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NZ616456B2 - Triazolopyridine compounds as mps-1 inhibitors - Google Patents
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NZ616456B2 - Triazolopyridine compounds as mps-1 inhibitors - Google Patents

Triazolopyridine compounds as mps-1 inhibitors Download PDF

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Publication number
NZ616456B2
NZ616456B2 NZ616456A NZ61645612A NZ616456B2 NZ 616456 B2 NZ616456 B2 NZ 616456B2 NZ 616456 A NZ616456 A NZ 616456A NZ 61645612 A NZ61645612 A NZ 61645612A NZ 616456 B2 NZ616456 B2 NZ 616456B2
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New Zealand
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kirstena
annotation
amino
phenyl
alkyl
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NZ616456A
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NZ616456A (en
Inventor
Hans Briem
Dirk Kosemund
Philip Lienau
Hartmut Schirok
Volker Schulze
Gerhard Siemeister
Detlef Stockigt
Antje Margret Wengner
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Bayer Intellectual Property Gmbh
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Priority claimed from PCT/EP2012/056914 external-priority patent/WO2012143329A1/en
Publication of NZ616456A publication Critical patent/NZ616456A/en
Publication of NZ616456B2 publication Critical patent/NZ616456B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems

Abstract

Provided are triazolopyridine derivative compounds of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include N,N-diethyl-4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}pheny1)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-methoxybenzamide and N-( 4-fluorobenzyl)-4-(2-{[4-(hydroxymethyl)-2-methoxyphenyl]amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzamide. The compounds are inhibitors of monopolar spindle 1 (Mps-1) kinase also known as tyrosine threonine kinase (TTK). The compounds may be useful in the treatment of cancer. 4-fluorobenzyl)-4-(2-{[4-(hydroxymethyl)-2-methoxyphenyl]amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzamide. The compounds are inhibitors of monopolar spindle 1 (Mps-1) kinase also known as tyrosine threonine kinase (TTK). The compounds may be useful in the treatment of cancer.

Description

TRIAZOLOPYRIDINE COMPOUNDS AS MPS-1 INHIBITORS The present invention relates to triazolopyridine compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
BACKGROUND OF THE INVENTION The present invention relates to chemical nds that inhibit Mps-1 (Monopolar Spindle 1) kinase (also known as Tyrosine Threonine Kinase, TTK). Mps-1 is a dual specificity Ser/Thr kinase which plays a key role in the tion of the mitotic checkpoint (also known as spindle checkpoint, spindle assembly checkpoint) thereby ensuring proper chromosome ation during mitosis [Abrieu A et al., Cell, 2001, 106, 83-93]. Every dividing cell has to ensure equal separation of the replicated chromosomes into the two daughter cells. Upon entry into mitosis, chromosomes are attached at their chores to the microtubules of the spindle apparatus. The c checkpoint is a surveillance mechanism that is active as long as unattached kinetochores are present and prevents mitotic cells from ng anaphase and thereby completing cell division with unattached chromosomes erbuijk SJ and Kops GJ, Biochemica et Biophysica Acta, 2008, 1786, 24-31; Musacchio A and Salmon ED, Nat Rev Mol Cell Biol., 2007, 8, 379-93]. Once all kinetochores are ed in a correct elic, i.e. bipolar, fashion with the mitotic spindle, the checkpoint is satisfied and the cell enters anaphase and ds through mitosis. The mitotic oint consists of complex network of a number of essential proteins, including members of the MAD (mitotic arrest deficient, MAD 1-3) and Bub (Budding uninhibited by benzimidazole, Bub 1-3) families, 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 the motor n , Mps-1 kinase as well as other components, many of these being over-expressed in proliferating cells (e.g. cancer cells) and tissues [Yuan B et al., Clinical Cancer Research, 2006, 12, 405-10]. The essential role of Mps-1 kinase activity in mitotic checkpoint signalling has been shown by silencing, al genetics as well as chemical inhibitors of Mps-1 kinase [Jelluma N et al., PLos ONE, 2008, 3, e2415; Jones MH et 01., Current Biology, 2005, 15, ; Dorer RK et 01., Current Biology, 2005, 15, 1070-76; Schmidt M et al., EMBO Reports, 2005, 6, 866-72].
There is ample evidence linking reduced but incomplete mitotic checkpoint function with aneuploidy and tumorigenesis r BA and Cleveland DW, Cancer Research, 2007, 67, 10103-5; King RW, Biochimica et Biophysica Acta, 2008, 1786, 4-14]. In contrast, complete inhibition of the mitotic checkpoint has been recognised to result in severe chromosome missegregation and induction of apoptosis in tumour cells [Kops GJ et al., Nature Reviews Cancer, 2005, 5, 773-85; Schmidt M and Medema RH, Cell Cycle, 2006, 5, 159-63; Schmidt M and Bastians H, Drug Resistance Updates, 2007, 10, 162-81].
Therefore, mitotic checkpoint abrogation h pharmacological inhibition of Mps-1 kinase or other components of the c checkpoint represents a new approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and mias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation.
Different compounds have been sed in prior art which show an inhibitory effect on Mps-1 kinase: A1 discloses 2-Anilinopurinones as inhibitors of Mps-1 for the treatment of proliferate disorders. WO 2010/124826 A1 discloses substituted imidazoquinoxaline compounds as inhibitors of Mps-1 kinase or TTK. A1 discloses substituted uinoxalines as Mps-1 inhibitors.
Substituted triazopyridine compounds have been sed for the treatment or prophylaxis of different diseases: A1 (Cellzome (UK) Ltd) relates to triazole derivatives as kinase inhibitors, especially inhibitors of ITK or PI3K, for the treatment or laxis of immunological, inflammatory or allergic disorders. Said triazole derivatives are exemplified as sing an amide, urea, carbamate or aliphatic amine tuent in position 2.
A1 discloses bicyclic heterorayl compounds and their use as phosphatidylinositol (PI) 3-kinase. Among other compounds also substituted lopyridines are mentioned.
A1 discloses lopyridine compounds and their use as ASK (apoptosis signal-regulating kinase) inhibitors for the treatment of autoimmune diseases and neurodegenerative diseases.
A1 (Cancer Research Technology Limited) s to [1,2,4]- triazolo-[1,5-a]-pyridine and [1,2,4]—triazolo-[1,5-c]—pyrimidine compounds which inhibit AXL receptor tyrosine kinase function, and to the treatment of diseases and conditions that are mediated by AXL receptor tyrosine kinase, that are ameliorated by the inhibition of AXL receptor ne kinase function etc., including proliferative conditions such as cancer, etc. Said compounds are ified as possessing a substituent in the 5-position of said compounds and a substituent in the 2-position.
A1 (Fovea Pharmaceuticals SA) relates to [1,2,4]—triazolo- [1,5-a]-pyridines, which are useful as selective kinase inhibitors, to s for producing such compounds and methods for treating or ameliorating kinase- mediated disorder.
However, the state of the art described above does not describe the triazolopyridine nds of general formula (I) of the present invention, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a e of same, as described herein and defined in the , and as referred to in this text as unds of the present invention", or their pharmacological activity.
In particular, said compounds of the present invention have surprisingly been found to effectively inhibit Mps-1 kinase and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation a nd/or survival, inappropriate ar immune responses, orinappropriate cellular inflammatory responses is mediated by Mps-1 kinase, such as, for example, haemotological tumours, solid s, and/or metastases thereof, e.g. leukaemias and myelodysplastic me, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, ine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or ases f.
W02011/063908 is also related to triazolopyridine compounds as Mps-1 tors. The effectiveness in ting Mps-1 kinase was measured in an Mps- 1 kinase assay with a concentration of 10 uM adenosine triphosphate (ATP). ation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena The cellular concentration of ATP in mammals is in the millimolar range.
Therefore it is important that a drug substance is also effective in inhibiting Mps-1 kinase in a kinase assay with a concentration of ATP in the millimolar range, e.g. 2 mM ATP, in order to potentially achieve an antiproliferative effect in a cellular assay.
For oral dosing it is essential, that a drug substance is hydrolytically stable in acidic medium, e.g. at pH 2, to avoid hydrolysis of the drug compound before absorption.
The half l inhibitory concentration (ICso) of the most potent compounds specified in W02011/063908, determined in an Mps-1 kinase assay with a concentration of 10 uM ATP, was lower than 2 nM (more potent than 2 nM).
However, all these compounds show either an ICso higher than 30 nM (less potent than 30 nM) in an Mps-1 kinase assay with a concentration of 2 mM ATP, or they show a low hydrolytic stability at pH 2 with more than 15 % decay after 24 h.
Surprisingly it was found, that the compounds of the present invention are characterized by an ICso lower than 2 nM (more potent than 2 nM) in an Mps-1 kinase assay with a concentration of 10 uM ATP, and an ICso lower than 30 nM (more potent than 30 nM) in an Mps-1 kinase assay with a concentration of 2 mM ATP, and a high hydrolytic stability, with less than 10 % decay after 24 h at pH 2.
Hence, the compounds of the t invention have sing and advantageous properties. These unexpected findings give rise to the present Dection invention. The compounds of the present invention are purposively selected from the general formula of WO2011/063908 due to their or inhibitory and stability properties.
SUMMARY of the INVENTION The present invention as claimed herein is described in the following items 1 to 13: 1. A compound of general formula (I) : N R4 R2 N R1 in which: R1 represents a phenyl group - which is substituted, one or more times, identica lly or differently, with a substituent selected from: -N(H)C(=O)R6, -C(=O)N(H)R6; and - which is ally substituted, one or more time s, identically or differently, with a substituent selected from: halo-, alkyl-, C1-C6-alkoxy-; R2 represents a Q2 Q3 R5b group; 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 wherein * indicates the point of attachment of said group with the rest of the molecule; R3 and R4 represent a hydrogen atom; R5 represents a hydrogen atom; Q1 represents CH; Q2 represents CH; Q3 represents CH or N; R5a represents a group selected from: halo-, C1-C6-alkyl-,C lkoxy-, halo-C1-C6-alkoxy-, (C 3-C6-cycloalkyl)-(CH 2)n-O-; R5b represents a group selected from: halo-, cyano-, C1-C6-alkoxy-, -N(H)C(=O)R8, -N(R7)C(=O)R 8, - (H)R 8, -C(=O)NR 8R7, R8-S(=O)-, R8-S(=O) 7)R 8; 2-, -S(=O)(=NR R6 represents a group ed from: -CH 2-(C 3-C6-cycloalkyl) or -CH2-aryl; wherein said group is optionally tuted, one or more times, cally or differently, with a substituent selected from: halo-, C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-; R7 represents a hydrogen atom, a C1-C6-alkyl- or a C3-C6-cycloalkyl- group; R8 represents a hydrogen atom or a C1-C6-alkyl- or C3-C6-cycloalkyl- group, - 6a - 6814134_1 (GHMatters) P89220.AU KIRSTENA 19/08/15 wherein said C1-C6-alkyl- or C3-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, -NHR7, , -N(C1-C3- alkyl)-C(=O)R 7, -N(C 7, C 7-S(=O) 1-C3-alkyl)-C(=O)OR lkyl-, R 2-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-; n represents an integer of 0 or 1; or a isomer, a tautomer, an e, a hydrate, a solvate, or a salt thereof, or a mixture of same. 2. The compound according to item 1, which is selected from the group consisting of: N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo- [1,5-a]pyridinyl]amino}methoxybenzamide, 2-[(4-cyanomethoxyphenyl)amino][1,2,4]triazolo[1,5-a]pyridinyl}- phenyl)(4-fluorophenyl)acetamide, N-(4-{2-[(2-ethoxyfluorophenyl)amino][1,2,4]triazolo[1,5-a]pyridinyl}- phenyl)(4-fluorophenyl)acetamide, N-ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5- a]pyridinyl]amino}methoxybenzamide, N-tert -butyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo- [1,5-a]pyridinyl]amino}methoxybenzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}-N-(2-hydroxyethyl)methoxybenzamide, N-(2-ethoxyethyl){[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1,5-a]pyridinyl]amino}methoxybenzamide, 3-ethoxy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5- a]pyridinyl]amino}-N-(2-hydroxyethyl)benzamide, - 6b - 6814134_1 (GHMatters) P89220.AU KIRSTENA 19/08/15 3-ethoxy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5- a]pyridinyl]amino}-N-(1-hydroxymethylpropanyl)benzamide, 3-ethoxy-N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1,5-a]pyridinyl]amino}benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}-N-(2-hydroxyethyl)(2,2,2-trifluoroethoxy)benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin no}-N-(2-hydroxymethylpropyl)methoxybenzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}-N-(1-hydroxymethylpropanyl)methoxybenzamide, N-{2-[acetyl(methyl)amino]ethyl}{[6-(4-{[(4-fluorophenyl)acetyl]amino}- phenyl)[1,2,4]triazolo[1,5-a]pyridinyl]amino}methoxy-N-methylbenzamide 2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy(methylsulfonyl)phenyl]amino}- [1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide, 3-ethoxy-N-ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1,5-a]pyridinyl]amino}benzamide, xy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5- a]pyridinyl]amino}-N-(2-hydroxymethylpropyl)benzamide, 3-ethoxy-N-ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1,5-a]pyridinyl]amino}-N-(2-methoxyethyl)benzamide, 3-ethoxy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5- a]pyridinyl]amino}-N-(2-hydroxyethyl)-N-methylbenzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}methoxy-N-methyl-N-[2-(methylamino)ethyl]benzamide, N-tert -butyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo- [1,5-a]pyridinyl]amino}(2,2,2-trifluoroethoxy)benzamide, - 6c - 8_1 (GHMatters) P94938.NZ KARENM 27/07/15 N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo- [1,5-a]pyridinyl]amino}(2,2,2-trifluoroethoxy)benzamide, N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo- [1,5-a]pyridinyl]amino}propoxybenzamide, 3-(cyclopropylmethoxy)-N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}- phenyl)[1,2,4]triazolo[1,5-a]pyridinyl]amino}benzamide, N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo- [1,5-a]pyridinyl]amino}isopropoxybenzamide, N,N -diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo- [1,5-a]pyridinyl]amino}(2-methoxyethoxy)benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}(2,2,2-trifluoroethoxy)-N-(2,2,2-trifluoroethyl)benzamide, xy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5- a]pyridinyl]amino}-N-[2-(methylsulfonyl)ethyl]benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}-N-(2-hydroxymethylpropyl)(2,2,2-trifluoroethoxy)benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}methoxy-N-methylbenzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]-N-(2-hydroxyethyl)methoxybenzamide, 3-ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]- pyridinyl)amino]-N-(2-hydroxyethyl)benzamide, xy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]- pyridinyl)amino]-N-(1-hydroxymethylpropanyl)benzamide, {4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]-N-(2-hydroxyethyl)(2,2,2-trifluoroethoxy)benzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]-N-(2-hydroxymethylpropyl)methoxybenzamide, - 6d - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 N-(4-fluorobenzyl)(2-{[2-methoxy(methylsulfonyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, 3-ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]- pyridinyl)amino]-N-(2-hydroxymethylpropyl)benzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]-N-(1-hydroxymethylpropanyl)methoxybenzamide, acetyl(methyl)amino]ethyl}[(6-{4-[(4- fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)amino] methoxy-N-methylbenzamide, N-(2-ethoxyethyl)[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo- [1,5-a]pyridinyl)amino]methoxybenzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]methoxy-N-methyl-N-[2-(methylamino)ethyl]benzamide, xy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]- pyridinyl)amino]-N-(2-hydroxyethyl)-N-methylbenzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]methoxy-N-methylbenzamide, N-tert -butyl[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5- a]pyridinyl)amino]methoxybenzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]methoxy-N-[2-(methylsulfonyl)ethyl]benzamide, 4-{2-[(2,4-dimethoxyphenyl)amino][1,2,4]triazolo[1,5-a]pyridinyl}-N-(4- benzyl)benzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]methoxy-N-(2,2,2-trifluoroethyl)benzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]-N-(1-hydroxymethylpropanyl)(2,2,2-trifluoroethoxy)- benzamide, - 6e - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 3-ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]- pyridinyl)amino]-N-[2-(methylsulfonyl)ethyl]benzamide, N-ethyl[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]- pyridinyl)amino]methoxybenzamide, N-tert -butylethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]- triazolo[1,5-a]pyridinyl)amino]benzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)- amino]-N-(2-hydroxymethylpropyl)(2,2,2-trifluoroethoxy)benzamide, {4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)3-(2,2,2-trifluoroethoxy)-N-(2,2,2-trifluoroethyl)benzamide, 4-(2-{[4-(dimethylamino)methylphenyl]amino}[1,2,4]triazolo[1,5-a]pyridin- 6-yl)-N-(4-fluorobenzyl)benzamide, 2-fluoro-N-(4-fluorobenzyl)[2-({4-[(1-hydroxymethylpropanyl)- carbamoyl]methoxyphenyl}amino)[1,2,4]triazolo[1,5-a]pyridinyl]- benzamide, N-(4-fluorobenzyl)[2-({4-[(1-hydroxymethylpropanyl)carbamoyl] methoxyphenyl}amino)[1,2,4]triazolo[1,5-a]pyridinyl]methylbenzamide, 2-chloro-N-(4-fluorobenzyl)[2-({4-[(1-hydroxymethylpropanyl)- carbamoyl]methoxyphenyl}amino)[1,2,4]triazolo[1,5-a]pyridin yl]benzamide, 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin- 2-yl)amino]ethoxy-N-ethylbenzamide, 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin- 2-yl)amino]ethoxy-N-ethyl-N-(2-methoxyethyl)benzamide, 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin- 2-yl)amino]ethoxy-N-(2-hydroxyethyl)benzamide, 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin- 2-yl)amino]-N-(2-hydroxyethyl)(2,2,2-trifluoroethoxy)benzamide, - 6f - 6702608_1 (GHMatters) .NZ KARENM 27/07/15 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin- 2-yl)amino]-N-ethyl(2,2,2-trifluoroethoxy)benzamide, N-ethyl[(6-{4-[(3-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]- pyridinyl)amino]methoxybenzamide, luorobenzyl)[2-({4-[(1-hydroxymethylpropanyl)carbamoyl] methoxyphenyl}amino)[1,2,4]triazolo[1,5-a]pyridinyl]methoxybenzamide 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}methoxy-N-(2,2,2-trifluoroethyl)benzamide, N-[4-(2-{[2-ethoxy(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]- pyridinyl)phenyl](4-fluorophenyl)acetamide, N-[4-(2-{[2-ethoxy(ethylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5- a]pyridinyl)phenyl](4-fluorophenyl)acetamide, 2-(4-fluorophenyl)-N-[4-(2-{[4-(methylsulfonyl)(2,2,2-trifluoroethoxy)- phenyl]amino}[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide, N-[4-(2-{[2-(difluoromethoxy)(methylsulfonyl)phenyl]amino}[1,2,4]triazolo- [1,5-a]pyridinyl)phenyl](4-fluorophenyl)acetamide, N-[4-(2-{[2-(difluoromethoxy)(ethylsulfonyl)phenyl]amino}[1,2,4]triazolo- [1,5-a]pyridinyl)phenyl](4-fluorophenyl)acetamide, N-[4-(2-{[2-(cyclopropyloxy)(methylsulfonyl)phenyl]amino}[1,2,4]triazolo- [1,5-a]pyridinyl)phenyl](4-fluorophenyl)acetamide, 4-(2-{[2-ethoxy(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridin- 6-yl)-N-(4-fluorobenzyl)benzamide, [2-ethoxy(ethylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridin (4-fluorobenzyl)benzamide, N-(4-fluorobenzyl)(2-{[4-(methylsulfonyl)(2,2,2-trifluoroethoxy)phenyl]- amino}[1,2,4]triazolo[1,5-a]pyridinyl)benzamide, - 6g - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 4-(2-{[2-(difluoromethoxy) (methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridinyl)-N-(4- fluorobenzyl)benzamide, 4-(2-{[2-(cyclopropyloxy)(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5- a]pyridinyl)-N-(4-fluorobenzyl)benzamide, N-(4-fluorobenzyl)methyl(2-{[4-(methylsulfonyl)(2,2,2-trifluoro- ethoxy)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridinyl)benzamide, N-(4-fluorobenzyl)methoxy(2-{[2-methoxy(methylsulfonyl)phenyl]- [1,2,4]triazolo[1,5-a]pyridinyl)benzamide, -difluorophenyl)-N-[4-(2-{[2-methoxy(methylsulfonyl)phenyl]amino}- [1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide, N-(2,4-difluorobenzyl)(2-{[2-methoxy(methylsulfonyl)phenyl]amino}- [1,2,4]triazolo[1,5-a]pyridinyl)benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}methoxy-N-(2-methoxyethyl)benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}methoxy-N,N-dimethylbenzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}methoxy-N-[2-(methylsulfonyl)ethyl]benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}methoxybenzamide, N-(2-fluoroethyl){[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1,5-a]pyridinyl]amino}methoxybenzamide, N-ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]- pyridinyl]amino}methoxy-N-methylbenzamide, -difluoroethyl){[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1,5-a]pyridinyl]amino}methoxybenzamide, - 6h - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 N-[2-(dimethylamino)ethyl]{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)- [1,2,4]triazolo[1,5-a]pyridinyl]amino}methoxy-N-methylbenzamide, (4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}methoxy-N-methyl-N-(2,2,2-trifluoroethyl)benzamide, dimethylamino)ethyl]{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)- [1,2,4]triazolo[1,5-a]pyridinyl]amino}methoxybenzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}-N-(3-fluoropropyl)methoxybenzamide, N-[4-(2-{[5-fluoromethoxy(methylsulfonyl)phenyl]amino}[1,2,4]triazolo- [1,5-a]pyridinyl)phenyl](4-fluorophenyl)acetamide, 2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy(methylsulfinyl)phenyl]amino}- ]triazolo[1,5-a]pyridinyl)phenyl]acetamide, N-[4-(2-{[5-fluoromethoxy(methylsulfinyl)phenyl]amino}[1,2,4]triazolo- [1,5-a]pyridinyl)phenyl](4-fluorophenyl)acetamide, N-[4-(2-{[4-(tert -butylsulfamoyl)methoxyphenyl]amino}[1,2,4]triazolo[1,5- a]pyridinyl)phenyl](4-fluorophenyl)acetamide, 2-(4-fluorophenyl)-N-[4-(2-{[4-(2-hydroxypropanyl)methoxyphenyl]- amino}[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide, N-(4-{2-[(2,4-dimethoxyphenyl)amino][1,2,4]triazolo[1,5-a]pyridinyl}- phenyl)(4-fluorophenyl)acetamide, 3-ethoxy-N-ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1,5-a]pyridinyl]amino}-N-methylbenzamide, N-[2-(dimethylamino)ethyl]ethoxy{[6-(4-{[(4- fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin yl]amino}benzamide, - 6i - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 (4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}-N-[2-(methylsulfonyl)ethyl](2,2,2-trifluoroethoxy)benzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}-N-(1-hydroxymethylpropanyl)(2,2,2-trifluoroethoxy)- benzamide, N-[2-(dimethylamino)ethyl]{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)- [1,2,4]triazolo[1,5-a]pyridinyl]amino}(2,2,2-trifluoroethoxy)benzamide, 2-(4-fluorophenyl)-N-[4-(2-{[4-(methylsulfinyl)(2,2,2-trifluoroethoxy)- phenyl]amino}[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}(trifluoromethoxy)benzamide, N-[4-(2-{[2-(difluoromethoxy)(propan ylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridinyl)phenyl](4- fluorophenyl)acetamide, N-[4-(2-{[2-(difluoromethoxy)fluorophenyl]amino}[1,2,4]triazolo[1,5-a]- pyridinyl)phenyl](4-fluorophenyl)acetamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}methylbenzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}methyl-N-(2,2,2-trifluoroethyl)benzamide, N-(2-fluoroethyl){[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1,5-a]pyridinyl]amino}methylbenzamide, 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}-N,N,3-trimethylbenzamide, 2-(4-fluorophenyl)-N-[4-(2-{[2-methyl(methylsulfonyl)phenyl]amino}- ]triazolo[1,5-a]pyridinyl)phenyl]acetamide, - 6j - 6702608_1 ters) P94938.NZ KARENM 27/07/15 2-(4-fluorophenyl)-N-[4-(2-{[2-methyl(methylsulfinyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)phenyl]acetamide, 2-(4-fluorophenyl)-N-{4-[2-({2-methyl[(methylsulfonyl)amino]phenyl}- amino)[1,2,4]triazolo[1,5-a]pyridinyl]phenyl}acetamide, 2-(4-fluorophenyl)-N-(4-{2-[(4-methoxy methylphenyl)amino][1,2,4]triazolo[1,5-a]pyridinyl}phenyl)acetamide, N-[4-(2-{[4-(dimethylamino)methylphenyl]amino}[1,2,4]triazolo[1,5-a]- pyridinyl)phenyl](4-fluorophenyl)acetamide, N-ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5- a]pyridinyl]amino}methylpyridinecarboxamide, -{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo[1,5-a]pyridin- 2-yl]amino}methyl-N-(2,2,2-trifluoroethyl)pyridinecarboxamide, N-[4-(2-{[2-fluoro(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]- nyl)phenyl](4-fluorophenyl)acetamide, 2-(4-fluoromethylphenyl)-N-[4-(2-{[2-methoxy(methylsulfonyl)phenyl]- amino}[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide, 2-(4-chlorophenyl)-N-[4-(2-{[2-methoxy(methylsulfonyl)phenyl]amino}- ]triazolo[1,5-a]pyridinyl)phenyl]acetamide, N-[4-(2-{[2-methoxy(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]- pyridinyl)phenyl]phenylacetamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino]methoxybenzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino]methoxy-N-(2-methoxyethyl)benzamide, - 6k - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino]-N-(2-fluoroethyl)methoxybenzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin no]methoxy-N,N-dimethylbenzamide, N-(2,2-difluoroethyl)[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]- triazolo[1,5-a]pyridinyl)amino]methoxybenzamide, N-[2-(dimethylamino)ethyl][(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}- [1,2,4]triazolo[1,5-a]pyridinyl)amino]methoxybenzamide, N-[2-(dimethylamino)ethyl][(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}- [1,2,4]triazolo[1,5-a]pyridinyl)amino]methoxy-N-methylbenzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin no]-N-(3-fluoropropyl)methoxybenzamide, N-(4-fluorobenzyl)(2-{[2-methoxy(methylsulfinyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, 4-(2-{[4-(tert -butylsulfamoyl)methoxyphenyl]amino}[1,2,4]triazolo[1,5-a]- pyridinyl)-N-(4-fluorobenzyl)benzamide, N-(4-fluorobenzyl)(2-{[4-(2-hydroxypropanyl)methoxyphenyl]amino}- [1,2,4]triazolo[1,5-a]pyridinyl)benzamide, N-[2-(dimethylamino)ethyl]ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]- phenyl}[1,2,4]triazolo[1,5-a]pyridinyl)amino]benzamide, 3-ethoxy-N-ethyl[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo- [1,5-a]pyridinyl)amino]-N-methylbenzamide, 3-ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]- pyridinyl)amino]-N-(2-fluoroethyl)benzamide, - 6l - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 N-[2-(dimethylamino)ethyl][(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}- [1,2,4]triazolo[1,5-a]pyridinyl)amino](2,2,2-trifluoroethoxy)benzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino]-N-(2-fluoroethyl)(2,2,2-trifluoroethoxy)benzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino](trifluoromethoxy)benzamide, [2-(difluoromethoxy)(ethylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5- a]pyridinyl)-N-(4-fluorobenzyl)benzamide, 4-(2-{[2-(difluoromethoxy)(propanylsulfonyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)-N-(4-fluorobenzyl)benzamide, 4-(2-{[2-(difluoromethoxy)fluorophenyl]amino}[1,2,4]triazolo[1,5- a]pyridinyl)-N-(4-fluorobenzyl)benzamide, N-ethyl[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5- a]pyridinyl)amino]methylbenzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino]methylbenzamide, {4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino]methyl-N-(2,2,2-trifluoroethyl)benzamide, 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino]-N-(2-fluoroethyl)methylbenzamide, N-(4-fluorobenzyl)(2-{[2-methyl(methylsulfonyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, N-(4-fluorobenzyl)(2-{[2-methyl(methylsulfinyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, - 6m - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 luorobenzyl)[2-({2-methyl[(methylsulfonyl)amino]phenyl}amino)- [1,2,4]triazolo[1,5-a]pyridinyl]benzamide, N-(4-fluorobenzyl){2-[(4-methoxymethylphenyl)amino][1,2,4]triazolo- [1,5-a]pyridinyl}benzamide, {4-[(4-chlorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin yl)amino]methoxy-N-(2,2,2-trifluoroethyl)benzamide, N-(4-chlorobenzyl)(2-{[2-methoxy(methylsulfonyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, N-(4-chlorobenzyl)(2-{[2-methyl (methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridinyl)benzamide, N-(4-chlorobenzyl)(2-{[2-methyl(methylsulfinyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, 4-(2-{[2-methoxy(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]- pyridinyl)-N-(4-methylbenzyl)benzamide, N-(4-methylbenzyl)(2-{[2-methyl(methylsulfonyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, N-(4-methylbenzyl)(2-{[2-methyl(methylsulfinyl)phenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, 4-[(6-{4-[(2,4-difluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin- 2-yl)amino]methoxy-N-(2,2,2-trifluoroethyl)benzamide, N-(2,4-difluorobenzyl)methyl(2-{[4-(methylsulfonyl)(2,2,2-trifluoro- ethoxy)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridinyl)benzamide, N-(4-fluorobenzyl)(2-{[4-(2-hydroxypropanyl)methoxyphenyl]amino}- [1,2,4]triazolo[1,5-a]pyridinyl)methoxybenzamide, - 6n - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy(S-methylsulfonimidoyl)phenyl]- amino}[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide, N-(4-fluorobenzyl)(2-{[2-methoxy(S-methylsulfonimidoyl)phenyl]amino}- [1,2,4]triazolo[1,5-a]pyridinyl)benzamide, 2-(4-fluorophenyl)-N-[4-(2-{[4-(hydroxymethyl)methoxyphenyl]amino}- [1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide, N-(4-fluorobenzyl)(2-{[4-(hydroxymethyl)methoxyphenyl]amino}[1,2,4]- triazolo[1,5-a]pyridinyl)benzamide, or a stereoisomer, a tautomer, an N-oxide, a e, a solvate, or a salt thereof, or a mixture of same. 3. A method of preparing a compound of general formula (I) according to item 1, in which method an intermediate compound of general formula (5) : N R4 2 N N R1 in which R1, R3, R4, and R5 are as defined for the compounds of general formula (I) in item 1, is allowed to react with an aryl halide of l a (5a) : R2-Y (5a) in which R2 is as defined for the compounds of general a (I) in item 1, and Y represents a halogen atom or a trifluoromethylsulphonyloxy or nonafluorobutylsulphonyloxy group, - 6o - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 thus ing a compound of general formula (I) : N R4 R2 N R1 in which R1, R2, R3, R4, and R5 are as defined for the nds of general formula (I) in item 1. 4. A method of preparing a compound of general formula (I) according to item 1, in which method an intermediate compound of general formula (7) : N R4 R2 N R1a in which R2, R3, R4, and R5 are as defined for the compounds of general formula (I) in item 1, and R1a is a phenyl group to which an -NH2 substituent is bound, is allowed to react with a compound of general formula : R1b-X (7a) in which R1b is R6, R6 is as defined for the compounds of general formula (I) in item 1, and X is a suitable functional group via which the R1b of the R1b-X compound (7a) can be coupled, via an amide coupling reaction, onto the –NH2 substituent bound to the phenyl group R1a of compound (7), thereby ing said X with said R1a, - 6p - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 thus providing a compound of l formula (I) : N R4 R2 N R1 in which R1, R2, R3, R4, and R5 are as defined for the compounds of general formula (I) in item 1.
. A compound according to any one of items 1 or 2, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, for use in the treatment or prophylaxis of a disease. 6. A pharmaceutical composition sing a compound according to any one of items 1 or 2, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically able salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or r. 7. A pharmaceutical combination comprising : - one or more compounds ing to any one of items 1 or 2, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same ; - one or more agents selected from : a taxane; an epothilone; ntrone; Predinisolone; Dexamethasone; ustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; rouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; ro-2´-deoxyadenosine; Thioguanine; an anti-androgen; Bortezomib; a platinum derivative; Chlorambucil; Methotrexate; and Rituximab. - 6q - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 8. The pharmaceutical combination ing to item 7 wherein the taxane is selected from: Docetaxel, Paclitaxel, or Taxol. 9. Use of a compound ing to any one of items 1 or 2, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, for the preparation of a medicament for the prophylaxis or treatment of a disease. 10. Use according to item 9, wherein said disease is a haemotological tumour, a solid tumour and/or metastases thereof. 11. A compound of general formula (7) : N R4 R2 N R1a in which R2, R3, R4, and R5 are as defined for the compounds of l formula (I) in any one of items 1 to 5, and R1a is a phenyl group to which an -NH2 substituent is bound. 12. Use of a compound of general formula (5) N R4 2 N N R1 - 6r - 6702608_1 (GHMatters) .NZ KARENM 27/07/15 in which R1, R3, R4, and R5 are as defined for the compounds of general formula (I) in item 1; for the preparation of a compound of general formula (I) according to item 1. 13. Use of a compound of general formula (7) according to item 11 for the ation of a compound of l formula (I) according to item 1.
Also decribed herein are novel compounds of general formula (I): (I) in which: R1 represents a phenyl or pyridyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: R6-(C 6-O-, -C(=O)R6, -C(=O)O-R6, -N(H)C(=O)R6, 1-C6-alkoxy)-, R -N(H)C(=O)NR 6R7, -NR 6R7, -C(=O)N(H)R6, NR6R7, R6-S-, R6-S(=O) (=O)2R6, -S(=O)2N(H)R 6; and - which is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, y-, nitro-, C1-C6-alkyl-, C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, - N(H)C(=O)R 8, -N(H)C(=O)NR8R7, -C(=O)N(H)R 8, -N(H)S(=O) 8; R2 represents a - 6s - 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15 group; wherein * indicates the point of attachment of said group with the rest of the molecule; Q1 represents a group selected from: N, CH, C-(C1-C6-alkyl), C-(C1-C6-alkoxy), C-halo; Q2 represents a group ed from: N, CH, CR5b; Q3 represents a group selected from: N, CH, CR5b; R5:11 ents a group selected from: halo-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, RS-(C1-C6-alkoxy)-, R8, —NR8R7, RS-S-, R8-S(=O)-, RS-S(=O)2-, (C3-C6-cycloalkyl)-(CH2)n-O-; R5b represents a group selected from: halo-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, 1-C6-alkyl-, alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, R8-(C1-C6-alkyl)-, 2)n(CHOH)(CH2)m-, RS-(C1-C6-alkoxy)-, RS-(CH2)n(CHOH)(CH2)p-O-, RS-(C1-C6-alkoxy-C1-C6-alkyl)-, RS-(C1-C6-alkoxy-C1-C6-alkyl)-O-, -O-(CH2)n-C(=O)NR8R7, R8, -C(=O)R8, -C(=O)O-R8, -OC(=O)-R8, -N(H)C(=O)R8, -N(R7)C(=O)R8, -N(H)C(=O)NR8R7, -N(R7)C(=O)NR8R7, —NR8R7, —NR7R7, -C(=O)N(H)R8, -C(=O)NR8R7, RS-S-, R8-S(=O)-, R8-S(=O)2-, -N(H)S(=O)R8, -N(R7)S(=O)R8, [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena -S(=O)N(H)R8, -S(=O)NR8R7, -N(H)S(=O)2R8, -N(R7)S(=O)2R8, -S(=O)2N(H)R8, -S(=O)2NR8R7, -S(=O)(=NR8)R7, -S(=O)(=NR7)R8, -N=S(=O)(R8)R7; R3 represents a hydrogen atom, a halogen atom, a hydroxy-, amino-, cyano-, nitro-, alkyl-, halo-C1-C4-alkyl-, alkoxy-, halo-C1-C4-alkoxy-, hydroxy-C1-C4-alkyl-, C1-C4-alkoxy-C1-C4-alkyl-, halo-C1-C4-alkoxy-C1-C4-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, halo-Cz-Cé-alkenyl-, halo-Cz-Cé-alkynyl-, C3-C6-cycloalkyl-, or halo-C3-C6- cycloalkyl- group; R4 represents a hydrogen atom, a n atom, a hydroxy-, amino-, cyano-, nitro-, alkyl-, halo-C1-C4-alkyl-, C1-C4-alkoxy-, halo-C1-C4- alkoxy-, hydroxy-C1-C4-alkyl-, C1-C4-alkoxy-C1-C4-alkyl-, 1-C4- alkoxy-C1-C4-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, z-Cé-alkenyl-, 1 5 halo-Cz-Cé-alkynyl-, C3-C6-cycloalkyl-, or halo-C3-C6-cycloalkyl- group; R5 represents a hydrogen atom; R6 represents a group selected from C3-C6-cycloalkyl-, 3- to 10-membered heterocyclyl-, aryl-, heteroaryl-, -(CH2)q-(C3-C6-cycloalkyl), -(CH2)q-(3- to 10-membered heterocyclyl), -(CH2)q-aryl, or -(CH2)q-heteroaryl, wherein said group being ally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, , nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, R8-(C1-C6-alkyl)-, R8-(CH2)n(CHOH)(CH2)m-, RS-(C1-C6-alkoxy)-, RS-(CH2)n(CHOH)(CH2)p-O-, RS-(C1-C6-alkoxy-C1-C6-alkyl)-, RS-(C1-C6-alkoxy-C1-C6-alkyl)-O-, aryl-, R8, -C(=O)R8, -C(=O)O-R8, [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena -OC(=O)-R8, -N(H)C(=O)R8, -N(R7)C(=O)R8, -N(H)C(=O)NR8R7, -N(R7)C(=O)NR8R7, —NR8R7, -C(=O)N(H)R8, -C(=O)NR8R7, R8-s-, R8-S(=O)-, R8-S(=O)2-, -N(H)S(=O)R8, -N(R7)S(=O)R8, -S(=O)N(H)R8, -S(=O)NR8R7, -N(H)S(=O)2R8, -N(R7)S(=O)2R8, -S(=O)2N(H)R8, -S(=O)2NR8R7, -S(=O)(=NR8)R7,- S(=O)(=NR7)R8, -N=S(=O)(R8)R7; R7 represents a hydrogen atom, a C1-C6-alkyl- or a C3-C6-cycloalkyl- group; R8 represents a hydrogen atom or a C1-C6-alkyl- or C3-C6-cycloalkyl- group, wherein said C1-C6-alkyl- or C3-C6-cycloalkyl- group is optionally tuted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, -NHR7, , -N(C1-C3-alkyl)-C(=O)R7, -N(C1-C3-alkyl)- C(=O)OR7, C1-C3-alkyl-, R7-S(=O)2-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-; n; m; p; represent, independently from each other, an integer of 0, 1, 2 or 3; q represents an integer of 0, 1, 2 or 3; or a stereoisomer, a er, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
The triazolopyridine compounds of general formula (I) effectively t Mps-1 kinase — even at high ATP concentrations — and show a high hydrolytic stability.
The t invention s to the triazolopyridine compounds of general formula (I) as described and defined herein, to methods of preparing said unpounds, to pharmaceutical compositions and combinations comprising said [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena nds, to the use of said compounds for manufacturing a pharmaceutical composition for the ent or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
Preferred embodiments of the present invention are specified hereinafter as well as in the dependent claims.
DETAILED DESCRIPTION of the INVENTION The terms as mentioned in the present text have preferably the following meanings : The term "halogen atom" or "halo-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
The term "C1-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, tyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, ylbutyl, 1- ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4- pentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, methylbutyl, methylbutyl, 2,3- dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms ("C1-C4-alkyl"), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, tyl, tert-butyl group, more particularly 1, 2 or 3 carbon atoms ("C1-C3-alkyl"), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
The term "halo-C1-C6-alkyl" is to be understood as preferably meaning a linear Dbranched, ted, monovalent hydrocarbon group in which the term "C1- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Cé-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a n atom, in cally or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F.
Said halo-C1-C6-alkyl group is, for example, —CF3, -CHF2, -CH2F, -CF2CF3, or CH2CF3.
The term "C1-C6-alkoxy" is to be understood as ably meaning a linear or ed, saturated, monovalent, hydrocarbon group of formula —O—(C1-C6- alkyl), in which the term "C1-C6-alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
The term "halo-C1-C6-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said halo-C1-C6-alkoxy group is, for e, —OCF3, -OCHF2, -OCH2F, -OCF2CF3, or - OCH2CF3.
The term "C1-C6-alkoxy-C1-C6-alkyl" is to be understood as preferably meaning a C1-C6-alkyl group, as defined supra, in which one or more of the en atoms is replaced, in identically or differently, by a C1-C6-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso- propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, ntyloxyalkyl, hexyloxyalkyl group, or an isomer thereof.
The term "halo-C1-C6-alkoxy-C1-C6-alkyl" is to be understood as preferably g a linear or branched, saturated, lent C1-C6-alkoxy-C1-C6-alkyl group, as defined supra, in which one or more of the hydrogen atoms is malaced, in identically or ently, by a halogen atom. Particularly, said [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena ation] kirstena Unmarked set by kirstena halogen atom is F. Said halo-C1-C6-alkoxy-C1-C6-alkyl group is, for example, — CH2CH20CF3, 'CH2CH20CHF2, 'CH2CH20CH2F, -CH2CH20CF2CF3, or CH2CH20CH2CF3.
The term "C2-C6-alkenyl" is to be understood as preferably meaning a linear or ed, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)methylvinyl, (Z)methylvinyl, homoallyl, (E)- butenyl, (Z)-butenyl, (E)-butenyl, (Z)-butenyl, pentenyl, (E)- pentenyl, (Z)-pentenyl, (E)-pentenyl, (Z)-pentenyl, (E)-pentenyl, ntenyl, hexenyl, (E)-hexenyl, (Z)-hexenyl, (E)-hexenyl, (Z)- hexenyl, (E)-hexenyl, (Z)-hexenyl, (E)-hexenyl, (Z)-hexenyl, isopropenyl, 2-methylpropenyl, 1-methylpropenyl, 2-methylpropenyl, (E)methylpropenyl, (Z)methylpropenyl, 3-methylbutenyl, 2- methylbutenyl, 1-methylbutenyl, 3-methylbutenyl, (E)methylbut enyl, (Z)methylbutenyl, (E)methylbutenyl, (Z)methylbutenyl, methylbutenyl, (Z)methylbutenyl, methylbutenyl, (Z) methylbutenyl, (E)methylbutenyl, methylbutenyl, 1,1- dimethylpropenyl, 1-ethylpropenyl, ylvinyl, 1-isopropylvinyl, 4- methylpentenyl, 3-methylpentenyl, 2-methylpentenyl, 1-methylpent- 4-enyl, 4-methylpentenyl, (E)methylpentenyl, (Z)methylpent enyl, (E)methylpentenyl, methylpentenyl, (E)methylpent enyl, (Z)methylpentenyl, (E)methylpentenyl, (Z)methylpent enyl, methylpentenyl, (Z)methylpentenyl, (E)methylpent enyl, methylpentenyl, (E)methylpentenyl, (Z)methylpent enyl, (E)methylpentenyl, (Z)methylpentenyl, (E)methylpent Dyl, (Z methylpentenyl,) ( E methylpentenyl,) (Z methylpent) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena enyl, (E)methylpentenyl, (Z)methylpentenyl, 3-ethylbutenyl, 2- ethylbutenyl, 1-ethylbutenyl, (E)ethylbutenyl, (Z)ethylbut enyl, (E)ethylbutenyl, (Z)ethylbutenyl, (E)ethylbutenyl, (Z) ethylbutenyl, (E)ethylbutenyl, (Z)ethylbutenyl, 2-ethylbut enyl, (E)ethylbutenyl, (Z)ethylbutenyl, 2-propylpropenyl, 1- propylpropenyl, 2-isopropylpropenyl, 1-isopropylpropenyl, (E) propenyl, (Z)propylpropenyl, (E)propylpropenyl, (Z) propylpropenyl, isopropylpropenyl, (Z)isopropylpropenyl, (E)- 1-isopropylpropenyl, (Z)isopropylpropenyl, (E)-3,3-dimethylprop enyl, (Z)-3,3-dimethylpropenyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3- dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienyl group.
Particularly, said group is vinyl or allyl.
The term "C2-C6-alkynyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl"). Said C2-C6-alkynyl group is, for example, ethynyl, propynyl, propynyl, butynyl, butynyl, butynyl, - ynyl, pentynyl, pentynyl, pentynyl, hexynyl, hexinyl, inyl, hexynyl, ynyl, 1-methylpropynyl, 2-methylbutynyl, 1-methylbut- , 1-methylbutynyl, 3-methylbutynyl, 1-ethylpropynyl, 3- methylpentynyl, 2-methylpentynyl, 1-methylpentynyl, 2-methylpent- 3-ynyl, 1-methylpentynyl, 4-methylpentynyl, 1-methylpentynyl, 4- methylpentynyl, 3-methylpentynyl, 2-ethylbutynyl, 1-ethylbutynyl, 1-ethylbutynyl, ylpropynyl, ropylpropynyl, 2,2-dimethyl- butinyl, methylbutynyl, methylbutynyl, or 3,3-dimethyl- butynyl group. Particularly, said alkynyl group is ethynyl, propynyl, or propinyl.
[Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena The term "C3-C6-cycloalkyl" is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms 6-cycloalkyl"). Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, utyl, cyclopentyl, or cyclohexyl or a ic hydrocarbon ring. Said cycloalkyl ring can optionally n one or more double bonds e.g. cycloalkenyl, such as a ropenyl, utenyl, cyclopentenyl or exenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated.
The term "heterocyclic ring", as used in the term "4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocyclic ring", or "4- to 6-membered heterocyclic ring" or "5- to 6-membered heterocyclic ring", for example, as used in the definition of compounds of general formula (I) as defined herein, is to be understood as meaning a saturated or partially unsaturated, mono-, bi- or poly-cyclic en atom-containing ring, said nitrogen atom being the point of attachment of said heterocyclic ring with the rest of the molecule. Said nitrogen atom-containing ring optionally further contains 1 or 2 heteroatom- containing groups selected from O, C(=O), S, S(=O), S(=O)2, NR’ in which R’ represents C1-C6-alkyl-, C3-C6-cycloalkyl-, -C(=O)-(C1-C6-alkyl) or -C(=O)-(C1-C¢,- cycloalkyl). Particularly, without being limited thereto, said en atom- containing ring can be a 4-membered ring, such as an azetidinyl ring, for example, or a 5-membered ring, such as a pyrrolidinyl ring, for example, or a 6-membered ring, such as a piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, for example, or a ered ring, such as a diazepanyl ring ring, for e, or an 8-, 9-, or 10-membered ring, such as a cycloheptylaminyl, cyclooctylaminyl, or cyclononylaminyl ring, respectively, for example; it being reiterated that any of the above-mentioned nitrogen atom-containing rings can further contain 1 or 2 heteroatom-containing groups Dected from O, C(=O), S, S(=O), , NR’ in which R’ is as defined supra.
[Annotation] kirstena None set by na ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena As mentioned supra, said nitrogen atom-containing ring can be bicyclic, such as, without being limited thereto, a 5,5-membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(1H)-yl) ring, or a 5,6-membered bicyclic ring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, or for example. As mentioned supra, said en atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited o, a 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5- dihydrooxazolyl, or 4H-[1,4]thiazinyl ring, for example, or, it may be benzo- fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
The term "3- to 10-membered cycloalkyl" is to be understood as preferably g a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, NH, NR’, wherein R’ represents a alkyl-, C3-C6-cycloalkyl-, - C(=O)-(C1-C6-alkyl) or -C(=O)-(C1-C6-cycloalkyl). Particularly, said ring can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said ring can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl"). Said heterocycloalkyl ring is for example, a monocyclic heterocycloalkyl ring such as an yl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, or chinuclidinyl group. Optionally, said heterocycloalkyl ring can contain one or more double bonds, e.g. anyl, 2H-pyranyl, 3H- diazirinyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5- dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3- [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl group, or, it may be benzo fused.
The term "aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a "C6-C14-aryl" group), particularly a ring having 6 carbon atoms (a "C6-aryl" group), e.g. a phenyl group, or a biphenyl group, or a ring having 9 carbon atoms (a "Cg-aryl" group), e.g. an indanyl or l group, or a ring having 10 carbon atoms (a "C1o-aryl" group), e.g. a tetralinyl, onaphthyl, or naphthyl group, or a ring having 13 carbon atoms, (a "C13-aryl" , e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "C14-aryl" group), e.g. an anthranyl group.
The term "heteroaryl" is understood as preferably meaning a monovalent, aromatic, mono- or bicyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" , particularly or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or ent, said heteroatom being such as oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic, or tricyclic, and in addition in each case can be benzocondensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, lyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives f, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, idazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo tives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, inyl, carbazolyl, acridinyl, phenazinyl, Denothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc. More particularly, [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena heteroaryl is selected from pyridyl, benzofuranyl, benzisoxazolyl, indazolyl, quinazolinyl, thienyl, quinolinyl, benzothienyl, pyrazolyl, or furanyl.
The term "alkylene" is understood as preferably meaning an optionally substituted hydrocarbon chain (or "tether") having 1, 2, 3, 4, 5, or 6 carbon atoms, i.e. an ally substituted —CH2- ("methylene" or "single ed tether" or, for e -C(Me)2-), -CH2-CH2- ("ethylene", "dimethylene", or "two-membered tether"), -CH2-CH2-CH2- ("propylene", "trimethylene", or "three-membered tether"), -CH2-CH2-CH2-CH2- ("butylene", "tetramethylene", or "four-membered tether"), -CH2-CH2-CH2-CH2-CH2- ylene", "pentamethylene" or "five-membered ether"), or —CH2-CH2-CH2-CH2-CH2-CH2- ("hexylene", "hexamethylene", or six-membered tether") group. Particularly, said alkylene tether has 1, 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms.
The term "C1-C6", as used throughout this text, e.g. in the context of the definition of "C1-C6-alkyl", "C1-C6-haloalkyl", "C1-C6-alkoxy", or "C1-C6- haloalkoxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term " is to be interpreted as any sub- range comprised therein, e.g. C1-C6, C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5 , C1- C6, particularly C1-C2, C1-C3,C1-C4, C1-C5, C1-C6, more particularly C1-C4; in the case of "C1-C6-haloalkyl" or -haloalkoxy" even more particularly C1-C2.
Similarly, as used herein, the term ", as used throughout this text, e.g. in the context of the definitions of -alkenyl" and "C2-C6-alkynyl", is to be tood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "CZ'C6" is to be interpreted as any sub-range [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena comprised therein, e.g. C2-C6, C3-C5, C3-C4, C2-C3, C2-C4, C2-C5, particularly C2- Further, as used herein, the term "C3'C6", as used throughout this text, e.g. in the context of the tion of "C3-C6-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be tood further that said term "C3- Ce," is to be interpreted as any sub-range comprised therein, e.g. C3'C6, C4-C5, C3'C5, C3-C4 , C4-C6, C5-C6; particularly C3-C6.
As used herein, the term "leaving group" refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. Preferably, a leaving group is selected from the group comprising: halo, in particular chloro, bromo or iodo, methanesulfonyloxy, enesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, mo-benzene)sulfonyloxy, (4-nitro- e)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl- benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl-benzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy.
As used herein, the term "one or more times", e.g. in the definition of the substituents of the compounds of the general formulae of the present ion, is understood as meaning "one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single d, salt, polymorph, isomer, hydrate, solvate or the like.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena The compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of le asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for e, the central bond adjoining two substituted aromatic rings of the specified compounds.
Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the t invention.
Preferred compounds are those which produce the more desirable biological activity. Separated, pure or lly purified isomers and stereoisomers or racemic or diastereomeric es of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The l s can be obtained by resolution of the racemic mixtures ing to conventional processes, for example, by the formation of reoisomeric salts using an optically active acid or base or ion of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The lly active bases or acids are then liberated from the separated astereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] na ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena without conventional tisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are ctured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The invention also includes all suitable isotopic ions of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass ent from the atomic mass usually or predominantly found in nature. es of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, , nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 365, 18F, 36Cl, 82Br, 123I, 124|, 129| and 131|, respectively. Certain isotopic variations of a compound of the ion, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14C, isotopes are ularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain eutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic ions of a compound of the invention can generally be prepared by conventional procedures known by nerson skilled in the art such as by the illustrative methods or by the [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na preparations described in the examples hereafter using riate isotopic variations of suitable reagents.
The present invention includes all possible stereoisomers of the compounds of the present ion as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single reomer, of a nd of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, the compounds of the present ion may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, viz. : H N N \« \NNJ \(/ \NH \(/ \N Na NJ 1H-tautomer tomer 4H-tautomer.
The present ion includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one en of the compounds of the present Drention is oxidised. The present invention includes all such possible N-oxides.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena The t invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention n polar solvents, in particular water, methanol or l for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in ular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri- tetra-, penta- etc. solvates or es, , respectively, are possible. The present invention includes all such es or solvates.
Further, the nds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic on salt, particularly any ceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present ion.
For example, see S. M. Berge, et 0!. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for e, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, D nitric acid, for example, or with an organic acid, such as formic, acetic, ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena cetic, c, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, c, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, ic, cyclopentanepropionic, digluconic, 3-hydroxy naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, eptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is iently acidic, is an alkali metal salt, for example a sodium or potassium salt, an ne earth metal salt, for e a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N- methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, ohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, l, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1- amino-2,3,4-butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl des, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and yl chlorides, bromides and iodides, aralkyl halides like benzyl and hyl bromides and others.
Those skilled in the art will further recognise that acid on salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. nernatively, alkali and alkaline earth metal salts of acidic compounds of the [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena invention are prepared by reacting the compounds of the invention with the riate base via a variety of known s.
The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
As used herein, the term "in vivo hydrolysable ester" is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl , C1-C6 alkoxymethyl esters, e.g. methoxymethyl, C1-C6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-C1-C6 alkyl esters, e.g. 1- cyclohexylcarbonyloxyethyl ; oxolenonylmethyl , e.g. 5-methyl- 1,3-dioxolenonylmethyl ; and C1-Cé-alkoxycarbonyloxyethyl esters, e.g. 1- ycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this ion.
An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in vivo ysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, carbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention avers all such esters.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena Furthermore, the present invention includes all le crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
In accordance with a first aspect, the present ion covers compounds of general formula (I): H N\ \ N—<\ in which: R1 ents a phenyl or a pyridyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: Ré-(C1-C6-alkoxy)-, R"-O-, -C(=O)R", -C(=O)O-R", -N(H)C(=O)R", -N(H)C(=O)NR"R7, —NR"R7, -C(=O)N(H)R", -C(=O)NR"R7, R"-S-, R"-S(=O)2-, (=O)2R", 2N(H)R"; and - which is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, nitro-, C1-C6-alkyl-, C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, - N(H)C(=O)R8, -N(H)C(=O)NR8R7, -C(=O)N(H)R8, -N(H)S(=O)2R8; R2 represents a [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena group; wherein * tes the point of attachment of said group with the rest of the molecule; Q1 represents a group selected from: N, CH, C6-alkyl), C-(C1-C6-alkoxy), ; Q2 represents a group selected from: N, CH, CR5b; Q3 represents a group selected from: N, CH, CR5b; R5:11 represents a group selected from: halo-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, RS-(C1-C6-alkoxy)-, R8, —NR8R7, RS-S-, R8-S(=O)-, RS-S(=O)2-, (C3-C6-cycloalkyl)-(CH2)n-O-; R5b represents a group selected from: halo-, hydroxy-, , nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, R8-(C1-C6-alkyl)-, R8-(CH2)n(CHOH)(CH2)m-, RS-(C1-C6-alkoxy)-, RS-(CH2)n(CHOH)(CH2)p-O-, RS-(C1-C6-alkoxy-C1-C6-alkyl)-, RS-(C1-C6-alkoxy-C1-C6-alkyl)-O-, -O-(CH2)n-C(=O)NR8R7, R8, -C(=O)R8, O-R8, -OC(=O)-R8, -N(H)C(=O)R8, -N(R7)C(=O)R8, -N(H)C(=O)NR8R7, -N(R7)C(=O)NR8R7, , —NR7R7, -C(=O)N(H)R8, -C(=O)NR8R7, RS-S-, R8-S(=O)-, R8-S(=O)2-, -N(H)S(=O)R8, -N(R7)S(=O)R8, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena -S(=O)N(H)R8, -S(=O)NR8R7, -N(H)S(=O)2R8, -N(R7)S(=O)2R8, 2N(H)R8, -S(=O)2NR8R7, -S(=O)(=NR8)R7, -S(=O)(=NR7)R8, -N=S(=O)(R8)R7; R3 represents a hydrogen atom, a halogen atom, a hydroxy-, , cyano-, , C1-C4-alkyl-, halo-C1-C4-alkyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, hydroxy-C1-C4-alkyl-, alkoxy-C1-C4-alkyl-, halo-C1-C4-alkoxy-C1-C4-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, halo-Cz-Cé-alkenyl-, halo-Cz-Cé-alkynyl-, C3-C6-cycloalkyl-, or halo-C3-C6- cycloalkyl- group; R4 represents a hydrogen atom, a n atom, a hydroxy-, amino-, cyano-, nitro-, C1-C4-alkyl-, halo-C1-C4-alkyl-, C1-C4-alkoxy-, halo-C1-C4- alkoxy-, y-C1-C4-alkyl-, C1-C4-alkoxy-C1-C4-alkyl-, halo-C1-C4- alkoxy-C1-C4-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, halo-Cz-Cé-alkenyl-, 1 5 halo-Cz-Cé-alkynyl-, C3-C6-cycloalkyl-, or halo-C3-C6-cycloalkyl- group; R5 represents a hydrogen atom; R6 represents a group selected from C3-C6-cycloalkyl-, 3- to 10-membered heterocyclyl-, aryl-, heteroaryl-, -(CH2)q-(C3-C6-cycloalkyl), -(CH2)q-(3- to 10-membered heterocyclyl), -(CH2)q-aryl, or q-heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, y-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, R8-(C1-C6-alkyl)-, R8-(CH2)n(CHOH)(CH2)m-, RS-(C1-C6-alkoxy)-, RS-(CH2)n(CHOH)(CH2)p-O-, RS-(C1-C6-alkoxy-C1-C6-alkyl)-, RS-(C1-C6-alkoxy-C1-C6-alkyl)-O-, aryl-, R8, -C(=O)R8, -C(=O)O-R8, [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena -OC(=O)-R8, -N(H)C(=O)R8, -N(R7)C(=O)R8, -N(H)C(=O)NR8R7, -N(R7)C(=O)NR8R7, —NR8R7, -C(=O)N(H)R8, -C(=O)NR8R7, R8-s-, R8-S(=O)-, R8-S(=O)2-, -N(H)S(=O)R8, -N(R7)S(=O)R8, N(H)R8, -S(=O)NR8R7, -N(H)S(=O)2R8, -N(R7)S(=O)2R8, -S(=O)2N(H)R8, 2NR8R7, -S(=O)(=NR8)R7,- S(=O)(=NR7)R8, -N=S(=O)(R8)R7; R7 represents a hydrogen atom, a C1-C6-alkyl- or a C3-C6-cycloalkyl- group; R8 represents a hydrogen atom or a C1-C6-alkyl- or C3-C6-cycloalkyl- group, wherein said C1-C6-alkyl- or C3-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, -NHR7, -NR7R7, -N(C1-C3-alkyl)-C(=O)R7, C3-alkyl)- C(=O)OR7, alkyl-, R7-S(=O)2-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-; n; m; p; represent, independently from each other, an integer of 0, 1, 2 or 3; q represents an integer of 0, 1, 2 or 3.
As defined supra, R1 is a substituted phenyl or pyridyl group. Preferably, R1 is a substituted phenyl group.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na - which is substituted, one or more times, identically or differently, with a substituent selected from: Ré-(C1-C6-alkoxy)-, R"-O-, -C(=O)R", -C(=O)O-R", (=O)R", -N(H)C(=O)NR"R7, —NR"R7, -C(=O)N(H)R", -C(=O)NR"R7, R"-S-, R"-S(=O)2-, -N(H)S(=O)2R", -S(=O)2N(H)R"; and - which is optionally substituted, one or more times, identically or differently, with a tuent ed from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R8, -C(=O)N(H)R8.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: Ré-(C1-C6-alkoxy)-, R"-O-, -N(H)C(=O)R", -N(H)C(=O)NR"R7, -C(=O)N(H)R", -C(=O)NR"R7; and - which is optionally tuted, one or more times, identically or differently, with a tuent selected from: halo-, hydroxy-, nitro-, C1-C6-alkyl-, C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, - N(H)C(=O)R8, -N(H)C(=O)NR8R7, -C(=O)N(H)R8, -N(H)S(=O)2R8.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 ents a phenyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: Ré-(C1-C6-alkoxy)-, R"-O-, -N(H)C(=O)R", -N(H)C(=O)NR"R7, -C(=O)N(H)R", -C(=O)NR"R7; and - which is optionally substituted, one or more times, identically or differently, with a substituent selected from: [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena halo-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R8, -C(=O)N(H)R8.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: -N(H)C(=O)R", -C(=O)N(H)R"; and - which is optionally tuted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R8, N(H)R8.
In another preferred embodiment, the invention relates to nds of a (I), wherein : R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: Ré-(C1-C6-alkoxy)-, R"-O-, -N(H)C(=O)R", -N(H)C(=O)NR"R7, -C(=O)N(H)R", - R"R7; and - which is optionally substituted, one or more times, cally or ently, with a substituent ed from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 ents a phenyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: -N(H)C(=O)R", -C(=O)N(H)R"; and [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena - which is optionally substituted, one or more times, identically or differently, with a tuent selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a -N(H)C(=O)R" substituent, and - which is optionally substituted, one or more times, identically or differently, with a tuent selected from: halo-, hydroxy-, nitro-, C1-C6-alkyl-, C1-C6-alkoxy-, y-C1-C6-alkyl-, - N(H)C(=O)R8, -N(H)C(=O)NR8R7, -C(=O)N(H)R8, -N(H)S(=O)2R8.
In a preferred embodiment, the invention relates to compounds of a (I), wherein : R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a -C(=O)N(H)R"substituent, and - which is optionally substituted, one or more times, cally or differently, with a tuent ed from: halo-, hydroxy-, nitro-, C1-C6-alkyl-, C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, - N(H)C(=O)R8, -N(H)C(=O)NR8R7, -C(=O)N(H)R8, -N(H)S(=O)2R8.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a (=O)R" substituent, and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] na Unmarked set by kirstena - which is optionally substituted, one or more times, identically or differently, with a substituent ed from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group - which is tuted, one or more times, identically or differently, with a -C(=O)N(H)R"substituent, and - which is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group - which is substituted, in para-position to the point of attachment of the phenyl group with the rest of the molecule, with -N(H)C(=O)R"; and - which is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, nitro-, alkyl-, C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, - N(H)C(=O)R8, -N(H)C(=O)NR8R7, -C(=O)N(H)R8, -N(H)S(=O)2R8.
In r preferred embodiment, the invention relates to compounds of a (I), wherein : R1 ents a phenyl group - which is substituted, in osition to the point of attachment of the phenyl group with the rest of the molecule, with D -C(=O)N(H)R"; and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na - which is optionally substituted, one or more times, identically or differently, with a tuent selected from: halo-, hydroxy-, nitro-, C1-C6-alkyl-, C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, - N(H)C(=O)R8, -N(H)C(=O)NR8R7, -C(=O)N(H)R8, -N(H)S(=O)2R8.
In another red embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group which is para-substituted with respect to the point of attachement of the phenyl group with the rest of the molecule, as ed in formula (I), with a substituent selected from: Ré-(C1-C6-alkoxy)-, R"-O-, -C(=O)R", -C(=O)O-R", (=O)R", -N(H)C(=O)NR"R7, —NR"R7, -C(=O)N(H)R", NR"R7, R"-S-, R"-S(=O)2-, -N(H)S(=O)2R", -S(=O)2N(H)R"; and - which is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R8, -C(=O)N(H)R8.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group which is para-substituted with respect to the point of attachement of the phenyl group with the rest of the molecule, as depicted in formula (I), with a substituent ed from: -C6-alkoxy)-, R"-O-, -N(H)C(=O)R", -N(H)C(=O)NR"R7, -C(=O)N(H)R", - C(=O)NR"R7; and - which is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R8, -C(=O)N(H)R8.
In another preferred embodiment, the invention relates to compounds of Dmula (I), wherein : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena represents a phenyl group which is ubstituted with respect to the point of attachement of the phenyl group with the rest of the molecule, as depicted in formula (I), with a substituent selected from: -N(H)C(=O)R", -C(=O)N(H)R"; and - which is optionally substituted, one or more times, identically or differently, with a tuent selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R8, -C(=O)N(H)R8.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R1 represents a phenyl group which is para-substituted with respect to the point of attachement of the phenyl group with the rest of the molecule, as depicted in a (I), with a substituent selected from: -N(H)C(=O)R", -C(=O)N(H)R"; and - which is optionally substituted, one or more times, identically or differently, with a tuent selected from: halo-, alkyl-, C1-C6-alkoxy-.
In r red embodiment, the invention relates to nds of formula (I), wherein : R1 represents a group selected from: [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena H H: H HE 7 7 F HV> n * indicates the point of attachment of said group with the rest of the molecule.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : Q1 represents a group selected from: CH, C-(C1-C6-alkyl), C-(C1-C6-alkoxy), C-halo.
Deferably, Q1 represents CH.
[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena In another red embodiment, the invention relates to compounds of formula (I), wherein : Q2 ents a group selected from: N, CH, C-R5C; wherein R5C is selected from the groups consisting of: halo-, cyano-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R7, -N(R7)C(=O)R7, -C(=O)N(H)R8, -C(=O)NR8R7, R8-S(=O)-, R8-S(=O)2-, -S(=O)(=NR7)R8.
Preferably, Q2 represents CH.
In another preferred embodiment, the invention s to compounds of formula (I), wherein : Q3 represents a group selected from: N, CH, C-R5C, wherein R5C is selected from the groups consisting of: halo-, cyano-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R7, -N(R7)C(=O)R7, -C(=O)N(H)R8, -C(=O)NR8R7, R8-S(=O)-, R8-S(=O)2-, -S(=O)(=NR7)R8. ably, Q3 represents CH or N.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : Q1 and Q2 represent CH, and Q3 represents CH or N.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R3 represents a hydrogen atom, halo-, hydroxy-, C1-C4-alkyl-, 1-C4-alkyl-, or C1-C4-alkoxy- group.
Preferably, R3 ents a hydrogen atom.
In another preferred embodiment, the invention relates to nds of formula (I), wherein : R4 represents a hydrogen atom, halo-, a C1-C6-alkyl-, halo-C1-C6-alkyl- or D C1-C6-alkoxy- group.
[Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Preferably, R4 represents a hydrogen atom.
In another preferred embodiment, the invention s to compounds of formula (I), wherein : R3 and R4 represent a hydrogen atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R5a represents a group selected from: halo-, C1-C6-alkyl-,C1-C6-alkoxy-, halo-C1-C6-alkoxy-, y-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, RS-(C1-C6-alkoxy)-, R8, RS-S-, RS-S(=O)2-, (C3-C6-cycloalkyl)-(CH2)n-O-.
Preferably, R5:11 is selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-, 1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, (C3-C6-cycloalkyl)-(CH2)n-O-.
More preferably, R5:11 is ed from: F-, methyl-, y-, ethoxy-, n-propoxy-, iso-propoxy-, cyclopropyl-O-, cyclopropyl-CHz-O-, CH3-O-CH2CH2-O-, CHFz-O-, CF3-O-, -O-.
In another preferred embodiment, the ion relates to compounds of formula (I), wherein : R5a represents a C1-C6-alkoxy-, group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R5a represents a C1-C3-alkoxy-, group.
D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena In another red embodiment, the invention relates to compounds of a (I), wherein : R5:11 represents a 1-C6-alkoxy-, group.
In another preferred embodiment, the ion relates to compounds of formula (I), wherein : R5:11 represents a 1-C3-alkoxy-, group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R5:11 represents a (C3-C6-cycloalkyl)-(CH2)n-O- group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R5b represents a group selected from: halo-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, R8, -C(=O)R8, O-R8, -N(H)C(=O)R8, -N(R7)C(=O)R8, -N(H)S(=O)2Rg, —NR8R7, —NR7R7, -C(=O)N(H)R8, -C(=O)NR8R7, R8-S(=O)-, RS-S(=O)2-, -S(=O)(=NR7)R8.
Preferably, R5b is selected from: halo-, , —NR7R7, C1-C6-alkoxy-, -N(H)C(=O)R8,-N(R7)C(=O)R8, -C(=O)N(H)R8, -C(=O)NR8R7, R8-S(=O)-, R8-S(=O)2-, -S(=O)(=NR7)R8, hydroxy-C1-C6-alkyl-, -N(H)S(=O)2Rg.
More preferably, R5b is selected from: fluoro-, cyano-, methoxy-, H, -C(OH)(CH3)2, -N(CH3)2, -C(=O)NH2, -C(=O)N(CH3)2, N(C2H5)2, -C(=O)N(CH3)(C2H5), -C(=O)NH(C2H5), ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena (=O)ONH CH3),( - C(=O)NH(C(CH3)3), -C(=O)NH(CH2CH20H), -C(=O)NH(CH2CH2F), C-(=O)NH(CH2CH20CH3),-C(=O)NH(CH2CH20CH2CH3), -C(=O)N,H(C(CH3)2CH20H) -C(=O)NH(CH2C(CH3)20H), -C(=O)NH(CH2CF3), S(=O)CH3, (CH3)S(=O)2-, (C2H5)S(=O)2-, -N(H)C(=O)CH3, * st * OATN \n/N CH s OAT/w CAN/YFH CH3 0 CH3 OH F CH3 CH * N A is H c CAN/V 0/ N/\/ \CH3 3 /\ OH I I o/ N CH3 CH3 H * C|:H3 * O\\ //0 AN F 0/ N/\/N\CH3 CAN/VS\CH3 I/|=>( H H CH3 F CAN/XI: * * H F OANA/ CAN/ml: F H H o¢\N/\CH3 * NH\S//O * o\\S,/o % A /\/ \ O 0 fl / CH3 \CH3 0’ \CH3 0=S=O * HN CH O=S=O * 3 o O=S—CH CAN/V \CHS II 3 X HSC k H NH CH3 HaC CH3 . 7 7 7 7 n * indicates the point of attachment of said group with the rest of the filecule.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by na [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena In another preferred embodiment, the invention relates to compounds of a (I), wherein : R5b represents a group selected from: -C(=O)N(H)R8, -C(=O)NR8R7, RS-S(=O)-, RS-S(=O)2-, -S(=O)(=NR7)R8.
In r preferred embodiment, the invention relates to compounds of formula (I), wherein : R5b represents a -C(=O)N(H)R8 group.
In another preferred embodiment, the invention relates to compounds of a (I), wherein : R5b represents a -C(=O)NR8R7 group.
In another preferred embodiment, the invention relates to nds of formula (I), wherein : R5b represents a R8-S(=O)- group.
In another red embodiment, the invention relates to compounds of formula (I), wherein : R5b represents a RS-S(=O)2-, group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R5b represents a -S(=O)(=NR7)R8 group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R5b represents a -C(=O)N(H)R7 group.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena In another preferred embodiment, the invention relates to nds of formula (I), n : R5b represents a R7-S(=O)2-, group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R" represents a group selected from: C3-C6-cycloalkyl-, 3- to 10-membered heterocyclyl-, aryl-, heteroaryl-, -(CH2)q-(C3-C6-cycloalkyl), -(CH2)q-(3- to 10-membered heterocyclyl), -(CH2)q-aryl, or q-heteroaryl; wherein said group is optionally substituted, one or more times, cally or differently, with a substituent selected from: halo-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, alkoxy-C1-C6-alkyl-, 1-C6-alkoxy-C1-C6-alkyl-; wherein q is 1 or 2.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R" represents a group selected from: q-(C3-C6-cycloalkyl), -(CH2)q-(3- to 10-membered heterocyclyl), -(CH2)q-aryl, or -(CH2)q-heteroaryl; wherein said group is optionally substituted, one or more times, identically or differently, with a substituent ed from: halo-, C1-C6-alkyl-; wherein q is 0 or 1.
The C3-C6-cycloalkyl- group preferably is a cyclopropyl- group; the aryl- group is preferably a phenyl- group; the heteroaryl- group is ably a pyridyl- group.
[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena In another preferred embodiment, the invention relates to nds of formula (I), wherein : R" represents a group selected from: -(CH2)-(C3-C6-cycloalkyl), -(CH2)-aryl; wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, 1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-.
The C3-C6-cycloalkyl- group preferably is a cyclopropyl- group; the aryl- group is ably a phenyl- group.
In another preferred embodiment, the invention s to compounds of formula (I), wherein : R" represents a group selected from: C3-C6-cycloalkyl) or -CH2-aryl; wherein said group is optionally substituted, one or more times, identically or differently, with a tuent selected from: halo-, C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-.
The C3-C6-cycloalkyl- group preferably is a cyclopropyl- group; the aryl- group is preferably a phenyl- group.
In another preferred embodiment, the ion relates to compounds of formula (I), wherein : R" represents a group selected from: -(CH2)-(C3-C6-cycloalkyl), -(CH2)-aryl; wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C6-alkyl-.
[Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena The C3-C6-cycloalkyl- group preferably is a cyclopropyl- group; the aryl- group is preferably a phenyl- group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R" represents a group selected from: -(CH2)-aryl; wherein said group is optionally tuted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C6-alkyl-.
The aryl- group is preferably a phenyl- group.
In r preferred embodiment, the invention relates to compounds of formula (I), wherein : R" represents a group ed from: -(CH2)-(C3-C6-cycloalkyl); wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C6-alkyl- The cycloalkyl- group preferably is a cyclopropyl- group.
In another preferred embodiment, the invention relates to nds of formula (I), n : R" represents a group selected from: -(CH2)-phenyl, -(CH2)-cyclopropyl; wherein said group is optionally substituted, one or more times, cally or differently, with a substituent selected from: halo-, C1-C6-alkyl-; wherein q is 0 or 1.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena In another preferred embodiment, the ion relates to compounds of formula (I), wherein : R7 ents a hydrogen atom, or a C1-C6-alkyl-.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R7 represents a hydrogen atom, or a C3-C6-cycloalkyl- group; In another preferred embodiment, the invention relates to nds of formula (I), wherein : R8 represents a hydrogen atom or a C1-C6-alkyl- group, n said C1-C6-alkyl-group is optionally substituted, one or more times, identically or differently, with a tuent selected from: halo-, hydroxy-, -NHR7, -NR7R7, -N(C1-C3-alkyl)-C(=O)R7, -N(C1-C3-alkyl)- C(=O)OR7, alkyl-, R7-S(=O)2-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-; In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R8 represents a en atom or C3-C6-cycloalkyl- group, wherein said cycloalkyl- group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, -NHR7, -NR7R7, C3-alkyl)-C(=O)R7, -N(C1-C3-alkyl)- C(=O)OR7, C1-C3-alkyl-, R7-S(=O)2-, alkoxy-, halo-C1-C3-alkoxy-; In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R8 ents a hydrogen atom or a C1-C6-alkyl- group, wherein said C1-C6-alkyl-group is optionally substituted, one or more times, identically or differently, with a substituent selected from: D halo-, C1-C3-alkyl-, O)2-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena In another preferred embodiment, the invention relates to compounds of formula (I), wherein : R8 ents a hydrogen atom or C3-C6-cycloalkyl- group, wherein said C3-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C3-alkyl-, R7-S(=O)2-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-; In another red embodiment, the invention relates to compounds of formula (I), wherein : R8 represents a hydrogen atom or a C1-C6-alkyl- group, wherein said C1-C6-alkyl-group is optionally tuted, one or more times, identically or differently, with a substituent selected from: halo-.
In another preferred ment, the invention relates to compounds of formula (I), n : n represents an integer of 0, 1 or 2.
Preferably, n ent 0 or 1.
In another preferred ment, the invention relates to compounds of formula (I), wherein : q represents an integer of 0, 1 or 2.
Preferably, q represents 1 or 2.
More preferably, q = 1.
It is to be understood that the present invention relates also to any combination of the red embodiments described above.
Some examples of combinations are given hereinafter. However, the invention not limited to these combinations.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena In r preferred embodiment, the invention relates to compounds of formula (I): H N\ \ /N—<\ R2 N’N / R1 (I) in which: R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: Ré-(C1-C6-alkoxy)-, R"-O-, -N(H)C(=O)R", -N(H)C(=O)NR"R7, -C(=O)N(H)R", - C(=O)NR"R7; and - which is optionally substituted, one or more times, identically or ently, with a substituent selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R8, -C(=O)N(H)R8; R2 represents a group; wherein * indicates the point of attachment of said group with the rest of the le; R5&1 represents a group selected from: halo-, C1-C6-alkyl-,C1-C6-alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, D halo-C1-C6-alkoxy-C1-C6-alkyl-, RS-(C1-C6-alkoxy)-, R8, RS-S-, [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena RS-S(=O)2-, (C3-C6-cycloalkyl)-(CH2)n-O-; R5b represents a group selected from: halo-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, R8, -C(=O)R8, -C(=O)O-R8, -N(H)C(=O)R8, -N(R7)C(=O)R8, —NR8R7, —NR7R7, -C(=O)N(H)R8, -C(=O)NR8R7, O)-, RS-S(=O)2-, -S(=O)(=NR7)R8; Q1 represents a group selected from: CH, C-(C1-C6-alkyl), C-(C1-C6-alkoxy), C-halo; Q2 represents a group selected from: N, CH, C-R5C; 1 0 wherein R5C is selected from the groups consisting of: halo-, cyano-, C1-C6-alkyl-, C1-C6-alkoxy-, -N(H)C(=O)R7, -N(R7)C(=O)R7, -C(=O)N(H)R8, -C(=O)NR8R7, R8-S(=O)-, O)2-, -S(=0)(=NR7)R8; Q3 represents a group selected from: N, CH, C-R5C, 1 5 wherein R5C is selected from the groups consisting of: halo-, cyano-, C1-C6-alkyl-, C1-C6-alkoxy-, (=O)R7, C(=O)R7, N(H)R8, -C(=O)NR8R7, R8-S(=O)-, RS-S(=O)2-, -S(=O)(=NR7)R8; R3 represents a hydrogen atom, halo-, hydroxy-, C1-C4-alkyl-, halo-C1-C4-alkyl-, or C1-C4-alkoxy- group; R4 represents a hydrogen atom, halo-, a C1-C6-alkyl-, halo-C1-C6-alkyl- or C1-C6-alkoxy- group; R5 represents a hydrogen atom.
R6 ents a group selected from: C3-C6-cycloalkyl-, 3- to bered cyclyl-, aryl-, heteroaryl-, q-(C3-C6-cycloalkyl), -(CH2)q-(3- to 10-membered heterocyclyl), -(CH2)q-aryl, or -(CH2)q-heteroaryl; wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena C1-C6-alkoxy-, 1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-; represents a hydrogen atom, a C1-C6-alkyl- or a C3-C6-cycloalkyl- group; represents a en atom or a C1-C6-alkyl- or cycloalkyl- group, wherein said C1-C6-alkyl- or C3-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, -NHR7, -NR7R7, -N(C1-C3-alkyl)-C(=O)R7, -N(C1-C3-alkyl)- C(=O)OR7, C1-C3-alkyl-, R7-S(=O)2-, C1-C3-alkoxy-, 1-C3-alkoxy-; represents an integer of 0, 1 or 2; and represents an integer of 0, 1 or 2.
In another preferred embodiment, the invention relates to compounds of a (I), wherein : R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: -N(H)C(=O)R", -C(=O)N(H)R"; and - which is optionally substituted, one or more times, identically or differently, with a substituent ed from: halo-, alkyl-, C1-C6-alkoxy-; ents a group; wherein * indicates the point of attachment of said group with the rest of the molecule; Q1 represents CH; Q2 represents CH; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena ed set by na Q3 represents CH or N; R5:11 represents a group selected from: halo-, C1-C6-alkyl-,C1-C6-alkoxy-, halo-C1-C6-alkoxy-, (C3-C6-cycloalkyl)-(CH2)n-O-; R5b represents a group selected from: halo-, cyano-, C1-C6-alkoxy-, -N(H)C(=O)R8, C(=O)R8, -C(=O)N(H)R8, -C(=O)NR8R7, R8-S(=O)-, R8-S(=O)2-, -S(=O)(=NR7)R8; R3, R4, and R5 represent a hydrogen atom; R" represents a group ed from: -(CH2)-(C3-C6-cycloalkyl) or -(CH2)-aryl; wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, cyano-, , C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-; R7 represents a hydrogen atom, a C1-C6-alkyl- or a C3-C6-cycloalkyl- group; R8 represents a hydrogen atom or a C1-C6-alkyl- or C3-C6-cycloalkyl- group, wherein said C1-C6-alkyl- or C3-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, -NHR7, -NR7R7, -N(C1-C3-alkyl)-C(=O)R7, -N(C1-C3-alkyl)- C(=O)OR7, C1-C3-alkyl-, R7-S(=O)2-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-; n represents an integer of 0, 1 or 2; q represents an integer of 1 or 2.
In another preferred embodiment, the invention relates to compounds of formula (I), n : R1 represents a phenyl group - which is tuted, one or more times, identically or differently, with D a substituent selected from: [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena -N(H)C(=O)R", -C(=O)N(H)R"; and - which is optionally substituted, one or more times, identically or differently, with a substituent ed from: halo-, alkyl-, C1-C6-alkoxy-; represents a group; wherein * indicates the point of attachment of said group with the rest of the molecule; Q1 represents CH; Q2 represents CH; Q3 represents CH or N; R5:11 represents a group selected from: halo-, C1-C6-alkyl-,C1-C6-alkoxy-, halo-C1-C6-alkoxy-, -cycloalkyl)-(CH2)n-O-; R5b represents a group selected from: halo-, cyano-, C1-C6-alkoxy-, -N(H)C(=O)R8, -N(R7)C(=O)R8, -C(=O)N(H)R8, NR8R7, R8-S(=O)-, R8-S(=O)2-, -S(=O)(=NR7)R8; R3, R4 and R5 represent a hydrogen atom; R6 represents a group selected from: -CH2-(cyclopropyl) or -CH2-(phenyl); wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-; represents a hydrogen atom, a C1-C6-alkyl- or a C3-C6-cycloalkyl- group; represents a hydrogen atom or a alkyl- or C3-C6-cycloalkyl- group, [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena wherein said C1-C6-alkyl- or cycloalkyl- group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, -NHR7, -NR7R7, -N(C1-C3-alkyl)-C(=O)R7, -N(C1-C3-alkyl)- R7, C1-C3-alkyl-, R7-S(=O)2-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-; represents an integer of 0 or 1; and represents an r of 1.
In another red embodiment, the ion relates to compounds of formula (I), wherein : R1 represents a phenyl group - which is substituted, one or more times, identically or differently, with a substituent selected from: -N(H)C(=O)R", -C(=O)N(H)R"; and - which is optionally tuted, one or more times, identically or differently, with a tuent selected from: halo-, C1-C6-alkyl-, C1-C6-alkoxy-; R2 represents a group; wherein * indicates the point of attachment of said group with the rest of the molecule; Q1 represents CH; Q2 represents CH; Q3 represents CH or N; R5:11 represents a group selected from: halo-, C1-C6-alkyl-,C1-C6-alkoxy-, halo-C1-C6-alkoxy-, (C3-C6-cycloalkyl)-(CH2)n-O-; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R5b ents a group selected from: halo-, cyano-, C1-C6-alkoxy-, -N(H)C(=O)R8, -N(R7)C(=O)R8, -C(=O)N(H)R8, -C(=O)NR8R7, R8-S(=O)-, R8-S(=O)2-, (=NR7)R8; R3, R4 and R5 represent a hydrogen atom; R" represents a group selected from: C3-C6-cycloalkyl) or -CH2-aryl; wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-; R7 represents a hydrogen atom, a C1-C6-alkyl- or a cycloalkyl- group; R8 represents a hydrogen atom or a C1-C6-alkyl- or C3-C6-cycloalkyl- group, wherein said C1-C6-alkyl- or C3-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, -NHR7, -NR7R7, -N(C1-C3-alkyl)-C(=O)R7, -N(C1-C3-alkyl)- R7, C1-C3-alkyl-, R7-S(=O)2-, C1-C3-alkoxy-, 1-C3-alkoxy-; n represents an integer of 0 or 1; and q represents an integer of 1.
It is to be understood that the present invention relates to any sub- combination within any ment of the t invention of compounds of l formula (I), supra.
More particularly still, the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena In ance with r aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
In a preferred embodiment, the present ion relates to a method of preparing compounds of general formula (I) of the present invention, in which method an intermediate compound of general formula (5) : N\ \ H2N—<\N/N / R1 in which R1, R3, R4, and R5 are as defined for the compounds of general a (I); supra, is allowed to react with an aryl halide of general formula (5a) : RZ-Y (5a) in which R2 is as defined for the compounds of general formula (I), supra, and Y represents a halogen atom, thus providing a compound of general formula (I) : H N\ \ N <\ [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena In another preferred embodiment, the present ion relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate compound of general formula (7) : H N\ \ 4, / in which R2, R3, R4, and R5 are as defined for the compounds of general formula (I), supra, and R1&1 is an aryl group to which an —NH2 substituent is bound, is allowed to react with a compound of general formula : R1b-X (7a) in which R1b is -C(=O)R", -C(=O)NR"R7, -S(=O)R", or -S(=O)2R", (R6 and R7 being as defined for nds of general formula (I), supra), and X is a suitable functional group (e.g. an —OH, -O-C1-C6-alkyl group, or a halogen atom), via which the R1b of the R1b-X nd (7a) can be coupled, via a coupling reaction, such as an amide coupling reaction for example, onto the —NH2 substituent bound to the aryl group R1&1 of compound (7), thereby replacing said X with said R1a, thus providing a compound of general formula (I) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena In accordance with a r aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), ularly in the method described herein.
In particular, the present invention covers : a) compounds of general formula (5) : N\ \ H2N—<\N/N / R1 (5) in which R1, R3, R4, and R5 are as defined for the compound of general formula (I); supra ; b) compounds of general formula (7) : H N\ \ N <\ RZ/ N / N/ R13 in which R2, R3, R4, and R5 are as defined for the nd of general formula a, supra, and R1&1 is an aryl group to which an —NH2 substituent is bound.
[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena In ance with yet another aspect, the present invention covers the use of an intermediate compound : a) of general formula (5) : N\ \ H2N—<\N/N / R1 in which R1, R3, R4, and R5 are as defined for the compound of general a (I), supra, as defined in the claims, b) of general formula (7) : H N\ \ N <\ RZ/ N / N/ R13 in which R2, R3, R4, and R5 are as defined for the compound of general formula (I), supra, and R1&1 is an aryl group to which an —NH2 substituent is bound, for the preparation of a nd of general formula (I).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena EXPERIMENTAL SECTION The ing Table lists the abbreviations used in this paragraph, and in the Examples section. NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
Names of nds were generated using the Autonom 2000 add-in of ISIS/Draw [MDL Information Systems Inc. (Elsevier MDL)] or the ICS naming tool 12.01 of ACD labs. In some cases generally accepted names of cially available reagents were used.
BINAP 2, 2'- bis((diphenylphosphino)-)-1 ,1'--binaphthyl 2-(dicyclohexylphosphino))-,3 6--dimethoxy- 2'-4'- 6'-tri--i- propyl- Brett- Phos 1 ,1'-biphenyl [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena DIEA N,N-diisopropylethylamine DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide U 'U_h 1,1'-bis(diphenylphosphino)ferrocene FI'I equivalent electrospray tion Ihour or hours hour or hours N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin yloxy)methylene]-N-methylmethanaminium hexafluorophosphate Hijnig Base N,N-diisopropylethylamine m.p.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena nuclear magnetic resonance spectroscopy: chemical shifts (6) are given in ppm. dichlorobis(triphenylphosphine)palladium(||) bis-(dibenzylideneacetone)-palladium(0) complex tris-(dibenzylideneacetone)-dipalladium(0)-chloroform complex dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(||) Pd(dppf)Cl2 . ro[1,1'-bis(diphenylphosphino)ferrocene]palladium(||) CH2Cl2 dichloromethane adduct Pd-Brett- chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i- Phos-pre-cat propyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(||) -X- chloro(2-di-tert-butylphosphino-Z‘,4',6'-tri-i-propyl-1,1'- Phos-pre-cat yl)[2-(2-aminoethyl)phenyl]palladium(||), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert- butylether adduct P ( )3 -Rac racemic -Rt room temperature Ireem temperature [Annotation] na None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na N- [((1H- riazol-yloxy)(dimethylamino)methylene]--N- methylmethanaminium tetrafluoroborate The schemes and procedures described below illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as ified in the Schemes can be modified in various ways. The order of transformations exemplified in the Schemes is therefore not intended to be limiting. In on, interconversion of any of the substituents, R1, R2, R3, R4, R5a, R5b, R" R7 or R8 can be ed before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other actions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena of substituents. riate protecting groups and their uction and cleavage are well-known to the person skilled in the art (see for example T.W.
Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
A first on scheme is outlined infra : [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Synthesis of compounds of general formula (I) of the present invention Scheme 1 R3 R3 R3 HzN R4 R4 \ \/0 H H R4 N \ll/ \[1/ \ \ \ I —> I —> H N—( N / 2 \ o N / Y s N / N’ Y y R5 R5 R5 (1) (2) (3) R1a-z (3a) R1-Z l RZ-Y R3 R3 R3 R4 R4 N N R4 \ H \ \ N\ N,N / Rm H2N_<\N’N / R1 Rz'N—<\N’N / Y R5 R5 R5 (6) (5) (4) RZ-Y RZ-Y R3 R3 N\ R Rz'N—QNflRl4R H \ H N \ \ N ’ Rz' —<\Nr\l\¢LR1a R1b_x R5 (7a) R5 wherein R1, R2, R3, R4 and R5 are as defined for the compounds of formula (I), supra, Y is a halogen atom as defined supra, and Z represents a suitable functional group via which the R1 of the R1-Z compound can be d, by a coupling reaction, onto the Y-bearing carbon atom of a compound (4), thereby replacing said Y with said R1 . Many aryl halides of the formula RZ-Y may be obtained commercially. Reagents of the general structure Rla-Z and R1-Z can for e be aryl boronic acids or aryl boronic esters. Many such reagents of the general structures Rla-Z and R1-Z are also commercially available. Reagents of the general structures Rla-Z and R1-Z can be prepared from aryl halides [see for example K.L. Billingslay, T.E. Barde, S.L ld, Angew. Chem. 2007, D9, 5455 or T.Graening, Nachrichten aus der Chemie, Jan 2009, 57, 34].
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na R161 can be converted to R1 in one or several steps. Typically, R161 can be a protected aryl-amine, especially -aryl-NH-Boc, or an arboxylic acid, [-aryl-C(O)OH] or an -aryl-carboxylic acid ester [—aryl-C(O)O-alkyl]. For example, when R161 is an aryl group to which an —NH2 substituent is bound, it may be allowed to react with a compound of general formula R1b-X (7a), in which R1b is -C(=O)R", -C(=O)NR"R7, -S(=O)R", or -S(=O)2R", (R6 and R7 being as defined as for nds of general formula (I) of the present invention as d in the claims), and X is a suitable functional group (e.g. an —OH, -O-C1- Cé-alkyl group, or a halogen atom), via which the R1b of the R1b-X compound (7a) can be coupled, via a coupling reaction, such as an amide coupling reaction for example, onto the —NH2 tuent bound to the aryl group R1&1 of compound (7), thereby replacing said X with said R1a, thus providing a compound of l formula (I) of the present invention.
Compounds of general formula (I) can be synthesised ing to the procedures depicted in Scheme 1.
The person d in the art will recognise that there are many precedented methods for synthesising suitable 3,4,6-substituted 5-halo-pyridinylamines of general formula (1); some 3,4,6-substituted 5-halo-pyridinylamines may be obtained commercially.
A suitably substituted 5-halo-pyridinylamine intermediate of general formula (1) is converted to the ponding intermediate of general formula (2) by reaction with a suitable oxycarbonylisothiocyanat, such as for example ethoxycarbonylisothiocyanat at temperatures ranging from room temperature to the boiling point of the solvent, preferably room temperature [see for example M. Nettekoven, B. Plillmann, S. t, Synthesis 2003, 1643 - 1652].
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediates of general a (2) may be converted to 6-Halo- [1,2,4]triazolo[1,5-a]pyridinylamine intermediates of general formula (3) by reaction with a suitable reagent, for example hydroxylamine hydrochloride, in presence of a suitable base, such as, for example DIPEA in a suitable solvent system, such as, for example, methanol, ethanol, 1-propanol, 2-propanol or mixtures of these solvents at elevated temperatures, e.g. 60°C. [see for example M. Nettekoven, B. Plillmann, S. Schmitt, Synthesis 2003, 1643 - 1652].
Intermediates of l formula (3) can reacted with suitable aryl s, preferably aryl bromides, in the presence of a suitable base, such as, for example NaOtBu or cesium carbonate, and a suitable catalyst/ligand system, such as for example a)3/rac-BINAP in a suitable solvent such as THF, toluene, DME, or NMP, or mixtures of these solvents at atures ranging from room temperature to the 200°C, to yield compounds of general a (4). The person skilled in the art will recognise that the appropriate choice of reaction conditions, such as ature, choice of solvent and catalyst system is critical for preferred derivatization at the amino group of intermediates of general formula (3). Intermediates of general formula (4) can be converted to compounds of general a (I) by reaction with a suitable reagent, like for example a boronic acid derivative in the presence of a le catalyst system, like for example Pd(OAc)2 and P(oTol)3, or PdCl2(PPh3)2 and PPh3 and a suitable base, like for example aqueous potassium carbonate in a suitable solvent, like for e THF, DME, ethanol or 1- propanol or mixtures of these ts at temperatures ranging from room temperature to 200°C, prefereably the g point of the used solvent.
In an alternative route for the synthesis of compounds of l formula (I), Intermediates of general formula (3) can be reacted d with a suitable reagent, like for example a boronic acid derivative in the presence of a Dtable catalyst system, like for example Pd(OAc)2 and P(oTol)3, or [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena PdCl2(PPh3)2 and PPh3 and a le base, like for example aqueous potassium carbonate in a suitable solvent, like for example THF, DME, ethanol or 1- propanol or mixtures of these solvents at temperatures ranging from room temperature to 200°C, prefereably the boiling point of the used solvent to furnish intermediates of the general formula (5).
Intermediates of l formula (5) can be converted to compounds of general formula (I) by reaction with with suitable aryl halides, of a (5a) as defined herein, preferably aryl bromides, or aryl trifluoromethylsulphonates or aryl uorobutylsulphonates, for example, optionally in the ce of a suitable base, such as, for example NaOtBu or cesium carbonate, and a le catalyst/ligand system, such as for example a)3/rac-BINAP in a suitable solvent such as for example THF, toluene, DME, or NMP, or mixtures of these solvents at temperatures ranging from room ature to the 200°C.
Also as depicted in Scheme 1, is a further alternative route for the sis of compounds of general formula (I): Intermediates of l formula (3) can be converted to intermediates of general formula (6) by a coupling reaction as described supra for synthesis of intermediate of general formula (5), thereby replacing said Y with said R1a moiety.
Intermediates of general formula (6) can then be converted to intermediates of general formula (7) by a coupling on as described supra for synthesis of of intermediates of general formula (4).
Intermediates of l formula (7) can then be converted to compounds of general a (I) by one or more further transformations. These can be modifications such as ge of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art, for example the formation of an amide bond, the formation of a urea, or the formation of a sulfonamide.
D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na ation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena Each of the Schemes 2 — 7, infra, illustrates specific transformations for the synthesis of some selected compounds according to general formula (I).
Scheme 2: Synthesis of nds of general formula (11) Scheme 2: Synthesis of compounds of general formula (11), wherein R2, R3, R4, R5 and R" are as defined for the compounds of general formula (I), supra. Y is a halogen as defined in the definitions. Rxy is n, hydroxy or C1-C6-alkyl. a) coupling reaction using conditions as described supra for synthesis of intermediates of general formula (5); b) coupling reaction using conditions as described supra for synthesis of intermediates of general formula (4); c) removal of a Boc-protecting group using conditions known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999); d) conditions for the formation of an amide bond, e.g. using coupling reagents like HATU or TBTU and a base like potassium carbonate or DIPEA in an inert solvent like THF, DMF, DCM or NMP.
[Annotation] na None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Scheme 3: Synthesis of compounds of general formula (12) Scheme 3: sis of compounds of general formula (12), wherein R2, R3, R4, R5 and R" are as defined for the compounds of general formula (I), supra. Rxy is n, hydroxy or alkyl. a) conditions for the formation of a sulfonamide, e.g. using a sulfonyl chloride and a base like DIPEA in an inert solvent like for example THF, DMF, DCM or NMP at temperatures ranging from room temperature to the 70°C.
Scheme 4: Synthesis of compounds of l formula (13) Scheme 4: Synthesis of compounds of general formula (13), wherein R2, R3, R4, R5, R" and R7 are as defined for the compounds of general formula (I), supra.
Rxy is n, hydroxy or C1-C6-alkyl. a) Conditions for the formation of an urea, e.g. using an isocyanate in an inert solvent like for example THF, DMF, DCM or NMP at temperatures ranging from room temperature to 70°C.
Alternatively, a two step procedure which involves reaction of 4-Nitrophenyl chloroformate in an inert solvent like for example THF or DCM and a base like pyridine at temperatures ranging from 0°C to room temperature, followed by reaction with an amine in an inert solvent like THF or DCM at temperatures aging from 0°C to 40°C, can be used.
[Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Scheme 5: sis of compounds of general formula (15) (15) Scheme 5: Synthesis of compounds of general formula (15), wherein R2, R3, R4, and R5 are as defined for the compounds of general formula (I), supra. Rxy is halogen, hydroxy or C1-C6-alkyl. RXZ is a leaving group, e.g. a halogen. RHEt is 3- to 10-membered heterocyclyl, as defined supra. a) Conditions for the formation of an amide bond, e.g. using coupling reagents like for example HATU or TBTU and a base like for example ium carbonate or DIPEA in an inert solvent like for example THF, DMF, DCM or NMP. Alternatively, an acid chloride and a base like for example pyridine can be used in an inert solvent like for example THF or DCM. b) Reaction with a heterocyclic amine, like e.g. piperidine in a polar solvent like for example DMF or NMP using a base like for example potassium carbonate and optionally using a catalytic ammount of ium iodide.
Scheme 6: Synthesis of nds of general formula (11) R4 ny [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Scheme 6: Synthesis of compounds of general a (11), wherein R2, R3, R4, R5 and R" are as defined for the nds of general formula (I), supra. Rxy is halogen, hydroxy or C1-C6-alkyl. a) removal of a Boc-protecting group using conditions known to the person d in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in c Synthesis, 3rd edition, Wiley 1999); b) ions for the formation of an amide bond, e.g. using coupling reagents like for example HATU or TBTU and a base like for example potassium carbonate or DIPEA in an inert solvent like for e THF, DMF, DCM or NMP; c) coupling reaction using conditions as described supra for sis of intermediates of general formula (4).
Scheme 7: Synthesis of compounds of general formula (22) Scheme 7: Synthesis of compounds of general formula (21), wherein R2, R3, R4, R5, R" and R7 are as defined for the compounds of general formula (I), supra.
D is halogen, hydroxy or C1-C6-alkyl. Ralkyl is C1-C6-alkyl. a) coupling reaction [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena using conditions as described supra for synthesis of intermediates of general formula (5); b) formation of an ester using conditions known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999), e.g. using thionyl chloride in the appropriate l at temperatures ranging from room temperature to 100°C; c) coupling reaction using conditions as described supra for synthesis of intermediates of general formula (4); d) hydrolysis for an ester using conditions known to the person d in the art (see for example T.W.
Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999), e.g. sodium hydroxide in a mixture of THF, methanol an water at r.t.; e) ions for the formation of an amide bond, e.g. using coupling ts like for example HATU or TBTU and a base like for example potassium carbonate or DIPEA in an inert solvent like for example THF, DMF, DCM or NMP.
The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the nds may be purified by crystallisation. In some cases, impurities may be stirred out using a suitable t. In some cases, the compounds may be purified by chromatography, particularly flash chromatography, using for example cked silica gel cartridges, e.g. from Separtis such as |solute® Flash silica gel (silica gel chromatography) or |solute® Flash NH2 silica gel (aminophase-silica-gel chromatography) in combination with a suitable chromatographic system such as a Flashmaster || (Separtis) or an a system (Biotage) and s such as, for example, gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using, for example, a Waters autopurifier ed with a diode array detector and/or on-line electrospray ionisation ass spectrometer in combination with a suitable pre-packed reverse phase [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
Analytical UPLC-MS was performed as follows: Method A: : UPLC Acquity (Waters) with PDA Detector und Waters ZQ mass spectrometer; Column: Acquity BEH C18 1.7 pm 2.1x50 mm; Temperature: 60°C; Solvent A: Water + 0.1% formic acid; Solvent B: acetonitrile; Gradient: 99 % A 9 1 % A (1.6 min) 9 1 % A (0.4 min); Flow: 0.8 ; Injection Volume: 1.0 uL (0.1mg-1mg/mL sample concentration); Detection: PDA scan range 210-400 nm — Fixed and ESI (+),scan range 170-800 Names of nds were generated using ACD/Name Batch ver. 12.00 or ACD/Name Batch ver. 12.01. Names of nds in table format were generated using ACD/Name Batch ver. 12.00.
S nthesis of Intermediate com ounds Intermediate Example Int1.1 ethyl omopyridinyl)carbamothioyl]carbamate WHOBrO H H Ethoxycarbonylisothiocyanat (16.7 g) was added to a stirred solution of 2- aminobrompyridine (20 g) in dioxane (200 mL). The mixture was stirred for 2h at r.t. A white solid precipitated. Hexane (20 mL) was added and the white solid was collected by filtration.
Yield: 30.4 g of the title compound. ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.22 (t, 3H), 4.19 (q, 2H), 8.08 (dd, 1H), 8.49 (d, 1H), 8.57 (br. d, 1H), 11.37 - 12.35 (m, 2H).
Intermediate e |nt1.2 6-bromo[1, iazolo[1, 5-a]pyridinamine N\ \ HM 13L N Br Hydroxylammoniumchlorid (39.8 g) was suspended in ol (200 mL) and ethanol (190 mL) and Hijnig Base (59 mL) was added at r.t. The mixture was heated to 60°C, |nt1.1 (30 g) was added portionwise, and the mixture was stirred at 60°C for 2h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum.
Yield: 19.3 g of the title nd. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 6.10 (s, 2H), 7.28 (dd, 1H), 7.51 (dd, 1H), 8.88 (dd, 1H).
Intermediate Example |nt2.1 4-(2-amino-[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-cyclopropyl-benzamide _ 0 ii» / 84 To a stirred solution of 426 mg (2 mmol) |nt1.2 in THF (30 mL) was added 615 mg (3 mmol, 1.5 eq) [4-[(cyclopropylamino)carbonyl]phenyl]-boronic acid, 163 mg (0.2 mmol, 0.1 eq) Pd(dppf)Cl2 and 6 mL potassium carbonate solution (1M in water, 3 eq) at r.t. in a microwave reactor. The solution was heated at 150 °C for 120 min under microwave irradiation. After cooling, the solution was filtered and purified by preparative reverse phase HPLC to give 49.9 mg (8.5 %) of the title compound.
UPLC-MS: RT = 0.69 min; m/z (ES+) 294.3 [MH+]; required MW = 293.3.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena Intermediate Example |nt3.1 tert-butyl [4-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]carbamate A" 0;; H30 CH3 To a stirred solution of |nt1.2 (5.82 g) in 1-propanol (400 mL) was added 2M potassium carbonate solution (41 mL), ert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), ed through Celite and the solvent was removed in vacuum. The residue was titurated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1H), 8.78 (dd, 1H), 9.44 (s, 1H).
Intermediate Example |nt3.2 minophenyl)[1, 2,4]triazolo[1, 5-a]pyridinamine N, / NH2 To a stirred suspension of |nt3.1 (7.05 g) in DCM (210 mL) was added TFA (66 mL). The e was stirred at r.t. for 1 h. The mixture was concentrated in vacuum. A ted solution of potassium ate was added, until pH 10 was reached and the mixture was extracted for three times with DCM and methanol (10:1 ). The organic phase was dried (sodium sulfate) and the solvent Ds removed in vacuum to give 4.6 g of the title compound.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 5.26 (s, 2H), 5.95 (s, 2H), 6.64 (d, 2H), 7.29 - 7.45 (m, 3H), 7.64 (dd, 1H), 8.60 - 8.70 (m, 1H).
Intermediate e |nt3.3 N-[4-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]phenylacetamide To a d sion of |nt3.2 (1.09 g) in DMF (45 mL) was added potassium ate (3.3 g), phenylacetic acid (791 mg) and TBTU (3.1 g). The mixture was stirred at r.t. for 24 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 870 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 3.67 (s, 2H), 6.04 (s, 2H), 7.22 - 7.28 (m, 1H), 7.30 - 7.37 (m, 4H), 7.40 (dd, 1H), 7.63 - 7.72 (m, 4H), 7.74 (dd, 1H), 8.84 (dd, 1H), 10.31 (s,1H).
Intermediate Example |nt3.4 N-[4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)phenyl](4-fluorophenyl)- acetamide To a stirred solution of |nt3.2 (8.80 g) in THF (475 mL) was added Hijnig Base (7.4 mL), (4-fluorophenyl)acetic acid (6.62 g), and HATU (16.3 g). The mixture was stirred at r.t. for 16 h. Water was added and the mixture was stirred at D. for 1 h. The precipitated solid was collected by filtration, was washed with [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by na methanol and diethyl ether and was dried in vacuum to give 10.6 g of the title compound. 1H-NMR (300MHz, DMSO'dé): 6 [ppm]: 3.63 (s, 2H), 6.01 (s, 2H), 7.03 - 7.19 (m, 2H), 7.27 - 7.41 (m, 3H), 7.58 - 7.79 (m, 5H), 8.80 (dd, 1H), 10.26 (s, 1H).
Intermediate Example |nt3.5 N-[4-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]cyclopropyl- acetamide To a stirred on of |nt3.2 (3.0 g) in THF (95 mL) was added Hijnig Base (2.75 mL), ropylacetic acid (1.65 g) and HATU (6.1 g). The mixture was stirred at r.t. for 16 h. Water was added and the mixture was stirred at r.t. for minutes. The precipitated solid was collected by filtration, was washed with water and methanol and was dried in vacuum to give 3.08 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.12 - 0.21 (m, 2H), 0.39 - 0.50 (m, 2H), 0.93 - 1.15 (m, 1H), 2.19 (d, 2H), 6.00 (br. s, 2H), 7.37 (d, 1H), 7.56 - 7.78 (m, 5H), 8.80 (d, 1H), 9.88 (s, 1H). ediate Example Int3.6 N-[4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)phenyl](2,4-difluoro- phenyl)acetamide To a stirred solution of |nt3.2 (1.50 g) in DMF (135 mL) was added potassium carbonate (4.6 g), (2,4-difluorophenyl)acetic acid (2.29 g), and HATU (5.06 g).
Ge mixture was stirred at r.t. for 72 h. Water was added and the mixture was stirred at room temperature for 1 h. The precipitated solid was collected by [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na filtration, was washed with methanol and diethyl ether and was dried in vacuum. Aminophase-silica-gel chromatography followed by preparative reverse phase HPLC gave 692 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.71 (s, 2H), 6.00 (s, 2H), 7.03 (td, 1H), 7.19 (td, 1H), 7.31 - 7.50 (m, 2H), 7.57 - 7.77 (m, 5H), 8.81 (d, 1H), 10.29 (s, 1H). ng with |nt3.2, the intermediates |nt3.7 and |nt3.8 were prepared analogously to the procedures described above.
Intermediate Example |nt3.7.
N-[4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)phenyl](4-fluoro methylphenyl)acetamide N/ / HZN 0 Intermediate e |nt3.8.
N-[4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)phenyl](4-ch lorophenyl)- acetamide Intermediate Example Int4.1 3-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)benzoic acid [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na To a stirred solution of |nt1.2 (7.0 g) in 1-propanol (480 mL) was added 2M potassium carbonate on (48 mL), 3-carboxyphenyl-boronic acid (10.7 g), triphenylphosphine (177 mg) and PdCl2(PPh3)2 (2.26 g). The mixture was heated to reflux for 15h. Water (1000 mL) was added and the e was washed with ethyl acetate (1000 mL). A 4N solution of hydrochloric acid was added to the aqueous phase until pH 5 was reached. A white solid percipitated, was collected by filtration, washed with water and ethanol and dried in .
Yield: 7.3 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 6.11 (br. s., 2H), 7.45 (d, 1H), 7.56 - 7.68 (m, 1H), 7.79 (dd, 1H), 7.90 - 8.04 (m, 2H), 8.21 (s, 1H), 8.88 - 9.07 (m, 1H), 13.13 (br. s., 1H). ediate Example |nt5.1 4-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)benzoic acid To a stirred solution of |nt1.2 (10.0 g) in 1-propanol (470 mL) was added 2M potassium carbonate solution (70 mL), 4-carboxyphenylboronic acid (10.3 g), triphenylphosphine (1.23 g) and PdCl2(PPh3)2 (3.30 g). The mixture was heated to reflux for 1 h. Water (1.0 L) was added and the e was extracted with ethyl acetate (2 x 400 mL). 1N hydrochloric acid was added to the aqueous phase until pH 5 was reached. The precipitated solid was collected by filtration, was washed with water and ethanol and was dried in vacuum to give D5 g of the title compound.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H-NMR (400MHz, 6): 6 [ppm]: 6.12 (br. s., 2H), 7.42 (d, 1H), 7.76 - 7.87 (m, 3H), 7.98 (d, 2H), 8.98 (d, 1H), 12.99 (br. s., 1H).
Intermediate Example |nt5.2 mino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-(4-fluorobenzyl)benzamide A suspension of |nt5.1 (1.0 g) in DMSO (20 mL) and DMF (20 mL) was d at 50°C for 2h. At 50°C to the stirred suspension potassium carbonate (2.72 g), 1- (4-fluorophenyl)methanamine (0.66 g) and TBTU (1.77 g) was added. The mixture was stirred at 50°C for 1 h. Water (600 mL) was added and the mixture was stirred at room temperature for 20 minutes. The precipitated solid was collected by filtration, was washed with water and ethanol and hexane and was dried in vacuum to give 1.29 g of the title compound. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 4.44 (d, 2H), 6.08 (s, 2H), 7.08 - 7.16 (m, 2H), 7.34 (dd, 2H), 7.41 (dd, 1H), 7.78 - 7.86 (m, 3H), 7.97 (d, 2H), 8.91 - 8.99 (m, 1H), 9.16 (t, 1H).
Intermediate Example |nt5.3 4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-benzylbenzamide To a stirred on of |nt5.1 (4.0 g) in 1-propanol (280 mL) was added 2M Dtassium carbonate solution (28 mL), [4-(benzylcarbamoyl)phenyl]boronic [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena acid (6.2 g), triphenylphosphine (0.25 g) and PdCl2(PPh3)2 (0.66 g). The mixture was heated to reflux for 1 h. The e was concentrated in vacuum, water (100 mL) and ethyl acetate (100 mL) was added and the mixture was stirred at r.t. for 15 minutes. The precipitated solid was collected by filtration, was washed with water and ethanol and was dried in vacuum to give 6.09 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 4.47 (d, 2H), 6.08 (s, 2H), 7.16 - 7.25 (m, 1H), 7.26 - 7.33 (m, 4H), 7.41 (dd, 1H), 7.75 - 8.02 (m, 5H), 8.97 (dd, 1H), 9.10 (t, 1H). ediate Example |nt5.4 4-(2-amino[1, iazolo[1, 5-a]pyridinyl)-N-(cyclopropylmethyl)benz- amide To a stirred suspension of |nt5.1 (3.0 g) in THF (80 mL) was added Hijnig Base (2.42 mL), 1-cyclopropylmethanamine (1.03 g) and TBTU (4.55 g). The mixture was stirred at r.t. for 72 h. Water was added and the mixture was stirred at r.t. for 20 minutes. The precipitated solid was collected by filtration, was washed with water and methanol and was dried in vacuum to give 1.45 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.14 - 0.26 (m, 2H), 0.32 - 0.47 (m, 2H), 0.91 - 1.10 (m, 1H), 3.13 (t, 2H), 6.02 - 6.13 (m, 2H), 7.41 (d, 1H), 7.76 - 7.85 (m, 3H), 7.87 - 7.99 (m, 2H), 8.59 (t, 1H), 8.96 (d, 1H).
Intermediate Example |nt5.5 mino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-(cyclopentylmethyl)benz- nude [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred suspension of |nt5.1 (5.0 g) in DMF (100 mL) was added potassium carbonate (13.6 g), 1-cyclopentylmethanamine hloride (5.4 g) and HATU (12.7 g). The mixture was stirred at r.t. for 16 h. The mixture was concentrated in . Water was added and the reaction mixture was extracted with a mixture of DCM and methanol (10:1). The organic phase was dried (sodium sulfate) and the solvent was removed in . Silica gel chromatography gave a solid that was recrystallized from ethyl acetate. Yield: 3.9 g of the title nd. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.22 (dd, 2H), 1.36 - 1.74 (m, 6H), 2.03 - 2.21 (m, 1H), 3.17 (t, 2H), 6.08 (s, 2H), 7.41 (d, 1H), 7.71 - 7.96 (m, 5H), 8.51 (t, 1H), 8.96 (s, 1H).
Intermediate Example |nt5.6 4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-(2,4-difluorobenzyl)benz- amide Starting with |nt5.1 and 2,4-difluorobenzylamine, intermediate example |nt5.6 was prepared analogously to the procedure for the preparation of ediate e |nt5.5. 1H-NMR (400MHz, DMSO-dé): 6 [ppm] = 4.50 (d, 13H), 6.12 (s, 2H), 7.07 (td, 1H), 7.19 - 7.28 (m, 1H), 7.39 - 7.47 (m, 2H), 7.82 - 7.90 (m, 3H), 7.99 (d, 2H), D31 (d, 1H), 9.11 (t, 1H).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena Intermediate Example |nt5.7 mino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-(3,4-difluorobenzyl)benz- amide Starting with |nt5.1 and 3,4-difluorobenzylamine, intermediate example |nt5.7 was prepared analogously to the procedure for the preparation of ediate example |nt5.5. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 4.48 (d, 2H), 6.08 - 6.14 (m, 2H), 7.18 (ddd, 1H), 7.34 - 7.48 (m, 3H), 7.81 - 7.92 (m, 3H), 7.99 (d, 2H), 9.01 (d, 1H), 9.16 (t, 1H).
Intermediate Example |nt5.8 4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-(3-fluorobenzyl)benzamide A ,N N H2N N Starting with |nt5.1 and 3-fluorobenzylamine, intermediate example |nt5.8 was prepared analogously to the procedure for the preparation of intermediate example |nt5.5. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 4.51 (d, 6H), 6.12 (s, 2H), 7.07 (t, 1H), 7.11 - 7.22 (m, 2H), 7.33 - 7.42 (m, 1H), 7.45 (d, 1H), 7.81 - 7.92 (m, 3H), 8.03 (d, 2H), 9.01 (s, 1H), 9.29 (t, 1H).
Starting with |nt5.1 the intermediates |nt5.9 and |nt5.10 were prepared ously to the procedures described above.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate Example |nt5.9. 4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-(4-ch lorobenzyl)benzamide AN N \l H Intermediate Example |nt5.10. 4-(2-amino[1, iazolo[1, 5-a]pyridinyl)-N-(4-methylbenzyl)benzamide /I\ N N \l H Intermediate Example Int6.1 4-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)fluorobenzoic acid To a stirred solution of |nt1.2 (4.45 g) in 1-propanol (150 mL) was added 2M potassium carbonate solution (31 mL), 4-carboxyfluorophenylboronic acid (3.92 g), triphenylphosphine (0.55 g) and PPh3)2 (1.50 g). The mixture was heated to reflux for 2 h. Water (800 mL) was added and the mixture was extracted with ethyl acetate (2 x 500 mL). 1N hloric acid was added to the aqueous phase until pH 3 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 3.10 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 6.13 (s, 2H), 7.41 (d, 1H), 7.59 - 7.96 (m, D), 9.06 (s, 1H), 13.24 (br. s., 1H).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena Intermediate Example |nt6.2 4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)fluoro-N-(4-fluorobenzyl)- benzamide To a stirred suspension of |nt6.1 (1.6 g) in DMF (60 mL) was added molecular sives (4A) and the mixture was stirred for 1.5 h. To the stirred mixture was added ium carbonate (4.1 g), 1-(4-fluorophenyl)methanamine (1.14 g) and HATU (3.35 g). The mixture was stirred at r.t. for 2 h. Solids were removed by filtration. The mixture was concentrated in vacuum. Water was added and the reaction e was extracted with a e of DCM and methanol (10:1). The organic phase was washed with a saturated solution of sodium bicarbonate, dried (sodium sulfate) and the solvent was removed in vacuum. ation of the residue with warm ethanol gave 0.55 g of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 4.43 (d, 2H), 6.11 (s, 2H), 7.10 - 7.18 (m, 2H), 7.32 - 7.38 (m, 2H), 7.41 (dd, 1H), 7.64 - 7.78 (m, 3H), 7.83 (dd, 1H), 8.84 - 8.91 (m, 1H), 9.03 (d, 1H). ediate Example |nt7.1 4-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)methylbenzoic acid [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena To a stirred solution of |nt1.2 (1.45 g) in 1-propanol (65 mL) was added 2M ium carbonate solution (10 mL), 4-carboxymethylphenylboronic acid (1.22 g), triphenylphosphine (0.17 g) and PdCl2(PPh3)2 (0.35 g). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 1N hydrochloric acid was added to the aqueous phase until pH 5 was d. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 0.8 g of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 2.57 (s, 3H), 6.37 (br. s., 2H), 7.52 (d, 1H), 7.65 (dd, 1H), 7.70 (s, 1H), 7.89 (d, 1H), 7.95 (dd, 1H), 9.06 (d, 1H), 12.87 (br. s., 1H).
Intermediate Example |nt7.2 4-(2-amino[1, iazolo[1, 5-a]pyridinyl)-N-(4-fluorobenzyl)methyl- benzamide To a stirred suspension of |nt7.1 (0.425 g) in DMF (12 mL) was added potassium carbonate (1.1 g), 1-(4-fluorophenyl)methanamine (0.31 g) and HATU (1.21 g).
The mixture was stirred at r.t. for 60 h. A saturated on of sodium bicarbonate was added, the mixture was stirred at r.t. for 20 minutes and the mixture was ted with ethyl acetate. The organic phase was dried (sodium e) and the solvent was removed in vacuum. Trituration of the residue with warm ethanol gave 0.58 g of the title compound.
[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 2.37 (s, 3H), 4.39 (d, 2H), 6.05 (s, 2H), 7.14 (t, 2H), 7.28 - 7.46 (m, 4H), 7.50 - 7.66 (m, 2H), 7.76 (d, 1H), 8.74 - 8.99 (m, 2H).
Starting with |nt7.1 the intermediate |nt7.3 was prepared analogously to the procedures bed above.
Intermediate Example |nt7.3. 4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-(2,4-difluorobenzyl) methylbenzamide Intermediate Example |nt8.1 4-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)chlorobenzoic acid To a stirred solution of |nt1.2 (2.0 g) in 1-propanol (100 mL) was added 2M potassium carbonate solution (15 mL), oxychlorophenylboronic acid (1.92 g), nylphosphine (0.25 g) and PdCl2(PPh3)2 (0.66 g). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 1N hydrochloric acid was added to the aqueous phase until pH 5 was reached. The precipitated solid was collected by filtration, was washed with water, l and ether and was Ded in vacuum to give 1.6 g of the title compound.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 6.13 (br. s., 2H), 7.41 (d, 1H), 7.73 - 7.88 (m, 3H), 7.92 (d, 1H), 9.04 (d, 1H), 13.37 (br. s., 1H).
Intermediate Example |nt8.2 4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)ch loro-N-(4-fluorobenzyl)- benzamide 2),- To a stirred suspension of |nt8.1 (0.425 g) in DMF (12 mL) was added potassium carbonate (1.1 g), 1-(4-fluorophenyl)methanamine (0.38 g) and HATU (1.40 g).
The mixture was d at r.t. for 24 h. Further 1-(4- fluorophenyl)methanamine (95 mg) and HATU (280 g) was added and the mixture was stirred at r.t. for 16 h. Solids were removed by filtration. A half- saturated on of sodium bicarbonate was added, the mixture was stirred at r.t. for 20 minutes and the mixture was extracted with a mixture of DCM and methanol (10:1). The organic phase was dried (sodium sulfate) and the t was removed in vacuum. Trituration of the residue with warm l gave 0.38 g of the title nd. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 4.42 (d, 2H), 6.10 (br. s, 2H), 7.09 - 7.20 (m, 2H), 7.33 - 7.43 (m, 3H), 7.50 (d, 1H), 7.77 (ddd, 2H), 7.89 (d, 1H), 8.94 - 9.06 (m, 2H). ediate Example |nt9.1 4-(2-amino[1,2,4]triazolo[1,5-a]pyridinyl)methoxybenzoic acid [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena To a stirred solution of |nt1.2 (0.52 g) in anol (24 m) was added 2M ium carbonate solution (3.6 mL), 4-carboxymethoxyphenylboronic acid (0.48 g), triphenylphosphine (63 mg) and PdCl2(PPh3)2 (170 mg). The e was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 2N hloric acid was added to the aqueous phase until pH 4 was d. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 466 mg of the title compound. 1H-NMR (300MHz, DMSO-dé, detected signals): 6 [ppm]: 3.98 (s, 3H), 4.46 (d, 2H), 6.08 (s, 2H), 7.07 - 7.18 (m, 2H), 7.29 - 7.47 (m, 5H), 7.75 - 7.88 (m, 2H), 8.72 (t, 1H), 9.03 (dd, 1H).
Intermediate Example |nt9.2 4-(2-amino[1, 2,4]triazolo[1, 5-a]pyridinyl)-N-(4-fluorobenzyl) methoxybenzamide To a stirred suspension of |nt9.1 (0.30 g) in DMF (8.5 mL) was added potassium carbonate (0.73 g), 1-(4-fluorophenyl)methanamine (0.20 g) and HATU (0.80 g).
The mixture was stirred at r.t. for 16 h. Solids were removed by filtration. The solvent was removed in vaccuum. Dichloromethane and methanol (10:1) and a half-saturated solution of sodium bicarbonate was added and the mixture was d at r.t. for 20 minutes. The mixture was extracted with a mixture of DCM and methanol (10:1). The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. ation of the residue with warm ethanol gave 0.36 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.98 (s, 3H), 4.46 (d, 2H), 6.08 (s, 2H), D7 - 7.18 (m, 2H), 7.29 - 7.47 (m, 5H), 7.75 - 7.88 (m, 2H), 8.72 (t, 1H), 9.03 (dd, 1H).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate Example |nt10.1 methyl 4-bromomethoxybenzoate To a stirred solution of methyl 4-bromohydroxybenzoate (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at r.t. for 2 h. Ethyl acetate was added and the mixture was washed with water. The c phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1H), 7.47 (d, 1H), 7.67 (d, 1H).
Intermediate Example |nt10.2 4-bromomethoxybenzoic acid 0 OH To a stirred solution of methyl 4-bromomethoxybenzoate (11.2 g) in THF (130 mL), ol (45 mL) and water (45 mL) was added a 1M on of lithium hydroxide in water (140 mL). The e was stirred at r.t. for 1 h.
The solvent was removed in vacuum. Water was added and 1N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by tion, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further cation.
DNMR (300MHz, DMSO-dé): 5 [ppm]: 3.87 (s, 3H), 7.42 (dd, 1H), 7.50 (d, 1H), 7.68 (d, 1H), 13.21 (br.s.,1H).
[Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ediate Example |nt10.3 4-bromo-N-(2-hydroxyethyl)methoxybenzamide O "N To a d sion of 4-bromomethoxybenzoic acid (1.65 g) in DCM (50 mL) was added DMF (0.5 mL) and oxalyl choride (0.98 g). The mixture was d at r.t. for 1 h. The solvent was removed in vacuum, and the e was dissolved in THF (40 mL). Hijnig Base (3.7 mL) and 2-aminoethanol (0.65 g) was added and the mixture was stirred at r.t. for 1 h. The solvent was removed in vacuum, a mixture of ethyl acetate and methanol (100:1) was added and the mixture was washed with a half-saturated solution of ammonium chloride. The organic phase was washed with saturated sodium chloride solution, dried (sodium e) and the solvent was removed in vacuum. Silica gel chromatography gave 1.87 g of the title compound. 1H-NMR (300MHz, CHLOROFORM-d): 6 [ppm]: 2.75 (br. s., 1H), 3.56 - 3.67 (m, 2H), 3.75 - 3.89 (m, 2H), 3.93 (s, 3H), 6.74 (br. s., 1H), 7.12 (dd, 1H), 7.40 (d, 1H), 7.55 (d, 1H).
Intermediate Example |nt10.4 4-bromo-N-(2-hydroxymethylpropyl)methoxybenzamide To a stirred suspension of 4-bromomethoxybenzoic acid (1.5 g) in DCM (30 mL) was added DMF (0.5 mL) and oxalyl choride (1.05 g). The mixture was 'rred at r.t. for 1 h. The solvent was removed in vacuum, and the residue was dissolved in DCM (40 mL). 1-Aminomethylpropanol (1.7 g) was added and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena the mixture was stirred for 3 h at r.t.. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with ted sodium chloride solution, dried (sodium e) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1.45 g of the title compound. 1H-NMR z, DMSO-dé): 6 [ppm]: 1.06 (s, 6H), 3.17 - 3.24 (m, 2H), 3.88 (s, 3H), 4.52 (s, 1H), 7.36 (dd, 1H), 7.50 (d, 1H), 7.63 (d, 1H), 8.34 (t, 1H).
Intermediate Example |nt10.5 4-bromo-N-(1-hydroxymethylpropanyl)methoxybenzamide H30 CH3 0 N To a d solution of 4-bromomethoxybenzoic acid (1.7 g) in DCM (22 mL) and DMF (1.0 mL) was added oxalyl chloride (1.19 g) at 0°C. The mixture was stirred at r.t. for 0.5 h. The solvent was removed in vacuum. The e was dissolved in DCM (30 mL) and 2-aminomethylpropanol (1.93 g) were added. The mixture was stirred at r.t. for 3 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum.
Aminophase-silica-gel chromatography gave 1.90 g of the title compound. 1H-NMR z, DMSO-dé): 6 [ppm]: 1.27 (s, 6H), 3.48 (d, 2H), 3.87 (s, 3H), 4.85 (t, 1H), 7.30 (dd, 1H), 7.40 (d, 1H), 7.57 - 7.62 (m, 2H).
Intermediate Example |nt10.6 DJromo-N-(2-ethoxyethyl)methoxybenzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred sion of 4-bromomethoxybenzoic acid (1.55 g) in DCM (40 mL) was added DMF (0.5 mL) and oxalyl choride (0.92 g). The mixture was stirred at r.t. for 1 h. The solvent was removed in , and the residue was dissolved in THF (40 mL). Hijnig Base (3.4 mL) and 2-ethoxyethanamine (0.89 g) was added and the mixture was d at r.t. for 1 h. The solvent was removed in vacuum, ethyl acetate was added and the mixture was washed with a half- saturated solution of ammonium chloride. The organic phase was washed with ted sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Recrystallization of the residue from diisopropyl ether and cyclohexane gave 1.8 g of the title compound. 1H-NMR (400MHz, CHLOROFORM-d): 6 [ppm]: 1.22 (t, 3H), 3.54 (q, 2H), 3.58 - 3.68 (m, 4H), 3.95 (s, 3H), 6.53 (br. s., 1H), 7.12 (dd, 1H), 7.43 (d, 1H), 7.58 (d, 1H). ediate Example |nt10.7 4-bromomethoxy-N-methyl-N-[2-(methylamino)ethyl]benzamide To a d suspension of 4-bromomethoxybenzoic acid (2.0 g) in DCM (150 mL) was added DMF (0.5 mL) and oxalyl choride (1.4 g). The mixture was stirred at r.t. for 1 h. The solvent was removed in vacuum, and the residue was dissolved in DCM (40 mL). This mixture was slowly added to a solution of N,N'— Unethylethane-1,2-diamine (2.24 g) in DCM (40 mL) at 0°C and the mixture was stirred at r.t. for 1 h. 4N aqueous hydrochloric acid was added (100 mL) [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena and the mixture was washed with DCM. Aqueous sodium hydroxide solution was added to the aqueous phase until pH8 was reached and the e was extracted with DCM. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.25 g of the title compound. 1H-NMR (500MHz, DMSO-dé): 6 [ppm]: 2.28 (br. s., 3H), 2.69 (br. s., 2H), 2.96 (s, 3H), 3.05 (br. s., 1H), 3.39 (br. s., 2H), 3.90 (s, 3H), 6.91 (dd, 1H), 7.12 (d, 1H), 7.61 (d, 1H).
Intermediate e |nt10.8 N-{2-[acetyl(methyl)amino]ethyl}bromomethoxy-N-methylbenzamide CH, 0 To a stirred solution of |nt10.7 (720 mg) in DCM (15 mL) was added pyridine (580 uL) and acetyl chloride (340 uL). The e was stirred at r.t. for 1 h.
Ethyl acetate was added and the e was washed with a half-saturated solution of um chloride. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.94 g of the title nd. 1H-NMR (500MHz, DMSO-dé, 80°C, selected signals): 6 [ppm]: 3.90 (s, 3H), 6.87 (dd, 1H), 7.07 (br. s., 1H), 7.62 (d, 1H).
Intermediate Example |nt10.9 tert-butyl {2-[(4-bromomethoxybenzoyl)(methyl)amino]ethyl}methyl- carbamate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ‘1‘ H3 0 :NTWS.
To a stirred on of |nt10.7 (890 mg) in DCM (35 mL) was added Hijnig Base (1.5 mL) and di-tert-butyl dicarbonate (775 mg). The mixture was stirred at r.t. for 16 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The c phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.0 g of the title compound. 1H-NMR (500MHz, DMSO-dé, 80°C): 6 [ppm]: 1.37 (s, 9H), 2.70 (br. s., 3H), 2.95 (s, 3H), 3.35 (br. s., 2H), 3.48 (br. s., 2H), 3.88 (s, 3H), 6.85 (dd, 1H), 7.02 (s, 1H), 7.59 (d, 1H).
Intermediate Example |nt10.10 omethoxy(methylsu lfanyl)benzene CH3 To a stirred solution of 1-bromofluoromethoxybenzene (4.0 g) in DMF (40 mL) was added sodium methanethiolate (2.76 g). The mixture was stirred at r.t. for 30 minutes and at 85°C for 2 h. Water was added and the e was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried m sulfate) and the t was removed in vacuum. Silica gel chromatography gave 280 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 2.46 (s, 3H), 3.82 (s, 3H), 6.74 (dd, 1H), 6.91 (d, 1H), 7.44 (d, 1H).
;-Lromomethoxy(methylsulfanyl)benzene ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena To a stirred solution of 1-bromofluoromethoxybenzene (10.0 g) in DMF (100 mL) was added sodium methanethiolate (4.44 g). The mixture was stirred at 65°C for 2 h. The mixture was cooled to 0°C and methyl iodide (4.55 mL) was added. The mixture was stirred at r.t. for 1 h and r sodium methanethiolate (4.44 g) was added. The mixture was stirred at 65°C for 1 h.
The mixture was cooled to 0°C and methyl iodide (4.55 mL) was added. The mixture was stirred at r.t. for 1 h. Water was added and the e was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 6.2 g of the title compound as a 2:1 mixture with the starting material. The e was used for the next step without purification.
Intermediate Example |nt10.11 1-bromomethoxy(methylsu lfonyl)benzene To a stirred solution of |nt10.10 (265 mg) in chloroform (10 mL) was added 3- chlorobenzenecarboperoxoic acid (mCPBA) (890 mg). The mixture was stirred at r.t. for 1 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with DCM. The c phase was washed with saturated sodium chloride solution, dried m e) and the solvent was removed in vacuum. Silica gel chromatography gave 252 mg of the title compound.
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.22 (s, 3H), 3.93 (s, 3H), 7.39 (dd, 1H), 7.50 (d, 1H), 7.84 (d, 1H).
Intermediate Example 12 4-bromomethoxy-N-(2,2,2-trifluoroethyl)benzamide To a stirred suspension of 4-bromomethoxybenzoic acid (2.0 g) in THF (100 mL) was added 2,2,2-trifluoroethylamine (1.26 g), HATU (3,87 g), and DIEA (1.7 mL). The mixture was stirred at r.t. for 12 h. Water (350 mL) and saturated sodium bicarbonate solution (350 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.57 g of the title compound. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 3.92 (s, 3H), 4.11 (qd, 2H), 7.43 (dd, 1H), 7.56 (d, 1H), 7.72 (d, 1H), 9.19 (t, 1H).
Intermediate Example |nt10.13 4-bromomethoxy-N-[2-(methylsulfonyl)ethyl]benzamide 0 o \\ l/ u/VS\CH.
To a stirred suspension of omethoxybenzoic acid (1.0 g) in THF (50 mL) was added 2-(methylsulfonyl)ethanamine hydrochloride (1.09 g), HATU (1.97 g), and DIEA (0.89 mL). The mixture was stirred at r.t. for 12 h. Water fio mL) and saturated sodium bicarbonate solution (350 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by na [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena acetate. The combined organic ts were dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 809 mg of the title compound. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 3.04 (s, 3H), 3.38 (t, 2H), 3.63 - 3.72 (m, 2H), 3.90 (s, 3H), 7.36 (dd, 1H), 7.51 (d, 1H), 7.69 (d, 1H), 8.84 (t, 1H).
Intermediate Example |nt11.1 methyl 4-bromoethoxybenzoate To a stirred solution of methyl 4-bromohydroxybenzoate (6.4 g) in DMF (35 mL) was added potassium carbonate (11.5 g and iodoethane (6.48 mg). The e was stirred at r.t. for 16 h. The solvent was removed in vacuum, ethyl acetate was added and the mixture was washed with water. The organic phase was washed with ted sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Trituration of the residue with warm l gave 5.7 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.34 (t, 3H), 3.82 (s, 3H), 4.14 (q, 2H), 7.42 (dd, 1H), 7.48 (d, 1H), 7.70 (d, 1H).
Intermediate Example |nt11.2 4-bromoethoxybenzoic acid H30 0 O OH To a stirred solution of methyl oethoxybenzoate (17.3 g) in THF (180 mL), methanol (60 mL) and water (60 mL) was added a 1M solution of lithium Ddroxide in water (200 mL). The mixture was stirred at r.t. for 1 h. Water was added and 1N hydrochloric acid was added until pH 4 was reached. The [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena itated solid was collected by filtration, was washed with water. The solid was dissolved in DCM and methanol (10:1 ). The solution was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Trituration of the residue with ether gave 15.4 g of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.34 (t, 3H), 4.13 (q, 2H), 7.40 (dd, 1H), 7.48 (d, 1H), 7.67 (d, 1H), 13.17 (br. s., 1H).
Intermediate Example |nt11.3 4-bromo-N-tert-butylethoxybenzamide To a stirred suspension of oethoxybenzoic acid (2.5 g) in DCM (25 mL) was added DMF (0.8 mL) and oxalyl choride (1.42 g). The mixture was d at r.t. for 1 h. The solvent was removed in , and the residue was dissolved in THF (50 mL). Hijnig Base (5.3 mL) and 2-methylpropanamine (1.13 g) was added and the mixture was d at r.t. for 1 h. The solvent was removed in vacuum, a mixture of DCM and methanol ) was added and the mixture was washed with a half-saturated solution of ammonium chloride. The c phase was washed with a half-saturated solution of sodium bicarbonate, dried (sodium sulfate) and the solvent was removed in vacuum. Recrystallization of the residue from isopropanol gave 2.4 g of the title compound. 1H-NMR (300MHz, CHLOROFORM-d): 6 [ppm]: 1.38 - 1.54 (m, 12H), 4.15 (q, 2H), 5.94 (br. s., 1H), 7.01 (dd, 1H), 7.37 (d, 1H), 7.52 (d, 1H).
Intermediate Example |nt11.4 u:romoethoxy-N-ethylbenzamide 101,3 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na H3CVO o N/\CH3 To a stirred suspension of 4-bromoethoxybenzoic acid (3.0 g) in DCM (35 mL) was added DMF (0.1 mL) and oxalyl choride (2.0 g). The mixture was stirred at r.t. for 1 h. The solvent was d in vacuum, and the residue was dissolved in DCM (30 mL). Ethanamine (1.6 g) was added and the mixture was d at r.t. for 3 h. Ethyl acetate was added and the mixture was washed with a half- saturated solution of sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was d in vacuum. Silica gel chromatography gave 2.7 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.08 (t, 3H), 1.34 (t, 3H), 3.17 - 3.29 (m, 2H), 4.13 (q, 2H), 7.32 (dd, 1H), 7.45 (d, 1H), 7.62 (d, 1H), 8.51 (t, 1H).
Intermediate Example |nt11.5 4-bromoethoxy-N-(2-hydroxyethyl)benzamide H3CVO 0 MN To a stirred suspension of 4-bromoethoxybenzoic acid (1.65 g) in DCM (50 mL) was added DMF (0.5 mL) and oxalyl choride (1.45 g). The mixture was stirred at r.t. for 1 h. The t was removed in vacuum, and the residue was dissolved in THF (50 mL). Hijnig Base (3.5 mL) and 2-aminoethanol (0.62 g) was added and the mixture was stirred at r.t. for 16 h. The solvent was removed in , ethyl acetate was added and the mixture was washed with a half- ted solution of sodium bicarbonate and with a saturated solution of ammonium chloride. The organic phase was dried m sulfate) and the [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena solvent was removed in vacuum. Silica gel chromatography gave 1.3 g of the title nd. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.34 (t, 3H), 3.20 - 3.33 (m, 2H), 3.40 - 3.53 (m, 2H), 4.13 (q, 2H), 4.71 (t, 1H), 7.33 (dd, 1H), 7.48 (d, 1H), 7.62 (d, 1H), 8.50 (t, 1H).
Intermediate Example |nt11.6 4-bromoethoxy-N-(2-hydroxymethylpropyl)benzamide To a d suspension of 4-bromoethoxybenzoic acid (1.8 g) in DCM (25 mL) was added DMF (0.1 mL) and oxalyl choride (1.19 g). The mixture was stirred at r.t. for 1 h. The solvent was removed in vacuum, and the residue was dissolved in DCM (25 mL). 1-Aminomethylpropanol (1.93 g) was added and the mixture was stirred at r.t. for 3 h. Ethyl acetate was added and the e was washed with a half-saturated solution of sodium onate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel tography gave 1.8 g of the title compound. 1H-NMR (300MHz, é): 6 [ppm]: 1.06 (s, 6H), 1.34 (t, 3H), 3.21 (d, 2H), 4.14 (q, 2H), 4.51 (s, 1H), 7.35 (dd, 1H), 7.48 (d, 1H), 7.62 (d, 1H), 8.32 (t, 1H).
Intermediate Example |nt11.7 4-bromoethoxy-N-(1-hydroxymethylpropanyl)benzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a d suspension of 4-bromoethoxybenzoic acid (1.7 g) in DCM (50 mL) was added DMF (0.5 mL) and oxalyl choride (1 .50g). The e was stirred at r.t. for 1 h. The solvent was removed in , and the residue was dissolved in THF (50 mL). Hijnig Base (3.6 mL) and 2-Aminomethylpropanol (0.98 g) was added and the mixture was stirred at r.t. for 16 h. The solvent was removed in vacuum, ethyl acetate and methanol ) were added and the mixture was washed with a half-saturated solution of sodium bicarbonate and with a saturated solution of ammonium chloride. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.66 g of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.27 (s, 6H), 1.34 (t, 3H), 3.44 - 3.51 (m, 2H), 4.13 (q, 2H), 4.84 (t, 1H), 7.29 (dd, 1H), 7.39 (d, 1H), 7.57 (br. s, 1H), 7.59 (d, 1H).
Intermediate Example |nt11.8 4-Bromoethoxy-N,N-diethylbenzamide To a stirred solution of 4-bromoethoxybenzoic acid (1.0 g) in THF (50 mL) was added Hiinig Base (0.82 mL), diethylamine (0.50 mL) and HATU (1.83 g).
The mixture was d at r.t. for 16 h. A mixture of ethyl acetate and hexane (3:1) was added and the mixture was washed with a half-saturated solution of sodium bicarbonate and with a saturated solution of um chloride. The organic phase was washed with saturated sodium chloride on, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 850 mg of the title nd. filo1 -NMR (300MHz, CHLOROFORM-d): 6 [ppm]: 0.98 - 1.34 (m, 6H), 1.47 (t, 3H), - 3.67 (m, 4H), 4.11 (q, 2H), 6.80 (dd, 1H), 6.89 (d, 1H), 7.54 (d, 1H).
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate Example |nt11.9 4-bromoethoxy-N-ethyl-N-(2-methoxyethyl)benzamide To a stirred solution of 4-bromoethoxybenzoic acid (0.83 g) in THF (25 mL) was added Hijnig Base (0.68 mL), 2-ethoxy-N-ethylethanamine (0.50 mL) and HATU (1.51 g). The mixture was stirred at r.t. for 16 h. Ethyl acetate was added and the mixture was washed with a half-saturated solution of sodium bicarbonate and with a saturated solution of ammonium de. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 870 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.90 - 1.15 (m, 3H), 1.31 (t, 3H), 3.09 - 3.59 (m, 9H), 4.09 (q, 2H), 6.80 (d, 1H), 7.02 (br. d, 1H), 7.57 (d, 1H).
Intermediate Example 10 4-bromoethoxy-N-(2-hydroxyethyl)-N-methylbenzamide To a stirred suspension of 4-bromoethoxybenzoic acid (1.5 g) in DCM (45 mL) was added DMF (0.1 mL) and oxalyl choride (1.01 g). The mixture was d at r.t. for 1 h. The solvent was d in vacuum, and the residue was dissolved in DCM (25 mL). 2-(methylamino)ethanol (1.38 g) was added and the mixture "5 d at r.t. for 2 h. Ethyl acetate was added and the mixture was [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena washed with a half-saturated on of sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution, dried m sulfate) and the solvent was removed in vacuum. Silica gel chromatography followed by aminophase-silica-gel chromatography gave 1.3 g of the title compound. 1H- NMR (400MHz, DMSO--d:6) 6 [ppm]: 1. 32 (t, 3H), 2.82 - 2.98 (m, 3H), 3.15 - 3.63 (m, 4H), 4.02 - 4.14 (m, 2H), 4.71 - 4.84 (m, 1H), 6.85 (dd, 1H), 6.98 - 7.13 (m, 1H), 7.51 - 7.63 (m, 1H). ediate Example |nt11.11 4-bromo-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)ethoxy-N-methyl- benzamide Hzch O NH/:| O\Sj<:H: To a stirred solution of |nt10.10 (1.3 g) in THF (15 mL) was added Hijnig Base (0.88 mL), imidazole (30 mg) and tert-butyl(chloro)dimethylsilane (0.78 g).
The e was stirred at r.t. for 16 h. Water was added and the mixture extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried m sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.45 g of the title compound. 1H- NMR (300MHz, DMSO--d:6) 6 [ppm]: -0.13- 0. 11 (m, 6H), 0.81 (d, 9H), 1.31 (t, 3H), 2.92 (br. s., 3H), 3.29 - 3.82 (m, 4H), 4.08 (q, 2H), 6.75 - 6.90 (m, 1H), 7.00 (d, 1H), 7.48 - 7.66 (m, 1H).
Intermediate Example |nt11.12 4-bromoethoxy-N-[2-(methylsulfonyl)ethyl]benzamide [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena H3CVO o o \\ // o N/\/ \CH To a stirred suspension of oethoxybenzoic acid (1.1 g) in THF (53 mL) was added 2-(methylsulfonyl)ethanamine hydrochloride (1.13 g), HATU (2.05 g), and DIEA (0.92 mL). The mixture was stirred at r.t. for 12 h. Water (350 mL) and saturated sodium bicarbonate solution (350 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 808 mg of the title compound. 1H-NMR (400 MHz, é): 6 [ppm] = 1.38 (t, 3H), 3.03 (s, 3H), 3.38 (t, 2H), 3.61 - 3.71 (m, 2H), 4.16 (q, 2H), 7.35 (dd, 1H), 7.49 (d, 1H), 7.69 (d, 1H), 8.82 (t, 1H).
Intermediate Example |nt11.13 1-bromoethoxyfluorobenzene H3CVO. : To a stirred solution of 2-bromofluorophenol (5.0 g) in DMF (30 mL) was added potassium ate (10.8 g) and iodoethane (6.12 g). The mixture was stirred at r.t. for 16 h. The t was removed in vaccuum. Water was added and the mixture was extracted with a mixture of ethyl acetate and hexane (3:1 ). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 5.06 g of th title compound as a crude product, that was used for the next step without purification.
DNMR (400MHz, DMSO-dé): 6 [ppm]: 1.31 (t, 3H), 4.08 (q, 2H), 6.71 (td, 1H), 7.00 (dd, 1H), 7.55 (dd, 1H).
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate Example |nt11.14 1-bromoethoxy(methylsu lfanyl)benzene To a stirred solution of oethoxyfluorobenzene (2.0 g) in DMF (20 mL) was added sodium methanethiolate (1.66 g). The e was stirred for 2 h at 65°C. The mixture was cooled to r.t. and ethyl iodide (1.3 mL) was added.
The mixture was stirred at r.t. for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium de solution, dried (sodium sulfate) and the t was removed in vacuum. Silica gel chromatography gave 1.65 g of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.24 - 1.36 (m, 3H), 2.45 (s, 3H), 4.08 (q, 2H), 6.73 (dd, 1H), 6.89 (d, 1H), 7.43 (d, 1H).
Intermediate Example |nt11.15 1-bromoethoxy(methylsu lfanyl)benzene H3CVO© o=?=o To a stirred solution of |nt11.14 (1.65 g) in chloroform (65 mL) was added 3- chlorobenzenecarboperoxoic acid (mCPBA) (4.49 g). The mixture was stirred at r.t. for 16 h. With ice bath cooling, a half-saturated solution of sodium bicarbonate and and a 0.2M on of sodium thiosulfate was added, the mixture was stirred for 30 minutes and the mixture was extracted with DCM.
The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel aromatography gave 1.35 g of the title compound.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena 1H- NMR (300MHz DMSO--d.,): 5 [ppm]=1. 35 (t, 3H), 3.22 (s, 3H), 4.20 (q, 2H), 7.37 (dd, 1H), 7.48 (d, 1H), 7.84 (d, 1H).
Intermediate Example |nt11.16 1-bromoethoxy(ethylsu lfanyl)benzene 8 CH To a d solution of 1-bromofluoroethoxybenzene (2.0 g) in DMF (19 mL) was added sodium ethanethiolate (1.66 g). The mixture was stirred at 65°C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium e) and the solvent was removed in vacuum. Silica gel chromatography gave 2.02 g of the title compound. 1H- NMR (300MHz, DMSO--d:6) 6 [ppm]=1. 20 (t, 3H), 1.30 (t, 3H), 2.96 (q, 2H), 4.08 (q, 2H), 6.77 (dd, 1H), 6.92 (d, 1H), 7.44 (d, 1H).
Intermediate Example 17 1-bromoethoxy(ethylsu lfanyl)benzene O=|SO|—\CH3 To a stirred solution of 16 (2.0 g) in chloroform (75 mL) was added 3- chlorobenzenecarboperoxoic acid ) (5.15 g). The e was stirred at r.t. for 2 h. With ice bath cooling, a half-saturated solution of sodium bicarbonate and and a 0.2M solution of sodium thiosulfate was added, the mixture was stirred for 30 minutes and the mixture was extracted with DCM.
The organic phase was washed with saturated sodium chloride solution, dried [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena (sodium e) and the solvent was removed in vacuum. Silica gel chromatography gave 1.71 g of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.07 (t, 3H), 1.35 (t, 3H), 3.31 (q, 2H), 4.20 (q, 2H), 7.33 (dd, 1H), 7.41 (d, 1H), 7.85 (d, 1H).
Intermediate Example |nt12.1 methyl 4-bromo(2,2,2-trifluoroethoxy)benzoate F Br O 0’ To a stirred solution of methyl 4-bromohydroxybenzoate (2.5 g) in acetonitrile (0.5 mL) and DMF (10 mL) in a microwave tube was added potassium carbonate (2.93 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.79 g). The mixture was heated to 150°C in a microwave oven for minutes. The solvent was removed in vacuum, ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride on, dried (sodium sulfate) and the solvent was removed in vacuum. Recrystallization of the residue from l gave 1.2 g of the title compound. The mother liquor was concentrated in vacuum and purified by hase-silica-gel chromatography followed by recrystallized from methanol and water to give further 0.64 g of the title compound. 1H-NMR (300MHz, FORM-d): 6 [ppm]: 3.93 (s, 3H), 4.47 (q, 2H), 7.56 (d, 1H), 7.58 - 7.70 (m, 2H). ediate Example |nt12.2 4-bromo(2,2,2-trifluoroethoxy)benzoic acid F Br D O OH [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred solution of 1 (1.83 g) in THF (30 mL), methanol (10 mL) and water (10 mL) was added a 1M on of lithium hydroxide in water (18 mL).
The mixture was stirred at r.t. for 1 h. Water was added and 2N hydrochloric acid was added until pH 4 was reached. The precipitated solid was collected by tion, was washed with water. The solid was suspended with toluene and concentrated in vacuum. Trituration of the residue with hexane gave 1.6 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 4.95 (q, 2H), 7.51 (dd, 1H), 7.65 (d, 1H), 7.74 (d, 1H), 13.29 (br. s., 1H).
Intermediate e |nt12.3 4-bromo-N-(2-hydroxyethyl)(2,2,2-trifluoroethoxy)benzamide F Br 0 MN To a stirred suspension of |nt12.2 (1.53 g) in DCM (35 mL) was added DMF (0.4 mL) and oxalyl choride (0.97 g). The mixture was stirred at r.t. for 1 h. The solvent was removed in vacuum, and the residue was dissolved in THF (25 mL).
Hijnig Base (2.7 mL) and 2-aminoethanol (0.47 g) was added and the mixture was stirred at r.t. for 16 h. The solvent was removed in vacuum, ethyl e was added and the mixture was washed with a half-saturated solution of sodium bicarbonate and with a saturated solution of ammonium chloride. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel tography gave 1.50 g of the title compound. 1H-NMR z, DMSO-dé): 6 [ppm]: 3.24 - 3.35 (m, 2H), 3.42 - 3.52 (m, 2H), 4.73 (t, 1H), 4.89 (q, 2H), 7.44 (dd, 1H), 7.62 (d, 1H), 7.70 (d, 1H), 8.50 (t, 1H).
Dermediate Example |nt12.4 o(2, 2, 2-trifluoroethoxy)-N-(2, 2, 2-trifluoroethyl)benzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena To a stirred suspension of 4-bromo(2,2,2-trifluoroethoxy)benzoic acid (2.0 g) in THF (100 mL) was added 2,2,2-trifluoroethylamine (0.99 g), HATU (3.05 g), and DIEA (1.03 mL). The mixture was stirred at r.t. for 12 h. Water (350 mL) and saturated sodium bicarbonate solution (350 mL) were added. The organic phase was separated and the s phase was extracted with ethyl acetate.
The combined organic extracts were dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.42 g of the title compound as colourless solid. 1H-NMR (400MHz, DMSO-dé): 6 [ppm] = 4.13 (qd, 2H), 4.95 (q, 2H), 7.52 (dd, 1H), 7.69 (d, 1H), 7.79 (d, 1H), 9.17 (t, 1H).
Intermediate e |nt12.5 4-bromo-N-(1-hydroxymethylpropanyl)(2, 2, 2-trifluoroethoxy)benz- amide H30 CH3 X/OH O N To a stirred suspension of 4-bromo(2,2,2-trifluoroethoxy)benzoic acid (1.8 g) in THF (70 mL) was added 1-aminomethylpropanol (0.85 g), HATU (2.75 g), and DIEA (1.23 mL). The mixture was stirred at r.t. for 12 h. Water (350 mL) and saturated sodium bicarbonate solution (350 mL) were added. The organic phase was separated and the s phase was extracted with ethyl acetate. The combined c extracts were dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.97 g of the ale compound.
[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena 1H-NMR (400MHz, é): 6 [ppm] = 1.31 (s, 6H), 3.52 (d, 2H), 4.88 (t, 1H), 4.94 (q, 2H), 7.43 (dd, 1H), 7.57 (d, 1H), 7.61 (s, 1H), 7.70 (d, 1H).
Intermediate Example |nt12.6 4-bromo-N-(2-hydroxymethylpropyl)(2,2,2-trifluoroethoxy)benzamide F Br 0 "W H30 CH.
To a stirred suspension of 4-bromo(2,2,2-trifluoroethoxy)benzoic acid (1.8 g) in THF (70 mL) was added 2-aminomethylpropanol (0.85 g), HATU (2.75 g), and DIEA (1.23 mL). The mixture was stirred at r.t. for 12 h. Water (350 mL) and saturated sodium bicarbonate solution (350 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.2 g of the title compound. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.10 (s, 6H), 3.26 (d, 2H), 4.56 (s, 1H), 4.95 (q, 2H), 7.49 (dd, 1H), 7.67 (d, 1H), 7.73 (d, 1H), 8.36 (t, 1H).
Intermediate Example |nt12.7 1-bromofluoro(2, 2, 2-trifluoroethoxy)benzene F Br FF>\\,. :O F To a stirred solution of 2-bromofluorophenol (1.5 g) in acetonitrile (0.5 mL) and DMF (8.5 mL) in a microwave tube was added potassium carbonate (2.1 g) and trifluoroethyl oromethanesulfonate (2.37 g). The mixture was heated to 150°C in a microwave oven for 30 s. In a second microwave me the same reaction was repeated. Both mixtures were combined. The [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena solvent was removed in vacuum, ethyl acetate and hexane (1:1) was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 4.0 g of the title compound. 1H-NMR (300MHz, FORM-d): 5 [ppm]: 4.39 (q, 2H), 6.62 - 6.78 (m, 2H), 7.53 (dd, 1H).
Intermediate Example |nt12.8 1-bromo(methylsu lfanyl)(2, 2, 2-trifluoroethoxy)benzene F Br S‘cw To a stirred solution of |nt12.7 (4.0 g) in DMF (15 mL) was added sodium methanethiolate (1.0 g). The mixture was stirred for 2 h at 60 °C. The mixture was cooled to r.t.. Water was added and the mixture was ted with ethyl acetate. The c phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 3.8 g of the crude title compound, that was used for the next step without purification. 1H-NMR (300MHz, CHLOROFORM-d): 6 [ppm]: 2.48 (s, 3H), 4.39 (q, 2H), 6.78 - 6.88 (m, 2H), 7.46 (d, 1H).
Intermediate Example |nt12.9 o(methylsu lfonyl)(2, 2, 2-trifluoroethoxy)benzene F Br FF>\\/O O=S=O [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred solution of |nt12.8 (3.8 g) in chloroform (100 mL) was added 3- chlorobenzenecarboperoxoic acid (mCPBA) (8.48 g). The mixture was stirred at r.t. for 16 h. With ice bath cooling, a half-saturated solution of sodium bicarbonate and and a 0.2M solution of sodium thiosulfate was added, the mixture was stirred for 30 minutes and the mixture was extracted with DCM.
The organic phase was washed with a 0.2M solution of sodium thiosulfate and a saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave a solid that was triturated with ether to give 2.1 g of the title compound. 1H-NMR z, CHLOROFORM-d): 6 [ppm]: 3.06 (s, 3H), 4.50 (q, 2H), 7.45 (d, 1H), 7.52 (dd, 1H), 7.81 (d, 1H).
Intermediate Example |nt13.1 -butylhydroxyiodobenzamide 32%. o " CH3 3-Hydroxyiodobenzoic acid (W02006/18325) (3.00 g) was ved in THF (50 mL) and tert-butylamine (997 mg), N-ethyl-diisopropylamine (1.76 g), and HATU (5.18 g) were added. The mixture was stirred ght at rt.
Subsequently, it was diluted with ethyl acetate (400 mL) and washed with satd. s sodium bicarbonate solution, ammonium chloride on, buffer solution (pH 2), and brine. The organic layer was dried over sodium sulfate, and the solvent was ated. The residue was purified by column tography on silica gel (eluent: cyclohexane / ethyl acetate gradient 4:1 to 1:1) to yield 2.5 g (60% yield, 88% purity) of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.35 (s, 9H), 7.00 (dd, 1H), 7.24 (d, 1H), 7.68 - 7.72 (m, 2H), 10.49 (br. s, 1H). gtermediate Example |nt13.2 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena N-tert-butyliodo(2,2,2-trifluoroethoxy)benzamide FFflVo 0 " CH3 N-tert-butylhydroxyiodobenzamide (|nt13.1) (1.20 g) was ved in DMF (7.8 mL) and acetonitrile (0.3 mL), and potassium carbonate (1.04 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (916 mg) were added. The mixture was heated for 30 min in a microwave oven to 150 °C. Subsequently, the reaction mixture was diluted with water and three times ted with ethyl acetate. The combined organic layers were washed three times with aqueous ammonium chloride solution, then with satd. aqueous sodium onate solution and with brine. It was dried over sodium sulfate, and the solvent was evaporated to yield 1.43 g (93%) of the title compound as white crystals. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.38 (s, 9H), 4.91 (q, 2H), 7.28 (dd, 1H), 7.45 (d, 1H), 7.78 (br. s, 1H), 7.87 (d, 1H).
Intermediate Example 1 N-ethylhydroxyiodobenzamide 0 "ACHB oxyiodobenzoic acid (W02006/18325) (3.00 g) was dissolved in THF (50 mL) and ethylamine (2M solution in THF, 6.8 mL), N-ethyl-diisopropylamine (1.76 g), and HATU (5.18 g) were added. The mixture was stirred overnight at rt. Subsequently, it was diluted with ethyl acetate (200 mL) and washed with 1/2 satd. aqueous ammonium chloride solution, satd. aqueous sodium onate solution, and brine. The organic layer was dried over sodium Dfate, and the solvent was evaporated. The residue was titurated with DCM, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena and the precipitate was ted by suction filtration to yield 1.67 g (49% yield) of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.10 (t, 3H), 3.20 - 3.28 (m, 2H), 7.04 (dd, 1H), 7.32 (d, 1H), 7.74 (d, 1H), 8.42 (t, 1H), 10.52 (br. s, 1H).
Intermediate Example 2 N-ethyliodo(2,2,2-trifluoroethoxy)benzamide FflVoF 0 "’\CH3 N-ethylhydroxyiodobenzamide (|nt14.1) (1.00 g) was dissolved in DMF (7.1 mL) and acetonitrile (0.29 mL), and potassium carbonate (950 mg) and 2,2,2-trifluoroethyl oromethanesulfonate (837 mg) were added. The mixture was heated for 30 min in a microwave oven to 150 °C. Subsequently, the reaction mixture was diluted with water and three times ted with ethyl acetate. The combined organic layers were washed three times with aqueous ammonium chloride solution, then with satd. s sodium bicarbonate solution and with brine. The organic layer was dried over sodium sulfate, and the t was evaporated to yield 1.25 g (98%) of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.13 (t, 3H), 3.25 - 3.33 (m, 2H), 4.89 (q, 2H), 7.30 (dd, 1H), 7.51 (d, 1H), 7.91 (d, 1H), 8.51 (t, 1H).
Intermediate Example |nt15.1 N,N-diethylhydroxyiodobenzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 3-Hydroxyiodobenzoic acid (W02006/18325) (10.0 g) was dissolved in a mixture of DCM (75 mL) and DMF (50 mL) and cooled to 0 °C. Oxalyl chloride (7.21 g) was added, and the mixture was stirred for 10 min. Subsequently, lamine (6.93 g) was added, and the mixture was warmed to r.t. and stirred for 1.5 h. The reaction mixture was then diluted with water and three times ted with ethyl e. The combined organic layers were washed with aqueous buffer solution (pH 2), satd. sodium bicarbonate solution, and brine, then dried over sodium sulfate, and the solvent was evaporated. The title compound (8.40 g, 66%) was obtained as an oil. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.07 (br. s, 6H), 3.16 (br. s, 2H), 3.39 (br. s, 2H), 6.55 (dd, 1H), 6.80 (d, 1H), 7.71 (d, 1H), 10.56 (br. s, 1H).
Intermediate Example |nt15.2 N,N-diethyliodo(2,2,2-trifluoroethoxy)benzamide FFflVo N,N-Diethylhydroxyiodobenzamide (|nt15.1) (1.00 g) was dissolved in DMF (6.5 mL) and acetonitrile (0.26 mL), and potassium carbonate (866 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (764 mg) were added. The mixture was heated for 30 min in a microwave oven to 150 °C. Subsequently, the on mixture was diluted with water and three times ted with ethyl acetate. The combined organic layers were washed three times with Dueous ammonium de solution, then with satd. aqueous sodium [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena bicarbonate solution and with brine. It was dried over sodium sulfate, and the solvent was evaporated to yield 1.25 g (99%) of the title compound as an oil. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 0.99 - 1.18 (m, 6H), 3.11 - 3.22 (m, 2H), 3.36 - 3.47 (m, 2H), 4.89 (q, 2H), 6.79 (dd, 1H), 7.11 (d, 1H), 7.86 (d, 1H).
Intermediate Example |nt15.3 N,N-diethyliodopropoxybenzamide HBO/V0 N,N-Diethylhydroxyiodobenzamide (|nt15.1) (630 mg) was dissolved in DMF (4.2 mL) and acetonitrile (0.17 mL), and potassium carbonate (546 mg) and 1-iodopropane (352 mg) were added. The mixture was heated for 30 min in a microwave oven to 150 °C. Subsequently, the reaction mixture was diluted with water and three times extracted with ethyl acetate. The combined c layers were washed three times with aqueous ammonium chloride solution, then with satd. aqueous sodium bicarbonate solution and with brine.
It was dried over sodium sulfate, and the solvent was ated to yield 670 mg (94%) of the title compound as an oil. 1H-NMR z, é): 6 [ppm]: 1.00 - 1.18 (m, 6H), 1.03 (t, 3H), 1.69 - 1.80 (m, 2H), 3.10 - 3.25 (m, 2H), 3.35 - 3.47 (m, 2H), 4.02 (t, 2H), 6.69 (dd, 1H), 6.90 (d, 1H), 7.80 (d, 1H).
Intermediate Example |nt15.4 3-(cyclopropylmethoxy)-N,N-diethyliodobenzamide [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] na Unmarked set by kirstena N,N-Diethylhydroxyiodobenzamide (|nt15.1) (618 mg) was dissolved in DMF (2.7 mL) and acetonitrile (0.1 mL), and potassium ate (535 mg) and 1-(bromomethyl)cyclopropane (275 g) were added. The mixture was heated for min in a microwave oven to 150 °C. uently, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed three times with aqueous ammonium chloride solution, then with satd. aqueous sodium bicarbonate solution and with brine. It was dried over sodium e, and the solvent was evaporated to yield 498 mg (63%) of the title compound as an oil. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 0.34 - 0.40 (m, 2H), 0.54 - 0.60 (m, 2H), 0.99 - 1.08 (m, 3H), 1.09 - 1.16 (m, 3H), 1.17 - 1.28 (m, 1H), 3.09 - 3.23 (m, 2H), 3.35 - 3.45 (m, 2H), 3.94 (d, 2H), 6.68 (dd, 1H), 6.89 (d, 1H), 7.80 (d, 1H).
Intermediate Example |nt15.5 N,N-diethyliodoisopropoxybenzamide N,N-Diethylhydroxyiodobenzamide (|nt15.1) (400 mg) was dissolved in DMF (2.7 mL) and acetonitrile (0.10 mL), and potassium carbonate (346 mg) and 2-iodopropane (224 mg) were added. The mixture was heated for 30 min in a microwave oven to 150 °C. Subsequently, the reaction mixture was diluted with water and three times extracted with ethyl acetate. The combined organic layers were washed three times with aqueous ammonium chloride solution, then with satd. aqueous sodium onate solution and with brine.
It was dried over sodium sulfate, and the solvent was evaporated to yield 425 mg (92%) of the title compound as an oil.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.00 - 1.18 (m, 6H), 1.29 (d, 6H), 3.11 - 3.25 (m, 2H), 3.34 - 3.47 (m, 2H), 4.72 (spt, 1H), 6.67 (dd, 1H), 6.94 (d, 1H), 7.80 (d, 1H).
Intermediate Example |nt15.6 ethyliodo(2-methoxyethoxy)benzamide \, O N,N-Diethylhydroxyiodobenzamide (|nt15.1) (423 mg) was dissolved in DMF (2.8 mL) and acetonitrile (0.11 mL), and potassium carbonate (266 mg) and 1-bromomethoxyethane (193 mg) were added. The mixture was heated for 30 min in a microwave oven to 150 °C. Thereafter, further 1-bromo methoxyethane (193 mg) was added, and the mixture was heated for additional 30 min. Subsequently, the reaction mixture was diluted with water and three times extracted with ethyl e. The ed organic layers were washed three times with s ammonium chloride solution, then with satd. aqueous sodium bicarbonate solution and with brine. It was dried over sodium sulfate, and the solvent was evaporated to yield 470 mg (94%) of the title compound as an oil. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 0.98 - 1.19 (m, 6H), 3.10 - 3.24 (m, 2H), 3.35 (s, 3H), 3.36 - 3.47 (m, 2H), 3.68 - 3.71 (m, 2H), 4.17 - 4.20 (m, 2H), 6.70 (dd, 1H), 6.94 (d, 1H), 7.81 (d, 1H).
Intermediate Example |nt16.1 tert-butyl {2-[(4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]- triazolo[1, 5-a]pyridinyl]amino}methoxybenzoyl)(methyl)amino]- ethyl}methylcarbamate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] na ed set by kirstena Starting with Intermediate Int3.4 and tert-butyl {2-[(4-bromo methoxybenzoyl)(methyl)amino]ethyl}methylcarbamate (|nt10.9), Inter- mediate Example Int16.1 was prepared analogously to the procedure for the preparation of Example11.2. 1H-NMR (500MHz, DMSO-dé): 6 [ppm]: 1.34 - 1.43 (m, 9H), 2.71 (br. s., 3H), 3.00 (s, 3H), 3.34 - 3.43 (m, 2H), 3.54 (t, 2H), 3.68 (s, 2H), 3.93 (s, 3H), 6.97 - 7.04 (m, 2H), 7.09 - 7.16 (m, 2H), 7.38 (dd, 2H), 7.62 (dd, 1H), 7.71 (s, 4H), 7.86 - 7.95 (m, 2H), 8.30 (d, 1H), 9.00 (d, 1H), 10.03 (s, 1H).
Intermediate Example |nt16.2 tert-butyl {2-[{4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo- [1 , 5-a]pyridinyl)amino]methoxybenzoyl}(methyl)amino]ethyl}methyl- carbamate 0 LNTR Starting with Intermediate Int5.2 and tert-butyl {2-[(4-bromo-3—methoxy- benzoyl)(methyl)amino]ethyl}methylcarbamate .9), Intermediate Example |nt16.2 was prepared analogously to the ure for the ation of Example2.5. 1H-NMR (500MHz, DMSO-dé): 6 [ppm]: 1.32 - 1.43 (m, 9H), 2.72 (br. s., 3H), D30 (5, 3H), 3.34 - 3.42 (m, 2H), 3.54 (t, 2H), 3.94 (s, 3H), 4.50 (d, 2H), 6.97 - [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 7.05 (m, 2H), 7.08 - 7.16 (m, 2H), 7.35 - 7.43 (m, 2H), 7.66 (dd, 1H), 7.85 - 7.92 (m, 2H), 7.94 - 8.04 (m, 4H), 8.30 (d, 1H), 8.87 (t, 1H), 9.15 (d, 1H). ediate Example |nt16.3 N-(cyclopropylmethyl){2-[(2-ethoxynitrophenyl)amino][1, 2,4]- triazolo[1, 5-a]pyridinyl}benzamide HN \N,N fix wvfij To a stirred suspension of |nt5.4 (103 mg) in toluene (3.0 mL) and NMP (0.3 mL) in a sealed tube was added 1-bromoethoxynitrobenzene (124 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-amino- ethyl)phenyl] palladium(|l) methyl-tert-butylether adduct (28 mg), X-Phos (16 mg), and sodium tert-butoxide (161 mg). The flask was twice degased and backfilled with argon. The mixture was heated to 130°C with an oil bath for 2 h. Water was added and the reaction mixture was extracted with a mixture of DCM and ol (100:1). The organic phase was washed with saturated sodium de solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel tography gave 150 mg of the title compound. 1H-NMR (300MHz, ..): 6 [ppm]: 0.11 - 0.28 (m, 2H), 0.33 - 0.47 (m, 2H), 0.93 - 1.10 (m, 1H), 1.44 (t, 3H), 3.14 (t, 2H), 4.25 (q, 2H), 7.74 (dd, 2H), 7.85 - 8.00 (m, 5H), 8.05 (dd, 1H), 8.50 (d, 1H), 8.63 (t, 1H), 8.94 (s, 1H), 9.29 (s, 1H).
Intermediate Example |nt16.4 4-{2-[(4-aminoethoxyphenyl)amino][1, 2,4]triazolo[1, 5-a]pyridinyl}-N- Dclopropylmethyl)benzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena /l§ IN N HN N H3CVO\© To a stirred solution of |nt16.3 (210 mg) in ethanol (100 mL) and DCM (60 mL) was added Raney Nickel (3.0 mg) and the mixture was stirred under a hydrogen atmosphere at r.t. for 20 h. The catalyst were removed by filtration and the solvent was removed in vacuum. Aminophase-silica-gel tography gave 31 mg of the title compound.
MW: 442,52; MS (ESI) found: [M+1] 443.
Intermediate Example |nt17.1 1-Bromo(difluoromethoxy)fluorobenzene To a d solution of 2-bromofluorophenol (21.0 g) in DMF (600 mL) was added cesium carbonate (107.5 g), sodium chlorodifluoroacetate (52.3 g) and water (29.4 mL). The e was stirred at 100 °C for 2 h. The mixture was filtrated and the resulting solution was ted with pentane (4 x 400 mL).
The combined c layers were washed with saturated sodium chloride solution, dried m sulfate) and the t was removed in vacuum, to give 7.14 g of the title nd as a crude product. Silica gel chromatography afforded 3.2 g of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm] = 7.10 - 7.16 (m, 1H), 7.34 (t, 1H), 7.33 - 7.36 (m, 1H), 7.79 (dd, 1H).
Dermediate Example |nt17.2 1-bromo(difluoromethoxy)(methylsu lfanyl)benzene [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred solution of |nt17.1 (1.0 g) in DMF (9.5 mL) was added sodium methanethiolate (460 mg). The mixture was stirred for 1 h at 60 °C. The mixture was cooled to r.t., water (150 mL) was added and the mixture was extracted twice with ethyl e. The organic layer was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 850 mg of the title compound.
Intermediate Example |nt17.3 1-bromo(difluoromethoxy)(methylsu lfonyl)benzene O=S=O To a stirred solution of |nt17.2 (812 mg) in DCM (10 mL) was added 3- chlorobenzenecarboperoxoic acid (mCPBA) (2.23 g) at 0 °C. The mixture was stirred at r.t. for 2 h. Subsequently, the reaction mixture was diluted with DCM (20 mL), washed twice with aqueous sodium sulfite solution (10 %), and sodium bicarbonate solution. The c layer was dried (sodium e) and the solvent was removed in vacuum. Silica gel chromatography gave 633 mg of the title compound. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 3.29 (s, 3H), 7.46 (t, 1H), 7.74 (dd, 1H), 7.81 (d, 1H), 8.06 (d, 1H).
Intermediate Example |nt17.4 naromo(difluoromethoxy)(ethylsulfanyl)benzene [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 8 CH To a stirred solution of 1 (500 mg) in DMF (4.75 mL) was added sodium ethanethiolate (276 mg). The e was stirred for 1 h at 60 °C. The mixture was cooled to r.t., water (150 mL) was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with ted sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 302 mg of the title compound.
Intermediate Example |nt17.5 1-bromo(difluoromethoxy)(ethylsu lfonyl)benzene O=S=O To a stirred solution of |nt17.4 (285 mg) in DCM (2.8 mL) was added 3- chlorobenzenecarboperoxoic acid (mCPBA) (625 g) at 0 °C. The mixture was stirred at r.t. for 2 h. uently, the on mixture was diluted with DCM (20 mL), washed twice with aqueous sodium sulfite solution (10 %), and sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 275 mg of the title nd. 1H-NMR (400MHz, DMSO'dé): 6 [ppm]: 1.12 (t, 3H), 3.38 (q, 2H), 7.26 - 7.66 (m, 1H), 7.69 (dd, 1H), 7.75 (d, 1H), 8.07 (d, 1H). fiermediate Example |nt18.1- romo(cyclopropyloxy)fluorobenzene ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena fig: To a stirred solution of ofluorophenol (1.0 g) in DMF (15 mL) in a microwave tube was added cesium carbonate (5.0 g), potassium iodide (130 mg) and bromocyclopropane (1.82 g). The e was heated in a microwave oven to 180° C for 1 h, to 200° C for 1 h and to 220° C for 1 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.14 g of the title nd. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.62 - 0.88 (m, 4H), 3.90 - 4.00 (m, 1H), 6.77 (td, 1H), 7.23 (dd, 1H), 7.48 - 7.63 (m, 1H).
Intermediate Example |nt18.2 1-bromo(cyclopropyloxy)(methylsu lfanyl)benzene 0 : CH3 To a stirred solution of |nt18.1 (1.4 g) in DMF (12 mL) was added sodium methanethiolate (546 mg). The mixture was for 2 h at 90 °C. The mixture was cooled to r.t., water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium e) and the solvent was removed in vacuum. Silica gel chromatography gave 1.17 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.59 - 0.85 (m, 4H), 2.46 (s, 3H), 3.95 (tt, 1H), 6.77 (dd, 1H), 7.18 (d, 1H), 7.43 (d, 1H). dermediate Example |nt18.3 1-bromo(cyclopropyloxy)(methylsu lfanyl)benzene [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred solution of |nt18.2 (1.15 g) in chloroform (45 mL) was added 3- chlorobenzenecarboperoxoic acid (mCPBA) (2.98 g). The mixture was stirred at r.t. for 2 h. With ice bath g, a half-saturated solution of sodium bicarbonate and and a 0.2M solution of sodium lfate was added, the mixture was stirred for 30 s and the mixture was extracted with DCM.
The c phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in . Silica gel chromatography gave 0.91 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.66 - 0.93 (m, 4H), 3.23 (s, 3H), 4.09 (tt, 1H), 7.43 (dd, 1H), 7.77 (d, 1H), 7.84 (d, 1H).
Starting with |nt10.2 the following intermediates were prepared analogously to the procedures described above. |nt10.14 4-bromo-N-ethylmethoxy-N- methylbenzamide |nt10.15 4-bromo-N-(2-fluoroethyl) methoxybenzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena |nt10.16 omethoxy-N-(2- methoxyethyl)benzamide |nt10.17 4-bromo-N-(3-fluoropropyl) methoxybenzamide |nt10.18 4-bromo-N-(2,2-difluoroethyl) methoxybenzamide |nt10.19 4-bromo-N-[2- (dimethylamino)ethyl]—3- ybenzamide 4-bromo-N-[2- (dimethylamino)ethyl]—3- methoxy-N-methylbenzamide |nt10.21 4-bromomethoxy-N-methyl-N- (2,2,2-trifluoroethyl)benzamide [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate Example |nt10.22.01 1-bromofluoromethoxy(methylsu lfanyl)benzene To a stirred on of sodium methanethiolate (0.47 g) in DMF (15 mL) at 0 °C was added 1-bromo-4,5-difluoromethoxybenzene (1.5 g). The mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with ethyl acetate. The c phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.46 g of the title compound.
Intermediate Example |nt10.22.02 1-bromofluoromethoxy(methylsu lfanyl)benzene O=S=O To a d on of |nt10.22.01 (485 mg) in chloroform (10 mL) at 0 °C was added 3-chlorobenzenecarboperoxoic acid (mCPBA) (1.30 g). The mixture was stirred at r.t. for 16 h. The mixture was cooled to at 0 °C and a half-saturated solution of sodium bicarbonate and a solution of disodium sulfurothioate was added, the mixture was stirred for 30 minutes at r.t. and the e was extracted with DCM. The organic phase was washed with saturated sodium chloride solution, dried (sodium e) and the solvent was removed in vacuum. Silica gel chromatography gave 311 mg of the title compound. gtermediate Example |nt10.23 [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena ed set by kirstena 1-bromomethoxy(methylsu lfinyl)benzene To a stirred solution of 10 (4.30 g) in DCM (150 mL) was added 3- chlorobenzenecarboperoxoic acid (mCPBA) (4.13 g; purity: 77% w/w) at 0 °C.
The mixture was stirred at r.t. for 1 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with DCM. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.43 g of the title compound.
Intermediate Example |nt10.24 1-bromofluoromethoxy(methylsu lfinyl)benzene To a stirred solution of |nt10.22.01 (1.45 g) in chloroform (60 mL) was added 3-chlorobenzenecarboperoxoic acid (mCPBA) (1.29 g; purity: 77% w/w) at 0 °C.
The mixture was stirred at r.t. for 1 h. The mixture was cooled to at 0 °C and a half-saturated solution of sodium onate and a solution of disodium sulfurothioate was added, the mixture was d for 30 minutes at r.t. and the mixture was extracted with DCM. The organic phase was washed with saturated sodium chloride on, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 950 mg of the title compound. gtermediate Example |nt10.25.01 [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena ed set by kirstena N-[(4-bromomethoxyphenyl)(methyl)oxido-7\6-su lfanylidene]-2, 2, 2- trifluoroacetamide To a stirred solution of 23 (1.6 g) in DCM (80 mL) was added 2,2,2- trifluoroacetamide (1.60 g), magnesiumioide (1.14 g) and diacetoxy(phenyl)-?\3- iodane (3.41 g) and the flask was twice degased and backfilled with argon. The mixture was stirred for 5 minutes at r.t.. Rhodium(||)acetat dimer (142 mg) was added and the mixture mixture was stirred at r.t. for 1 h. The reaction mixture was filtered h celite and the solvent was removed in vaccuum.
Silica gel chromatography gave 1.97 g of the title compound.
Intermediate Example |nt10.25.02 1-bromomethoxy(S-methylsu lfonimidoyl)benzene To a stirred solution of |nt10.25.01 (1.95 g) in methanol (50 mL) was added potassium carbonate (1.50 g) and the mixture mixture was stirred at r.t. for 30 minutes. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum to give 1.36 g of the title compound that was used in the fixt step without r purification.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate Example |nt10.25.03 tert-butyl [(4-bromomethoxyphenyl)(methyl)oxido-7\6-sulfanylidene]- H30’ o=is|—CH3 N 0 CH3 Y YH 0 CH To a stirred sion of |nt10.25.02 (850 mg) in THF (25 mL) was added sodium hydride (60 % w/w in oil; 193 mg) at 0 °C and the mixture was stirred at 0 °C for 30 minutes. Di-tert-butyl dicarbonate (1.40 g) was added and the mixture was stirred at r.t. for 16 hours. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the t was removed in . Aminophase-silica- gel chromatography gave 890 mg of the title compound.
Intermediate Example |nt10.25.04 tert-butyl [(4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1,2,4]triazolo- [1 , 5-a]pyridinyl]amino}methoxyphenyl)(methyl)oxido-7\6-su lfanyl- idene]carbamate N/ / A IN HN N 0 H30’ o=fi—CH3 N 0 CH3 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred sion of |nt3.4 (350 mg) in toluene (10 mL) and NMP (5 mL) was added 25.03 (529 mg), (2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (80 mg) and X-Phos (47 mg) and the flask was twice d and lled with argon. The mixture was stirred for 5 minutes at r.t.. Powdered potassium phosphate (1.03 g) was added and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 1 h. The reaction mixture was filtered through an aminophase-silica-gel column and the solvent was removed in vaccuum. Aminophase-silica-gel chromatography gave a solid that was triturated with ethanol to give 438 mg of the title compound. ediate Example |nt10.25.05 tert-butyl [{4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]triazolo- [1 , 5-a]pyridinyl)amino]methoxyphenyl}(methyl)oxido-7\6-su lfanyl- idene]carbamate N/ / A N N \ I H HN N H C’ O=|S|‘CH3 N 0 CH3 To a stirred suspension of |nt5.2 (100 mg) in toluene (3 mL) and NMP (1.5 mL) was added |nt10.25.03 (151 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (23 mg) and X-Phos (13 mg) and the flask was twice degased and backfilled with argon. The mixture was stirred for 5 minutes at r.t.. ed potassium phosphate (293 mg) was added and the flask was twice degased and fickfilled with argon. The mixture was heated to reflux for 1 h. The reaction xture was ed through an aminophase-silica-gel column and the solvent [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena was removed in m. Aminophase-silica-gel chromatography gave a solid that was triturated with ethanol to give 153 mg of the title compound.
Intermediate Example |nt10.26 4-bromo-N-tert-butylmethoxybenzenesulfonamide O=S=O HN CH \ECHS3 To a stirred solution of 4-bromomethoxybenzenesulfonyl chloride (350 mg) in DMF (4.6 mL) was added N,N-diisopropylethylamine (0.18 mL) and tert- butylamine (0.26 mL). The mixture was d for 16 h. After evaporation of the reaction e the resulting residue was partitioned between water (50 mL) and ethyl acetate (30 mL). The organic phase was separated, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography afforded 315 mg of the title compound.
Intermediate Example |nt10.27.01 o(ch loromethyl)methoxybenzene To a stirred solution momethoxyphenyl)methanol (660 mg) in DCM (20 mL) was added N,N-Diisopropylethylamin (1.59 mL) and methanesulfonyl chloride (0.36 mL) and the e was stirred at r.t. for 16 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with DM. The organic phase was washed with saturated sodium chloride solution, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena dried m e) and the solvent was removed in vacuum. Silicagel chromatography gave 700 mg of the title compound.
Intermediate Example |nt10.27.02 2-[(4-bromomethoxybenzyl)(ethyl)amino]methylpropanol To a stirred solution of |nt10.27.01 (700 mg) in DMF (17 mL) was added potassium carbonate (1.23 g), potassium iodide (50 mg) and 2-(ethylamino) methylpropanol hydrochloride (0.69 g). The mixture was stirred at 60 °C for minutes and at r.t. for 60 h. The solvent was removed in vaccuum. Water was added, and the mixture was extracted with DCM and methanol (100 : 1 mixture). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the t was removed in vacuum.
Silicagel chromatography gave 900 mg of the title compound.
Intermediate Example |nt10.28.01 [(4-bromomethoxybenzyl)oxy](tert-butyl)dimethylsilane )3 J [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena for 3 h. A half-saturated solution of sodium onate was added and the mixture was extracted with ethyl e and hexane (1 :1 mixture). The c phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 2.7 g of the title compound.
Intermediate Example |nt10.28.02 N-[4-(2-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)methoxyphenyl]- amino}[1, 2,4]triazolo[1, 5-a]pyridinyl)phenyl](4-fluorophenyl)- acetamide N/ / A ,N HN N 0 H30’ HSC—ISi CH3 H3O \KCHS To a stirred suspension of |nt3.4 (100 mg) in toluene (4 mL) and NMP (1 mL) was added |nt10.28.01 (183 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (23 mg), X-Phos (13 mg) and powdered potassium phosphate (293 mg) and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 2 h. The solvent was removed in vaccuum. Silica-gel chromatography gave the title compound as crude product (100 mg) that was used for the next step (deprotection) without purification.
Intermediate Example |nt10.28.03 az-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)methoxyphenyl]amino}- [1,2,4]triazolo[1,5-a]pyridinyl)-N-(4-fluorobenzyl)benzamide [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by na [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena H3078: CH3 "3‘3 \FCHS To a stirred suspension of |nt5.2 (100 mg) in toluene (4 mL) and NMP (1 mL) was added |nt10.28.01 (183 mg), (2-dicyclohexylphosphino-2',4',6'-tri-ipropyl-1 ,1'-biphenyl)[2-(2-aminoethyl)phenyl] ium(||) methyl-tert-butyl- ether adduct (23 mg), X-Phos (13 mg) and powdered potassium phosphate (293 mg) and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 2 h. The solvent was removed in vaccuum. Silica-gel chromatography gave the title compound as crude product (120 mg) that was used for the next step (deprotection) without purification. ediate Example |nt10.29 2-(4-bromomethoxyphenyl)propanol HO OH CH3 To a stirred solution of |nt10.1 (5.3 g) in THF (250 mL) was added methyl magnesium bromide (21.5 mL; c = 3.0 M) at r.t. and the mixture was heated to reflux for 1 h. A half-saturated aqueous solution of ammounim chloride was added and the mixture was extracted with ethyl acetate. The organic phase fis washed with saturated sodium chloride solution, dried (sodium sulfate) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena and the solvent was removed in vacuum. Silicagel chromatography gave 3.09 g of the title nd.
Starting with |nt11.2 the following intermediates were ed analogously to the procedures described above. 4-bromoethoxy-N-ethyl-N- benzamide 4-bromoethoxy-N-(2- fluoroethyl)benzamide 4-bromo-N-[2- (dimethylamino)ethyl] ethoxybenzamide ng with |nt12.2 the following intermediates were prepared analogously to the procedures described above.
[Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena |nt12.10 4-bromo-N-(2-fluoroethyl) (2,2,2-trifluoroethoxy)benzamide |nt12.11 4-bromo-N-[2-(dimethylamino)- ethyl](2,2,2-trifluoroethoxy)- benzamide |nt12.12 4-bromo-N-[2-(methylsulfonyl)- ethyl](2,2,2-trifluoroethoxy)- benzamide ng with 8 the following intermediate was prepared analogously to the procedures described above. |nt12.13 4-bromo(2,2,2-trifluoro- ethoxy)phenyl methyl sulfoxide Intermediate Example |nt15.07.01 ethyl 4-amino(trifluoromethoxy)benzoate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred on of 4-amino(trifluoromethoxy)benzoic acid (5.0 g) in ethanol (100 mL) was added thionyl chloride (2.47 mL) at 0 °C. The mixture was heated to reflux for 3 h. The solvent was d in vacuum. The residue was ved in ethyl acetate and the mixture was washed with a half- ted solution of sodium bicarbonate and with saturated sodium chloride on, dried (sodium sulfate) and the solvent was removed in vacuum, to give 4.81 g of the title compound, that was used for the next step without purification.
Intermediate Example |nt15.07.02 ethyl 4-bromo(trifluoromethoxy)benzoate To a stirred solution of |nt15.07.01 (4.8 g) in concentrated aqueous hydrobromic acid (53 mL) was added at 5 °C 9.0 mL of a 3M solution of sodium nitrite. The mixture was stirred for 10 minutes and copper(1) bromide (2.76 g) was added. The mixture was stirred for 5 minutes and water (125 mL) was added and the mixture was stirred for 1h. The mixture was ted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in . Silica gel chromatography gave 4.1 g of the title compound. nermediate Example |nt15.07.03 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] na Unmarked set by kirstena 4-bromo(trifluoromethoxy)benzoic acid To a stirred solution of |nt15.07.02 (4.1 g) in ethanol (150 mL) was added 9.8 mL of a 2M on of sodium hydroxide and the solution was stirred for 2 h at r.t.. An aqueous on of hydrochloric acid was added until pH 3 was reached. About 100 mL of solvent were removed in m, water was added and the residue was extracted with ethyl acetate. The solution was dried (sodium sulfate) and the solvent was d in vacuum, to give 3.4 g of the title compound, that was used for the next step without purification.
Intermediate Example |nt15.07.04 4-bromo(trifluoromethoxy)benzamide F 0 O NH2 To a stirred solution of |nt15.07.03 (1.50 g) in DCM (80 mL) was added DMF (0.05 mL) and oxalyl choride (0.85 g). The mixture was stirred at r.t. for 0.5 h.
The solvent was removed in vacuum, and the residue was dissolved in DCM (40 mL). A concentrated solution of ammonia in water (2.0 mL) was added and the mixture was stirred at r.t. for 1 h. Water was added and the reaction mixture was extracted with DCM. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.32 g of the title compound.
Starting with |nt17.1 the following ediate was prepared analogously to D9 procedures described above.
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena |nt15.08 4-bromo(difluoromethoxy)- phenyl isopropyl sulfone ng with 4-bromomethylbenzoic acid the following intermediates were prepared analogously to the procedures described above. |nt15.11 4-bromo-N,N,3-trimethyl- benzamide |nt15 12 o-N-(2-fluoroethyl) methylbenzamide |nt15.13 4-bromomethyl-N-(2,2,2- trifluoroethyl)benzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Starting with omethyl(methylsulfanyl)benzene the following intermediates were prepared analogously to the procedures described above. |nt15.14 4-bromomethylphenyl methyl sulfone 4-bromomethylphenyl methyl sulfoxide ediate Example |nt15.17.01 -bromoethenylmethylpyridine To a d solution of 2,5-dibromomethylpyridine (5.1 g) in 1-propanol (200 mL) was added 2M potassium carbonate solution (30 mL), 2,4,6-trivinylboroxin- pyridine x (2.0 g), triphenylphosphine (219 mg) and PPh3)2 (1.40 g). The mixture was heated to reflux for 2 h. The reaction mixture was filtered and the solvent was removed in vaccuum. Water (100 mL) was added and the mixture was extracted with ethyl acetate and hexanes (1:1 mixture). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel firomatography gave 1.66 g of the title compound.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate Example Int15.17.02 potassium omethylpyridinecarboxylate To a stirred solution of |nt15.17.01 (1.66 g) in e (65 mL) and water (65 mL) was added a potassium permanganate (2.65 g). The e was stirred at r.t. for 60 h. The reaction mixture was filtered and the solvent was removed in vaccuum to give 2.4 g of the title compound as a crude product, that was used for the next step without purification.
Intermediate Example Int15.17.03 methyl 5-bromomethylpyridinecarboxylate To a stirred suspension of the crude product |nt15.17.02 (2.4 g) in methanol (90 mL) was added thionyl dichloride (2.01 mL). The mixture was heated to reflux for 2 h. The solvent was removed in vaccuum. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium de solution, dried m sulfate) and the solvent was removed in vacuum. gel chromatography gave 1.0 g of the title nd.
Intermediate Example Int15.17.04 -bromomethylpyridinecarboxylic acid [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena To a stirred solution of |nt15.17.03 (1.0 g) in THF (20 mL), methanol (5 mL) and water (5 mL) was added an aqueous solution of lithium hydroxide (6.1 mL; c = 1M). The mixture was stirred at r.t. for 1 h. Aqueous hydrochloric acid was added, until pH 4 was d. The mixture was extracted with chloroform using a continous liquid/liquid extractor (from Normag Labor- und Prozesstechnik GmbH, |lmenau, Germany) for 16 h. The solvent was removed in vacuum to give 870 mg of the title compound.
Starting with |nt15.17.04 the following intermediates were prepared analogously to the procedures described above. |nt15.18 o-N-ethylmethyl- necarboxamide |nt15.19 5-bromomethyl-N-(2,2,2- trifluoroethyl)pyridine carboxamide ng with 1-bromofluoro(methylsulfanyl)benzene the following Dermediates was prepared analogously to the procedures described above.
[Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena |nt15.20 4-bromofluorophenyl methyl sulfone [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena EXAMPLES Compounds of the t invention Example01.1 N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]- triazolo[1, 5-a]pyridinyl]amino}methoxybenzamide NJ:W; To a d suspension of |nt3.4 (150 mg) in toluene (3.5 mL) and NMP (0.5 mL) was added 4-bromo-N,N-diethylmethoxybenzamide (237 mg), szdba3 (19 mg) and NAP (26 mg). The flask was twice degased and backfilled with argon. The e was stirred at r.t. for 5 minutes. Caesium carbonate (405 mg) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 20 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave a solid that was titurated with cyclohexane to give 27 mg of the title compound. 1H- NMR (300MHz, DMSO--d:6) 6 [ppm]: 1. 10 (t, 6H), 3.33 (br. s, 4H), 3.64 (s, 2H), 3.87 (s, 3H), 6.91 - 7.00 (m, 2H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.57 - 7.77 (m, 5H), 7.90 (dd, 1H), 8.17 (s, 1H), 8.27 (d, 1H), 9.09 (s, 1H), 10.27 (s, 1H). ng with Intermediate , the Examples Example01.2 to Example01.5 were prepared analogously to the procedure for the preparation of fiample01.1.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example01.2 N-(4-{2-[(4-cyanomethoxyphenyl)amino][1, 2,4]triazolo[1, ridin yl}phenyl)(4-fluorophenyl)acetamide HN N O 1H- NMR (300MHz, DMSO--d:6) 6 [ppm]: 3. 64 (s, 2H), 3.90 (s, 3H), 7.13 (s, 2H), 7.34 (dd, 2H), 7.39 - 7.49 (m, 2H), 7.63 - 7.77 (m, 5H), 7.93 (dd, 1H), 8.45 (d, 1H), 8.69 (s, 1H), 9.12 (d, 1H), 10.28 (s, 1H).
Starting materials: Intermediate |nt3.4; omethoxybenzonitrile e01.3 N-(4-{2-[(2-ethoxyfluorophenyl)amino][1,2,4]triazolo[1,5-a]pyridin yl}phenyl)(4-fluorophenyl)acetamide HG:\/O\©NN—/43—04% 1H- NMR (400MHz, DMSO--d.): 6 [ppm]: 1. 37 (t, 3H), 3.64 (s, 2H), 4.10 (q, 2H), 6.76 (td, 1H), 6.93 (dd, 1H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.58 (d, 1H), 7.64 - 7.74 (m, 4H), 7.87 (dd, 1H), 7.90 (s, 1H), 8.08 - 8.18 (m, 1H), 9.05 (s, 1H), .28 (s, 1H).
Starting materials: Intermediate |nt3.4; 1-bromoethoxyfluorobenzene Example01.4 Dethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5- a]pyridinyl]amino}methoxybenzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena N, / HN N O H c’ o N/\CH3 1H- NMR (300MHz, DMSO--d¢,). 6 [ppm]=1. 10 (t, 3H), 3.19 - 3.29 (m, 2H), 3.64 (s, 2H), 3.91 (s, 3H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.44 - 7.52 (m, 2H), 7.59 - 7.78 (m, 5H), 7.91 (dd, 1H), 8.21 - 8.35 (m, 3H), 9.11 (d, 1H), 10.28 (s, 1H).
Starting materials: Intermediate |nt3.4; commercial 4-bromo-N-ethyl methoxybenzamide Example01.5 N-tert-butyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]- triazolo[1, 5-a]pyridinyl]amino}methoxybenzamide N/W; H3>kC 1H- NMR (300MHz, DMSO--d:6) 6 [ppm]: 1. 36 (s, 9H), 3.64 (s, 2H), 3.91 (s, 3H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.39 - 7.50 (m, 2H), 7.55 (s, 1H), 7.60 - 7.78 (m 5H), 7.91 (dd, 1H), 8.13 - 8.39 (m, 2H), 9.10 (d, 1H), 10.28 (s, 1H).
Starting materials: ediate |nt3.4; commercial 4-bromo-N-tert-butyl methoxybenzamide Example01.6 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5-a]- pyridinyl]amino}-N-(2-hydroxyethyl)methoxybenzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena ed set by kirstena N/C43—03% To a stirred suspension of |nt3.4 (100 mg) in toluene (4.0 mL) and NMP (0.4 mL) in a sealed tube was added |nt10.3 (114 mg), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)- phenyl] palladium(||) methyl-tert-butylether adduct (23 mg), X-Phos (13 mg), and powdered potassium phosphate (294 mg). The flask was twice degased and lled with argon. The mixture was heated to 130°C with an oil bath for 2 h. Water was added and the reaction mixture was extracted with a mixture of DCM and methanol (100:1). The organic phase was washed with ted sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was titurated with warm ethanol to give 40 mg of the title compound. 1H- NMR (300MHz, DMSO--d:6) 6 [ppm]: 3. 30- 3. 36 (m, 2H), 3.41 - 3.54 (m, 2H), 3.64 (s, 2H), 3.91 (s, 3H), 4.72 (t, 1H), 7.06 - 7.19 (m, 2H), 7.34 (dd, 2H), 7.46 -7.55 (m, 2H), 7.59 - 7.78 (m, 5H), 7.91 (dd, 1H), 8.21 -8.37 (m, 3H), 9.11 (s, 1H), 10.28 (s, 1H).
Starting with Intermediate |nt3.4, the Examples Example01.7 to Example01.11 were prepared ously to the procedure for the ation of Example01.6. e01.7 N-(2-ethoxyethyl){[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]- triazolo[1, 5-a]pyridinyl]amino}methoxybenzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena N/CW; :A/Ov"3 1H- NMR (400MHz, DMSO--d6). 5 [ppm]: 1.09 (t, 3H), 3.34 - 3.50 (m, 6H), 3.64 (S, 2H), 3.91 (S, 3H), 7.13 (t, 2H), 7.35 (dd, 2H), 7.47 - 7.54 (m, 2H), 7.61 - 7.76 (m, 5H), 7.91 (dd, 1H), 8.23 - 8.34 (m, 2H), 8.39 (t, 1H), 9.12 (S, 1H), 10.29 (S, 1H).
Starting materials: Intermediate |nt3.4; 4-bromo-N-(2-ethoxyethyl) methoxybenzamide .6) Example01.8 xy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo- [1 , 5-a]pyridinyl]amino}-N-(2-hydroxyethyl)benzamide 143—in 1H- NMR (300MHz, DMSO--:d.,) 5 [ppm]: 1. 42 (t, 3H), 3.24 - 3.35 (m, 2H), 3.42 - 3.53 (m, 2H), 3.64 (s, 2H), 4.17 (q, 2H), 4.70 (t, 1H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.45 - 7.54 (m, 2H), 7.59 - 7.78 (m, 5H), 7.91 (dd, 1H), 8.14 (s, 1H), 8.23- 8.36 (m, 2H), 9.11 (s, 1H), 10.27 (s, 1H).
Starting materials: Intermediate ; 4-bromoethoxy-N-(2-hydroxyethyl)- benzamide .5) Example01.9 qthoxy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo-, 5-a]pyridinyl]amino}-N-(1-hydroxymethylpropanyl)benzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H- NMR (300MHz, DMSO-{16): 6 [ppm]: 1. 29 (s,6H), 1.42 (t, 3H), 3.49 (d, 2H), 3.64 (s, 2H), 4.17 (q, 2H), 4.92 (t, 1H), 7.06 - 7.19 (m, 2H), 7.27 - 7.50 (m 5H), 7.58 - 7.77 (m, 5H), 7.91 (dd, 1H), 8.13 (s, 1H), 8.29 (d, 1H), 9.09 (s, 1H), .28 (s, 1H).
Starting materials: Intermediate |nt3.4; 4-bromoethoxy-N-(1-hydroxy methylpropanyl)benzamide (|nt11.7) Example01 . 10 3-ethoxy-N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)- [1 , 2,4]triazolo[1, 5-a]pyridinyl]amino}benzamide .3;it? 1H-NMR (300MHz, DMSO-dé, detected s): 6 [ppm]: 1.09 (t, 6H), 1.39 (t, 3H), 3.64 (s, 2H), 4.13 (q, 2H), 6.89 - 6.99 (m, 2H), 7.13 (t, 2H), 7.29 - 7.39 (m, 2H), 7.58 - 7.76 (m, 5H), 7.90 (dd, 1H), 8.07 (s, 1H), 8.28 (d, 1H), 9.09 (s, 1H),10.28(s,1H).
Starting materials: Intermediate ; 4-bromoethoxy-N,N-diethyl- benzamide .8) Example01.11 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5-a]- pyridinyl]amino}-N-(2-hydroxyethyl)(2,2,2-trifluoroethoxy)benzamide N,0—0—>_© 1H-NMR (300MHz, DMSO-dé): 5 [ppm]: 3.25 - 3.37 (m, 2H), 3.49 (q, 2H), 3.64 (s, 2H), 4.73 (t, 1H), 4.89 (q, 2H), 7.13 (t, 2H), 7.27 - 7.42 (m, 2H), 7.54 - 7.78 (m, 7H), 7.92 (dd, 1H), 8.22 (s, 1H), 8.25 - 8.40 (m, 2H), 9.12 (d, 1H), 10.28 (s, 1H).
Starting materials: Intermediate |nt3.4; o-N-(2-hydroxyethyl)(2,2,2- trifluoroethoxy)benzamide (|nt12.3) Example01.12 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5-a]- pyridinyl]amino}-N-(2-hydroxymethylpropyl)methoxybenzamide N/43—04% To a stirred suspension of |nt3.4 (100 mg) in toluene (3.0 mL) and NMP (1.0 mL) was added |nt10.4 (167 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (23 mg) and X-Phos (13 mg) and the flask was twice d and backfilled with argon. The mixture was stirred for 5 s at r.t.. Powdered potassium phosphate (294 mg) was added and the flask was twice degased and Dckfilled with argon. The e was heated to reflux for 2 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was recrystallized from ethanol to give 106 mg of the title compound. 1H- NMR (400MHz, DMSO--d¢,). 6 [ppm]: 1. 08 (s, 6H), 3.23 (d, 2H), 3.64 (s, 2H), 3.92 (s, 3H), 4.58 (s, 1H), 7.13 (t, 2H), 7.35 (dd, 2H), 7.48 - 7.57 (m, 2H), 7.60 - 7.77 (m, 5H), 7.91 (dd, 1H), 8.16 (t, 1H), 8.23 - 8.39 (m, 2H), 9.11 (d, 1H), .30 (s, 1H).
Starting with ediate |nt3.4, the Examples Example01.13 to Example01.18 were prepared analogously to the procedure for the preparation of Example01.12.
Example01.13 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5-a]- pyridinyl]amino}-N-(1-hydroxymethylpropanyl)methoxy- benzamide N/W; 1I-I- NMR (300MHz, DMSO--d:¢,) 6 [ppm]: 1. 29 (s, 6H), 3.49 (d, 2H), 3.64 (s, 2H), 3.91 (s, 3H), 4.93 (t, 1H), 7.06 - 7.18 (m, 2H), 7.29 - 7.49 (m, 5H), 7.60 - 7.77 (m, 5H), 7.90 (dd, 1H), 8.19 - 8.35 (m, 2H), 9.09 (d, 1H), 10.28 (s, 1H).
Starting materials: Intermediate |nt3.4; 4-bromo-N-(1-hydroxymethyl- propanyl)methoxybenzamide .5) aample01.14 [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena N-{2-[acetyl(methyl)amino]ethyl}{[6-(4-{[(4-fluorophenyl)acetyl]amino}- phenyl)[1, iazolo[1, 5-a]pyridinyl]amino}methoxy-N-methyl- benzamide N/CW; 1I-I- NMR (500MHz, DMSO--d:¢,) 6 [ppm]: 1. 97 (s, 3H), 2.71 - 3.13 (m, 6H), 3.55 (br. d, 4H), 3.70 (s, 2H), 3.95 (s, 3H), 6.99 - 7.07 (m, 2H), 7.10 - 7.19 (m, 2H), 7.35 - 7.45 (m, 2H), 7.64 (dd, 1H), 7.73 (s, 4H), 7.91 (dd, 1H), 7.95 (br. s., 1H), 8.32 (d, 1H), 9.02 (s, 1H), 10.05 (s, 1H).
Starting materials: Intermediate |nt3.4; N-{2-[acetyl(methyl)amino]ethyl} bromomethoxy-N-methylbenzamide (|nt10.8) Example01.15 2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy(methylsulfonyl)phenyl]amino}- [1 , 2,4]triazolo[1, 5-a]pyridinyl)phenyl]acetamide N/W; O=S=O 1H- NMR z, DMSO-db): 6 [ppm]: 3.16 (s, 3H), 3.64 (s, 2H), 3.96 (s, 3H), 7.08 - 7.17 (m, 2H), 7.30 - 7.37 (m, 2H), 7.42 (d, 1H), 7.52 (dd, 1H), 7.65 - 7.76 (m, 5H), 7.93 (dd, 1H), 8.48 (d, 1H), 8.64 (s, 1H), 9.12 (dd, 1H), 10.29 (s, 1H).
Starting materials: Intermediate |nt3.4; 1-bromomethoxy(methyl- sulfonyl)benzene (|nt10.11) Example01.16 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 3-ethoxy-N-ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]- triazolo[1,5-a]pyridinyl]amino}benzamide 1I-I- NMR (400MHz, DMSO--de,). 6 [ppm]=1. 10 (t, 3H), 1.42 (t, 3H), 3.21 - 3.27 (m 2H), 3.64 (s, 2H), 4.17 (q, 2H), 7.13 (t, 2H), 7.35 (dd, 2H), 7.44 - 7.51 (m, 2H), 7.59 - 7.77 (m, 5H), 7.91 (d, 1H), 8.14 (s, 1H), 8.25 - 8.34 (m, 2H), 9.11 (s, 1H), 10.29 (s, 1H).
Starting materials: Intermediate |nt3.4; oethoxy-N-ethylbenzamide (|nt11.4) Example01.17 3-ethoxy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo- [1 , 5-a]pyridinyl]amino}-N-(2-hydroxymethylpropyl)benzamide EVE;rt) 1|-|- NMR (400MHz, DMSO--d:6) 6 [ppm]: 1. 08 (s, 6H), 1.42 (t, 3H), 3.23 (d, 2H), 3.64 (s, 2H), 4.18 (q, 2H), 4.57 (s, 1H), 7.09 - 7.17 (m, 2H), 7.31 - 7.38 (m 2H), 7.48 - 7.55 (m, 2H), 7.64 (d, 1H), 7.66 - 7.76 (m, 4H), 7.91 (dd, 1H), 8.10 - 8.18 (m, 2H), 8.32 (d, 1H), 9.05 - 9.17 (m, 1H), 10.29 (s, 1H).
Starting materials: ediate |nt3.4; 4-bromoethoxy-N-(2-hydroxy methylpropyl)benzamide (|nt11.6) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na Example01.18 3-ethoxy-N-ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]- triazolo[1, 5-a]pyridinyl]amino}-N-(2-methoxyethyl)benzamide ,3;E 1H- NMR (300MHz, DMSO--d¢,). 6 [ppm]: 1. 08 (t,3H), 1.39 (t, 3H), 3.22 (s, 3H), 3.46 (br. s., 6H), 3.64 (s, 2H), 4.12 (d, 2H), 6.92 - 7.03 (m, 2H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.56 - 7.78 (m, 5H), 7.90 (dd, 1H), 8.07 (s, 1H), 8.28 (d, 1H), 9.09 (s, 1H), 10.28 (s, 1H).
Starting materials: Intermediate |nt3.4; 4-bromoethoxy-N-ethyl-N-(2- methoxyethyl)benzamide (|nt11.9) Example01 . 19 3-ethoxy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo- [1 , 5-a]pyridinyl]amino}-N-(2-hydroxyethyl)-N-methylbenzamide ,3;E To a stirred suspension of |nt3.4 (100 mg) in toluene (3.0 mL) and NMP (0.5 mL) was added |nt11.11 (176 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) -tert-butyl- Dier adduct (16 mg) and X-Phos (9 mg) and the flask was twice degased and ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena lled with argon. The e was stirred for 5 minutes at r.t.. Powdered potassium phosphate (294 mg) was added and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for1 h. Further chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2- aminoethyl)phenyl] palladium(||) methyl-tert-butylether adduct (16 mg) and X- Phos (9 mg) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 2h. Water was added and the reaction mixture was extracted with ethyl acetate and methanol (10:1 ). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Ethanol (5 mL) and 2N hydrochloric acid (1 mL) was added to the residue and the e was stirred for 15 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl e. The organic phase was washed with ted sodium chloride solution, dried (sodium e) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was titurated with diisopropyl ether to give 84 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.40 (t, 3H), 2.95 (br. s., 3H), 3.32 - 3.60 (m, 4H), 3.64 (s, 2H), 4.12 (q, 2H), 4.79 (br. s., 1H), 6.98 - 7.08 (m, 2H), 7.13 (t, 2H), 7.35 (dd, 2H), 7.62 (d, 1H), 7.65 - 7.76 (m, 4H), 7.90 (dd, 1H), 8.07 (s, 1H), 8.28 (d, 1H), 9.09 (br. d, 1H), 10.28 (s, 1H).
Example01. 20 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5-a]- pyridinyl]amino}methoxy-N-methyl-N-[2-(methylamino)ethyl]- benzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a d suspension of Intermediate Example |nt16.1 (125 mg) in DCM (3 mL) was added TFA (1.5 mL). The mixture was stirred at r.t. for 2 h. A halfsaturated solution of sodium bicarbonate was added until pH 9 was reached.
The precipitated solid was collected by filtration. Purification by aminophase- -gel chromatography gave 78 mg of the title nd. 1H-NMR (500MHz, DMSO-dé, detected signals): 6 [ppm]: 2.30 (s, 3H), 2.72 (t, 2H), 3.01 (s, 3H), 3.45 (t, 2H), 3.70 (s, 2H), 3.95 (s, 3H), 7.06 (dd, 1H), 7.10 (d, 1H), 7.12 - 7.18 (m, 2H), 7.36 - 7.44 (m, 2H), 7.64 (dd, 1H), 7.73 (s, 4H), 7.91 (dd, 1H), 7.93 (br. s, 1H), 8.31 (d, 1H), 8.96 - 9.07 (m, 1H), 10.05 (s, 1H).
Example01.21 N-tert-butyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]- triazolo[1, 5-a]pyridinyl]amino}(2, 2, 2-trifluoroethoxy)benzamide ‘3le. Q N-[4-(2-Amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl](4-fluorophenyl)acet- amide (|nt3.4) (100 mg), N-tert-butyliodo(2,2,2-trifluoroethoxy)benz- amide |nt13.2 (133 mg), chloro(dicyclohexyl(2',4',6'-triisopropyl-3,6-di- methoxybiphenylyl)phosphine- [2-(2-aminoethyl)phenyl] palladium(||) (8.8 fl), Brett-Phos (5.9 mg), and sodium tert-butoxide (48.6 mg) were pre-mixed, and ed toluene (2.0 mL) was added. The mixture was heated for 12h to ation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 130 °C, then diluted with ethyl acetate and washed with satd. aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The crude product was ed by flash chromatography on silica gel (20 g, eluent: ethyl acetate/ cyclohexane 5:1) to yield 34 mg (18%) of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.40 (s, 9H), 3.68 (s, 2H), 4.95 (q, 2H), 7.13 - 7.20 (m, 2H), 7.35 - 7.41 (m, 2H), 7.56 - 7.63 (m, 3H), 7.68 (d, 1H), 7.70 - 7.79 (m, 4H), 7.96 (dd, 1H), 8.19 (s, 1H), 8.34 (d, 1H), 9.14 (s, 1H), 10.31 (s, 1H).
Example01.22 N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo- ]pyridinyl]amino}(2,2,2-trifluoroethoxy)benzamide N, / A N \I F HN N 0 FFX/0 o r\IJ\/\CH3 N-[4-(2-Amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl](4-fluorophenyl)acet- amide (|nt3.4) (40.5 mg), N,N-diethyliodo(2,2,2-trifluoroethoxy)benz- amide |nt15.2 (54 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) tert butyl methylether adduct (3.7 mg), X-Phos (2.1 mg), and sodium tert-butoxide (19.7 mg) were pre- mixed, and degassed e (1.3 mL) was added. The mixture was heated for 8 h to 130 °C, then diluted with DCM and washed with satd. s sodium carbonate solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (20 g, eluent: ethyl acetate/ exane Ddient 2:1 to 4:1) to yield 25 mg (35%) of the title compound.
[Annotation] na None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H- NMR z :d.,) 5 [ppm]=1. 13 (t, 6H), (4H underwater), 3.68 (s, 2H), 4.92 (q, 2H), 7.10 (dd, 1H), 7.13 - 7.19 (m, 2H), 7.19 - 7.21 (m, 1H), 7.35 - 7.41 (m, 2H), 7.67 (d, 1H), 7.69 - 7.78 (m, 4H), 7.94 (dd, 1H), 8.13 (s, 1H), 8.33 (d, 1H), 9.12 (br. s, 1H), 10.30 (s, 1H).
Example01.23 N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo- [1 , 5-a]pyridinyl]amino}propoxybenzamide N/l: Hc/VK?43—04% N-[4-(2-Amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl](4-fluorophenyl)acet- amide (|nt3.4) (79 mg), N,N-diethyliodopropoxybenzamide |nt15.3 (95 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2- thyl)phenyl] palladium(||) tert butyl methylether adduct (7.2 mg), X Phos (4.2 mg), and sodium tert-butoxide (38.5 mg) were pre-mixed, and degassed toluene (1.6 mL) was added. The mixture was heated for 8 h to 130 °C, then diluted with DCM and washed with satd. aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate, and the t was evaporated. The crude product was purified by flash chromatography on silica gel (20 g, eluent: ethyl acetate/ cyclohexane gradient 2:1 to 8:1) to yield 45 mg (35%) of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.04 (t, 3H), 1.13 (t, 6H), 1.79 - 1.90 (m 2H), 3.30 - 3.40 (m, 4H), 3.68 (s, 2H), 4.07 (t, 2H), 6.97 - 7.01 (m, 2H), 7.13 - 7.20 (m, 2H), 7.36 - 7.41 (m, 2H), 7.66 (d, 1H), 7.74 (d, 4H), 7.94 (dd, 1H), 8.05 (s, 1H), 8.31 (d, 1H), 9.13 (s, 1H), 10.31 (s,1H).
D [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena Example01. 24 3-(cyclopropylmethoxy)-N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]- amino}phenyl)[1, 2,4]triazolo[1, 5-a]pyridinyl]amino}benzamide N/CW; N-[4-(2-Amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl](4-fluorophenyl)acet- amide (|nt3.4) (61 mg), 3-(cyclopropylmethoxy)-N,N-diethyliodobenzamide |nt15.4 (76 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)[2-(2-aminoethyl)phenyl] ium(||) tert butyl methylether adduct (5.6 mg), X-Phos (3.2 mg), and sodium tert-butoxide (29.8 mg) were pre- mixed, and degassed toluene (1.9 mL) was added. The mixture was heated for 8 h to 130 °C, then d with satd. sodium carbonate solution and extracted with DCM. The organic layer was dried over sodium e, and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (20 g, eluent: ethyl acetate/ cyclohexane gradient 2:1 to 4:1) to yield 30 mg (28%) of the title compound. 1H- NMR (400MHz, DMSO--d:6) 6 [ppm]: 0. 39 (q, 2H), 0.58 - 0.64 (m, 2H), 1.12 (t, 6H), 1.30 - 1.40 (m, 1H), 3.31 - 3.39 (m, 4H), 3.68 (s, 2H), 3.98 (d, 2H), 6.97 - 7.01 (m, 2H), 7.16 (t, 1H), 7.38 (dd, 1H), 7.66 (d, 1H), 7.70 - 7.77 (m, 4H), 7.93 (d, 1H), 7.95 - 7.97 (m, 1H), 8.31 (d, 1H), 9.13 (br. s, 1H), 10.30 (br. s, 1H).
Example01.25 N,N-diethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo- [1 , 5-a]pyridinyl]amino}isopropoxybenzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena A IN HN N 0 Hcho CH3 F o r\|:\cH3 N-[4-(2-Amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl](4-fluorophenyl)acet- amide (|nt3.4) (79 mg), N,N-diethyliodoisopropoxybenzamide |nt15.5 (95 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2- aminoethyl)phenyl] palladium(||) tert butyl methylether adduct (7.2 mg), X Phos (4.2 mg), and sodium tert-butoxide (38.5 mg) were pre-mixed, and degassed toluene (1.6 mL) was added. The mixture was heated for 8 h to 130 °C, then diluted with ethyl acetate and washed with satd. aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The crude t was purified by flash chromatography on silica gel (20 g, eluent: ethyl e/ cyclohexane gradient 2:1 to 8:1) to yield 27 mg (20%) of the title compound. 1H- NMR (400MHz, DMSO--d:6) 6 [ppm]: 1. 13 (t, 6H), 1.36 (d, 6H), 3.30 - 3.40 (m 4H), 3.68 (s, 2H), 4.72 - 4.80 (m, 1H), 6.98 (dd, 1H), 7.00 - 7.02 (m, 1H), 7.13 - 7.20 (m, 2H), 7.35 - 7.41 (m, 2H), 7.66 (d, 1H), 7.70 - 7.77 (m, 4H), 7.94 (dd, 1H), 8.01 (s, 1H), 8.33 (d, 1H), 9.13 (br. s, 1H), 10.31 (s, 1H).
Example01.26 ethyl{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo- [1 , 5-a]pyridinyl]amino}(2-methoxyethoxy)benzamide E;To [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena N-[4-(2-Amino[1,2,4]triazolo[1,5-a]pyridinyl)phenyl](4-fluorophenyl)acet- amide (|nt3.4) (60 mg), N,N-diethyliodo(2-methoxyethoxy)benzamide 6 (75 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) tert butyl methylether adduct (5.5 mg), X-Phos (3.2 mg), and sodium tert-butoxide (29 mg) were pre-mixed, and degassed toluene (0.9 mL) was added. The e was heated for 8 h to 130 °C, then diluted with DCM and washed with satd. s sodium carbonate solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (20 g, eluent: ethyl acetate/ cyclohexane gradient 2:1 to 1:0) to yield 12 mg (12%) of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.13 (t, 6H), 3.31 - 3.44 (m, 4H), 3.38 (s, 3H), 3.68 (s, 2H), 3.74 - 3.78 (m, 2H), 4.22 - 4.26 (m, 2H), 7.03 (dd, 1H), 7.05 (d, 1H), 7.13 - 7.20 (m, 2H), 7.35 - 7.41 (m, 2H), 7.67 (d, 1H), 7.70 - 7.78 (m, 4H), 7.94 (dd, 1H), 8.12 (s, 1H), 8.34 (d, 1H), 9.13 - 9.14 (m, 1H), 10.31 (s, 1H).
Example01.27 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5-a]- pyridinyl]amino}(2, 2, luoroethoxy)-N-(2, 2, 2-trifluoroethyl)- benzamide N/ / A N \ I F HN N 0 o H/YF To a stirred suspension of |nt3.4 (85 mg) in toluene (3.0 mL) and NMP (0.4 mL) was added |nt12.4 (156 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- qpyH,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- e er adduct (14 mg) and X-Phos (8 mg) and the flask was twice degased and [Annotation] kirstena None set by na ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena backfilled with argon. The mixture was d for 5 minutes at r.t.. ed potassium phosphate (250 mg) was added and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with warm ethanol to give 122 mg of the title compound. 1H- NMR (400 MHz, DMSO--d:6) 6 [ppm]-— 3. 68 (s, 2H), 4.06 - 4.20 (m, 2H), 4.95 (q, 2H), 7.10 - 7.23 (m, 2H), 7.38 (dd, 2H), 7.65 - 7.81 (m, 7H), 7.96 (dd, 1H), 8.36 (s, 1H), 8.41 (d, 1H), 8.93 (t, 1H), 9.16 (d, 1H), 10.32 (s, 1H).
Example01.28 3-ethoxy{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo- [1 , 5-a]pyridinyl]amino}-N-[2-(methylsu lfonyl)ethyl]benzamide N /W: Starting with |nt3.4 and |nt11.12, Example01.28 was prepared analogously to the procedure for the preparation of Example01.27. 1H- NMR (400 MHz, DMSO--d:6) 6 [ppm]-— 1 46 (t, 3H), 3.04 (s, 3H), 3.39 (t, 2H), 3.60 - 3.74 (m, 4H), 4.20 (q, 2H), 7.10 - 7.22 (m, 2H), 7.38 (dd, 2H), 7.47 - 7.56 (m, 2H), 7.63 - 7.81 (m, 5H), 7.95 (dd, 1H), 8.24 (s, 1H), 8.37 (d, 1H), 8.62 (t, 1H), 9.15 (s, 1H), 10.33 (s, 1H).
Example01. 29 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5-a]- pyridinyl]amino}-N-(2-hydroxymethylpropyl)(2,2,2-trifluoro- ethoxy)benzamide N/ / A N \ I F HN N O 0 NW H30 CH3 Starting with |nt3.4 and 6, Example01.29 was prepared analogously to the procedure for the preparation of Example01.27. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.12 (s, 6H), 3.27 (d, 2H), 3.68 (s, 2H), 4.60 (s, 1H), 4.95 (q, 2H), 7.11 - 7.21 (m, 2H), 7.32 - 7.43 (m, 2H), 7.63 - 7.81 (m, 7H), 7.96 (dd, 1H), 8.18 (t, 1H), 8.25 (s, 1H), 8.37 (d, 1H), 9.15 (d, 1H), 10.32 (s, 1H).
Example01.30 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, iazolo[1, 5-a]- pyridinyl]amino}methoxy-N-methylbenzamide N/ / A N \ / HN N O H3C/ N/ 3 H Starting with |nt3.4 and omethoxy-N-methylbenzamide, Example01.30 was prepared analogously to the procedure for the preparation of Example01.27. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 2.79 (d, 3H), 3.68 (s, 2H), 3.94 (s, 3H), 7.12 - 7.20 (m, 2H), 7.34 - 7.42 (m, 2H), 7.47 - 7.54 (m, 2H), 7.64 - 7.80 (m, fl), 7.94 (dd, 1H), 8.25 - 8.38 (m, 3H), 9.14 (d, 1H), 10.31 (s,1H).
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example01.31 4-{[6-(4-{[(4-fluorophenyl)acetyl]amino}phenyl)[1, 2,4]triazolo[1, 5-a]- pyridinyl]amino}methoxy-N-(2,2,2-trifluoroethyl)benzamide N, / N HN N o H c’ o N H F Starting with |nt3.4 and |nt10.12, Example01.31 was prepared analogously to the procedure for the preparation of Example01.27. 1H- NMR (400 MHz, DMSO--d¢,). 6 [ppm]-— 3. 70 (s, 2H), 3.96 (s, 3H), 4.10 (dd, 2H), 7.12 - 7.20 (m, 2H), 7.36 - 7.43 (m, 2H), 7.57 - 7.65 (m, 2H), 7.66 - 7.71 (m 1H), 7.75 (s, 4H), 7.95 (dd, 1H), 8.35 - 8.42 (m, 2H), 8.98 (t, 1H), 9.12 - 9.18 (m, 1H), 10.47 (s, 1H).
Example01.32 2-{[2-ethoxy(methylsulfonyl)phenyl]amino}[1, 2,4]triazolo[1, 5-a]- pyridinyl)phenyl](4-fluorophenyl)acetamide O=|S|—CH3O| To a stirred suspension of |nt3.4 (200 mg) in toluene (5.0 mL) and NMP (2.5 mL) was added 15 (232 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (46 mg) and X-Phos (27 mg) and the flask was twice degased and backfilled with argon. The mixture was stirred for 5 s at r.t.. ed tassium phosphate (587 mg) was added and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 2 h. The reaction [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena mixture was filtered through an aminophase-silica-gel column and the solvent was removed in vaccuum. Aminophase-silica-gel chromatography gave a solid that was triturated with warm DCM to give 150 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.43 (t, 3H), 3.15 (s, 3H), 3.64 (s, 2H), 4.22 (q, 2H), 7.08 - 7.16 (m, 2H), 7.31 - 7.38 (m, 2H), 7.41 (d, 1H), 7.51 (dd, 1H), 7.62 - 7.78 (m, 5H), 7.93 (dd, 1H), 8.41 - 8.54 (m, 2H), 9.10 (dd, 1H), .27 (s, 1H).
Example01.33 N-[4-(2-{[2-ethoxy(ethylsulfonyl)phenyl]amino}[1, 2,4]triazolo[1, 5-a]- pyridinyl)phenyl](4-fluorophenyl)acetamide N, / A ,N HN N O HchO (3H3 O=|s|—/ To a stirred suspension of |nt3.4 (100 mg) in toluene (2.5 mL) and NMP (1.4 mL) was added |nt11.17 (122 mg), (2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (23 mg) and X-Phos (13 mg) and the flask was twice d and backfilled with argon. The mixture was stirred for 5 s at r.t.. Powdered potassium phosphate (293 mg) was added and the flask was twice degased and backfilled with argon. The e was heated to reflux for 35 minutes. The reaction mixture was filtered through an aminophase-silica-gel column and the solvent was removed in vaccuum. Aminophase-silica-gel chromatography gave a solid that was triturated with warm DCM to give 68 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.08 (t, 3H), 1.43 (t, 3H), 3.22 (q, 2H), 3.64 (s, 2H), 4.21 (q, 2H), 7.09 - 7.17 (m, 2H), 7.31 - 7.38 (m, 3H), 7.47 (dd, ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H), 7.64 - 7.76 (m, 5H), 7.93 (dd, 1H), 8.45 - 8.55 (m, 2H), 9.11 (dd, 1H), .27 (s, 1H).
Example01.34 2-(4-fluorophenyl)-N-[4-(2-{[4-(methylsulfonyl)(2,2,2-trifluoroethoxy)- ]amino}[1,2,4]triazolo[1,5-a]pyridinyl)phenyl]acetamide A N \ I F HN N 0 o=s=o To a stirred suspension of |nt3.4 (500 mg) in toluene (15 mL) and NMP (5 mL) in a sealed tube was added |nt12.9 (600 mg), chloro(2-dicyclohexylphosphino- 2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl- utylether adduct (114 mg), X-Phos (67 mg), and powdered potassium phosphate (1.03 g). The tube was twice degased and backfilled with argon. The mixture was heated to 120°C with an oil bath for 16 h. The solvent was removed in vaccuum. Aminophase-silica-gel chromatography gave a solid that was triturated with ethanol to give 600 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 3.17 (s, 3H), 3.64 (s, 2H), 5.00 (q, 2H), 7.07 - 7.19 (m, 2H), 7.30 - 7.39 (m, 2H), 7.57 - 7.77 (m, 7H), 7.94 (dd, 1H), 8.50 (d, 1H), 8.56 (s, 1H), 9.12 (d, 1H), 10.27 (s, 1H).
Example01.35 N-[4-(2-{[2-(difluoromethoxy)(methylsulfonyl)phenyl]amino}[1, 2,4]- triazolo[1, 5-a]pyridinyl)phenyl](4-fluorophenyl)acetamide [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Yfij SQ Starting with |nt3.4 and |nt17.3, Example01.35 was prepared analogously to the procedure for the preparation of Example01.27. 1H- NMR (40 0MHz, DMSO--d¢,). 6 — 3. 22 (s, 3H), 3.68 (s, 2H), 7.16 (t, 2H), 7.27 (t, 1H), 7.38 (dd, 2H), 7.68 - 7.80 (m, 6H), 7.82 (dd, 1H), 7.98 (dd, 1H), 8.65 (d, 1H), 9.13 - 9.16 (m, 1H), 9.46 (s, 1H), 10.31 (s, 1H).
Example01.36 N-[4-(2-{[2-(difluoromethoxy)(ethylsulfonyl)phenyl]amino}[1, 2,4]- triazolo[1, 5-a]pyridinyl)phenyl](4-fluorophenyl)acetamide Yfij SQ Starting with |nt3.4 and |nt17.5, Example01.36 was prepared analogously to the procedure for the preparation of Example01.27. 1H- NMR (400 MHz, DMSO--d:6) 6 [ppm]—-1. 13 (t, 3H), 3.28 (q, 2H), 3.68 (s, 2H), 7.16 (t, 2H), 7.27 (t, 1H), 7.38 (dd, 2H), 7.65 (s, 1H), 7.69 - 7.81 (m, 6H), 7.98 (dd, 1H), 8.67 (d, 1H), 9.15 (s, 1H), 9.48 (s, 1H), 10.30 (s, 1H).
Example01.37 N-[4-(2-{[2-(cyclopropyloxy)(methylsulfonyl)phenyl]amino}[1, 2,4]- triazolo[1, 5-a]pyridinyl)phenyl](4-fluorophenyl)acetamide [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na o=s—(:H3 To a stirred suspension of |nt3.4 (98 mg) in toluene (2.5 mL) and NMP (1.4 mL) was added |nt18.3 (118 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-ipropyl-1 ,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (22 mg) and X-Phos (13 mg) and the flask was twice degased and lled with argon. The mixture was stirred for 5 s at r.t.. Powdered potassium phosphate (288 mg) was added and the flask was twice degased and backfilled with argon. The mixture was heated to 85° C with an oil bath for for minutes. The reaction mixture was filtered through an aminophase-silica-gel column and the solvent was removed in vaccuum. Aminophase-silica-gel chromatography gave a solid that was triturated with warm DCM to give 65 mg of the title nd. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.72 - 0.94 (m, 4H), 3.16 (s, 3H), 3.64 (s, 2H), 4.03 - 4.14 (m, 1H), 7.06 - 7.19 (m, 2H), 7.27 - 7.40 (m, 2H), 7.53 (dd, 1H), 7.61 - 7.78 (m, 6H), 7.92 (dd, 1H), 8.48 (d, 1H), 8.55 (s, 1H), 9.09 (d, 1H), .26 (s, 1H).
Example02.1 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]pyridin yl)amino]-N-(2-hydroxyethyl)methoxybenzamide AN N I H HN N H30’ ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena ed set by kirstena To a stirred suspension of |nt5.2 (100 mg) in toluene (4.0 mL) and NMP (1.0 mL) in a sealed tube was added |nt10.3 (114 mg), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)- phenyl] palladium(||) methyl-tert-butylether adduct (23 mg), X-Phos (13 mg), and powdered potassium phosphate (294 mg). The flask was twice degased and backfilled with argon. The mixture was heated to 130°C with an oil bath for 2 h. A mixture of DCM and methanol (100:1) added, solids were removed by filtration and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was titurated with warm ethanol to give 70 mg of the title nd. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.30 - 3.35 (m, 2H), 3.42 - 3.54 (m, 2H), 3.91 (s, 3H), 4.45 (d, 2H), 4.71 (t, 1H), 7.13 (t, 2H), 7.28 - 7.39 (m, 2H), 7.45 - 7.55 (m, 2H), 7.68 (d, 1H), 7.83 - 8.05 (m, 5H), 8.22 - 8.40 (m, 3H), 9.11 (t, 1H), 9.27 (s, 1H).
Starting with Intermediate |nt5.2, the es Example02.2 to Example02.4 were prepared analogously to the procedure for the preparation of Example02.1.
Example02.2 3-ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5- a]pyridinyl)amino]-N-(2-hydroxyethyl)benzamide A ,N N HN N H3CVO O N 1H-NMR (400MHz, DMSO-dé): 5 [ppm]: 1.43 (t, 3H), 3.27 - 3.34 (m, 2H), 3.44 - E2 (m, 2H), 4.17 (q, 2H), 4.46 (d, 2H), 4.71 (t, 1H), 7.08 - 7.17 (m, 2H), 7.30 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena - 7.38 (m, 2H), 7.47 - 7.54 (m, 2H), 7.69 (d, 1H), 7.88 - 8.04 (m, 5H), 8.21 (s, 1H), 8.28 - 8.35 (m, 2H), 9.12 (t, 1H), 9.28 (d, 1H).
Starting materials: Intermediate |nt5.2; 4-bromoethoxy-N-(2-hydroxy- benzamide (|nt11.5) Example02.3 3-ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5- a]pyridinyl)amino]-N-(1-hydroxymethylpropanyl)benzamide 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.29 (s, 6H), 1.42 (t, 3H), 3.43 - 3.53 (m, 2H), 4.18 (q, 2H), 4.45 (d, 2H), 4.87 - 4.96 (m, 1H), 7.07 - 7.18 (m, 2H), 7.28 - 7.51 (m, 5H), 7.68 (d, 1H), 7.87 - 8.05 (m, 5H), 8.19 (s, 1H), 8.30 (d, 1H), 9.12 (t, 1H), 9.26 (d, 1H).
Starting materials: Intermediate |nt5.2; 4-bromoethoxy-N-(1-hydroxy propanyl)benzamide (|nt11.7) Example02.4 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]pyridin yl)amino]-N-(2-hydroxyethyl)(2,2,2-trifluoroethoxy)benzamide A IN N F HN N OH DNMR (300MHz, DMSO-dé): 6 [ppm]: 3.29 - 3.36 (m, 2H), 3.43 - 3.53 (m, 2H), 4.45 (d, 2H), 4.68 - 4.77 (m, 1H), 4.90 (q, 2H), 7.06 - 7.19 (m, 2H), 7.29 - 7.40 ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena (m, 2H), 7.56 - 7.74 (m, 3H), 7.85 - 8.07 (m, 5H), 8.24 - 8.39 (m, 3H), 9.12 (t, 1H), 9.24 - 9.33 (m, 1H).
Starting materials: Intermediate |nt5.2; o-N-(2-hydroxyethyl)(2,2,2- trifluoroethoxy)benzamide (|nt12.3) Example02.5 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, iazolo[1, 5-a]pyridin yl)amino]-N-(2-hydroxymethylpropyl)methoxybenzamide A IN N HN N H30’ To a stirred suspension of |nt5.2 (100 mg) in e (3.0 mL) and NMP (1.5 mL) was added |nt10.4 (167 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (23 mg) and X-Phos (13 mg) and the flask was twice degased and backfilled with argon. The mixture was stirred for 5 minutes at r.t.. Powdered potassium phosphate (294 mg) was added and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 2 h. Water was added and the reaction mixture was extracted with ethyl acetate. The c phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was recrystallized from ethyl acetate to give 72 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.08 (s, 6H), 3.23 (d, 2H), 3.92 (s, 3H), 4.45 (d, 2H), 4.58 (s, 1H), 7.07 - 7.20 (m, 2H), 7.30 - 7.38 (m, 2H), 7.49 - 7.57 (m, 2H), 7.69 (d, 1H), 7.86 - 8.05 (m, 5H), 8.16 (t, 1H), 8.26 - 8.39 (m, 2H), 37 - 9.17 (m, 1H), 9.27 (d, 1H).
[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena ionNone set by kirstena ation] kirstena Unmarked set by kirstena Starting with Intermediate |nt5.2, the Examples Example02.6 to Example02.7 were prepared ously to the procedure for the preparation of Example02.5.
Example02.6 N-(4-fluorobenzyl)(2-{[2-methoxy(methylsulfonyl)phenyl]amino}- [1 , 2,4]triazolo[1, 5-a]pyridinyl)benzamide k IN N HN N H3C/ ( 3 1H-NMR (400MHz, DMSO'dé): 6 [ppm]: 3.17 (s, 3H), 3.96 (s, 3H), 4.45 (d, 2H), 7.08 - 7.18 (m, 2H), 7.31 - 7.38 (m, 2H), 7.43 (d, 1H), 7.52 (dd, 1H), 7.72 (dd, 1H), 7.88 - 8.00 (m, 4H), 8.03 (dd, 1H), 8.49 (d, 1H), 8.69 (s, 1H), 9.12 (t, 1H), 9.25 - 9.32 (m, 1H).
Starting materials: Intermediate |nt5.2; 1-bromomethoxy(methyl- sulfonyl)benzene (|nt10.11) Example02.7 3-ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5- a]pyridinyl)amino]-N-(2-hydroxymethylpropyl)benzamide A IN N HN N Hch0 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.08 (s, 6H), 1.43 (t, 3H), 3.23 (d, 2H), n18 (q, 2H), 4.45 (d, 2H), 4.57 (s, 1H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.48 - 7.57 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena (m, 2H), 7.68 (d, 1H), 7.85 - 8.06 (m, 5H), 8.14 (t, 1H), 8.21 (s, 1H), 8.32 (d, 1H), 9.12 (t, 1H), 9.27 (d, 1H).
Starting materials: Intermediate |nt5.2; 4-bromoethoxy-N-(2-hydroxy methylpropyl)benzamide (|nt11.6) Example02.8 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, iazolo[1, 5-a]pyridin yl)amino]-N-(1-hydroxymethylpropanyl)methoxybenzamide A IN N HN N H30’ To a d suspension of |nt5.2 (250 mg) in toluene (6.5 mL) and NMP (3.0 mL) was added |nt10.5 (314 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] ium(||) methyl-tert-butyl- ether adduct (57 mg) and X-Phos (34 mg) and the flask was twice degased and backfilled with argon. The mixture was stirred for 5 minutes at r.t.. ed potassium phosphate (734 mg) was added and the flask was twice degased and backfilled with argon. The e was heated to reflux for 2 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography followed by silica gel chromatography gave 210 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.28 (br. s., 6H), 3.50 (d, 2H), 3.92 (s, 3H), 4.46 (d, 2H), 4.94 (t, 1H), 7.09 - 7.17 (m, 2H), 7.31 - 7.37 (m, 2H), 7.38 - 7.43 (m, 2H), 7.47 (dd, 1H), 7.68 (dd, 1H), 7.87 - 8.05 (m, 5H), 8.24 - 8.34 (m, a), 9.12 (t, 1H), 9.26 (dd, 1H).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example02.9 N-{2-[acetyl(methyl)amino]ethyl}[(6-{4-[(4-fluorobenzyl)carbamoyl]- phenyl}[1, 2,4]triazolo[1, 5-a]pyridinyl)amino]methoxy-N-methyl- benzamide LEA/Y3H3 0 Starting with ediate |nt5.2 and N-{2-[acetyl(methyl)amino]ethyl} bromomethoxy-N-methylbenzamide (|nt10.8), Example02.9 was prepared analogously to the ure for the preparation of Example02.8. 1H-NMR (500MHz, DMSO-dé): 6 [ppm]: 1.97 (s, 3H), 2.72 - 3.15 (m, 6H), 3.55 (br. d, 4H), 3.96 (s, 3H), 4.52 (d, 2H), 7.00 - 7.07 (m, 2H), 7.10 - 7.18 (m, 2H), 7.36 - 7.44 (m, 2H), 7.68 (d, 1H), 7.90 (d, 2H), 7.96 - 8.06 (m, 4H), 8.33 (d, 1H), 8.89 (t, 1H), 9.18 (s, 1H).
Example02. 10 N-(2-ethoxyethyl)[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1,2,4]- triazolo[1, 5-a]pyridinyl)amino]methoxybenzamide /l§ IN N HN N H30’ o N/\/O\/CH3 To a stirred suspension of |nt5.2 (100 mg) in e (3.0 mL) and NMP (0.3 mL) in a sealed tube was added |nt10.6 (125 mg), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2- filinoethyl)phenyl] palladium(||) methyl-tert-butylether adduct (23 mg), X- Phos (13 mg), and sodium tert-butoxide (133 mg). The flask was twice degased [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena and backfilled with argon. The e was heated to 130°C with an oil bath for 2 h. Water was added and the reaction mixture was ted with a mixture of DCM and methanol (100:1). The organic phase was washed with saturated sodium chloride solution, dried m sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was titurated with warm ethanol to give 70 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.09 (t, 3H), 3.34 - 3.50 (m, 6H), 3.91 (s, 3H), 4.45 (d, 2H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.47 - 7.56 (m, 2H), 7.69 (d, 1H), 7.87 - 8.05 (m, 5H), 8.29 - 8.35 (m, 2H), 8.40 (t, 1H), 9.12 (t, 1H), 9.28 (s, 1H).
Example02.11 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, iazolo[1, 5-a]pyridin yl)amino]methoxy-N-methyl-N-[2-(methylamino)ethyl]benzamide AIN N HN N H30’ 0 TN To a stirred suspension of Intermediate Example |nt16.2 (65 mg) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at r.t. for 2 h. A halfsaturated solution of sodium bicarbonate was added until pH 9 was reached.
The precipitated solid was collected by filtration. Purification by aminophase- silica-gel tography gave 38 mg of the title compound. 1H-NMR (500MHz, DMSO-dé, ed signals): 6 [ppm]: 2.30 (s, 3H), 2.69 - 2.76 (m, 2H), 3.01 (s, 3H), 3.45 (t, 2H), 3.95 (s, 3H), 4.52 (d, 2H), 7.04 - 7.18 (m, 4H), 7.41 (dd, 2H), 7.68 (d, 1H), 7.90 (d, 2H), 7.96 - 8.06 (m, 4H), 8.31 (d, 1H), 8.84 - 8.91 (m, 1H), 9.18 (s, 1H). aampleOZAZ [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 3-ethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5- a]pyridinyl)amino]-N-(2-hydroxyethyl)-N-methylbenzamide k IN N HN N HchO To a stirred suspension of |nt5.2 (100 mg) in toluene (3.0 mL) and NMP (1.3 mL) was added |nt11.11 (176 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (16 mg) and X-Phos (9 mg) and the flask was twice degased and backfilled with argon. The mixture was stirred for 5 s at r.t.. Powdered potassium phosphate (294 mg) was added and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 1 h. Water was added and the reaction mixture was extracted with ethyl acetate and methanol (10:1 ). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum.
Ethanol (5 mL) and 2N hydrochloric acid (1 mL) was added to the residue and the mixture was stirred for 15 s. A aturated on of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium de solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica- gel chromatography gave a solid that was titurated with diisopropyl ether to give 27 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.40 (t, 3H), 2.96 (br. s., 3H), 3.32 - 3.63 (m, 4H), 4.13 (q, 2H), 4.45 (d, 2H), 4.79 (br. s., 1H), 6.99 - 7.08 (m, 2H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.67 (d, 1H), 7.86 - 8.05 (m, 5H), 8.13 (s, 1H), 8.28 (d, 1H), 9.12 (t, 1H), 9.26 (s, 1H).
Example02.13 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, ridin no]methoxy-N-methylbenzamide AIN N HN N H30/ To a stirred suspension of |nt5.2 (90 mg) in toluene (3.0 mL) and NMP (0.4 mL) was added 4-bromomethoxy-N-methylbenzamide (104 mg), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2- aminoethyl)phenyl] palladium(||) methyl-tert-butylether adduct (14 mg) and X- Phos (8 mg) and the flask was twice degased and backfilled with argon. The mixture was stirred for 5 minutes at r.t.. Powdered potassium phosphate (254 mg) was added and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 3 h.
Water was added and the reaction mixture was extracted with ethyl e.
The organic phase was washed with saturated sodium chloride solution, dried (sodium e) and the solvent was removed in vacuum. gel chromatography gave a solid that was ated with warm ethanol to give 95 mg of the title compound. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 2.80 (d, 3H), 3.94 (s, 3H), 4.49 (d, 2H), 7.12 - 7.21 (m, 2H), 7.38 (dd, 2H), 7.48 - 7.56 (m, 2H), 7.72 (d, 1H), 7.90 - 7.98 (m, 2H), 7.98 - 8.08 (m, 3H), 8.27 - 8.38 (m, 3H), 9.15 (t, 1H), 9.31 (d, 1H).
Example02. 14 N-tert-butyl[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo- [1 , 5-a]pyridinyl)amino]methoxybenzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ng with |nt5.2 and 4-bromo-N-tert-butylmethoxybenzamide, e02.14 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.40 (s, 9H), 3.95 (s, 3H), 4.49 (d, 2H), 7.12 - 7.21 (m, 2H), 7.38 (dd, 2H), 7.46 (d, 1H), 7.51 (dd, 1H), 7.60 (s, 1H), 7.72 (d, 1H), 7.90 - 7.98 (m, 2H), 7.99 - 8.07 (m, 3H), 8.29 - 8.35 (m, 2H), 9.16 (t, 1H), 9.30 (d, 1H).
Example02.15 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, iazolo[1, 5-a]pyridin yl)amino]methoxy-N-[2-(methylsulfonyl)ethyl]benzamide AIN N HN N H3C/ o o \\// o N/\/ \CH Starting with |nt5.2 and |nt10.13, Example02.15 was prepared analogously to the procedure for the ation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 3.05 (s, 3H), 3.39 (t, 2H), 3.68 (q, 2H), 3.95 (s, 3H), 4.49 (d, 2H), 7.11 - 7.21 (m, 2H), 7.38 (dd, 2H), 7.49 - 7.57 (m, 2H), 7.72 (d, 1H), 7.91 - 7.98 (m, 2H), 7.98 - 8.08 (m, 3H), 8.37 (d, 1H), 8.41 (s, 1H), 8.64 (t, 1H), 9.16 (t, 1H), 9.31 (d, 1H).
Example02.16 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 4-{2-[(2,4-dimethoxyphenyl)amino][1, 2,4]triazolo[1, 5-a]pyridinyl}-N-(4- fluorobenzyl)benzamide 2 I2 I Z/\ \ E>—z Starting with |nt5.2 and 1-bromo-2,4-dimethoxybenzene, Example02.16 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, é): 6 [ppm] = 3.76 (s, 3H), 3.84 (s, 3H), 4.48 (d, 2H), 6.55 (dd, 1H), 6.65 (d, 1H), 7.12 - 7.21 (m, 2H), 7.33 - 7.41 (m, 2H), 7.61 (d, 1H), 7.86 - 7.93 (m, 3H), 7.93 - 8.03 (m, 4H), 9.14 (t, 1H), 9.21 (d, 1H).
Example02.17 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, iazolo[1, 5-a]pyridin yl)amino]methoxy-N-(2,2,2-trifluoroethyl)benzamide Starting with |nt5.2 and |nt10.12, e02.17 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 3.96 (s, 3H), 4.05 - 4.17 (m, 2H), 4.49 (d, 2H), 7.12 - 7.21 (m, 2H), 7.34 - 7.42 (m, 2H), 7.54 - 7.65 (m, 2H), 7.73 (d, 1H), 7.91 - 7.98 (m, 2H), 7.99 - 8.08 (m, 3H), 8.39 (d, 1H), 8.46 (s, 1H), 8.95 (t, 1H), 9.16 (t, 1H), 9.32 (d, 1H). aample02.18 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, iazolo[1, 5-a]pyridin yl)amino]-N-(1-hydroxymethylpropanyl)(2, 2, 2-trifluoroethoxy)- benzamide Starting with |nt5.2 and |nt12.5, Example02.18 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.33 (s, 6H), 3.54 (d, 2H), 4.49 (d, 2H), 4.90 - 5.00 (m, 3H), 7.12 - 7.21 (m, 2H), 7.34 - 7.44 (m, 3H), 7.57 - 7.64 (m, 2H), 7.73 (d, 1H), 7.91 - 7.98 (m, 2H), 7.99 - 8.09 (m, 3H), 8.28 (s, 1H), 8.35 (d, 1H), 9.16 (t, 1H), 9.30 (d, 1H).
Example02. 19 xy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, iazolo[1, 5- a]pyridinyl)amino]-N-[2-(methylsulfonyl)ethyl]benzamide A’N N HN N HchO o o \\// N/\/s o \CH 3 Starting with |nt5.2 and |nt11.12, Example02.19 was prepared analogously to the ure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.43 (t, 3H), 3.01 (s, 3H), 3.35 (t, 2H), 3.59 - 3.68 (m, 2H), 4.17 (q, 2H), 4.46 (d, 2H), 7.09 - 7.19 (m, 2H), 7.30 - 7.38 (m, 2H), 7.45 - 7.53 (m, 2H), 7.66 - 7.72 (m, 1H), 7.87 - 7.93 (m, 2H), 7.96 - 8.05 (m, 3H), 8.26 (s, 1H), 8.34 (d, 1H), 8.59 (t, 1H), 9.12 (t, 1H), 9.27 (d, 1H).
Qample02.20 ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena N-ethyl[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]- pyridinyl)amino]methoxybenzamide Starting with |nt5.2 and 4-bromo-N-ethylmethoxy-benzamide, Example013.21 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.10 (t, 3H), 3.26 (q, 2H), 3.91 (s, 3H), 4.45 (d, 2H), 7.13 (t, 2H), 7.34 (dd, 2H), 7.46 - 7.52 (m, 2H), 7.68 (d, 1H), 7.88 - 7.93 (m, 2H), 7.98 (d, 3H), 8.29 - 8.35 (m, 3H), 9.12 (t, 1H), 9.28 (s, 1H).
Example02.21 N-tert-butylethoxy[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]- triazolo[1, ridinyl)amino]benzamide Starting with |nt5.2 and |nt11.3, Example02.21 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.40 (s, 9H), 1.46 (t, 3H), 4.21 (q, 2H), 4.49 (d, 2H), 7.17 (t, 2H), 7.38 (dd, 2H), 7.46 (s, 1H), 7.50 (d, 1H), 7.59 (s, 1H), 7.71 (d, 1H), 7.90 - 7.98 (m, 2H), 7.99 - 8.08 (m, 3H), 8.21 (s, 1H), 8.33 (d, 1H), 9.16 (t, 1H), 9.30 (s, 1H).
Dample02.22 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena {4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]pyridin yl)amino]-N-(2-hydroxymethylpropyl)(2,2,2-trifluoroethoxy)benz- amide N/ / A,~ 1 F HN N H30 CH3 Starting with |nt5.2 and |nt12.6, Example02.22 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.12 (s, 6H), 3.28 (d, 2H), 4.49 (d, 2H), 4.60 (s, 1H), 4.95 (q, 2H), 7.17 (t, 2H), 7.38 (dd, 2H), 7.63 - 7.78 (m, 3H), 7.91 - 7.99 (m, 2H), 7.99 - 8.09 (m, 3H), 8.19 (t, 1H), 8.31 (s, 1H), 8.37 (d, 1H), 9.15 (t, 1H), 9.31 (s, 1H).
Example02.23 4-[(6-{4-[(4-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, ridin yl)amino](2, 2, 2-trifluoroethoxy)-N-(2, 2, 2-trifluoroethyl)benzamide F Starting with |nt5.2 and |nt12.4, Example02.23 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 4.06 - 4.20 (m, 2H), 4.49 (d, 2H), 4.95 (q, 2H), 7.11 - 7.21 (m, 2H), 7.33 - 7.43 (m, 2H), 7.67 - 7.78 (m, 3H), 7.92 - 7.98 (m, 2H), 7.99 - 8.09 (m, 3H), 8.38 - 8.46 (m, 2H), 8.94 (t, 1H), 9.16 (t, D), 9.29 - 9.35 (m, 1H).
Example02.24 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 4-(2-{[4-(dimethylamino)methylphenyl]amino}[1, 2,4]triazolo[1, 5-a]- nyl)-N-(4-fluorobenzyl)benzamide A IN N HN N Starting with |nt5.2 and 4-bromo-N,N,3-trimethylaniline, Example02.24 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 2.22 (s, 3H), 2.86 (s, 6H), 4.48 (d, 2H), 6.53 - 6.64 (m, 2H), 7.11 - 7.20 (m, 2H), 7.33 - 7.41 (m, 3H), 7.51 (d, 1H), 7.84 - 7.93 (m, 3H), 7.96 - 8.03 (m, 2H), 8.24 (s, 1H), 9.10 (d, 1H), 9.12 (t, 1H).
Example02.25 4-(2-{[2-ethoxy(methylsulfonyl)phenyl]amino}[1, 2,4]triazolo[1, 5-a]- pyridinyl)-N-(4-fluorobenzyl)benzamide /N H HN N H3CVO O=S—CH Starting with |nt5.2 and |nt11.15, Example02.25 was ed analogously to the procedure for the preparation of Example01.32. 1H-NMR (400MHz, é): 6 [ppm]: 1.44 (t, 3H), 3.16 (s, 3H), 4.22 (q, 2H), 4.46 (d, 2H), 7.05 - 7.17 (m, 2H), 7.31 - 7.38 (m, 2H), 7.42 (d, 1H), 7.51 (dd, 1H), 7.71 (dd, 1H), 7.87 - 8.05 (m, 5H), 8.49 (d, 1H), 8.53 (s, 1H), 9.10 (t, 1H), 9.27 (dd, 1H).
Example02.26 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 4-(2-{[2-ethoxy(ethylsulfonyl)phenyl]amino}[1, 2,4]triazolo[1, 5-a]- nyl)-N-(4-fluorobenzyl)benzamide o=|s|—/ Starting with |nt5.2 and |nt11.17, Example02.26 was prepared analogously to the procedure for the preparation of e01.33. 1H-NMR (300MHz, DMSO-d.): 6 [ppm]: 1.08 (t, 3H), 1.43 (t, 3H), 3.23 (q, 2H), 4.21 (q, 2H), 4.45 (d, 2H), 7.06 - 7.19 (m, 2H), 7.28 - 7.39 (m, 3H), 7.47 (dd, 1H), 7.72 (d, 1H), 7.85 - 8.08 (m, 5H), 8.50 (d, 1H), 8.59 (s, 1H), 9.12 (t, 1H), 9.28 (d, 1H). e02.27 N-(4-fluorobenzyl)(2-{[4-(methylsu lfonyl)(2, 2, 2-trifluoroethoxy)- phenyl]amino}[1, 2,4]triazolo[1, 5-a]pyridinyl)benzamide Starting with |nt5.2 and |nt12.9, Example02.27 was prepared analogously to the procedure for the preparation of Example01.32. 1H-NMR (300MHz, DMSO-d.): 6 [ppm]: 3.17 (s, 3H), 4.46 (d, 2H), 5.00 (q, 2H), 7.06 - 7.19 (m, 2H), 7.34 (dd, 2H), 7.56 - 7.67 (m, 2H), 7.73 (d, 1H), 7.85 - 8.09 6, 5H), 8.50 (d, 1H), 8.62 (s, 1H), 9.10 (t, 1H), 9.28 (s, 1H).
[Annotation] na None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example02.28 4-(2-{[2-(difluoromethoxy)(methylsulfonyl)phenyl]amino}[1, 2,4]triazolo- [1 , 5-a]pyridinyl)-N-(4-fluorobenzyl)benzamide AN’N N II \CH3 Starting with |nt5.2 and |nt17.3, Example02.28 was prepared analogously to the procedure for the ation of e01.27.1H-NMR (400 MHZ, DMSO- dé): 6 [ppm] = 3.23 (s, 3H), 4.49 (d, 2H), 7.13 - 7.20 (m, 2H), 7.28 (t, 1H), 7.35 - 7.41 (m, 2H), 7.71 (d, 1H), 7.78 (dd, 1H), 7.83 (dd, 1H), 7.92 - 7.98 (m, 2H), 8.00 - 8.05 (m, 2H), 8.08 (dd, 1H), 8.66 (d, 1H), 9.14 (t, 1H), 9.29 - 9.33 (m, 1H), 9.51 (s,1H).
Example02.29 4-(2-{[2-(cyclopropyloxy)(methylsulfonyl)phenyl]amino}[1,2,4]triazolo- [1 , 5-a]pyridinyl)-N-(4-fluorobenzyl)benzamide Vfij C o=s—CH3 Starting with |nt5.2 and |nt18.3, Example02.29 was prepared analogously to the procedure for the preparation of Example01.37. 1H-NMR (500MHz, DMSO-dé): 6 [ppm]: 0.83 - 0.96 (m, 4H), 3.21 (s, 3H), 4.13 fit, 1H), 4.50 (d, 2H), 7.13 - 7.21 (m, 2H), 7.39 (dd, 2H), 7.59 (dd, 1H), 7.73 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena (d, 1H), 7.76 (d, 1H), 7.93 - 8.05 (m, 4H), 8.07 (dd, 1H), 8.53 (d, 1H), 8.68 (s, 1H), 9.16 (t, 1H), 9.32 (d, 1H).
Example03.1 2-fluoro-N-(4-fluorobenzyl)[2-({4-[(1-hydroxymethylpropanyl)- carbamoyl]methoxyphenyl}amino)[1, 2,4]triazolo[1, 5-a]pyridinyl]- To a stirred suspension of |nt6.2 (100 mg) in toluene (4.0 mL) and NMP (1.0 mL) in a sealed tube was added |nt10.5 (119 mg), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)- phenyl] palladium(||) methyl-tert-butylether adduct (22 mg), X-Phos (13 mg), and powdered potassium phosphate (280 mg). The flask was twice degased and backfilled with argon. The mixture was heated to 130°C with an oil bath for 2 h. A mixture of DCM and methanol (100:1) added, solids were removed by filtration and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was titurated with ethyl acetate to give 40 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.29 (s, 6H), 3.49 (d, 2H), 3.92 (s, 3H), 4.44 (d, 2H), 4.92 (t, 1H), 7.08 - 7.21 (m, 2H), 7.30 - 7.51 (m, 5H), 7.63 - 7.75 (m, 3H), 7.82 (d, 1H), 8.02 (dd, 1H), 8.24 - 8.37 (m, 2H), 8.85 - 8.96 (m, 1H), 9.32 (d, 1H).
Dample04.1 [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na ed set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena N-(4-fluorobenzyl)[2-({4-[(1-hydroxymethylpropanyl)carbamoyl] methoxyphenyl}amino)[1, 2,4]triazolo[1, 5-a]pyridinyl]methylbenz- amide To a stirred suspension of |nt7.2 (100 mg) in toluene (4.0 mL) and NMP (1.0 mL) in a sealed tube was added 5 (120 mg), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)- phenyl] palladium(||) methyl-tert-butylether adduct (22 mg), X-Phos (13 mg), and powdered potassium phosphate (282 mg). The flask was twice degased and backfilled with argon. The mixture was heated to 130°C with an oil bath for 2 h. A mixture of DCM and methanol (100:1) added, solids were removed by filtration and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 45 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 1.29 (s, 6H), 2.39 (s, 3H), 3.49 (d, 2H), 3.92 (s, 3H), 4.41 (d, 2H), 4.89 - 4.97 (m, 1H), 7.09 - 7.21 (m, 2H), 7.31 - 7.50 (m, 6H), 7.61 - 7.73 (m, 3H), 7.96 (dd, 1H), 8.23 - 8.35 (m, 2H), 8.85 (t, 1H), 9.19 (dd, 1H).
Example04. 2 N-(4-fluorobenzyl)methyl(2-{[4-(methylsu lfonyl)(2, 2, 2-trifluoroethoxy )phenyl]amino}[1, 2,4]triazolo[1, 5-a]pyridinyl)benzamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Starting with |nt7.2 and |nt12.9, Example04.2 was prepared analogously to the ure for the preparation of Example04.1. 1H-NMR z, DMSO-dé): 6 [ppm]: 2.39 (s, 3H), 3.17 (s, 3H), 4.41 (d, 2H), .00 (q, 2H), 7.09 - 7.21 (m, 2H), 7.32 - 7.40 (m, 2H), 7.46 (d, 1H), 7.58 - 7.76 (m, 5H), 8.00 (dd, 1H), 8.51 (d, 1H), 8.60 (s, 1H), 8.84 (t, 1H), 9.22 (dd, 1H).
Example05.1 2-chloro-N-(4-fluorobenzyl)[2-({4-[(1-hydroxymethylpropanyl)- carbamoyl]methoxyphenyl}amino)[1, 2,4]triazolo[1, 5-a]pyridinyl]- To a stirred suspension of |nt8.2 (100 mg) in toluene (3.0 mL) and NMP (0.3 mL) in a sealed tube was added |nt10.5 (115 mg), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)- phenyl] palladium(||) methyl-tert-butylether adduct (221 mg), X-Phos (12 mg), and powdered ium phosphate (268 mg). The flask was twice degased and backfilled with argon. The mixture was heated to 100°C with an oil bath for 3 h. A mixture of DCM and methanol (100:1) added, solids were removed by filtration and the solvent was removed in vacuum. hase-silica-gel ography followed by preparative reverse phase HPLC gave a solid that [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na was tallized from DCM and diisopropyl ether to give 35 mg of the title compound. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 1.29 (s, 6H), 3.50 (d, 2H), 3.92 (s, 3H), 4.43 (d, 2H), 4.92 (t, 1H), 7.09 - 7.21 (m, 2H), 7.34 - 7.43 (m, 4H), 7.46 (dd, 1H), 7.53 (d, 1H), 7.68 (d, 1H), 7.82 (dd, 1H), 7.94 - 8.04 (m, 2H), 8.25 - 8.35 (m, 2H), 9.02 (t, 1H), 9.30 (d, 1H). e06.1 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]- pyridinyl)amino]ethoxy-N-ethylbenzamide k IN N HN N To a stirred suspension of |nt5.4 (1500 mg) in toluene (44.0 mL) and NMP (9.0 mL) was added 4-bromoethoxy-N-ethylbenzamide (|nt11.4) (1762 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-amino- ethyl)phenyl] palladium(||) methyl-tert-butylether adduct (242 mg) and X-Phos (140 mg). The flask was twice degased and backfilled with argon. The mixture was stirred at r.t. for 5 minutes. Sodium utoxide (2.35 g) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 2 h. Water was added and the precipitated solid was isolated by filtration. Aminophase-silica-gel chromatography gave a solid that was triturated with DCM to give 2.2 g of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.16 - 0.25 (m, 2H), 0.36 - 0.45 (m, 2H), 0.95 - 1.05 (m, 1H), 1.10 (t, 3H), 1.42 (t, 3H), 3.14 (t, 2H), 3.20 - 3.28 (m, 2H), 4.17 (q, 2H), 7.43 - 7.53 (m, 2H), 7.67 (d, 1H), 7.82 - 8.05 (m, 5H), 8.19 (s, 1H), 8.31 (d, 2H), 8.62 (t, 1H), 9.27 (d, 1H).
[Annotation] na None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena e06.2 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]- pyridinyl)amino]ethoxy-N-ethyl-N-(2-methoxyethyl)benzamide To a stirred suspension of |nt5.4 (96 mg) in toluene (3.0 mL) was 4-bromo ethoxy-N-ethyl-N-(2-methoxyethyl)benzamide (|nt11.9) (206 mg), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)- phenyl] palladium(||) methyl-tert-butylether adduct (13 mg) and X-Phos (8 mg) and the flask was twice degased and backfilled with argon. The mixture was stirred for 5 minutes at r.t.. Sodium tert-butoxide (150 mg) was added and the flask was twice degased and backfilled with argon. The mixture was heated to reflux for 2 h. Water was added and the reaction e was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica- gel chromatography ed by Aminophase-silica gel chromatography gave a solid that was ated with a mixture of ethyl acetate and hexane to give 62 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 0.17 - 0.25 (m, 2H), 0.36 - 0.47 (m, 2H), 0.92 - 1.14 (m, 4H), 1.40 (t, 3H), 3.14 (t, 2H), 3.23 (s, 3H), 3.31 - 3.58 (m, 6H), 4.13 (q, 2H), 6.93 - 7.05 (m, 2H), 7.66 (d, 1H), 7.85 - 7.97 (m, 4H), 8.00 (dd, 1H), 8.13 (s, 1H), 8.28 (d, 1H), 8.62 (t, 1H), 9.26 (s, 1H).
Dample06.3 [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]- pyridinyl)amino]ethoxy-N-(2-hydroxyethyl)benzamide A!N N HN N To a stirred suspension of |nt5.4 (80 mg) in toluene (4.0 mL) and NMP (1.0 mL) in a sealed tube was added |nt11.5 (112 mg), chloro(2-dicyclohexylphosphino- 2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl- tert-butylether adduct (22 mg), X-Phos (13 mg), and powdered ium phosphate (276 mg). The flask was twice degased and backfilled with argon.
The mixture was heated to 130°C with an oil bath for 2 h. A mixture of DCM and methanol (100:1) added, solids were removed by filtration and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was ted with warm ethanol to give 75 mg of the title compound. 1H-NMR z, DMSO-dé): 6 [ppm]: 0.18 - 0.24 (m, 2H), 0.38 - 0.44 (m, 2H), 0.96 - 1.08 (m, 1H), 1.43 (t, 3H), 3.14 (t, 2H), 3.30 - 3.34 (m, 2H), 3.48 (q, 2H), 4.17 (q, 2H), 4.69 - 4.74 (m, 1H), 7.47 - 7.54 (m, 2H), 7.68 (dd, 1H), 7.86 - 7.98 (m, 4H), 8.01 (dd, 1H), 8.21 (s, 1H), 8.28 - 8.36 (m, 2H), 8.62 (t, 1H), 9.28 (dd, 1H).
Example06.4 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1, iazolo[1, 5-a]- pyridinyl)amino]-N-(2-hydroxyethyl)(2,2,2-trifluoroethoxy)benzamide r:"is?O [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena Starting with Intermediate |nt5.4 and ; 4-bromo-N-(2-hydroxyethyl)(2,2,2- trifluoroethoxy)benzamide .3); Example06.4 was prepared analogously to the procedure for the preparation of Example06.3. 1H-NMR (400MHz, DMSO-dé): 6 [ppm]: 0.17 - 0.24 (m, 2H), 0.36 - 0.45 (m, 2H), 0.96 - 1.07 (m, 1H), 3.14 (t, 2H), 3.30 - 3.35 (m, 2H), 3.44 - 3.52 (m, 2H), 4.70 - 4.78 (m, 1H), 4.90 (q, 2H), 7.58 - 7.73 (m, 3H), 7.87 - 7.98 (m, 4H), 8.02 (dd, 1H), 8.26 - 8.37 (m, 3H), 8.63 (t, 1H), 9.29 (dd, 1H).
Starting materials: Intermediate |nt5.4; 4-bromo-N-(2-hydroxyethyl)(2,2,2- trifluoroethoxy)benzamide (|nt12.3) Example06.5 4-[(6-{4-[(cyclopropylmethyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]- pyridinyl)amino]-N-ethyl(2,2,2-trifluoroethoxy)benzamide A IN N F HN N mino[1,2,4]triazolo[1,5-a]pyridinyl)-N-(cyclopropylmethyl)benzamide |nt5.4 (100 mg, 76% purity), N-ethyliodo(2,2,2-trifluoroethoxy)benzamide |nt14.2 (111 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) (18 mg), X-Phos (12 mg), and sodium tert-butoxide (43.4 mg) were pre-mixed, and degassed toluene (1.5 mL) was added. The mixture was heated for 6h to 130 °C. uently, DCM was added, and the mixture was washed with satd. aqueous sodium ate solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/ cyclohexane nt 4:1 to 8:1). The product was titurated with DCM/tert butyl ether/pentane and collected by suction gration to yield 30 mg (21%) of the title compound.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena 1H-NMR (400MHz, DMSO-dé): 5 [ppm]: 0.22 - 0.28 (m, 2H), 0.41 - 0.49 (m, 2H), 1.00 - 1.11 (m, 1H), 1.15 (t, 3H), 3.18 (t, 2H), 3.26 - 3.37 (m, 2H), 4.93 (q, 2H), 7.63 (d, 1H), 7.66 (s, 1H), 7.73 (d, 1H), 7.90 - 8.02 (m, 4H), 8.06 (d, 1H), 8.31 (s, 1H), 8.32 - 8.40 (m, 2H), 8.66 (t, 1H), 9.32 (s, 1H).
Example07.1 N-ethyl[(6-{4-[(3-fluorobenzyl)carbamoyl]phenyl}[1, 2,4]triazolo[1, 5-a]- pyridinyl)amino]methoxybenzamide Starting with Int5.8 and 4-bromo-N-ethylmethoxy-benzamide, Example07.1 was prepared analogously to the procedure for the preparation of Example02.13. 1H-NMR (400 MHz, DMSO-dé): 6 [ppm] = 1.14 (t, 3H), 3.25 - 3.32 (m, 2H), 3.95 (s, 3H), 4.53 (d, 2H), 7.04 - 7.12 (m, 1H), 7.12 - 7.22 (m, 2H), 7.35 - 7.43 (m, 1H), 7.48 - 7.57 (m, 2H), 7.72 (d, 1H), 7.91 - 8.00 (m, 2H), 8.00 - 8.10 (m, 3H), 8.31 - 8.40 (m, 3H), 9.19 (t, 1H), 9.32 (s, 1H).
Example08.1 N-(4-fluorobenzyl)[2-({4-[(1-hydroxymethylpropanyl)carbamoyl] yphenyl}amino)[1, 2,4]triazolo[1, 5-a]pyridinyl]methoxybenz- amide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena To a stirred suspension of |nt9.2 (100 mg) in toluene (3.0 mL) and NMP (1.0 mL) was added |nt10.5 (115 mg), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(||) methyl-tert-butyl- ether adduct (21 mg) and X-Phos (12 mg) and powdered potassium phosphate (271 mg). The flask was twice d and lled with argon. The mixture was heated to reflux for 3 h. The solvent was removed in vacuum. Aminophase- silica-gel tography followed by preparative reverse phase HPLC gave 200 mg of the title compound. 1H-NMR (300MHz, é): 6 [ppm]: 1.29 (s, 6H), 3.49 (d, 2H), 3.92 (s, 3H), 4.01 (s, 3H), 4.47 (d, 2H), 4.92 (t, 1H), 7.04 - 7.19 (m, 2H), 7.30 - 7.54 (m, 7H), 7.68 (d, 1H), 7.82 (d, 1H), 8.02 (dd, 1H), 8.25 - 8.34 (m, 2H), 8.74 (t, 1H), 9.33 (s, 1H).
Example09.1 N-(4-fluorobenzyl)methoxy(2-{[2-methoxy(methylsulfonyl)phenyl]- amino}[1, 2,4]triazolo[1, 5-a]pyridinyl)benzamide Starting with |nt9.2 and |nt10.11, Example09.1 was prepared analogously to the procedure for the preparation of Example01.32. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.17 (s, 3H), 3.96 (s, 3H), 4.01 (s, 3H), 4.47 (d, 2H), 7.08 - 7.18 (m, 2H), 7.30 - 7.39 (m, 2H), 7.40 - 7.47 (m, 2H), 7.49 - 7.55 (m, 2H), 7.72 (d, 1H), 7.82 (d, 1H), 8.05 (dd, 1H), 8.49 (d, 1H), 8.68 (s, 1H), 8.74 (t, 1H), 9.35 (d, 1H).
Example10. 1 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena 2-(2,4-difluorophenyl)-N-[4-(2-{[2-methoxy(methylsulfonyl)phenyl]- amino}[1, 2,4]triazolo[1, 5-a]pyridinyl)phenyl]acetamide HN5'" H30’ : 48 O=S—CH Starting with |nt3.6 and |nt10.11, Example10.1 was prepared analogously to the procedure for the preparation of Example01.32. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.16 (s, 3H), 3.72 (s, 2H), 3.96 (s, 3H), 6.98 - 7.08 (m, 1H), 7.19 (td, 1H), 7.37 - 7.47 (m, 2H), 7.52 (dd, 1H), 7.61 - 7.79 (m, 5H), 7.93 (dd, 1H), 8.48 (d, 1H), 8.59 (s, 1H), 9.11 (d, 1H), 10.31 (s, 1H).
Example1 1.1 N-(2,4-difluorobenzyl)(2-{[2-methoxy(methylsulfonyl)phenyl]amino}- [1 , 2,4]triazolo[1, 5-a]pyridinyl)benzamide Starting with |nt5.7 and 11, Example11.1 was ed analogously to the ure for the preparation of Example1.27. 1H-NMR (400M Hz, DMSO-dé): 6 [ppm] = 3.20 (s, 3H), 4.00 (s, 3H), 4.51 (d, 2H), 7.07 (t, 1H), 7.23 (t, 1H), 7.40 - 7.50 (m, 2H), 7.56 (d, 1H), 7.75 (d, 1H), 7.92 - 7.98 (m, 2H), 7.99 - 8.09 (m, 3H), 8.52 (d, 1H), 8.69 (s, 1H), 9.11 (t, 1H), 9.31 (s, 1H).
The ing Examples wer prepared analogously to the procedures described gove: [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ngsbm " RAIN AT: AT: AT: " Ego: mg RAIN AT: AIM RAIN -0: a: 63 Ego: i i "iv a: i a: c w: XE N; c AT: am N: 03 8.8 a: - - é AT: "3.093 N: mam - o: iv AT: AT: RAIN 8s AT: *8 é "3.093 NE :23 é - NE RAIN é i RAIN RAIN "N12 3m AIM v: 3w N2: w: m: :6 a: "N12 a: a: 8: AIM i AT: AT: AT: 8: is g AT: m: é 28 - é é Q i :5 2;. 522+: 522+: a: é mg RAIN mm." SK omw is 03 as as om: N3 A :xfi :xfi 35380:: V -N-EE§9Q -N-EE§9Q mEmz E: zififimosemsbmg :ostE -NV-z->xo£me-m-moc_em:> mEEmNcm£35m>xo£mE 52285335-:-2: zififimosemsbmg :ostE -ZKZ->xo£mE-m-moEEm:> mEEmNcm9>£mE=u BQmem. Dz BQESQ 239m [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " a: ADE a: AIM AIF " a: A: MM." Ego: EM MM.M om: AIM - AIF - MM." a: é Ego: 0:- AIM c SM AIM 2% oMA: c A23 é A5855 M: MMM :s a: AIM - A5855 i AIF AIM MM." om: AIF MMA: -wor- AIM MMM i M; - a: i é AIF A23 AIF "NI: MMM AIM AIF I: BM M; "NI: 3M :m ME i 8: é AIM - A23 8: AIM In: AIM AIF AIF 8.0 é MOM M: a: ".22-; I: 5 ".22-; é M: :m AIM SM AIv AIM AIM SM MMM AIM SK- In: a: -IEEQESEEE-2: :xfi :ka :A.>cmcn_moc_Em:>umum -Méucéoé o£mE-M-moEEMI> mNcmn:>£m:>co::2>£mEV SEEE-2: :AEEQMOEEMIBSM -Méucéoé :osNME mEE :osNME ->xo£mE-m-moEEm:> mEEmNcmn 239m 239m [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena i AIM " a: Ego: .0: ME MMM 5 M; Ego: $.M -86 A23 ME AIF AIM 3M AIF c é AIF AIM AIF c AIv A5855 a: AIM MM.M AIM MM." é A23 é A5855 a: i AIM é AIM FMM $.M PM." a: 0: MM." - 8M MMA: i 8M i PM." - AIF AIF AIF "NI: AIM AIM I: - AIF "NI: 22 AIM M; a: é é 8: é a AIM 2M i MMM 8: AIM é AIM AIF MMM AMA: ".22-; - MOM CM a: AIF M; i MMM a: é AIF AIF oMM AIM AIF SK A23 AIF ".22-; M: AIM 8K 8s A23 i i-o:+-:>£meo::é-z -2382353803773: -moEEm3382353803: -MA -Ixfi -MSEEEMA ->xo£mE-m-moEEm:> -VE-$-§-I>£¢-2 228%:th :Aacmfimosem IBONME mEEMNcmn :AIEEQ _Em:>-N-c=ut>M:c -N:@£>£mE-Z->xo£mE mEEm 2qu 2qu [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " a: a: a: AIF " AIM AIM AIF Ego: on Ego: -ME 8s EM M: om: é a: a: AIF é - a: - - c MMA: c AIM ME BM AIM A23 FMM A5855 MM." M: 2% - - a: - a: AIM AIF A5855 ME AIF AIF -OON- AIM AIM vMM MM.M SM MA: I: é é é a: a: A3 AIM AIM - - AIv MMM "NI: MOM AIF A: M: 26 "NI: 8.0 MM." A: MMA: A23 a: a: AIF 8: AIv - - AIF 8: MM.M AIM AIM 3M- M: AIF ".22-; ME 0: ME a: é i - é a: AIF A3 MMM AIF AIM AIM EM ".22-; o: 8M 8M ME é 8M- is -§+-:>£meo§_3d-z :xfi :ka -Aacofieosizwi :A.>cmcn_moc_Em:>umum oé -Ncmn>xo£mE-m-moEEm:> -Méucéoé mEEm z -IEEQESEEE-2: :AEEQMOEEMIBSM :osNME :osNME -Z->xo£mE-m-moEEm:> mEEMNcmnIEHmE 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena n n k " AT: " KS EN Ev i Ego: AIM EN RAIN XE é i a: a: a: Ego: 2% AT: - 8s a: 3w c am N; E w: K3315 c "iv mm.m "Em o: AT: RAIN - "3.093 i - - - a: - i RAIN 5N- 8s mm." 9: 8.8 "3.093 RAIN i a: i cc 28 w: a: RAIN RAIN AT: AT: - RAIN N3 8.8 "N12 w: 2% RAIN 9: - AT: a: a: a: a: "N12 8: AIM £2.15 is i o: a: 8: 63 AT: mg i 522+: i - - i w: mm." é AT: 26 :.m 8+ NE v: XE 86 522+: mg RAIN RAIN SK 63 AT: 52285335-:-2: :xfi :xfi semsbmg 9Q -Z->xo£mE-m-moEEm:> -eoszE-NKNKNV.>£me -:EHROEESEEEEYNH-Z 52285335-:-2: :icmiosemsbmg -N-EE§9Q :ostE mns>£m :ostE ->xo£mE-m-moEEm:> mEEmNcmn 239m BaEaxm.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na *8 é " AIM AIM é é AIF M; Ego: EM VMM 8M AIF ME a: i A23 oMA: "Egg AIF AIM c AIF MTM 5% MMM AIF c AIM é AIF i A5855 a: - é é é MMM é A5855 AIM AIM a: 8.0 -NON- vMM SM MMM $.M AIM AIM é a M; AIF AIM AIM a: AIF "NI: MOM 8M AIF AIF "NI: M: AB é a: a: 8: AIM AIF A23 a: CM i AIM MTM Mo.M M: 0on - MMA: ".22-; - é a - I: MTM MMM- MOM A23 AIF MMM AIv ".22-; AIF MM; 3+ 0: AIF AIF FMM AIM vMM A23 i -IEEQESEEE-2: IMAMA :AEEQMOEEMIBSM -M-EE§9Q -TMANA -95333Q :osNME -oLo::-MV-z-MoEEMs> -Ncmn>xo£mE-m-:>M_EM_ mEEm -M-eo=:-M:-Mvi-z -:>co::2>£mEV-v->xo£mE :moEEmEcmcq IBONME -o;o::-$-~-:>:m;a:> mEESmum3>cmcq 239m maeem ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena iv i "Egg AIM m3 38 "Egg AIM -0: m: Ed i a: AT: o: AT: é AT: is 0 am AT: 0 3m i "A5855 - é Q a: RAIN *3 "A5855 RAIN N; -MON- F: a: m: é 8.0 9:- AT: AT: RAIN is é RAIN "N12 $.m AT: "N12 $.m SK *3 i a: a: a: 80 AIM Q RAIN N3 38 ts Rs 80 AIM w; 522+: i - - 2% 522+: é - a: AT: AT: F: BK a: AT: AT: a: BK E 63 é -Nvi-z-:>8fi88:-$-~ -.>£mev+->xo£me-% -Mosemsémfisécsm Enrich223%:kaer mEesmumsémfisi -N-eo::-m:éi-z -iccsmafimev+5653 -Htfizmosemsémfi -iééucéoéLEONE" -icmfieoszi-~-38% mEEsmum 2qu 2qu ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Ego: AIM iv a: AT: "Egg .x: mg AT: 63 iv i a: Q AT: 03 rm v2 c g g a: 28 w: ME :m c .BV "3.093 is i - a: RAIN "3-093 o: .x: RAIN AT: AT: 5 $.m No.0 5 - AT: -VON- 0: om: 8w é i i - .é AT: SK AIM RAIN ME RAIN "N12 w: we." m3 8.8 @1283 5; rm é AT: AT: 38 AT: AT: .BV a: 8: is :m é F: AT: AIM Ra AT: a: N: 522+: i - Q i ".22-; 5 RAIN 2+ .x: BK - i v: OE i: was 8.0 So rm AIM 8s RAIN 0: 3.0 -.33-tm:-§éi-z ->xo£mE-N-:>oE§a -Htfizmosemsémfi -oézucévmioENmE -eoszi-N-:>8§.> 52"; dii -N-cao§>£me-N->xo%E -Nééaéosega -Hoc_E£.>8fi>xo£me Enrich223%:kaer i-~-:>cmfiw>-o @2538238888: 2qu 2qu [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na i AT: " m? BK AT: "Egg: -2: i AIM 0:- 8.5 é RAIN AT: RAIN Ego: i c m: c om: $8.15 Es a: a: 63 g $8.15 :3 usuémzo "3.093 FEAT: RAIN "iv é Kim -mON- mod. Rs mod a: é a: a: 0: - i AT: ems v: .110ka mow "N12 6:915 2;. Rs @1283 m; AT: AT: AT: RAIN 8s i é AIM v: AT: 8: as 63 i 8.8 "32+: 23 a: AT: 63 é RAIN AT: h: :2 AIM 8s é ow." 38 522+: SM 63x3 a: a: AT: AT: -Nvi-z-:>8fi88:-$-~ -:>-N-cmn_8n_>x8_u>c-d-v: -moEEm:>cmcn_>xo£mE-N $3335. mEESmums>cmcqs>6 -TxN" : -3652va :ostEfltfi : ->xo£m§_u-§:di-z "0:53?ch :23?" -o;o::-$-~-:>:m%§> mEESmumSEmcq 2qu 2qu [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " a: " 5 Ego: AIM 5+ AT: :w 5.8 Ego: RAIN EN v: a: AT: - gm é *8 N2. Q AT: AT: i c RAIN 3N c a: a: Q 2% 8+ w: AT: "3.093 i :s m: :23 - AIM 26 "3.093 RAIN RAIN 0: 2.0- is £5.15 -oON- w: RAIN RAIN XE i i *8 AT: :6 AT: a: a: iv AT: 63 "N12 M: a: we." m: a: é "N12 w: mm." é AT: 8: Kim - - N3 8: 31% RAIN RAIN SK :23 é AT: 2mm v2 i 522+: a - mod - AT: AT: i *8 i RAIN m: 3w N: mm.m RAIN RAIN 9: i i 522+: o: 5m 8s a: g AT: 5.8 i-§-E>£m-z->xo£m-m 53803773: -mk -cxfi -N-EE§9Q :ostEfltfi Licmfimosem :ostE -z-moc_em:> wEEmNcwn z +5§+->xo£m-m -moEEm3382353803: Licmfi -Moc_E§>-N-EE§o mEEmNcmn Queen 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " a: ADE AIF AIF " AIM AIM Ego: AKM MM." A23 5 - Ego: é a: c AIv MMM AIM c 0: SM MMM is- SK A5855 AIF - a: AIM i AIF A5855 AIM -NON- AIM o: a: 5 M; :s a: é é AIM AIM - AIF "NI: MM AIM a: MMM oMA: "NI: EM o: é a: a: 8: AIM *8 - AIF AIF 8: AIM AIF 3+ o: 5M E oMA: ".22-; é é i é - - é AIF 8M AIv AIM oM.M 3.0 ".22-; MM; 23 MM." M: MFMAIFAEVMMAIF£31563 é -IEEQESEEE-2: :ka:AIEmfiMoEEMIBSM -Méucéoé oé -N->x8_u>c- 220505 IEEEYMIZMSEME -MAMAMVM-IEBIEQR mEEmNcm£>xo£mEoeru -IEEQESEEE-2: :ka:AIEmfiMoEEMIBSM :osNME :-Z-moEEm:> -MMd-M-:>-M-cao§>£me mEEmNcm£>xo£mEoeru 239m 239m [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena " RAIN :2 RAE 5w RAIN AIM Ego: N: *8 "Egg RAIN *8 a: - a: 8.05: c is w? 8s E: c 8+ E "3.093 a: Q - a: RAIN RAIN - MS RAIN 2% -wON- - "3-093 w: i *8 é 9:- AT: RAIN AT: "N12 vi 3+ RAIN NS $.m SK i 8: is RAIN 63 AT: @1283 AIM AT: 38 522+: i i mm." 63 ts i - Q £2.15 w: RAIN m: .fimv5.021i336fi3 522+: AT: F3 N: BK 5: 63 i 5236565-z 52285335-:-2: :xfi Ls>cm§osems>§m -N-EE§9Q -eoszE-Naiafisega -Nvi-z-:>8fi88:-$-~ -Nis-NéégaafimVEYE -cxfi mEEmNcm£>xo£m -ercévq :ostE -A>xo£mogo::.5 Eosegémfi :ostE mEESmums>cmcqs> 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena .02 mm: AT: é " AT: "Egg w: 63 is 63 :6 Egg: mm." i RAIN AT: 0 AT: a: a: ME AT: a: 5: "A5855 a: AT: i "A5855 a: Q i AT: - AT: -oON- ts o: 5mm é - i - 63 m; 8.8 Rs we." @128: 8s v: mm: AT: AT: "N12 mm.m EN AT: a; 5.8 RAIN AIM é AT: :m 8: is 5 é AT: AT: 522+: é a: .x: a 0; Q 8s o: 63 é $.m E .x: was AT: 522+: m: KEN RAIN was Ed -:>8fio_osz+5i-2: fimosemsbmum -Néucévmigogcu c:-m-mo£E§> m£>xo£me -88EE-%$-$-2 -N-caee+-§xo£me -MosemEcmcqséoraa -Eucévfl228%:kaer igémiaé @2538322853: 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena " a: " a: Egg: fig. RAIN o: é Egg: m: AT: v; 5.8 "iv 0; - Q AT: AT: 0 a: AT: 0 "A5855 :s m: a: AT: NE "A5855 i: 63 é i AT: - w: RAIN 0; -oFN- a: RAIN NE i v2 - 2.8 we." mg i a: RAE AT: "N12 as 5 - AT: "N12 w: RI: AT: Cw m: é 8: RAIN § 8: AIM - Ea é o: 63 AT: E: 522+: 8.0 522+: i v2 - AT: AT: SA g SK 63 AT: 02 AIM we." Q i -88EE-%$-$-2 -EEEESFYEEBE tEHtNKEoEEm +1-Ecmfiiéégafi @2538322853: -:>8fio_osz+5i-2: fimosemsbmum -NéucivmioENmE -.>£me-m-moc_em:> @253ch 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena é é " -03 mm." é " a: AT: AT: Ego: Sm N2: Ego: AT: Q 0; c RAIN RAIN om: c AT: - AT: "3.093 a: a: 9: *3 Q £8.15 i "3.093 $3.15 58.15 RAIN -CN- S is- AT: 3w N: - :6 i 63 "N12 93 :s AT: 5.: "N12 KENDZIMQRN w: mm." £315 AT: 8: AIM RAIN :23 a: i 3 8: RAIN KEN a é a: $8.21N63 m: mg om: i i - w; 2.8 522+: mg 2+ is AT: AT: 522+: w: 8s we." AT: AT: -:-2: :xfi :icmiosemsbmg -N-EE§9Q -cxfi -N-EE§9Q :ostE -Z-.>£mE-m-moEEm:> -:>;Bo_oszE-N€Nv wEEmNcwn i-o:+-:>£meo::é-z -2382353803773: Licmfimosem :ostE -.>£me-m-mosem:> mEEmNcmn 239m 2qu [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena -IF FMM -2: -oMK a: " AIF I: AIF Ego: AIF Ego: AIM M: é BM é AIM AIM - é a: M "Egg I: c - AIM MMM MMA: I a: A5855 é MMM AIF 8M BM AIF - A5855 AIM AIF -NFN- A5855 I: AIM - AIF MOM é MI- A23 A3 : é ME M: A23 AIF "NI: 2M PM." ME is ANIsao: 3M AIM AIM MM." é AIF 8: AIM AIM AIM AIF IzzIF AIM a: a: AIv MMM i é i é I22 é M; MM." a: AIF 3.8 ".22-; MTM M; MM." Mod -IEEQESEEE-2: :ka :AEEQMOEEMIBSM -Méucéoé :osNME IEBEEM"22-35%? wEEGNCwQ -Nvi-Z-:>cmcn_ogo::-$-w -.>£mEV-v-.>£mE-N: -moEEmEcmcqséorsm -Eucafiézeoficzvai mEESmumEcmcMEAMb 239m BaEme [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena RAIN RAIN .35 Rs AT: " Ego: é a: 8.98.15 AT: Ego: RAIN mm." "Ev 8.05: i é c AT: SA N: c RAIN i i é $8.15 SA i 38 "3.093 - "Em "3.093 "Em F: 9% -MFN- mm." 8s 8s AT: i 63 é AT: AT: RAIN RAIN :m "N12 N: as RAIN i 3N *3 :23 .x: a: a: "N12 a: 8: AIM g N: v: 8: AIM m: mm: 9; é - - a: 5.15 522+: AT: 522+: i mos- RAIN AT: AT: oi NE n: a: a: i 53 as 63 é Q -Nvi-Z-:>cmcn_ogo::-$-w -mk -.>£mev+-.>£me-% -moEEmEcwcaséEsm Enrich223%:kaer ms>cmcqs>6 >8fi88:-$-~ -.>£oE:+-.>£me-@ 532385238953 :ostEfltfi Eosem $8533-9EUEQHU wEEmuwum Bamem. 2qu ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " A: m: NM: 8.8 HEIDI AAIm AAIN a: 3w - AAIN AmV n: AAIv AAIA HEIDI AmV AEV AAIA AAIA c m3 8s c AmV AIV SA is.
"A5855 A23 AmV AAIA AAIN o: .AAE- AAIN Raw AAIAV Cw -EN- AIV AEV omsa :s 5: AmV AAIA AAIA AmV AAIA .AIA RE m: AAIN AIM AI: SA AmV AmV - AIV NAIsA m3 A23 8: AAIm AAIA NE m: m3 AEV AEV AAIm om: mi: AAIAN AI AAIA 8.0 N: IEzIA AmV .AIAA oovVIsAz- AmV - - AAIv AAIA INN m3 E V EV A23 m V IF ANN m3 mm." AmV AIV $3 -mA 3>cmcqeosz+YN -.>£mE-N->xo£mE-v: -AvANA -IVA-AV-EEI>%-mA EOEEEAIEEQ :28qu mEESmuchEmcq oEEgVEBEEV-§-NVi-z -IVEEEAEBE-N :ostcthA EoEEm +1-AI>EmEqA.>-o-EEI§o mU_ESmum:>cmcn_oIo:: BaEme 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena : AIF 5: AIF "Egg AIM I: AIF 5: AIM MMM .23 AIv .& 2+ MM." 5: .& - 5: AIF "Egg - - 5: My 8M MM." My M; A5855 ME .3 8.0 3M M: M: MMA: AIF AIF - AIM SK AIF AIM - - AIM 8.0 AIF -mFN- 8s .& .3 .& .& A5855 AIM .& M: .& MM." EA: 5: AIM .NIsaoMV MMM AIM Mod .NIsaoMV $.M AIF : ME RM AIM .& AIv AIF AIF AIM - .3 AIF ".22-; 5 $.M MM." I: - 5: 5 .& .& BK M: - .& 8; AIM oMK M: 8M a; ".22-; MMM AIM AIM MM." M; -eoszimiEvoafimi -MoEEMIBBMAIEmfi -M.asoficzvaiicmfi -losemszéuca? -xoeS-M-mEuI§E$E 22% -Aacmfieosziwi-23 I‘M.:AIEmfiMoEEMIBSM -MEIEQFMiBONME -z-.>£me+-mosems> -IEBEOJIEMMMV mEESOeSM¢EEE 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " a: a: 63 RAIN .Es AT: Ego: N2. a: 26 Q 2.15 - "Egg é c AT: a: AT: c AT: :s SA 9; i "3.093 5 é a: RAIN "3.093 AIM AT: 3.21553553er New -oFN- RAIN 8w i N2: N; i Q AT: a: AT: - "N12 w: AT: AT: w; 3K ME *3 i 8: AIM - 63 i @128: AIM AIM AT: 5w 8.8 522+: i mm." RR was 6 V i a: 63 AT: AT: N? RAIN RAE AT: 522+: NS 03 0: v: 63 Q -mk -mk -v-eo=:-%éi-z -:>cmcn_:>co::2>£mEV +1-Ecmfiiéégafi mEESmumSEmchosz -A.>cmfi.>£me-m-eo§i-N :ostEHtN" -v->xo£me-%éi-z -:>cmcn_:>co::2>£mEV tfi E0555 E0555 -:>8;%>-o-£uc>% @253ng 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na M: AIF AIF AIM i "Egg AIM A: A23 é A23 "Egg AIF A3 é :6 AIF ME My MOM My A3 ME :6 MMM A5855 A5855 A3 AIM AIF AIM AIF AIM é -CN- M: AIM M: a: é é a: é SM AIv AIM M: ANIsaoMV SM AIF - SM EM AIF AIM 8.5 ANIsaoMV a: é o: AIF AIF AIM M: A3 i MMK MMA: ".22-; é - SK A3 é - AIF M; 8M a: AIF M; 2.8 ".22-; 2M ts A23 AIF AIF -Mvi-zéémfieozuiM IEBEIMEIBEM: -Mosemsémfiséesm -EucafiéLEONMEIAMA: mEEMBUMIEmfiAIE -v->xo£me-%éi-z éoIaafimé NmEfltMAEoEEM -M-I>8IQA.>-M-EE>% mEesmugémfi 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena :m é i " a: MMM a: " ADE AIM Ego: OMM AIM In: MOM AIF Ego: MOM AIF M; MMM a: - MMM - i é My 8M A23 My AIv AIF A5855 AIF 8M 26 AIM - M: i AIM MMM A5855 5 -wFN- *3 AIM AIM BM AIM 8M MTM é AIF ME M: a: a: - a: AIM AIM "NI: 0: :m M: MMM "NI: MMM AIM AIF In: AIM a: a: a: 8: AIM - - AIF 8: AIM é - é a: M: 9%. ".22-; é MMM ME MM.M Q é 0: 0: - FMM 3M AIM SM- AIF AIM Ma ".22-; MM.M AIM AIM 8M MM AIF -AECBESFE$§+ -3:ka225233585 -A.>-M-EE§9Q220% ->xo£mE-M-AoEEM @253ch -AECBESFE$§+ -3:ka225233585 -A.>-M-EE§9Q220% -Mv-z->xo£mE-M-AoEEM mEEMNCBIEngofimE 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] na ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena " N: :M MMM " AIM Ego: 0: -9: -MMK - AIM RM .26 AIF Ego: é a: AIF c AIM AIM ME EM AIM AIF A5855 é AIM a: é o: AIM AIM 0: a: - a: 5 FMM A5855 i AIM I: M; -oFN- MOM M: ME BM M; a: a: AIM - AIF é - a: 3% AIM 8s AIF "NI: AIF 0: SM a: - i "NI: RR - a: é 8: a AIM MMM MM." MMM 8.0 8: AIM AIM AIM MMM AIF ".22-; - 5+ a: AIF AIM AIF é - A23 a: a: $.M AIM M: Q a: a: ".22-; 3M 3K MM." RR é MM -A.>Ncgeo=:-§$-83 -Ecxfi -Ecxfi Igcofisaemes -I>-M-EE§9Q -I>-M-EE§9Q :0st -m-:>£mEo::-NYZ-SEEM wEEGNCwQflXOLer—I -A.>Ncgeo=:-§$-83 Igcofisaemes :0st -ZAZ->xo£mE-m-HoEEm wU_EmNcw£>cqu_U 239m 239m [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena é A: " a: AIM .03 AIF AIF " a: Ego: 0: :M M: FMM a: a: é - AIM é Ego: M; 8M - - My AIM ME M: MTM o: My AIM 8M- é AIM a: MM.M AIF A5855 - AIF FMMAIF A5855 a: é AIM 8M Q -ONN- 8M AIF EM M: MMM A23 AIM a: - - 0: AIF Ma AIM a: "NI: AIM MMM 0M6 ME "NI: MM.M AIM MMM é MOM AIF 8: - A23 AIM £2.15 8: é AIM M: MMM AIF AIM - i ".22-; - 23 MMM é a: 9;; ".22-; é MOM a: AIM 8M 8.0 8M AIM AIM M: MOM MMM AIM Ms a: AIM AIM -0:-v-:>£mEo:EU-NANYZ -5:ka -5:ka -A.>Ncgo_o=:-§-$ Igcofisaemes .NézuanvmK E-m-HoEEm:> -A.>Ncgeo=:-§$-83 Igcofisaemes .NézuanvmK EBONM mEEMNcmn -EE§EE£E$§3MI-z EBONM ->xo£mE-m-HoEEm:> wEEMNcmn Bamem. 2qu [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " AIM 5 " AIM AIM 5 - NMM oMM Ego: AIM RR 5 3+ a5 - A5 a: - Ego: a5 RR- Mg PM." % o: AIM MMM AIF c 8M 0: PM." AIF My MTM AIM as 5 - AIM A5855 - AIF A5855 - a: AIM AIM 5 55 AIF EM -FNN- MMM ME A5 a: vMM M; M? a: MM." 5 AIM AIM BM AIF - "NI: 8M 0: 8M AIM - AIF a5 a5 "NI: M: AIM M: - 5 8: AIM AIM ME a: FMM Mos- 8: AIM 5 AIM a: 5% - 5 55 AIM MM ".22-; - 5 ME a: AIM AIM AIF NM; MOM as MM." a5 AIF AIF ".22-; :3 RM AIF Rs a5 a5 A5 -IEBAOEESEBEEMI-z -AECBESFE$§+ 55thLgcmfisaemes -A.>-M-EE§9Q220% -z->xo£mE-M-HoEEM mEEMNCBIEBE -AECBESFE$§+ 55thLgcmfisaemes -A.>-M-EE§9Q220% -M-:>%aeo::-M5-z-SEEM mu_efic8>xo£me 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena AIM AIv -MMM AIF " AIM AIM "Egg RR- i AIM A3 a: i Ego: a: é o: AIM as 3% a: c 9% 8.0 c E A5855 - a: AIF AIM AIF - AIM A5855 8.0 AIM - -NNN- M: 8M vMK A23 a: é i AIM - é M; AIM 8M ANIsaoMV MMM MM." M; "NI: MOM 9: AIF a: a: - AIM M; AIF AIM 8: AIM AIF a: é ".22-; i - é a: i - A23 AIM QM M: Mos M: 5% ".22-; I: ME I: a: AIF Mai-véficgeoszi-z -SEEJMIEEEV-v->xo£mE -TVANA c__ut>M:c-Q I33-tm:+:é+ ->xo£mE-N-:>oEm::M -TVANA -:>-o-c__ut>M:c-Q :moEEmEcmcq LEONE: mn :moEEmEcmcq LEONE: -AaNcgeoszii mEEMNcmn 2qu 2qu ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na AIM é AB 5M 0M6 MMM AIF "Egg AIM M; :3 "Egg AIM AIF 5 *8 MM.M - a: AIF A3 c 8M AIM E: c 9% 8M é 8.0 AIM 5 A5855 8M é A3 AIF AIF - :6 A5855 AIM AIF -MNN- é SM 9% 8M é AIF é A23 AIM é ANIsaoMV 8; AIF AIF SM AIM é 8.0 A23 8M AIM :m i é AIM 3M ANIsaoMV vMM AIM AIM AIF AIF MM+ MOM a: ".22-; i In: A23 AIM AIF ".22-; i é AIM é MM.o MM.M AIM AIF vMM a: é :2 8+ a: 8M- 0M6 -M->xe_o>c- -MA A cafiéiva -HoEEm:>-N-cmM_EM:>£mE -:>cmcn_>xo£mE-NLDAEHmE 228%:th EOEEM -8877:29533? mEEMNcmnsficmn -3va-véficgeoszi-z -N-:>-N-cmM_8M_>xE_u>c-Nv -moEEmEcmcMSonmE 223%:th : mEEMNchSAMb 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena :5 A5 5 MM AIM -MMM MM.M MM AIM 0: MMM Ego: a: AIF 0M6 a5 AIM - - AIF Ego: 5 AIM 5 My M: ME EM AMM My AIM AIF 8M 5 - a: 3M 5 A5855 5 CM 5 AIM AIM - AIF 8.0 A5855 AIM 8M o: -VNN- M: AIM A5 M: 5+ M; 5 - AIF 5 AIF AIM MM AIM AIM a: A5 AIF "NI: 8M 0: o: 5 "NI: M: :m a5 BM a5 8: AIM AIM 63 AIF AIM MM 8: AIM .35 0: $.M - AMM ".22-; 5 5 MM 5 a5 AIF AIF 5 - MOM AIM 8M - M: 8+ AIM M: MOM a5 5 ".22-; M: MMM AIM A25 AIM oM.M AIF -EE§EE£E$§3MI-z -eoszi$-M:+->xo£m-M 526%305832328 ufiLEONMEAiMA: nEEMAI>-M +3:-v-.>£m-z->xo£m-M -EoEMeSA32888:: -MALEONMEVAMALIEEQ -z-Ao:_EMA.>-M-E_uI§o mEEMNEBEBE 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena o\/% - " a5 AIF AIM 8M M; " 5 AIM AIM AIM AIF Ego: 5+ as MTM 63 ME AIF Ego: a: a5 a5 AIM AIF AIM 5 My SM c MM." 5 a5 5 vMM AIM a: M: a: vMM MM A5855 5 - - AIF - -mNN- M? AIM M: MOM RM MM." 8M AIF AIM a: AIM - A5855 - AIF AIF 5 M3 5 AIF AIM "NI: EM 3% a: MS- 5 5 "NI: MTM AIM AIM EM a5 a: a5 8: AIM AIM AIM SK- MM MM 8: AIM A5 63 M: SM AIF ".22-; 5 A5 :s a: AIF AIF 5 0: MM." - - 5 E fie AIF A: M: 5 5 ".22-; EM AIM AIM o: a: MM 553+:$-M:+->xo£m-M 526%305832328 -EucafluéLOIONMEVAMA: $30553: mEEMNcmnifimeosz -IEBAOEESEBEEMI-z -AECBESFE$§+ 5:th225233585 -A.>-M-EE§9Q220% -eoszEMkMAMIM-SEEM $5383on 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena - Rs SM 8M Mg Ego: M? - - é: BM - :s I: a: AIF AIF "Egg AIM AIF My M: AIM My om: 5 AIM AIM é A5855 é a: AIF AS MMM MMM A5855 AIF M; -oNN- é I: A23 a: M; AIF Q AIF - AIF AIF "NI: SM AIF MM." MS. é i ME N: é i 8: AIF 5 AIM as MMM 8.0 ANIsaoMV AIM AIM 9% M; ".22-; é M3 a: AIM AIM AIF ".22-; A3 a: AIM AIF MMM AIM A: a: a: i 9% M: a: é -AECBESFE$§+ -3:ka225233585 -A.>-M-EE§9Q220% -M-:>£meosz-d-z-SEEM -AAAXOEmEOEEMAMAMV @253ch -AECBESFE$§+ -3:ka225233585 -A.>-M-E_uc>q§-fl220% -88:§M-€E§ $538365? 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena RAIN -8.w é " RAIN AT: " AT: Ego: AT: é :23 was AT: -N: é Ba - 63 i Ego: c c $315 i AT: RAIN wow AT: a: mm." NE 8w 5.0 "3.093 é w: a: RAIN AT: AT: "3.093 AT: a: RAIN -NNN- RAIN RAIN SK was *8 5 6.58 Q 63 3.0 i a: a: - Ed RAIN "N12 mg w: m: "N12 2% NE 8w mow F: 2.0 8: AIM RAIN AT: - AT: AT: 8: is - RAIN RAIN N: 5.: 522+: i i é 8w é é 522+: Q NE - a: a: 5 m: 8s 8s RAIN 3w Ed m: RAIN mm." a: mow Ed AT: -A>xo£mEoLo:EE-dWNIu -mk -38832953353+ tfi -TxN" .:>.o.c=u.:\8_EbK E0555 i-z-:>-o-c%c§c mEEmNcmnc>NcmnEosz éxofimeeoszid3: -:>co::2>-N-cmn_8n:-v :moEEmEcmcq LEONE: -:>Ncgeo::-$-z mEEmNcwn Bawam. maeem [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena " a: a: " a: ADE a: Ego: OMM AIF SM- AIF Ego: oM.M AIF 8M MMM 3M AIv - i - é - é c c A5855 a: SM ME RM vMM AIM MMM M; M; AIF AIM 5 AIF -wNN- OMM AIM AIM AIF AIM AIM - a: a: a: é A5855 é 8M a: a: i "NI: ME AIM F: 8M MMM MMM "NI: MMM M: 8M M; 8: AIM - - - AIF 8: AIM é - - AIF AIF ".22-; é MMM MMM M; i ".22-; i 0: I: 3M i é a: AIF AIF AIM M; M: AIM AIM AIM AMM MMM EmEESEE-MIWMIV -moEEmEcmcquOJFV -EucafluéLEONMEI‘AMA: z-:>-o mEEMNcmnsficmn -883:$23592 -2263:>oEm€mu:>Ncmn -EucafloéLOIONMEI‘AMA: -.>£mE-M-AoEEMA.>-M mEEMNcmn 2qu 239m [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " a: AIM " *3 i AIF a: Ego: M: AIM 26 AIF é M: 0: 0: - Ego: a: - é c OE a: c AIM o: 8M AIM AIF A5855 o: EM i - a: AIM MS. AIF AIF A5855 A23 -oNN- M: AIM AIM 8.0 é as é A3 2+- MM." "NI: 0: AIM a: AIF EM AIM 26 "NI: 5+ AIM A23 a: MOM a: 8: AIM :m AIM AIF 8: AIM a - - ".22-; é MM." In: é i é CM M: a: SM MMM AIM om: 8M 8.0 ".22-; MMM AIM AIF AIM IMM AIF geo=:-§$-83 -Ecxfi -5:ka :wéofiséemefi -A.>-M-EE§9Q mU_EmNcm£>£mE-m-HoEEm -A.>Ncgeo=:-§$-83 :wémfiséemes -A.>-M-EE§9MA 220% 220% -MAMAMEIEBEM-SEEM mEEmNcmnSEHmEoszty 239m 239m [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena " 5: AIF M; " -MMM .03 Ego: FMM AIM 8M AIM 8.0 é - Ego: AIM é AIM AIM AIF AIF AIF My a: 3M ME My RM é A5855 é 0: A23 a: a: é AIF AIF - MOM EM -OMN- é 5 SM AIF A5855 AIM MMM MMM 8M AIF - AIF é MS.
MM.M 8+ AIM AIM "NI: AIM rm a: é "NI: 8M 8M MMM i AIM 5 .é a: 8: AIM 3M MMM 8: AIM AIM AIM 8.0 ".22-; é é MM FMM - a; AIF é - a: a: AIF MM.M a: AIM 8M AIF i ".22-; MTM ME RM MOM i -AECBESFE$§+ -3:ka225233585 -A.>-M-EE§9Q220% -M-:>£meo::-Mv-z-SEEM mEEMNEBEBE éficgeoszi-z -IEPIEEBEV-33ng -EAtMAEoEEMEEfi -iééEEQFé220% @253ch 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " M: Ego: AIM AIM o: RR é "MK a: A3 é AIM - Mg Ego: é AIF 8.0 c AIM 3M c 0: o: MMM A23 AIM AIF A5855 M: é - i AIF A5855 AIM AIF i AIM o: ME i -FMN- MM." a: M; i é 3.0 AIF AIF M; AIM é M: 8M AIF "NI: M: - AIF "NI: 3M é A23 AIF :m a: a: a: 8: AIM AIM é 8: AIM 0: 8.5 ME é In: ".22-; é - a: AIM 5M é AIM AIM MMM a; 8M ME M: a: AIF AIF ".22-; MM.M as A23 é AIM AIF Mai-véficgeoszi-z -AIEEEEBEV-EEBE -3:ka -Aaéaficivq Mud-véficgeoszii -A.>coI=2>£mE:-3265 :YMA:Aosemwémiosem -Eéaacafié EIQ 220% mEEmNcmn :20ch mEEMNcmn 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena é é " AIM o: " a: 63 8+ AIM M+.M *3 Ego: AIM é Ego: M: Ma c ME M: AIM c AIM a: AIF A5855 a: AIF AIM A5855 MS. é AIF a: a: M: AIM -NMN- A3 a: AIM M; 5+ AI+ MMM é as 8.0 F: a: - - a: AIM "NI: MBM - +3 8.0 "NI: 8+ AIF M: £8.15 8: AIM AIF MM." - AIF 8: AIM - é ".22-; AIM MM." MOM é 63 é é MM." M: - MM.M 03 a: AIM MMM ".22-; 3M AIM AIM a: 5M0.MAIF AIF -+-:>Ncgeo=:-+v-z -:>cmcn:>£mE-N->xo£mE -MA :ostEflifi mEEmNcmnw>b¢=ut>Mzu -A.>Ncgo_o.6-+:$-83 953%225233585 -:>-N-c__ut>M:c-Q EOEEM EBONM -NANANV-Z->xo£mE-m-SEEM mEEmNcmnSEHmEoszty 2qu 239m [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " " Ego: AIM o: a: AIF AIF Ego: AIM AIM AIM é RR é é a: a: AIF é My AIF 8+ My Q MMM 0: Rs A5855 FMM MOM - - i AIM ME AIF A5855 AIM -MMN- N: AIM 9: 8M 8.0 é AIF é "NI: AIv a: i 8+ é AIM AIM AIF MOM 8.0 "NI: 8M AIF a: a: a: a: 8: AIM o: M: - AIF 8: AIM é AIF 8M I: M: 8M ".22-; é - é ".22-; é - - - Mg OMM MM." A23 AIM $.M MTM MM." ME MM.M AIF -Mwé-véficgeozuii -IEQBEBEV+5653 -Iztfizmosemsémfi -Aaééucafié220% @253ch éficgeozuii -IEPIEEBEV-33ng -Iztfizmosemsémfi -iééucéoé220% @253ch 2qu 2qu [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena - " AIF - " AIM Ego: AIM a: MM.M Ego: AIM .0; AIF A23 ME é a: AIF é AIM AIF é My M: AIM o: AIM 0: MBM A5855 - a: a: a: a: AIM AEMMMAIF A5855 AIM AIF AIF AIF -VMN- M: RR MS M; M: i - é Q é AIv - - - é "NI: M: o: 8M "NI: OMM OE N: o: MMM 8: AIM I: AIF AIM 8: AIM AIM AIM AIF AIM AIF ".22-; é - é a: £5.13 ".22-; é é a: é a: i 8M MM." M: SM é MM.M o: o: o: SM :6 -Mwé-véficgeozuii -AEEEEBEV-3365 -Iztfizmosemsémfi -iééucéoé220% @253ch IEBEV-v->xo£me-%é-v -MoEEMIEmfiicoIa uézeogczvai -.>£me-$-z-:>-o £53823ch 2qu 2qu [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " .0; " Ego: AIM MS. é AIF Ego: AIM .0; .9: -ME AIF é AIM MMM A3 i c AIM AIM 8M as c AIM MMM A5855 a: AIM 26 M: a: a: a: AIM AIM AIF -mMN- CM. a: AIM AIM M: M: AIF é é A5855 é CM. - é 8M a: - é "NI: MTM :s M: - "NI: 8M :s M: MM." MMM M; EM 8: AIM AIM AIM 8M - 8: AIM AIM AIM AIF AIM AIF IEZIF é é a: AIM 3.0 é é a: a: a: i MM.M 0: M: a: AIF IEZIF MM.M 0: M: o: MOM 8.0 Mai-véficmegmeii -IESEMIEBEV-IEEE -3:ka -Aaééucivq Mai-véficmegmeii BEV-EEBE -3:ka Eosemsémfi -Aaééucivq 220% wEEGNcwn émfi 220% mEEmNcmn wages Basso ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena " 8M 3+ AIF Ego: SK a: AIF AIF "Egg AIM M: o: a: MS. i - AIF M: AIF é é My AIM AIF :6 My M: ME é A5855 a: M: é MMM as A5855 AIF AIM EM é - AIF AIM Mg -omw- + o: M: AIM a: AIF Au: AIF - AIF a: i é o: AIF "NI: 8+ AIF é MOM ANIsao: CM BK A23 a: BM - 5 8: AIM Au: M: - AIF AIF AIM AIM o: 8M MM.M ".22-; é BK M: - AIF ME i Q ".22-; é *8 AIF AIM AIF 3M AIM o: A23 AIM M; Ma MMM 8M a: a: i -eosEuiM:$¢:+ 5832328 -EucafloéLOIONMEVAMA: -z->xo£mE-M-AoEEM:>-M -eoscczad mEEMNCBIEB :888Eu-§v-z -IEBEIEMIIEBE -eoszEMMINIMAEoIa :kaEosemsémfiaxofim -AaééucévqLEONE" @253ch 2qu 2qu [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena AIM RAIN AT: AT: "Egg AT: 63 é é a: 63 é 0 8+ mod mm." SK was mg "A5855 - "Em AT: AT: -NMN- ems AT: AT: i é i 5 @1283 m? 8+ 0: N: Ea is RAIN AT: w; AT: AT: 522+: i é - 63 é é :2 o: we." N: :3 mow iwé-véficgeoszi-z -N-:>-N-caoa>xe_u>cé -Moc_em:>8fi>xo£me -Eucévfl228%:kaer %_Efi:8>xo£me$:>-o [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena Example12.82 2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy(S-methylsulfonimidoyl)phenyl]- amino}[1, 2,4]triazolo[1, 5-a]pyridinyl)phenyl]acetamide o=s—CH3 To a stirred suspension of |nt10.25.04 (430 mg) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at r.t. for 1 h. A saturated on of potassium carbonate was added until pH 9 was reached. The mixture was extracted with DCM. The solution was dried (sodium sulfate) and the solvent was removed in . Aminophase-silica-gel chromatography gave a solid that was recrystallized from dicloromethane to give 302 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.03 (s, 3H), 3.64 (s, 2H), 3.93 (s, 3H), 4.01 (s, 1H), 7.07 - 7.18 (m, 2H), 7.30 - 7.39 (m, 2H), 7.45 (d, 1H), 7.52 (dd, 1H), 7.63 - 7.77 (m, 5H), 7.92 (dd, 1H), 8.43 (d, 1H), 8.51 (s, 1H), 9.11 (d, 1H), 10.29 (s, 1H).
Example12.83 N-(4-fluorobenzyl)(2-{[2-methoxy(S-methylsulfonimidoyl)phenyl]- [1, 2,4]triazolo[1, 5-a]pyridinyl)benzamide N, / g ,N M HN N H3C’ o=fi—CH3 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena To a d suspension of |nt10.25.05 (132 mg) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at r.t. for 1 h. Asaturated solution of potassium carbonate was added until pH 9 was reached. The mixture was extracted with DCM. The on was dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was recrystallized from dicloromethane to give 51 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.03 (s, 3H), 3.94 (s, 3H), 4.02 (s, 1H), 4.45 (d, 2H), 7.05 - 7.19 (m, 2H), 7.26 - 7.38 (m, 2H), 7.46 (d, 1H), 7.52 (dd, 1H), 7.70 (d, 1H), 7.84 - 8.07 (m, 5H), 8.43 (d, 1H), 8.56 (s, 1H), 9.12 (t, 1H), 9.27 (d, 1H).
Example12.84 2-(4-fluorophenyl)-N-[4-(2-{[4-(hydroxymethyl)methoxyphenyl]amino}- [1, 2,4]triazolo[1, 5-a]pyridinyl)phenyl]acetamide N/ / A ,N HN N 0 To a stirred solution of |nt10.28.02 (100 mg) in ethanol (5 mL) was added a hydrochloric acid (2.0 mL; c = 2N). The mixture was stirred at r.t. for 10 minutes. A saturated solution of potassium carbonate was added until pH 9 was reached. The mixture was extracted with DCM and methanol (10:1 mixture).
The solution was dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was recrystallized from ethanol to give 50 mg of the title nd. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.64 (s, 2H), 3.84 (s, 3H), 4.43 (d, 2H), D7 (t, 1H), 6.88 (d, 1H), 6.97 (s, 1H), 7.07 - 7.18 (m, 2H), 7.30 - 7.39 (m, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena 2H), 7.58 (d, 1H), 7.64 - 7.75 (m, 4H), 7.83 - 7.93 (m, 2H), 8.13 (d, 1H), 9.05 (s, 1H), 10.27 (s, 1H).
Example12.85 N-(4-fluorobenzyl)(2-{[4-(hydroxymethyl)methoxyphenyl]amino}- [1 , 2,4]triazolo[1, 5-a]pyridinyl)benzamide A/N N To a stirred solution of |nt10.28.03 (120 mg) in ethanol (5 mL) was added a hloric acid (2.0 mL; c = 2N). The mixture was stirred at r.t. for 10 minutes. A saturated solution of potassium ate was added until pH 9 was reached. The mixture was extracted with DCM and methanol (10:1 mixture).
The solution was dried (sodium sulfate) and the t was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was recrystallized from ethanol to give 70 mg of the title compound. 1H-NMR (300MHz, DMSO-dé): 6 [ppm]: 3.84 (s, 3H), 4.39 - 4.50 (m, 4H), 5.08 (t, 1H), 6.88 (d, 1H), 6.97 (d, 1H), 7.07 - 7.19 (m, 2H), 7.34 (dd, 2H), 7.62 (d, 1H), 7.83 - 8.03 (m, 6H), 8.13 (d, 1H), 9.11 (t, 1H), 9.23 (d, 1H). -24o- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Further, the compounds of formula (I) of the present invention can be converted to any salt as described , by any method which is known to the person d in the art. Similarly, any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
Pharmaceutical compositions of the compounds of the invention This ion also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular ion or disease. Therefore, the present invention includes ceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side s ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A ceutically effective amount of nd is preferably that amount which es a result or exerts an influence on the particular ion being treated. The compounds of the present invention can be stered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like. a; oral administration, the nds can be formulated into solid or liquidparations such as capsules, pills, s, troches, lozenges, melts, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, ants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
In r ment, the compounds of this invention may be tableted with conventional tablet bases such as e, e and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents ed to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to e the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and s, for e talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic ies of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or es may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They e the active ingredient in admixture with a dispersing or g agent, a suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by use already mentioned above. Additional excipients, for example those [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena sweetening, ing and ng agents described above, may also be present.
The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally ing phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, an eate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The ons may also contain sweetening and flavoring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for e, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more coloring agents ; one or more flavoring ; and one or more sweetening agents such as SUCFOSG or saccharin .
Syrups and elixirs may be formulated with sweetening agents such as, for example, ol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a ent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier nich can be a e liquid or mixture of liquids such as water, saline, [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or hylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolane methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable tant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or fying agent and other pharmaceutical nts.
Illustrative of oils which can be used in the eral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl ate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for e dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and uccinates; non-ionic detergents, for e, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene- oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, beta-aminopropionates, and 2- alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic Dfactant having a hydrophile-lipophile balance (HLB) preferably of from [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena about 12 to about 17. The ty of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene .
The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable sing or g agents and ding agents such as, for example, sodium ymethylcellulose, cellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation t of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile able solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer’s on, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are tionally employed as ts or suspending media.
Dr this purpose, any bland, fixed oil may be employed including synthetic [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a le ritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and hylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled s. The construction and use of transdermal patches for the delivery of ceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11, 1991, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand ry of pharmaceutical agents.
Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
It may be desirable or necessary to introduce the pharmaceutical composition to the t via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug ly to the brain y involve placement of a drug delivery catheter into the patient’s ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011,472, issued Dril 30, 1991.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena The compositions of the invention can also n other conventional pharmaceutically acceptable compounding ients, generally referred to as carriers or diluents, as necessary or d. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
Such ingredients and ures include those bed in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & logy 1999, 53(6), 324-349; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.
Commonly used pharmaceutical ingredients that can be used as riate to formulate the composition for its intended route of administration e: acidifying agents les include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium ate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoal) ; aerosol propellants (examples e but are not limited to carbon dioxide, CClez, FzClC-CCle and CClF3) air displacement agents (examples include but are not limited to nitrogen and argon) ; [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena ation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena antifungal vatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate) ; antimicrobial preservatives (examples include but are not d to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal) ; antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated yanisole, ted hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite) ; binding materials (examples include but are not limited to block polymers, l and synthetic rubber, polyacrylates, ethanes, silicones, polysiloxanes and styrene-butadiene copolymers) ; buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium de injection and bacteriostatic water for ion) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red) ; clarifying agents (examples e but are not limited to bentonite) ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena emulsifying agents (examples e but are not limited to acacia, cetomacrogol, cetyl alcohol, yl monostearate, lecithin, sorbitan monooleate, yethylene 50 monostearate) ; encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin) ; humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol) ; levigating agents (examples include but are not limited to mineral oil and glycerin) ; oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil) ; ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment) ; penetration enhancers dermal delivery) (examples include but are not limited to droxy or polyhydroxy alcohols, mono-or polyvalent alcohols, ted or unsaturated fatty alcohols, saturated or rated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerol) ; solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, panol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation) ; [Annotation] kirstena None set by kirstena [Annotation] na ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax) ; suppository bases (examples include but are not limited to cocoa butter and polyethylene s (mixtures)) ; surfactants (examples include but are not limited to konium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate) ; suspending agents (examples e but are not limited to agar, ite, carbomers, carboxymethylcellulose , hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum) ; sweetening agents (examples include but are not limited to aspartame, se, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose) ; tablet anti-adherents (examples include but are not limited to magnesium stearate and talc) ; tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch) ; tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, ol and starch) ; tablet coating agents (examples include but are not d to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ; tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate) ; tablet disintegrants les include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch) ; tablet glidants (examples include but are not limited to dal silica, corn starch and talc) ; tablet lubricants (examples e but are not limited to calcium stearate, magnesium stearate, mineral oil, c acid and zinc stearate) ; tablet/capsule opaquants (examples include but are not limited to titanium dioxide) ; tablet polishing agents (examples include but are not d to carnuba wax and white wax) ; thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin) ; tonicity agents (examples include but are not limited to dextrose and sodium chloride) ; viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, ymethylcellulose sodium, cellulose, polyvinyl idone, sodium alginate and tragacanth) ; and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, yethylene sorbitol monooleate, and polyoxyethylene stearate).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile |V on: A 5 mg/mL solution of the desired compound of this invention can be made using sterile, able water, and the pH is adjusted if necessary. The on is diluted for stration to 1 — 2 mg/mL with sterile 5% dextrose and is administered as an IV on over about 60 minutes.
Lyophilised powder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 — 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 — 0.4 mg/mL, and is administered either IV bolus or by N infusion over 15 — 60 minutes.
Intramuscular suspension: The following on or suspension can be prepared, for intramuscular injection: 50 mg/mL of the d, water-insoluble compound of this invention mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80 9 mg/mL sodium chloride 9 mg/mL benzyl alcohol Hard Shell es: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Ca sules: A mixture of active ingredient in a digestible oil such as flybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by tional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of dal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Immediate Release s/Capsules: These are solid oral dosage forms made by tional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Combination therapies The compounds of this invention can be administered as the sole ceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable e s. The t invention relates also to such combinations. For example, the compounds of this invention can be combined with known anti-hyperproliferative or other tion , and the like, as well as with Dmixtures and combinations thereof. Other indication agents include, but are not limited to, anti-angiogenic , mitotic inhibitors, ting agents, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, ical response modifiers, or anti-hormones.
The additional pharmaceutical agent can be aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, tine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, ECG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, h, capecitabine, latin, casodex, ne, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, nic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukin ox, depo-medrol, deslorelin, dexrazoxane, lstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, e, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, nic acid, etopophos, etoposide, fadrozole, farston, stim, finasteride, fligrastim, idine, fluconazole, fludarabine, 5-fluorodeoxyuridine osphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, tane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, yurea, ibritumomab an, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-ZB, interferon alfa-n1, interferon alfa-n3, interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulfate, ole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, l, Unustine, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6- [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, cin C, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, en, nilutamide, nolvadex, 1570, OCT-43, octreotide, ondansetron HCl, d, latin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran, 7, fene, actimmune, affinitak, terin, arzoxifene, asoprisnil, atamestane, ntan, sorafenib, n, CCI-779, CDC-501, celebrex, mab, crisnatol, cyproterone acetate, decitabine, DN- 101, bicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium- 166 DOTMP, onic acid, interferon gamma, intron-PEG,ixabepilone, keyhole limpet hemocyanin, 82, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, mal MTP-PE, MX-6, nafarelin, bicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R- 1549, raloxifene, ranpirnase, 13-cis -retinoic acid, satraplatin, seocalcitol, T- 138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, dar, vapreotide, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or combinations thereof.
Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer herapy drug regimens in the 11th n of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, omycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, mide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, bazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.
Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic es in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby orated by reference, such as aminoglutethimide, L-asparaginase, oprine, 5- azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, ohydroxynonyl adenine, ethinyl estradiol, 5- fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, axel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), ycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, e, and vinorelbine.
[Annotation] kirstena None set by na ation] na MigrationNone set by kirstena [Annotation] na Unmarked set by na [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, fen and topotecan.
The compounds of the invention may also be administered in combination with n therapeutics. Such protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, 1 + ZDP, ABT-828, ErbBZ-specific immunotoxin, SON-35, MT-103, rinfabate, AS-1402, B43-genistein, L-19 based mmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine, APC- 8024, NGR-hTNF, th1.3, ION-311, Endostatin, volociximab, PRO-1762, lexatumumab, SON-40, pertuzumab, EMD-273063, L19-IL-2 fusion n, PRX- 321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, alpha-particle- emitting radioisotope-llinked lintuzumab, EM-1421, HyperAcute vaccine, tucotuzumab celmoleukin, mab, HPVE7, Javelin - prostate cancer, Javelin - melanoma, NY-ESO-1 vaccine, EGF vaccine, CYTMelQbG10, WT1 peptide, omab, ofatumumab, zalutumumab, cintredekin besudotox, WX- 6250, Albuferon, rcept, denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, mab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
[Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena Generally, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, provide for the administration of lesser amounts of the administered chemotherapeutic agents, e for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, provide for ng a broader spectrum of different cancer types in mammals, especially humans, provide for a higher response rate among treated ts, provide for a longer survival time among treated patients ed to standard chemotherapy treatments, provide a longer time for tumor ssion, and/or yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
Methods of Sensitizing Cells to Radiation In a ct embodiment of the present invention, a compound of the present invention may be used to sensitize a cell to radiation. That is, ent of a cell with a compound of the present invention prior to ion treatment of ‘3: cell renders the cell more susceptible to DNA damage and cell death thancell would be in the absence of any treatment with a compound of the [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ion. In one aspect, the cell is treated with at least one compound of the ion.
Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more nds of the invention in combination with conventional radiation therapy.
The present invention also es a method of rendering a cell more susceptible to cell death, wherein the cell is treated one or more compounds of the invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of the invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or g the cell.
In one embodiment, a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more nds of the invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention e, but are not limited to, chemotherapeutic agents (e.g., cisplatinum), ionizing radiation (X-rays, ultraviolet ion), carcinogenic agents, and mutagenic agents.
In another ment, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the y is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an Dnormal accumulation of DNA damage in a cell.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena In one aspect of the invention, a compound of the invention is administered to a cell prior to the radiation or orther induction of DNA damage in the cell. In another aspect of the invention, a compound of the invention is administered to a cell concomitantly with the radiation or orther ion of DNA damage in the cell. In yet another aspect of the invention, a compound of the invention is stered to a cell immediately after radiation or orther induction of DNA damage in the cell has begun.
In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.
As mentioned supra, the compounds of the present invention have surprisingly been found to effectively inhibit Mps-1 and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell , proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, eration and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, eration and/or survival, inappropriate cellular immune responses, or inappropriate ar inflammatory responses is mediated by Mps-1, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and ysplastic syndrome, malignant lymphomas, head and neck tumours including brain s and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine s, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or ases thereof.
In accordance with another aspect therefore, the present invention covers a unpound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na hydrate, a solvate, or a salt thereof, ularly a pharmaceutically acceptable salt f, or a mixture of same, as described and defined herein, for use in the treatment or laxis of a disease, as ned supra. r particular aspect of the present invention is therefore the use of a compound of general formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a e, a solvate, or a salt f, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
The diseases referred to in the two preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with rolled cell , proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory ses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by Mps-1, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax ing non-small cell and small cell lung tumours, intestinal tumours, endocrine tumours, mammary and other gynaecological tumours, ical tumours including renal, bladder and Estate tumours, skin tumours, and sarcomas, and/or metastases thereof.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena The term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
Preferably, the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
Method of treating hyper-proliferative disorders The present invention relates to a method for using the compounds of the present ion and compositions thereof, to treat mammalian hyper- proliferative disorders. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell on, and/or e apoptosis. This method comprises administering to a mammal in need f, ing a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is ive to treat the disorder. Hyper- proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid , such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those ers also e lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal Dcinoma, ve lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena Examples of s of the respiratory tract e, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial a and pleuropulmonary ma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs e, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, geal, gallbladder, gastric, pancreatic, rectal, small- intestine, and salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal , ureter, urethral and human papillary renal cancers.
Eye s include, but are not limited to intraocular ma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct oma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s a, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal, gpopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena cancer and squamous cell. Lymphomas include, but are not d to AIDS- related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt ma, Hodgkin’s disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant s histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, c myelogenous leukemia, and hairy cell ia.
These disorders have been well characterized in humans, but also exist with a r etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The term "treating" or "treatment" as stated throughout this nt is used tionally, e.g., the management or care of a subject for the purpose of combating, alleviating, ng, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
Methods of treating kinase disorders The present invention also provides methods for the treatment of disorders associated with aberrant n extracellular kinase activity, including, but not limited to stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
Effective amounts of compounds of the present ion can be used to treat Eh disorders, including those diseases (e.g., cancer) mentioned in the ound section above. Nonetheless, such cancers and other diseases can [Annotation] kirstena None set by kirstena ation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena be treated with compounds of the t invention, regardless of the mechanism of action and/or the relationship between the kinase and the disorder.
The phrase "aberrant kinase activity" or "aberrant tyrosine kinase ty," includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not d to, over-expression of the gene or polypeptide; gene amplification ; mutations which produce tutively-active or hyperactive kinase activity ; gene mutations, deletions, substitutions, additions, etc.
The present invention also es for methods of inhibiting a kinase activity, especially of mitogen extracellular kinase, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof. Kinase activity can be inhibited in cells (e.g., in , or in the cells of a mammalian subject, especially a human patient in need of treatment.
Methods of treating angiogenic disorders The present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal enesis.
Inappropriate and ectopic expression of angiogenesis can be deleterious to an sm. A number of pathological conditions are associated with the growth of eous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al.
New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD; see, Lopez et al. Invest.
Dththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental lasias, angiofibroma, inflammation, rheumatoid arthritis (RA), [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na osis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis.
Moreover, the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell eration or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
Dose and administration Based upon standard laboratory techniques known to evaluate nds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in s, and by ison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the t treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will lly range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. finically useful dosing schedules will range from one to three times a day sing to once every four weeks dosing. In on, "drug holidays" in which a [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena ation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The e daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will ably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the ing diagnostician, the ty of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of ent and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. ably, the diseases of said method are haematological s, solid tumour and/or metastases thereof.
[Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without eatment of the tumour growth.
Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
The example g experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
Biological assay: Proliferation Assay Cultivated tumor cells (MCF7, hormone ent human mammary carcinoma cells, ATCC HTBZZ; NCI-H460, human non-small cell lung carcinoma cells, ATCC HTB-177; DU 145, hormone-independent human prostate carcinoma cells, ATCC HTB-81; aTu, human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa- MaTu-ADR, multidrug-resistant human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa human cervical tumor cells, ATCC CCL-Z; B16F10 mouse melanoma cells, ATCC CRL-6475) were plated at a density of 5000 cells/well (MCF7, DU145, aTu-ADR), 3000 cells/well (NCI-H460, HeLa-MaTu, HeLa), or 1000 cells/well (B16F10) in a 96-well multititer plate in 200 pl of their respective growth medium supplemented 10% fetal calf serum. After 24 hours, the cells of one plate (zero-point plate) were stained with l violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 pl), to which the test substances were added in various concentrations (0 uM, as well as in the range of 001-30 uM; the final concentration of the solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in the presence of test substances. Cell proliferation was determined by ng the cells with crystal : the cells were fixed by Dding 20 ul/measuring point of an 11% ic aldehyde solution for 15 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena minutes at room ature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature. The cells were stained by adding 100 ul/measuring point of a 0.1% crystal violet solution (pH 3.0).
After three washing cycles of the stained cells with water, the plates were dried at room temperature. The dye was dissolved by adding 100 ul/measuring point of a 10% acetic acid solution. The extinction was ined by photometry at a wavelength of 595 nm. The change of cell number, in percent, was calculated by normalization of the measured values to the extinction values of the zero-point plate (=0%) and the extinction of the untreated (0 pm) cells (=100%). The |C50 values were determined by means of a 4 parameter fit using an inhouse software.
Mps-1 kinase assay with 10 [M ATP The human kinase Mps-1 phosphorylates a biotinylated substrate peptide.
Detection of the phosphorylated product is achieved by time-resolved fluorescence resonance energy transfer ET) from Europium-labelled anti- o-Serine/Threonine antibody as donor to streptavidin labelled with linked allophycocyanin (SA-XLent) as acceptor. Compounds are tested for their inhibition of the kinase activity.
N-terminally GST-tagged human full length recombinant Mps-1 kinase (purchased from |nvitrogen, uhe, Germany, cat. no PV4071) was used. As substrate for the kinase reaction a biotinylated peptide of the amino-acid sequence biotin-Ahx-PWDPDDADITEILG (C-terminus in amide form, purchased from Biosynthan GmbH, Berlin) was used.
For the assay 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate er e, Frickenhausen, y), 2 uL of a solution of Mps-1 in assay buffer [0.1 mM sodium-ortho-vanadate, 10 mM MgCl2, 2 mM DTT, 25 mM Hepes pH D, 0.05% BSA (w/v), 0.001% Pluronic F-127] were added and the mixture was ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena incubated for 15 min at 22°C to allow pre-binding of the test compounds to Mps-1 before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 uL of a solution of 16.7 (M adenosine-tri- phosphate (ATP, 16.7 (M => final conc. in the 5 uL assay volume is 10 (M) and peptide substrate (1.67 (M => final conc. in the 5 uL assay volume is 1 (M) in assay buffer and the resulting e was incubated for a reaction time of 60 min at 22°C. The concentration of Mps-1 in the assay was adjusted to the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme concentrations were in the range of about 0.5 nM (final conc. in the 5 uL assay volume). The reaction was stopped by the addition of 5 uL of a solution of T ion reagents (100 mM Hepes pH 7.4, 0.1% BSA, 40 mM EDTA, 140 nM Streptavidin-XLent [# 61GSTXLB, Fa. Cis Biointernational, Marcoule, France], 1.5 nM anti-phospho(Ser/Thr)-Europium- antibody [#AD0180, PerkinElmer LAS, Rodgau-Jiigesheim, Germany]. Instead of the 1.5 nM anti-phospho(Ser/Thr)-Europium-antibody a mixture of 2 nM unlabeled anti-phospho ser/thr-pro antibody MPM-Z [Millipore cat. # 05-368] and 1 nM LANCE EU-W1024 labeled anti-mouse IgG antibody n-Elmer, product no. AD0077] can be used).
The resulting mixture was incubated 1 h at 22°C to allow the binding of the phosphorylated peptide to the anti-phospho(Ser/Thr)-Europium-antibody.
Subsequently the amount of orylated ate was evaluated by measurement of the resonance energy transfer from the Europium-labelled anti-phospho(Ser/Thr) antibody to the Streptavidin-XLent. Therefore, the fluorescence ons at 620 nm and 665 nm after excitation at 350 nm was measured in a x TR-FRET reader (PerkinElmer LAS, Rodgau-Jiigesheim, Germany). The "blank-corrected normalized ratio" (a Viewlux specific readout, similar to the traditional ratio of the emissions at 665 nm and at 622 nm, in which blank and Eu-donor crosstalk are subtracted from the 665 nm signal Dfore the ratio is calculated) was taken as the measure for the amount of [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na phosphorylated substrate. The data were normalised (enzyme reaction without tor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Test compounds were tested on the same microtiter plate at 10 different concentrations in the range of 20 uM to 1 nM (20 uM, 6.7 uM, 2.2 uM, 0.74 uM, 0.25 uM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the 100fold conc. stock solutions by serial 1:3 dilutions) in duplicate values for each concentration and |C50 values were calculated by a 4 parameter fit using an e software.
Mps-1 kinase assay with 2 mM ATP The human kinase Mps-1 phosphorylates a biotinylated ate peptide.
Detection of the phosphorylated product is achieved by time-resolved scence resonance energy transfer (TR-FRET) from Europium-labelled anti- phospho-Serine/Threonine antibody as donor to streptavidin labelled with cross-linked allophycocyanin (SA-XLent) as acceptor. Compounds are tested for their inhibition of the kinase activity.
N-terminally GST-tagged human full length recombinant Mps-1 kinase ased from |nvitrogen, Karslruhe, Germany, cat. no PV4071) was used. As substrate for the kinase reaction a biotinylated e of the amino-acid ce biotin-Ahx-PWDPDDADITEILG (C-terminus in amide form, purchased from Biosynthan GmbH, Berlin) was used.
For the assay 50 nl of a ld concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 uL of a solution of Mps-1 in assay buffer [0.1 mM sodium-ortho-vanadate, 10 mM MgCl2, 2 mM DTT, 25 mM Hepes pH 7.7, 0.05% BSA (w/v), 0.001% ic F-127] were added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to Mps-1 before the start of the kinase reaction. Then the kinase reaction was arted by the addition of 3 uL of a solution of 3.33 mM adenosine-tri- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena ed set by kirstena ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena phosphate (ATP, 3.3 mM => final conc. in the 5 uL assay volume is 2 mM) and e substrate (1.67 (M => final conc. in the 5 uL assay volume is 1 (M) in assay buffer and the resulting mixture was incubated for a reaction time of 60 min at 22°C. The concentration of Mps-1 in the assay was adjusted to the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme trations were in the range of about 0.5 nM (final conc. in the 5 uL assay volume). The reaction was stopped by the addition of 5 uL of a solution of TR-FRET detection reagents (100 mM Hepes pH 7.4, 0.1% BSA, 40 mM EDTA, 140 nM Streptavidin-XLent [# 61GSTXLB, Fa. Cis Biointernational, Marcoule, ], 1.5 nM anti-phospho(Ser/Thr)-Europium- antibody [#AD0180, PerkinElmer LAS, Rodgau-Jiigesheim, Germany]. Instead of the 1.5 nM anti-phospho(Ser/Thr)-Europium-antibody a mixture of 2 nM unlabeled anti-phospho ser/thr-pro antibody MPM-Z [Millipore cat. # 05-368] and 1 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077] can be used).
The resulting mixture was incubated 1 h at 22°C to allow the binding of the phosphorylated peptide to the anti-phospho(Ser/Thr)-Europium-antibody.
Subsequently the amount of phosphorylated ate was evaluated by measurement of the resonance energy transfer from the Europium-labelled anti-phospho(Ser/Thr) dy to the Streptavidin-XLent. Therefore, the fluorescence ons at 620 nm and 665 nm after excitation at 350 nm was measured in a Viewlux TR-FRET reader (PerkinElmer LAS, Rodgau-Jiigesheim, Germany). The "blank-corrected ized ratio" ( a Viewlux specific readout, similar to the traditional ratio of the emissions at 665 nm and at 622 nm, in which blank and Eu-donor crosstalk are subtracted from the 665 nm signal before the ratio is ated) was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = a) % inhibition). Test compounds were tested on the same microtiter plate at [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena different concentrations in the range of 20 uM to 1 nM (20 uM, 6.7 uM, 2.2 pM, 0.74 pM, 0.25 pM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the 100fold conc. stock solutions by serial 1:3 dilutions) in duplicate values for each concentration and |C50 values were ated by a 4 parameter fit using an inhouse software.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Mps-1 Inhibition; Mps-1 Inhibition; e Number Assay with 10 pM ATP; Assay with 2 mM ATP; |C5o in nM |C5o in nM Example01.4 s 1.0 31.0 Example01.5 $1.0 $1.0 Example01.6 $1.0 $1.0 Example01.7 $1.0 $1.0 Example01.8 $1.0 $1.0 Example01.9 $1.0 $1.0 Example01.10 $1.0 Example01.11 $1.0 Example01.12 $1.0 Example01.13 $1.0 e01.14 $1.0 Example01.15 $1.0 Example01.16 $1.0 Example01.17 $1.0 Example01.18 $1.0 , ample01.19 $1.0 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena Example01.20 Example01.21 e01.22 Example01.23 Example01.24 Example01.25 Example01.26 —21 Example01.27 Example01.28 Example01.29 Example01.30 Example01.31 Example01.32 Example01.33 Example01.34 e01.35 Example01.36 Example01.37 Example02.1 $1.0 1 .1 Example02.2 $1.0 $1.0 Example02.3 $1.0 $1.0 Example02.4 $1.0 $1.0 ample02.5 31.0 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena e02.6 Example02.7 $1.0 Example02.8 31.0 Example02.9 s 1.0 2.2 Example02.10 Example02.11 Example02.12 e02.13 Example02.14 Example02.15 Example02.16 Example02.17 Example02.18 Example02.19 Example02.20 Example02.21 e02.22 Example02.23 e02.24 Example02.25 Example02.26 6— Example02.27 ample02.28 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena e02.29 Example03.1 $1.0 Example04.1 $1.0 e04.2 $1.0 Example05.1 31.0 29 Example06.1 31.0 29 Example06.2 —21 Example06.3 31.0 21 Example06.4 31.0 11 Example06.5 31.0 19 Example07.1 31.0 14 Example08.1 31.0 4.3 Example09.1 51.0 19 Example10.01 —11 Example11.01 1—1 Example12.01 Example12.02 Example12.03 Example12.04 Example12.05 e12.06 Example12.07 ample12.08 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example12.09 Example12.10 Example12.11 Example12.12 1- Example12.13 Example12.14 Example12.15 Example12.16 Example12.17 Example12.18 Example12.19 Example12.20 Example12.21 Example12.22 Example12.23 Example12.24 Example12.25 Example12.26 e12.27 Example12.28 e12.29 Example12.30 ample12.31 ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena e12.34 Example12.35 2.1 Example12.36 3.5 Example12.37 13 Example12.38 29 Example12.39 16 Example12.40 Example12.41 7.2 Example12.42 12 Example12.43 s 1.0 Example12.44 1.6 Example12.45 1.4 Example12.46 3.5 Example12.47 2.4 Example12.48 1.3 Example12.49 3.4 Example12.50 3.1 Example12.51 2.6 Example12.52 4 Example12.53 ample12.541.1 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena ation] kirstena Unmarked set by na Example12.55 s 1.0 Example12.56 $1.0 Example12.57 $1.0 Example12.58 $1.0 Example12.59 $1.0 Example12.60 5.0 Example12.61 6.1 Example12.62 3.5 Example12.63 26 Example12.64 1.6 Example12.65 $1.0 Example12.66 2.0 Example12.67 5.0 Example12.68 1.9 Example12.69 4.5 Example12.70 9.5 Example12.71 8.8 Example12.72 16 Example12.73 16 Example12.74 16 Example12.75 5.
Example12.76 7.4 ample12.7711 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —Example12.82 s 1.0 —Example12.84 $1.0 Spindle ly Checkpoint Assay The spindle assembly checkpoint assures the proper ation of chromosomes during mitosis. Upon entry into mitosis, chromosomes begin to condensate which is accompanied by the phosphorylation of histone H3 on serine 10. Dephosphorylation of histone H3 on serine 10 begins in anaphase and ends at early telophase. Accordingly, phosphorylation of histone H3 on serine can be utilized as a marker of cells in mitosis. Nocodazole is a microtubule destabilizing substance. Thus, zole interferes with microtubule cs and mobilises the spindle assembly checkpoint. The cells arrest in mitosis at GZ/M transition and exhibit phosphorylated histone H3 on serine 10.
An inhibition of the e assembly oint by Mps-1 inhibitors overrides the mitotic ge in the presence of nocodazole, and the cells complete mitosis prematurely. This alteration is detected by the decrease of cells with phosphorylation of histone H3 on serine 10. This decline is used as a marker to determine the capability of compounds of the t invention to induce a mitotic breakthrough.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Cultivated cells of the human cervical tumor cell line HeLa (ATCC CCL-2) were plated at a density of 2500 cells/well in a 384-well microtiter plate in 20 ul Dulbeco's Medium (w/o phenol red, w/o sodium te, w 1000 mg/mL glucose, w pyridoxine) supplemented with 1% (v/v) glutamine, 1% (v/v) penicillin, 1% (v/v) streptomycin and 10% (v/v) fetal calf serum. After incubation overnight at 37°C, 10 l nocodazole at a final concentration of 0.1 ug/mL were added to cells. After 24 h incubation, cells were arrested at GZ/M phase of the cell cycle progression. Test compounds solubilised in dimethyl ide (DMSO) were added at various concentrations (0 (M, as well as in the range of 0.005 (M — 10 (M; the final concentration of the t DMSO was 0.5% (v/v)). Cells were incubated for 4 h at 37°C in the ce of test compounds. Thereafter, cells were fixed in 4% (v/v) paraformaldehyde in phosphate buffered saline (PBS) at 4°C overnight then permeabilised in 0.1% (v/v) Triton XTM 100 in PBS at room temperature for 20 min and blocked in 0.5% (v/v) bovine serum albumin (BSA) in PBS at room temperature for 15 min. After washing with PBS, 20 uL/well antibody solution (anti-phospho-histone H3 clone 3H10, FITC; Upstate, Cat# 16-222; 1:200 dilution) was added to cells, which were incubated for 2 h at room temperature. Afterwards, cells were washed with PBS and 20 l HOECHST 33342 dye solution (5 ug/mL) was added to cells and cells were incubated 12 min at room temperature in the dark. Cells were washed twice with PBS then covered with PBS and stored at 4°C until is. Images were acquired with a Perkin Elmer OPERATM High-Content Analysis reader. Images were analyzed with image analysis software MetaXpressTM from Molecular devices utilizing the Cell Cycle application module. In this assay both labels HOECHST 33342 and phosphorylated Histone H3 on serine 10 were measured. HOECHST 33342 labels DNA and is used to count cell number. The staining of phosphorylated Histone H3 on serine 10 determines the number of mitotic cells. Inhibition of Mps-1 decreases the number of mitotic cells in the ce of nocodazole indicating an riate mitotic progression. The raw assay data were further analysed by [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena four ter logistic regression analysis to determine the |C50 value for each tested compound.
It will be apparent to persons skilled in the art that assays for other Mps kinases may be performed in analogy using the appropriate reagents.
Thus the compounds of the present invention effectively inhibit one or more Mps-1 kinases and are therefore suitable for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or opriate cellular inflammatory responses is mediated by Mps-1, more particularly in which the diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are haemotological s, solid tumours and/or metastases thereof, e.g. mias and myelodysplastic me, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax ing all cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
Hydrolytic ity Assay The hydrolytic stability assay investigates the stability of a compound in an aqueous buffer system. Standard solution stability assay is run in 0.05 M Phosphate buffer at pH 7.4 (pH of blood plasma) at 37°C. As compounds in the GI tract are exposed to a wide y of pHs any relevant pH (as pH 2 to te the acidic condition of the GI tract in the following experiment) can D chosen. Compounds are incubated in relevant solution at 37°C and analyzed [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na by HPLC immediately after incubation and after 1, 2 and 24 hrs. Degredation rate (decay in %) is calculated by relating peak areas after 1, 2 and 24 hrs to the time zero injection.
Compound is available as 10 mM in DMSO (solution 1). 2.5 uL of solution 1 is dissolved in 1 mL acetonitrile leading to solution 2. Poorly soluble compounds may demand another dilution step of solution 2 (1 :5 and 1:10 respectively) in Acetonitrile). Solution 2 is incubated at 37°C in a ed HPLC autosampler. 1 mL buffer pH 2 is transferred into an HPLC vial. 100 uL of solution 2 is added to the buffer pH 2 solution and mixed ghly. Immediately after mixing the combined solution is injected into the HPLC to give the time zero ion. Injections are repeated after 1, 2 and 24 hrs.
The degredation rate (decay in %) is calculated using HPLC software Millennium and Excel respectively.
Hydrolysis at pH 2; Example Number Decay in % after 24 h Exampleom Exampleom Exampleom Examplem Exampleors Exampleow Exampleon Exampleors Exampleom Example01.10 Example01.11 Example01.12 Example01.13 Example01.14 Example01.15 Example01.16 ampleom [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Exampleom Exampleomo Exampleo1.21 Example01.22 < 10 % Example01.23 < 10 % Example01.24 < 10 % Example01.25 < 10 % Example01.26 < 10 % Example01.27 < 10 % Example01.28 < 10 % Example01.29 < 10 % Example02.1 < 10 % Example02.2 < 10 % Example02.3 < 10 % Example02.4 < 10 % e02.5 < 10 % Example02.6 < 10 % Example02.7 < 10 % e02.8 < 10 % Example02.9 < 10 % Example02.10 < 10 % Example02.11 < 10 % Example02.12 < 10 % Example02.13 < 10 % Example02.14 < 10 % e02.15 < 10 % Example02.16 < 10 % Example02.17 < 10 % e02.18 < 10 % Example02.19 < 10 % Example02.20 < 10 % Example02.21 < 10 % Example02.22 < 10 % Example02.23 < 10 % Example02.24 < 10 % Example03.1 < 10 % Example04.1 < 10 % , ample05.1 < 10 % Example06.1 < 10 % [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example06.2 Example06.3 Example06.4 Example06.5 Example07.1 Example08.1 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Comparison with compounds specified in W0201 1/063908 Mps-1 tion in tion Assay with 10 pM ATP: Mps-1 Inhibition; Structure Assay with 10 pM ATP; |C5o in nM [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Comparison with compounds specified in W0201 1/063908 Mps-1 Inhibition in Inhibition Assay with 2 mM ATP: Mps-1 tion; Structure Assay with 2 mM ATP; |C5o in nM H~ N’ *2) 55 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena Comparison with compounds specified in W0201 1/063908 Hydrolytic stability: Hydrolysis at pH 2; Structure Decay in % after 24 h [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena The half maximal inhibitory concentration (IC50) of the most potent compounds ied in WO2011/063908, ined in an Mps-1 kinase assay with a tration of 10 µM ATP, was lower than 2 nM (more potent than 2 nM). However, all these compounds show either an IC50 higher than 30 nM (less potent than 30 nM) in an Mps-1 kinase assay with a concentration of 2 mM ATP, or they show a low ytic stability at pH 2 with more than 15 % decay after 24 h.
The compounds of the present invention are characterized by - an IC50 lower than 2 nM (more potent than 2 nM) in an Mps-1 kinase assay with a concentration of 10 µM ATP, and - an IC50 lower than 30 nM (more potent than 30 nM) in an Mps-1 kinase assay with a concentration of 2 mM ATP, and - a high hydrolytic stability, with less than 10 % decay after 24 h at pH 2.
In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated es but not to preclude the ce or addition of further features in various embodiments of the invention. 6702608_1 (GHMatters) P94938.NZ KARENM 27/07/15

Claims (1)

1. A compound of general formula (I) : N R4 R2 N R1 in which: R1 represents a phenyl group 10 - which is substituted, one or more times, cally or ently, with a substituent selected from: -N(H)C(=O)R6, -C(=O)N(H)R6; and - which is optionally substituted, one or more times, identically or differently, with a substituent selected from: 15 halo-, C1-C6-alkyl-, C1-C6-alkoxy-; R2 represents a Q2 Q3 R5b group; wherein * indicates the point of attachment of said group with the rest 20 of the molecule; R3 and R4 represent a en atom; R5 represents a hydrogen atom; 6814134_1 (GHMatters) P89220.AU KIRSTENA 19/
NZ616456A 2011-04-21 2012-04-16 Triazolopyridine compounds as mps-1 inhibitors NZ616456B2 (en)

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EP11163342.6 2011-04-21
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EP11167872.8 2011-05-27
EP11167872 2011-05-27
PCT/EP2012/056914 WO2012143329A1 (en) 2011-04-21 2012-04-16 Triazolopyridines

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