preparation 3') in Step A, and the compound of Preparation 11'' in Step C.
Step B: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin yl)-N-phenyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process described in Step B of Example 49 starting from compound of the above Step, it being understood that the product is finally subjected to a step of conversion into salt form in the presence of 1M HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected product is obtained.
Elemental microanalysis: (%, theoretical:measured) %C=60.12:59.77; %H=4.92:4.76; %N=10.79:10.39; %Cl-=4.55:5.17 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H N O 40 40 4 5 [M+H] calculated: 657.3071 [M+H] measured: 657.3066 E Ex xa am mp plle e 2 21 11 1..5 5- -( (4 4- -F Fllu uo or ro o- -5 5- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - (1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide (1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 21 12 2..5 5- -( (4 4- -F Fllu uo or ro o- -5 5- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- (1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide (1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide Example 213.N-(1-Ethyl-1H-pyrazolyl)(5-fluoro{[(3S)(morpholin Example 213.N-(1-Ethyl-1H-pyrazolyl)(5-fluoro{[(3S)(morpholin ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 214.N-(1-Cyclopropyl-1H-pyrazolyl)(5-fluoro{[(3S)(morpholin Example 214.N-(1-Cyclopropyl-1H-pyrazolyl)(5-fluoro{[(3S)(morpholin y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- - 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 28'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=66.24:66.53; %H=5.84:5.39; %N=10.59:10.92 %Cl =4.89:5.68 Example 215.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 215.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -[ [1 1- -( (t tr riif fllu uo or ro om me et th hy yll) )- - 1H-pyrazolyl]-1H-pyrrolecarboxamide 1H-pyrazolyl]-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 21 16 6..N N- -[ [1 1- -( (D Diif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- - ( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 21 17 7..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-[1-(2-methoxyethyl)-1H-pyrazol- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-[1-(2-methoxyethyl)-1H-pyrazol- 4 4- -y yll] ]- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 218.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 218.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(oxetanyl)-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(oxetanyl)-1H- p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 219.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 219.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -[ [1 1- -( (t te et tr ra ah hy yd dr ro of fu ur ra an n- - 3 3- -y yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 22 20 0..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -[ [1 1- -( (2 2- -h hy yd dr ro ox xy y- -2 2- -m me et th hy yllp pr ro op py yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 22 21 1..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- - N-phenyl-1H-pyrrolecarboxamide N-phenyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 22 22 2..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - b]pyridinyl)-N-phenyl-1H-pyrrolecarboxamide b]pyridinyl)-N-phenyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 22 23 3..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 22 24 4..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro- 2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro- 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 225.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 225.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -N N,,1 1,,2 2- -t tr riim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e Example 226.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 226.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (2 2- -h hy yd dr ro ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -p ph he en ny yll- -1 1H H- - p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 22 27 7..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (2 2- -h hy yd dr ro ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 22 28 8..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl- 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 22 29 9..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl- 2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl- 1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 23 30 0..N N- -( (5 5- -C Cy ya an no o- -1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- - ( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 19'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=66.43:67.09; %H=5.57:5.21; %N=11.62:11.48 %Cl =4.90:4.75 High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O 40 39 6 4 [M+H] calculated: 687.3097 [M+H] measured: 687.3073 Example 231.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 231.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 23 32 2..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 23 33 3..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 23 34 4..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazol 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazol y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 23 35 5..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 23 36 6..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 23 37 7..1 1- -E Et th hy yll- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 238.1-Ethyl(5-fluoro{[(3S)(morpholinylmethyl)-3,4- Example 238.1-Ethyl(5-fluoro{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 239.1-Ethyl(5-fluoro{[(3S)(morpholinylmethyl)-3,4- Example 239.1-Ethyl(5-fluoro{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 24 40 0..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 24 41 1..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(2-methoxyethyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(2-methoxyethyl)methyl-N-(1- methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 24 42 2..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(2-methoxyethyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(2-methoxyethyl)methyl-N-(1- m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 24 43 3..1 1- -( (2 2- -F Fllu uo or ro oe et th hy yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 24 44 4..1 1- -( (2 2- -F Fllu uo or ro oe et th hy yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 24 45 5..1 1- -( (2 2- -F Fllu uo or ro oe et th hy yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 246.1-(2,2-Difluoroethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- Example 246.1-(2,2-Difluoroethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 247.1-(2,2-Difluoroethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- Example 247.1-(2,2-Difluoroethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 24 48 8..1 1- -( (2 2,,2 2- -D Diif fllu uo or ro oe et th hy yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 24 49 9..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazol 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazol yl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide yl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 25 50 0..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 25 51 1..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- - 1H-pyrrolo[2,3-b]pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 25 52 2..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) [2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide [2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 25 53 3..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3- b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 254.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 254.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 255.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 255.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -N N- - p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 25 56 6..1 1- -[ [2 2- -( (D Diim me et th hy ylla am miin no o) )e et th hy yll] ]- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 25 57 7..1 1- -[ [2 2- -( (D Diim me et th hy ylla am miin no o) )e et th hy yll] ]- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N- phenyl-1H-pyrrolecarboxamide phenyl-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 25 58 8..1 1- -[ [2 2- -( (D Diim me et th hy ylla am miin no o) )e et th hy yll] ]- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 25 59 9..1 1- -[ [2 2- -( (D Diim me et th hy ylla am miin no o) )e et th hy yll] ]- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- - methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 26 60 0..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - carbonyl}phenyl)-N-(4-hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl}- carbonyl}phenyl)-N-(4-hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl}- 2-methyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide 2-methyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 26 61 1..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - carbonyl}phenyl)-N-(4-hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl}- carbonyl}phenyl)-N-(4-hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl}- 2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 262.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- Example 262.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -{ {2 2- -[ [( (2 2- -m me et th ho ox xy ye et th hy yll) )( (m me et th hy yll) )a am miin no o] ]e et th hy yll} }- - 2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - carboxamide carboxamide E Ex xa am mp plle e 2 26 63 3..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)(trifluoromethyl)-1H-pyrrolecarboxamide yl)(trifluoromethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 26 64 4..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (t tr riif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 265.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 265.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro- 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (t tr riif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 266.2-(Difluoromethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- Example 266.2-(Difluoromethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 26 67 7..2 2- -( (D Diif fllu uo or ro om me et th hy yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide Example 268.2-(Difluoromethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- Example 268.2-(Difluoromethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 269.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 269.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (m me et th ho ox xy ym me et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 27 70 0..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (m me et th ho ox xy ym me et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 27 71 1..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (m me et th ho ox xy ym me et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 27 72 2..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazol 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazol y yll) )- -2 2- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 273.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 273.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 274.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 274.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- - 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 27 75 5..2 2- -( (2 2,,2 2- -D Diif fllu uo or ro oe et th hy yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide Example 276.2-(2,2-Difluoroethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- Example 276.2-(2,2-Difluoroethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1- m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 277.2-(2,2-Difluoroethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- Example 277.2-(2,2-Difluoroethyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 27 78 8..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 27 79 9..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 28 80 0..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(2-methoxyethyl)methyl-N-(1- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)(2-methoxyethyl)methyl-N-(1- m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 281.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 281.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) ( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 282.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 282.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 28 83 3..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro-1H- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridinyl)(morpholinylmethyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)(morpholinylmethyl)-1H-pyrrolecarboxamide Example 284.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 284.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H-pyrazolyl) [ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 285.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- Example 285.5-(5-Fluoro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - b b] ]p py yr riid diin n- -5 5- -y yll) )- -2 2- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 28 86 6..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 28 87 7..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (t tr riif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 28 88 8..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (t tr riif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3- b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 289.5-(5-Fluoro{[(3S)(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 289.5-(5-Fluoro{[(3S)(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 290.5-(2-{[(3S)(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 290.5-(2-{[(3S)(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -5 5- -f fllu uo or ro op ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 29 91 1..5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -( (D Diif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide Example 292.5-(2-{[(3S)(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 292.5-(2-{[(3S)(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 293.5-(5-Fluoro{[(3S)(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 293.5-(5-Fluoro{[(3S)(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 29 94 4..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (f fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - b]pyridinyl)-1H-pyrrolecarboxamide b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 29 95 5..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (f fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 2 29 96 6..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (f fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 297.5-(5-Fluoro{[(3S)[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin- Example 297.5-(5-Fluoro{[(3S)[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- - p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 2 29 98 8..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aS S) )- -h he ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- - 8 8( (1 1H H) )- -y yllm me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide Example 299.5-(5-Fluoro{[(3S)[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin- Example 299.5-(5-Fluoro{[(3S)[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 30 00 0..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aR R) )- -h he ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- - 8 8( (1 1H H) )- -y yllm me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H- p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 301.5-(5-Fluoro{[(3S)[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin- Example 301.5-(5-Fluoro{[(3S)[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- 8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- - y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 30 02 2..5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -( (A Am miin no om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -5 5- -f fllu uo or ro op ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrazolyl)-1H-pyrrolecarboxamide pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 30 03 3..5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -( (A Am miin no om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 30 04 4..5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -( (A Am miin no om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 30 05 5..5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (3 3- -C Cy ya an no oa az ze et tiid diin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -5 5- -f fllu uo or ro op ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 1H-pyrazolyl)-1H-pyrrolecarboxamide 1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 30 06 6..5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (3 3- -C Cy ya an no oa az ze et tiid diin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 2(1H)-yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 30 07 7..5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -[ [( (3 3- -C Cy ya an no oa az ze et tiid diin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 2(1H)-yl]carbonyl}fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 308.5-(5-Fluoro{[(3S)(1-oxaazaspiro[3.3]heptylmethyl)-3,4- Example 308.5-(5-Fluoro{[(3S)(1-oxaazaspiro[3.3]heptylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - ( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 309.5-(5-Fluoro{[(3S)(1-oxaazaspiro[3.3]heptylmethyl)-3,4- Example 309.5-(5-Fluoro{[(3S)(1-oxaazaspiro[3.3]heptylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - ( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 31 10 0..N N- -( (1 1- -E Et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- - { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - benzodioxolyl)-1H-pyrrolecarboxamide benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 31 11 1..N N- -( (1 1- -C Cy yc cllo op pr ro op py yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- - 5-(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- -(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxolyl)-1H-pyrrolecarboxamide benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 31 12 2..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- - ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-[1- ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-[1- ( (t tr riif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 31 13 3..N N- -[ [1 1- -( (D Diif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- - d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 31 14 4..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -[ [1 1- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1,,2 2- - dimethyl(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- dimethyl(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 31 15 5..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- - ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-[1- ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-[1- ( (o ox xe et ta an n- -3 3- -y yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 316.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3S)(morpholin Example 316.N-(4-Hydroxyphenyl)-1,2-dimethyl(6-{[(3S)(morpholin y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -[ [1 1- - ( (t te et tr ra ah hy yd dr ro of fu ur ra an n- -3 3- -y yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 317.N-[1-(2-Hydroxymethylpropyl)-1H-pyrazolyl]-N-(4- Example 317.N-[1-(2-Hydroxymethylpropyl)-1H-pyrazolyl]-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - carboxamide carboxamide E Ex xa am mp plle e 3 31 18 8..1 1,,2 2- -D Diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- - (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol- (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol- 5- -y yll) )- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 319.1,2-Dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)- Example 319.1,2-Dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)- -(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- -(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 320.N-(4-Fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3- Example 320.N-(4-Fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3- b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 32 21 1..N N- -( (4 4- -F Fllu uo or ro op ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole c ca ar rb bo ox xa am miid de e Example 322.N-(4-Hydroxyphenyl)-N,1,2-trimethyl(6-{[(3S)(morpholin Example 322.N-(4-Hydroxyphenyl)-N,1,2-trimethyl(6-{[(3S)(morpholin y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- - p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 32 23 3..N N- -( (2 2- -H Hy yd dr ro ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- - y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -p ph he en ny yll- - 1H-pyrrolecarboxamide 1H-pyrrolecarboxamide E Ex xa am mp plle e 3 32 24 4..N N- -( (2 2- -H Hy yd dr ro ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 32 25 5..N N- -( (2 2- -H Hy yd dr ro ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- - 1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- 1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 326.N-(2-Hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol Example 326.N-(2-Hydroxypyrimidinyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- - 1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 327.N-(5-Cyanomethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2- Example 327.N-(5-Cyanomethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2- d diim me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 32 28 8..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- - 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 32 29 9..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- - 5-yl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- -yl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 33 30 0..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (6 6- - {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 331.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin- Example 331.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin- 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 332.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo- Example 332.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo- [ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 33 33 3..1 1- -E Et th hy yll- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]- - p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 33 34 4..1 1- -E Et th hy yll- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 33 35 5..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 33 36 6..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -( (2 2- -m me et th ho ox xy ye et th hy yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- - d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole carboxamide carboxamide Example 337.1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- Example 337.1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-1H- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 338.1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3- Example 338.1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)methyl-N-(1-methyl-2,3- d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - carboxamide carboxamide E Ex xa am mp plle e 3 33 39 9..1 1- -( (2 2,,2 2- -D Diif fllu uo or ro oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso- quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 34 40 0..1 1- -( (2 2,,2 2- -D Diif fllu uo or ro oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- - dihydro-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- dihydro-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 34 41 1..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (6 6- - { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 34 42 2..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- - 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}-1,3-benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 34 43 3..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o- - [ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrole 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrole carboxamide carboxamide Example 344.N-(4-Hydroxyphenyl)methyl(6-{[(3R)methyl-3,4- Example 344.N-(4-Hydroxyphenyl)methyl(6-{[(3R)methyl-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 345.N-(4-Hydroxyphenyl)methyl(6-{[(3R)methyl-3,4-dihydroiso- Example 345.N-(4-Hydroxyphenyl)methyl(6-{[(3R)methyl-3,4-dihydroiso- q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 34 46 6..1 1- -[ [2 2- -( (D Diim me et th hy ylla am miin no o) )e et th hy yll] ]- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- - 3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- - methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 34 47 7..1 1- -[ [2 2- -( (D Diim me et th hy ylla am miin no o) )e et th hy yll] ]- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- - 3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- - methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 34 48 8..1 1- -[ [2 2- -( (D Diim me et th hy ylla am miin no o) )e et th hy yll] ]- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- - 3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1- 3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1- m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 349.N-(4-Hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl} Example 349.N-(4-Hydroxyphenyl){2-[(2-methoxyethyl)(methyl)amino]ethyl} methyl(6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzo- methyl(6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzo- d diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 35 50 0..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -{ {2 2- -[ [( (2 2- -m me et th ho ox xy ye et th hy yll) )( (m me et th hy yll) )a am miin no o] ]e et th hy yll} }- -2 2- - m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo o- - dioxolyl)-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrole dioxolyl)-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrole carboxamide carboxamide Example 351.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo- Example 351.N-(4-Hydroxyphenyl)methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo- [2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- [2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -2 2- -( (t tr riif fllu uo or ro om me et th hy yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 35 52 2..2 2- -( (D Diif fllu uo or ro om me et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- - d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole c ca ar rb bo ox xa am miid de e Example 353.N-(4-Hydroxyphenyl)(methoxymethyl)methyl-N-(1-methyl-2,3- Example 353.N-(4-Hydroxyphenyl)(methoxymethyl)methyl-N-(1-methyl-2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- dihydro-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 35 54 4..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (6 6- - { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 35 55 5..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- - -yl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- -yl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)(2,2,2-trifluoroethyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 35 56 6..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -2 2- -( (2 2,,2 2,,2 2- -t tr riif fllu uo or ro oe et th hy yll) )- - 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 35 57 7..2 2- -( (2 2,,2 2- -D Diif fllu uo or ro oe et th hy yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- - dihydro-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- dihydro-1H-pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrole c ca ar rb bo ox xa am miid de e Example 358.N-(4-Hydroxyphenyl)(2-methoxyethyl)methyl-N-(1-methyl-2,3- Example 358.N-(4-Hydroxyphenyl)(2-methoxyethyl)methyl-N-(1-methyl-2,3- d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - carboxamide hydrochloride carboxamide hydrochloride The title compound is obtained in accordance with the process described in Step B of Example 49 using Example 88 as starting material, it being understood that the product is finally dissolved in acetonitrile and converted into salt form in 0.1M aqueous HCl solution.
After a lyophilisation step, the expected product is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=65.80:64.71; %H=6.01:5.74; %N=10.23:10.03; %Cl-=4.32:6.47 High-resolution mass spectrometry (ESI/+): Empirical formula: C H N O 45 48 6 7 [M+H] calculated: 785.3657 [M+H] measured: 785.3658 E Ex xa am mp plle e 3 35 59 9..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1- -m me et th hy yll- -5 5- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-2,3- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl)(morpholinylmethyl)-1H-pyrrole dihydro-1H-pyrrolo[2,3-b]pyridinyl)(morpholinylmethyl)-1H-pyrrole c ca ar rb bo ox xa am miid de e Example 360.N-(4-Hydroxyphenyl)methyl(6-{[(3R)methyl-3,4-dihydroiso- Example 360.N-(4-Hydroxyphenyl)methyl(6-{[(3R)methyl-3,4-dihydroiso- q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide pyrrolo[2,3-b]pyridinyl)[2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 36 61 1..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (6 6- - { {[ [( (3 3S S) )- -3 3- -( (t tr riif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- - benzodioxolyl)-1H-pyrrolecarboxamide benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 36 62 2..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]- - pyridinyl)(6-{[(3S)(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- pyridinyl)(6-{[(3S)(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 36 63 3..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(trifluoromethyl)-3,4-dihydroisoquinolin- pyrrolo[2,3-b]pyridinyl)(6-{[(3S)(trifluoromethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 364.5-(6-{[(3S)(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 364.5-(6-{[(3S)(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 365.5-(6-{[(3S)(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 365.5-(6-{[(3S)(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 36 66 6..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (D Diif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 36 67 7..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (F Fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 1H-pyrazolyl)-1H-pyrrolecarboxamide 1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 36 68 8..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (F Fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 36 69 9..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (F Fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 37 70 0..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aS S) )- -H He ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- -8 8( (1 1H H) )- - ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4- ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrole hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrole c ca ar rb bo ox xa am miid de e Example 371.5-(6-{[(3S)[(9aS)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- Example 371.5-(6-{[(3S)[(9aS)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- y yllm me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- - h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- - pyrrolecarboxamide pyrrolecarboxamide E Ex xa am mp plle e 3 37 72 2..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aS S) )- -H He ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- -8 8( (1 1H H) )- - ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4- ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 373.5-(6-{[(3S)[(9aR)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- Example 373.5-(6-{[(3S)[(9aR)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- y yllm me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- - h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- - carboxamide carboxamide E Ex xa am mp plle e 3 37 74 4..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aR R) )- -H He ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- -8 8( (1 1H H) )- - ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4- ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H- p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 37 75 5..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -[ [( (9 9a aR R) )- -H He ex xa ah hy yd dr ro op py yr ra az ziin no o[ [2 2,,1 1- -c c] ][ [1 1,,4 4] ]o ox xa az ziin n- -8 8( (1 1H H) )- - y yllm me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin yl)-1H-pyrrolecarboxamide yl)-1H-pyrrolecarboxamide Example 376.5-(6-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- Example 376.5-(6-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 377.5-(6-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- Example 377.5-(6-{[(3S)(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 37 78 8..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -( (A Am miin no om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 37 79 9..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -[ [( (3 3- -C Cy ya an no oa az ze et tiid diin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- - methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide E Ex xa am mp plle e 3 38 80 0..5 5- -( (6 6- -{ {[ [( (3 3S S) )- -3 3- -[ [( (3 3- -C Cy ya an no oa az ze et tiid diin n- -1 1- -y yll) )m me et th hy yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1- 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1- m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 381.5-(6-{[(3S)[(3-Cyanoazetidinyl)methyl]-3,4-dihydroisoquinolin- Example 381.5-(6-{[(3S)[(3-Cyanoazetidinyl)methyl]-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1- 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1- m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Example 382.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(6- Example 382.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(6- { {[ [( (3 3S S) )- -3 3- -( (1 1- -o ox xa a- -6 6- -a az za as sp piir ro o[ [3 3..3 3] ]h he ep pt t- -6 6- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e E Ex xa am mp plle e 3 38 83 3..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]- - pyridinyl)(6-{[(3S)(1-oxaazaspiro[3.3]heptylmethyl)-3,4-dihydroiso- pyridinyl)(6-{[(3S)(1-oxaazaspiro[3.3]heptylmethyl)-3,4-dihydroiso- quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide Example 384.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 384.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H- p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=67.28:67.73; %H=5.65:5.30; %N=10.06:9.41 %Cl-=5.09:5.79 E Ex xa am mp plle e 3 38 85 5..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride High-resolution mass spectrometry (ESI+): Empirical formula: C H Cl N O 41 41 6 4 [M+H] calculated: 713.3253 [M+H] measured: 713.3272 Example 386.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 386.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (5 5- -c cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride Step A: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl][5-chloro[(3S)(morpholino- methyl)-3,4-dihydro-1H-isoquinolinecarbonyl]phenyl]-N-(5-cyano-1,2-dimethyl- pyrrolyl)-1,2-dimethyl-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. -1 -1 IR: ν -CN-: 2210 cm ; ν -C=O-: 1631 cm Step B: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2- dimethyl-1H-pyrrolecarboxamide hydrochloride The compound of Step A is deprotected in accordance with the protocol described in Step D of Example 1. The product thereby obtained is finally subjected to a step of conversion into salt form in the presence of HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected product is obtained.
H NMR (500 MHz, dmso-d6) δ ppm: 11.2 (bs, 1H), 9.39 (bs,1H), 7.83 (d, 1 H), 7.54 (d, 1 H), 7.33 (s, 1 H), 7.14 (m, 2 H), 7 (m, 2 H), 6.8 (d, 2 H), 6.62 (d, 2 H), 6.57 (bs, 1 H), .26 (s, 1 H), 5.26 (m, 1 H), 4.64/4.03 (AB, 2 H), 4.01/3.92 (2m, 4 H), 3.75/3.43/3.15/3.02 (4m, 4 H), 3.59 (s, 3 H), 3.3/3.15 (2m, 2 H), 2.97 (s, 3 H), 2.69/2.52 (dd+d, 2 H), 2.06 (s, 3 H), 1.91 (s, 3 H) Elemental microanalysis: (%, theoretical:measured) %C=65.34:65.50; %H=5.62:5.15; %N=11.15:10.84 %Cl-=4.70:4.44 High-resolution mass spectrometry (ESI+): Empirical formula: C H Cl N O 41 41 6 4 [M+H] calculated: 717.2952 [M+H] measured: 717.2951 E Ex xa am mp plle e 3 38 87 7..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - c]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- c]pyridinyl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=66.62:66.36; %H=5.59:5.62; %N=10.84:10.72 %Cl-=4.57:4.55 High-resolution mass spectrometry (ESI+): Empirical formula: C H N O 43 42 6 6 [M+H] calculated: 739.3239 [M+H] measured: 739.3241 Example 388.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 388.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e d diih hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process described in Step B of Example 49 using Example 71 as starting material, it being understood that the product is finally subjected to a step of conversion into salt form in the presence of 1M HCl in ether.
After filtration and lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured) %C=62.73:62.96; %H=5.64:4.95; %N=10.45:10.32; %Cl=13.23:12.91 High-resolution mass spectrometry (ESI+): Empirical formula: C H Cl N O 42 43 6 4 [M+H] calculated: 731.3107 [M+H] measured: 731.3111 E Ex xa am mp plle e 3 38 89 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrrolo[2,3-c]pyridinyl)-1H-pyrrolecarboxamide hydrochloride pyrrolo[2,3-c]pyridinyl)-1H-pyrrolecarboxamide hydrochloride The procedure is in accordance with the general protocol of Example 1 using the appropriate Preparations. The product obtained is finally dissolved in acetonitrile and converted into salt form using 0.1M aqueous HCl solution. After a lyophilisation step, the expected compound is obtained in the form of a solid.
Elemental microanalysis: (%, theoretical:measured) %C=65.88:66.28; %H=5.53:5.15; %N=10.98:10.95; %Cl-=4.63:4.47 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H Cl N O 42 41 6 4 [M+H] calculated: 729.2951 [M+H] measured: 729.2954 Example 390.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 390.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)- 2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)- N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The procedure is in accordance with the general protocol of Example 1 using the appropriate Preparations, it being understood that Step D is not carried out. The expected product is obtained in free base form.
Elemental microanalysis: (%, theoretical:measured) %C=70.72:69.77; %H=5.79:5.96; %N=11.78:11.43 High-resolution mass spectrometry (ESI+): Empirical formula: C H Cl N O 42 41 6 3 [M+H] calculated: 713.3001 [M+H] measured: 713.2998 E Ex xa am mp plle e 3 39 91 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[3,2-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride pyrrolo[3,2-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=65.88:65.69; %H=5.33:4.87; %N=10.98:10.86; %Cl-=4.63:4.51 High-resolution mass spectrometry (ESI+-/FIA): Empirical formula: C H Cl N O 42 41 6 4 [M+H] calculated: 729.2951 [M+H] measured: 729.2953 E Ex xa am mp plle e 3 39 92 2..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -[ [3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )p pr ro op py yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so o- - q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -p ph he en ny yll- -1 1H H- - pyrrolecarboxamide hydrochloride pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=68.19:68.33; %H=6.00:5.49; %N=10.78:10.71; %Cl-=4.55:4.46; %Cl = 9.58:9.78 High-resolution mass spectrometry (ESI+-/FIA): Empirical formula: C H Cl N O 42 43 4 4 [M+H] calculated: 703.3046 [M+H] measured: 703.3042 E Ex xa am mp plle e 3 39 93 3..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -[ [3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )p pr ro op py yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so o- - q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- - 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride 1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride High-resolution mass spectrometry (ESI+-/FIA): Empirical formula: C H Cl N O 44 45 6 4 [M+H] calculated: 757.3264 [M+H] measured: 757.3263 Example 394.5-(5-Chloro{[(3R)[3-(morpholinyl)propyl]-3,4- Example 394.5-(5-Chloro{[(3R)[3-(morpholinyl)propyl]-3,4- d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - (1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide (1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process described in Step B of Example 49 using Example 393 as starting material, it being understood that the product is not subjected to the step of conversion into salt form.
Elemental microanalysis: (%, theoretical:measured) %C=69.60:69.56; %H=6.21:6.24; %N=11.07:11.08 High-resolution mass spectrometry (ESI+-/FIA): Empirical formula: C H Cl N O 44 47 6 4 [M+H] calculated: 759.3420 [M+H] measured: 759.3422 Example 395.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 395.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(3-cyanomethoxyphenyl)-N-(4-hydroxyphenyl)-1,2- 2(1H)-yl]carbonyl}phenyl)-N-(3-cyanomethoxyphenyl)-N-(4-hydroxyphenyl)-1,2- d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The procedure is in accordance with the general protocol of Example 1 using the appropriate Preparations. The product obtained is finally dissolved in acetonitrile and converted into salt form using 0.1M aqueous HCl solution. After a lyophilisation step, the expected compound is obtained in the form of a solid.
High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H Cl N O 42 40 5 5 [M+H] calculated: 730.2791 [M+H] measured: 730.2790 E Ex xa am mp plle e 3 39 96 6..N N- -( (3 3- -F Fllu uo or ro o- -4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- - yl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}- yl)(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}- 1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 11 and (3S)(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (see Preparation 3') in Step A, and the compound of Preparation 20'' in Step C. The product obtained is finally subjected to a step of conversion into salt form in the presence of 1M HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured) %C=65.79:65.43; %H=5.39:5.19; %N=11.31:11.21; %Cl-=4.77:4.34 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H F N O 39 39 6 6 [M+H] calculated: 707.2988 [M+H] measured: 707.2988 Example 397.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 397.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxypyrimidinyl)-1,2- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxypyrimidinyl)-1,2- d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e High-resolution mass spectrometry (ESI+): Empirical formula: C H Cl N O 39 39 6 5 [M+H] calculated: 707.2743 [M+H] measured: 707.2746 E Ex xa am mp plle e 3 39 98 8..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(3-cyanophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(3-cyanophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H- pyrrolecarboxamide hydrochloride pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=66.85:66.75; %H=5.34:5.42; %N=9.51:9.73; %Cl=9.62:9.67; %Cl =4.81:4.71 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl N O 41 38 5 4 [M+H] calculated: 700.2685 [M+H] measured: 700.2686 E Ex xa am mp plle e 3 39 99 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(3-fluorohydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 2(1H)-yl]carbonyl}phenyl)-N-(3-fluorohydroxyphenyl)-1,2-dimethyl-N-(1-methyl- 1H-pyrazolyl)-1H-pyrrolecarboxamide hydrochloride 1H-pyrazolyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and (3S)(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (see Preparation 3') in Step A, and the compound of Preparation 20'' in Step C. The product obtained is finally subjected to a step of conversion into salt form in the presence of 1M HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured) %C=62.21:61.32; %H=5.36:5.18; %N=11.46:11.14; %Cl= 9.66:10.16; %Cl =4.83:5.23 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA ): Empirical formula: C H Cl F N O 38 38 6 4 [M+H] calculated: 697.2700 [M+H] measured: 697.2704 E Ex xa am mp plle e 4 40 00 0..M Me et th hy yll 2 2- -[ [{ {[ [5 5- -( (5 5- -c ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro o- - iis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll] ]c ca ar rb bo on ny yll} }( (4 4- - hydroxyphenyl)amino]pyridinecarboxylate hydrochloride hydroxyphenyl)amino]pyridinecarboxylate hydrochloride The title compound is a secondary product which forms in the course of synthesis of Example 110 (in the final Step before the step of conversion into salt form) owing to hydrolysis of the nitrile function into a methyl ester function. The compound is separated from that of Example 110 by chromatography over silica gel in a mixture of methanol and dichloromethane.
Elemental microanalysis: (%, theoretical:measured) %C=63.90:64.43; %H=5.36:5.01; %N=9.09:9.34; %Cl =4.60:4.46 High-resolution mass spectrometry (ESI+/HR and ESI-/LR): Empirical formula: C H Cl N O 41 40 5 6 [M+H] calculated: 734.2740 [M+H] measured: 734.2743 Example 401.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 401.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (3 3- -c cy ya an no o- -4 4- -f fllu uo or ro op ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- - d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=65.25:64.23; %H=5.07:4.71; %N=9.28:9.36; %Cl= 9.40:9.59; %Cl =4.70:4.50 High-resolution mass spectrometry (ESI+-/FIA/ HR, ESI-/FIA): Empirical formula: C H Cl F N O 41 37 5 4 [M+H] calculated: 718.2591 [M+H] measured: 718.2593 Example 402.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 402.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -{ {1 1- -[ [( (3 3S S o or r R R) )- - tetrahydrofuranyl]-1H-pyrazolyl}-1H-pyrrolecarboxamide hydrochloride tetrahydrofuranyl]-1H-pyrazolyl}-1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=65.20:65.92; %H=5.87:5.78; %N=11.13:10.36 %Cl =4.69:4.79) High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O 41 43 6 5 [M+H] calculated: 719.3359 [M+H] measured: 719.3362 Example 403.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 403.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -{ {1 1- -[ [( (3 3R R o or r S S) )- - tetrahydrofuranyl]-1H-pyrazolyl}-1H-pyrrolecarboxamide hydrochloride tetrahydrofuranyl]-1H-pyrazolyl}-1H-pyrrolecarboxamide hydrochloride Elemental microanalysis: (%, theoretical:measured) %C=65.20:66.04; %H=5.87:5.87; %N=11.13:10.62; %Cl =4.69:4.76 High-resolution mass spectrometry (ESI/+): Empirical formula: C H FN O 41 43 6 5 [M+H] calculated: 719.3359 [M+H] measured: 719.3350 The compounds of Examples 402 and 403 are obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 22'' in Step C. The diastereoisomers obtained are separated by chiral chromatography and then converted into salt form and lyophilised as described in the general process to yield the title compounds.
E Ex xa am mp plle e 4 40 04 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (2 2- -c cy ya an no op py yr riim miid diin n- -4 4- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- - dimethyl-1H-pyrrolecarboxamide hydrochloride dimethyl-1H-pyrrolecarboxamide hydrochloride E Ex xa am mp plle e 4 40 05 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)- 2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)- N N- -( (p py yr riid da az ziin n- -4 4- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e d diih hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C, it being understood that Step D is not carried out. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl N O 40 39 8 3 [M+H] calculated: 715.2906 [M+H] measured: 715.2909 Example 406.N-(5-Cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2- Example 406.N-(5-Cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2- dimethyl(2-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- dimethyl(2-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 25 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=68.46:68.27; %H=6.03:5.12; %N=11.68:11.75; %Cl =4.93:4.73 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H N O 41 42 6 4 [M+H] calculated: 683.3340 [M+H] measured: 683.3334 E Ex xa am mp plle e 4 40 07 7..N N- -( (3 3- -F Fllu uo or ro o- -4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -5 5- -( (5 5- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- - ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1- ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1- methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide hydrochloride methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 12 and the compound of Preparation 3' in Step A, and the compound of Preparation 20'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=64.23:63.94; %H=5.80:5.00; %N=11.52:11.56; %Cl =4.86:4.99 High-resolution mass spectrometry (ESI+-/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H F N O 39 41 6 5 [M+H] calculated: 693.3195 [M+H] measured: 693.3191 E Ex xa am mp plle e 4 40 08 8..N N- -( (5 5- -C Cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -5 5- -( (5 5- - methoxy{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- methoxy{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 12 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=67.32:67.30; %H=6.05:5.28; %N=11.22:11.15; %Cl =4.73:4.59 High-resolution mass spectrometry (ESI+-/FIA/HR and ESI-/FIA): Empirical formula: C H N O 42 44 6 5 [M+H] calculated: 713.3446 [M+H] measured: 713.3443 Example 409.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]- Example 409.N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]- p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - carbonyl}phenyl)-1H-pyrrolecarboxamide hydrochloride carbonyl}phenyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 25 and the compound of Preparation 3' in Step A, and the compound of Preparation 11'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=68.98:68.95; %H=5.93:4.76; %N=11.49:11.43 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H N O 42 42 6 4 [M+H] calculated: 695.3340 [M+H] measured: 695.3341 E Ex xa am mp plle e 4 41 10 0..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- - p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so o- - quinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrolecarboxamide hydrochloride quinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process described in Step B of Example 49 using Example 409 as starting material. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI/FIA/HR and ESI-/FIA): Empirical formula: C H N O 42 44 6 4 [M+H] calculated: 697.3497 [M+H] measured: 697.3497 E Ex xa am mp plle e 4 41 11 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -2 2- -m me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -1 1- - [2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide hydrochloride [2-(morpholinyl)ethyl]-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 96 using the acid of Preparation 30, the compound of Preparation 1', and the compound of Preparation 1''. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H Cl N O 39 41 6 4 [M+H] calculated: 693.2951 [M+H] measured: 693.2947 E Ex xa am mp plle e 4 41 12 2..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -[ [3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )p pr ro op py yll] ]- -3 3,,4 4- -d diih hy yd dr ro oiis so o- - quinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4- quinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 6' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=66.06:65.61; %H=5.93:5.22; %N=10.75:10.69; %Cl =4.53:4.68 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H Cl N O 43 45 6 4 [M+H] calculated: 745.3264 [M+H] measured: 745.3260 E Ex xa am mp plle e 4 41 13 3..N N- -( (5 5- -C Cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- - dimethyl(7-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- dimethyl(7-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}-2,3-dihydro-1,4-benzodioxinyl)-1H-pyrrolecarboxamide carbonyl}-2,3-dihydro-1,4-benzodioxinyl)-1H-pyrrolecarboxamide h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 13 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=66.44:66.40; %H=5.83:4.84; %N=10.81:10.79; %Cl =4.56:4.22 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H N O 43 44 6 6 [M+H] calculated: 741.3395 [M+H] measured: 741.3397 E Ex xa am mp plle e 4 41 14 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(5-methyl-5H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(5-methyl-5H- p py yr rr ro ollo o[ [3 3,,2 2- -d d] ]p py yr riim miid diin n- -2 2- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=64.23:64.38; %H=5.39:5.25; %N=12.79:12.62; %Cl =4.62:4.39 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H Cl N O 41 40 7 4 [M+H] calculated: 730.2903 [M+H] measured: 730.2904 E Ex xa am mp plle e 4 41 15 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4- 2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4- hydroxyphenyl)methyl-1H-pyrrolecarboxamide hydrochloride hydroxyphenyl)methyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 3 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=64.95:65.14; %H=5.45:5.34; %N=11.36:11.36; %Cl =4.79:4.67 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl N O 40 39 6 4 [M+H] calculated: 703.2794 [M+H] measured: 703.2795 Example 416.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 416.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuterio- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuterio- m me et th hy yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 25'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=63.51:63.41; %H=5.63:5.42; %N=11.69:11.61; %Cl =4.93:4.85 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl D N O 38 36 3 6 4 [M+H] calculated: 682.2982 [M+H] measured: 682.2986 E Ex xa am mp plle e 4 41 17 7..N N- -( (5 5- -C Cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -5 5- -( (4 4- - m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 31 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=67.32:67.56; %H=6.05:5.84; %N=11.22:11.21; %Cl =4.73:4.71 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H N O 42 44 6 5 [M+H] calculated: 713.3446 [M+H] measured: 713.3446 E Ex xa am mp plle e 4 41 18 8..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -5 5- -( (4 4- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- - 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrazolyl)-1H-pyrrolecarboxamide hydrochloride pyrazolyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 31 and the compound of Preparation 3' in Step A, and the compound of Preparation 1'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.86:65.51; %H=6.09:6.09; %N=11.82:11.73; %Cl =4.98:5.14 High-resolution mass spectrometry (ESI/FIA/HR, ESI-/FIA): Empirical formula: C H N O 39 42 6 5 [M+H] calculated: 675.3289 [M+H] measured: 675.3286 E Ex xa am mp plle e 4 41 19 9..N N- -( (3 3- -C Cy ya an no op ph he en ny yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- - 1H-pyrrolecarboxamide hydrochloride 1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 41'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI+): Empirical formula: C H FN O 41 38 5 4 [M+H] calculated: 684.2988 [M+H] measured: 684.2975 E Ex xa am mp plle e 4 42 20 0..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuterio- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuterio- m me et th hy yll) )- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 25'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI/+): Empirical formula: C D H FN O 38 3 36 6 4 [M+H] calculated: 666.3285 [M+H] measured: 666.3265 E Ex xa am mp plle e 4 42 21 1..N N- -( (5 5- -C Cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- - (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H F N O 41 41 6 4 [M+H] calculated: 701.3246 [M+H] measured: 701.3282 E Ex xa am mp plle e 4 42 22 2..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (2 2- - {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)- {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)- 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 25 and the compound of Preparation 3' in Step A, and the compound of Preparation 1'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=67.00:67.47; %H=6.07:5.54; %N=12.34:12.46; %Cl =5.20:4.58 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H N O 38 40 6 4 [M+H] calculated: 645.3184 [M+H] measured: 645.3182 Example 423.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 423.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -[ [1 1- -( (o ox xe et ta an n- -3 3- -y yll) )- -1 1H H- - p py yr ra az zo oll- -4 4- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 26'' in Step C.
Elemental microanalysis: (%, theoretical:measured) %C=68.17:67.82; %H=5.86:5.97; %N=11.92:11.48 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H FN O 40 41 6 5 [M+H] calculated: 705.3202 [M+H] measured: 705.3207 E Ex xa am mp plle e 4 42 24 4..N N- -( (4 4- -H Hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -( (2 2- -m me et th ho ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -5 5- -( (2 2- - {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)- {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)- 1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 25 and the compound of Preparation 3' in Step A, and the compound of Preparation 12'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=66.05:65.63; %H=5.83:5.45; %N=11.85:11.93; %Cl =5.00:4.91 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H N O 39 40 6 5 [M+H] calculated: 673.3133 [M+H] measured: 673.3129 E Ex xa am mp plle e 4 42 25 5..N N- -( (3 3- -C Cy ya an no o- -5 5- -m me et th ho ox xy yp ph he en ny yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- - ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- 1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride 1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=67.25:66.55; %H=5.51:5.28; %N=9.33:8.55 %Cl =4.73:4.67 Example 426.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 426.5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -( (2 2- -m me et th ho ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- - dimethyl-1H-pyrrolecarboxamide dimethyl-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 12'' in Step C.
High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H FN O 39 39 6 5 [M+H] calculated: 691.3038 [M+H] measured: 691.3060 Example 427.N-(3-Cyanomethoxyphenyl)(5-fluoro{[(3S)(morpholin Example 427.N-(3-Cyanomethoxyphenyl)(5-fluoro{[(3S)(morpholin ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=67.24:66.41; %H=5.51:5.35; %N=9.33:8.97 %Cl =4.73:4.81 Example 428.N-(5-Cyano-1,2-dimethyl-1H-pyrrolyl)(4-fluoro{[(3S) Example 428.N-(5-Cyano-1,2-dimethyl-1H-pyrrolyl)(4-fluoro{[(3S) ( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- - h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 26 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=66.79:66.97; %H=5.74:5.36; %N=11.40:11.45; %Cl =4.81:4.53 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H F N O 41 41 6 4 [M+H] calculated: 701.3246 [M+H] measured: 701.3245 Example 429.N-(5-Cyano-1,2-dimethyl-1H-pyrrolyl)(4-fluoromethoxy Example 429.N-(5-Cyano-1,2-dimethyl-1H-pyrrolyl)(4-fluoromethoxy { {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- - N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 27 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.75:65.43; %H=5.78:5.57; %N=10.95:10.81; %Cl =4.62:4.54 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H F N O 42 43 6 5 [M+H] calculated: 731.3352 [M+H] measured: 731.3351 E Ex xa am mp plle e 4 43 30 0..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [3 3- -( (t tr riif fllu uo or ro om me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]- - pyridinyl)-1H-pyrrolecarboxamide pyridinyl)-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and racemic 3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline in Step A, and the compound of Preparation 11'' in Step C.
High-resolution mass spectrometry (ESI+-/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H Cl F N O 38 31 3 5 3 [M+H] calculated: 698.2140 [M+H] measured: 698.2144 E Ex xa am mp plle e 4 43 31 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(1,3-dimethyl-1H-pyrazolyl)-N-(4-hydroxyphenyl)- 2(1H)-yl]carbonyl}phenyl)-N-(1,3-dimethyl-1H-pyrazolyl)-N-(4-hydroxyphenyl)- 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=64.19:64.37; %H=5.80:5.18; %N=11.52:11.55; %Cl =4.86:4.68 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl N O 39 41 6 4 [M+H] calculated: 693.2951 [M+H] measured: 693.2952 and Example 432.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 432.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(1,5-dimethyl-1H-pyrazolyl)-N-(4-hydroxyphenyl)- 2(1H)-yl]carbonyl}phenyl)-N-(1,5-dimethyl-1H-pyrazolyl)-N-(4-hydroxyphenyl)- 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=64.19:64.43; %H=5.80:5.22; %N=11.52:11.60; %Cl =4.86:4.66 High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H Cl N O 39 41 6 4 [M+H] calculated: 693.2951 [M+H] measured: 693.2953 The compounds of Examples 431 and 432 are obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the mixture of Preparation 27'' in Step C. At the end of Step D, the isomers are separated by preparative HPLC using acetonitrile and water-TFA as eluants. After evaporating off the solvent and neutralising with sodium bicarbonate, the products are subjected to a step of conversion into salt form in the presence of 1M HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the title products are obtained.
E Ex xa am mp plle e 4 43 33 3..N N- -( (5 5- -C Cy ya an no o- -1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- - d diim me et th hy yll- -5 5- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- - yl]carbonyl}phenyl)-1H-pyrrolecarboxamide hydrochloride yl]carbonyl}phenyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 25 and the compound of Preparation 3' in Step A, and the compound of Preparation 19'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=68.12:68.29; %H=5.86:5.40; %N=11.92:12.05; %Cl =5.03:4.92 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H N O 40 40 6 4 [M+H] calculated: 669.3184 [M+H] measured: 669.3184 E Ex xa am mp plle e 4 43 34 4..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride dihydro-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process described in Step B of Example 49 using Example 385 as starting material. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=67.15:68.03; %H=5.90:5.50; %N=11.19:10.59 %Cl =4.72:5.55 Example 435.N-(4-Cyanopyridinyl)(5-fluoromethoxy{[(3S)(morpholin- Example 435.N-(4-Cyanopyridinyl)(5-fluoromethoxy{[(3S)(morpholin- 4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- - 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 14 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA): Empirical formula: C H F N O 41 39 6 5 [M+H] calculated: 715.3039 [M+H] measured: 715.3040 Example 436.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 436.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(5-cyanothiophenyl)-N-(4-hydroxyphenyl)-1,2- 2(1H)-yl]carbonyl}phenyl)-N-(5-cyanothiophenyl)-N-(4-hydroxyphenyl)-1,2- d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=63.07:63.09; %H=5.02:4.78; %N=9.43:9.35; %S=4.32:4.09; %Cl =4.77:4.59 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI+-/FIA): Empirical formula: C H Cl N O S 39 36 5 4 [M+H] calculated: 706.2249: [M+H] measured: 706.2250 Example 437.N-(3-Cyanofluorophenyl)(5-fluoro{[(3S)(morpholin Example 437.N-(3-Cyanofluorophenyl)(5-fluoro{[(3S)(morpholin y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- - 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ES+): Empirical formula: C H F N O 41 37 2 5 4 [M+H] calculated: 702.2894 [M+H] measured: 702.2886 Example 438.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 438.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (p py yr ra az ziin n- -2 2- -y yll) )- -1 1H H- - p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=63.95:63.96; %H=5.37:5.17; %N=11.78:11.61; %Cl =4.97:4.57 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 38 37 6 4 [M+H] calculated: 677.2638 [M+H] measured: 677.2639 E Ex xa am mp plle e 4 43 39 9..5 5- -( (5 5- -F Fllu uo or ro o- -4 4- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2- m me et th ho ox xy yp py yr riim miid diin n- -5 5- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 14 and the compound of Preparation 3' in Step A, and the compound of Preparation 12'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI-/FIA): Empirical formula: C H F N O 40 41 6 6 [M+H] calculated: 721.3144 [M+H] measured: 721.3144 E Ex xa am mp plle e 4 44 40 0..N N- -( (5 5- -C Cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -4 4- -m me et th ho ox xy y- -2 2- - {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)- {[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)- N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 14 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.75:65.98; %H=5.78:5.50; %N=10.95:10.87; %Cl =4.62:4.42 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H F N O 42 43 6 5 [M+H] calculated: 731.3352 [M+H] measured: 731.3353 E Ex xa am mp plle e 4 44 41 1..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (5 5- -c cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - phenyl-1H-pyrrolecarboxamide hydrochloride phenyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 29'' in Step C, it being understood that Step D is not carried out. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=66.75:66.44; %H=5.74:5.59; %N=11.39:11.45; %Cl =4.81:4.43 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 41 41 6 3 [M+H] calculated: 701.3001 [M+H] measured: 701.2998 Example 442.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 442.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (5 5- -c cy ya an no ot th hiio op ph he en n- -3 3- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- - d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 42'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=63.07:63.14; %H=5.02:4.87; %N=9.43:9.41; %S=4.32:4.24; %Cl =4.77:4.57 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O S 39 36 5 4 [M+H] calculated: 706.2249 [M+H] measured: 706.2252 E Ex xa am mp plle e 4 44 43 3..5 5- -( (5 5- -F Fllu uo or ro o- -4 4- -h hy yd dr ro ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- - dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H- p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) )- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e Step A: 5-(5-Fluoromethoxy{[(3S)(morpholinylmethyl)-3,4-dihydroiso- quinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin- 5-yl)-N-phenyl-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 (Steps A to C) using the acid of Preparation 28 and the compound from Preparation 3' in Step A, and the compound of Preparation 30'' in Step C.
Step B: 5-(5-Fluorohydroxy{[(3S)(morpholinylmethyl)-3,4-dihydroiso- -(5-Fluorohydroxy{[(3S)(morpholinylmethyl)-3,4-dihydroiso- q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- - b b] ]p py yr riid diin n- -5 5- -y yll) )- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e To a solution of the compound of Step A (1 g; 1.37 mmol) in anhydrous dichloromethane (10 mL) there is added, dropwise at 0°C, a 1M solution of boron tribromide in dichloromethane (1.8 mL; 1.8 mmol). After stirring for 15 hours at ambient temperature, the reaction mixture is poured dropwise into a solution of ethanol (15 mL) at -10°C. After stirring for one hour, saturated aqueous sodium bicarbonate solution is added, and the reaction mixture is extracted with dichloromethane. After drying over MgSO , the residue is purified on a silica gel column using a mixture of dichloromethane and methanol as eluant to yield the expected product.
High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H F N O 42 41 6 4 [M+H] calculated: 713.3246 [M+H] measured: 713.3244 E Ex xa am mp plle e 4 44 44 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -N N- -( (5 5- -m me et th ho ox xy yp py yr ra az ziin n- -2 2- -y yll) )- -1 1,,2 2- - dimethyl-1H-pyrrolecarboxamide hydrochloride dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=62.99:62.72; %H=5.42:5.24; %N=11.30:11.19; %Cl =4.77:4.67 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 39 39 6 5 [M+H] calculated: 707.2743 [M+H] measured: 707.2747 E Ex xa am mp plle e 4 44 45 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1- ( (t tr riid de eu ut te er riio om me et th hy yll) )- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll] ]- -1 1H H- -p py yr rr ro olle e- -3 3- - c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Step A: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuteriomethyl)-1H- pyrrolo[2,3-b]pyridinyl]-1H-pyrrolecarboxamide The intermediate is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 31'' in Step C.
Step B: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuteriomethyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl]-1H-pyrrolecarboxamide hydrochloride The procedure is in accordance with the protocol described in Step B of Example 49, it being understood that the product is then subjected to a step of conversion into salt form in the presence of 1M HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the title product is obtained.
Elemental microanalysis: (%, theoretical:measured) %C=65.45:65.33; %H=5.78:5.59; %N=10.90:10.82; %Cl =4.60:4.28 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl D N O 42 40 3 6 4 [M+H] calculated: 734.3295 [M+H] measured: 734.3300 Example 446.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 446.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (5 5- -f fllu uo or ro op py yr ra az ziin n- -2 2- -y yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- - d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=62.28:62.16; %H=5.10:4.97; %N=11.04:11.35; %Cl =4.85:4.48 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl F N O 38 36 6 4 [M+H] calculated: 695.2543 [M+H] measured: 695.2545 E Ex xa am mp plle e 4 44 47 7..5 5- -( (4 4- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrazolyl)-1H-pyrrolecarboxamide hydrochloride pyrazolyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 26 and the compound of Preparation 3' in Step A, and the compound of Preparation 1'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.28:65.27; %H=5.77:5.51; %N=12.02:1.90; %Cl =5.07:4.74 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H F N O 38 39 6 4 [M+H] calculated: 663.3090 [M+H] measured: 663.3084 Example 448.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 448.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -[ [5 5- -c cy ya an no o- -1 1- -( (t tr riid de eu ut te er riio om me et th hy yll) )- -1 1H H- -p py yr rr ro oll- -3 3- -y yll] ]- -N N- -( (4 4- - h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 32'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=64.69:64.23; %H=5.45:5.47; %N=11.32:11.16; %Cl =4.77:4.56 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl D N O 40 36 3 6 4 [M+H] calculated: 706.2982 [M+H] measured: 706.2985 E Ex xa am mp plle e 4 44 49 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-[5-cyanomethyl(trideuteriomethyl)-1H-pyrrol 2(1H)-yl]carbonyl}phenyl)-N-[5-cyanomethyl(trideuteriomethyl)-1H-pyrrol yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 33'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.07:64.55; %H=5.62:5.51; %N=11.11:10.98; %Cl =4.68:4.58 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl D N O 41 38 3 6 4 [M+H] calculated: 720.3139 [M+H] measured: 720.3143 Example 450.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 450.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (3 3- -c cy ya an no o- -1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -5 5- -y yll) )- -N N- -( (4 4- - h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 34'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=63.24:62.62; %H=5.31:5.09; %N=13.24:13.04; %Cl =4.79:4.37 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 39 38 7 4 [M+H] calculated: 704.2747 [M+H] measured: 704.2747 E Ex xa am mp plle e 4 45 51 1..5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- 2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H- pyrazolo[3,4-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride pyrazolo[3,4-b]pyridinyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 17'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.64:66.28; %H=5.51:5.45; %N=13.07:12.17 %Cl =4.73:5.51 Example 452.N-(1,3-Dimethyl-1H-pyrazolyl)(5-fluoro{[(3S)(morpholin Example 452.N-(1,3-Dimethyl-1H-pyrazolyl)(5-fluoro{[(3S)(morpholin y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- - 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=65.68:64.77; %H=5.94:5.55; %N=11.78:10.69 %Cl =4.97:6.48 and E Ex xa am mp plle e 4 45 53 3..N N- -( (1 1,,5 5- -D Diim me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- - ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e Elemental microanalysis: (%, theoretical:measured) %C=65.68:65.43; %H=5.94:5.62; %N=11.78:10.95 %Cl =4.97:5.60 The compounds of Examples 452 and 453 are obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the mixture of Preparation 27'' in Step C. At the end of Step D, the isomers are separated by preparative HPLC using acetonitrile and water-TFA as eluants. After evaporating off the solvent and neutralising with sodium bicarbonate, the products are subjected to a step of conversion into salt form in the presence of 1M HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the title products are obtained.
Example 454.5-(5-Chloro{[3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- Example 454.5-(5-Chloro{[3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)- yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)- 1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 1 using the acid from Preparation 1 and racemic 3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline in Step A, and the compound of Preparation 18'' in Step C.
Elemental microanalysis: (%, theoretical:measured) %C=64.77:64.81; %H=4.55:4.52; %N=10.21:10.33 High-resolution mass spectrometry (ESI+/HR): Empirical formula: C H Cl F N O 37 31 3 5 3 [M+H] calculated: 686.2140 [M+H] measured: 686.2145 E Ex xa am mp plle e 4 45 55 5..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -m me et th hy yll- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]- - c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -{ {5 5- -c cy ya an no o- -2 2- -m me et th hy yll- -1 1- -[ [2 2- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )e et th hy yll] ]- -1 1H H- -p py yr rr ro oll- -3 3- -y yll} }- - N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 1' in Step A, and the compound of Preparation 35'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.71:66.07; %H=5.78:5.82; %N=10.95:10.66; %Cl =4.62:4.45 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 42 43 6 4 [M+H] calculated: 731.3107 [M+H] measured: 731.3109 Example 456.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- Example 456.5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-{2-[2-(morpholinyl)- carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-{2-[2-(morpholinyl)- e et th ho ox xy y] ]p py yr riim miid diin n- -5 5- -y yll} }- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 1' in Step A, and the compound of Preparation 36'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=63.41:63.51; %H=5.59:5.26; %N=11.09:11.10; %Cl =4.68:4.46 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 40 41 6 5 [M+H] calculated: 721.2900 [M+H] measured: 721.2907 E Ex xa am mp plle e 4 45 57 7..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(6-cyanomethoxypyridinyl)-N-(4-hydroxyphenyl)- 2(1H)-yl]carbonyl}phenyl)-N-(6-cyanomethoxypyridinyl)-N-(4-hydroxyphenyl)- 1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride 1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=64.15:63.95; %H=5.25:4.79; %N=10.95:10.97; %Cl =4.62:4.22 High-resolution mass spectrometry (ESI+/HR): Empirical formula: C H Cl N O 41 39 6 5 [M+H] calculated: 731.2743 [M+H] measured: 731.2746 Example 458.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 458.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,4-dimethyl-1H-pyrrolyl)-N-(4- 2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,4-dimethyl-1H-pyrrolyl)-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e h hy yd dr ro oc ch hllo or riid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 37'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.34:65.68; %H=5.62:5.31; %N=11.15:11.15; %Cl =4.70:4.33 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 41 41 6 4 [M+H] calculated: 717.2951 [M+H] measured: 717.2954 E Ex xa am mp plle e 4 45 59 9..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2(1H)-yl]carbonyl}phenyl)-N-(5-cyanoethylmethyl-1H-pyrrolyl)-N-(4- 2(1H)-yl]carbonyl}phenyl)-N-(5-cyanoethylmethyl-1H-pyrrolyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 38'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.71;65.29; %H=5.78:5.51; %N=10.95:10.95; %Cl =4.62:4.39 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 42 43 6 4 [M+H] calculated: 731.3107 [M+H] measured: 731.3109 E Ex xa am mp plle e 4 46 60 0..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3R R) )- -3 3- -[ [3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yll) )p pr ro op py yll] ]- -3 3,,4 4- - d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- - [1-(tetrahydrofuranyl)-1H-pyrazolyl]-1H-pyrrolecarboxamide hydrochloride [1-(tetrahydrofuranyl)-1H-pyrazolyl]-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 6' in Step A, and the compound of Preparation 22'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=64.58:64.24; %H=6.05:5.88; %N=10.51:10.53; %Cl =4.43:4.39 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 43 47 6 5 [M+H] calculated: 763.3369 [M+H] measured: 763.3371 Example 461.5-(5-Chloro{[(3R)[3-(morpholinyl)propyl]-3,4-dihydroiso- Example 461.5-(5-Chloro{[(3R)[3-(morpholinyl)propyl]-3,4-dihydroiso- q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (5 5- -c cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -1 1,,2 2- - dimethyl-N-phenyl-1H-pyrrolecarboxamide hydrochloride dimethyl-N-phenyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 6' in Step A, and the compound of Preparation 29'' in Step C, it being understood that Step D is not carried out. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=67.44:66.68; %H=6.05:5.80; %N=10.97:10.95; %Cl =4.63:4.57 High-resolution mass spectrometry (ESI+/HR): Empirical formula: C H Cl N O 43 45 6 3 [M+H] calculated: 729.3314 [M+H] measured: 729.3316 Example 462.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 462.5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (5 5- -m me et th hy yll- -1 1,,2 2- - o ox xa az zo oll- -3 3- -y yll) )- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the appropriate amine in Step C.
Elemental microanalysis: (%, theoretical:measured) %C=67.10:66.64; %H=5.63:5.40; %N=10.30:10.24 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 38 38 5 5 [M+H] calculated: 680.2634 [M+H] measured: 680.2637 Example 463.N-(2-Ethoxypyrimidinyl)(5-fluoro{[(3S)(morpholin Example 463.N-(2-Ethoxypyrimidinyl)(5-fluoro{[(3S)(morpholin y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- - 1,2-dimethyl-1H-pyrrolecarboxamide 1,2-dimethyl-1H-pyrrolecarboxamide The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 8 and the compound of Preparation 3' in Step A, and the compound of Preparation 39'' in Step C.
Elemental microanalysis: (%, theoretical:measured) %C=68.17:67.52; %H=5.86:5.60; %N=11.92:11.43 E Ex xa am mp plle e 4 46 64 4..5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (5 5- -h hy yd dr ro ox xy yp py yr riid diin n- -2 2- -y yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide dihydrochloride pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide dihydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and the compound of Preparation 3' in Step A, and the compound of Preparation 40'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 41 40 7 4 [M+H] calculated: 730.2903 [M+H] measured: 730.2907 Example 465.5-(4-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- Example 465.5-(4-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (5 5- -c cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -N N- -( (4 4- - hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 29 and the compound of Preparation 3' in Step A, and the compound of Preparation 18'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=65.34:64.81; %H=5.62:5.27; %N=11.15:10.95 %Cl =4.70:5.09 High-resolution mass spectrometry (ESI+): Empirical formula: C H Cl N O 41 41 6 4 [M+H] calculated: 717.2951 [M+H] measured: 717.2952 E Ex xa am mp plle e 4 46 66 6..5 5- -( (4 4- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- - 2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -N N- -( (4 4- -h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -( (1 1- -m me et th hy yll- -1 1H H- - pyrazolyl)-1H-pyrrolecarboxamide hydrochloride pyrazolyl)-1H-pyrrolecarboxamide hydrochloride The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 29 and the compound of Preparation 3' in Step A, and the compound of Preparation 1'' in Step C. The compound obtained is converted into salt form and lyophilised as described in the general process to obtain the title compound.
Elemental microanalysis: (%, theoretical:measured) %C=66.77:62.82; %H=5.63:5.29; %N=11.74:11.75; %Cl =5.01:5.23 High-resolution mass spectrometry (ESI+/HR, ESI-/LR): Empirical formula: C H Cl N O 38 39 6 4 [M+H] calculated: 679.2794 [M+H] measured: 679.2796 Example 467.5-(5-Chloro{[3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- Example 467.5-(5-Chloro{[3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- h hy yd dr ro ox xy yp ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -N N- -p ph he en ny yll- -1 1H H- -p py yr rr ro olle e- -3 3- -c ca ar rb bo ox xa am miid de e The title compound is obtained in accordance with the process of Example 1 using the acid of Preparation 1 and 1,2,3,4-tetrahydroisoquinoline in Step A, and the compound of Preparation 2'' in Step C.
Elemental microanalysis: (%, theoretical:measured) %C=72.97:72.93; %H=5.25:5.08; %N=7.29:7.34 High-resolution mass spectrometry (ESI/FIA/HR and MS/MS): Empirical formula: C H Cl N O 30 3 3 [M+H] calculated: 576.2048 [M+H] measured: 576.2067 P PH HA AR RM MA AC CO OL LO OG GI IC CA AL L S ST TU UD DY Y EXAMPLE A: Inhibition of Bcl-2 by the fluorescence polarisation technique 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 2.50x10 M, is mixed with a fluorescent peptide (Fluorescein-REIGAQLRRMADDLNAQY), at a final concentration of 1.00x10 M in a buffer solution (Hepes 10 mM, NaCl 150 mM, Tween20 0.05%, pH 7.4), in the presence or absence of increasing concentrations of test compounds. After incubation for 2 hours, the fluorescence polarisation is measured.
The results are expressed in IC (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.
E EX XA AM MP PL LE E B B: : I In n v viittr ro o c cy yt to ot to ox xiic ciit ty y The cytotoxicity studies were carried out on the RS4;11 leukaemia tumour line.
The cells are distributed onto microplates and exposed to the test compounds for 48 hours.
The cell viability is then quantified by a colorimetric assay, the Microculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942).
The results are expressed in IC (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.
Table 1: IC of Bcl-2 inhibition (fluorescence polarisation test) and of cytotoxicity for RS4;11 cells IC (nM) Bcl-2 FP IC (nM) MTT RS4;11 IC (nM) Bcl-2 FP IC (nM) MTT RS4;11 50 50 50 50 Example 1 5.0 33.6 Example 29 6.6 47.5 ND 1660 4.7 771 Example 2 Example 30 Example 3 24.6 94.9 Example 31 7.2 89.3 Example 4 ND 231 Example 32 13.3 240 Example 5 21.2 44.8 Example 33 10.9 57.8 .2 69 8.2 47 Example 6 Example 34 Example 7 25.6 90.6 Example 35 50.0 560 Example 8 ND 255 Example 36 71.4 >600 Example 9 22.4 87.5 Example 37 60.4 >600 16.2 205 7.5 134 Example 10 Example 38 Example 11 14.2 202 Example 39 7.2 19.7 Example 12 5.5 39.6 Example 40 64.4 431 Example 13 4.4 19.8 Example 41 10.0 22.6 3.7 8.23 5.2 4.36 Example 14 Example 42 Example 15 11.1 69.4 Example 43 5.1 28.9 Example 16 12.6 22.7 Example 44 3.0 5.41 Example 17 8.0 75.2 Example 45 38.9 403 3.9 27.6 76.6 >600 Example 18 Example 46 Example 19 6.0 65.5 Example 47 5.9 44.5 Example 20 4.9 164 Example 48 4.4 14.9 Example 21 4.7 79.9 Example 49 4.0 14.1 6.6 45.7 5.9 33.1 Example 22 Example 50 Example 23 3.6 25.4 Example 51 26.7 354 Example 24 6.2 79.1 Example 52 28.9 433 Example 25 4.0 33.3 Example 53 43.5 293 4.1 541 18.0 30.5 Example 26 Example 54 Example 27 5.2 93.4 Example 55 209.6 >600 Example 28 7.5 95.3 Example 56 75.0 >600 IC (nM) Bcl-2 FP IC (nM) MTT RS4;11 IC (nM) Bcl-2 FP IC (nM) MTT RS4;11 50 50 50 50 Example 57 80.0 >600 Example 102 2 6.51 133.3 >600 3.9 15.4 Example 58 Example 108 Example 59 134.0 >600 Example 109 91.5 930 Example 60 ND 18.3 Example 110 8.5 39.5 Example 61 4.5 37.8 Example 115 3.6 18.3 14.3 127 3.4 47.8 Example 62 Example 116 Example 63 5.1 11.2 Example 122 3.4 82.4 Example 65 21.9 113 Example 126 4.2 49.2 Example 66 16.9 241 Example 127 5.3 111 12.5 98.6 18.1 275 Example 67 Example 129 Example 68 2.1 20.7 Example 207 4.6 32.2 Example 69 5.3 3.68 Example 209 7.4 25.4 Example 70 8.5 63.5 Example 210 8.8 47.2 6.1 12.9 6.3 236 Example 71 Example 214 Example 72 7.7 43.6 Example 230 5.1 18.3 Example 73 8 42.6 Example 358 14.8 165 Example 74 4 45.4 Example 384 9.7 216 52.9 367 5.7 28.7 Example 75 Example 385 Example 81 ND 249 Example 386 2.6 9.23 Example 82 19.5 427 Example 387 20.6 243 Example 88 15.9 69.6 Example 388 3.6 16.5 8.4 37.8 14.7 208 Example 92 Example 389 Example 93 19.7 368 Example 390 21.2 173 Example 94 8.6 104 Example 391 30.3 255 Example 95 7 174 Example 392 3.8 11.4 13.5 161 2.1 1.95 Example 96 Example 393 Example 97 19 98 Example 394 2.5 2.76 Example 98 7.6 68.3 Example 395 3.5 7.57 Example 99 6.4 108 Example 396 15.7 116 22.9 193 4.5 37.1 Example 100 Example 397 Example 101 21.1 743 Example 398 3.9 13.4 IC (nM) Bcl-2 FP IC (nM) MTT RS4;11 IC (nM) Bcl-2 FP IC (nM) MTT RS4;11 50 50 50 50 Example 399 9.9 155 Example 432 3.4 76.6 49 469 2.6 48.2 Example 400 Example 433 Example 401 8 24.3 Example 434 3.5 45.7 Example 402 26.1 241 Example 435 14.9 441 Example 403 24.2 289 Example 436 49.1 338 24.4 85.5 4.4 70.5 Example 404 Example 437 Example 406 4.2 10.6 Example 438 11.3 379 Example 407 20.6 150 Example 439 6.1 329 Example 408 5.4 4.46 Example 440 2.6 13.6 12.2 41.9 3.5 132 Example 409 Example 441 Example 410 9.9 61.6 Example 442 3 42.8 Example 411 5.5 32.8 Example 443 ND 57.9 Example 412 3.1 0.398 Example 444 5.5 181 3.1 9.43 2 19 Example 413 Example 445 Example 415 3.8 29.9 Example 446 7.8 249 Example 416 2.9 42.5 Example 447 20 >600 Example 417 3 11 Example 448 2.4 12.1 .1 159 1.7 11.9 Example 418 Example 449 Example 419 2.8 15.8 Example 450 2.7 53.2 Example 420 6.1 51.8 Example 451 2.9 102 Example 421 2.5 3.73 Example 452 8.3 112 9.2 101 6.9 99.9 Example 422 Example 453 Example 423 11.7 344 Example 454 6.5 158 Example 424 13.6 102 Example 455 1.9 11.8 Example 425 4.2 62 Example 456 2.7 80.6 .2 139 ND 80.4 Example 426 Example 457 Example 427 2.2 23.3 Example 458 10.5 197 Example 428 3.5 59.2 Example 459 2.5 5.93 Example 429 3.1 109 Example 460 2.8 22.9 19.9 328 3.1 18.6 Example 430 Example 461 Example 431 3 89 Example 462 13.3 368 IC (nM) Bcl-2 FP IC (nM) MTT RS4;11 IC (nM) Bcl-2 FP IC (nM) MTT RS4;11 50 50 50 50 Example 463 ND 40.8 Example 466 ND 493 36.6 723 19.2 188 Example 464 Example 467 Example 465 ND 50.6 ND: not determined EXAMPLE C: Induction of caspase activity in vivo.
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. 1x10 RS4;11 cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after the graft, the animals are treated orally with the various compounds. Sixteen hours after treatment, the tumour masses are recovered and lysed, and the caspase 3 activity is measured in the tumour lysates.
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 treated mice divided by the activity for the control mice.
The results obtained show that the compounds of the invention are capable of inducing apoptosis in RS4;11 tumour cells in vivo.
E EX XA AM MP PL LE E D D: : Q Qu ua an nt tiif fiic ca at tiio on n o of f t th he e c clle ea av ve ed d f fo or rm m o of f c ca as sp pa as se e 3 3 iin n v viiv vo o..
The ability of the compounds of the invention to activate caspase 3 is evaluated in a xenograft model of RS4;11 leukaemia cells. 1x10 RS4;11 cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after the graft, the animals 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 quantified in the tumour lysates.
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.
The results show that the compounds of the invention are capable of inducing apoptosis in RS4;11 tumour cells in vivo.
Table 2: Caspase activation factors (cleaved caspase 3 MSD test in the tumours of treated mice versus control mice) in vivo, after treatment by the oral route (exact doses in brackets) Activation factor Time period after which Compound tested the tumour is removed (T) ± SEM (versus control) Example 25 2 hours 45.7 ± 2.0 (25 mg/kg) 2 hours 72.3 ± 5.4 (12.5 mg/kg) Example 28 Example 47 2 hours 12.3 ± 2.4 (25 mg/kg) Example 61 2 hours 76.0 ± 5.2 (12.5 mg/kg) Example 67 2 hours 29.8 ± 4.0 (25 mg/kg) 2 hours 46.8 ± 16.1 (25 mg/kg) Example 71 Example 74 2 hours 24.5 ± 7.4 (12.5 mg/kg) Example 108 2 hours 22.6 ± 2.4 (12.5 mg/kg) Example 230 2 hours 42.2 ± 9.3 (25 mg/kg) 2 hours 52.0 ± 8.6 (12.5 mg/kg) Example 386 Example 388 2 hours 85.7 ± 3.7 (25 mg/kg) Example 421 2 hours 38.7 ± 10.7 (12.5 mg/kg) Example 449 2 hours 50.5 ± 3.4 (12.5 mg/kg) E EX XA AM MP PL LE E E E: : A An nt tii- -t tu um mo ou ur r a ac ct tiiv viit ty y iin n v viiv vo o The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of RS4;11 leukaemia cells. 1x10 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 regimes (daily treatment for five 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 accordingly show that the compounds of the invention are capable of inducing significant tumour regression, which can be total, during the treatment period.
EXAMPLE F: Pharmaceutical composition: Tablets 1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 467 5 g Wheat starch ................................................................................................. 20 g Maize starch ............................................................................................................. 20 g Lactose ..................................................................................................................... 30 g Magnesium stearate ................................................................................................. 2 g Silica ........................................................................................................................ 1 g Hydroxypropylcellulose .......................................................................................... 2 g

Claims (5)

WHAT WE CLAIM IS : 1.Compound of formula (I): wherein: 5 ♦ A and A , each independently of the other, represent a hydrogen or halogen atom, a linear or branched (C -C )polyhaloalkyl group, a linear or branched (C -C )alkyl 1 6 1 6 group or a cycloalkyl group, ♦ T represents a hydrogen atom, a linear or branched (C -C )alkyl group optionally substituted by from one to three halogen atoms, a group (C -C )alkyl-NR R , or a 1 4 1 2 10 group (C -C )alkyl-OR , 1 4 6 ♦ R and R , each independently of the other, represent a hydrogen atom or a linear or branched (C -C )alkyl group, or R and R form with the nitrogen atom carrying them a heterocycloalkyl, ♦ R represents a linear or branched (C -C )alkyl group, a linear or branched 3 1 6 15 (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a cycloalkyl 2 6 2 6 group, a (C -C )cycloalkyl-(C -C )alkyl group wherein the alkyl moiety is linear 3 10 1 6 or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated, ♦ R represents an aryl group, a heteroaryl group, a cycloalkyl group or a linear or branched (C -C )alkyl group, it being understood that one or more of the carbon 5 atoms of the preceding groups, or of their possible substituents, may be deuterated, ♦ R represents a hydrogen or halogen atom, a linear or branched (C -C )alkyl group, 5 1 6 or a linear or branched (C -C )alkoxy group, ♦ R represents a hydrogen atom or a linear or branched (C -C )alkyl group, 6 1 6 ♦ R , R , R and R , each independently of the others, represent R , a halogen atom, a a b c d 7 10 linear or branched (C -C )alkoxy group, a hydroxy group, a linear or branched (C -C )polyhaloalkyl group, a trifluoromethoxy group, -NR R ', nitro, R -CO- 1 6 7 7 7 (C -C )alkyl-, R -CO-NH-(C -C )alkyl-, NR R '-CO-(C -C )alkyl-, NR R '-CO- 0 6 7 0 6 7 7 0 6 7 7 (C -C )alkyl-O-, R -SO -NH-(C -C )alkyl-, R -NH-CO-NH-(C -C )alkyl-, R -O- 0 6 7 2 0 6 7 0 6 7 CO-NH-(C -C )alkyl-, a heterocycloalkyl group, or the substituents of one of the 15 pairs (R ,R ), (R ,R ) or (R ,R ) form together with the carbon atoms carrying them a b b c c d a ring composed of from 5 to 7 ring members, which may contain from one to 2 hetero atoms selected from oxygen and sulphur, it also being understood that one or more carbon atoms of the ring defined hereinbefore may be deuterated or substituted by from one to 3 groups selected from halogen and linear or branched 20 (C -C )alkyl, ♦ R and R ', each independently of the other, represent a hydrogen, a linear or branched (C -C )alkyl, a linear or branched (C -C )alkenyl, a linear or branched
1 6 2 6 (C -C )alkynyl, an aryl or a heteroaryl, or R and R ', together with the nitrogen 2 6 7 7 atom carrying them, form a heterocycle composed of from 5 to 7 ring members, 25 it 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 quaternary nitrogens), 30 - "cycloalkyl" means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to 10 ring members, - "heterocycloalkyl" means any mono- or bi-cyclic, non-aromatic, condensed or spiro group composed of from 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, SO and nitrogen, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined 5 and the groups alkyl, alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3 groups selected from: linear or branched (C -C )alkyl optionally substituted by a group selected from methoxy, hydroxy or morpholine; (C -C )spiro; linear or branched (C -C )alkoxy 3 6 1 6 optionally substituted by a morpholine; (C -C )alkyl-S-; hydroxy; oxo (or N-oxide where appropriate); nitro; cyano; -COOR'; -OCOR'; NR'R''; linear or branched (C - 10 C )polyhaloalkyl; trifluoromethoxy; (C -C )alkylsulphonyl; halogen; aryl optionally 6 1 6 substituted by one or more halogen atoms; heteroaryl; aryloxy; arylthio; cycloalkyl; heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups, it being understood that R' and R'', each independently of the other, represent a hydrogen atom or linear or branched (C -C )alkyl group optionally substituted by a methoxy, 15 its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
2.Compound of formula (I) according to claim 1, wherein A represents a hydrogen atom or a methyl group.
3.Compound of formula (I) according to claim 1 or claim 2, wherein A represents a linear 20 or branched (C -C )alkyl group optionally substituted by a group selected from halogen, hydroxy, linear or branched (C -C )alkoxy, NR'R'' and morpholine. 4.Compound of formula (I) according to claim 1 or claim 2, wherein A represents a linear or branched (C -C )polyhaloalkyl group or a cyclopropyl group. 5.Compound of formula (I) according to one of claims 1 to 3, wherein A and A both 25 represent a methyl group. 6.Compound of formula (I) according to one of claims 1 to 5, wherein T represents a methyl, aminomethyl, (morpholinyl)methyl, (4-methylpipérazinyl)methyl, 2- (morpholinyl)ethyl, [2-(morpholinyl)ethoxy]methyl, hydroxymethyl, [2- (dimethylamino)ethoxy]methyl, hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl, 1- 5 oxaazaspiro[3.3]heptylmethyl, 3-(morpholinyl)propyl or trifluoromethyl group. 7.Compound of formula (I) according to one of claims 1 to 6, wherein R and R each represent a hydrogen atom and (R ,R ), together with the carbon atoms carrying them, form a 1,3-dioxolane group or a 1,4-dioxane group; or R , R and R each represent a a c d hydrogen atom and R represents a hydrogen or halogen atom or a methoxy group. 10 8.Compound of formula (I) according to one of claims 1 to 6, wherein: R and R each represent a hydrogen atom, R represents a hydrogen or halogen atom and R represents a hydroxy or methoxy group; or: R and R each represent a hydrogen atom, R represents a a d b hydroxy or methoxy group and R represents a halogen atom. 9.Compound of formula (I) according to one of claims 1 to 6, wherein R , R and R each a b d 15 represent a hydrogen atom and R represents a group selected from R -CO-NH- (C -C )alkyl-, R -SO -NH-(C -C )alkyl-, R -NH-CO-NH-(C -C )alkyl- and R -O-CO-NH- 0 6 7 2 0 6 7 0 6 7 (C -C )alkyl-. 10.Compound of formula (I) according to one of claims 1 to 9, wherein R represents a phenyl, 4-hydroxyphenyl, 3-fluorohydroxyphenyl, 2-hydroxypyrimidine or 3- 20 hydroxypyridine group. 11.Compound of formula (I) according to one of claims 1 to 10, wherein R represents an aryl or heteroaryl group. 12.Compound of formula (I) according to one of claims 1 to 10, wherein R represents a group selected from methyl, phenyl, 1H-pyrazole, 1H-indole, 1H-indazole, pyridine, 25 pyrimidine, 1H-pyrrolo[2,3-b]pyridine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 1H- benzimidazole, 1H-pyrrole, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-b]pyridine, 5H- pyrrolo[3,2-d]pyrimidine, thiophene, pyrazine, 1H-pyrazolo[3,4-b]pyridine, 1,2-oxazole, and 1H-pyrazolo[1,5-a]pyrimidine, those groups optionally having one or more substituents selected from halogen, linear or branched (C -C )alkyl, linear or branched (C -C )alkoxy, cyano, cyclopropyl, oxetane, tetrahydrofuran, -CO-O-CH , 1 6 3 5 trideuteriomethyl, 2-(morpholinyl)ethyl and 2-(morpholinyl)ethoxy. 13.Compound of formula (I) according to claim 9, wherein R represents a linear or branched (C -C )alkyl or a heteroaryl optionally substituted by a linear or branched (C -C )alkyl, and R represents a 4-hydroxyphenyl group. 1 6 4 14.Compound of formula (I) according to claim 1, selected from the following group: 10 (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide, (5-chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-
(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H-pyrrolecarboxamide, 15 -N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(6-{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxolyl)-1H-pyrrolecarboxamide, -N-(4-hydroxyphenyl)-1,2-dimethyl(6-{[(3R)methyl-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-N-(pyridinyl)-1H-pyrrole 20 carboxamide, (5-fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol yl)-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- 25 carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3- b]pyridinyl)-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H-pyrrole- 3-carboxamide, 30 (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)-N-(5-cyanomethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2- dimethyl-1H-pyrrolecarboxamide, -N-(5-cyanomethyl-1H-pyrrolyl)(5-fluoro{[(3S)(morpholinylmethyl)- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2- dimethyl-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- 5 carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)- 1,2-dimethyl-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridinyl)-1H-pyrrolecarboxamide, 10 -N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)(5-fluoro{[(3S)(morpholinyl- methyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)- 1,2-dimethyl-1H-pyrrolecarboxamide, (5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]- carbonyl}phenyl)-N-[5-cyanomethyl(trideuteriomethyl)-1H-pyrrolyl]-N- 15 (4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 15.Compound of formula (I) according to claim 1 which is 5-(5-chloro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- 20 hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide. 16.Compound of formula (I) according to claim 1 which is 5-(5-chloro{[(3R)methyl- 3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N- (pyridinyl)-1H-pyrrolecarboxamide. 17.Compound of formula (I) according to claim 1 which is N-(4-hydroxyphenyl)-1,2- dimethyl-N-(1-methyl-1H-pyrazolyl)(6-{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolecarboxamide. 18.Compound of formula (I) according to claim 1 which is N-(4-hydroxyphenyl)-1,2- dimethyl(6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxolyl)-N-(pyridinyl)-1H-pyrrolecarboxamide. 5 19.Compound of formula (I) according to claim 1 which is 5-(5-fluoro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-1H-pyrrolecarboxamide. 20.Compound of formula (I) according to claim 1 which is 5-(5-chloro{[(3S) 10 (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-1H-pyrrole carboxamide. 21.Compound of formula (I) according to claim 1 which is 5-(5-chloro{[(3S) 15 (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H-pyrrolecarboxamide. 22.Compound of formula (I) according to claim 1 which is 5-(5-chloro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano 20 methyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide. 23.Compound of formula (I) according to claim 1 which is N-(5-cyanomethyl-1H- pyrrolyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide. 24.Compound of formula (I) according to claim 1 which is 5-(5-chloro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano- 1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole carboxamide. 25.Compound of formula (I) according to claim 1 which is 5-(5-chloro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4- hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl)- 1H-pyrrolecarboxamide. 26.Compound of formula (I) according to claim 1 which is N-(5-cyano-1,2-dimethyl-1H- 5 pyrrolyl)(5-fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide. 27.Compound of formula (I) according to claim 1 which is 5-(5-chloro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[5-cyano 10 methyl(trideuteriomethyl)-1H-pyrrolyl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H- pyrrolecarboxamide. 28.Process for the preparation of compounds of formula (I) according to claim 1, characterised in that there is used as starting material the compound of formula (II): (II) wherein R , R , R and R are as defined for formula (I), a b c d which compound of formula (II) is subjected to a Heck reaction, in an aqueous or organic medium, in the presence of a palladium catalyst, of a base, of a phosphine and of the compound of formula (III): (III) wherein the groups A and A are as defined for formula (I) and Alk represents a linear or branched (C -C )alkyl, to obtain the compound of formula (IV): (IV) wherein A , A , R , R , R and R are as defined for formula (I) and Alk is as defined 1 2 a b c d hereinbefore, the aldehyde function of which compound of formula (IV) is oxidised to a carboxylic acid to form the compound of formula (V): wherein A , A , R , R , R and R are as defined for formula (I) and Alk is as defined 1 2 a b c d hereinbefore, which compound of formula (V) is then subjected to peptide coupling with a compound of 5 formula (VI): (VI) wherein T and R are as defined for formula (I), to yield the compound of formula (VII): (VII) wherein A , A , R , R , R , R , T and R are as defined for formula (I) and Alk is as 1 2 a b c d 5 defined hereinbefore, the ester function of which compound of formula (VII) is hydrolysed to yield the 5 corresponding carboxylic acid or carboxylate, which may be converted into an acid derivative such as the corresponding acyl chloride or anhydride before being coupled with an amine NHR R wherein R and R have the same meanings as for formula (I), to yield 3 4 3 4 the compound of formula (I), which compound of formula (I) may be purified according to a conventional separation 10 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 separation technique, it being understood that, at any time considered appropriate in the course of the above- described process, certain groups (hydroxy, amino…) of the reagents or intermediates of 15 synthesis may be protected and then deprotected according to the requirements of synthesis. 29.Process for the preparation of compounds of formula (I'), particular cases of the compounds of formula (I) according to claim 1 as defined hereinbelow: (I') wherein: - A , A , R , R , R , R , T and R are as defined for formula (I), 1 2 a d 3 4 5 - R and R are such that one represents a hydrogen and the other a group selected 5 from R -CO-NH-(C -C )alkyl-, R -SO -NH-(C -C )alkyl-, R -NH-CO-NH- 7 0 6 7 2 0 6 7 (C -C )alkyl- and R -O-CO-NH-(C -C )alkyl-, R being as defined for formula (I), 0 6 7 0 6 7 which preparation process uses as starting material a compound of formula (II'): (II') wherein: 10 - R and R are as defined for formula (I), - Hal represents a halogen atom, - X and X are such that one represents a (C -C )alkyl-NH group while the other 1 2 0 6 2 represents a hydrogen atom, which compound of formula (II') is then subjected to peptide coupling with a compound of formula (VI): (VI) wherein T and R are as defined for formula (I), 5 to yield the compound of formula (III'): (III') wherein: - R , R , T and R are as defined for formula (I), a d 5 - Hal represents a halogen atom, 10 - X and X are such that one represents a (C -C )alkyl-NH group while the other 1 2 0 6 2 represents a hydrogen atom, which compound of formula (III') is subjected to a Heck reaction, in an aqueous or organic medium, in the presence of a palladium catalyst, of a base, of a phosphine and of a compound of formula (IV'): (IV') wherein A , A , R and R are as defined for formula (I), 1 2 3 4 to form the compound of formula (V'): (V') wherein: - A , A , R , R , R , R , T and R are as defined for formula (I), 1 2 a d 3 4 5
5 - X and X are such that one represents a (C -C )alkyl-NH group while the other 1 2 0 6 2 represents a hydrogen atom, which compound of formula (V') is then subjected to an acylation or sulphonylation reaction to yield the compound of formula (I'), which compound of formula (I') may be purified according to a conventional separation 10 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 separation technique, it being understood that, at any time considered appropriate in the course of the above- described process, certain groups (hydroxy, amino…) of the reagents or intermediates of 15 synthesis may be protected and then deprotected according to the requirements of synthesis. 30.Process according to claim 28 or 29 for the preparation of a compound of formula (I) wherein one of the groups R or R is substituted by a hydroxy function, characterised in that the amine NHR R is subjected beforehand to a reaction protecting the hydroxy function prior to any coupling with the carboxylic acid formed from the compound of 5 formula (VII), or with a corresponding acid derivative thereof, the resulting protected compound of formula (I) subsequently undergoes a deprotection reaction and is then optionally converted into one of its addition salts with a pharmaceutically acceptable acid or base. 31.Pharmaceutical composition comprising a compound of formula (I) according to any 10 one of claims 1 to 27 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. 32.Pharmaceutical composition according to claim 31 for use as a pro-apoptotic agent. 33.Pharmaceutical composition according to claim 31 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system. 15 34.Pharmaceutical composition according to claim 31 for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the 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. 20 35.Use of a pharmaceutical composition according to claim 31 in the manufacture of a medicament for use as a pro-apoptotic agent. 36. Use of a pharmaceutical composition according to claim 31 in the manufacture of a medicament intended for the treatment of cancers, diseases of the immune system and auto-immune diseases. 37.Use of a pharmaceutical composition according to claim 31 in the manufacture of a medicament intended for the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant 5 haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer. 38.Compound of formula (I) according to one of claims 1 to 27, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers 10 of the 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. 39.Use of a compound of formula (I) according to one of claims 1 to 27, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of a 15 medicament intended for the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the 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. 20 40.Combination of a compound of formula (I) according to any one of claims 1 to 27 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies. 41.Pharmaceutical composition comprising a combination of formula (I) according to any one of claims 1 to 27 and an anti-cancer agent selected from genotoxic agents, mitotic 25 poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies, in combination with one or more pharmaceutically acceptable excipients. 42.Combination according to claim 40 for use in the treatment of cancers. 43.Use of a compound of formula (I) according to any one of claims 1 to 27 and an anti- cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies, in the manufacture of a medicament for use in the treatment of cancers. 5 44.Use of a compound of formula (I) according to any one of claims 1 to 27 in the manufacture of a medicament for use in the treatment of cancers wherein the medicament is for sequential or simultaneous administration with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies 45.Compound of formula (I) according to any one of claims 1 to 27 for use in association with radiotherapy in the treatment of cancers. 46.A compound of claim 1, substantially as herein described with reference to any example 15 thereof. 47.A process of claim 28 or 29, substantially as herein described with reference to any example thereof. 20 48.A pharmaceutical composition of claim 31, substantially as herein described with reference to any example thereof. 49.A use of any one of claims 35-37, 39, 43 and 44, substantially as herein described with reference to any example thereof. 50.A combination of claim 40, substantially as herein described with reference to any example thereof.
NZ626623A 2013-07-23 2014-06-24 New pyrrole compounds, a process for their preparation and pharmaceutical compositions containing them NZ626623B (en)

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FR13/57258 2013-07-23
FR1357258A FR3008975A1 (en) 2013-07-23 2013-07-23 NOVEL PYRROLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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